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CD8 virtual memory T (TVM) cells are Ag-naive CD8 T cells that have undergone partial differentiation in response to common γ-chain cytokines, particularly IL-15 and IL-4. TVM cells from young individuals are highly proliferative in response to TCR and cytokine stimulation but, with age, they lose TCR-mediated proliferative capacity and exhibit hallmarks of senescence. Helminth infection can drive an increase in TVM cells, which is associated with improved pathogen clearance during subsequent infectious challenge in young mice. Given the cytokine-dependent profile of TVM cells and their age-associated dysfunction, we traced proliferative and functional changes in TVM cells, compared with true naive CD8 T cells, after helminth infection of young and aged C57BL/6 mice. We show that IL-15 is essential for the helminth-induced increase in TVM cells, which is driven only by proliferation of existing TVM cells, with negligible contribution from true naive cell differentiation. Additionally, TVM cells showed the greatest proliferation in response to helminth infection and IL-15 compared with other CD8 T cells. Furthermore, TVM cells from aged mice did not undergo expansion after helminth infection due to both TVM cell–intrinsic and –extrinsic changes associated with aging.

Study design Qualitative study. Objectives The benefits of exercise to reduce shoulder pain in people with spinal cord injury (SCI) are well documented. Digital health interventions offer a potential solution to overcome barriers to access rehabilitation support for exercise. The aim of this project was to gain people’s perspectives to inform the development of a self-guided web-based exercise intervention. Shoulder Pain Intervention delivered over the interNet (SPIN) is a self-guided web-based intervention to prescribe, monitor, and progress evidence-based exercises for people living with SCI and shoulder pain. Setting Community in Auckland, New Zealand. Methods The Person-Based Approach was used as the framework. Using an Interpretive Descriptive methodology, data were collected in individual and focus group interviews, exploring participants’ perceptions of this intervention idea. Data were analysed using conventional content analysis. Results Sixteen participants took part and asked Is it right for me?. This had three main sub-themes. Should I use it?, whether I believe it will work for me right now; Can I use it?, whether I can operate the intervention competently and confidently and Will I use it?, whether it will be responsive to my unique needs, and keep me coming back. Conclusions Participants expressed their expectations and tipping points when considering using an intervention like this. These findings will inform and guide design and development of an acceptable technology-based intervention to increase the likelihood of engagement with a self-guided web-based exercise programme. The model developed from these themes could be used to inform future self-guided intervention development.

Most transcriptome-wide association studies (TWASs) so far focus on European ancestry and lack diversity. To overcome this limitation, we aggregated genome-wide association study (GWAS) summary statistics, whole-genome sequences and expression quantitative trait locus (eQTL) data from diverse ancestries. We developed a new approach, TESLA (multi-ancestry integrative study using an optimal linear combination of association statistics), to integrate an eQTL dataset with a multi-ancestry GWAS. By exploiting shared phenotypic effects between ancestries and accommodating potential effect heterogeneities, TESLA improves power over other TWAS methods. When applied to tobacco use phenotypes, TESLA identified 273 new genes, up to 55% more compared with alternative TWAS methods. These hits and subsequent fine mapping using TESLA point to target genes with biological relevance. In silico drug-repurposing analyses highlight several drugs with known efficacy, including dextromethorphan and galantamine, and new drugs such as muscle relaxants that may be repurposed for treating nicotine addiction.

Aim The prevalence of Type 2 diabetes in Samoa has increased substantially over the last 30 years. Identifying common symptoms in those living with diabetes may be instrumental in directing those at risk to seek early evaluation, diagnosis, and treatment. Additionally, identifying associations between diabetes experiences and health-related quality of life is useful for understanding the lived experience of having diabetes in this setting. Here we present the first description of diabetes-related symptoms in an adult cohort of Samoans with diabetes and prediabetes and describe associations between symptom presence and sex, glycemic control (HbA1c ≥ 8.0%), and health-related quality of life (HRQL). We also assessed whether reported symptoms were independently associated, when adjusting for other factors, with increased odds of having diabetes. METHODS Analyses were conducted on n = 123 adult Samoan participants selectively sampled from the observational cohort Soifua Manuia study, and who were living with either prediabetes or diabetes. Participants completed a series of anthropometric, biochemical, and questionnaire measures including the Revised Diabetes Symptoms Checklist (DSC-R) questionnaire between 2017-2019. Differences in symptom presence by sex, diabetes status (prediabetes vs. diabetes), glycemic control (HbA1c < or ≥ 8.0%), and HRQL were assessed using Independent Sample T-tests, Mann Whitney U tests and Chi-square tests of association. Multivariate logistic regression was used to assess which symptoms, when controlling for other factors, were associated with increased odds of having diabetes. RESULTS In a small sample of adult Samoans, we observed high symptom burdens among those with prediabetes and diabetes, and sex differences in the reported impact of diabetes symptoms on health-related quality of life. We identified three specific symptoms – frequent urination, difficulty thinking clearly, and chest/heart pains – that may be useful indicators of diabetes in this setting. DISCUSSION A high prevalence of symptoms was observed among those with prediabetes and among those with diabetes. It is recommended that individuals experiencing any of the measured symptoms seek early evaluation and engage in diabetes self-care behaviors to prevent diabetes-related complications and/or progression to diabetes among those in the early stages of the disease.

Soil-transmitted helminths cause widespread disease, infecting ~1.5 billion people living within poverty-stricken regions of tropical and subtropical countries. As adult worms inhabit the intestine alongside bacterial communities, we determined whether the bacterial microbiota impacted on host resistance against intestinal helminth infection. We infected germ-free, antibiotic-treated and specific pathogen-free mice, with the intestinal helminth Heligmosomoides polygyrus bakeri. Mice harboured increased parasite numbers in the absence of a bacterial microbiota, despite mounting a robust helminth-induced type 2 immune response. Alterations to parasite behaviour could already be observed at early time points following infection, including more proximal distribution of infective larvae along the intestinal tract and increased migration in a Baermann assay. Mice lacking a complex bacterial microbiota exhibited reduced levels of intestinal acetylcholine, a major excitatory intestinal neurotransmitter that promotes intestinal transit by activating muscarinic receptors. Both intestinal motility and host resistance against larval infection were restored by treatment with the muscarinic agonist bethanechol. These data provide evidence that a complex bacterial microbiota provides the host with resistance against intestinal helminths via its ability to regulate intestinal motility.

The aim of this study was to understand whether the paradoxical association of missense variant rs373863828 in CREB3 regulatory factor (CREBRF) with higher BMI but lower odds of diabetes is explained by either metabolically favorable body fat distribution or greater fat-free mass.This study explored the association of the minor allele with dual-energy x-ray absorptiometry-derived body composition in n = 421 Samoans and used path analysis to examine the mediating role of fat and fat-free mass on the relationship between rs373863828 and fasting glucose.Among females, the rs373863828 minor A allele was associated with greater BMI. There was no association of genotype with percent body fat, visceral adiposity, or fat distribution in either sex. In both females and males, lean mass was greater with each A allele: 2.16 kg/copy (p = 0.0001) and 1.73 kg/copy (p = 0.02), respectively. Path analysis showed a direct negative effect of rs373863828 genotype on fasting glucose (p = 0.004) consistent with previous findings, but also an indirect positive effect on fasting glucose operating through fat-free mass (p = 0.027).The protective effect of rs373863828 in CREBRF, common among Pacific Islanders, on type 2 diabetes does not operate through body composition. Rather, the variant's effects on body size/composition and fasting glucose likely operate via different, tissue-specific mechanisms.

Previously, we discovered that deletion of c-Rel in the Eµ-Myc mouse model of lymphoma results in earlier onset of disease, a finding that contrasted with the expected function of this NF-κB subunit in B-cell malignancies. Here we report that Eµ-Myc/cRel−/− cells have an unexpected and major defect in the CHK1 pathway. Total and phospho proteomic analysis revealed that Eµ-Myc/cRel−/− lymphomas highly resemble wild-type (WT) Eµ-Myc lymphomas treated with an acute dose of the CHK1 inhibitor (CHK1i) CCT244747. Further analysis demonstrated that this is a consequence of Eµ-Myc/cRel−/− lymphomas having lost expression of CHK1 protein itself, an effect that also results in resistance to CCT244747 treatment in vivo. Similar down-regulation of CHK1 protein levels was also seen in CHK1i resistant U2OS osteosarcoma and Huh7 hepatocellular carcinoma cells. Further investigation revealed that the deubiquitinase USP1 regulates CHK1 proteolytic degradation and that its down-regulation in our model systems is responsible, at least in part, for these effects. We demonstrate that treating WT Eµ-Myc lymphoma cells with the USP1 inhibitor ML323 was highly effective at reducing tumour burden in vivo. Targeting USP1 activity may thus be an alternative therapeutic strategy in MYC-driven tumours.

The development of resistance and the activation of bypass pathway signalling represents a major problem for the clinical application of protein kinase inhibitors. While investigating the effect of either a c-Rel deletion or RelAT505A phosphosite knockin on the Eµ-Myc mouse model of B-cell lymphoma, we discovered that both NF-κB subunit mutations resulted in CHK1 inhibitor resistance, arising from either loss or alteration of CHK1 activity, respectively. However, since Eµ-Myc lymphomas depend on CHK1 activity to cope with high levels of DNA replication stress and consequent genomic instability, it was not clear how these mutant NF-κB subunit lymphomas were able to survive. To understand these survival mechanisms and to identify potential compensatory bypass signalling pathways in these lymphomas, we applied a multi-omics strategy. With c-Rel−/− Eµ-Myc lymphomas we observed high levels of Phosphatidyl-inositol 3-kinase (PI3K) and AKT pathway activation. Moreover, treatment with the PI3K inhibitor Pictilisib (GDC-0941) selectively inhibited the growth of reimplanted c-Rel−/− and RelAT505A, but not wild type (WT) Eµ-Myc lymphomas. We also observed up-regulation of a RHO/RAC pathway gene expression signature in both Eµ-Myc NF-κB subunit mutation models. Further investigation demonstrated activation of the RHO/RAC effector p21-activated kinase (PAK) 2. Here, the PAK inhibitor, PF-3758309 successfully overcame resistance of RelAT505A but not WT lymphomas. These findings demonstrate that up-regulation of multiple bypass pathways occurs in CHK1 inhibitor resistant Eµ-Myc lymphomas. Consequently, drugs targeting these pathways could potentially be used as either second line or combinatorial therapies to aid the successful clinical application of CHK1 inhibitors.

Background: The availability of whole-genome sequencing data in large studies has enabled the assessment of coding and noncoding variants across the allele frequency spectrum for their associations with blood pressure. Methods: We conducted a multiancestry whole-genome sequencing analysis of blood pressure among 51 456 Trans-Omics for Precision Medicine and Centers for Common Disease Genomics program participants (stage-1). Stage-2 analyses leveraged array data from UK Biobank (N=383 145), Million Veteran Program (N=318 891), and Reasons for Geographic and Racial Differences in Stroke (N=10 643) participants, along with whole-exome sequencing data from UK Biobank (N=199 631) participants. Results: Two blood pressure signals achieved genome-wide significance in meta-analyses of stage-1 and stage-2 single variant findings ( P -8 ). Among them, a rare intergenic variant at novel locus, LOC100506274 , was associated with lower systolic blood pressure in stage-1 (beta [SE]=−32.6 [6.0]; P =4.99×10 -8 ) but not stage-2 analysis ( P =0.11). Furthermore, a novel common variant at the known INSR locus was suggestively associated with diastolic blood pressure in stage-1 (beta [SE]=−0.36 [0.07]; P =4.18×10 -7 ) and attained genome-wide significance in stage-2 (beta [SE]=−0.29 [0.03]; P =7.28×10 -23 ). Nineteen additional signals suggestively associated with blood pressure in meta-analysis of single and aggregate rare variant findings ( P -6 and P -4 , respectively). Discussion: We report one promising but unconfirmed rare variant for blood pressure and, more importantly, contribute insights for future blood pressure sequencing studies. Our findings suggest promise of aggregate analyses to complement single variant analysis strategies and the need for larger, diverse samples, and family studies to enable robust rare variant identification.

El enredo en las artes de pesca es reconocido como la principal amenaza moderna para las poblaciones de cetáceos a nivel mundial. A continuación, se presenta la primera evidencia de interacciones entre las pesquerías artesanales marino-costeras y los cetáceos a lo largo de la costa del Pacífico de El Salvador. Entre los años 2017 y 2022, se registraron cinco eventos de enredo, dos en especies de delfines oceánicos, Stenella longirostris y S. attenuata, tres casos de ballenas jorobadas, Megaptera novaeangliae, uno de ellos fue una madre y una cría dependiente, enredadas en el mismo arte de pesca. Estos cinco incidentes fueron documentados en el oeste de El Salvador, cerca del Puerto de Acajutla y constituyen el primer informe de enredo de cetáceos en el país, incluyendo un caso que afecta a una población de ballenas migratorias en peligro de extinción y a una especie de delfín amenazada. Cabe destacar que, dos casos de animales vivos enredados involucraron intentos/exitosos de liberación de los animales por parte de pescadores locales voluntarios, guardarrecursos y personal de la fuerza naval no entrenados en el rescate de cetáceos. Este informe destaca la necesidad de gestionar y mitigar las interacciones de la pesca con los cetáceos en El Salvador, incluyendo la formación de los equipos de rescate, para reducir la amenaza de enredo de los cetáceos y el riesgo para la vida humana durante los intentos de rescate.

A missense variant, rs373863828, in CREBRF is associated with obesity in Polynesians. We investigate whether rs373863828 and other factors are associated with body mass index (BMI) rate-of-change between 2010 and 2017-19 in Samoans.We used sex-stratified models to test whether BMI rate-of-change was associated with rs373863828, baseline BMI, age, residence, physical activity, and household asset score in a cohort study of 480 Samoan adults measured in both 2010 (mean age 43.8 years) and 2017-19.Mean BMI increased from 32.1 to 33.5 kg/mIn Samoans, the minor A allele of rs373863828 is associated with an increased rate-of-change in BMI in females. On average, BMI of females with the AA genotype increased 0.30 kg/m

To determine whether cognitive and psychological symptom profiles differentiate clinical diagnostic classifications (eg, history of mild traumatic brain injury [mTBI] and posttraumatic stress disorder [PTSD]) in military personnel.US Active-Duty Service Members ( N = 209, 89% male) with a history of mTBI ( n = 56), current PTSD ( n = 23), combined mTBI + PTSD ( n = 70), or orthopedic injury controls ( n = 60) completed a neuropsychological battery assessing cognitive and psychological functioning. Latent profile analysis was performed to determine how neuropsychological outcomes of individuals clustered together. Diagnostic classifications (ie, mTBI, PTSD, mTBI + PTSD, and orthopedic injury controls) within each symptom profile were examined.A 5-profile model had the best fit. The profiles differentiated subgroups with high (34.0%) or normal (21.5%) cognitive and psychological functioning, cognitive symptoms (19.1%), psychological symptoms (15.3%), and combined cognitive and psychological symptoms (10.0%). The symptom profiles differentiated participants as would generally be expected. Participants with PTSD were mainly represented in the psychological symptom subgroup, while orthopedic injury controls were mainly represented in the high-functioning subgroup. Further, approximately 79% of participants with comorbid mTBI and PTSD were represented in a symptomatic group (∼24% = cognitive symptoms, ∼29% = psychological symptoms, and 26% = combined cognitive/psychological symptoms). Our results also showed that approximately 70% of military personnel with a history of mTBI were represented in the high- and normal-functioning groups.These results demonstrate both overlapping and heterogeneous symptom and performance profiles in military personnel with a history of mTBI, PTSD, and/or mTBI + PTSD. The overlapping profiles may underscore why these diagnoses are often difficult to diagnose and treat, but suggest that advanced statistical models may aid in identifying profiles representing symptom and cognitive performance impairments within patient groups and enable identification of more effective treatment targets.

Camel milk consists of an essential macro/micronutrient for human nutrition in the arid and urban regions. This review study aimed to use meta-analysis statistical techniques for assessment and correction of publication bias, exploration of heterogeneity between studies, and detailed assessment of the effect of a comprehensive set of moderators including breed, season, country, year of publication, and the interaction between composition elements. This could provide a single synthesis of the camel milk composition to warrant strong generalizability of results, examine variability between available studies, and analyze differences in camel milk composition among different exposures. Such a finding will aid future researchers and health professionals in acquiring a more precise understanding of camel milk composition and drawing more clinical implications. Six searching databases and bibliographic were used including PubMed/MEDLINE, ScienceDirect, Springer, EBSCOhost, Scopus, and Web of Science from January 1980 to December 2021. The DerSimonian–Laird estimator was used to create the current random-effects meta-analysis. This systematic review and meta-analysis included a total of 7298 camel milk samples from 23 countries. This review comprises 79 studies published in the English language on or after 1980, including a subgroup of 117 analyses consisting of seasons, sub-breeds, and countries. The contents of macro/micronutrients in camel milk were identified as follows: protein, 3.17%; fat, 3.47%; lactose, 4.28%; ash, 0.78%; and total solids, 11.31%; calcium, 112.93 mg/100 g; iron, 0.45 mg/100 g; potassium, 116.13 mg/100 g; magnesium, 9.65 mg/100 g; sodium, 53.10 mg/100 g; zinc, 1.68 mg/100 g; vitamin C, 5.38 mg/100 g; vitamin A, 0.36 mg/100 g; vitamin B1,0.05 mg/100 g; vitamin B2, 0.13 mg/100 g; vitamin B3, 0.51 mg/100 g; vitamin B6, 0.09 mg/100 g; and vitamin B12, 0.0039 mg/100 g. Our meta-regression analysis found that fat and total solids were statistically significant moderators of protein; moreover, total solids content is a statistically significant moderator of fat. Discrepancies observed in camel milk profiles are dependent upon several factors, including number of included studies, number of samples, different analytical techniques, feeding patterns, camel's breeds, geographical locations, and seasonal variations.

Study Objectives Digital technology use is associated with poor sleep quality in adolescence and young adulthood although research findings have been mixed. No studies have addressed the association between the two using a genetically informative twin design which could extend our understanding of the etiology of this relationship. This study aimed to test: (1) the association between adolescents’ perceived problematic use of digital technology and poor sleep quality, (2) whether the association between problematic use of technology and poor sleep quality remains after controlling for familial factors, and (3) genetic and environmental influences on the association between problematic use of technology and poor sleep quality. Methods Participants were 2232 study members (18-year-old twins) of the Environmental Risk (E-Risk) Longitudinal Twin Study. The sample was 48.9% male, 90% white, and 55.6% monozygotic. We conducted regression and twin difference analyses and fitted twin models. Results Twin differences for problematic use of technology were associated with differences for poor sleep quality in the whole sample (p < 0.001; B = 0.15) and also when we limited the analyses to identical twins only (p < 0.001; B = 0.21). We observed a substantial genetic correlation between problematic use of technology and sleep quality (rA = 0.31), whereas the environmental correlation was lower (rE = 0.16). Conclusions Adolescent reported problematic use of digital technology is associated with poor sleep quality—even after controlling for familial factors including genetic confounds. Our results suggest that the association between adolescents’ sleep and problematic digital technology use is not accounted for by shared genetic liability or familial factors but could reflect a causal association. This robust association needs to be examined in future research designed to test causal associations.

This cohort study assesses 5-year race-stratified neonatal mortality and prevalence of preterm births in the US using birth-based and fetuses-at-risk approaches.

BackgroundMultiple sclerosis, a chronic inflammatory disease in young and middle-aged adults, is one of the leading causes of non-traumatic disability in adults. Diet is known to have an important role in the modulating inflammatory processes and influencing molecular pathways.PurposeThis study aims to examine the association of the inflammatory capacity of diet measured by DII with MS in Jordan.MethodsThis prevalent case-control study included participants of both sexes, aged between 20 and 60 years. The cases (n = 541) had a confirmed diagnosis of prevalent Multiple Sclerosis (MS) in the previous 3 years, and controls (n = 607) were apparently healthy individuals matched on sex and age (42 ± 4 years). A validated Arabic food frequency questionnaire (FFQ) was utilized to obtain estimated dietary intake. Dietary data from the FFQ were analyzed using ESHA’s Food Processor® nutrition analysis software, and the results were used to calculate the DII scores. Logistic regression analyses, controlling for covariates such as age, sex, body mass index, and smoking status, were used to measure the association between DII score and MS outcomes.ResultsCases represent a mixed sample of MS phenotypes and controls were comparable on age and sex. However, controls tended to be taller, lighter, had a lower BMI, and had a lower smoking rate. After controlling for age, BMI, sex, and smoking status, there was a consistent increase in MS risk according to DII score, with a 10-fold increase in odds in quartile 4 vs. quartile 1 [ORquartile 4vs1 = 10.17 (95% CI: 6.88; 15.04)]. For each point increase in DII score, there was nearly a doubling of odds [OR1 = 1.75 (95% CI: 1.59; 1.92)]. Individual nutrients and food values aligned according to their contribution to the DII score calculations.ConclusionThe findings of this study, obtained in MS patients with varied illness duration over the previous 3 years, are consistent with an association between the overall inflammatory potential of diet and MS odds. Our findings among MS participants showed a significantly more pro-inflammatory DII scores than age- and sex-matched controls. Our results also suggest that MS group had a diet rich in pro-inflammatory foods and nutrients.

OBJECTIVES: Globally, there is growing evidence of a double burden of malnutrition with obesity coexisting alongside micronutrient deficiencies across the life course. An emergent double burden poses a threat to health during childhood in Samoa: among 2–4-year-olds with overweight/obesity, 42.9% were anemic. Previous research suggests that obesity-related inflammation may increase the risk of iron deficiency or anemia in children. To test this hypothesis, we examined whether overweight/obesity at 2–4 is associated with anemia at 3.8–6 years old among Samoan children. METHODS: Data were obtained from the Ola Tuputupua’e “Growing Up” cohort study. Overweight/obesity at 2–4 years old was classified by body mass index-for-age Z-score > +2 SD. Anemia was defined as hemoglobin < 110 g/L for under 5-year-olds and < 115 g/L for 5–6-year-olds. Prevalence ratios (PRs) for anemia at 3.8–6 years old were estimated by fitting modified Poisson regression models. RESULTS: In our sample of 197 children, 16.24% (n = 32) were affected by overweight/obesity at 2–4 years old and 26.90% (n = 53) had anemia at 3.8–6 years old. After covariate adjustment, the prevalence of anemia was 18% lower among children with overweight/obesity at 2–4 years old compared to those without (PR:0.82; 95% CI:0.42–1.63); however, the corresponding confidence interval was imprecise and inclusive of a higher prevalence. CONCLUSIONS: There was not strong evidence to support a relationship between overweight/obesity and anemia in Samoan children, suggesting that obesity-related inflammation may not be related to iron deficiency nor anemia in this setting. Further investigation of the antecedents of overweight/obesity and anemia is critical to inform integrated action to improve health in Samoa.

The body depends on its physical barriers and innate and adaptive immune responses to defend against the constant assault of potentially harmful microbes. In turn, successful pathogens have evolved unique mechanisms to adapt to the host environment and manipulate host defenses. Helicobacter pylori (Hp), a human gastric pathogen that is acquired in childhood and persists throughout life, is an example of a bacterium that is very successful at remodeling the host-pathogen interface to promote a long-term persistent infection. Using a combination of secreted virulence factors, immune subversion, and manipulation of cellular mechanisms, Hp can colonize and persist in the hostile environment of the human stomach. Here, we review the most recent and relevant information regarding how this successful pathogen overcomes gastric epithelial host defense responses to facilitate its own survival and establish a chronic infection. Expected final online publication date for the Annual Review of Physiology, Volume 84 is February 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Background: Plasma proteins are critical mediators of cardiovascular processes and are the targets of many drugs. Previous efforts to characterize the genetic architecture of the plasma proteome have been limited by a focus on individuals of European descent and leveraged genotyping arrays and imputation. Here we describe whole genome sequence analysis of the plasma proteome in individuals with greater African ancestry, increasing our power to identify novel genetic determinants. Methods: Proteomic profiling of 1301 proteins was performed in 1852 Black adults from the Jackson Heart Study using aptamer-based proteomics (SomaScan). Whole genome sequencing association analysis was ascertained for all variants with minor allele count ≥5. Results were validated using an alternative, antibody-based, proteomic platform (Olink) as well as replicated in the Multi-Ethnic Study of Atherosclerosis and the HERITAGE Family Study (Health, Risk Factors, Exercise Training and Genetics). Results: We identify 569 genetic associations between 479 proteins and 438 unique genetic regions at a Bonferroni-adjusted significance level of 3.8×10 -11 . These associations include 114 novel locus-protein relationships and an additional 217 novel sentinel variant-protein relationships. Novel cardiovascular findings include new protein associations at the APOE gene locus including ZAP70 (sentinel single nucleotide polymorphism [SNP] rs7412-T, β=0.61±0.05, P =3.27×10 -30 ) and MMP-3 (β=-0.60±0.05, P =1.67×10 -32 ), as well as a completely novel pleiotropic locus at the HPX gene, associated with 9 proteins. Further, the associations suggest new mechanisms of genetically mediated cardiovascular disease linked to African ancestry; we identify a novel association between variants linked to APOL1-associated chronic kidney and heart disease and the protein CKAP2 (rs73885319-G, β=0.34±0.04, P =1.34×10 -17 ) as well as an association between ATTR amyloidosis and RBP4 levels in community-dwelling individuals without heart failure. Conclusions: Taken together, these results provide evidence for the functional importance of variants in non-European populations, and suggest new biological mechanisms for ancestry-specific determinants of lipids, coagulation, and myocardial function.

Inflammatory bowel diseases (IBD) such as Crohn’s disease and ulcerative colitis are chronic relapsing diseases that affect the gastrointestinal tract, most commonly the colon. A link between the gut and the lung is suggested since patients with IBD have an increased susceptibility for chronic inflammatory lung disease. Furthermore, in the absence of overt lung disease, IBD patients have worsened lung function and more leukocytes in sputum than healthy individuals, highlighting a conduit between the gut and lung in disease. To study the gut-lung axis in the context of IBD, we used TCRδ-/- mice, which are highly susceptible to dextran sulfate sodium (DSS) due to the importance of γδ T cells in maintenance of barrier integrity. After induction of experimental colitis using DSS, the lungs of TCRδ-/- mice exhibited signs of inflammation and mild emphysema, which was not observed in DSS-treated C57BL/6 mice. Damage to the lung tissue was accompanied by a large expansion of neutrophils in the lung parenchyma and an increase in alveolar macrophages in the lung wash. Gene expression analyses showed a significant increase in Csf3, Cxcl2, Tnfa, and Il17a in lung tissue in keeping with neutrophil infiltration. Expression of genes encoding reactive oxygen species enzymes and elastolytic enzymes were enhanced in the lungs of both C57BL/6 and TCRδ-/- mice with colitis. Similarly, surfactant gene expression was also enhanced, which may represent a protective mechanism. These data demonstrate that severe colitis in a susceptible genetic background is sufficient to induce lung inflammation and tissue damage, providing the research community with an important tool for the development of novel therapeutics aimed at reducing co-morbidities in IBD patients.

Supplementary Figures 7-10 from Helicobacter pylori Cytotoxin-Associated Gene A Activates the Signal Transducer and Activator of Transcription 3 Pathway In vitro and In vivo

Supplementary Table 1 from Helicobacter pylori Cytotoxin-Associated Gene A Activates the Signal Transducer and Activator of Transcription 3 Pathway In vitro and In vivo

Supplementary Figure 11 from Helicobacter pylori Cytotoxin-Associated Gene A Activates the Signal Transducer and Activator of Transcription 3 Pathway In vitro and In vivo

Supplementary Figures 4-6 from Helicobacter pylori Cytotoxin-Associated Gene A Activates the Signal Transducer and Activator of Transcription 3 Pathway In vitro and In vivo

Supplementary Legends 1-8 from Helicobacter pylori Cytotoxin-Associated Gene A Activates the Signal Transducer and Activator of Transcription 3 Pathway In vitro and In vivo

Coaches and psychologists can use time-motion analysis to elaborate specific interventions for female BJJ athletes, increasing specific training context and reducing unnecessary psychological and physical demands and injuries. Therefore, the present study aimed to analyze high-level BJJ female athletes in the 2020 Pan-American Games by comparing the weight categories on the time-motion analysis. The time-motion analysis (i.e., approach, gripping, attack, defensive actions, transition, mounting, guard, side control, and submissions) of 422 high-level female BJJ combats was divided and compared by weight category as follows: Rooster (n = 8), Light Feather (n = 18), Feather (n = 122), Light (n = 84), Middle (n = 74), Medium Heavy (n = 44), Heavy (n = 36), Super Heavy (n = 36), using p ≤ 0.05. The main results indicated that the Super heavyweight category [3.1 (5.8;119.9) s] had a shorter gripping time than other weight categories, p ≤ 0.05. In contrast, roosters [7.2 (3.5;64.6) s] had longer gripping, transition [14.0 (4.8;29.6) s], and attack time [76.2 (27.7, 93.2)] than the light feather, middlers, and heavier weight categories, p ≤ 0.05. These findings should be considered for the psychological interventions and training prescription.

The dynein-2 complex must be transported anterogradely within cilia to then drive retrograde trafficking of the intraflagellar transport (IFT) machinery containing IFT-A and IFT-B complexes. Here, we screened for potential interactions between the dynein-2 and IFT-B complexes and found multiple interactions among the dynein-2 and IFT-B subunits. In particular, WDR60 (also known as DYNC2I1) and the DYNC2H1–DYNC2LI1 dimer from dynein-2, and IFT54 (also known as TRAF3IP1) and IFT57 from IFT-B contribute to the dynein-2–IFT-B interactions. WDR60 interacts with IFT54 via a conserved region N-terminal to its light chain-binding regions. Expression of the WDR60 constructs in WDR60-knockout (KO) cells revealed that N-terminal truncation mutants lacking the IFT54-binding site fail to rescue abnormal phenotypes of WDR60-KO cells, such as aberrant accumulation of the IFT machinery around the ciliary tip and on the distal side of the transition zone. However, a WDR60 construct specifically lacking just the IFT54-binding site substantially restored the ciliary defects. In line with the current docking model of dynein-2 with the anterograde IFT trains, these results indicate that extensive interactions involving multiple subunits from the dynein-2 and IFT-B complexes participate in their connection.

Patients with atopic dermatitis (AD) display a defective skin barrier, consequently they may experience inflammatory flares with different exposures, including masks. Actually, beside scattering case reports, no study focused on the possible AD flaring due to masks.In this multicenter prospective study AD patients with facial manifestation were followed with teledermatology and evaluated by two board-certified dermatologists at the baseline (T0) and after 1 month (T1) in which patients started to wear masks6 hours per day. Demographics and clinical parameters, included and not limited to Eczema Area and Severity Index (EASI) and Dermatology Life Quality Index (DLQI), were carefully collected and analyzed.We enrolled 57 AD patients (M/F 28/29, 33.91 ± 12.26 yoa) that wore surgical masks (38 (66.7%)), community masks (11 (19.3%) and N95 (8 (14.0%)). Both DLQI and EASI increase during the time period (p0.0001). DLQI variation was not influenced by age, BMI, and gender, mask type used and AD therapy (p=0.99), whilst EASI variation was significantly influenced by BMI, gender, and therapy (p=0.004).Mask wearing may prove detrimental to patients with atopic eczema and the same may not necessarily be the case for asthma patients.

Sleep is a fundamental state, important for health, well-being and longevity. Yet consistently poor/ insufficient sleep or symptoms of insomnia affect as many as a third of the adult population worldwide. In order to reduce the impact of insomnia and poor sleep quality, it is first of interest to understand their aetiology. Numerous behavioural genetic studies have indicated that insomnia and sleep quality are under partial genetic control (accounting for between 31%-44% of the variance according to recent meta-analyses). However, attempts to elucidate the genetic pathways involved have been slower than anticipated, and replete with inconsistencies. There have been non-replications of initially promising genetic variants involved in insomnia-related phenotypes for many reasons. For example, the effects of individual genes are small; and/or that genetic factors interact with the environment to exert their effects on insomnia-related phenotypes. With regards this latter point, there have been a handful of studies highlighting a probable role for gene-environment interaction (GxE) in insomnia-related phenotypes, but this field is also replete with inconsistencies. This is likely due to 1) the selection of individual genetic variants in isolation, rather than the consideration of a broader array of genetic effects, in interaction with the environment; 2) different ways of conceptualising ‘environmental risk’; 3) different ways of conceptualising insomnia; and/or 4) direct (genetic) and indirect (GxE) effects being moderated by other factors such as sex. One way to overcome this first point is to examine the contribution of Polygenic Risk Scores (PRS). PRS use GWAS data to create a summarised effect of multiple genetic variants acting upon a phenotype. PRS can then be used in regression analyses to examine associations with the trait in question, as well as in models exploring possible gene-environment interaction. An understanding of the extent of gene-environment interaction influencing insomnia will enable us to identify who may be at risk for insomnia, and who may benefit from preventative interventions. Thus, the overall aim of this research is to understand more about the role of gene-environment interaction (GxE) in the aetiology of insomnia, and the possibility of sex-specific GxE effects.

The cation/proton exchange illustration during the reduction/reoxidation process of {P5W30}.