Mycobacterium avium complex (MAC)] treatment and has been used in patients coinfected with HIV/AIDS  to a much lower degree than RIF , Mycobacterium leprae and other non-tuberculous mycobacteria and it yields higher MIC values against actively growing Mycobacteria , a member of rifamycin family, was approved by the FDA in 1992 and was recognized in 2009 as an essential medicine by WHO  in the rpoB gene in Mtb is significantly associated with mutations from codons 507–533 of rpoB, within an 81 bp fragment of rpoB gene. A high level of rifamycin resistance (RIF and RFB) is exhibited by strains with mutations in codons 526 and 531  , reduced cell wall permeability, or inactivation of drugs—was at play  were also associated with RIF resistance  and can be countered by using EPIs (De Vos et al., in vitro. Since RFB has exhibited reduced toxicity and other pharmacological advantages over RIF in HIV/AIDS patients, it should be tested in combination with molecules reported to increase drug efficacy and possess potential immunomodulatory activity in a murine model.There have been reports that rpoB mutation, but the method is time consuming: it takes several weeks to generate a susceptibility profile. This prolonged duration can result in a delay in treatment and the generation of drug resistance over time. Furthermore, there have been reports about the compensatory mutation in rpoA and rpoC regions that improve the fitness cost in RIF-resistant Mtb strains (De Vos et al., The conventional drug susceptibility assay can provide appropriate results for detecting Mtb in China and many other high TB burden countries. Furthermore, studies of this kind will be useful for developing combination treatment regimen effective against mycobacterial diseases based on rpoB gene mutations (Deshpande et al., rpoB gene and facilitate the analysis of drug resistance to RFB associated with double mutations in the rpoB gene.The current study is interesting and will help in epidemiology studies about the burden of RIF and RFB resistance against SS and ND have made substantial, direct and intellectual contribution to the work, critically reading an earlier version of this manuscript and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Executive functions are a set of top-down higher order cognitive processes that are vulnerable to sleep loss . Importantly, all these conditions may have different effects on cognitive functions. For instance, Shekleton et al.  suggesteThe inclusion of standardized measures of sleep disturbance and symptoms severity would additionally allow to explore the reciprocal relationships between poor sleep, executive functions and depression. As aforementioned, executive functions are impaired in major depression (Snyder et al., To conclude, the study of de Almondes et al.  highlighAB contributed writing the draft of the manuscript; CL contributed revising the paper.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Pacific Water (PW) enters the Arctic Ocean through Bering Strait and brings in heat, fresh water, and nutrients from the northern Bering Sea. The circulation of PW in the central Arctic Ocean is only partially understood due to the lack of observations. In this paper, pathways of PW are investigated using simulations with six state‐of‐the art regional and global Ocean General Circulation Models (OGCMs). In the simulations, PW is tracked by a passive tracer, released in Bering Strait. Simulated PW spreads from the Bering Strait region in three major branches. One of them starts in the Barrow Canyon, bringing PW along the continental slope of Alaska into the Canadian Straits and then into Baffin Bay. The second begins in the vicinity of the Herald Canyon and transports PW along the continental slope of the East Siberian Sea into the Transpolar Drift, and then through Fram Strait and the Greenland Sea. The third branch begins near the Herald Shoal and the central Chukchi shelf and brings PW into the Beaufort Gyre. In the models, the wind, acting via Ekman pumping, drives the seasonal and interannual variability of PW in the Canadian Basin of the Arctic Ocean. The wind affects the simulated PW pathways by changing the vertical shear of the relative vorticity of the ocean flow in the Canada Basin. Pathways of the Arctic Pacific Water are investigated in ocean modelsVariability of the Pacific Water due to wind is examinedMechanisms of the Pacific Water variability are suggested In the Makarov Basin and above the Lomonosov Ridge, the thickness of the PW layer decreases to less than 150 m with the PW fraction decreasing to less than 60% [Ekwurzel et al., Jones and Anderson, Alkire et al., As it crosses the shallow Chukchi Sea, PW cools by ∼0.7°C and loses ∼0.6 × 10Aagaard and Carmack, Steele et al., Anderson et al., Carmack et al., Polyakov et al., Shimada et al., Steele et al., Woodgate et al., Rainville and Woodgate, The freshwater fraction of PW contributes significantly to the formation of a strongly stratified Arctic halocline [Giles et al., Woodgate, et al.One critical question is whether wind‐driven spin‐up of the Beaufort Gyre can increase the vertical shear in the upper ocean velocity, thin the halocline and allow vertical heat transfer from the Atlantic Water to the base of the sea ice and so substantially reduce sea ice cover [e.g., Jones [McLaughlin et al. [Steele et al. [McLaughlin et al. [Steele et al. [McLaughlin et al., Morison et al., Proshutinsky et al., Steele et al., Timmermans et al., Different circulation patterns of PW in the Arctic Ocean have been inferred from water properties by Jones , McLaughn et al. , and Stee et al. . The latn et al.  proposede et al.  analyzedMcLaughlin et al., Steele and Boyd, McLaughlin et al., Steele et al., McLaughlin et al., Steele et al., Swift et al., The lateral extent of PW across the Canada Basin and the Makarov Basin Figure  is thougAlkire et al., Morison et al., Arctic Climatology Project, Morison et al. [Woodgate et al., [The 2003–2005 return of the frontal zone between Canadian Basin and Eurasian Basin polar waters to the pre‐1990s near‐climatological conditions and a partial return of PW into the Makarov Basin observed in 2003–2006 were accompanied by the shift of the Transpolar Drift from the Mendeleev‐Alpha Ridge toward the Lomonosov Ridge [ et al.,  found a Shtokman [Coachman et al. [Stigebrandt [Proshutinsky [Woodgate et al. [The sea level gradient between the Pacific and Atlantic Oceans as a mechanism for driving the inflow of PW through Bering Strait—a hypothesis first proposed by Shtokman  and thenn et al. , Stigebrgebrandt , Proshuthutinsky , and Wooe et al. , 2010. CProshutinsky and Johnson, Steele et al., Coachman et al., Aagaard et al., Roach et al., Woodgate et al., Basin‐scale atmospheric circulation [e.g., Gudkovich, Aagaard and Carmack, Rampal et al., Sea ice conditions which influence both rates of air‐ocean momentum transfer and ocean stratification on seasonal and interannual scales [e.g., The present study is motivated by the questions formulated above and is driven by several hypotheses. We expect that the strength and patterns of PW circulation in the Arctic Ocean are highly variable and depend on at least three major factors, namely:Investigation of how these multiple factors influence the PW dynamics based on observational data alone is difficult because extensive long‐term measurements with high spatial resolution are required. Besides, because of the complexity of the PW dynamics due to the coinfluence of the factors mentioned above, it is difficult to clearly separate underlying physical processes using currently available observational data.To investigate PW dynamics in this paper, the results from regional and global models obtained in the coordinated AOMIP experiments, and in the follow‐up research under the umbrella of the Forum for Arctic Modelling and Observational Synthesis (FAMOS), were analyzed with the aim of answering the above questions. Six regional and global Ocean General Circulation Models  [Madec et al., The key components of six coupled sea ice‐ocean models employed in the Pacific Water model experiment are described in Table Holloway et al., Proshutinsky et al., Jahn et al., Johnson et al., Clement Kinney et al., Köberle and Gerdes, Karcher et al., Kauker et al., Aksenov et al., http://www.whoi.edu/projects/AOMIP.All the six models participated in the previous phases 2 and 3 of the AOMIP experiments and were described in AOMIP publications [Nurser and Bacon, The model horizontal resolution in the Arctic Ocean in the five models, COCO, ECCO2, ICMMG, NAOSIM, and ORCA, was similar, from 23 to 37 km, rendering these models as noneddying in the Arctic, whereas OCCAM was eddy permitting at the ∼8 km resolution [e.g., Nguyen et al., Aksenov et al., −1 drift in the baroclinic circulation after ∼20 years .Five models of the current model set  used NCEP atmospheric reanalyses and one model (ECCO2) used JRA25 atmospheric forcing. For the present experiments, models were integrated over 1989–2007 from 41 year long spin‐ups for ICMMG, NAOSIM, and ORCA, a 20 year long spin‐up of COCO, a 4 year long spin‐up of OCCAM, and no spin‐up for ECCO2. The latter was forced with an optimized atmospheric forcing and lateral boundary fluxes, reducing model drift [Woodgate et al., Clement Kinney et al., Two out of the six models were global (OCCAM and ORCA), three were regional , and one (ECCO2) was a model nested in an outer global model with optimized oceanic exchanges through the open lateral boundaries at 55°N in the Atlantic and Pacific oceans. In two regional models, ICMMG and NAOSIM, the annual mean barotropic inflow in Bering Strait was constrained to its mean annual climatological value of 0.8 Sv [Hunke and Dukowicz, Hibler, Therefore, although the present study was not set up as a controlled forcing experiment, the wind forcing across the entire model set except one model (ECCO2) was the same. Given that the four models  used the same elastic‐viscous‐plastic (hereafter EVP) rheology in sea ice dynamical model [2.2To examine the pathways of PW in the Arctic Ocean in the models, a “passive tracer,” which does not affect water density and thus is passive with respect to ocean dynamics, was released in Bering Strait. The idea was to run models for the period 1989–2007 with an initial spin‐up for a 41 year from a state with the ocean and sea ice at rest (spin‐up period was shorter for some models) and to investigate PW tracer evolution, in particular area coverage and concentration, under the influences of external forcing. The challenge for this study was to identify periods that may represent a stable ocean circulation and link simulated PW tracer distribution patterns to external factors, such as PW inflow through Bering Strait and winds.Thompson and Wallace, Steele et al., Proshutinsky and Johnson, Proshutinsky et al., Under the assumption that wind forcing is the major factor responsible for ice and ocean circulation in the Arctic Ocean, we have used the AO index to identify periods of more or less stable atmospheric and oceanic circulation regimes. The AO index represents a dominant mode of the atmospheric sea level pressure (SLP) variability in the Northern Hemisphere [Steele et al., The analysis of model results was focused on ocean circulation from 1989 to 1996 (high AO and a cyclonic atmospheric circulation) and from 1997 to 2007  [Following the approach described above a set of three experiments was designed.Experiment 1. In the first coordinated experiment (hereinafter Exp1), at the beginning of the period 1989–1996  the passive PW tracer was set to unity through the whole water column at a section across Bering Strait, and to zero elsewhere , the tracer was released in Bering Strait as in Exp1 but throughout the period 1958–2007, starting on the 1 January 1958, on 0:00 hours GMT, in order to investigate possible drivers of PW variability and the PW contribution to Arctic fresh water. The experiment was performed with three models—ICMMG, NAOSIM, and ORCA.Experiment 3. This experiment (hereinafter Exp3) was designed to test the sensitivity of the simulated ocean circulation to the horizontal resolution and atmospheric forcing and was performed only with the ORCA 1°, 1/4°, and 1/12° global configurations, since there were three existing runs at different resolutions with the same model configuration. In the experiment, the passive PW tracer was released in Bering Strait as in Exp1 but throughout the period 1983–2007 in the ORCA 1° configuration. The model stream functions of the ocean circulation, oceanic relative vorticity, and Ekman pumping for the cyclonic 1989–1996 and anticyclonic 1997–2007 periods were analyzed to examine forcing mechanisms for the PW dynamics and pathways.2.3For the analysis presented here, monthly and annual volume, heat and freshwater oceanic transports between the Arctic Ocean and Pacific and Atlantic oceans were calculated at key sections across Bering, Fram and Davis Straits and the straits of the Canadian Arctic Archipelago Figure .refS = 34.8, which is the estimated mean salinity of the Arctic [Aagaard and Carmack, amamoto‐Kawai et al., Rabe et al., Jahn et al., Monthly time series of PW content (PWC) and freshwater content (FWC) were obtained for each of the Arctic regions depicted in Figure Jones and Anderson [pwS = 32.0 [Jones et al., refS = 34.8 is taken, so PW is the product of PW fraction and a constant scaling factor (1 − pwS/refS). We also derived the vertically integrated content of the Pacific fraction of fresh water (PFWC)  [e.g., r et al.  and Curry et al.  .Oden in July–August 2005, Arctic Ocean Section 2005 (hereinafter AOS05) which began from the Alaskan shelf in the vicinity of Barrow and crossed the Arctic Ocean and ended near Svalbard [Jones et al., Louis S. St‐Laurent summer cruises (hereinafter LSSL03/04) [Yamamoto‐Kawai et al., Simulated PW parameters and PW fractions in the Arctic Ocean were compared with published observed distributions of these parameters obtained from various Arctic cruises: (a) the trans‐Arctic cruise of the Ice Breaker Jones et al. [Jones and Anderson [Alkire et al., Carmack et al., Falck et al., The vertical distribution of PW fraction across the Fram and Davis Straits estimated by s et al.  and JoneAnderson  from end3All six models listed in Table Steele et al. [Nguyen et al. [Watanabe [The models' performance was assessed by examining the inflow through Bering Strait and the outflows through Fram and Davis Straits, with a focus on the upper circulation in the Arctic Ocean. Once validated, we used the model results to identify PW pathways through the Arctic Ocean and diagnose the Arctic freshwater content change due to changes in the PW storage in different regions of the Arctic Ocean. We did not investigate different types of PW as defined by e et al.  .3.1Karcher et al., Golubeva and Platov, Holloway et al., Gerdes et al., Watanabe, Aksenov et al., Popova et al., Nguyen et al., Jahn et al., Johnson et al., Clement Kinney et al., Clement Kinney et al. [In this section, only the comparison relevant to the present analysis is given, but more detailed assessments of each model may be found elsewhere [e.g., y et al. . It willFieg et al., −3 Sv = 103 m3 s−1). These values are close to the observational estimates of 159 ± 34 mSv .3.2Carmack et al., 3 yr−1 at the end of the integration period.The mean summer 2003/2004 vertical distributions of the PW fraction in the Beaufort Sea and Central Arctic Ocean simulated in Exp1 were compared with the observations from the LSSL03/04 and AOS05 cruises in the same area  fraction of PW tracer above the Alaskan shelf slope at depths ∼50–80 m Figure . This coDuring 1997–2004 in ICCMG, PW at the surface, as well as at ∼100 m, initially follows the Mendeleev‐Alpha Ridge, then turns toward the Beaufort Sea, with part of this flow branching toward Fram Strait Figures i and 6i.Summarizing, all models participating in the analysis, except NAOSIM, simulate a shallower than observed PW layer in the Canada Basin. ECCO2 and NAOSIM show the best agreement of the PW distribution across the Arctic Ocean with the AOS05 measurements. On the other hand, ORCA demonstrates the best agreement between the observed during the LSSL03/04 cruise and simulated spatial mean PW fraction in the Beaufort Sea in the top ∼200 m in 2003/2004, although the simulated PW fraction is too low in this model. In all models, the total simulated PW content is lower than observed, probably due to the relatively short periods of the PW tracer releases in Exp1 (∼10 years). One of the implications of this analysis is that the short‐period PW model tracer releases can be used for pathways examination but have a limited application in the analysis of the PW content in the Arctic Ocean.3.3Timmermans et al., For the 1989–1996 cyclonic, and 1997–2007 anticyclonic circulation regimes, the models simulate two pathways of PW in the Arctic Ocean Figures  and 6. TTimmermans et al., The shelf route enables PW to spread westward toward the Siberian shelf. If there were no wind, under the influence of the Pacific‐Atlantic ocean sea level pressure gradient, PW would flow into the Arctic and then turn east along the Alaskan Shelf slope due to the Coriolis force [e.g., Steele et al. [The models show several differences in simulating PW pathways. In the COCO and OCCAM models, PW mainly follows the western pathway Figure , wherease et al. . The patIn all models but COCO, which exhibits a sharp decrease of PW fraction with depth, the spread of PW is similar in the top 100 m Figure . In the Aksenov et al., The simulations show consistency between increased vertical downward Ekman velocity (pumping) between 1989–1996 and 1997–2004 and deepening of the pseudopotential density surfaces   in all six models shows maxima of 20–27 m in the Canadian Basin, decreasing toward the Eurasian Basin of the Arctic Ocean Figure . This paCarmack et al. [Although different in detail, the vertically integrated PFWC in the models exhibits a similar distribution with maxima in the Canadian Basin; a pattern which is also evident in the observations , the PWC is ∼200 m in the Canadian Basin (not shown), similar to the observed value of ∼220 m [e.g., Alkire et al., Abrahamsen et al., Karcher et al., In the last decade, with a strong anticyclonic atmospheric circulation dominating the Arctic Ocean , the Pacific‐Atlantic front has partially recovered to its pre‐1990s position [e.g., In summary, long‐term variations in the vertically integrated total FW and PW distributions in the models reflect the cyclonic (high AO) and anticyclonic  circulation regimes and show accumulation of the total and Pacific fresh water in the Beaufort Sea during the anticyclonic years and a decrease of their storage during cyclonic years Figures  and 11.3 loss of Arctic freshwater content, and in the decade 1997–2007 with lower and neutral AO induces, when anticyclonic circulation was accompanied by a sharp increase in the freshwater storage  [Rabe et al., 3, whereas the ICMMG peak‐to‐peak change is ∼6000 km3.We use the ICMMG, NAOSIM, and ORCA model results for 1958–2007 to quantify the contribution of PW to the Arctic freshwater content variability in our simulations. We use results from continuous tracer releases for five decades (Exp2). Figure e Figure . The modPW that accumulated in the Canadian Basin prior to the 1980s was exported from the Arctic, such that the PW remaining in the basin was at a minimum in the late 1990s. Since the end of the 1990s, the PW content increased in the model simulations, surpassing the 1980s level by the mid‐2000s Figure .As in the FWC results above, the simulated interannual change of PWC is dominated by variations in the Canadian Basin. Correlations between PWC change in the Canadian Basin in 1981–2007 (this period was chosen to avoid drift of PWC at the beginning of the integrations) simulated in ICMMG, NAOSIM and ORCA and the AO are 0.7, 0.9 and 0.7, . Since the PFWC change is equal to the PWC change multiplied by a constant factor Appendix , it is aAt the interannual scale, correlations between FWC change and Ekman pumping  show accumulation of PW in the Canadian Basin during the anticyclonic 1997–2007 years and release of PW toward Fram Strait during the cyclonic 1989–1996 years. This is consistent with the accumulation of the surface fresh water due to negative curl of total surface stress over the Canadian Basin in anticyclonic years [e.g., Since five out of six models in this study were forced with the same NCEP atmospheric winds, we examined whether the differences among the model circulations and PW pathways were related to different model resolutions, especially associated with how the models simulate topographically guided rim currents and ocean eddies. To test this, a set of sensitivity experiments (Exp3) were carried out with the ORCA model. These experiments included runs of the ORCA model with horizontal resolutions of 1/4°, 1°, and 1/12°.Holloway et al. [Increasing model resolution from 1° (not eddy resolving) to 1/4°  and 1/12°  resulted in a more anticyclonic barotropic circulation in the Canadian Basin Figure . Holloway et al.  found th4.2Proshutinsky et al., From model results and observations [Rabe et al., On interannual time scales, FWC in the Beaufort Gyre and Canadian Basin simulated by NAOSIM shows a notable covariability with Ekman pumping [4.3Falck et al. [Dodd et al. [Dodd et al., Steele et al., Karcher et al., de Steur et al., Rabe et al., We now compare observed and simulated PW export in three models ICMMG, NAOSIM, and ORCA with the long‐term PW tracer release Exp2) that reached quasi‐equilibrium of the PW tracer content in the Arctic Ocean. It should be noted that it takes ∼20 years for the models to reach quasi‐equilibrium between the inflow through Bering Strait and outflow of PW tracer from the Arctic. k et al.  and Doddd et al.  reported that rea4.4Gerdes et al. [Jahn et al. [Jahn et al. [Forcing imbalances, relaxation techniques, unresolved eddies, and missing processes in the mixed layer and upper part of the halocline, such as salt release from sea ice, all affect the models' performance. Here we only address the effects of the model resolution and accuracy of the model bathymetry. Higher‐resolution models better resolve narrow straits in the Canadian Arctic Archipelago. The experiments with the ORCA global model at 1°, 1/4°, and 1/12° horizontal resolution show that if the model configuration and forcing are the same, and the topography unchanged , higher‐resolution models simulate higher outflow west of Greenland and lower outflow east of Greenland. s et al.  found thn et al.  examinedn et al.  conclude5The dynamics of PW in the Arctic Ocean has been analyzed using model experiments with tracer releases in six coupled sea‐ice ocean models. In this intercomparison, we have analyzed PW pathways across the Arctic Ocean and through the Canadian Arctic Archipelago and Fram Strait and explained the drivers of the PW variability. In support of earlier proposed schematics of the PW circulation in the Arctic, the models simulated the two main pathways of PW. The eastward PW route follows the Alaskan shelf and then across the western Beaufort Sea and through the Canadian Arctic Archipelago and Baffin Bay in the Labrador Sea, while the western PW route leads along the Siberian shelf and then in the Transpolar Drift and through Fram Strait to the Nordic Sea and in the North Atlantic. The contribution of the pathways varied between models. In ICCMG, NAOSIM, and ORCA, there is a clear relationship between PW pathways and AO regimes: during the cyclonic years (1989–1996), the eastern pathway dominates, whereas during the anticyclonic years (1997–2007), the western one prevails. Other models do not show such a strong adherence to the AO circulation regimes.Variations in the storage of the PW and associated FWC in the Arctic Ocean over the last 50 years have been examined using models and comparison with observations. There was a decrease in Pacific freshwater storage during the 1980s to 1990s and an increase during the last decade. Variations in FWC were similar to those of the PWC with a minimum in the 1990s. The simulated 1990s to 2009 anomalies are comparable with the freshwater inventory obtained from hydrography. The PW outflow through Fram and Davis Straits reflected the changes in PW in the Arctic Ocean, with a decrease in the PW export during last two decades. The model transit time for PW to cross the Arctic Ocean was estimated at 10–15 years, and the time for the PW outflow to reach a quasi‐equilibrium was ∼20 years. Sensitivity tests with ORCA were carried out to isolate the effects of model resolution, wind forcing, and Bering Strait on the dynamics of PW in the Arctic Ocean. In the ICMMG, NAOSIM and ORCA simulations, the Ekman convergence is a primary driver of the seasonal variability of PW in the Canadian Basin.Penduff et al., The most challenging issue of the present intercomparison study is that there are significant differences between the models and the observations, namely: (i) the models differ in their simulation of the upper ocean circulation in the Arctic Ocean and (ii) the models differ in simulating oceanic outflow into the North Atlantic, in particular disagreeing on the partitioning of the outflow between the Canadian straits and Fram Strait. The higher‐resolution models are expected to perform better in the Arctic where the Rossby deformation radius is small and the seafloor has complex small‐scale bathymetry. However, from the present study, it is not immediately obvious that such an improvement occurs. Moreover, a simplistic refinement of the model resolution in some cases paradoxically leads to stronger model biases, suggesting that model tuning for the high‐resolution models might be more challenging than for the lower‐resolution ones. In particular, the choice of mixing and advection schemes, lateral boundary conditions, and treatment of the oceanic bottom boundary layer have proven to be crucial for the simulations [Yang, Another probable source of the divergence in model results is the forcing. Despite five out six models in this study being forced with NCEP reanalysis, the surface ocean circulation differs significantly. As sea ice dynamics moderates the atmospheric momentum transfer to the ocean, differences in sea ice cover in the models lead to different forcing of the ocean. Figure In this study, we have not discussed observational accuracy. Detection of the PW is based on the fine discrimination of chemical tracers which are not strictly conservative, but involved in the ecosystem. The nitrate/phosphate and Si techniques remain the only means to observe PW in the Arctic, and, as there are not independent methods, the accuracy of these techniques has some limitations, which need to be better quantified.Model validation is a crucial part of the model development process. More data in the Arctic Ocean are now becoming available, including new data on ocean turbulence measurements, biogeochemical tracers, that are extensively used to identify water masses, and radionuclides to track the spread of the water masses. It is important for the ocean models to take advantage of the new observations and, vice versa, the observational campaigns could significantly benefit from robust high‐resolution model simulations.


Locating a stimulus on the skin is a well-described perceptual task, but little is known about how this ability remains stable under ecological conditions. Specifically, the effect of recent stimulation has been the subject of very few studies in the tactile domain Craig, , but is Day and Singer  found a In the study of Li et al.  these quIn summary, the two preliminary experiments showed that tactile spatial perception is stable with time and that vibro-tactile stimulation reduces sensitivity to a subsequently applied touch stimulus. The main experiment found that adaptation results in perceived spatial expansion. Li et al.  propose In a different test of such a model, my own study tested the effects of adaptation following exposure to tactile motion on the dorsal side of the forearm. The study used a 15 cm/s motion stimulus which moved along a 19 cm path but only touched the skin for 4.5 cm at the proximal and distal ends of motion. Exposure to this stimulation resulted in an inwards position shift  of a stimulus at the edge of the gap (Brooks et al., Li et al. have shown results for only one stimulus size of adaptation, but could the observed spatial expansion be size dependent? Calzolari et al.  show thaRather than considering aftereffects to arise as a result of fatiguing neurons, they might represent the optimization of perception to the recent statistics of the environment. In vision there is increasing evidence that perception is optimized to statistical regularities of the environment (Seriès and Seitz, Unlike many previous studies, Li et al.  show preIn summary, it is clear that sustained pressure leads to repulsive spatial aftereffects. Li et al.  have shoThe author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Global mental health has rapidly attracted increasing attention by health policy makers and researchers during the last 10 years. The groundwork for this shift was laid in data being made available on the prevalence . Efforts by researchers and innovators supported by funders like the Grand Challenges Canada (GCC website), National Institute of Mental Health of USA (NIMH Hubs website), Department of International Development of UK (PRIME), European Commission  are extremely relevant towards this objective. In addition, a number of researchers are working towards generating and aggregating critical evidence that will help in achieving the objectives of global commitments.This issue of Global Mental Health is intended to shed light on some of the evidence and experience that are relevant to implementing each of the five key objections of the Action Plan. Those objectives are to: (1) update mental health laws in line with international human rights instruments; (2) improve service coverage for serious mental illness by 20%; (3) have at least two functioning multi-sectoral prevention/promotion programmes; (4) reduce national suicide rate by 10%; and (5) establish minimal biennial national core dataset collection and reporting. For each of these objectives we present overview/review papers that summarize the research literature relevant to meeting that objective, and original research papers that look at current areas of innovation and attention. This issue we hope therefore contributes towards filling the knowledge gaps for implementers working to reach the Action Plan objectives, as well as pointing out the needs and opportunities ahead in creating the learning to meet these goals.Taking up each of these objectives in turn, first Marianne Schulze provides an overview of human rights principles for developing policies and laws on mental health, highlighting the need for all policies and laws to conform to international human rights agreements like the UN Convention on the Rights of Persons with Disabilities. Szmukler & Bach  flesh thet al. (et al. (The idea of ‘task sharing’ or task-shifting describes the idea of optimizing the skillsets of non-specialized workers to provide much of the steps in mental health care and promotion, such as through community health workers. It is increasingly turned to as a model for achieving the expanded service coverage goal of the Action Plan, and closing treatment gaps more broadly. The paper by Javadi et al.  provides (et al.  then furet al. (et al. (In terms of prevention and promotion, Tol  provideset al.  describe (et al.  summarizet al. (et al. (Finally, timely and actionable information is a critical element in better planning. Lora & Sharan  provide et al.  in a stu (et al.  extend tThese papers, though not the last word in identifying knowledge gaps on the path towards achieving the goals of the WHO Action Plan, do illustrate how much we do know to build on moving forward, as well as where to sharpen future efforts in generating, aggregating and disseminating information and evidence for more effective implementation of global mental health activities.


Dear Editor,We read with interest the article by Fothergill et al.  presentiGiven the frequent use of flavouring substances in the food industry , as wellThe question therefore arises, why we were not able to reproduce the experimental findings of Fothergill et al. , but alsThis question becomes particularly relevant as the presumed role for cinnamon supplements in a glycemic control has repeatedly been suggested but hitherto not been firmly established ,10. Furt


Biodiversity conservation is one of the grand challenges facing society. Many people interested in biodiversity conservation have a background in wildlife biology. However, the diverse social, cultural, political, and historical factors that influence the lives of people and wildlife can be investigated fully only by incorporating social science methods, ideally within an interdisciplinary framework. Cultural hierarchies of knowledge and the hegemony of the natural sciences create a barrier to interdisciplinary understandings. Here, we review three different projects that confront this difficulty, integrating biological and ethnographic methods to study conservation problems. The first project involved wildlife foraging on crops around a newly established national park in Gabon. Biological methods revealed the extent of crop loss, the species responsible, and an effect of field isolation, while ethnography revealed institutional and social vulnerability to foraging wildlife. The second project concerned great ape tourism in the Central African Republic. Biological methods revealed that gorilla tourism poses risks to gorillas, while ethnography revealed why people seek close proximity to gorillas. The third project focused on humans and other primates living alongside one another in Morocco. Incorporating shepherds in the coproduction of ecological knowledge about primates built trust and altered attitudes to the primates. These three case studies demonstrate how the integration of biological and social methods can help us to understand the sustainability of human–wildlife interactions, and thus promote coexistence. In each case, an integrated biosocial approach incorporating ethnographic data produced results that would not otherwise have come to light. Research that transcends conventional academic boundaries requires the openness and flexibility to move beyond one’s comfort zone to understand and acknowledge the legitimacy of “other” kinds of knowledge. It is challenging but crucial if we are to address conservation problems effectively. Biodiversity conservation is inherently a “wicked” problem  and the drivers of that trade, providing guidance for the development of conservation strategies , mentored by one biological anthropologist (Jo Setchell) and one social anthropologist (Sandra Bell).et al. et al. et al. et al. et al. et al. Conflicts over conservation endeavors, whether directly between wildlife and people or between stakeholders over wildlife conservation strategies and implementation, are a major threat to the long-term survival of wildlife and to the livelihoods of subsistence communities in developing countries, particularly near protected areas . Specifically, her observations of the effect of wildlife foraging on crops planted by her Gabonese colleagues’ families, living in villages inside Loango National Park and in or close to the buffer zone of the park, sparked an interest in the implications of conservation for the people who live alongside the park.et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. When wildlife forages on crops, this behavior is often termed “crop-raiding,” although the intention implied by “raiding” is inappropriate Hill . We therEmilie based herself in two remote villages in Loango National Park for more than a year. She used a combination of participant observation, an ethnographic journal, and semistructured interviews to investigate the institutional and social context of crop-foraging, and quantitative survey methods to assess the biophysical aspect of crop-foraging by medium to large mammals.et al. Emilie first investigated the context of conservation at her study site, and how this limits, or intensifies, conflict over wildlife. She showed that protected areas were implemented as a top-down conservation strategy in Gabon. The process excluded local populations from the decision-making processes and eroded or prevented feelings of ownership over their natural resources in local people, thus contributing to institutional vulnerability. This lack of trust prevents communication that would be beneficial to both the people and the national park. Emilie also found that people in Loango have an understanding of sustainability that shares common ground with Western conservation principles. However, farmers cite crop-foraging as the major reason for disliking protected areas and conservation, and these sentiments can result in unobtrusive subversion of conservation efforts, such as feigning ignorance of known conservation laws and legal processes to oppose the imposition of conservation strategies while avoiding direct confrontation Fairet . In so dLoxodonta africana) caused the most crop damage, and crop-foraging by elephants followed rainfall and was higher in fields located near permanent water points, probably as a result of seasonal changes in the availability of water and access to the herbaceous vegetation present in swamps . Moreover, most fields at the study sites are isolated from each other, creating islands of agricultural land surrounded by wild habitat, and Emilie’s results demonstrate that field isolation renders some fields more vulnerable to crop-foraging than others. These findings are valuable, as most sites where crop-foraging has been studied are located in East and South Africa in areas with high human density and a high degree of deforestation, while Gabon has very low human densities (<0.2 inhabitants/km2 at the study site) and extensive forest coverage  and natural science  allowed a holistic view of the problem. Emilie used this integrated framework to provide recommendations for the management of crop-foraging in Gabon protected areas network that were scientifically sound and socially appropriate Fairet .et al. et al. et al. Wildlife tourism has the potential to produce revenue that can be used for conservation as well as to promote public awareness of conservation issues  in Bouhachem forest, Northern Morocco. For her doctoral research, Siân was thus able to practice participatory action research, a style of research that entails sustained engagement and building of trust with participants in a project. Siân’s aim was to investigate how effective ethnographic methods could be toward creating a conservation strategy that involves local people and draws on their extensive ecological knowledge.Conservation projects for individual species are more effective if they incorporate local people’s knowledge and perceptions of that species  on Atlantic salmon  in Scotland  and the largest wild canid in the forest, the African wolf (Canis lupus lupaster), are relatively uncomplicated, relating directly to goats as prey and wolves as predators. The shepherds’ relationship with their dogs (Canis familiaris) is more ambiguous. Shepherds appear to resent the presence of dogs, but accept their role as a protector of livestock. The position of dogs in Bouhachem society mirrors the position of dogs elsewhere, symbolically existing “between the human and non-human worlds”  in Kenya , to integrate the datasets, producing results that would not otherwise have come to light . Such interdisciplinary projects are challenging to conduct. Many authors have described the boundaries of understanding and communication between academic disciplines with regard to conservation (Campbell Interdisciplinary research can provide detailed understanding of the context of a conservation problem and make recommendations for improvement Robinson . Howeveret al. et al. The case studies we present serve to highlight the need for researchers to become skilled at bridging disciplinary boundaries to provide a better understanding of the complexity of the context in which conservation occurs (Chan


Rehabilitation in the context of HIV management in Africa is still a neglected field which holds great promise for the improvement of the quality of life as well as integration of people living with HIV back into their communities and homes. However, rehabilitation has not been incorporated into HIV care despite the fact that a large number of people living with HIV experience disability. The dearth of literature and lack of models of care to roll out rehabilitation for people living with HIV in Africa are astounding. Well-resourced countries have emerging approaches on the management of disability in the context of HIV. However, epidemic countries are still lacking such an approach neglecting the devastating effects of disability on individual livelihoods and antiretroviral treatment adherence. Thus, rehabilitation needs to be integrated into the response to HIV. This article advocates for the development and implementation of a model of care to guide rehabilitation of people living with HIV in South Africa. The protocol submitted is a PHD in Health Sciences .et al.et al.et al.The World Health Organization's International Classification of Functioning, Disability and Health (ICF) has changed the disability paradigm from unilateral into multidimensional, in that disability is not only seen to affect an individual's body but their social being as well (World Health Organisation et al. (et al.et al. (et al.Worthington et al.  used qua. et al.. Worthin.et al.  explored. et al..et al.’s (et al.As an imperative in the rehabilitation of people living with HIV, the authors of this article identified three concepts to be included in the rehabilitation framework for a South African setting bearing in mind the ICF and Worthington et al.’s , 2009 coet al.’s . Secondls et al.. Thirdlys et al. and a reet al., Community-based rehabilitation which utilises local resources in areas with limited infrastructure (Iemmi et al.Canada is amongst the leading countries addressing rehabilitation of people living with HIV and for over 15 years has mobilised a working group of stakeholders forming the Canadian Working Group on HIV and Rehabilitation CWGHR . CWGHR het al.et al.A Model of Care ‘is a multifaceted concept, broadly defining the way in which health care is delivered including the values and principles; the roles and structures; and the care management and referral processes. Where possible the elements should be based on best practice evidence and defined standards and provide structure for the delivery of health services and a framework for subsequent evaluation of care’ (Davidson et al.These shortfalls often promote a convergence between research and the health care setting (Davidson The strategies involved in the development of the Australian rehabilitation models of care have been summarised and presented in a synthesis of Australian models of care in rehabilitation  New Sou. The modet al.et al.Reflections on working models enable researchers and health practitioners to identify gaps and causes of challenges within the system. For instance, the South Australia Department of Health 2 identifiet al.In order to guide the process of model development one has to identify logical steps and processes (Davidson Initial steps towards the development of such a model have commenced. For example, Phase 1: understanding the health policy context in South Africa is explored in preliminary work on HIV and disability. Evidence has been provided by Hanass-Hancock, Strode and Grant  and Hanaet al. (et al. (et al. (Secondly, Phase 2: definition and understanding the current state of play: Nixon  clearly et al. , Hanass- (et al.  and Van  (et al.  concede et al.et al.et al.Thirdly, Phase 3: translating evidence-based research and expert opinion into best practice: although South Africa is effectual in research pertaining to HIV and disability (Cobbing et al.et al.Consequently Phases 4 and 5: consulting broadly with stakeholders and incorporating feedback, as appropriate to produce a finalised model of care and endorsement of the model of care by Advisory Group and Health Networks are not yet initiated in South Africa. However, with expert opinions and reflection we will be able to develop evidence-based and feasible interventions. Only after this process, we will be able to agree on a model of care that is suitable to South Africa and that will be able to feed into the broader health agenda in South Africa. Such a model should involve communication both formal and informal in repetitive meetings to share information and solicit feedback regarding the sustainability and the running of the model. Furthermore, evaluation is often achieved by involving key stakeholders to give feedback on the progress and impact of the model (Cormack et al.et al.The need to develop a model to guide rehabilitation of people living with HIV in South Africa is essential as we address the cumulative disabling effects of the virus and its treatment. The process of development of the model needs to adhere to key processes that have already been tested in resource-rich contexts and now need to be further tailored to meet the needs of a resource poor context. A framework as in


Mycobacterium smegmatis  and negative control (SOD or TEMPOL) to justify the exceptional HPLC profile obtained in the experiment.Stoichiometric ratio of superoxide and oxyethidium formation is 1:1 in superoxide reaction with DHE . Although reaction rate constant of TEMPOL with superoxide is much lower than that of SOD it has a similar in vivo efficacy which is ascribed to its smaller size and higher pentrability , but not by TEMPOL, has a role in growth. Noteworthy, DPI is a non-specific inhibitor of flavoenzymes, in addition, it inhibits pentose phosphate pathway and tricarboxylic acid cycle  and generally ineffective against bacteria. In particular, mycobacterial ETC is more complex than mitochondrial ETC due to diversity of components and branching (Cook et al., SOD is a standard negative control for the detection of superoxide due to the fact that it reacts with superoxide at 1,000 times higher rate in comparison to DHE (Zielonka et al., DHE-HPLC assay needs a careful standardization and should be supported by another standard method of superoxide estimation to affirm its biological role (Forman et al., The author confirms being the sole contributor of this work and approved it for publication.The author declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The integration of information between functionally specialized and widely distributed brain regions  is fundamentally important for cognition (Bressler and Menon, Recently, Mahjoory et al.  investigMahjoory et al.  showed tThere are several important issues to bear in mind when considering the consistency of EEG measures in the source-space, not least of which is the physiological state of participants at the time of recording. The resting condition is a challenging state for source-level analysis, and likely represents a major source of inconsistency in the source localization and connectivity outcomes. Related to this is the arousal state of the subjects. This has been shown to affect physiological significance of source localization and alter connectivity estimates using various methods and modalities (Kaufmann et al., Based on the findings of Mahjoory et al. , we highThere are several limitations of Mahjoory et al. , many ofMahjoory et al.  presenteAll authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Dear Editor,I read with great interest the article by Khadir F et al. that was published in your prestigious journal discussing about the protective effects of arbutin on lipid peroxidation in cyclosporine-treated rats . The aut


We agree with Moreau and Candidi  that theMost researchers in the last decade utilize the Sebanz et al.  definitiA more restrictive definition of joint action was first proposed by Bratman, , who disAccording to Sebanz et al. , “our brRelated work on joint action (e.g., Gonzalez et al., While philosophical discussions within social neurosciences may have called for a shift away from “isolation paradigms” (Becchio et al., In summary, we suggest researchers adopt the broad definition of Sebanz et al.  as it prUtilizing the Sebanz et al.  definitiSSB and PJB have made substantial, direct, and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


We read with interest the recent article by Leckey et al., reporting that consumption of a ketone diester drink impaired 31 km cycling time trial performance , but no symptoms were reported with a single bolus (Clarke et al., d-isoform, not l-BHB; the only way to accurately detect both is using mass spectrometry analysis. Additionally, AcAc is unstable and rapidly degrades when stored for over 48 h (Price et al., 4 converts AcAc into a stabilized BHB derivative, which can be analyzed after longer storage (Lincoln et al., Finally, we wish to highlight the importance of analytical techniques in the study of ketone metabolism. Enzymatic assays of BHB only detect the per-se impaired performance, as implied in the title and abstract of this paper. Contrasting results from existing studies using different ketone compounds, performance tests, dosages, and analytic techniques highlight that further research is required to determine the role of exogenous ketones in athletic performance (Cox et al., To conclude, consumption of the AcAc diester was ergolytic in a 31 km cycling time trial in the doses and formulation studied by Leckey et al. However, it is unclear if this would be the case were dosing and formulation optimized to achieve higher BHB levels and improve tolerability. Given the nature of the GI symptoms described, it is unknown whether hyper-ketonemia All authors agreed on discussion points for the commentary. BS wrote the initial draft with help from AK. AP, KF, and DD extensively revised and edited commentary. All authors reviewed and agreed final version prior to submission.BS is an employee of HVMN Inc., which sells exogenous ketone products. She has the option to purchase stock in HVMN Inc. AP is a scientific consultant for Pruvit Ventures, which sells exogenous ketone supplement products. She is also an inventor on intellectual property related to exogenous ketone supplementation for various uses. DD is an inventor on intellectual property related to exogenous ketone supplementation for various uses. The other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Peripheral machine interfaces are an important field of exoprosthetic research since they facilitate the communication between human and robotic device and thus their collaboration. Castellini et al.  give a vFrom the users’ perspective, predictability of motion behavior and transparency of control appear to be crucial for embodiment irrespective of the considered extremity (Castellini et al., One of the technical suggestions of Castellini et al. is the investigation of semi-autonomous systems. While this is promising due to decreasing cognitive effort, such devices need to be carefully designed since increased autonomy might reduce the users’ experience of agency, i.e., the feeling to be able to control the device, and thereby embodiment. Correspondingly, some users prefer retaining control over improving task performance which might recommend to customize autonomy (Gopinath et al., While being less explored, afferent feedback to the user appears to be psychologically crucial for embodiment since it relies on multisensory integration of vision, touch, and proprioception (Giummarra et al., In conclusion, human-oriented approaches should be researched to enable considering users’ experiences and assessment in device and control design (Beckerle et al., The author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Hasan et al.  is problematic: The results of the cross-classification may still at least partially reflect stimulus effects. The current study thus shows no clear support for modality-dependent  or modality-independent (due to stimulus dependencies) identity classification as such.Hasan et al.  use a refamiliar person recognition (only) but could also be at least partially attributed to generic paired association learning: the study only included a small number of stimuli and each stimulus was presented on average 58 times per participant within the experiment, with the content of audio-only and video-only stimuli overlapping with that of the audiovisual stimuli. In such a design, associations between the stimuli representing the modalities could be formed, even for unrelated pairs of stimuli , potentially resulting similar classification outcomes: Tanabe et al. (It further remains unclear whether Hasan et al.  have shoe et al. , for exae et al.  study maWhile there are several methodological and conceptual issues in Hasan et al.'s  study, tThe author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The growing complexity of functional materials and the major challenges this poses to structural science are discussed. The diversity of structural materials science and the contributions that computation is making to the field are highlighted. IUCrJ.The growing complexity of many classes of functional materials poses major challenges to structural science to which technical developments and the increasingly predictive power of computation make key contributions. These themes are clearly illustrated by the articles published in the field during the last year and especially by those in et al.  has been intensively studied over several decades, owing both to the subtlety of its structural properties and to the very wide ranging applications arising from its piezoelectric behaviour. New insight into structural changes and phase relations is provided by the study of Zhang, Yokota  al. 2017. Using aet al. (20173.The paper represents a particularly elegant example of the elucidation of structure–property relations in current materials science; while the continuing challenges posed by perovskite-structured materials is also illustrated in the work of Kang  al. 2017, which det al. (2017The theme of structural changes during phase transitions again forms the basis of the work of Matvienko  al. 2017, which ret al. (2018The characterization of disorder remains a perennial challenge in the structural science of materials. The work of Kim  al. 2018 provideset al. (2017et al. (2017et al. (2017The determination of structure–function relationships in nano structures is an active and growing field, especially in supported nano-structured catalytic materials. Here, in addition to TEM, X-ray spectroscopy is providing powerful tools as illustrated by the recent work of Dann  al. 2017 and Roge al. 2017, which a al. 2017, which het al. (2017Computation now pervades all aspects of structural science. The growing power of structure prediction methods is highlighted by the recent work of Collins  al. 2017, which uBond-valence methods continue to provide a simple but useful approach to understanding and validating inorganic crystal structures. Chen & Adams 2017 report aet al. (2017Further illustration of the role of current computational methodologies is provided by the study of Ma  al. 2017, which uet al. (2017It is of interest to note how machine-learning techniques are contributing to the field as in the work of Park  al. 2017, which uIUCrJ.In conclusion, it is hoped that this brief editorial highlights the diversity of structural materials science and the contributions which computation is making to the field. Articles based on these topics will continue to be welcomed by


Macromolecular Big Data provide numerous challenges and a number of initiatives that are starting to overcome these issues are discussed. However, recent systematic surveys have revealed that a large fraction of representative sets of studies published in biomedical journals cannot be reproduced in another laboratory. This increased focus on reproducibility has likely contributed to the growing rate of retractions among scientific publications  – was limited to atomic coordinates, and was later supplemented by the ‘header’ containing the metadata describing the parameters of data collection  the sheer size of the data, which is 2–3 orders of magnitude greater than structure factors, (2) difficulties in organizing, acquiring, curating and managing the associated metadata, and (3) the deep-rooted tendency of researchers to keep their data private. Progress in storage technologies has almost eliminated the first challenge – the cost of hardware required to accommodate diffraction data has dropped significantly. The other two challenges still remain formidable, as discussed in the paper by Kroon-Batenburg, Helliwell, McMahon and Terwilliger in this issue of et al., 2016et al., 2016et al., 2014et al., 2016et al., 2016The initiatives surveyed in the paper include dedicated diffraction data repositories such as the SBGrid . For obvious reasons, such datasets not only have to be associated with a detailed description of the protein, but must also include which compounds were introduced and None of the current diffraction data repositories provides much, if any, information about the macromolecular sample. Ideally, one would like to have structural data integrated with data from expression, purification, and crystallization – as well as information about biomedical experiments. Creation of such integrated resources remains a dream that may be a major goal of BD2K type of program.


The study of de Assis and de Almondes, Systematic reviews are considered to provide the highest level of evidence for assessing the effectiveness of therapeutic interventions  the definition and pursuit of the research question, (2) fails to meet established eligibility criteria and (3) lack of methodological quality assessment of the included studies.The research question distinguishes a systematic review from a narrative one and guides the search strategy and eligibility criteria. It generally contains a careful selection of PICO(S) criteria , Comparator(s), Outcome(s), and Study Design) , MEDLINE is the primary component of PubMed. Even accessing MEDLINE through other interface, its results are already covered in PubMed search. Also, accordingly to Cochrane, three main databases  are recommended to find relevant studies (Chandler et al., According to eligibility criteria, author cited that retrieved studies should “fully” meet the following inclusion criteria: aging subjects with cognitive impairments or dementia; at least one session of exercise; comparator criteria not presented; pre-post measures of BDNF and reported parameters of executive functions.Misjudgments are noticeable considering eligibility criteria indicated above and, following the established, only Baker et al.  and NascInconsistencies are also related to intervention and outcome criteria. Even though exercise type was not determined by de Assis and Almondes as the intervention criteria, retrieved studies only reported aerobic training and three resistance training studies were excluded, as observed on selection process flow-chart. Moreover, measures of BDNF and executable functions must be performed pre and post exercise protocol, but Suzuki et al.  reportedAs a final point, it is important to emphasize that de Assis and Almondes did not assess risk of bias of included studies. There is broad consensus among the scientific community on the relevance of assessing the methodological quality of the studies, especially when carrying out a research synthesis (Johnson et al., In sum, for all of the reasons stated above, we genuinely believe that it is important to point methodological issues regarding the conduction of systematic reviews aiming to improve quality of evidence synthesis that provide subsides to the evidence-based practice. Although we have outlined some major points in which we disagree in the de Assis and Almondes's review, we agree that “exercise influence on cognition is still a poorly explored field” and, even more importantly, that “further experimental research should concern better control.” Those statements provide courses on which any future research might proceed.FS contributed to the idea and writing. MM and RP contributed to the writing.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Tephra layers in marine sediment cores from scientific ocean drilling largely record high‐magnitude silicic explosive eruptions in the Japan arc for up to the last 20 million years. Analysis of the thickness variation with distance of 180 tephra layers from a global data set suggests that the majority of the visible tephra layers used in this study are the products of caldera‐forming eruptions with magnitude (M) > 6, considering their distances at the respective drilling sites to their likely volcanic sources. Frequency of visible tephra layers in cores indicates a marked increase in rates of large magnitude explosive eruptions at ∼8 Ma, 6–4 Ma, and further increase after ∼2 Ma. These changes are attributed to major changes in tectonic plate interactions. Lower rates of large magnitude explosive volcanism in the Miocene are related to a strike‐slip‐dominated boundary (and temporary cessation or deceleration of subduction) between the Philippine Sea Plate and southwest Japan, combined with the possibility that much of the arc in northern Japan was submerged beneath sea level partly due to previous tectonic extension of northern Honshu related to formation of the Sea of Japan. Changes in plate motions and subduction dynamics during the ∼8 Ma to present period led to (1) increased arc‐normal subduction in southwest Japan (and resumption of arc volcanism) and (2) shift from extension to compression of the upper plate in northeast Japan, leading to uplift, crustal thickening and favorable conditions for accumulation of the large volumes of silicic magma needed for explosive caldera‐forming eruptions. Increase in volcanic activity in Japan at ∼8, 4–6, and ∼2 MaTephra layers in distal sediment cores represent magnitude 6 or greater eruptionsTectonic changes driving rates of explosive volcanism in Japan Most drill sites that we used data from are typically several hundred kilometers from the nearest volcanic sources, allowing us to look at the very large magnitude volcanic events, which are able to deposit tephra further from source. Changes in rates of explosive eruptions are investigated in the overall data set, and also regionally: northeast Japan, Sea of Japan, and southwest Japan Figure . VisibleMahony et al. [Data collection methods are described in y et al. . This stThe record of visible tephra layers in ocean drilling cores is quantified for each core by the number of tephra layers per unit time interval. Numbers of tephra layers were initially counted per 100 ka for each drill hole. Next, the average numbers of tephra layers were calculated across all the drill holes with material to that age, for each 100 ka interval. These data were then averaged over 500 ka and 1 Ma intervals, and also for each region. These data are indicative of but do not represent the rate of volcanic events. Due to the averaging method being per drill hole with material of that age, we can include data from each individual drill hole rather than just using drill site composite records. This gives us a more complete record as there can be differences between drill holes just a few tens of meters apart.Wetzel, Jutzeler et al., There are several factors that control whether a particular volcanic event is recorded in a particular core. A tephra layer should ideally show great lateral consistency for a few hundred meters. However, a visible tephra layer may be present in one drill site and not in another, because of differences in tephra dispersal related to wind conditions and volcano location. Relatively small magnitude eruptions may form a visible tephra layer in cores close to the source but not in cores further away from the source. Visible tephra layers can be destroyed by bioturbation or erosion by bottom currents, with thinner layers being more prone to being destroyed. Sedimentation rate and paleoenviromental conditions can affect the rate of bioturbation, and so the preservation potential for tephra layers Wetzel, . Here thHere we choose to represent these data as a proxy for the volcanic event rates by averaging the number of tephra layers per unit time for a collection of cores Figure . We haveReimann and Filzmoser, McDonald, We have not calculated the variance of the number of tephra layers as it can be inappropriate to make an estimate for nonnormal distributions and problematic too for data which include zeros [e.g., Peaks in explosive volcanism in the mid 15–13 Ma) Miocene are based on only a few cores and require additional cores to confirm. Rates of large magnitude explosive volcanism using visible tephra layers as a proxy are low 13–8 Ma then increase from 8 Ma, and again at 2.5–2 Ma  or eroded Wetzel, .Crosweller et al., Brown et al., Wessel and Smith, We calibrated the magnitudes (M) of the eruptions that form visible tephra layers in Japanese ocean drilling cores by analysis of a global data set of 181 isopach maps of Quaternary tephra fall deposits from large‐magnitude explosive eruptions collated in the LaMEVE database  [Deligne et al., Deligne et al., Deligne et al. [Table e et al.  are deriFigure For each magnitude and 50 km distance bin, the number of events was calculated with thickness values recorded either at that distance or greater Table . Our anaFigure 4There is an excellent record of explosive volcanism on Japan in the form of detailed tephrochronology and records of caldera‐forming events. Here we compare land‐derived records with the ocean drilling data on visible tephra layers.4.1Geyer and Marti, Kiyosugi et al., Land‐based records of the Quaternary volcanic history of Japan were collected from the LaMEVE database and the Collapse Caldera DataBase (CCDB) [4.2Kimura et al., Yoshida et al., Machida, Kimura et al.'s [Kimura et al. [Kimura et al., Kimura et al. [Kiyosugi et al., Tephrochronology of land and lake deposits in Japan extend back to the Pliocene [et al.'s  terrestra et al.  record, a et al.  show a tKimura et al. [Yoshida et al. [Yoshida et al. [Machida, Over the last 5 Ma, a et al.  record 7a et al.  describea et al.  in the nMachida, . Finally5Ninkovich and Donn, Fiske et al., Carey et al., Our observations Figures  and 3 ofWe now consider these different factors in turn, starting with those that we infer are less important.5.1Sparks et al., Baines and Sparks, Machida and Arai, Suto et al., In Japan, dominant westerly stratospheric winds influence the deposition of tephra from small to intermediate magnitude eruptions. However, M > 6 caldera‐forming eruptions discharge tephra to heights of tens of kilometers into the atmosphere [5.2Sato and Amano, Otofuji et al., Tamaki et al., Late Cenozoic plate movements would not have affected the tephra layer record at the sites on the upper plate in Japan, due to relatively small horizontal tectonic motions of the core sites relative to volcanic sources. Sea of Japan opening occurred between 30 and 14 Ma [Hall, Mahony et al., Pickering et al., Regalla et al., Doubrovine and Tarduno, Ninkovich and Donn, There is obviously larger motion of core sites on the subducting plate relative to the volcanic sources over the time frame of our study. Fifteen southwest Japan sites are on the overriding plate, while eleven are on the subducting plate. During 18–7 Ma, the locations of the southwest Japan subducting plate cores would have moved northeast relative to the plate boundary at ∼ 5–8 cm/yr (∼50–80 km/Myr) [5.3Mahony et al., Pickering et al., Hall et al., Mahony et al., Faccenna et al., Our analysis indicates a marked increase in rates of large magnitude explosive volcanism since ∼8 Ma. Major tectonic changes have occurred in Japan since 20 Ma. The plate boundary in southwest Japan was predominantly sinistral strike slip with a minor convergent component between 18–7 Ma [Kamata and Kodama, Mahony et al., Sato, Prior to 8 Ma, relative motion between the Philippine Sea Plate and southwest Japan was dominated by strike‐slip faulting (and perhaps some slow convergence) and was associated with low rates of back arc volcanism [We attribute the increase in rates of caldera‐forming explosive eruptions from 8 Ma in Japan to interacting tectonic and igneous processes. On the large scale, the onset of increasing explosive volcanism is attributed to both uplift and eventual exposure of NE Japan, as well as changes in plate boundary dynamics in both southwest and northeast Japan, which affected magma production and favored the generation of large volumes of silicic magma necessary for large caldera‐forming eruptions.Kodama et al., Sato, Regalla et al., Sato, Yoshida et al., Yoshida et al., Southern Kyushu has rotated 30° anticlockwise since 6 Ma, accompanied by back‐arc extension and more rapid subduction [Seno and Maruyama, Seno, Hall, Mahony et al., Pickering et al., Pollitz, Sato, Regalla et al., Sato, Sato, Regalla et al., Between 8 and 5 Ma major changes occurred. Subduction of the Philippine Sea Plate became more arc normal [Prueher and Rea, Kamata and Kodama, Mahony et al., A further marked increase in large magnitude explosive volcanism is indicated in the marine tephra record around 2–1.5 Ma Table . This in6Yoshida et al., Kimura et al., The large‐scale physical processes of tectonics and volcanism/magmatism are inextricably linked, and we demonstrate how changes in tectonics can drive changes in the rate of large magnitude volcanic events. Our data set enables a comprehensive study of the ocean drilling programs cores located around Japan. Our detailed eruption deposits study and comparison with global thickness data from 180 deposits, reveals that tephra layers observed in ocean drilling cores located at least 100 km from source volcanoes are likely to be M > 6. This inference is also supported by comparison of the marine tephra record with the Pliocene‐Quaternary terrestrial tephra record and observed numbers of calderas. We observe increases in numbers of volcanic tephra layers at 8, 4–6, and ∼2 Ma both in the data set as a whole, and also when divided by core location regions. The increase in numbers of volcanic tephra layers in northeast Japan starting at 8 Ma is broadly consistent with the increases in studies of the Pliocene‐Quaternary terrestrial record [Supporting Information S1Click here for additional data file.Data Set S1Click here for additional data file.Data Set S2Click here for additional data file.


Neuropsychiatric conditions are a leading cause of disability globally , potential participants cannot provide adequately informed consent  or unimportant to participants, then the research will have little future potential to inform acceptable and needed services for that community. Ideally, survey research would be embedded into ongoing mental health programming. If partnering with local mental health service providers is not possible–and sadly in LMIC contexts mental health services will often not exist–investigators can partner with governments, international NGOs, or community-based organizations interested in providing mental health services and can help them develop appropriate programs based on survey results. Through sustainable partnership, researchers can build the capacity of local organizations to use results to advocate for themselves for funding, policy reform, or new laws to improve mental health locally. If no potential organizational partner exists, groups of community members formed through participatory research or existing community social structures could serve the same role (see Vreeman . et al.  developeet al. (et al.At an absolute minimum, GMH researchers must act to keep participants safe during survey research and take steps to monitor any negative ramifications of the survey on individuals’ safety or well-being. Murray et al.  present . et al.. Respondet al.The extent to which investigators are responsible for the mental health treatment of such participants, both in terms of time and resources, will vary. Investigators should consider the level of risk the individual undertook in participating, their dependency on the researcher to receive any form of care, and the depth of the relationship between the researcher and participant including the level of trust engendered when individuals provided sensitive details about their mental health (Belsky & Richardson, et al.et al.et al.et al.et al, Although we have focused on GMH research conducted in LMIC, many issues discussed apply equally to mental health research in high-income countries despite the potential for greater access to treatment resources in these contexts. Guidance on ethically conducting GMH research, including intervention research, is increasingly available (Ellis et al.The Working Group on Mental Health and Psychosocial Support convened at Harvard's Humanitarian Action Summit in 2009 argued that mental health research in disaster and conflict settings must directly benefit the community under study in order to be ethical (Allden


The last 10 years have seen major advances in the understanding of the pathobiology of systemic lupus erythematosus (SLE). These improvements have led to discoveries of new molecules that target specific points in the immunological cascade that contribute to the immune hyperactivity and loss of tolerance in this heterogeneous autoimmune disease. Despite a large number of clinical trials assessing new molecules in patients with active SLE, belimumab (Benlysta®) is the only biologic agent that has been approved for clinical use. Whilst the track record of these large and expensive clinical trials has been disappointing, it has been very encouraging to see that investigators from industry and academia have not been dissuaded from further investment to fill the huge unmet need for better understanding of the immunopathology of SLE and the search for novel and effective treatments.This special issue of Immunologic Research brings together internationally acclaimed experts in the field of SLE to provide cutting edge updates in this rapidly moving research area We included original articles and reviews to cover basic science and clinical aspects of SLE including the possible role of infections and updates on the antiphospholipid syndrome (APS).+CD25++ Tregs of patients with active SLE, markers related to Treg function (CD27) and homing (CCR6) were altered. This is a controversial area with conflicting findings in the literature; therefore, this study suggests that analysing subpopulations of Tregs may be more fruitful in dissecting the potential role of these T cells in the pathogenesis of SLE.The first original article by Schmidt et al.  investigHormones are clearly important in the pathogenesis of SLE and, given that the disorder is 9–10 times more common in females, oestrogens must play a major role. Another hormone that is emerging is prolactin, produced by the anterior pituitary gland and other cells including immune cells. Jara et al.  review tSLE is commonly a disorder of young women of child-bearing age. Many large lupus centres have clinical services designed to counsel women and manage their pregnancies and the perinatal period. Martinez-Sanchez et al.  describeCardiovascular disease is over-represented in women with SLE and whilst the risks are considerably increased, the event rate of cardiovascular disease in SLE is relatively low, making this a difficult area to study when it comes to prevention trials. Szabo et al.  summarisWatad el al  follow tVitamin D levels are low in most, if not all, patients with SLE for a variety of reasons. Many patients are photosensitive and therefore have rigorous photoprotection strategies. Marinho et al.  argue peThe central role of the microbiome in the maintenance of health and its potential role in a variety of human diseases including autoimmune rheumatic diseases is just beginning to be explored. Katz-Agranov and Zandman-Goddard  provide The possible role of viral infections in the pathogenesis of SLE has long fascinated researchers especially given the central importance of the interferon signature in this disease. However, conclusive evidence has still not been demonstrated in the literature. Hod et al.  review tFurther insights into infections are described by Mahroum et al.  who descIt is well recognised that B cell malignancies are over-represented in patients with SLE. In a large study from Israel, Azrielant et al.  utilisedAntiphospholipid syndrome increases the risk of premature mortality and contributes significantly to morbidity in patients with SLE; therefore, the final section of this issue is devoted to this autoimmune thrombotic disorder. The classical autoantibodies associated with this syndrome are the lupus anticoagulant, anticardiolipin and anti-β2 glycoprotein 1 antibodies. Alessandri et al.  describeStroke is a feared complication of APS, and Carmel-Neiderman et al.  assessedFinally, the early detection of subclinical vascular disease may be a powerful tool to predict future cardiovascular events. Saponjski et al.  used 64-This issue offers a compelling collection of incisive articles for the reader to get up to date with advances in the fields of SLE and APS, and we congratulate the many authors on their timely contributions.


In the past 20 years of research regarding effects of mobile phone-derived electromagnetic fields (EMFs) on human cognition, attention has been one of the first and most extensively investigated functions. Different domains investigated covered selective, sustained, and divided attention. Here, the most relevant studies on this topic have been reviewed and discussed. A total of 43 studies are reported and summarized: of these, 31 indicated a total absence of statistically significant difference between real and sham signal, 9 showed a partial improvement of attentional performance (mainly increase in speed of performance and/or improvement of accuracy) as a function of real exposure, while the remaining 3 showed inconsistent results  or even a worsening in performance (reduced speed and/or deteriorated accuracy). These results are independent of the specific attentional domain investigated. This scenario allows to conclude that there is a substantial lack of evidence about a negative influence of non-ionizing radiations on attention functioning. Nonetheless, published literature is very heterogeneous under the point of view of methodology , dosimetry , and statistical analyses, making arduous a conclusive generalization to everyday life. Some remarks and suggestions regarding future research are proposed. Nowadays almost the totality of human beings on the Earth is directly or indirectly exposed to the electromagnetic fields (EMFs) emitted by mobile phones, base stations, and other types of wireless communication technologies. This is a logical consequence of the fact that there are more mobile devices than living people on the planet: the estimate of total world population was around 7.44 billion at the end of 2017  have been seen as one of the potentially mostly influenced aspects of human brain functioning. In the past years, these studies have been extensively reviewed  as wellHere, the main findings obtained in the last 20 years of research with respect to mobile phone effects on human attention will be briefly reviewed and discussed. The focus will be on laboratory volunteer studies , involving only mobile phone-like signals and aimed to investigate attentional performance as a main outcome. Although some of these studies had multiple outcomes , only attentional performance results have been considered here. Literature search was conducted at the end of 2017 on both PubMed and WoS databases and covered the period between 1998 and 2017. Almost all the studies reported here have been conducted on healthy adults, while just a few of them investigated effects on adolescents or children and on patients . A summary of all included studies, with experimental characteristics  is reported in Table In the first study investigating the effects of MW emissions on the brain, visual monitoring was also tested . In a siPreece et al. published one of the first studies on attention and vigilance . The autKoivisto et al.  with a sJech et al.  for the A similar effect to the one evidenced by Koivisto et al.  was reported by Edelstyn and Oldershaw  after onCroft et al.  investigIn a study on university students, performance at different tasks was assessed, including an auditory vigilance test . ParticiCurcio et al.  exposed Hamblin et al.  studied In 2005, Haarala et al.  carried In a unique effort to simulate a real-life exposure, Besset et al.  planned Schmid et al.  in a metKeetley et al.  aimed atThe first study on individuals with IEI-EMF was carried out with a single-blind protocol, exposing participants for 30 min . No effeSimilar to other studies that attempted to control for methodological limitations  of previously published studies, Russo et al.  enrolledTerao et al.  investigFritzer et al.  conducteTo disentangle the differential effects of different signals , an experimental study was carried out to assess the effects of 30 min of irradiation on several attentional tasks . ResultsIn 2008, a study attempted to test the possible cumulative effects of brief (15 min) and repeated (three times) exposures in a single daily session . By usinAnother study directly aiming at comparing the possible effects of GSM and UMTS signals was proposed by Kleinlogel et al. . FollowiIn a study mainly aimed at investigating EEG features during an auditory oddball paradigm, Stefanics et al.  exposed To investigate the impact of TETRA signals on cognitive function, Riddervold et al.  exposed In a high-resolution PET study, vigilance was assessed after 33 min of GSM exposure : again, In the same year, another attempt to compare possible cognitive effects of GSM and 3G UMTS signals was carried out . Three tIn an fMRI study, attentional performance was assessed after 45 min of GSM exposure by means of a somatosensory Go-No Go task . No expoIn the same vein of previously discussed Regel et al.’s studies, Schmid et al.  exposed Recently, another study on adolescents was carried out  comparinTrunk et al.  investigTwo associate studies tested the effects of two levels of TETRA-like exposure (“low” and “high”) on volunteers exposed for 150 min , 55. In Recently, a single-blinded study was carried out to test the effect of both GSM and UMTS on a considerably large sample  composedVerrender et al.  aimed atFinally, a recent study was conducted on emergency physicians  to test The first studies on humans addressing attentional performance changes as a consequence of RF EMFs exposure date back to almost 20 years ago. In this mini-literature review, of 43 studies, 31 indicated the absence of statistically significant differences between real and sham signal, 9 showed changes in the direction of a partial improvement of attentional performance as a function of real exposure, while the remaining three showed very mixed and contrasting results  have not been replicated in more methodologically sound studies : this is the case, for example, of the pioneering study by Koivisto et al.  who showThe same happened when sample size was controlled for: in some cases, the effect previously shown on sustained attention measures  was notOther very central methodological issues are related to both a correct dosimetry assessment and a comparability among different experimental settings. As shown in Table If we take into consideration all these differences in methodology and experimental setting, it becomes very difficult to come to a general conclusion on potential everyday life effects.On the basis of the present systematic review of literature, some future research issues can be outlined as well as aspects that would merit further investigation.As a first, it is mandatory to control for procedural aspects, by exposing participants for similar or equivalent periods of time: a rapid look at Table Linked to the previous issue is the one of medium- and long-term effects to repeated EMFs exposure: this is a very relevant exposure procedure because it mimics very well what happens in the real life. To date, only one study  tried toEven related to methods is the topic of sample characteristics. As stressed in previous reviews , indiviFinally, some more research should be carried out “on the field,” namely on individuals that are exposed to RF EMF for working reasons . ThOn the basis of reviewed literature, we can reasonably conclude that there is no evidence of a negative influence of mobile phone emitted EMFs on different aspects of human attention. As pointed out in GC conceived of, wrote, and edited this review.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Intensive agriculture, which depends on unsustainable levels of agrochemical inputs, is environmentally harmful, and the expansion of these practices to meet future needs is not economically feasible. Other options should be considered to meet the global food security challenge. The plant microbiome has been linked to improved plant productivity and, in this microreview, we consider the endosphere – a subdivision of the plant microbiome. We suggest a new definition of microbial endophyte status, the need for synergy between fungal and bacterial endophyte research efforts, as well as potential strategies for endophyte application to agricultural systems. Agricultural practices are under pressure to provide increased yields to feed the growing global population, which is expected to reach 9.7 billion by 2050 DESA, . In the et al. , maceration or disruption, and then plating the tissues onto a medium which supports growth of the organisms. More sporadic within the literature are descriptions of controls undertaken to ensure that the outer tissue is indeed free of viable microorganisms. It is clear that plant tissue surface sterilization should be tailored to the tissue sample type. Here, we propose that the total final surface wash from the plant tissue section should be concentrated and cultured to determine the absence of viable organisms (Robinson , et al. .et al., et al. (et al. (Until recently, only 1% of microbes present in bulk soil have been amenable to culture. However, the development of an isolation chip, the ‘ichip’ (Nichols , et al.  seemingl (et al. , could bet al., et al., et al., The best strategy for the application of endophytes in agricultural systems is not yet known. The most obvious approach is to add inoculants to the soil or as seed dressings. There are reports of this approach being successful for sugar cane (e.g. Silva et al., Epichloë, which protects grasses against root‐grazing nematodes, may be toxic to vertebrates (Schardl et al., Despite the success of a few well‐known endophyte–plant relationships (Hardoim et al., et al., Several important questions remain unanswered concerning the practical use of endophyte ‘supplements’ in agriculture. However, with the correct management, they hold potential for the control of current and emerging pathogens, as well as biotic stresses, as we encounter deviation in these through climate change (Howden


There seems to be a broad consensus among today's parents that early exposure to digital media is less enriching than real-life experiences (Wooldridge, Embodied cognition highlights that the development of cognitive processes crucially depends on active interactions between one's body and the environment (Barsalou, Radesky et al.  note thaHowever, going beyond Radesky et al. , simple Supporting Radesky et al. , while cMoreover, Eisen and Lillard  observedTo sum up, the extent to which the advantages of real-life learning might be substitutable by touchscreen devices seems to be heavily context-dependent. Even in the absence of joint engagement, which was shown to greatly benefit learning according to Radesky et al. , interacThe author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


C. difficile infections (CDI) with a cure rate of 85–90% after the first FMT  has been used as a treatmentof last resort for recurrent Caudovirales with decreased diversity, richness and evenness when compared to healthy controls. Longitudinal studies of patients who received FMT (n = 9) and standard therapy, vancomycin (n = 5) demonstrated that FMT led to the transfer of viruses from the donor to the recipients  or slightly higher Caudovirale richness.The patients that were administered FMT were divided into two groups of “responders” and “non-responders” based on whether they were cured of CDI or recurred after FMT. In particular, after FMT, they noticed a significant decrease in the abundance of Microviridae was observed in the patients before FMT when compared to the controls but this increased after FMT. Fifteen viral species were found to be enriched between FMT responders and non-responders. Viral species belonging to the Microviridae family such as Eel River Basin pequenovirus was the most abundant in the responders  of those who responded to the antibiotic therapy. However, the bacterial community was significantly affected (Zuo et al., Moreover, Zuo et al. performed 16S rRNA gene sequencing to determine changes in the bacterial community and noted increase in Broecker et al. investigated the long term bacterial and virome changes in a patient after FMT for recurrent CDI, and found the virome at several months post-FMT related to the donor virome (Broecker et al., Caudovirales order and from the family Microviridae which have double and single stranded DNA respectively (Kim et al., Caudovirales was implicated in the efficacy of FMT. However, in other intestinal diseases, it is not clear cut as to the role of Caudovirales likely due to other risk factors involved (Norman et al., Caudovirales richness was observed in patients with inflammatory bowel disease (Norman et al., There is no doubt that bacteriophages play a role in the intestinal microbiota with a potential to alter the composition and function of the host microbiota. The question is what constitutes a healthy gut phageome and how do they influence the human gut microbiota? Most of the phages in healthy human gut microbiota belong to the The next question one may be tempted to ask is, how stable is the “phagebiota” in individuals and what are the effects of antibiotic perturbations on the phageome? Research by Ly et al. showed that transmission of viruses was common between members of the same household over a 6-month period (Ly et al., C. difficile, though this is not trivial. Indeed, previous work revealed that using a single phage, ΦCD27 (Meader et al., C. difficile growth in vitro and in vivo (Nale et al., C. difficile growth in a batch fermentation model spiked with feces from four healthy volunteers (Nale et al., These studies have highlighted the underappreciated role viruses play in addition to bacterial colonization in the intestinal microbiota. However, as individual phages are specific in action toward their bacterial host, it would be advantageous to isolate phages that target pathogenic bacteria such as C. difficile infection. The ability to develop a synthetic mixture of phages as treatment for infectious diseases, will go a long way in this era of antibiotic resistance. Not only will this be beneficial in severe CDI, but could also be useful as a therapy for other diseases related to the intestinal microbiota.Much work remains to be done on phage therapy for The author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


There is an old saying that you must walk a mile in someone's shoes to truly understand them. This mini-review will synthesize and discuss recent research that attempts to make humans “walk a mile” in an artificial musculoskeletal system to gain insight into the principles governing human movement control. In this approach, electromyography (EMG) is used to sample human motor commands; these commands serve as inputs to mathematical models of muscular dynamics, which in turn act on a model of skeletal dynamics to produce a simulated motor action in real-time (i.e., the model's state is updated fast enough produce smooth motion without noticeable transitions; Manal et al.,  As the name implies, an essential component of an MMM is a musculoskeletal model: a mathematical representation of bones, muscles, and connective tissue. The model specifics depend on the application Winters, . For simFor a musculoskeletal model to produce functional movement the muscle models must be activated in a coordinated fashion; this is typically achieved in one of two ways. The first is by using a central nervous system (CNS) model that codifies the principles governing human movement control. In such models, muscle activation patterns are generated by minimizing a quantity of interest such as energy , biomechanics. Capitalizing on this strength, de Rugy et al.  used an The studies above have provided valuable insights into how the CNS controls movement; however, the simulated muscles functioned primarily as pure force generators. In reality, muscles have various mechanical properties that influence the translation between EMG and muscular force. In contrast to limb dynamics , i.e., the variance is proportional to the command magnitude Clamann, . It has Such an approach was taken by de Rugy et al. , who incWe will lastly touch upon the utility of MMMs is to gain insight into the effects of sensory feedback manipulations on movement control. Most studies using MMMs in this capacity focus on proprioceptive information because an MMM serves as a natural virtual prosthesis, and proprioception is typically impoverished with prosthetic devices (Antfolk et al., Many studies using MMMs or prosthetic arms have concentrated on kinetic feedback because interaction forces are critical for object manipulation yet cannot be directly perceived with vision (Chiel and Beer, Since motion can be visually perceived, kinematic vibrotactile stimulation should be most beneficial for MMM control when vision is absent. This has indeed been shown in studies using vibrotactile stimulation to convey hand position (Witteveen et al., An important caveat of using MMMs to test motor adaptation hypotheses is that an MMM acts in parallel with the actual neuromusculoskeletal system Figure  and simuFuture research should also investigate the ramifications of limb motion when controlling MMMs. While some studies maintain both real and simulated limbs in an isomeric state (e.g., de Rugy et al., This mini-review addressed the ways in which MMMs can serve as tools to probe fundamental questions in human sensorimotor control and learning including CNS coordination of force-sharing among muscles, adaptation to modifications of neural dynamics, and the limits of sensory feedback augmentation. The power of MMMs stems from the experimental control they offer: model dynamics are mathematically specified and are therefore known quantities, and manipulations can be performed selectively to control for confounds associated with real neuromuscular interventions. The main limitation is the challenge of validating human adaptations to simulated manipulations given that experimental analogs are often impossible. Nevertheless, the knowledge gained from creatively employing MMMs in research has significant implications for fields such as neuroscience, biomechanics, engineering, and rehabilitation.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.