In the last few years, a growing amount of evidence highlighted the urgent need for research aimed at assessing mental health status in low- and middle-income countries (LMICs): this revealed a substantial gap between the burden caused by mental disorders and the resources devoted to prevent and treat them  over LMICs, with a great amount of studies carried out and published by authors affiliated with HICs (Fodor et al., In response to this call for an evaluation of a “global mental health,” substantial scientific effort was devoted to address the psychological and social needs of populations living in humanitarian settings in LMICs.European Journal of Psychotraumatology collected some of the work that has been done so far in LMICs. Manuscripts address important issues such as the quantification of effects of cumulative trauma exposure in war survivors (Wilker et al., This special issue of the The paper by Wilker et al.  analyzedHermenau et al.  undertooThe relation between traumatic experiences and spirit possession in LMICs is analyzed in a systematic review of 21 articles undertaken by Hecker et al. Pathological spirit possession is a phenomenon occurring globally and has particular relevance in LMICs. Reported prevalence rates differed conspicuously depending on cultural background and the particular study populations (Hecker et al., The systematic review carried out by Strohmeier and Scholte collected 14 studies focused on trauma-related mental health problems in national humanitarian staff. In line with current literature focused on mental health conditions in LMICs (Barbui & Tansella, Jansen et al.  propose This cluster of manuscripts approaches global mental health using different study designs, which report both the patients and staff perspectives. Aware of the complexity and extent of the topic, we believe that these papers will contribute to the scientific debate in this field and represent a relevant piece of work in the reasoning on how to orient further research pathways. This become even more important in this historical time frame, where populations living in humanitarian conditions and affected by different types of trauma – including refugees inside and outside Europe Turner, , asylum Marianna PurgatoDepartment of Mental HealthJohns Hopkins Bloomberg School of Public HealthJohns Hopkins University, Baltimore, MD, USAWHO Collaborating Centre for Research and Training in Mental Health and Service EvaluationDepartment of Neurological, Biomedical and Movement SciencesSection of Psychiatry, University of Verona, Verona, ItalyEmail: marianna.purgato@univr.itMiranda OlffDepartment of Psychiatry, Academic Medical CenterUniversity of Amsterdam, Amsterdam, The NetherlandsArq Psychotrauma Expert Group, DiemenThe Netherlands


In recent years, it has been brought forth that dog-human relationships share several characteristics with the maternal bond that unites a child with their principal caregiver Serpell,  and thatIn an elegant first experiment in which domestic dogs and tamed wolves were reunited for 30 min with their owners, Nagasawa et al.  found thFirstly, bonding in humans undeniably has roots in the relationship between a child and their primary caregiver, which is usually their mother Feldman, . In NagaSecondly, given that all dogs tested by Nagasawa et al.  were aduThirdly, why did the two sub-groups of dogs (short and long gaze) respond differently to the reunion? In many species, including dogs , we were astonished to learn that at least one member of the research group participated in the study with his own two dogs (see Grimm, Despite the comments above, we agree that oxytocin, especially when nasally administered to dogs (see Experiment 2 in Romero et al., SF drafted the article based on written comments made by SF and VP about the research report published by Nagasawa et al.  in ScienThe 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.


Talhelm et al.  reportedWe think that some relevant detailed data have been overlooked in their analysis, which has significant implications for the paper's conclusion and subsequent discussions. When comparing wheat with rice statistics, the authors grouped the corn and soybeans farming area with the wheat area  = −0.60, P < 0.001, to that of rice at the provincial level; (3) In several provinces that were categorized by the authors as “wheat provinces” e.g., Jilin and Liaoning provinces (in contrast to the “rice provinces”), there were actually many more rice fields than wheat  In Northern China, corn and wheat are equally important crops, and in many provinces corn is more widely planted than wheat; (2) Similar to wheat, the percentage of corn farm is also negatively correlated, r In NorthThese results suggest that there would be an equal chance for corn farming to affect population psychology in Northern China. The term “rice vs. wheat agriculture” coined by Talhelm et al.  cannot aThe detailed data which were overlooked not only affect the conclusion of Talhelm et al. , but alsThus the theory would then predict that there should be psychological differences between rice-growing East/South East Asian and the rest of world. This prediction is inconsistent with the dominant view in psychology that Western populations show different psychological traits as compared with non-Western populations. Non-Westerns, which include groups as diverse as Arabs, East Asians, Russians, and farmers in Africa and South America, have been shown to rely more on holistic reasoning and have more interdependent views of self than Westerners (Henrich et al., This paper is well publicized, and has led to much discussion within both the general public and the scientific community, including a critical commentary by Ruan et al. . Many haFurthermore, the psychological differences observed by Talhelm et al.  cannot bIndeed, while the cost of wheat production is much less than that of rice, the cost of corn production is between the two or closer to that of rice in modern China (Garnaut et al., Talhelm et al.  providesThe 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.


The series of articles in this special edition reflect much of the current thinking in regards to the role of metals in aging and neurodegeneration, and highlight the deep involvement of metal ions in critical pathways that may contribute to onset/progression of neurological disease. Furthermore, metal homeostasis may impact directly on signaling cascades relevant to cognition, or may indirectly contribute to functional decline via an effect on specific pathologies in the degenerating brain. As such, the behavioral manifestations associated with normal and pathological aging may be remediated by therapeutics that intervene in metal ion dyshomeostasis.The broader perspective on the role of metal ions in cognition is outlined in the first two articles. Opazo et al.  provide The remaining articles are split out according to disease, beginning with ALS. Lovejoy and Guillemin  provide Dang et al.  then speBourassa et al.  tackle tThe next series of articles have a focus on AD, with discussions around both the mechanistic and therapeutic implications of altered metal ion homeostasis. McCord and Aizenman  provide Wong et al.  explore Hancock et al.  then revFinally, Bhattacharjee et al.  provide Finishing this section, Braidy et al.  briefly The next three articles focus on the role of metals in other conditions, and utilize a variety of different models. Sun et al.  examinedMalakooti et al.  then expC. elegans as a model system to explore the underlying mechanisms of PD. They propose that a failure in axonal transport is fundamental, with the subsequent impairment in trafficking of metal ion homeostasis proteins (focusing on iron) resulting in downstream oxidative stress and neuronal loss. They also note the potential for the loss of synaptic connections in this model.Finally, Chege and McColl  provide The last manuscript in this special edition is by Marx and Gilon , and preThe sum of these articles, which add to my own recent work in the area, present an overview of the many different pathways through which metals may intersect in the pathogenesis of a variety of neurodegenerative diseases, and which may subsequently manifest (directly or indirectly) in behavioral deficits.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.


As the worldwide burden of chronic disease continues to rise, disease prevention and health promotion become increasingly important components of public health. Although many complementary and alternative medicine (CAM) practices have emphasized health promotion and the area of CAM health care holds much opportunity and challenge for issues of public health, CAM research to date has been dominated by more clinically restrictive issues , 2. HoweThis special issue includes original research papers and systematic reviews investigating the issues related to CAM practices in the public health arena as well as outcomes of CAM treatment for chronic disease prevention and/or management (tertiary prevention). Brucea javanica oil by Y. Liu et al.; a systematic review and meta-analysis of the efficacy of compound kushen on cancer pain by X. Ma et al.; an analysis of Qigong's effect on chronic fatigue syndrome by L. P. Yuen et al.; a systematic review of acupuncture for allergic rhinitis and asthma by L. Zhou et al.; and an analysis of the effects of guided imagery on patients on mechanical ventilation by B. Brakovich et al.There are 14 articles in this issue, from six countries and on a wide variety of topics. The topics addressed are almost equally divided between treatment of specific conditions of public health importance and disease prevention through risk factor reduction. A smaller number of articles address issues related to traditional medicine use among the general public. Articles on treatment of conditions include a large clinical study by J.-F. Tang et al. on safety and evaluation of Danhong injection; a basic science study onArticles on prevention and risk factor reduction were a randomized controlled trial of Tai Chi on weight loss, metabolic syndrome, and bone mineral density by T. C.-Y. Kwok et al.; an analysis of body constitution through Traditional Chinese Medicine by C.-H. Lee et al.; a survey of apitherapy use for disease prevention by S. Trumbeckaite et al.; an exploration of the possible effect of CAM on antibiotic resistance by W. B. V. Leeuwen et al.; and a survey of the effect of Traditional Chinese Medicine on decreasing stroke risk among users of corticosteroids for dermatitis by J.-L. Shen et al.Finally, F. Xu et al. described the validation of a questionnaire based on Traditional Chinese Medicine to assess health status; S. H. Ng et al. described use of the Theory of Planned Behaviour related to Traditional Chinese Medicine use; and G. D. Hughes et al. characterized the use of herbal medicines for noncommunicable disease.These articles tended to focus more on single herbal or other traditional preparations or procedures for both treatment and prevention, with very little emphasis on health behaviour, which is typically a cornerstone of public health programs. Behaviours related to diet, physical activity, and stress reduction are known to be increasingly important factors in determining the health of the public and are also areas of importance and emphasis for many CAM practitioners. It is necessary for CAM professions to become visible in this arena and for CAM research to extend into this direction rather than focusing narrowly on specific therapies if these efforts are to be recognized and utilized for the benefit of populations.Cheryl HawkCheryl HawkJon AdamsJon AdamsJan HartvigsenJan Hartvigsen


The incidence of cardiac arrhythmia and heart failure continues to rapidly increase, leading to a growing epidemic which constitutes a serious financial burden for society  have identified common variants in the general population for atrial fibrillation. Yao et al. (In this issue, genetic aspects of arrhythmia were described by 3 different groups. Crump and Abbott  providedo et al.  gave an Duygu et al.  providedmiRNAs are endogenous non-coding RNAs which post-transcriptionally regulate gene expressions (Condorelli et al., Finally Stagnaro and Caramel  proposedIn conclusion, this research topic offers a detailed and updated summary about genetic and epigenetic basis of arrhythmia and heart failure, and provides a forum for discussion on ways to translate these genetic and epigenetic findings into novel therapies for arrhythmia and heart failure.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.


Vision is the process of extracting behaviorally-relevant information from patterns of light that fall on retina as the eyes sample the outside world. Traditionally, non-human primates have been viewed by many as the animal model-of-choice for investigating the neuronal substrates of visual processing, not only because their visual systems closely mirror our own  to investigate visual function. The experimental approaches covered by these studies range from psychophysics and electrophysiology to histology and genetics, testifying to the richness and depth of visual neuroscience in non-primate species. Below, we briefly summarize the contributions to this Research Topic.in-vivo electrophysiology and, in one case, genetic manipulation  focus on the visual system of two rodent species more commonly used as laboratory animals: rats and mice. Following a trend that has been established over the past 6–7 years, the mouse studies investigate tuning properties of visual neurons in low-level visual centers through LeDue et al.  investigLiu et al.  present In rats, Meier and Reinagel  investigIn a second study, Reinagel  investigRosselli et al.  also invRat pattern vision is also the topic of the study of Vermaercke et al. , who comTwo reviews focus on the plasticity of the rodent visual system during development (Priebe and McGee, Bonaccorsi et al.  provide Two other reviews compare the anatomy, connectivity, parcellation and hierarchical organization of the visual systems of different species, with a special focus on primates and rodents (Homman-Ludiye and Bourne, In a similar spirit, Laramée and Boire  focus onWhile this Research Topic was mostly focused on non-primate systems, we included one exception: a review of what is known about the visual system of a new world monkey, the marmoset (Solomon and Rosa, Object recognition is a topic that is also addressed by two bird studies, one research article (Wood and Wood, Taking a broader view on avian vision, Soto and Wasserman  review tHigh-level visual functions, such as shape processing and object recognition, are also addressed by several behavioral studies on fish in this Research Topic.The perception of illusory shapes and boundaries is the subject of two reviews/opinions (Agrillo et al., Along these lines, Fuss et al.  present In their review, Rosa Salva et al.  stress tTwo other behavioral studies investigate object categorization (Newport et al., Siebeck et al.  examine Finally, one research article uses the retina of an amphibian, the bullfrog, to study the effect of dopamine on the processing of visual information (Xiao et al., The Topic also includes two articles focusing on motion perception and visual tracking behavior in insect models (Aptekar et al., Finally, in their review, Egelhaaf et al.  take a bAs the depth and breadth of the contributions to this Research Topic attest, “simpler” brains have a great deal to teach us about vision. From insects to fish, birds, amphibians, and finally mammals, research aimed at understanding vision in simple animal models is flourishing.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 were interested to read the article by Hjortebjerg et al. on the relationship between road traffic noise and behavioral problems in children. We were especially interested in the variables considered in this study, because we believe it is insufficient to assess the influence of the noise environment on behavioral disorders of children without also factoring in the impact of parents’ mental and neurological health.EHP (Hjortebjerg et al. mentioned that environmental factors such as noise can cause anxiety and mood swings in adults, and an earlier study published in EHP  concludeEHP . Thus, i


The cell surface of fungi, bacteria, and sea organisms is highly glycosylated. These glycans are oligo- or polysaccharide molecules that can be secreted or attached to protein or lipids forming glycoconjugates. They present extraordinary structural diversity that could explain their involvement in many fundamental cellular processes, including growth, differentiation, and morphogenesis. Considerable advances have been made on the structural elucidation of these glycans. Their primary structures were determined based on a combination of mass spectrometry and NMR spectroscopy techniques. The combination of these sensitive and powerful techniques has allowed us to increase our structural knowledge of a wide variety of glycans expressed by different fungi, bacteria and sea organisms.The Research topic “Glycan diversity in fungi, bacteria, and sea organisms” covered important aspects related to polysaccharides, glycoproteins and glycolipids from different organisms and their biological functions.Some contributions to this Research topic have highlighted the importance of glycosaminoglycans analogs with unique structures from different marine invertebrates. Many sulfated fucans (SFs), sulfated galactans (SGs), and glycosaminoglycans (GAGs) of new structures have been characterized and described (Vieira and Mourão, Pomin  has descPavão  emphasizSargassum muticum and Fucus vesiculosus, respectively (Deal et al., Plouguerné et al.  reviewedThe diversity of the composition of the fungal cell surface and important aspects related to structure and function of fungal glycans has also been reviewed in this Research topic. These contributions highlighted the importance of surface molecules of fungal cells for the fungal pathogenesis, physiology, and immune recognition.Guimarães et al.  focused A review from Barreto-Bergter and Figueiredo  showed tFonsecae monophora isolated from clinical and environmental origins.Burjack et al.  demonstrCryptococcus neoformans immunoreactive antigens by Teixeira et al. (Mannoproteins with different molecular masses were identified and characterized as a et al.  with potIn addition to glycans from sea organisms and fungal cells, this Research topic included a mini review on the lipopolysaccharide from bacteria. Serrato  has descAll these articles strongly indicate that knowledge on structure and functions of glycans from fungi, bacteria and sea organisms may open new perpectives allowing to identify specific targets for new generation of antifungal drugs, development of new classes of immunomodulators, antigens, and adjuvants and also marine carbohydrate-based drug development.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.


Finn et al. present an excellent summary of current and emerging methods by which to monitor preterm infants during stabilization in the delivery room, but I disagree with their characterization of the usefulness of Doppler ultrasound, and they fail to comment on the impact of delayed cord clamping on heart rate in the first minutes of postnatal life. Furthermore, I believe recent work using Electrical Cardiometry ICON device  to measuHR assessments in the DR are accurate compared with clinical and pulse oximetry assessments (Doppler ultrasound shows potential for clinical use, however future evidence is needed to support this conclusion.” Phillipos et al. (via Bluetooth to an external recorder. This allows proper assessment and documentation of the neonatal heart rate at cesarean section and facilitates delayed cord clamping and resuscitation with the cord intact. Doppler ultrasound is established as a method for measuring and documenting the fetal heart rate, so it is hard to argue that this will not apply moments later when the fetus is ex-utero as a neonate.Doppler heart rate monitoring is a well-established standard for the fetal heart rate. The authors state that with Doppler ultrasound “essments .” The Phs et al.  do in fas et al. , 4. At ts et al.  in IrelaFinn et al. state “However, clinical experience is required for accurate assessments and continuous measurements are not practical.” After the first minute or so when oximetry is functioning, precordial Doppler is redundant but continuous measurements using a lightweight transducer makes continued hands-free measurements perfectly practical for several minutes after birth.What is the normal heart rate for term and preterm neonate during the first minutes after birth? Finn et al. point out that the standard charts  were derThe 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.


Traumatic brain injury (TBI) from penetrating or closed forces to the cranium can result in a range of forms of neural damage, which culminate in mortality or impart mild to significant neurological disability. In this regard, diffuse axonal injury (DAI) is a major neuronal pathophenotype of TBI and is associated with a complex set of cytoskeletal changes. The neurofilament triplet proteins are key structural cytoskeletal elements, which may also be important contributors to the tensile strength of axons. This has significant implications with respect to how axons may respond to TBI. It is not known, however, whether neurofilament compaction and the cytoskeletal changes that evolve following axonal injury represent a component of a protective mechanism following damage, or whether they serve to augment degeneration and progression to secondary axotomy. Here we review the structure and role of neurofilament proteins in normal neuronal function. We also discuss the processes that characterize DAI and the resultant alterations in neurofilaments, highlighting potential clues to a possible protective or degenerative influence of specific neurofilament alterations within injured neurons. The potential utility of neurofilament assays as biomarkers for axonal injury is also discussed. Insights into the complex alterations in neurofilaments will contribute to future efforts in developing therapeutic strategies to prevent, ameliorate or reverse neuronal degeneration in the central nervous system (CNS) following traumatic injury. Diffuse axonal injury (DAI), regarded as an integral process in all grades of traumatic brain injury (TBI), results typically from head rotational acceleration/deceleration, as well as the propagation of force through the brain following impact , DAI is better described as lesions in multiple, yet common, loci throughout the white matter tracts  in neurons and a major component of the axonal cytoskeleton (Perrot et al., in vitro, NFs are obligate heteropolymers in vivo and must include NFL (Lee et al., While NFL can form a homopolymer Neurofilaments are particularly long-lived proteins with NFL half-life estimated at approximately 3 weeks (Millecamps et al., The function of NFs is not fully understood. Although the importance of IFs for mechanical strength has been long recognized, the varied composition and regulation of neurofilaments suggest that they have a more complex role (reviewed in Capano et al., in vivo and in vitro models of trauma, although the effects of this upregulation are not yet characterized (Dash et al., Neurofilaments undergo a number of posttranslational modifications, including phosphorylation and glycosylation. Phosphorylation has been well characterized (reviewed in Dale and Garcia, It is thought that phosphorylation at these sites, particularly in NFM (Jacomy et al., in vitro stretch injury (Staal and Vickers, Neurofilament phosphorylation has also been intimately tied to myelination and axonal transport (de Waegh et al., Compared to phosphorylation, the role of NF glycosylation is less well studied. The head region of NFL and NFM are modified by the addition of O-linked N-acetylglucosamine moieties, while glycosylation occurs at the KSP repeats of NFH (Dong et al., NF accumulation in injury may develop out of primary mechanical failure of the NF network (Meythaler et al., In vivo and in vitro models of injury employing tacrolimus and cyclosporin A have demonstrated reductions in axonal pathology (Okonkwo and Povlishock, Pathways that may mediate side-arm shortening or loss include calcium-dependent calpain and calcineurin activation, which may be consequences of calcium accumulation post-injury. Evidence supporting calcineurin-mediated dephosphorylation as a factor in NF compaction comes from trauma studies investigating the impact of known calcineurin inhibitors. Similarly, evidence supporting calpain proteolysis of NF side-arms comes from a weight drop study demonstrating that administration of a calpain inhibitor prior to injury attenuated axonal pathology (Buki et al., In vitro studies using a fluid pressure pulse to induce a mild axonal stretch injury in unmyelinated axons have shown that by 48 h post injury, 51% of injured axons showed elevated SMI312 immunoreactivity for phosphorylated NFs (Chung et al., Rotational head injuries in pigs have demonstrated that NF compaction in axonal varicosities contain high levels of all NF subtypes, although NFL accumulates before NFM and NFH, suggesting a temporal sequence of cytoskeletal breakdown or differential subunit transport (Chen et al., In vitro axonal stretch injury with subsequent transmission electron microscopy has demonstrated that microtubule breakage occurs in abnormally convoluted axons post-injury (Tang-Schomer et al., NF compaction has long been thought to contribute to disrupted axonal transport in the setting of injury. Microtubules are essential for axonal growth and transport (Nixon and Yuan, Although both NF compaction and microtubule disruption were thought to contribute to axonal transport block after trauma, a growing body of evidence suggests that NF compaction and defective transport, as measured by APP, are separate pathophenotypes of DAI. Tacrolimus, a selective inhibitor of calcineurin-activated phosphatases (Liu et al., Although NF compaction and impaired axonal transport are largely distinct (DiLeonardi et al., Given the role of NFs in TBI and a range of neurodegenerative conditions, these proteins may be useful plasma biomarkers for axonal injury and neuronal damage Petzold, . It has In a population of pediatric TBI cases, patients whose initial computed tomography scan showed DAI had significantly higher serum levels of pNFH compared to those without DAI (Žurek et al., 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.


Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders characterized by impaired social communication, abnormal language development, restricted interests, and repetitive and stereotyped behaviors  and how that mechanism fails in fragile X syndrome  gene encoding the transcriptional repressor MeCP2 (Moretti and Zoghbi, Xu and Pozzo-Miller comment on a study which identified a novel AT-hook domain of MeCP2 that plays important roles in chromatin organization, providing a mechanism that determines the clinical course of Rett syndrome and related disorders (Baker et al., Bellini et al. provide an overview of post-translational modifications as a mechanism for MeCP2 to control its involvement in synaptic plasticity and homeostasis (Bellini et al., in vivo newborn neurons that mutations of MBD affect the roles of MeCP2 in neuronal development (Zhao et al., Rett syndrome is primarily caused by mutations in the methyl-CpG-binding protein 2 (Investigating the genes and genetic pathways involved in ASDs is essential to unraveling the pathogenesis of these disorders (Krumm et al., Deficits in synapses and neural circuits underlie cognitive dysfunction in ASDs (Zoghbi and Bear, The advances in technical approaches and disease models have provided unprecedented opportunities to investigate neural and synaptic deficits in ASDs. In addition to mouse and rat models, other animals such as drosophila and C. elegans are now used to study autism (Doll and Broadie, Mecp2y−/ mice, suggesting that radical scavengers might be an option for treating neuronal dysfunction in Rett syndrome (Janc and Muller, Mecp2 knockout mice, demonstrating that histone deacetylase-6 is a potential pharmacological target for treating Rett syndrome (Xu et al., Pharmacological manipulation of neurotransmitter systems or signaling pathways linked to ASDs may provide therapeutic benefits for patients (Delorme et al., Lastly, Wang et al. provide a comprehensive review of current targeted pharmacological treatments for fragile X and Rett syndromes, and discuss related issues in both preclinical and clinical studies of potential therapies for ASDs (Wang et al., The increasing need for effective treatment of ASDs, together with the advancement of disease models and other technologies, are promoting studies toward identifying potential therapies. It is inspiring to see that research in animal models is translating into patients with ASDs. The successful development of mechanism-based treatment for autism will continuously require more extensive multidisciplinary collaboration among different research sectors (Katz et al., We thank the authors and reviewers for their efforts and hope that this research topic will enrich our knowledge of ASDs and spur new research interests in autism related biology.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.


In plant glycobiology, free “metabolic” carbohydrates consist of small sugars , sucrose-derived oligosaccharides , starch and its breakdown products  Are increased sugar levels associated with changed hormone levels in buds and how does this change over time? (ii) Do bud IAA levels depend on IAA biosynthesis from tryptophan within the bud, or is indol-3-aldehyde, a phloem-mobile lateral bud inhibitor (Nakajima et al., It cannot be excluded that light dependent signaling mechanisms, or any other positive factors, may have remained undetected in the pea apical dominance paper (Mason et al., Despite these critical notes, it should be recognized that the paper of Mason et al.  boosts fIn line with the earlier ideas of Allsopp , recent Clearly, we are only at the beginning of our understanding of the complexity of cellular sugar homeostasis, and deciphering how this exactly connects to hormonal regulatory mechanisms is an important challenge.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.


This article reviews advances in decoding methods for brain-machine interfaces (BMIs). Recent work has focused on practical considerations for future clinical deployment of prosthetics. This review is organized by open questions in the field such as what variables to decode, how to design neural tuning models, which neurons to select, how to design models of desired actions, how to learn decoder parameters during prosthetic operation, and how to adapt to changes in neural signals and neural tuning. The concluding discussion highlights the need to design and test decoders within the context of their expected use and the need to answer the question of how much control accuracy is good enough for a prosthetic. The field of brain-machine interfaces (BMIs) for control of motor prostheses is quickly growing , yet due to its accuracy and execution speed the method has remained popular since its first use by Wu et al.  Aggarwa. While pLinear filtering, or discrete Wiener filtering, is fading in popularity. It is still used by some research groups, either because of its computational form (Badreldin et al., Several other methods have been used in the recent literature: kernel autoregressive moving average (KARMA; Wong et al., What values should a decoder predict? Ideally, a prosthetic should offer accurate, intuitive control that works under all likely usage contexts. In most prior work, desired positions or velocities of end-effectors were decoded. Homer et al. (r as the difference between the decoded cursor position and the previous cursor position. The cursor position’s update is a linear combination of the decoded velocity and the decoded velocity vector rotated to the direction of Δr.r et al.  proposedDecoders aim to predict user intentions, and it is possible that intentions may be slightly different from the observed limb movements used for parameter fitting. Fan et al.  showed tTwo recent studies have explored decoding torque values, to allow a prosthetic to interact with objects with mass more naturally. Chhatbar and Francis  showed tBesides kinematics and forces, the target location of a reach may be directly decoded to improve the trajectory of the reach. Shanechi et al.  presenteTo address the need for BMI control of limbs with many degrees of freedom, an important consideration for clinical deployment, Wong et al.  used priBesides the biomimetic approach of designing a prosthetic so that it can be controlled like a natural limb, another approach is to use operant conditioning of neuron ensembles (for a review, see Sakurai et al., How should we model neural activity? Recent studies have explored the aspects of neural models beyond movement tuning, with the hope of improving user-friendliness. Considering that a system with high latency is difficult to control, Willett et al. (t et al.  trained In a clinical setting, it is important that a prosthetic can be turned off when not used, to avoid undesired movements. Aggarwal et al.  classifiXu et al.  includedWhich neurons should we include in decoding? BMI researchers have long sought ways to reduce computational load to decoders and noise in neural data by excluding irrelevant neurons. Several recent studies have provided tools for finding relevant neurons. Chen et al. (n et al.  used varCao et al.  determinAlso using a supervised approach, Brockmeier et al.  proposedHow can we design movement models to assist decoding? Kalman and point process filters include movement models which can encode prior beliefs about how variables change over time. Cleverly engineering these models may make prostheses easier to control. Two studies examined how to improve the user’s ability to stop a BMI cursor when desired. Golub et al. (b et al.  designedb et al.  added a In a general examination of movement models, Gowda et al.  analyzedHow can we improve decoder parameters during decoding? To handle poor initial parameter fits or changes in neural tuning after practice, continuous learning of decoder parameters may be required in a clinical device. There has been much recent work, mostly from Jose Carmena’s Lab (for a review, see Carmena, Information about the target locations of reaches can help improve the parameter learning process. Kowalski et al.  proposedIn Suminski et al.’s  study, iMerel et al.  modeled Are neural signals stable over long time periods? There has been controversy as to whether updating of decoder parameters is required for long-term prosthetic usability. Recent studies have analyzed stability of signals over long time spans. Flint et al. (t et al.  and Schet et al.  showed tt et al.  found sit et al.  found siIf decoder updates are needed, how can we improve the accuracy of updates? Recent studies have proposed heuristics to improve adaptation. Zhang and Chase (nd Chase  used twond Chase  proposedBesides updating baseline firing rates via windowed estimates, other methods for tracking baseline changes have been proposed. Bishop et al.  found thk-means.Using a reinforcement learning approach to adaptation, two studies from the same group (Mahmoudi et al., As researchers focus more on practical hurdles to clinical deployment of neural prostheses, it becomes more and more important to develop and test BMI decoders in the contexts in which actual prostheses will be used, i.e., to control artificial limbs, natural limbs via functional electrical stimulation (Moritz et al., An important question which has been thus far neglected in the field is how much control accuracy is enough? Full restoration of human ability in terms of movement accuracy may come at computational and other costs, e.g., number of recording channels, which likely trade off against other figures of merit of a prosthetic system. While we should continually endeavor to improve BMI technology, from a practical standpoint, we should also answer the question of how much control is good enough, so that engineers can design systems with clear requirements in mind.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.


Nitrogen (N) is an essential element in biological systems and one that often limits production in both aquatic and terrestrial systems. Due to its requirement in biological macromolecules, its acquisition and cycling have the potential to structure microbial communities, as well as to control productivity on the ecosystem scale. In addition, its versatile redox chemistry is the basis of complex biogeochemical transformations that control the inventory of fixed  N in local environments, on a global scale and over geological time.Although many of the pathways in the microbial nitrogen cycle were described more than a century ago, additional fundamental pathways have been discovered only recently. These findings imply that we still have much to learn about the microbial nitrogen cycle, the organisms responsible for it and their interactions in natural and human environments. Progress in N cycle research has been facilitated by recent rapid technological advances, especially in genomics and isotopic approaches.nifH gene expression indicate complex regional and taxonomic sensitivities to micronutrient limitation.The papers in this issue reflect current research focus on N loss and input processes. The papers are ordered by topic beginning with N fixation, the only biological process that can increase the inventory of fixed N, Knapp  reviewedNext we include a series of papers about nitrification, a process which does not directly affect the fixed N inventory, but which links mineralization to the N loss processes by producing oxidized forms of N that can then be used as respiratory substrates. Nitrification has been the subject of increasing research interest since the discovery a decade ago that archaea were involved in ammonium oxidation. A large body of literature has since developed documenting the diversity, abundance and activity of ammonia oxidizing bacteria and archaea (AOB and AOA). For this collection, Casciotti and Buchwald  reviewedBeggiatoa mats, but even higher rates in sediments without mats. The presence of sulfide reduced denitrification rates, even though the community contained large numbers of sequences associated with taxa that are capable of linking sulfide oxidation with nitrate reduction. Kirkpatrick et al. (The next topic in the collection deals with the processes by which fixed N is lost from marine ecosystems. Low oxygen environments are of particular interest for nitrogen transformations because they are the sites of fixed N loss via denitrification and anammox. Francis et al.  report ok et al.  and Fuchk et al.  report ok et al. . In the k et al.  found thk et al.  report oFinally, we include a single paper on the use of nitrogen by the phytoplankton in the surface ocean. Bertrand and Allen  review tThe 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.


The controversial issue on the independent versus synergic functional role of the vomeronasal and main olfactory systems, motivated the present Research Topic , accessory-olfactory (AOB) bulbs, and primary olfactory cortex. The work by Pedraza and De Carlos  presentsThe initial dogma regarding VNS and MOS as independent sensory modalities was supported by the dissimilar centripetal distribution of their tributary fibers. However, with the refinement of the tract-tracing techniques numerous sites of central convergence between the two systems have emerged. Three original studies performed in adult mice deal with the connectivity of the MOS and VNS. The paper by Hintiryan et al.  providesIt is now clear that plasticity in the adult nervous system is more common than originally suspected (see Merkle et al., Four review articles present and analyze current concepts of the MOS-AOS interaction. In this framework, the assays by Suárez et al.  and MuciThe 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.


This is an end point mechanism for inhibiting chloride secretion-induced water drag and resulting secretory diarrhea. VIP in the extracellular space may be related to creating an antiviral environment, but at the cost of inducing secretory diarrhea, which upon chronic persistence may often be fatal and contribute to marked cachexia. Some recent hypotheses have suggested the plausible role of ENS-stimulated VIP release and its protective effects on intestinal epithelial barrier  approved to manage HIV and HAART- induced non-infectious diarrhea (Crutchley et al., In summary, HIV associated diarrhea remains a major cause of morbidity and mortality even now, with presentations comparable to the earliest report of “slim disease”, the cachectic manifestation, from rural Uganda (Serwadda et al., 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.


Together, this suggests that a hyperbaric and thermal physiological bottleneck at bathyal depths contributes to bathymetric zonation. The peak of the unimodal diversity–depth pattern typically occurs at these depths even though the area represented by these depths is relatively low. Although it is recognised that, over long evolutionary time scales, shallow-water diversity patterns are driven by speciation, little consideration has been given to the potential implications for species distribution patterns with depth. Molecular and morphological evidence indicates that cool bathyal waters are the primary site of adaptive radiation in the deep sea, and we hypothesise that bathymetric variation in speciation rates could drive the unimodal diversity–depth pattern over time. Thermal effects on metabolic-rate-dependent mutation and on generation times have been proposed to drive differences in speciation rates, which result in modern latitudinal biodiversity patterns over time. Clearly, this thermal mechanism alone cannot explain bathymetric patterns since temperature generally decreases with depth. We hypothesise that demonstrated physiological effects of high hydrostatic pressure and low temperature at bathyal depths, acting on shallow-water taxa invading the deep sea, may invoke a stress–evolution mechanism by increasing mutagenic activity in germ cells, by inactivating canalisation during embryonic or larval development, by releasing hidden variation or mutagenic activity, or by activating or releasing transposable elements in larvae or adults. In this scenario, increased variation at a physiological bottleneck at bathyal depths results in elevated speciation rate. Adaptation that increases tolerance to high hydrostatic pressure and low temperature allows colonisation of abyssal depths and reduces the stress–evolution response, consequently returning speciation of deeper taxa to the background rate. Over time this mechanism could contribute to the unimodal diversity–depth pattern.Bathymetric biodiversity patterns of marine benthic invertebrates and demersal fishes have been identified in the extant fauna of the deep continental margins. Depth zonation is widespread and evident through a transition between shelf and slope fauna from the shelf break to 1000 m, and a transition between slope and abyssal fauna from 2000 to 3000 m; these transitions are characterised by high species turnover. A unimodal pattern of diversity with depth peaks between 1000 and 3000 m, despite the relatively low area represented by these depths. Zonation is thought to result from the colonisation of the deep sea by shallow-water organisms following multiple mass extinction events throughout the Phanerozoic. The effects of low temperature and high pressure act across hierarchical levels of biological organisation and appear sufficient to limit the distributions of such shallow-water species. Hydrostatic pressures of bathyal depths have consistently been identified experimentally as the maximum tolerated by shallow-water and upper bathyal benthic invertebrates at  Introduction 407Origin of the deep-sea fauna and the colonisation of the deep sea 408Physiological limitation by low temperature and high hydrostatic pressure 410Tolerance of high hydrostatic pressure and low temperature 411Adaptations to high hydrostatic pressure and low temperature 413Bathymetric variation in evolution 415The stress-induced evolutionary mechanism in the deep sea 416Conclusions 418Acknowledgements 419References 419et al., et al., et al., et al., et al., Many macroevolutionary patterns display both ecological and biogeographical components. Clear bathymetric patterns have been identified in the extant biodiversity of the deep continental margins, a region covering approximately 40% of the total ocean surface area   of the Phanerozoic (Jablonski et al., et al., et al., Phylogenetic analyses have supported the relatedness of extant deep-sea and shallow-water species, predominantly consistent with diversification and invasion of deep-sea environments from shallow water, albeit over differing timescales. Bresiliid shrimp from deep-sea vents and seeps are reported to have radiated less than 20 Ma and from shallow ancestry (Shank et al., et al., et al., et al., Pagodulid snails appear to have radiated even more recently, from a shallow-water Antarctic lineage, and colonised the deep sea approximately 3 Ma (Barco ca. 250 Ma (see Raupach et al., et al., in situ (Osborn et al., et al., et al., et al., Echinus acutus is extending its bathymetric range, indicating that migrations to the deep sea are still occurring (Tyler & Young, Palaeontological and molecular data indicate that echinoids have made migrations to the deep sea over multiple timescales; generalist omnivores migrated to the deep sea in low numbers over the last 200 Myr in contrast to the majority of specialist detritivore clades, which made independent off-shelf migrations between approximately 75 and 55 Ma (Smith & Stockley, et al., et al., Reemergence from the deep sea has also been reported, e.g. for lithodid crabs (Hall & Thatje, et al., et al., et al., et al., Since shallow-water fauna are adapted to relatively warm conditions currently dominating the upper oceans except at high latitudes, the low temperatures prevalent in the deep sea are considered to limit invasion by such fauna (deep-sea temperature is typically between 4 and −1°C; Gage & Tyler, et al., et al., et al., In both warm and cold isothermal water columns the major limiting factor for range extension into the deep sea is predicted to be tolerance of high hydrostatic pressure (Young et al., et al., et al., et al., Thermal tolerance is proposed to relate directly to the physiological ability of an organism to avoid the transition from aerobic to anaerobic metabolism, with a systemic to molecular hierarchy of limitation (see Pörtner, et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., There are significant physical effects of hydrostatic pressure on proteins and lipoprotein membranes (reviewed by Pradillon, 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., Listeria monocytogenes after exposure to 10°C for 4 h following culture at 37°C, has been reported to result in a 100-fold increase in survival of exposure to 300 MPa for 20 min (Wemekamp-Kamphuis et al., Cellular responses to thermal and hyperbaric environmental challenges can contribute directly to biogeographic limitation (e.g. see Tomanek, in situ temperatures at bathyal depths could support the contribution of hydrostatic pressure to bathymetric zonation.Evidently, hydrostatic pressure and temperature both have significant biological effects perturbing every level of biological organisation sufficiently to limit biogeographic range Table . It appeet al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Euphausia superba (George, Allocentrotus fragilis during adaptation to the deep-sea environment (Oliver et al., Maja brachydactyla appear to be greater under hyperbaric conditions, potentially critical in restricting bathymetric distributions (Thatje & Robinson, Recently, attempts to determine potential for invasion of the deep sea have focused on mollusc and echinoderm propagule tolerance of hydrostatic pressure and low temperature in shallow-water species, with and without close phylogenetic links to deep-sea species, in order to test the validity of theories of deep-sea colonisation (Young, Tyler & Emson,  George, . Whilst  George, , it is cet al., et al., et al., Palaemonetes varians tolerates pressures equivalent to 1000 m depth for at least a month and retains the ability to feed and successfully moult at this pressure, despite naturally inhabiting depths of less than 10 m (Cottin et al., et al., et al., Stephonyx biscayensis is determined by the combination of low-temperature and high-pressure effects (Brown & Thatje, Thorough investigation of both temperature and hydrostatic pressure tolerances of adult specimens of shallow-water species are few and focus on crustaceans, but have also demonstrated tolerance of pressures outside known natural distributions (Naroska, et al., et al., et al., et al., Existing studies of hyperbaric pressure tolerance of shallow-water benthic invertebrates consistently indicate limitation at bathyal depths ; Table 2et al., In vitro evidence indicates that critical enzyme functionality can be maintained under different pressure and temperature regimes by changes of relatively few amino acids at critical positions in a protein chain, or by the inclusion of stabilizing compounds in the intracellular matrix (Carney, Allocentrotus fragilis, in contrast to selection in the shallow-water urchin Stronglyocentrotus purpuratus (Oliver et al., et al., et al., et al., et al., et al., Allocentrotus fragilis contrasts with selection in the shallow-water urchin Stronglyocentrotus purpuratus and may reflect adaptation to environmental effects of the deep-sea (Oliver et al., The oxygen requirements of cold and deep-living species do not appear to be elevated (Childress  Carney, . Indeed,et al., Allocentrotus fragilis is in contrast to selection in the shallow-water urchin Stronglyocentrotus purpuratus and may indicate that membranes or membrane-related functions have undergone environmental selection (Oliver et al., et al., The reduced fluidity of bio-membranes under increased hydrostatic pressure and decreased temperature necessitates homeoviscous adaptations in membrane structure and composition (Hazel & Williams, et al., et al., Adaptations to high pressure can result in near pressure insensitivity, e.g. in malate dehydrogenases (see Somero, Hyperbaric and thermal effects do appear to have made significant adaptive demands on shallow-water organisms colonising the deep sea, further supporting the influence of these factors in establishing bathymetric zonation patterns. However, it is not immediately clear how the physiological effects of hydrostatic pressure or low temperature could contribute to the unimodal pattern of diversity with depth, despite diversity typically peaking at similar depths to the proposed physiological bottleneck even though the area represented by these depths is relatively low. Is there other evidence suggesting a cause for this bathymetric diversity phenomenon?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., Variation in the production of novel taxa has been identified as causative of another, somewhat analogous, evolutionary pattern in biodiversity. A meta-analysis of nearly 600 latitudinal biodiversity gradients assembled from the literature has corroborated the high generality of the latitudinal diversity decline, including for the marine environment of both hemispheres (Hillebrand, 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., 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., et al., et al., et al., et al., et al., et al., et al., Although evolutionary rates reflect the interplay of mutation with selection and genetic drift Kimura, , moleculOver time a bathyal peak in evolutionary rate clearly could result in a unimodal pattern of diversity peaking at these depths, despite the relatively low area they represent. Consequently, it appears a distinct possibility that an evolutionary role for high hydrostatic pressure and low temperature may have been neglected. Indeed, reanalysis of existing diversity–depth data using quadratic depth and temperature functions may offer evidence for such a role. But how could these factors stimulate the rate of evolution at bathyal depths?et al., et al., et al., Existing evidence suggests that adaptive radiation is the predominant mode of biological diversification (see Glor, et al., et al., et al., et al., et al., et al., et al., et al., et al., 2008d, 2011et al., et al., et al., et al., et al., et al., The ubiquitous cellular stress response affords cells a transient increase in tolerance to any form of damage-inflicting environmental challenge in larval and adult organisms, allowing time for stressor-specific adaptation to re-establish cellular homeostasis Kültz, , 2005. SParamunida suggests a period of rapid diversification following origination between 17 and 21 Ma (Cabezas et al., et al., Mutation in germ cells, adaptive canalisation during embryonic or larval development, release of hidden genetic variation or mutagenic activity, or activation or release of transposable elements in larvae or adults, increase genetic or phenotypic variation. Elevated variation unrelated to hydrostatic pressure tolerance may promote increased parapatric or sympatric speciation into vacant niches, whilst taxa remain bathymetrically constrained . Models et al., It is clear that understanding marine evolutionary dynamics demands increased knowledge of links between continental margin fauna (Clarke & Crame, Following climate-driven dysoxic mass extinctions in the deep sea, shallow-water organisms have recolonised the deep sea and the extant deep-sea fauna appears predominantly to comprise both ancient and more recent radiations of shallow-water lineages. The physiological effects of high hydrostatic pressure and low temperature across hierarchical levels of biological organisation appear capable of limiting the distribution of such shallow-water species. Experimental assessment of hyperbaric limitation across a range of shallow-water taxa supports the proposition of a physiological bottleneck at bathyal depths, imposed by the combined effects of high hydrostatic pressure and low temperature. Organisms inhabiting the deep sea appear to be functionally adapted to the high-pressure and low-temperature conditions that prevail, suggesting that hyperbaric and thermal effects have made significant adaptive demands on shallow-water organisms colonising deeper water. Together this supports the hypothesis that a hyperbaric and thermal bottleneck at bathyal depths contributes to bathymetric zonation.A unimodal pattern of diversity with depth typically peaks at similar depths to the proposed physiological bottleneck. It is recognised that speciation rates contribute to a similar latitudinal pattern in shallow-water diversity. Existing molecular and morphological evidence supports the proposition that bathyal depths are the primary site of adaptive radiation in the deep sea. We hypothesise that a peak in speciation rates at bathyal depths could establish the unimodal bathymetric biodiversity pattern over time.We hypothesise that demonstrated physiological effects of high hydrostatic pressure and low temperature may promote a stress–novelty evolutionary mechanism, increasing mutagenic activity in germ cells, inactivating canalisation during embryonic or larval development, releasing hidden variation or mutagenic activity, or activating or releasing transposable elements in larvae or adults. In this scenario speciation rate is increased at bathyal depths resulting in production of novel taxa. Adaptation that increases tolerance to high hydrostatic pressure and low temperature allows colonisation of abyssal depths and reduces the stress–evolution response, consequently returning speciation in deeper taxa to the background rate. Over time this mechanism could contribute to the unimodal diversity–depth pattern.


This Research Topic focusses on both classes of models and considers several aspects and their relative merits that: span from synapses to the whole brain; comparisons of their predictions with EEG and MEG spectra of spontaneous brain activity; evoked responses, seizures, and fitting data—to infer brain states and map physiological parameters.In general, mean field models of neural activity can be divided into two classes: neural mass and neural field models. The main difference between these classes is that field models prescribe how a quantity characterizing neural activity  evolves over Some of the contributions consider extensions of neural mass and field models and their relation with other classes of models, with a particular focus on modeling the action of anesthetics:Liley and Walsh  hypothesThe roles of neural mass, conductance based, and neural field models in dynamic causal modeling (DCM) are reviewed and explored by Moran et al. . These aModolo et al.  discuss The contribution of Pinotsis et al.  introducOther articles in this Research Topic relate to the use of field models to explain aberrant neural activity and dynamics recorded during cognitive tasks: Kerr et al.  integratFrequency-dependent effects in deep brain stimulation in epileptic patients are studied using computational modeling and intracerebral EEG data in Mina et al. . This paBhattacharya's paper (Bhattacharya, In Srinivasan et al.  the authIn another paper, Robinson et al.  explore Finally, beim Graben and Rodrigues  reduce aIn addition to papers focussing on applications, this Research Topic includes theoretical papers studying the mathematical aspects of mean field theory: Bressloff and Wilkerson  study riIn Gray and Robinson , the autRoy and Jirsa  show howThe above anthology of papers provides illustrative examples of recent advances in biophysical modeling. This line of work speaks to the hope that such models may help explain neural dynamics that underpin disorders like epilepsy or Parkinson's disease as well as normal functions like attention or working memory; an endeavor we hope the articles in this volume will progress.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.


Perrin's recent comment Perrin,  emphasizIn negative ALS clinical trials (UKMND-LiCALS Study Group et al., In conclusion, we believe that the potential beneficial effect of lithium for neurodegenerative disorders deserves serious reconsideration.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 agree with Martin et al. that, as yet, late recurrence of hepatitis C virus (HCV) following treatment has not been studied in this highly exposed group of patients. To clarify the point made in our study,


Of critical importance for clinical psychological science is why do people differ in their very ability to govern and regulate their thoughts and behaviors? This concern speaks to the paramount nature of executive function (EF) that encompasses a set of general-purpose cognitive control mechanisms regulating lower-level processes and, in turn, enabling self-regulation and self-directed behavior toward a goal Banisch, . ConsequWe are thankful to Snyder et al.  for recealerting , orienting , and executive (involving the top-down control of attention to resolve response conflicts). Because the notion of “executive network of attention” is defined as similarly to common EF, Snyder et al. (Theoretically, Snyder et al.  also uphr et al.  argued tFirst, a strict reading of their account is at odds with previous evidence of alerting and orienting networks impairments in a wide range of distinct psychopathological conditions (e.g., Lundervold et al., Second, because psychopathology is associated with impairments in the executive network of attention, Snyder et al.  argued tAltogether, although we agree with Snyder et al.  that an AH had the initial ideas and wrote the first draft of the manuscript. All authors then revised the manuscript critically and contributed to and have approved the final manuscript.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.


Adaptation and homeostasis, the ability to reach stable attractor states within changing environments, are the most typical characteristics of biological systems. A recent study by Benucci et al.  reportedWhile it is an intriguing idea, assigning V1 a role as a probability detector that integrates incoming information over a considerable time of multiple seconds, our own data (Nortmann et al., Although the stimulation protocols in the studies outlined here have differed in several aspects, we think a link between them exists. The biased stimulation protocol in Benucci et al.  inevitabRegardless of the underlying neural mechanisms: which benefits are provided by cortical adaptation in the hundreds of milliseconds up to second ranges? One may ask the question the other way around: which disadvantages are brought about by longer adaptation times? As often, the answer depends on the task. We suggest that this is when eye movements come into play. For inspection of fine details within natural scenes, high-frequency sampling is useful (Rucci et al., In the study by Benucci et al. , the denThe 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.


Materials with the much-loved perovskite structure are being used to develop and test new methods for interpreting local structural arrangements in crystals, and these methods are in turn uncovering unexpected new structural insight. Nature Materials published in September 2014). Indeed the nature of their phase transitions and phase transition sequences are probably some of the most extensively studied of all crystal systems.Crystallographers have been drawn to the family of perovskite-structured materials for over 70 years, both because their apparent structural simplicity  in 1970  obtained from careful diffraction experiments from powdered samples is correctly touted as a way to determine local structural arrangements  of single crystals; simplicity of measurement; differences in neutron or X-ray scattering contrast; impact of powder averaging etc. They then concentrate on two methods for analysing the PDFs – ‘small box’ and ‘big box’ methods. Again this is a choice that can only be made on a case-by-case basis: small box methods such as PDFgui  refinements (Tucker et al., 2007How to decide whether a single-crystal diffuse scattering measurement or pair distribution function measurement – or indeed a combination of the two – is preferable for a given structural disorder problem is the main topic of an article by Whitfield  al. 2016 in this RMCprofile (Tucker et al., 2007et al., 2014When assessing the big box methods the authors do not use the routinely available RMC codes such as e.g. Keeble et al., 2013et al., 2015et al. (2016There is now a wealth of evidence to show that the more local structure is investigated the more we are obliged to reassess our understanding of crystalline structure and behaviour and, perhaps typically, perovskite-structured systems are again at the forefront ( al. 2016 emphasiz


Just as there is a huge morphological and functional diversity of neuron types specialized for specific aspects of information processing in the brain, astrocytes have equally distinct morphologies and functions that aid optimal functioning of the circuits in which they are embedded. One type of astrocyte, the Bergmann glial cell (BG) of the cerebellum, is a prime example of a highly diversified astrocyte type, the architecture of which is adapted to the cerebellar circuit and facilitates an impressive range of functions that optimize information processing in the adult brain. In this review we expand on the function of the BG in the cerebellum to highlight the importance of astrocytes not only in housekeeping functions, but also in contributing to plasticity and information processing in the cerebellum. It has been proposed that PCs remain in the upstate because calcium-dependent K+ channels gradually inactivate after hyperpolarization (Wang et al., + but under which conditions this happens in the intact brain requires further investigation.Astrocytes including BGs act as large sinks for redistribution of ionic gradients and could thereby have significant impact on neurotransmission and excitability of neurons (Newman et al., in vivo (Bekar et al., BGs like other astrocytes express receptors for the neurotransmitter noradrenaline and activation of such receptors can trigger calcium elevations (Salm and McCarthy, Possibly, noradrenaline release also contributes to BG activation during sensorimotor stimulation. Indeed during head-fixed treadmill locomotion (Nimmerjahn et al., In vivo two-photon microscopy recently revealed that zebrin-positive zones not only define sharp anatomical borders, but also show a sharp delineation of functional responses to sensory stimuli (Tsutsumi et al., The modular organization of the cerebellum into parasagittal zones as defined e.g., by Zebrin, or other markers Figure  has been+ (Wang et al., post hoc immunohistochemistry for zone-delimiting proteins, or transgenic mouse models that allow direct visual selection of BGs in cerebellar zones should advance our knowledge in this regard. A combination of targeted electrophysiology (Kitamura et al., BG are versatile in their function and highly integrated in the cerebellar circuit. However, many questions remain about their exact contribution to information processing in the cerebellum. High surface-to-volume ratios and thin stalks endow BG microdomains (Grosche et al., 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.


Since its widespread introduction in the early 1980s, immunoglobulin therapy (IG) has been extensively investigated to understand its mechanism of action and clinical benefits. Research has also continued to improve its production. The survival benefits of IG for patients with primary immunodeficiency (PID) are accepted , or subcSimple replacement of the antibody defect in PID is now known to be an incomplete explanation of the mechanism of IG. A range of immunomodulatory and anti-inflammatory mechanisms are involved . These mThe increased demand for IG has also seen the rapid development of new manufacturing methods replacing the traditional Cohn fractionation system . This sylow B cells. Matucci et al. (This Research Topic of Frontiers in Immunology has been assembled by an editorial team which have experienced sufficient “dark forebodings”  regardini et al.  discuss i et al.  discuss Taken together, this body of work mitigates our “dark forebodings” regarding the lack of clarity on the mechanism of action of IG. More work is also needed to optimize therapeutic practice. Kerr et al.  note theThe final component of this Research Topic of Frontiers in Immunology examines the manufacture of IG therapies and its effect on the efficacy and safety of the products. Goldacker et al.  show thaOverall, the therapeutics of diseases caused by a deficiency or an inappropriate type of antibodies continues to be an exciting and fruitful area of clinical research, and well suited to contribute to the ongoing evolution in medicine toward more individualized and patient centric paradigms. We hope that this Research Topic of Frontiers in Immunology contributes to this debate. Such a wide debate between experts is necessary to enable the new challenges in immunoglobulin usage.Albert Farrugia provides contractual consulting services to companies which manufacture therapeutic immunoglobulin. Marcella Visentini and Isabella Quinti have no conflict of interest to declare.


A recent study by Forsaa et al.  details In this study, Forsaa et al.  utilizedForsaa et al.  suggest As shown by Forsaa et al's  long-terCurrently, complete understanding of the pathophysiology of dyskinesias and motor fluctuations remains elusive. However, both appear to be associated with the degree of dopamine depletion and the use of levodopa (L-Dopa) . This is limiting in that it is a fairly crude measure of “freezing,” which may not allow for identifying of subtler aspects of gait. However, until recently, more expansive questionnaires detailing in-depth descriptions of FOG were unavailable (Nieuwboer et al., Given the high frequency of FOG in the PD population and its inherent negative consequences, more research into the pathophysiology, treatment and prevention of this symptom is necessary. Forsaa et al.  demonstrThe 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.


The Editorial on the Research TopicMechanical Loading and BoneTobias et al. and Janz et al. address important methodological issues concerning the use of accelerometers to record physical activity in a way that is relevant to mechanical loading of bone. Two separate papers by Toshihiro Sugiyama et al. discuss how understanding of skeletal responses to mechanical loading can help interpret the mechanism of action of bone anabolic drugs. The paper by Zengin et al. illustrates how understanding of mechanical loading responses can be used to interpret ethnic differences in skeletal structure. Of the six laboratory papers, those by Meakin et al. and Vazquez et al. focus on methodological approaches to study mechanical loading in vivo and in vitro, respectively. Four of the papers explore the mechanisms involved in mediating different aspects of mechanical loading responses of bone. García-López et al. report their findings concerning the mechanisms involved in the inhibition of bone resorption by cyclical mechanical strain in vitro; Kang and Robling review the role of the Wnt pathway in mechanotransduction; Alzahrani et al. review the mechanisms involved in distraction osteogenesis; and Betts and Müller review theories and models of mechanical regulation of bone regeneration after bone injury.This Research Topic comprises 11 interesting and topical articles describing a mixture of clinical and laboratory approaches to how mechanical loading influences the skeleton. Of the five clinical papers, those by Janz et al. use conventional counts per minute thresholds but apply a relatively high threshold denoting vigorous PA on the basis that such activity is more likely to be osteogenic, as borne out by their results. By contrast, Tobias et al. extracted the number of counts beyond specific g thresholds on the basis that these are more directly related to ground reaction forces.The papers by Tobias and Janz represent contrasting approaches to study the relationships between physical activity and bone measures based on accelerometry. While the former addresses the role of physical activity in preserving bone in older people, and the latter examines its role in bone accrual in childhood. Moreover, these papers utilize distinct approaches to extract relevant information about mechanical loading from accelerometry data. Toshihiro Sugiyama et al. suggest that the reason why gains in bone at the outer surface are limited is because simultaneous gains at the inner surface act to limit strain at the outer surface. In a further hypothesis article, the same authors, Sugiyama et al. suggest that the anti-sclerostin inhibitors blosozumab and romosozumab are particularly effective at simulating bone formation as a consequence of their ability to overcome negative feedback of the mechanostat by interfering with this process due to its dependence on sclerostin. In their review of ethnic differences in bone health, Ayse Zengin et al. conclude that differences in fracture rate between ethnic groups cannot adequately be explained by differences in areal bone mineral density, suggesting the need to describe these based on more detailed measures of bone structure. Differences in the latter may in turn reflect ethnic differences in muscle mass and force, or alternatively how the skeleton responds to mechanical loading by these factors.The remaining three clinical papers illustrate how understanding of mechanical loading responses can be used to explain findings from epidemiological to interventional studies of the skeleton. In their hypothesis article on teriparatide effects on bone, Meakin et al. and Vazquez et al. describe contrasting methodological approaches to studying the mechanisms that mediate mechanical loading responses. Meakin et al. describe how use of in vivo studies based on a range of animal models has contributed to our understanding of the type of strain stimulus to which the skeleton is most responsive. Vazquez focuses on in vitro models of mechanical strain responses, describing a novel 3D osteocyte–osteoblast co-culture system.The papers by García-López et al. report that cyclical strain of osteoblast monolayers reduces expression of the bone resorptive cytokine RANKL, but surprisingly other cytokines that might be expected to mediate this response show a paradoxical increase in expression. The review by Kang and Robling focuses on the role of Wnt signaling in mediating osteogenic responses to mechanical strain and suggests that while LRP5 is known to be involved, the closely related receptor LRP6 may also play a hitherto unrecognized role.The remaining four laboratory papers describe different aspects of the mechanisms involved in mechanical loading responses. Alzahrani et al. discuss how characterization of the molecular pathways involved in mediating responses to mechanical loading can be used to select improved protocols for distraction osteogenesis, a surgical technique used to treat bony deformities via limb lengthening. Finally, in their paper, Betts and Müller review the different experimental studies, models, and theories that explain how mechanical stimuli are sensed and incorporated during bone regeneration as part of the healing process after bone injury.In their review article, Together, the 11 papers published in this Research Topic provide a good illustration of how mechanical loading underpins many facets of bone biology, including the pathogenesis and treatment of osteoporosis and other clinical disorders associated with skeletal fragility.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.


Recently, Bettina Maria Fischer and colleagues of the Institute of Toxicology in Karlsruhe have published data on a gene expression based predictive test system for chemical carcinogens . The auIdentification of chemical carcinogens represents a cutting-edge topic in toxicology (Liu et al., 2015; Bustaff


Major depressive disorder (MDD) affects more than 10% of the population, although our understanding of the underlying aetiology of the disease and how antidepressant drugs act to remediate symptoms is limited. Major obstacles include the lack of availability of good animal models that replicate aspects of the phenotype and tests to assay depression-like behaviour in non-human species. To date, research in rodents has been dominated by two types of assays designed to test for depression-like behaviour: behavioural despair tests, such as the forced swim test, and measures of anhedonia, such as the sucrose preference test. These tests have shown relatively good predictive validity in terms of antidepressant efficacy, but have limited translational validity. Recent developments in clinical research have revealed that cognitive affective biases (CABs) are a key feature of MDD. Through the development of neuropsychological tests to provide objective measures of CAB in humans, we have the opportunity to use ‘reverse translation’ to develop and evaluate whether similar methods are suitable for research into MDD using animals. The first example of this approach was reported in 2004 where rodents in a putative negative affective state were shown to exhibit pessimistic choices in a judgement bias task. Subsequent work in both judgement bias tests and a novel affective bias task suggest that these types of assay may provide translational methods for studying MDD using animals. This review considers recent work in this area and the pharmacological and translational validity of these new animal models of CABs.http://dx.doi.org/10.1111/bph.2014.171.issue-20This article is part of a themed section on Animal Models in Psychiatry Research. To view the other articles in this section visit  Recently, there has been a move towards establishing translational methods for research into MDD, although the nature of this disease presents challenges for emulating aspects of the disorder in non-human species  are initially associated with a specific spatial location. Judgement bias is then evaluated by measuring the latency to approach both the reference locations and intermediate positions. A negative bias in this version of the task is seen when the animal makes a slower response to an intermediate position, indicating a reduced anticipation of finding the reward. Where an aversive food outcome such as quinine-treated food is used, the slowed responding is proposed to show an expectation that the intermediate location is associated with the aversive outcome. Using this approach, Richter et al.  showed t et al., , a congeet al., et al., Only one judgement bias study has been reported for mice where odour cues were used to predict rewarding or aversive food outcomes , retinoic acid (the active ingredient of the anti-acne medication roaccutane) or FG7142 (a benzodiazepine inverse agonist) that caused severe anxiety in humans (Dorow et al., et al., Pharmacological and psychosocial stress manipulations were used to assess the validity of the approach (Stuart et al., et al., et al., One potential issue with this task is the possibility that the drugs or affective state manipulations have a direct effect on learning and memory or appetite which thus leads to a subsequent bias in the memory of that experience. Initial experiments suggested that effects are not associated with impairments in learning, as animals performing the task show similar rates of learning on treatment and control discrimination learning sessions. Sedative effects can also be controlled for within the protocol as latencies to approach the bowl are recorded (Stuart et al., et al., et al., A possible criticism of the findings in the affective bias test is that response biases are seen after acute treatments. The field of depression has been dominated by the notion that antidepressant drugs have a delayed onset of clinical efficacy. This criticism has been applied to established assays of depression-like behaviour such as the FST and also used to support the improved validity of tests of anhedonia. However, a key issue with the delayed onset of action of antidepressant drugs is that this observation is based on the subjective reporting of mood in patients and does not necessarily mean that the acute biochemical effects of the drug are not relevant to its efficacy. In fact, the recent observation that acute treatment with antidepressant and prodepressant drugs in healthy volunteers can cause CABs (e.g. Harmer et al., Overall, the results for the affective bias task suggest this approach has good predictive and translational validity. The data obtained correspond well with similar acute drug studies carried out in healthy volunteers performing emotional recognition and characterization tasks (see Pringle et al., et al., et al., et al., et al., Although not necessarily defined specifically as a measure of CAB in MDD, probabilistic reversal learning tasks do offer a translational method to study how reward and punishment processing are altered in this disorder (Swainson et al., et al., A rodent probabilistic reversal learning task has been evaluated in one study where serotonergic manipulations, including the antidepressant, citalopram, were investigated in normal rats (Bari The focus of this review is two behavioural approaches which have been developed to study CABs in depression using rodents. Although still in the early days of development, results so far suggest that CABs can be studied in rodents, with both decision-making during ambiguous cue interpretation and learning and memory being similarly biased by affective states in rodents and humans.et al., et al., et al., et al., et al., et al., In terms of affective state induced cognitive biases, the results from judgement bias tasks provide robust and relatively well-replicated findings that animals in a putative negative affective state exhibit negative judgements when interpretation of ambiguous cues is evaluated. Results from the affective bias test also suggest that both stress-induced negative affective states and prodepressant drug treatments negatively bias reward-associated learning and memory, resulting in a relative decrease in the value attributed to a rewarding experience. These observations correspond well with data from patients with MDD (Mathews and MacLeod, et al., Pharmacological studies using these approaches are still limited and further studies in this area are needed. In terms of understanding the value of the tasks for preclinical drug development and safety pharmacology, more detailed studies using drugs with known antidepressant and prodepressant effects in humans would be of value. Pharmacological studies also offer a route to understanding more about the neural and neurochemical mediators of CABs and studies using rodents can help reveal the neurobiological processes which modulate these behaviours. This type of work has the potential to deliver a greater understanding of the relationship between CABs and MDD which may also reveal novel drug targets for improved treatments. The development of translational animal models of CABs in MDD can also be used to investigate the emerging cognitive neuropsychological hypothesis of MDD and antidepressant efficacy (Harmer,


Their paper highlights the importance of clarifying the mental health challenges associated with eye diseases, such as macular degeneration and diabetic retinopathy (Mathew et al., Visual disorders are associated with a substantial economic and personal burden Rein, . The recGall et al.  argue thFurthermore, Gall et al.  also fouThe 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.


Recently published results seemed to show power law scaling of phase synchronization, a characteristic that we have previously interpreted as indicative of critical dynamics, in “empty room” MEG recordings. Here we show that the results we previously reported on scaling of phase synchronization in human MEG data are not compromised by these apparently anomalous results. By extensively reanalysing the empty room MEG data using identical methods to those previously used for analysis of human MEG data, we demonstrate the validity of our prior results and explain the anomalous empty room results.PLOS Computational Biology ……1]…a powThe editors of We accept the principle of this criticism. If power law scaling can be demonstrated, by PLI or any other metric, in MEG data recorded from an empty room then this is conceptually problematic for interpretation of power law scaling in human MEG data as a marker of self-organized criticality, or any other complex biological dynamics.To assess the extent to which this criticism actually applies to the results reported by , we haveWe begin by clarifying exactly how the MEG data in Kitzbichler et al.  were colThe paper by Shriki et al.  reportedThus, it was clear, on close review of the methods used in the two papers, that the results were based on different pre-processing pipelines and somewhat different estimators of phase synchronization. In short, the two methods differed in detail and they were not exactly the same.To investigate the impact of these differences in MEG pre-processing and estimation of phase synchronization, we reanalysed the Cambridge and NIMH data previously reported by Shriki et al. using the methods implemented by Kitzbichler et al. Specifically, we used a pre-processing pipeline that optionally included notch filtering to remove line noise, and we used the wavelet-based estimator of PLI as originally proposed.Some of the results of this reanalysis are summarised in Specifically in relation to Dr Farmer’s comment that highlighted this issue and motivated our reanalysis of these data, we conclude that the methods and results reported by Kitzbichler et al. are not, in fact, compromised by the apparently problematic results reported by Shriki et al. The evidence for power law scaling of synchronization metrics in empty room data provided by Shriki et al. is not reproduced when exactly the same methods described by Kitzbichler et al. are applied to analysis of the empty room data reported by Shriki et al. We therefore consider that the observation of power law scaling in PLI measures on empty room data reported by Shriki et al.  does notCare should be taken when applying the PLI metric to new MEG data whose background noise structure may not be previously well understood. Standard pre-processing steps have to be applied, such as line-noise removal or signal-space separation, but one should be mindful of the fact that all of them also change the covariance structure of the data.More generally, we conclude from this analysis that it is indeed a useful “sanity check” to test any proposed method for MEG analysis on data recorded from an empty room. Consistency of results between empty room and human recordings may be indicative of a confounding effect of the instrumentation or analysis: in this case, the presence of low amplitude line noise substantially contributed to the existence of power law scaling in the empty room data reported by Shriki et al. . We also


This Research Topic presents knowledge on transition metal metabolism in various infections from the dual perspective of offender and defender.To date, the implication of divalent metals have been described in two different immune strategies that aim to fight microbial invaders. One consists in depriving microbes of essential divalent metals whereas the other aims at overloading invaders with toxic concentrations of metal. The contributions in this section present, in different situations, various aspects of this metal economy at the host-microbe interface.metal homeostasis as hosts interact with bacteria. Diaz-Ochoa et al.  a bacterium that does not require iron for its metabolism.Lastly, n et al.  review tn et al.  review Fn et al.  present 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.


Philosophical Transactions of the Royal Society.The summer of 2022 has seen remarkable hydrological conditions across much of the Northern Hemisphere. Europe has seen what could be the most severe drought conditions to hit the continent for more than 500 years , with exDrought risk in the Anthropocene—reflects the recognition that the Earth System is human-influenced to an extent that we are said to be living in a new geological era [et al.  [et al. (Using machine learning to identify novel hydroclimate states) [First, it is clear that droughts are profoundly human-influenced, and we expect them to be even more so in the future. The title of this themed issue—ical era . Droughtections)  explains states)  use a neet al. in [et al.  [Besides anthropogenic climatic changes, human activity has impacted the Earth's surface and catchments through land use change, urbanization and infrastructure construction. These changes have modified the ways in which meteorological droughts propagate into hydrological droughts. The expansion of irrigated agriculture and water use in cities and industries means that human water withdrawals are often the most significant drivers of water scarcity. Since the introduction of the concept of planetary boundaries by Rockström t al. in , there hndaries)  continueet al.'s article (Benchmark worst droughts during the summer monsoon in India) [et al.'s article  [et al.  [Second, the processes by which droughts materialize are extraordinarily complex. They vary enormously across space. Readers will obtain insights into the complexity of local processes by reading the basin-scale and regional analyses in this themed issue, including Mishra n India) , which estralia) , which asystems)  illustraet al.'s article examines the response of birds in the Murray-Darling Basin, which adds to ongoing debates in the literature on the ecological impacts of droughts. Ecosystems are naturally resilient to droughts, but when they are already degraded because of other anthropogenic impacts, extreme droughts may push ecosystems into a state from which they cannot recover—more research is required to establish under what conditions that hypothesis is true. This emphasizes the point that climate change needs to be viewed in the context of multiple stressors on the environment.Finally, droughts have multiple impacts and those impacts are profoundly modified by adaptation responses. Quentin Grafton Barbier's  review aet al.  [et al. [et al. [et al. [et al.  [This themed issue documents important scientific advances that are improving understandings of droughts and the evidence needed for drought management. There have been rapid advances in drought forecasting, which are documented in the paper by AghaKouchak casting) . These a [et al.  for anal [et al.  demonstr [et al.  applies hailand)  reports As one would expect from the Chief Executive of England's Environment Agency (which has responsibility for regulating the water environment and drought planning), Sir James Bevan's concluding article (Drought risk in the Anthropocene: from the jaws of death to the waters of life)  focuses


In the recent article by Thomas et al. , the autInfluence of vegetation structure, seasonality, and soil properties on rodent diversity and community assemblages in west Mount Kilimanjaro, TanzaniaThe authors apologize for the error.