Investigation of the frequencies of functionally signif icant gene variants in the context of medical biology and gene geography is a relevant issue for studying the genetic structure of human populations. The transition from a traditional to an urbanized lifestyle leads to a higher incidence of civilizational diseases associated with metabolic disorders, including type 2 diabetes mellitus. The goal of the present paper is to analyze the frequencies of functionally signif icant gene alleles in the metabolic prof iles of indigenous Siberian peoples to identify the gene pool resilience, evaluate the susceptibility of various ethnic groups to metabolic disorders under changing environmental conditions, and predict the epidemiological situation that may occur in the near future. The study was performed in the monoethnic samples of eastern and western Buryats, Teleuts, Dolgans, and two territorial groups of Yakuts. A real-time PCR was used to determine the frequencies of single nucleotide polymorphisms (SNPs) G103894T, rs12255372, and C53341T, rs7903146 in the TCF7L2 gene. The results obtained were compared to the frequencies identif ied for Russians from Eastern Siberia and the values available in the literature. The frequencies of the polymorphic variants studied in the samples from the indigenous Siberian peoples place them in between Caucasian and East Asian populations, following the geographicgradient of polymorphism distribution. A signif icantly lower occurrence of type 2 diabetes risk alleles TCF7L2 (103894T)and TCF7L2 (53341T) in the samples of indigenous Siberian peoples compared to Russians was observed, which agreeswith their lower susceptibility to metabolic disorders compared to the newcomer Caucasian population. Taking intoaccount urbanization, a reduced growth in type 2 diabetes incidence may be predicted in indigenous Siberian peoples,i. e. Buryats, Yakuts, Dolgans, and Teleuts, compared to the newcomer Caucasian population. A further study of populationstructure with respect to different metabolic prof ile genes is required to better understand the molecular geneticfoundations of the adaptive potential of indigenous Siberian peoples Investigation into the peculiarities of the population geneticstructure of ethnic groups in the context of medical biologyand gene geography is a relevant issue in human genetics. Tobetter understand molecular genetic foundations of adaptivepotential that ethnic groups develop as they evolve under specificclimatic and geographic conditions and adapt to specificdietary patterns, it is important to analyze the frequencies ofthe candidate gene alleles proven to be functionally significantbased on studies in individual populations.Type 2 diabetes mellitus (DM2) is among the leading mortalityand disability factors in a working-age population . DM2 is a metabolic syndrome componentand above that is linked to increased risk of multiple associatedpathological states, primarily including cardiovasculardiseases  andchronic renal failureIncretin hormone secretion defect, a key element of DM2pathogenesis, is associated with TCF7L2 gene polymorphismsince it is this gene’s product that regulates the production ofpancreatic β-cells from pluripotent stem cells and is involvedin glucose-stimulated insulin secretion .In addition, the gene also targets the brain, where TCF7L2determines the intensity of the anorexigenic effect and affectsthe central glucose homeostasis mechanism . In the liver, the gene is involved in the regulationof triglycerides and low- and very low-density lipoproteinexchange. It is also involved in gluconeogenesis and acts asan insulin resistance mediator .It was found that SNPs G103894T, rs12255372, andC53341T, rs7903146 in introns 3 and 4 of gene TCF7L2were associated with DM2 . The linkof TCF7L2 (103894T ) and TCF7L2 (53341T ) alleles withincreased risk of DM2 was demonstrated in a number ofpopulations around the world, including Russia . It was shown that the TCF7L2 (53341T )variant was linked to increased risk of DM2 compared toTCF7L2 (103894T ), with homozygous alleles showing highersusceptibility to the disease than heterozygous ones The TCF7L2 polymorphisms are also linked to BMI, totalbody fat volume, as well as subcutaneous and visceral fat. TCF7L2 (53341T )allele is associated with the risk of myocardial ischemia andmyocardial infarction as syntropic diseases with commonpathogenetic elements . Gene TCF7L2 is also linked to renal embryogenesis,i. e. its polymorphisms are associated with variousdegrees of chronic renal failure, a vascular complication ofDM2 . It was proved that TCF7L2 polymorphism inloci rs7903146 and rs12255372 was associated with risks ofgastric, breast, and colorectal cancer . The effect of natural selectionon locus rs7903146 in gene TCF7L2 was discovered and astatistically significant link between 53341Т allele frequencyand several climatic geographic factors was shown .Studies on the frequencies of gene alleles associated withthe risk of DM2 and other metabolic disorders in indigenousSiberian populations have remained relevant throughout therecent decade . However,the distribution of the polymorphic variants of functionallysignificant gene TCF7L2 in Siberian populations remainsunderstudied. Polymorphism frequencies in locus rs7903146for some Siberian peoples, including Buryats and Yakuts,were presented in . Unfortunately, theauthors did not indicate the area where genetic material wascollected, which seems necessary for these large heterogeneousethnic groups populating vast territoriesThe present paper reports the results of a study into thefrequencies of polymorphisms G103894T, rs12255372, andC53341T, rs7903146 in gene TCF7L2 associated with severaldiseases in the populations of indigenous Siberian ethnicgroups, namely Buryats, Teleuts, Yakuts and Dolgans, incomparison to Russians living in Siberia.The genetic material for the present research was collectedin the field in 2000–2006. Blood samples were taken fromapparently healthy volunteers under their informed consentand with the approval of the local healthcare authorities andthe Ethics Committee of the Institute of Cytology and Genetics,SB RAS. Before blood sampling, all volunteers filled ina special demographic questionnaire to specify their ancestors’nationalities down to 3 to 4 generations.The data obtained were used to form 7 population samplescovering Southern and Eastern Siberia. Persons of Buryatnationality with no outsider ancestors living in Alkhanay andOrlovsky settlements in the Aginsky Buryat Okrug (ABO) ofZabaykalsky Krai were included in the Eastern Buryat group (N = 132). Ethnic Buryats from settlements of Ekhirit-BulagatskyDistrict of Ust-Ordynsky Buryat Okrug (UOB) ofthe Irkutsk Region (N = 278) were included in the Westernsample. Also included in the study were Teleuts from the BelovoDistrict of the Kemerovo Region (N = 116). Two ethni-callyhomogeneous samples of Yakuts were formed as follows:the Nyurbinsky group included the residents of settlementsNyurbachan and Syultsy of the Nyurbinsky District(N = 109), and the Ust-Aldansky group – the residents of theDyupsya settlement of the Ust-Aldansky District (N = 100).The residents of the town of Dudinka and settlements Volochankaand Ust-Avam of the Taymyr Dolgan-Nenets Okrugof Krasnoyarsk Krai identifying as ethnic Dolgans were includedin the Dolgan sample (N = 180). The seventh samplecombined Russians from Zabaykalsky Krai and the IrkutskRegion (N = 133).DNA samples were isolated from the leukocyte fractionof venous blood using the BioSilica kits (Russia). Real-timeSNP genotyping in genes TCF7L2 and TCF7L2  was performed applyingcompeting TaqMan-probes complementary to polymorphicDNA segments. Primer and probe designs wereselected using the sequences available in the NCBI database(http://www.ncbi.nlm.nih.gov/) with UGENE  and Oligo Analyzer  software(Table 1).Amplification was performed in 25-μl final volume, themaster mix included 300 nM primers, 100 nM TaqMan probes,65 mM TrisHCl (рН 8.9), 16 mM (NH4)2SO4, 2.5 mM MgCl2,0.05 % Tween-20, 0.2 mM dNTP, 0.5–10 ng DNA, and 0.5 UTaq DNA polymerase . Reactionconditions were as follows: initial denaturation for 3 min at96 °С was followed by 46 cycles including denaturation at96 °С for 5 s, primer annealing, and extension at 61 °С for 30 s.Allele variant frequencies in the populations were determinedbased on observed genotype frequencies. The matchbetween empirically observed genotype frequency distributionand theoretically expected distribution at the Hardy–Weinbergequilibrium was tested using Pearson’s chi-squared (theequilibrium holds at p > 0.05). The statistical confidence ofallele frequency differences between the studied sampleswas evaluated using the chi-squared test with Yates continuitycorrection; the results were considered statisticallysignificant at p < 0.025 .Genotyping results for TCF7L2  and in samples of Buryats, Teleuts, Yakuts,Dolgans, and Russians from Eastern Siberia are presented inTable 2.The genotype distribution matched the Hardy–Weinbergequilibrium for all polymorphic loci and samples. The frequenciesof alleles TCF7L2 (103894T ) and TCF7L2 (53341T ) inthe studied samples and some ethnic groups described in theliterature , as well as comparisonof populations , are presented in Tables 3–4.It was shown that TCF7L2 (103894T ) allele frequency inthe Russians sample (23.1 %) matched that in other Caucasiangroups (22–37 %) . The frequencyin the studied samples of indigenous Siberian peoplesvaries from 5.4 % for Western Buryats to 9.5 % for Teleuts,with no statistically significant differences observed. However,the allele frequency in all samples of indigenous populationswas significantly lower than in Russians from Eastern Siberiaand other Caucasian groups described in the literature . At the same time, it was significantlyhigher than in several East Asian populations, i. e. Chinese andVietnamese. We could also see a significant difference betweenTeleuts and Japanese not observed for other studied groups.This in-between position of indigenous Siberian populations,as exemplified by Buryats and Teleuts, had been demonstratedearlier in the polymorphism frequencies of some other metabolicprofile genes .TCF7L2 (53341T ) allele frequency in the Russians sample(25.9 %) matched that in other Caucasian groups (23–40 %). The studied samples of indigenouspopulations showed a significantly lower value comparedto Russians varying from 4.5 % in Yakuts from the NyurbinskyDistrict to 11.3 % in Teleuts. Statistically significantdifferences were discovered between Teleuts and the sampleswith the lowest frequency values, namely Eastern Buryats(4.9 %) and Yakuts from the Nyurbinsky District. The data onTCF7L2 (53341T) allele frequency in the samples of Buryats(6.3 %) and Yakuts (4.3 %) resembling the results obtainedin our study were presented by Trifonova et al. (2020). Unfortunately,the authors did not indicate sample sizes and theparticipants’ places of residence, so confidence evaluationwas impossible to perform. The frequency values do not show significant differences between the samples of Eastern Buryatsand Yakuts from the Nyurbinsky District and the samples ofindigenous East Asian populations, namely Chinese, Japaneseand Vietnamese, available in the literature. Yakuts from theUst-Aldansky District demonstrated a significantly higherTCF7L2 (53341T ) allele frequency than Vietnamese, whileDolgans showed differences compared to some Chinesepopulations as well. Western Buryats and Teleuts showedsignificantly higher allele frequencies than all the East Asiansamples described in the literature. It was also shown thatthis polymorphism frequency in populations of indigenousSiberian peoples was significantly lower than in the Caucasiangroups described in the literature . Thus, TCF7L2 (53341T ) allele frequencies also confirmthe trend that places samples of indigenous Siberianpeoples in-between East Asian and Caucasian populationsInvestigation of the frequencies of functionally significantgene variants in the context of medical biology and genegeographyis a relevant issue for studying the population geneticstructure of indigenous Siberian peoples. In the presentpaper, we have determined the frequencies of the 103894Tand 53341T alleles in gene TCF7L2 associated with DM2 andother metabolic disorders in the populations of Buryats, Yakuts,Dolgans, and Teleuts, as well as a sample of Russians fromEastern Siberia. It was shown that these frequencies in Russiansfall within the same range as in other Caucasian populations.Meanwhile, the populations of indigenous Siberianethnic groups show significantly lower TCF7L2 (103894T )and TCF7L2 (53341T ) polymorphism frequencies, whichplaces them in-between Caucasian and East Asian populations.It was shown in several papers that indigenous Siberian andFar Eastern ethnic groups, as well as the ethnic groups from theEuropean part of Russia with a mongoloid component in theirgene pool, had lower incidence rates of metabolic syndromeand its DM2 component compared to Caucasians .It is primarily explained by the traditional lifestyle implyinga sufficient amount of physical activity and diet consistingmostly of animal source foods rich in proteins and fats withlimited carbohydrate component .Ethnic peculiarities in DM2 prevalence and manifestationsare also caused by distinctions from the European gene pool,i. e. a unique combination of frequencies of functionallysignificant genes developed as a result of adaptation to localenvironmental conditions . Differences in living conditions between indigenousand newcomer populations are alleviated due to urbanization,centuries-long traditions, and acquired dietary patterns change,and, as a result, civilizational diseases associated with metabolicdisorders, including DM2, become increasingly commonin indigenous populations . Investigation ofthe polymorphism distribution of the functionally significantgenes associated with risks of diseases in indigenous Siberianpopulations makes it possible to identify the gene pool resilience,evaluate the susceptibility of various ethnic groups tometabolic disorders under changing environmental conditions,and predict the epidemiological situation in the near future.Lower prevalence of DM2 among indigenous Siberianpopulations agrees with reduced populational frequencies ofstudied alleles TCF7L2 (103894T ) and TCF7L2 (53341T )associated with DM2 and several syntropic diseases, discoveredin the present paper. The reduced frequencies ofthese polymorphisms may affect the incidence rates of thediseases in the studied populations. With urbanization takeninto account, one might predict reduced growth in incidencerates of DM2 and other pathological states associated withstudied polymorphisms in indigenous Siberian ethnic groupscompared to newcomer Caucasians.The high frequency of TCF7L2 (53341T ) polymorphismin Teleuts from the Kemerovo Region compared to Buryatsand Yakuts may be attributed to a Caucasian component thatthis ethnic group adopted in their gene pool in the process offormation . With more comfortableliving conditions close to cities of Prokopyevsk, Kemerovo,and Novokuznetsk and a richer European-type diet, Teleutsmay face an increased risk of DM2 and associated diseases.Increased incidence of cardiovascular diseases has been observedin this ethnic group in recent decades . However, polymorphism frequencies of otherfunctionally significant genes are to be investigated to drawbetter-grounded conclusions.Ethnic peculiarities in the frequency distribution of polymorphismsin gene TCF7L2  and in the populations of Buryats, Yakuts,Dolgans, and Teleuts, as well as a sample of Russians fromEastern Siberia, have been studied in the present paper. Locusrs12255372 has been studied in various territorial groups ofBuryats and Yakuts for the first time, and the same goes forloci rs12255372 and rs7903146 in the Dolgan and Teleutpopulations. It has been shown that the samples of indigenousSiberian populations fall in-between Caucasian and East Asianpopulations with respect to studied polymorphism frequencies,following the geographic polymorphism distributiongradient.Significantly lower occurrence of TCF7L2 (103894T ) andTCF7L2 (53341T ) alleles associated with DM2 and othermetabolic disorders in the samples of indigenous Siberianpeoples compared to Russians was demonstrated, which agreeswith their lower susceptibility to metabolic disorders, includingDM2, compared to the newcomer Caucasian populationdescribed in the literature. With the transition to urbanizedlifestyle taken into account, one might predict reduced growthin incidence rates of DM2 and other pathological states associatedwith the studied polymorphisms in indigenous Siberianethnic groups, namely Buryats, Yakuts, Dolgans, and Teleuts,compared to newcomer Caucasians.To better understand the nature of ethnic differences, furtherinvestigation into population structure with respect to othermetabolic profile genes is required.The authors declare no conflict of interest.Ametov A.S., Kamynina L.L., Akhmedova Z.G. The clinical aspectsof effectiveness of incretin therapy (Wnt-pathogenic path and polymorphismof gene TCF7L2). Rossiyskiy Meditsinskiy Zhurnal =Medical Journal of the Russian Federation. 2016;22(1):47-51. DOI10.18821/0869-2106-2016-22-1-47-51. (in Russian)Anjum N., Jehangir A., Liu Y. Two TCF7L2 variants associated withtype 2 diabetes in the Han nationality residents of China. J. Coll.Physicians Surg. Pak. 2018;28(10):794-797.Asfandiyarova N.S. A review of mortality in type 2 diabetes mellitus.Sakharnyi Diabet = Diabetes Mellitus. 2015;18(4):12-21. DOI10.14341/DM6846. (in Russian)Avzaletdinova D.S., Sharipova L.F., Kochetova O.V., Morugova T.V.,Erdman V.V., Somova R.S., Mustafina O.E. The association ofTCF7L2rs7903146 polymorphism with type 2 diabetes mellitusamong Tatars of Bashkortostan. Sakharnyi Diabet = Diabetes Mellitus.2016;19(2):119-124. DOI 10.14341/DM2004138-45. (in Russian)Bairova T.A., Dolgikh V.V., Kolesnikova L.I., Pervushina O.A. Nutriciogeneticsand risk factors of cardiovascular disease: associated researchin Eastern Siberia populations. Byulleten’ VSNTs SO RAMN =Bulletin of the East Siberian Scientific Center SB RAMS. 2013;4(92):87-92. (in Russian)Baturin A.K., Sorokinа E.Yu., Pogozheva A.V., Keshabyants E.E., KobelkovaI.V., Kambarov A.O., Elizarova E.V., Tutelyan V.A. The associationof rs993609 polymorphisms of gene FTO and rs659366polymorphisms of gene UCP2 with obesity among Arctic Russianpopulation. Voprosy Pitaniya = Problems of Nutrition. 2017;86(3):32-39. (in Russian)Bennett C.N., Ross S.E., Longo K.A., Bajnok L., Hemati N., JohnsonK.W., Harrison S.D., MacDougald O.A. Regulation of Wntsignaling during adipogenesis. J. Biol. Chem. 2002;277(34):30998-31004. DOI 10.1074/jbc.M204527200.Bondar’ I.A., Filipenko M.L., Shabel’nikova O.Yu., Sokolova E.A.Rs7903146 variant of TCF7L2 gene and rs18012824 variant ofPPARG2 gene (Pro12Ala) are associated with type 2 diabetes mellitusin Novosibirsk population. Sakharnyi Diabet = Diabetes Mellitus.2013;4:17-22. DOI 10.14341/DM2013417-22. (in Russian)Cauchi S., El Achhab Y., Choquet H., Dina C., Krempler F., WeitgasserR., Nejjari C., Patsch W., Chikri M., Meyre D., Froguel P.TCF7L2 is reproducibly associated with type 2 diabetes in variousethnic groups: a global meta-analysis. J. Mol. Med. 2007;85(7):777-782. DOI 10.1007/s00109-007 0203-4.Cygankova D.P., Mulerova T.A., Ogarkov M.Yu., Saarela Ye.Yu., BarbarashO.L. Traditional lifestyle change as a reason for metabolicdisorders risk increase in residents of Gornaya Shoriya. ConsiliumMedicum. 2018;20(5):66-70. DOI 10.26442/2075-1753_2018.5. 66-71. (in Russian)Franceschini N., Shara N.M., Wang H., Voruganti V.S., Laston S.,Haack K., Lee E.T., Best L.G., MacCluer J.W., Cohran B., Dyer T.D., Howard B.V., Cole S.A., North K.E., Umans J.G. The association ofgenetic variants of type 2 diabetes with kidney function. Kidney Int.2012;82(2):220-225. DOI 10.1038/ki.2012.107.Hallmark B., Karafet T.M., Hsieh P.H., Osipova L.P., Watkins J.C.,Hammer M.F. Genomic evidence of local adaptation to climate anddiet in indigenous Siberians. Mol. Biol. Evol. 2018;36(2):315-327.DOI 10.1093/molbev/msy211.Han X., Luo Y., Ren Q., Zhang X., Wang F., Sun X., Zhou X., Ji L.Implication of genetic variants near SLC30A8, HHEX, CDKAL1,CDKN2A/B, IGF2BP2, FTO, TCF2, KCNQ1, and WFS1 in type 2diabetes in a Chinese population. BMC Med. Genet. 2010;11:81.DOI 10.1186/1471-2350-11-81.Haupt A., Thamer C., Heni M., Ketterer C., Machann J., Schick F.,Machicao F., Stefan N., Claussen C.D., Häring H.U., Fritsche A.,Staiger H. Gene variants of TCF7L2 influence weight loss and bodycomposition during lifestyle intervention in a population at risk fortype 2 diabetes. Diabetes. 2010;59(3):747-750. DOI 10.2337/db09-1050.Ievleva K.D., Bairova T.A., Sheneman E.A., Ayurova Zh.G.,Bal’zhieva V.V., Novikova E.A., Bugun O.V., Rychkova L.V.,Kolesnikova L.I. The protective effect of the G-allele of PPARG2rs1801282 polymorphism against overweight and obesity in Mongoloidadolescents. Zhurnal Mediko-Biologicheskikh Issledovaniy =Journal of Medical and Biological Research. 2019;7(4):452-463.DOI 10.17238/issn2542-1298.2019.7.4.452. (in Russian)Katsoulis K., Paschou S.A., Hatzi E., Tigas S., Georgiou I., Tsatsoulis A.TCF7L2 gene variants predispose to the development of type 2diabetes mellitus among individuals with metabolic syndrome.Hormones(Athens). 2018;17(3):359-365. DOI 10.1007/s42000-018-0047-z.Kaya E.D., Arikoğlu H., Kayiş S.A., Öztürk O., Gönen M.S. Transcriptionfactor 7-like 2 (TCF7L2) gene polymorphisms are strong predictorsof type 2 diabetes among nonobese diabetics in the Turkishpopulation. Turk. J. Med. Sci. 2017;47(1):22-28. DOI 10.3906/sag-1507-160.Kichigin V.A., Kochemirova T.N., Akimova V.P. Ethnic peculiarities inprevalence of cardiovascular risk factors in urban population. ActaMedica Eurasica. 2017;4:16-23. (in Russian)Kurtanov Kh.A., Sydykova L.A., Pavlova N.I., Filippova N.P., DodokhovV.V., Apsolikhova G.A., Solov’eva N.A., D’yakonova A.T.,Neustroeva L.M., Varlamova M.A., Borisova N.V. Polymorphismof the adiponutrin gene (PNPLA3) in the indigenous inhabitantsof the Republic of Sakha (Yakutia) with type 2 diabetes mellitus.Al’manakh Klinicheskoy Meditsiny = Almanac of Clinical Medicine.2018;46(3):258-263. DOI 10.18786/2072-0505-2018-46-3-258-263.(in Russian)Mel’nikova E.S., Rymar O.D., Ivanova A.A., Mustafina S.V., ShapkinaM.Ju., Bobak M., Maljutina S.K., Voevoda M.I., MaximovV.N. Association of polymorphisms of genes TCF7L2, FABP2,KCNQ1, ADIPOQ with the prognosis of the development of type 2diabetes mellitus. Terapevticheskiy arkhiv = Therapeutic Archive.2020;92(10):40-47. DOI 10.26442/00403660.2020.10.000393. (inRussian)Melzer D., Murray A., Hurst A.J., Weedon M.N., Bandinelli S., CorsiA.M., Ferrucci L., Paolisso G., Guralnik J.M., Frayling T.M.Effects of the diabetes linked TCF7L2 polymorphism in a representativeolder population. BMC Med. 2006;4:34. DOI 10.1186/1741-7015-4-34.Nobrega M.A. TCF7L2 and glucose metabolism: time to look beyondthe pancreas. Diabetes. 2013;62(3):706-708. DOI 10.2337/db12-1418.Orlov P.S., Kulikov I.V., Ustinov S.N., Gafarov V.V., Malyutina S.K.,Romashchenko A.G., Voyevoda M.I., Maksimov V.N. Associationanalysis of some single nucleotide polymorphism markers of thesecond type of diabetes with myocardial infarction. Byulleten’ SORAMN = Bulletin of Siberian Branch of Russian Academy of MedicalSciences. 2011;31(5):19-24. (in Russian)Ostaptseva A.V., Shabaldin A.V., Akhmatianova V.R., Minina V.I.,Glushkov A.N., Druzhinin V.G., Zorkoltseva I.V., Shabaldin E.V.,Glushkova O.A., Makarchenko O.S., Ageyeva T.N. Molecular geneticanalysis of interleukin 4 gene polymorphism among Teleutians,Shorians, and Caucasians of Kemerovo region. MeditsinskayaImmunologiya = Medical Immunology. 2006;8(5-6):737-740. (inRussian)Ovsyannikova O.V., Podkhomutnikov V.M., Kolbasko A.V., LuzinaF.A., Gus’kova E.V. Cardiovascular disease in rural Kuzbass aborigines– Teleut. Rossiyskiy Kardiologicheskiy Zhurnal = RussianJournal of Cardiology. 2007;6:59-62. (in Russian)Potapov V.A., Nosikov V.V., Shamkhalova M.N., Shestakova M.V., SmetaninaS.A., Bel’chikova L.N., Suplotova L.A. TCF7L2 rs12255372and SLC30A8 rs13266634 confer susceptibility to type 2 diabetes ina Russian population. Russ. J. Genet. 2010;46(8):1001-1008. DOI10.1134/S1022795410080132.Rosales-Reynoso M.A., Arredondo-Valdez A.R., Juárez-Vázquez C.I.,Wence-Chavez L.I., Barros-Núñez P., Gallegos-Arreola M.P., Flores-Martínez S.E., Morán-Moguel M.C., Sánchez-Corona J. TCF7L2and CCND1 polymorphisms and its association with colorectal cancerin Mexican patients. Cell Mol. Biol. 2016;62(11):13-20. DOI10.14715/cmb/2016.62.11.3.Saxena R., Gianniny L., Burtt N.P., Lyssenko V., Giuducci C., SjögrenM., Florez J.C., Almgren P., Isomaa B., Orho-Melander M.,Lindblad U., Daly M.J., Tuomi T., Hirschhorn J.N., Ardlie K.G.,Groop L.C., Altshuler D. Common single nucleotide polymorphismsin TCF7L2 are reproducibly associated with type 2 diabetes and reducethe insulin response to glucose in nondiabetic individuals. Diabetes.2006;55(10):2890-2895. DOI 10.2337/db06-0381.Sladek R., Rocheleau G., Rung J., Dina C., Shen L., Serre D., Boutin P.,Vincent D., Belisle A., Hadjadj S., Balkau B., Heude B., CharpentierG., Hudson T.J., Montpetit A., Pshezhetsky A.V., Prentki M.,Posner B.I., Balding D.J., Meyre D., Polychronakos C., Froguel P.A genome-wide association study identifies novel risk loci fortype 2 diabetes. Nature. 2007;445(7130):881-885. DOI 10.1038/nature05616.Smetanina S.A. Molecular-genetic and hormonal-metabolic associationsamong women of the Russian population of reproductive agewith obesity and early menarche. Meditsinskaya Nauka i ObrazovaniyeUrala = Medical Science and Education in Ural. 2015;2(1):126-129. (in Russian)Tabikhanova L.E., Osipova L.P., Voronina E.N., Bragin A.O., FilipenkoM.L. Polymorphism of lipid exchange genes in some populationsof South and East Siberia. Vavilovskii Zhurnal Genetiki i Selektsii =Vavilov Journal of Genetics and Breeding. 2019;23(8):1011-1019.DOI 10.18699/VJ19.578The 1000 Genomes Project Consortium. An integrated map of geneticvariation from 1,092 human genomes. Nature. 2012;491(7422):56-65. DOI 10.1038/nature11632.Timpson N.J., Lindgren C.M., Weedon M.N., Randall J., OuwehandW.H., Strachan D.P., Rayner N.W., Walker M., Hitman G.A.,Doney A.S., Palmer C.N., Morris A.D., Hattersley A.T., Zeggini E.,Frayling T.M., McCarthy M.I. Adiposity-related heterogeneity inpatterns of type 2 diabetes susceptibility observed in genome-wideassociation data. Diabetes. 2009;58(2):505-510. DOI 10.2337/db08-0906.Trifonova E.A., Popovich A.A., Bocharova A.V., Vagaitseva K.V.,Stepanov V.A. The role of natural selection in the formation of thegenetic structure of populations by SNP markers in association withbody mass index and obesity. Mol. Biol. 2020;54(3):349-360. DOI10.1134/S0026893320030176.Tsyretorova S.S., Bardymova T.P., Protasov K.V., Donirova O.S.,Mistyakov M.V. Ethnic features of diabetes mellitus and coronaryheart disease. Sibirskiy Meditsinskiy Zhurnal (Irkutsk) = SiberianMedical Journal (Irkutsk). 2015;136(5):15-21. (in Russian)Vikulova O.K., Zheleznyakova A.V., Lebedeva N.O., Nikitin A.G.,Nosikov V.V., Shestakova M.V. Genetic factors in the developmentof kidney chronic disease in patients with diabetes mellitus. Russ.J. Genet. 2017;53(4):420-432. DOI 10.1134/S1022795417030140.Xi B., Takeuchi F., Meirhaeghe A., Kato N., Chambers J.C., MorrisA.P., Cho Y.S., Zhang W., Mohlke K.L., Kooner J.S., Shu X.O.,Pan H., Tai E.S., Pan H., Wu J.Y., Zhou D., Chandak G.R., DIAGRAMConsortium, AGEN-T2D Consortium, SAT2D Consortium.Associations of genetic variants in/near body mass index-associatedgenes with type 2 diabetes: a systematic meta-analysis. Clin. Endocrinol.(Oxf .). 2014;81(5):702-710. DOI 10.1111/cen.12428.Zhang M., Tang M., Fang Y., Cui H., Chen S., Li J., Xiong H., Lu J.,Gu D., Zhang B. Cumulative evidence for relationships betweenmultiple variants in the VTI1A and TCF7L2 genes and cancer incidence.Int. J. Cancer. 2018;142(3):498-513. DOI 10.1002/ijc.31074.


Scientific Reports 10.1038/srep11362, published online 12 June 2015Retraction of: Fig. 1e HFD/p-Src lane 1 and 3;Fig. 4c NCD/Ve-cadherin lane 1 and 3Fig. 5e HFD+ APN/ICAM-1 lane 1 and 2Fig. 5f HFD/beta-catenin lane 2 and HFD+ APN/beta-catenin lane 1Fig. S1d HFD/beta-catenin all lanesFig. S4c NCD/beta-catenin lane 1 and 3.The Authors have retracted this Article. After publication of this Article, concerns have been raised about irregularities in the western blot data. In particular, the following bands appear to be duplicated:Additionally, the beta-catenin subpanel in Fig. 5f was subsequently reused in another study  and descDilip Shah, Nadan Wang, Benjamin T. Suratt, Jianxin Sun, Ying Zhu, Kenneth Walsh and Ross Summer agree to this retraction. Freddy Romero, Bishnuhari Paudyal and Caleb B. Kallen have not responded to any correspondence from the editor or publisher about this retraction. The Publisher has not been able to obtain a current email address for Michelle Duong.


Scientific Reports 10.1038/s41598-021-84517-x, published online 04 March 2021Correction to: The original version of this Article contained an error in Reference 32, which was incorrectly given as:et al. Exogenic basalt on asteroid (101955) Bennu. Nat. Astron. https://doi.org/10.1038/s41550-020-1195-z (2020).DellaGiustina, D. N. The correct reference is listed below:et al. Variations in color and reflectance on the surface of asteroid (101955) Bennu. Science370, abc3660. https://doi.org/10.1126/science.abc3660 (2020).DellaGiustina, D. N. The original Article has been corrected.


T and H16/1AT, of Gram-stain-positive, coagulase-negative staphylococci were isolated from separate healthy domestic dogs in Scotland. Both strains were genome sequenced and their inferred DNA–DNA hybridisation indicates that H8/1T and H16/1AT represent two novel species of the genus Staphylococcus. On the basis of the results of genome sequence analysis  H8/1T is most closely related to Staphylococcus devriesei and H16/1AT most closely related to Staphylococcus felis. Also, average nucleotide identity distinguished H8/1T and H16/1AT from S. devriesei and S. felis as did minor phenotypic differences. On the basis of these results, it is proposed that H8/1T and H16/1AT represent novel species with the respective names Staphylococcus caledonicus and Staphylococcus canis. The type strain of S. caledonicus is H8/1T (=NCTC 14452T=CCUG 74789T). The type strain of S. canis is H16/1AT (=NCTC 14451T=CCUG 74790T)Two strains, H8/1 Staphylococcus  before plating onto mannitol salt agar (Oxoid) and then incubation at 37 °C for 24 h. Both isolates are Gram-stain-positive, catalase-positive cocci and were whole-genome sequenced using HiSeq technology (Illumina) with 2×250 bp paired-end reads, read trimming and assembly . Reads were trimmed using Trimmomatic version 0.30 [de novo using SPAdes version 3.7 [https://tygs.dsmz.de/) [Staphylococcus. The TYGS phylogenetic tree generated by the Genome blast Distance Phylogeny approach (GBDP) indicated that H8/1T is most closely related to, but distinct from Staphylococcus devriesei CCUG 58238T with H16/1AT most closely related to, but distinct from Staphylococcus felis DSM 7377T  values calculated with the Type (Strain) Genome Server using the recommended settings of the Genome-to-Genome Distance Calculator (GGDC) 2.1 [blast (ANIb) [S. caledonicus H8/1T with S. devriesei CCUG 58238T. Divergence between ANI and tetranucleotide signature correlation index has been described previously with a possible explanation being that evolutionary or environmental forces may impede modifications in this genome signature despite genetic drift occurring [Staphylococcus was generated using CSI Phylogeny 1.4 [Staphylococcus aureus DSM 20231T as the reference genome, this analysis produced a single-nucleotide polymorphism tree comprising 19637 nucleotide positions  Genome Server (TYGS) (smz.de/) . The resSM 7377T . A 16S rS. felis . Althougparisons . Indeed,GDC) 2.1  and by At (ANIb) , MUMmer t (ANIb)  and the t (ANIb)  (Table 1t (ANIb) . With ont (ANIb)   according to the manufacturer’s instructions alongside the type strains of S. devriesei DSM 25293T and S. felis DSM 7377T  and for DNAse activity using DNAse agar (Oxoid). In each case, both H8/1T and H16/1AT tested negative for these activities.Phenotypic characterisation of H8/1SM 7377T . H8/1T i. felis, . AdditioT and H16/1AT were susceptible to all the antimicrobials tested, which were as follows: amoxicillin/clavulanic acid, benzylpenicillin, cefovecin, cefoxitin (screen), ceftiofur, chloramphenicol, clindamycin, doxycycline, enrofloxacin, erythromycin, gentamicin, inducible clindamycin resistance, kanamycin, marbofloxacin, neomycin, nitrofurantoin, oxacillin, pradofloxacin, tetracycline and trimethoprim/sulfamethoxazole. No known antimicrobial resistance genes (perfect and strict hits) were identified in either H8/1T and H16/1AT on using The Comprehensive Antibiotic Resistance Database (CARD) (https://card.mcmaster.ca/) [Antimicrobial sensitivity testing was performed using the Vitek2 system (bioMérieux) according to the manufacturer’s instructions. Using the AST-GP80 card and applying the CLSI 2017 interpretations for coagulase-negative staphylococci, both H8/1ter.ca/) .Staphylococcus caledonicus , the country where the type strain was isolated).d-glucose, d-fructose, maltose, trehalose, d-mannitol and sucrose but not from d-mannose, lactose, xylitol, melibiose, raffinose, d-xylose, methyl α-d-glucopyranoside or N-acetylglucosamine. Has arginine dihydrolase activity and is able to reduce nitrates to nitrites. Catalase-positive and negative for clumping factor, coagulase and DNAse.Gram-stain-positive, non-spore forming, facultative anaerobe, forms non-pigmented, smooth, circular colonies about 1–2 mm in diameter with entire margins on Columbia horse blood agar after 18 h incubation at 37 °C. Able to produce acid from S. caledonicus, H8/1T (=NCTC 14452 T=CCUG 74789T), was isolated from a healthy dog in Scotland during 2018. The draft genome of H8/1T is 2 503 367 bases in length with a DNA G+C content of 33.6 mol%, it comprises 38 contigs with an average coverage of approximately 85-fold. The genome sequence data from H8/1T is available under these accession numbers: BioSample, SAMN15065541; Sequence Read Archive, SRR11909362; and assembly, JABTXV000000000.The type strain of Staphylococcus canis .d-glucose, d-fructose, d-mannose, maltose, lactose, trehalose and d-mannitol but not from xylitol, melibiose, raffinose, d-xylose, sucrose or methyl α-d-glucopyranoside. Has alkaline phosphatase and urease activity and is able to reduce nitrates to nitrites. Catalase-positive and negative for clumping factor, coagulase and DNAse.Gram-stain-positive, non-spore forming, facultative anaerobe, forms non-pigmented, smooth, circular colonies about 1–2 mm in diameter with entire margins on Columbia horse blood agar after 18 h incubation at 37 °C. Able to produce acid from Staphylococcus canis, H16/1AT (=NCTC 14451T=CCUG 74790T), was isolated from a healthy dog in Scotland during 2018. The draft genome of H16/1AT is 2 229 149 bases in length with a DNA G+C content of 34.8 mol%, it comprises 143 contigs with an average coverage of approximately 92-fold. The genome sequence data from Staphylococcus canis H16/1AT is available under these accession numbers: BioSample, SAMN14548534; Sequence Read Archive, SRR11498036; and assembly, JABANU000000000.The type strain of Click here for additional data file.


None showed focal spasm that exclusively involved DCB-treated lesions. Among 27 patients with vasospastic features, DCB-treated segments showed less vasoconstriction than spastic counterparts (p < 0.001). A total of 110 DCB-treated lesions were analyzed to assess vasomotor function. Vasomotor function, defined as a combined constrictor and dilator response, was comparable between DCB-treated and angiographically normal segments (p = 0.173), while significant differences were observed against spastic counterparts (p < 0.001). In our study, DCB-treated lesions were not particularly vulnerable to vasospasm and were found to have vasomotor function similar to angiographically normal segments, supporting safety of DCB-only strategy in treating de novo native coronary lesions.Balloon-injured coronary segments are known to harbor abnormal vasomotion. We evaluated whether de novo coronary lesions treated using drug-coated balloon (DCB) are prone to vasospasm and how they respond to ergonovine and nitrate. Among 132 DCB angioplasty recipients followed, 89 patients underwent ergonovine provocation test at 6–9 months follow-up. Within-subject ergonovine- and nitrate-induced diameter changes were compared among three different sites: DCB-treated vs. angiographically normal vs. segment showing prominent vasoreactivity (spastic). No patient experienced clinically refractory vasospastic angina or symptom-driven revascularization during follow-up. Ergonovine induced vasospasm in seven patients; all were multifocal spasm either involving ( Drug-coated balloon (DCB) angioplasty is an emerging treatment approach for obstructive coronary artery disease (CAD). It has demonstrated its safety and efficacy in the treatment of in-stent restenosis and small vessel CAD and, currently, many on-going trials are exploring its value in a broader range of lesions ,2,3. ThePercutaneous transluminal coronary angioplasty (PTCA), including plain old balloon angioplasty (POBA) or stenting, unavoidably results in significant vascular injury, leading to a variety of deleterious consequences, such as dissection, thrombus formation, impairment of physiologic vasomotion, and restenosis . In partThis prospective all-comers study evaluated all patients with significant CAD who received percutaneous coronary intervention (PCI) with DCB-only angioplasty, concomitant DCB angioplasty and POBA, or concomitant DCB angioplasty and drug-eluting stent (DES) implantation for de novo lesions in the native coronary arteries at the Korea University Ansan Hospital between July 2019 and December 2020. The patients with a life expectancy shorter than 2 years and those who refused to provide their consent were excluded. DCB angioplasty was performed in accordance with the recent recommendations . SpecifiThe presence of significant vasospasm and coronary artery vasomotor function were assessed via intracoronary injection of ergonovine and isosorbide dinitrate . All par-Constrictor response (%):  after ergonovine administration—MLD after nitrate administration)/MLD after nitrate administration × 100-Dilator response (%): (MLD after nitrate administration—MLD at baseline)/MLD at baseline × 100Coronary spasm was defined as transient, total, or near-total occlusion (>90%) of a coronary artery as recommended . Spasm wThe reference vessel diameter (RVD), measured at the proximal and distal portions of each segment of interest, was used to calculate the diameter stenosis (DS) for quantitative comparative analysis. Segments with a percent change of >50% after the ergonovine provocation test were considered to have significant vasoconstriction, and patients who had at least one or more coronary segments showing significant vasoconstriction (>50%) were considered to have vasospastic features.Vasomotor response to ergonovine and isosorbide dinitrate was compared among three different segments: DCB-treated segments, angiographically normal arterial segments (control), and segments showing prominent vasoconstrictive response to ergonovine (spastic) . The cont-test. Ergonovine-induced percent diameter changes (constrictor response) between DCB-treated vs. spastic segments were compared using paired t-test or Wilcoxon signed-rank test based on normality test. Differences in combined constrictor and dilator responses across the three segments were analyzed using general linear model two-way repeated measures analysis of variance (ANOVA). Repeated measures ANOVA incorporated the Bonferroni test for pair-wise comparison. Statistical analyses were performed using the SPSS software . Statistical significance was set at p-values of <0.05.Continuous variables are expressed as means ± standard deviations and dichotomous variables as counts and percentages. Differences in MLD between baseline and after drug administration were analyzed using a paired A total of 132 patients who underwent DCB angioplasty for de novo native coronary lesions were analyzed. Clinical characteristics of the study population is described in During the median follow-up period of 18.5 months, two patients underwent repeated PCI due to recurrent ACS; one patient presented with unstable angina due to a de novo stenotic lesion in the treated vessel (2 months post-PCI); and one patient presented with non-ST elevation myocardial infarction due to post-POBA restenosis of the proximal right coronary artery but whose DCB-treated proximal left anterior descending artery remained patent. Albeit asymptomatic, three patients underwent redo DCB angioplasty owing to post-DCB angioplasty restenosis and one patient underwent DCB angioplasty owing to a newly-developed lesion at the follow-up angiography. One patient complained a sublingual nitroglycerin-responsive, alcohol-related nocturnal chest pain during the follow-up. His symptom was controlled by prescribing calcium channel blocker and oral nitrates, and he later showed ergonovine-induced multifocal vasospasm at the follow-up angiography . In summAmong 132 enrollees, patients who underwent 6–9 months of follow-up invasive coronary angiography and those excluded for the ergonovine provocation test are summarized in the CONSORT flow diagram in p = 0.069; DS (%): 27.64 ± 10.07 vs. 31.46 ± 13.64, p = 0.498]. However, ergonovine-induced constrictor response (%) was significantly lower in the DCB-treated segments than in the spastic segments : 24.19 ± 0.97 vs. 24.66 ± 12.53, p = 0.845).In seven patients with documented vasospasm, RVD and DS were similar between eight DCB-treated segments and their spastic counterparts [DCB-treated vs. spastic: RVD (mm): 2.98 ± 0.56 vs. 2.61 ± 0.37, p < 0.001; DS (%): 12.72 ± 7.14 vs. 24.21 ± 8.59 vs. 17.56 ± 10.45, p < 0.001). DCB-treated segments showed similar RVD (p > 0.999), but greater DS compared to spastic segments (p < 0.001).A total of 274 segments  from 82 patients were analyzed after excluding those from seven vasospasm cases. Angiographic characteristics of the analyzed segments are presented in p < 0.001; DCB-treated: 1.90 ± 0.42 vs. 1.58 ± 0.41, p < 0.001; spastic: 1.94 ± 0.46 vs. 1.37± 0.44, p < 0.001, p < 0.001; DCB-treated: 1.90 ± 0.42 vs. 2.06 ± 0.40, p < 0.001; spastic: 1.94 ± 0.46 vs. 2.22 ± 0.47, p < 0.001, After ergonovine administration, most segments showed significant constriction [MLD (mm): baseline vs. ergonovine: control: 2.54 ± 0.57 vs. 2.20 ± 0.57, Intriguingly, some DCB-treated segments were found to be unaffected by ergonovine. 35.5% (39 out of 110) of DCB-treated segments had a diameter of at least 20% greater than the adjacent arterial portions after ergonovine administration . These cp < 0.001, p = 0.173), while these were significantly greater in the spastic segments than in the DCB-treated and control segments (control vs. spastic: p < 0.001; DCB-treated vs. spastic: p < 0.001, Vasomotor function, as comprehensively assessed as a combined constrictor and dilator response, was analyzed using repeated measure ANOVA. Within-subject difference in the ergonovine- and nitrate-induced serial percent diameter changes was statistically significant across the three segments (ergonovine vs. nitrate: control: −18.78 ± 10.45 vs. 7.79 ± 8.48; DCB-treated: −22.95 ± 15.57 vs. 9.36 ± 10.73; spastic: −37.03 ± 17.56 vs. 15.55 ± 15.19, Coronary artery spasm is not only a functional abnormality of the coronary artery, causing transient, reversible myocardial ischemia, but it indeed plays a role in the pathogenesis of ACS . A previThe introduction of metallic stents was a major breakthrough in overcoming the limitations of PTCA, such as abrupt vessel closure, acute recoil, dissection, and vasospasm. However, permanent vessel caging by metallic implants constitutes barriers to physiological vasomotion and expansile vessel remodeling. Further, DESs implantation produces prolonged endothelial dysfunction in stented artery  and, as The mechanisms underlying the observed favorable findings may be multifactorial. Ergonovine, an ergot derivative, exerts vasoconstrictive effects by stimulating alpha-adrenergic and serotonin receptors  and inhiThis study is limited by a relatively small population. Angiographically normal segments, not evidenced by intravascular imaging, may harbor atherosclerosis. Unlike acetylcholine affecting both the endothelium and vascular smooth muscle, the ergonovine effect primarily represents endothelium-independent constriction . Thus, oAbnormal coronary vasomotion, as invasively assessed using intracoronary vasoactive substances, is an independent prognosticator for adverse cardiovascular events ,30. Thus


Muti HS, Heij LR, Keller G, et al. Development and validation of deep learning classifiers to detect Epstein-Barr virus and microsatellite instability status in gastric cancer: a retrospective multicentre cohort study. Lancet Digit Health 2021; published online Aug 17. https://doi.org/10.1016/S2589-7500(21)00133-3—In figure 2A of this Article, the colours were missing. This correction has been made as of Aug 19, 2021.


Streptomyces sp. HO1518. A total of ninety-eight aminooligosaccharides, including eighty potential new compounds, were detected mainly based on the characteristic fragment ions originating from quinovosidic bond cleavages in their molecules. Following an LC-MS-guided separation technique, seven new aminooligosaccharides (10–16) along with four known related compounds (17–20) were obtained directly from the crude extract of strain HO1518. Compounds 10–13 represent the first examples of aminooligosaccharides with a rare acarviostatin II02-type structure. In addition, all isolates displayed considerable inhibitory effects on three digestive enzymes, which revealed that the number of the pseudo-trisaccharide core(s), the feasible length of the oligosaccharides, and acyl side chain exerted a crucial influence on their bioactivities. These results demonstrated that the UPLC-QTOF-MS/MS-based metabolomics approach could be applied for the rapid identification of aminooligosaccharides and other similar structures in complex samples. Furthermore, this study highlights the potential of acylated aminooligosaccharides with conspicuous α-glucosidase and lipase inhibition for the future development of multi-target anti-diabetic drugs.A rapid and sensitive method using ultra-high performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS/MS) was applied for the analysis of the metabolic profile of acarviostatin-containing aminooligosaccharides derived from  Acarbose, a typical anti-diabetes drug functioning as an α-glucosidases inhibitor, potently inhibits the α-glucosidases in vivo to retard carbohydrate digestion and avoid blood glucose elevation +; HRESIMS: m/z 1273.4938 [M + H]+ .Acarviostatin II02 : White amorphous powder, c 1.01, H2O). UV (H2O) end absorption; IR νmax 3337, 1726, 1407, 1149, 1026 cm−1. 1H (500 MHz) and 13C (125 MHz) NMR spectroscopic data, see m/z 1329 [M + H]+; HRESIMS: m/z 1329.5234 [M + H]+ .D6-O-Isobutyryl-acarviostatin II02 : White amorphous powder, c 1.02, H2O). UV (H2O) end absorption; IR νmax 3329, 1721, 1365, 1147, 1014 cm−1. 1H (500 MHz) and 13C (125 MHz) NMR spectroscopic data, see m/z 1343 [M + H]+; HRESIMS: m/z 1343.5365 [M + H]+ .D6-O-Isovaleryl-acarviostatin II02 : White amorphous powder, c 0.99, H2O). UV (H2O) end absorption; IR νmax 3305, 1647, 1407, 1150, 1013 cm−1. 1H (500 MHz) and 13C (125 MHz) NMR spectroscopic data, see m/z 1357 [M + H]+; HRESIMS: m/z 1357.5520 [M + H]+ .D6-O-Propionyl-acarviostatin II03 : White amorphous powder, c 0.90, H2O). UV (H2O) end absorption; IR νmax 3304, 1734, 1402, 1148, 1023 cm−1. 1H (500 MHz) and 13C (125 MHz) NMR spectroscopic data, see m/z 1491 [M + H]+; HRESIMS: m/z 1491.5727 [M + H]+ .D6-O-Butyryl-acarviostatin II03 : White amorphous powder, c 0.53, H2O). UV (H2O) end absorption; IR νmax 3324, 1729, 1568, 1149, 1024 cm−1. 1H (500 MHz) and 13C (125 MHz) NMR spectroscopic data, see m/z 1505 [M + H]+; HRESIMS: m/z 1505.5872 [M + H]+ .D6-O-2-Methyl-butyryl-acarviostatin II03 : White amorphous powder, c 1.03, H2O). UV (H2O) end absorption; IR νmax 3303, 1645, 1406, 1149, 1014 cm−1. 1H (500 MHz) and 13C (125 MHz) NMR spectroscopic data, see m/z 1519 [M + H]+; HRESIMS: m/z 1519.6039 [M + H]+ .D6-9–20 were conducted based on a previously reported method. Commercial α-amylase inhibitor acarbose was used as the positive control [The PPA inhibitory activities of compounds 9–20 was evaluated according to the previously reported method. Acarbose was also used as the positive control [The sucrase inhibition assay of compounds  control .9–20 was performed according to the method outlined by McDougall et al. with slight modification [The lipase inhibition assay of compounds fication . Orlistax: 4.342 Å; y: 24.299 Å; z: 47.471 Å) and the grid box dimensions (30 × 30 × 30 Å) were set. The results of molecular docking were evaluated on the basis of the binding energy, criteria of binding structure, and possible interactions between ligand and the critical catalytic triad of protein 1LPB.The molecular docking simulations were performed by AutoDock Vina software, version 1.5.7 . The cryStreptomyces sp. HO1518. A total of ninety-eight aminooligosaccharides, including eighty new compounds, were detected and characterized from the extract of stain HO1518. Among them, twenty structural intriguing oligomers that ended with the 4-amino-4-deoxy-D-quinovopyranose unit at the non-reducing terminus were reported for the first time. The subsequent MS-guided fractionation method resulted in the isolation of seven new oligosaccharides (10–16) and four known analogs (17–20). Notably, compounds 10–13 are the first reported examples of oligosaccharides with a rarely occurring acarviostatin II02-type structure. All the compounds exhibited significant inhibitory activities against three digestive enzymes, among which compounds 9–16, 19 and 20 sharing two pseudo-trisaccharides were the most effective inhibitors of α-amylase and lipase. Furthermore, primary structure-activity relationships of 9–20 revealed that the number of the pseudo-trisaccharide core and acyl side chain play pivotal roles in their biological activity, which was evidenced by molecular docking analysis. These results of this study highlighted the advantages of UPLC-QTOF-MS/MS for the rapid structural identification of oligosaccharides, and this strategy could be extended to other investigations for high-throughput analysis of natural products with similar structures. More importantly, this study not only provided new lead compounds for further scientific research towards anti-diabetic drug discovery, but also shed light on the structural optimization of aminooligosaccharides analogs for medicinal scientists.In summary, the hyphenated system UPLC-QTOF-MS/MS that could provide qualitative retention time and reliable mass spectrometry information was utilized to reveal the metabolic profiling of aminooligosaccharides secreted by


Burkholderia spp. is an opportunistic pathogen associated with respiratory infections. Cefiderocol (CFDC), a siderophore cephalosporin approved in US and EU, is active in vitro against carbapenem-resistant Gram-negative bacteria including Burkholderia spp. This study examined in vitro and in vivo activity of CFDC against Burkholderia spp.Burkholderia spp. collected in 2014 - 2019 in 13 countries were determined by broth microdilution method according to CLSI guidelines. Only for CFDC, iron-depleted CAMHB was used. In a rat lung infection model, B. cepacia ATCC 25416  was used. Male CD  rats were infected by intrabronchial inoculation of the bacterial suspension including 1% nutrient agar. The humanized PK in plasma by administration of CFDC 2 g every 8 h (3-h infusion) and MEM 1 g every 8 h (0.5-h infusion) were recreated via the continuous intravenous infusion for 4 days, and the viable cfu in lungs were counted.MICs of CFDC and 13 marketed antibacterial drugs against 462 clinical isolates of 50/MIC90 of ≤ 0.031/1 µg/mL, which was the lowest among the tested antibiotics. Among 185 MEM non-susceptible isolates, 94% of the isolates exhibited ≤ 4 µg/mL of CFDC MIC. In a rat lung infection model, CFDC and MEM showed bactericidal activity with 2.8 and 2.4 log10 CFU/lung decrease compared with non-treated control, respectively. By recreating the humanized PK exposure in this model, 100% and ca.35% of fT >MIC of CFDC and MEM in plasma has been achieved, respectively. The bactericidal activities of both compounds vs B. cepacia ATCC 25416 would be reasonable because the fT >MIC achieved in this model exceeds the target fT >MIC  required to cause 1 log10 reduction in murine thigh infection models1,2). Against 462 strains, including 185 MEM non-susceptible isolates, CFDC showed MIC1) M. Sabet. 2019. AAC 2) R. Nakamura. 2019. AACIn vitro activity of CFDC and comparator agents against Burkholderia spp.Burkholderia spp. In critically ill patients, the recommended dosing regimen achieves 100% of fT >MIC of ≤ 4 ug/mL3).3) N. Kawaguchi. 2021. AACCFDC has potential for treating respiratory tract infections caused by Merime Oota, BSc, Shionogi TechnoAdvance Research & Co., Ltd. (Employee) Toriko Yoshitomi, -, Shionogi TechnoAdvance Research & Co., Ltd. (Employee) Rio Nakamura, BSc, Shionogi TechnoAdvance Research & Co., Ltd. (Employee) Miki Takemura, MS, SHIONOGI & CO., LTD. (Employee) Yoshinori Yamano, PhD, Shionogi (Employee) Meredith Hackel, PhD MPH, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Daniel F. Sahm, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor)


Hospitalized COVID-19 patients tend to be older and frequently have hypertension, diabetes or CHD, but whether these co-morbidities are more common than in the general older population is unclear. We estimated associations between pre-existing diagnoses and hospitalized COVID-19 alone or with mortality . In 269,070 UK Biobank participants aged 65+, 507 (0.2%) became COVID-19 hospital inpatients, of which 141 (27.8%) died. Common preexisting co-morbidities in hospitalized inpatients were hypertension (59.6%), history of falls/fragility fractures (29.4%), CHD (21.5%), T2 diabetes (19. 9%) and asthma (17.6%). However, in adjusted models, pre-existing diagnoses of dementia, T2 diabetes, COPD, pneumonia, depression, atrial fibrillation and hypertension emerged as independent risk factors for COVID-19 hospitalization, the first five remaining statistically significant for related mortality. There are specific high risk pre-existing co-morbidities for COVID-19 hospitalization and deaths in community based older men and women.


The dependences of the crystal structure of CrAs on temperature (30–400 K) and on pressure (0–9.46 GPa) are reported. The investigation shows twinning accompanying the temperature-induced isosymmetrical phase transition and the existence of a distinct Cr–Cr distance within the structure showing anomalous behavior. TN = 267 K can induce a change in the microstructure by twinning due to a crossing of the orthohexagonal setting of the unit-cell parameter ratio c/b. Within the crystal structure, one particular Cr–Cr distance exhibits anomalous behavior in that it is nearly unaffected by temperature and pressure in the paramagnetic phase, which is stable above 267 K and at high pressures. The distinction of this shortest Cr–Cr distance might be of importance for the superconducting properties of CrAs.The crystal structure of CrAs was investigated using synchrotron X-ray single-crystal diffraction for separate dependences on temperature (30–400 K) and on pressure (0–9.46 GPa). The isosymmetrical magnetostructural phase transition at  The iderk Fig. 1.aCmcm, with a′ = ahex, b′ = c′ = chex. A slight displacement of the atomic positions leads to the loss of the C-centering and the symmetry reduction to space group Pmcn following the P63/mmc→Cmcm→Pmcn group–subgroup relation  are of second order, the low-temperature transitions in MnP (from the ferro- to the helimagnetic state) and in CrAs are of first order and accompanied by abrupt changes in the unit-cell parameters, though the precise changes in MnP are controversial  at about 33 GPa at very low temperatures   on the kappa diffractometer  equipped with a Pilatus CdTe 1M area detector.For the measurements in the range 35–275 K at ambient pressure, the temperatures were set using a Cryocool G2b-LT helium gas jet cryostat.et al., 1986The high-pressure measurements to 9.5 GPa at room temperature were carried out using several diamond anvil cells, each pre-loaded with a CrAs single crystal, a ruby chip, and a 4:1 methanol–ethanol mixture as pressure-transmitting medium. The pressure during all measurements in diamond anvil cells was determined using the ruby luminescence method  showed no significant difference in the overall quality of the fit. However, refinement of the parameters yCr and yAs, which are fixed to ¼ in Pnma but free in Pn21a, show that within the errors they do not deviate from the centrosymmetric value ¼ in the whole temperature range. This observation is similar to the findings of Selte & Kjekshus , the observed diffraction patterns exhibit extinction rules that are in accordance with space groups us 1973b regardin3.2.aTN, the structural phase transition is clearly visible from the large abrupt changes of all unit-cell parameters. The relative changes on cooling Δa/a ≃ −0.40%, Δb/b ≃ +3.51%, Δc/c ≃ −0.83% and ΔV/V ≃ +2.25% confirm the previous observations from the literature. Below the transition temperature, the unit-cell parameters change smoothly; a and c decrease in a comparable way, b first increases and eventually stays nearly constant below about 200 K, where due to the lack of further change in b, the volume V is dominated by the behavior of a and c  Å, b = 3.467 (2) Å, c = 6.200 (3) Å and V = 121.4 (1) Å3. The fitted unit-cell volume at zero pressure, the bulk modulus and the first derivative of the bulk modulus are V0 = 121.3 (2) Å3, B0 = 28 (4) GPa and B0′ = 36 (5), respectively. Compared to other MnP-type compounds [e.g. MnP: B0 = 116 (12) GPa, B0′ = 4.2 (8)  GPa, B0′ = 4  GPa, B0′ = 8.8 (33) . In addition to the standard refinements with harmonic atomic displacement parameters (ADPs), refinements with anharmonic ADPs were carried out, as this was suggested by a visual inspection of the Fobs density maps. The resulting parameters show consistently that around the transition temperature the displacement parameters of the atoms show a significant anharmonicity, indicating that around and during the phase transition, the atoms show increased and anharmonic movement around their mean positions or that there is an increased degree of static disorder of the atoms which are slightly moved away from their highly symmetrical special positions.This formation of twin domains during the phase transition is furthermore coupled to increased displacement parameters of the atoms , as the Cr atoms carry the magnetic moment and they and their interactions are of particular importance for the magnetic and eventually superconducting properties. Above the phase transition, the distances CrI–CrI and CrI–CrIV follow the general trend and increase with temperature. However CrI—CrII, the strongest covalent Cr—Cr bond and strongest homoatomic interaction, is remarkable as it shows anomalous behavior in that it stays constant above TN. At the phase transition, the same distinction between the three Cr–Cr distances is seen. Here, CrI–CrI and CrI–CrIV increase (upon cooling) due to the phase transition, while CrI–CrII, the shortest Cr–Cr distance, decreases even further. CrI–CrI directly determines the length of the b axis of the unit cell, so that its increase is equivalent to the observed discontinuity in the temperature dependence of the b unit-cell parameter. CrI–CrIV, lying almost in the bc plane, increases as well. The decrease in CrI–CrII, which is oriented approximately along the a axis, leads to the abrupt shortening of this axis. Besides this decrease in the distance CrI–CrII, the transition is also accompanied by a slight straightening of the CrI–CrII–CrI chains  and the ∠CrI–CrII–CrI angle gets closer to the ideal value of 180°. CrI–CrII thus shows two distinctions: decreasing at TN and staying constant above TN. Below the transition, CrI–CrII and CrI–CrIV decrease with temperature, while CrI–CrI increases and is eventually constant below about 200 K.The most interesting distances in the CrAs structure are the Cr–Cr distances  – which decrease during the phase transition .In CrAs on compression, all Cr–As and Cr–Cr distances decrease with the exception of CrII Fig. 7, which ins Fig. 8 and the 4.et al.  and also in good agreement with those reported by Selte et al.  with the MnP-type structure shows that at least the behavior of the relevant interatomic T–T distances on compression are similar  global, Synchrotron-275K, Synchrotron-270K, Synchrotron-260K, Synchrotron-250K, Synchrotron-240K, Synchrotron-220K, Synchrotron-200K, Synchrotron-185K, Synchrotron-170K, Synchrotron-155K, Synchrotron-140K, Synchrotron-125K, Synchrotron-110K, Synchrotron-95K, Synchrotron-80K, Synchrotron-65K, Synchrotron-50K, Synchrotron-35K, Synchrotron-1.03GPa, Synchrotron-2.53GPa, Synchrotron-3.13GPa, Synchrotron-4.45GPa, Synchrotron-6.05GPa, Synchrotron-7.32GPa, Synchrotron-8.09GPa, Synchrotron-9.46GPa, Lab-400K, Lab-390K, Lab-380K, Lab-370K, Lab-360K, Lab-350K, Lab-340K, Lab-330K, Lab-320K_02, Lab-320K_01, Lab-310K_02, Lab-310K_01, Lab-300K_02, Lab-300K_01, Lab-290K, Lab-280K_02, Lab-280K_01, Lab-275K, Lab-270K, Lab-250K, Lab-240K. DOI: 10.1107/S2052520621005655/xk5084Synchrotron-275Ksup2.hklStructure factors: contains datablock(s) Synchrotron-275K. DOI: 10.1107/S2052520621005655/xk5084Synchrotron-270Ksup3.hklStructure factors: contains datablock(s) Synchrotron-270K. DOI: 10.1107/S2052520621005655/xk5084Synchrotron-260Ksup4.hklStructure factors: contains datablock(s) Synchrotron-260K. DOI: 10.1107/S2052520621005655/xk5084Synchrotron-250Ksup5.hklStructure factors: contains datablock(s) Synchrotron-250K. DOI: 10.1107/S2052520621005655/xk5084Synchrotron-240Ksup6.hklStructure factors: contains datablock(s) Synchrotron-40K. DOI: 10.1107/S2052520621005655/xk5084Synchrotron-220Ksup7.hklStructure factors: contains datablock(s) Synchrotron-220K. DOI: 10.1107/S2052520621005655/xk5084Synchrotron-200Ksup8.hklStructure factors: contains datablock(s) Synchrotron-200K. DOI: 10.1107/S2052520621005655/xk5084Synchrotron-185Ksup9.hklStructure factors: contains datablock(s) Synchrotron-185K. DOI: 10.1107/S2052520621005655/xk5084Synchrotron-170Ksup10.hklStructure factors: contains datablock(s) Synchrotron-170K. DOI: 10.1107/S2052520621005655/xk5084Synchrotron-155Ksup11.hklStructure factors: contains datablock(s) Synchrotron-155K. DOI: 10.1107/S2052520621005655/xk5084Synchrotron-140Ksup12.hklStructure factors: contains datablock(s) Synchrotron-140K. DOI: 10.1107/S2052520621005655/xk5084Synchrotron-125Ksup13.hklStructure factors: contains datablock(s) Synchrotron-125K. DOI: 10.1107/S2052520621005655/xk5084Synchrotron-110Ksup14.hklStructure factors: contains datablock(s) Synchrotron-110K. DOI: 10.1107/S2052520621005655/xk5084Synchrotron-95Ksup15.hklStructure factors: contains datablock(s) Synchrotron-95K. DOI: 10.1107/S2052520621005655/xk5084Synchrotron-80Ksup16.hklStructure factors: contains datablock(s) Synchrotron-80K. DOI: 10.1107/S2052520621005655/xk5084Synchrotron-65Ksup17.hklStructure factors: contains datablock(s) Synchrotron-65K. DOI: 10.1107/S2052520621005655/xk5084Synchrotron-50Ksup18.hklStructure factors: contains datablock(s) Synchrotron-50K. DOI: 10.1107/S2052520621005655/xk5084Synchrotron-35Ksup19.hklStructure factors: contains datablock(s) Synchrotron-35K. DOI: 10.1107/S2052520621005655/xk5084Synchrotron-1.03GPasup20.hklStructure factors: contains datablock(s) Synchrotron-1.03GPa. DOI: 10.1107/S2052520621005655/xk5084Synchrotron-2.53GPasup21.hklStructure factors: contains datablock(s) Synchrotron-2.53GPa. DOI: 10.1107/S2052520621005655/xk5084Synchrotron-3.13GPasup22.hklStructure factors: contains datablock(s) Synchrotron-3.13GPa. DOI: 10.1107/S2052520621005655/xk5084Synchrotron-4.45GPasup23.hklStructure factors: contains datablock(s) Synchrotron-4.45GPa. DOI: 10.1107/S2052520621005655/xk5084Synchrotron-6.05GPasup24.hklStructure factors: contains datablock(s) Synchrotron-6.05GPa. DOI: 10.1107/S2052520621005655/xk5084Synchrotron-7.32GPasup25.hklStructure factors: contains datablock(s) Synchrotron-7.32GPa. DOI: 10.1107/S2052520621005655/xk5084Synchrotron-8.09GPasup26.hklStructure factors: contains datablock(s) Synchrotron-8.09GPa. DOI: 10.1107/S2052520621005655/xk5084Synchrotron-9.46GPasup27.hklStructure factors: contains datablock(s) Synchrotron-9.46GPa. DOI: 10.1107/S2052520621005655/xk5084Lab-400Ksup28.hklStructure factors: contains datablock(s) Lab-400K. DOI: 10.1107/S2052520621005655/xk5084Lab-390Ksup29.hklStructure factors: contains datablock(s) Lab-390K. DOI: 10.1107/S2052520621005655/xk5084Lab-380Ksup30.hklStructure factors: contains datablock(s) Lab-380K. DOI: 10.1107/S2052520621005655/xk5084Lab-370Ksup31.hklStructure factors: contains datablock(s) Lab-370K. DOI: 10.1107/S2052520621005655/xk5084Lab-360Ksup32.hklStructure factors: contains datablock(s) Lab-360K. DOI: 10.1107/S2052520621005655/xk5084Lab-350Ksup33.hklStructure factors: contains datablock(s) Lab-350K. DOI: 10.1107/S2052520621005655/xk5084Lab-340Ksup34.hklStructure factors: contains datablock(s) Lab-340K. DOI: 10.1107/S2052520621005655/xk5084Lab-330Ksup35.hklStructure factors: contains datablock(s) Lab-330K. DOI: 10.1107/S2052520621005655/xk5084Lab-320K_02sup36.hklStructure factors: contains datablock(s) Lab-320K_02. DOI: 10.1107/S2052520621005655/xk5084Lab-320K_01sup37.hklStructure factors: contains datablock(s) Lab-320K_01. DOI: 10.1107/S2052520621005655/xk5084Lab-310K_02sup38.hklStructure factors: contains datablock(s) Lab-310K_02. DOI: 10.1107/S2052520621005655/xk5084Lab-310K_01sup39.hklStructure factors: contains datablock(s) Lab-310K_01. DOI: 10.1107/S2052520621005655/xk5084Lab-300K_02sup40.hklStructure factors: contains datablock(s) Lab-300K_02. DOI: 10.1107/S2052520621005655/xk5084Lab-300K_01sup41.hklStructure factors: contains datablock(s) Lab-300K_01. DOI: 10.1107/S2052520621005655/xk5084Lab-290Ksup42.hklStructure factors: contains datablock(s) Lab-290K. DOI: 10.1107/S2052520621005655/xk5084Lab-280K_02sup43.hklStructure factors: contains datablock(s) Lab-280K_02. DOI: 10.1107/S2052520621005655/xk5084Lab-280K_01sup44.hklStructure factors: contains datablock(s) Lab-280K_01. DOI: 10.1107/S2052520621005655/xk5084Lab-275Ksup45.hklStructure factors: contains datablock(s) Lab-275K. DOI: 10.1107/S2052520621005655/xk5084Lab-240Ksup46.hklStructure factors: contains datablock(s) Lab-240K. DOI: 10.1107/S2052520621005655/xk5084Lab-250Ksup47.hklStructure factors: contains datablock(s) Lab-250K. DOI: 10.1107/S2052520621005655/xk5084Lab-270Ksup48.hklStructure factors: contains datablock(s) Lab-270K. DOI: 10.1107/S2052520621005655/xk5084sup49.pdfTables S1-S12 , Appendix A and Figs. S1-S4. DOI: 2087357, 2087358, 2087359, 2087360, 2087361, 2087362, 2087363, 2087364, 2087365, 2087366, 2087367, 2087368, 2087369, 2087370, 2087371, 2087372, 2087373, 2087374, 2087375, 2087376, 2087377, 2087378, 2087379, 2087380, 2087381, 2087382, 2087383, 2087384, 2087385, 2087386, 2087387, 2087388, 2087389, 2087390, 2087391, 2087392, 2087393, 2087394, 2087395, 2087396, 2087397, 2087398, 2087399, 2087400, 2087401, 2087402, 2087403CCDC references:


The model reflects age, platelet count, hepatitis B e antigen positivity, serum albumin and total bilirubin levels, cirrhosis development, and liver stiffness values measured by transient elastography. Our new model showed better performance for predicting hepatocellular carcinoma development (Harrell’s p < 0.05). Our nomogram showed acceptable performance in predicting HCC in Asian HBV-infected patients receiving potent antiviral therapy.Hepatocellular carcinoma (HCC) risk prediction is important to developing individualized surveillance approaches. We designed a novel HCC prediction model using liver stiffness on transient elastography for patients receiving antiviral therapy against hepatitis B virus (HBV) infection. We recruited 2037 patients receiving entecavir or tenofovir as first-line antivirals and used the Cox regression analysis to determine key variables for model construction. Within 58.1 months (median), HCC developed in 182 (8.9%) patients. Patients with HCC showed a higher prevalence of cirrhosis (90.7% vs. 45.9%) and higher liver stiffness values (median 13.9 vs. 7.2 kPa) than those without. A novel nomogram (score 0–304) was established using age, platelet count, cirrhosis development, and liver stiffness values, which were independently associated with increased HCC risk, along with hepatitis B e antigen positivity and serum albumin and total bilirubin levels. Cumulative HCC probabilities were 0.7%, 5.0%, and 22.7% in the low- (score ≤87), intermediate- (88–222), and high-risk (≥223) groups, respectively. The c-index value was 0.799 , higher than that of the PAGE-B (0.726), modified PAGE-B (0.756), and modified REACH-B (0.761) models (all  Globally, approximately 240 million individuals are chronically infected with hepatitis B virus (HBV), which remains a major etiology of hepatocellular carcinoma (HCC) and cirrhosis, especially in endemic areas, including the Republic of Korea ,2,3. A hSeveral efforts were made to evaluate HCC development in patients with CHB. Several models, such as the GAG-HCC, CU-HCC, and REACH-B, were designed with sufficiently good prognostic performance ,14,15. AIn the current era of potent AVT, we aimed to establish a novel prediction model for HCC development optimized for patients with CHB receiving ETV and TDF based on liver stiffness on transient elastography, one of the most reliable fibrosis markers, and validate its role in comparison with that of other prediction models.Between 2007 and 2018, patients who started AVT with ETV or TDF against chronic HBV infection at Yonsei University Severance Hospital were consecutively screened for eligibility. The inclusion criteria were as follows: (1) age ≥19 years, (2) patients who received ETV or TDF in first-line AVT, (3) reliable liver stiffness values available, (4) no previous history of HCC at enrollment, (5) no previous history of decompensated cirrhosis with Child-Pugh class C at enrollment, and (6) no history of previous organ transplant. The exclusion criteria were as follows: (1) co-infection with other hepatitis viruses, (2) HCC development within 6 months since AVT initiation, (3) death or orthotropic liver transplant within 6 months since AVT initiation, (4) uncontrolled advanced malignancy at enrollment, and (5) other significant medical illnesses.3/μL and imaging findings suggestive of cirrhosis, including a blunted, nodular liver edge accompanied by splenomegaly (>12 cm), or (2) clinical signs of portal hypertension, such as gastroesophageal varices ), intermediate- ), and high-risk  groups according to the 25th (87 points) and 75th percentiles (223 points) of the risk score distribution of the nomogram. The 2-, 3-, and 5-year cumulative probabilities of HCC development in the low- (scores: ≤87), intermediate- (88–222), and high-risk (≥223) groups were 0%, 0.2%, and 0.7%; 1.1%, 2.9%, and 5.0%; and 7.5%, 13.3%, and 22.7%, respectively , together with categorized serum albumin levels , total bilirubin levels (<2.0 and ≥2.0 mg/dL), and HBeAg positivity, which were reported to be closely associated with the HCC risk among subjects with chronic HBV infection ,13,15. Tc-index was 0.805 (95% CI: 0.777–0.834), and the 2-, 3-, and 5-year TDAUCs were 0.809 (95% CI: 0.783–0.834), 0.808 (95% CI 0.782–0.834), and 0.805 (95% CI 0.779–0.831), respectively.Harrell’s c-index value of the prediction model was 0.799 (95% CI: 0.769–0.829), and the 2-, 3-, and 5-year TDAUCs were 0.802 (95% CI: 0.776–0.827), 0.802 (95% CI: 0.776–0.828), and 0.799 (95% CI 0.773–0.826), respectively . Calibrap < 0.001), mPAGE-B , and mREACH-B  models. The 2-, 3-, and 5-year TDAUCs of the new nomogram  were also significantly higher than those of the PAGE-B , mPAGE-B , and mREACH-B  models (p < 0.001).The c-index value of the new nomogram for predicting HCC development (0.799) was significantly higher than that of the PAGE-B  models . Furthern = 324, 36.0%).For external validation, we recruited 901 patients from Gangnam Severance Hospital and Yongin Severance Hospital using the same criteria. During follow-up (median: 51.8 [IQR 34.4–73.1] months), HCC developed in 56 (6.2%): 10 patients without cirrhosis and 46 patients with cirrhosis in this cohort. The c-index value and 2-, 3-, and 5-year TDAUC of the nomogram were also acceptable: 0.785 (95% CI: 0.729– 0.840) and 0.782 (95% CI: 0.722–0.841), 0.777 (95% CI: 0.719–0.835), and 0.771 (95% CI: 0.714–0.827), respectively, in overall patients. In subgroup analysis, Harrell’s C-index, 2-, 3-, and 5-year TDAUC values were 0.749 (95% CI: 0.692–0.806), 0.649 (95% CI: 0.522–0.775), 0.651 (95% CI: 0.524–0.779), and 0.651 (95% CI: 0.525–0.776), respectively, in patients without cirrhosis and 0.668 (95% CI: 0.585–0.750), 0.653 (95% CI: 0.571–0.736), 0.651 (95% CI: 0.570–0.732), and 0.653 (95% CI: 0.573–0.733), respectively, in patients with cirrhosis  during the long-term follow-up period of approximately 60 months, allowed for statistical reliability and adequate power [Our study has several strengths. Firstly, our nomogram showed consistently superior c-index and TDAUC values for predicting HCC development during the long-term follow-up period, compared with that of other conventional risk prediction models, including the PAGE-B, mPAGE-B, and mREACH-B models, which showed high performance in previous literature ,16,30. Cte power . The higte power . Finallyn = 571, 28.0%), HCC surveillance can be mitigated safely, until the value calculated by our nomogram reaches more than 87. Accordingly, repeated assessment of HCC risk at every visit is required in routine practice. Contrary, because the intermediate- and high-risk groups  had significantly higher annual incidence rates of HCC , a more sensitive imaging study of detecting HCC rather than abdominal ultrasonography, for example, magnetic resonance imaging with or without contrast, is required. Further prospective studies on personalized surveillance strategies according to individual risk and cost-effectiveness are required.The 5-year cumulative incidence of HCC was <1% in the low-risk group (score: ≤87). Generally, the currently recommended bi-annual surveillance strategy is cost-effective when the annual incidence rate of HCC ranges ≥0.2% in patients with chronic HBV infection and ≥1.5% in those with cirrhosis ,34. TherThe type of AVT does not seem to influence the risk of HCC development. Our study included similar proportions of patients who first started AVT with ETV (45.0%) and TDF (55.0%), and the type of AVT was not associated with HCC development in univariate analysis. There is controversy on whether TDF is more advantageous than ETV in reducing HCC risk ; howeverUnsolved issues remain in our study. Firstly, the findings of this study were potentially subject to selection bias. Considering that our institute is the second largest tertiary hospital with approximately 2500 beds in the Republic of Korea, our study population was more likely to cover patients with advanced liver disease and a high prevalence of cirrhosis in comparison with the nationwide cohort . HoweverThis study developed a novel nomogram to predict HCC using baseline information readily available among treatment-naïve patients with chronic HBV infection who started their first-line AVT with potent nucleos(t)ide analogs. The nomogram consistently showed better prognostic performance over that of conventional models. Further studies are required to validate our results among independent cohorts, including Western populations.


Agastache foeniculum (Pursch) Kuntze (Lamiaceae), Gaultheria procumbens L. (Ericaceae), Heliopsis helianthoides (L.) Sweet (Asteraceae), Liatris spicata (L.) Willd. (Asteraceae), Pycnanthemum incanum (L.) Michx. (Lamiaceae), Smallanthus uvedalia (L.) Mack. ex Mack. (Asteraceae), and Verbena hastata L. (Verbenaceae) by hydrodistillation. The essential oils were analyzed by gas chromatographic techniques. The essential oil of A. foeniculum was dominated by estragole (88–93%), while methyl salicylate (91%) dominated the G. procumbens essential oil. Germacrene D was the major component in H. helianthoides (42%) and L. spicata (24%). 1,8-Cineole (31%) and α-terpineol (17%) were the main compounds in P. incanum essential oil. The essential oil of S. uvedalia showed α-pinene (24%), perillene (15%), and β-caryophyllene (17%) as major components. Verbena hastata essential oil was rich in 1-octen-3-ol (up to 29%) and palmitic acid (up to 22%). Four of these essential oils, H. helianthoides, L. spicata, P. incanum, and V. hastata, are reported for the first time. Additionally, the enantiomeric distributions of several terpenoid components have been determined.As part of our evaluation of essential oils derived from Native American medicinal plants, we have obtained the essential oils of  Plants have been used in traditional medicine since prehistoric times. The therapeutic properties of medicinal plants are generally attributed to secondary metabolites produced by the plants as protection against pathogens and herbivory. As with many other aboriginal peoples, Native North Americans have used plants as medicines throughout their history. Although not as extensively documented as traditional Chinese medicine or Ayurvedic medicine, there are several sources of information regarding Native American ethnopharmacology ,2,3. As Agastache foeniculum (Pursch) Kuntze (Lamiaceae) is native to north central United States and southern Canada, but has been recorded in southern Alabama [A. foeniculum as a cold medicine [A. foeniculum have been extensively studied, and the oils are typically dominated by methyl chavicol (estragole) with smaller amounts of (E)-anethole [A. foeniculum include flavonoids , polyphenolics , pentacyclic triterpenoids , and sterols  [ Alabama . The pla Alabama . Cheyennmedicine . Essentianethole . Nonvolaastanol) .Gaultheria procumbens L. (Ericaceae) naturally ranges in eastern North America from Canada, south through Alabama and Georgia [G. procumbens to treat headaches, colds  or to treat arthritis, rheumatism, and lumbago  [G. procumbens along with the roots of Epigaea repens for chronic indigestion, and they also chewed the leaves as a substitute for chewing tobacco [Gaultheria fragrantissima Wall., the essential oil of G. procumbens is dominated by methyl salicylate. Commercial G. fragrantissima essential oil  has 99.7% methyl salicylate, while methyl salicylate in G. procumbens essential oil typically ranges 96.6–99.8% [ Georgia . Severalawatomi) . The Che tobacco . Much li.6–99.8% .Heliopsis helianthoides (L.) Sweet (Asteraceae) is native to North America from Saskatchewan, Canada east to the Atlantic coast of Newfoundland and south to the Gulf of Mexico, with the western range extending as far as New Mexico [H. helianthoides, ssp. helianthoides, generally occurring east of the Mississippi River; ssp. occidentalis, found in the Great Plains region; and ssp. scabra, which is predominant in the Ozark region  [H. helianthoides as a stimulant [Scutellaria incana “for young women”, presumably for menstruation-related discomforts, and sore feet were relieved by soaking in an infusion of what was called “swamp sunflower” [N-alkylamides [H. helianthoides.w Mexico ,11,12. Tnflower” . Guaianonflower” , N-alkylylamides , and ligylamides  have beeLiatris spicata (L.) Willd. (Asteraceae) is the eastern United States and Canada, east of the Mississippi River, from the south along the Gulf of Mexico including southern Alabama and northern Florida areas, north to Ontario and Quebec [L. spicata [The natural range of d Quebec ,16,17. Td Quebec . The gua spicata .Pycnanthemum incanum (L.) Michx. (Lamiaceae) ranges naturally in the eastern United States from the Mississippi River east to the Atlantic coast and from southern Ontario, Canada south to the Gulf of Mexico, though it is primarily found from the Appalachian mountain region beginning in north Georgia north into Ontario, Canada [P. incanum externally to treat headaches [P. incanum to be β-ionone, myrcene, linalool, and pulegone [, Canada ,19. The eadaches . Dein anpulegone .Smallanthus uvedalia (L.) Mack. ex Mack. (Asteraceae) is the southeastern United States, from the Ohio river basin south to the Gulf of Mexico [Smallanthus uvedalia was reportedly used internally by Native American Indians for laxative properties as well as a stimulant and also to treat swollen glands, especially mastitis [ent-kaurane diterpenoids have been isolated and characterized from S. uvedalia [S. uvedalia from several locations in north Alabama have been analyzed previously [The natural range of f Mexico . Smallanmastitis . The Chemastitis . Interesmastitis . A numbeuvedalia . The leaeviously ,24.Verbena hastata L. (Verbenaceae) ranges throughout North America [V. hastata has shown antiplasmodial [V. hastata [ America . The Che America . The ethasmodial , antinocasmodial , and antasmodial . The iri hastata .The purpose of this study was to extend our understanding of the volatile phytochemistry of Native American aromatic medicinal plants by examination of the essential oils of these seven plant species, to determine their chemical compositions as well as the enantiomeric distributions of terpenoid constituents.The essential oils of each species were obtained by hydrodistillation of dried plant material .A. foeniculum were collected from cultivated plants in Newville, Alabama. Hydrodistillation gave pale yellow essential oils in yields ranging from 1.48% to 2.30% yield. The essential oil compositions are compiled in The aerial parts of three different plant samples of A. foeniculum essential oil was dominated by the phenylpropanoid methyl chavicol (=estragole). There are apparently five different chemotypes of A. foeniculum based on essential oil chemical profiles: (1) methyl chavicol, (2) spathulenol/bornyl acetate, (3) γ-cadinene/α-cadinol, (4) limonene, and (5) isomenthone [A. foeniculum essential oils belong to the methyl chavicol chemotype, however [The menthone ,34. Most however ,40,41,42A. foeniculum and has shown anti-inflammatory and anti-edematogenic [Methyl chavicol contributes to the anise-like aroma of atogenic ,44, cytoatogenic , and antatogenic ,47. Unfoatogenic ,49.G. procumbens was obtained in 4.25% yield and the major component was methyl salicylate (91.1%)  . Methyl 1.1% . Meo 99.96% ,50,51,52G. procumbens essential oil, methyl salicylate, is well-known as an anti-inflammatory, antipyretic, analgesic agent [The major component of ic agent , and accic agent ,55,56.H. helianthoides was obtained in 0.95% yield. The major component in the essential oil was germacrene D (42.4%), with a lesser amount of 4-vinylguaicol (5.5%)  . As far Centaurea hadimensis Wagenitz, K. Ertugrul & H. Dural (44.3%) [Centaurea pseudoscabiosa Boiss. & Buhse (36.0%) [Eupatorium cannabinum L. (33.5%) [Polymnia canadensis L. (63.6%) [Rudbeckia fulgida Aiton (30.1%) [Rudbeckia hirta L. (23.6%) [Solidago canadensis L. (64.1%) [Symphyotrichum novae-angliae (L.) G.L. Nesom (25.5%) [Verbesina macrophylla (Cass.) F.S. Blake (37.3%) [Verbesina turbacensis Kunth (36.9%) [Liatris spicata . Germacrene D has shown antimicrobial and cytotoxic activities [Although not necessarily a phytochemical marker of the family, germacrene D has been found to be a major component in several members of the Asteraceae. For example, germacrene D is the dominant compound in the essential oils of  (44.3%) , Centaur (36.0%) , Eupator (33.5%) , Polymni 63.6%) , Rudbeck (30.1%) , Rudbeck (23.6%) , Solidag 64.1%) , Symphyo (25.5%) , Verbesi (37.3%) , Verbesi (36.9%) , and Lia.6% , Rud.1% , SymL. spicata essential oil is presented in L. spicata.The essential oil composition of P. incanum growing wild in South Carolina. The essential oil was rich in oxygenated monoterpenoids, including 1,8-cineole (30.7%), α-terpineol (16.9%), borneol (8.2%), and cis-sabinene hydrate (5.6%). The sesquiterpene hydrocarbons (E)-β-caryophyllene (11.0%), and germacrene D (5.0%) were also relatively abundant. To our knowledge, this is the first reported analysis of P. incanum essential oil. Volatiles obtained from a diethyl ether extract have been analyzed by gas chromatography-olfactometry to determine the key odorants [P. incanum essential oil and the volatiles from the previously published diethyl ether extract [odorants . Althoug extract . ConcentS. uvedalia from South Carolina is summarized in S. uvedalia essential oil were α-pinene (23.9%), (E)-β-caryophyllene (16.9%), perillene (14.5%), germacrene D (12.2%), and limonene (6.1%). In comparison, S. uvedalia from northern Alabama (collected in September 2018) contained α-pinene (62.6%), limonene (11.4%), and β-pinene (6.0%), with lesser concentrations of (E)-β-caryophyllene (3.8%) [S. uvedalia samples collected in February, 2016, from northern Alabama were rich in (E)-β-caryophyllene (24.5% and 16.5%) and caryophyllene oxide (19.8% and 14.2%) [S. uvedalia may be attributed to geographical location and/or seasonal variation.The essential oil composition of e (3.8%) . Neitherα-pinene .9%, (E)-Erechtites hieracifolia (L.) Raf. [S. uvedalia (this work). Likewise, (+)-β-pinene was the only enantiomer in Coreopsis capillacea Kunth (syn. C. triloba S.F. Blake) [Achillea ligustica All. [S. uvedalia (this work) and Solidago canadensis L. [E. hieracifolia [C. capillacea [There does not seem to be a trend in the major enantiomers for essential oils of the Asteraceae see . For exaL.) Raf. , but (–). Blake) , while (ica All. . (+)-Limensis L. , whereasacifolia  and C. cpillacea .V. hastata were collected and investigated (E)-β-ionone, and (E)-nerolidol were the same for the three samples, however. As far as we know, this is the first report on the essential oil composition of V. hastata.Three different specimens of stigated . AlthougVerbena essential oil compositions to compare. However, several Verbena officinalis L. essential oils have been reported, and these samples also show wide variation in composition. The major components in V. officinalis essential oil from Morocco were spathulenol (10.8%), limonene (7.5%), 1,8-cineole (7.5%), caryophyllene oxide (7.3%), and ar-curcumene (6.0%) [V. officinalis from Italy was rich in geranial (45.5%) and isobornyl formate (41.4%) [Verbena officinalis from Algeria, on the other hand, showed limonene (17.7%), geranial (14.8%), carvone (14.2%), and caryophyllene oxide (12.4%) as major components [There are few e (6.0%) . In cont (41.4%) . Verbenamponents .V. hastata essential oils as it was in P. incanum essential oil (above). Notably, (–)-1-octen-3-ol is the major enantiomer, generally greater than 97%, in mushrooms [The (–)-enantiomer of 1-octen-3-ol was the only stereoisomer observed in ushrooms , and is ushrooms . Interesushrooms .V. hastata. (–)-Linalool also dominated in the essential oil of Lantana camara L. (Verbenaceae) from Madagascar [Lippia alba (Mill.) N.E. Brown (Verbenaceae) from Uruguay was dominated by the (+)-enantiomer [A racemic mixture was observed for α-terpineol, but there was a higher concentration of (–)-linalool over (+)-linalool in dagascar . In contantiomer .A. foeniculum, G. procumbens, and H. helianthoides were obtained from plants cultivated in at Kirkland Gardens, in Newville, Alabama , tubers , or young plants . All the plants were grown in full sun, except the G. procumbens, which was located in a partially shaded location (4 h/day average sunlight), and all were watered at least once a week. The plants were cultivated directly in the ground, which was clayey-loamy sand, which was amended with composted chicken manure, worm castings, kelp meal, and bone meal at time of planting. Pycnanthemum incanum and S. uvedalia were collected in the wild from a fully shaded forest understory roadside location near a small waterfall in northern South Carolina. The plants were located beside highway 276 near the North Carolina–South Carolina border , S. uvedalia (SKL31820), and V. hastata (SKL51321) were deposited in the University of Alabama in Huntsville Herbarium (HALA); cultivated plants were not vouchered. For each species, the plant material was air-dried in the laboratory (around 23 °C) for 10 days. The dried plant materials of each species were chopped and hydrodistilled using a Likens–Nickerson apparatus with continuous extraction with dichloromethane for 4 h. The dichloromethane was evaporated using a stream of dry nitrogen to give the essential oils , gas chromatography-flame ionization detection (GC-FID), and chiral GC-MS as previously described .GC-MS: Shimadzu GCMS-QP2010 Ultra, electron impact (EI) mode (electron energy = 70 eV), scan range = 40–400 atomic mass units, scan rate = 3.0 scans/s, and GC-MS solution software; ZB-5ms fused silica capillary column (30 m length × 0.25 mm inner diameter) with a (5% phenyl)-polymethylsiloxane stationary phase and a film thickness of 0.25 μm; He carrier gas with a column head pressure of 552 kPa and flow rate of 1.37 mL/min; injector temperature = 250 °C, ion source temperature = 200 °C; GC oven temperature 50–260 °C (2 °C/min), 1-μL injection of 5% solution of EO in dichloromethane . The essential oil components were identified by MS fragmentation, and retention indices compared with those in the databases ,30,31,322 carrier gas, and flow rate = 1.0 mL/min. The composition percentages were calculated from raw peak areas without standardization.GC-FID: Shimadzu GC 2010 equipped with flame ionization detector, a split/splitless injector, and Shimadzu autosampler AOC-20i, with a ZB-5 capillary column (30 m length × 0.25 mm inner diameter) with a (5% phenyl)-polymethylsiloxane stationary phase and a film thickness of 0.25 μm; oven temperature was programmed the same as above for GC-MS; injector temperature = 250 °C, detector temperature = 280 °C, NChiral GC-MS: Shimadzu GCMS-QP2010S, EI mode (electron energy = 70 eV) with scan range of 40–400 amu and scan rate of 3.0 scans/s; Restek B-Dex 325 capillary column (30 m × 0.25 mm ID × 0.25 μm film); GC oven temperature program, 50–120 °C (1.5 °C/min), 120–200 °C (2 °C/min), and kept at 200 °C for 5 min; He carrier gas, flow rate = 1.8 mL/min; 0.1-μL injection of 3% solution of EO in dichloromethane . The monoterpenoid enantiomers were identified by comparison of retention times with authentic samples obtained from Sigma-Aldrich . Relative enantiomer percentages were determined based on peak areas. Chiral GC-MS chromatograms are available as Heliopsis helianthoides, Liatris spicata, Pycnanthemum incanum, and Verbena hastata, were reported for the first time. Additionally, the enantiomeric distributions of several terpenoid components have been determined. The chemical compositions presented add to our knowledge of the phytochemistry of the medicinal plants.This report presented the essential oil compositions of seven aromatic medicinal plants used by Native Americans. Four of these essential oils,


MUC1-C integrates activation of the IFN-γ pathway with suppression of the tumor immune microenvironment in triple-negative breast cancer. J Immunother Cancer. 2021;9:e002115. doi: 10.1136/jitc-2020-002115.Yamashita N, Long M, Fushimi A, This article has been corrected since it first published. The provenance and peer review statement has been added.


Correction to: Microbiome 9, 241 (2021)https://doi.org/10.1186/s40168-021-01195-7Supplementary Data was missing from this article and has now been uploaded.The original article has been updated.Additional file 1: Supplementary Table S1. Details of the search terms used in the respective databases. Supplementary Table S2a. Additional summary of African Gut Microbiome studies. Supplementary Table S2b. Additional summary of African Urogenital Microbiome studies. Supplementary Table S2c. Additional summary of African Microbiome studies (Other body sites).