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Abstract The patterns of spread of influenza A viruses in local populations in tropical and sub-tropical regions are unclear due to sparsity of representative spatiotemporal sequence data. We sequenced and analyzed 58 influenza A(H3N2) virus genomes sampled between December 2015 and December 2016 from nine health facilities within the Kilifi Health and Demographic Surveillance System (KHDSS), a predominantly rural region, covering approximately 891 km2 along the Kenyan coastline. The genomes were compared with 1571 contemporaneous global sequences from 75 countries. We observed at least five independent introductions of A(H3N2) viruses into the region during the one-year period, with the importations originating from Africa, Europe, and North America. We also inferred 23 virus location transition events between the nine facilities included in the study. International virus imports into the study area were captured at the facilities of Chasimba, Matsangoni, Mtondia, and Mavueni, while all four exports from the region were captured from the Chasimba facility, all occurring to Africa destinations. A strong spatial clustering of virus strains at all locations was observed associated with local evolution. Our study shows that influenza A(H3N2) virus epidemics in local populations appear to be characterized by limited introductions followed by significant local spread and evolution. Knowledge of the viral lineages that circulate within specific populations in understudied tropical and subtropical regions is required to understand the full diversity and global ecology of influenza viruses and to inform vaccination strategies within these populations.

Abstract The epidemiology and circulation patterns of various rhinovirus types within populations remains under-explored. We generated 803 VP4/VP2 gene sequences from rhinovirus-positive samples collected from acute respiratory illness (ARI) patients, including both in-patient and outpatient cases, between 1st January and 31st December 2014 from eleven surveillance sites across Kenya and used phylogenetics to characterise virus introductions and spread. RVs were detected throughout the year, with the highest detection rates observed from January to March and June to July. We detected a total of 114 of the 169 currently classified types. Our analysis revealed numerous virus introductions into Kenya characterized by local expansion and extinction, and extensive spatial mixing of types within the country due to the widespread transmission of the virus after an introduction. This work demonstrates that in a single year, the circulation of rhinovirus in Kenya was characterized by substantial genetic diversity, multiple introductions, and extensive geographical spread.

Abstract Elevated triglycerides (TG) are a risk factor for cardiometabolic disorders. There are limited data on lipidomics profiles associated with serum triglycerides concentrations, although these could advance our understanding of the mechanisms underlying these associations. We conducted a lipidomics study of 308 Nigerians with replication in 199 Kenyans. Regression models were used to assess the association of TG with 480 lipid metabolites. Association and mediation analyses were conducted to determine the relationship among TG, metabolites, and several cardiometabolic traits. Ninety-nine metabolites were significantly associated with TG, and 91% of these associations replicated. Overrepresentation analysis identified enrichment of diacylglycerols, monoacylglycerols, diacylglycerophosphoethanolamines, monoacylglycerophosphocholines, ceramide phosphocholines, and diacylglycerophosphocholines. TG-cardiometabolic trait associations were largely mediated by TG-associated metabolites. Associations with type 2 diabetes, waist circumference, body mass index, total cholesterol, and low-density lipoprotein cholesterol concentration were independently mediated by metabolites in multiple subpathways. This lipidomics study in sub-Saharan Africans demonstrated that TG is associated with several non-TG lipids classes, including phosphatidylethanolamines, phosphatidylcholines, lysophospholipids, and plasmalogens, some of which may mediate the effect of TG as a risk factor for cardiometabolic disorders. The study identifies metabolites that are more proximal to cardiometabolic traits, which may be useful for understanding the underlying biology as well as differences in TG-trait associations across ancestries.

Abstract The role of sub-Saharan Africa in the global spread of influenza viruses remains unclear due to insufficient spatiotemporal sequence data. Here, we analyzed 222 codon-complete sequences of influenza A viruses (IAVs) sampled between 2011 and 2013 from five countries across sub-Saharan Africa (Kenya, Zambia, Mali, Gambia, and South Africa); these genomes were compared with 1209 contemporaneous global genomes using phylogeographical approaches. The spread of influenza in sub-Saharan Africa was characterized by (i) multiple introductions of IAVs into the region over consecutive influenza seasons, with viral importations originating from multiple global geographical regions, some of which persisted in circulation as intra-subtype reassortants for multiple seasons, (ii) virus transfer between sub-Saharan African countries, and (iii) virus export from sub-Saharan Africa to other geographical regions. Despite sparse data from influenza surveillance in sub-Saharan Africa, our findings support the notion that influenza viruses persist as temporally structured migrating metapopulations in which new virus strains can emerge in any geographical region, including in sub-Saharan Africa; these lineages may have been capable of dissemination to other continents through a globally migrating virus population. Further knowledge of the viral lineages that circulate within understudied sub-Saharan Africa regions is required to inform vaccination strategies in those regions.

Abstract To assess the aetiologies, clinical characteristics, treatment regimens, and outcomes of acute chemical injuries treated at an emergency eye clinic. Retrospective, observational study of all cases of chemical eye injury that presented acutely to the Greenlane Clinical Centre in Auckland, New Zealand from 1 January 2012 through 31 December 2021. Patient demographics, activity at the time of injury, causative chemical, clinical characteristics of injury at presentation, severity (Dua) classification, admission and discharge best corrected visual acuity (BCVA), treatment regimen, time to epithelisation and number of follow-up appointments were recorded. In total, 1522 cases involving 1919 eyes were studied. The mean age was 40.6 ± 18.8 years and 65% were male. The majority of cases occurred at home (62%) and cleaning was the most common activity (38%). There were 1490 Grade I (98%), 22 Grade II (1.5%), 5 Grade III (0.3%), 1 Grade IV (0.07%), 0 Grade V, and 4 Grade VI (0.3%) cases. An epithelial defect was noted in 409 cases (26.9%), of which re-epithelialisation occurred within one week for 378 cases (92%) and within 30 days for 384 cases (94%). Moderate vision loss (BCVA ≤ 6/12) attributed to the injury occurred in 152 (10%), while severe vision loss (BCVA ≤ 6/60) occurred in 30 (2%). Lack of irrigation at the scene was associated with an increased risk of severe injury and longstanding visual impairment (p = 0.0001). Most acute chemical injuries are mild with good clinical outcomes. Although rare, severe injuries are associated with a lack of irrigation at the scene and worse visual outcomes.

Abstract Influenza viruses undergo rapid evolutionary changes, which requires continuous surveillance to monitor for genetic and potential antigenic changes in circulating viruses that can guide control and prevention decision making. We sequenced and phylogenetically analyzed A(H1N1)pdm09 virus genome sequences obtained from specimens collected from hospitalized patients of all ages with or without pneumonia between 2009 and 2018 from seven sentinel surveillance sites across Kenya. We compared these sequences with recommended vaccine strains during the study period to infer genetic and potential antigenic changes in circulating viruses and associations of clinical outcome. We generated and analyzed a total of 383 A(H1N1)pdm09 virus genome sequences. Phylogenetic analyses of HA protein revealed that multiple genetic groups (clades, subclades, and subgroups) of A(H1N1)pdm09 virus circulated in Kenya over the study period; these evolved away from their vaccine strain, forming clades 7 and 6, subclades 6C, 6B, and 6B.1, and subgroups 6B.1A and 6B.1A1 through acquisition of additional substitutions. Several amino acid substitutions among circulating viruses were associated with continued evolution of the viruses, especially in antigenic epitopes and receptor binding sites (RBS) of circulating viruses. Disease severity declined with an increase in age among children aged

Abstract Genetic characterisation of circulating influenza viruses directs annual vaccine strain selection and mitigation of infection spread. We used next-generation sequencing to locally generate whole genomes from 116 A(H1N1)pdm09 and 118 A(H3N2) positive patient swabs collected across Uganda between 2010 and 2018. We recovered sequences from 92% (215/234) of the swabs, 90% (193/215) of which were whole genomes. The newly-generated sequences were genetically and phylogenetically compared to the WHO-recommended vaccines and other Africa strains sampled since 1994. Uganda strain hemagglutinin (n = 206), neuraminidase (n = 207), and matrix protein (MP, n = 213) sequences had 95.23–99.65%, 95.31–99.79%, and 95.46–100% amino acid similarity to the 2010–2020 season vaccines, respectively, with several mutated hemagglutinin antigenic, receptor binding, and N-linked glycosylation sites. Uganda influenza type-A virus strains sequenced before 2016 clustered uniquely while later strains mixed with other Africa and global strains. We are the first to report novel A(H1N1)pdm09 subclades 6B.1A.3, 6B.1A.5(a,b), and 6B.1A.6 (± T120A) that circulated in Eastern, Western, and Southern Africa in 2017–2019. Africa forms part of the global influenza ecology with high viral genetic diversity, progressive antigenic drift, and local transmissions. For a continent with inadequate health resources and where social distancing is unsustainable, vaccination is the best option. Hence, African stakeholders should prioritise routine genome sequencing and analysis to direct vaccine selection and virus control.

Abstract Reports of cognitive impairment in inflammatory bowel disease (IBD) have been mixed. IBD and cardiovascular disease are often co-morbid, yet it remains unknown whether vascular comorbidity confers a risk for decreased cognitive functioning, as observed in other populations. Participants with IBD were recruited from a longitudinal study of immune-mediated disease. Participants were administered a standardized neuropsychological test protocol, evaluating information processing speed, verbal learning and memory, visual learning and memory, and verbal fluency/executive function. Cognitive test scores were standardized using local regression-based norms, adjusting for age, sex, and education. Vascular risk was calculated using a modified Framingham Risk Score (FRS). We tested the association between FRS and cognitive test scores using a quantile regression model, adjusting for IBD type. Of 84 IBD participants, 54 had ulcerative colitis and 30 had Crohn’s disease; mean (SD) age was 53.36 (13.95) years, and a high proportion were females (n = 58). As the risk score (FRS) increased, participants demonstrated lower performance in information processing speed (β = − 0.12; 95% CI − 0.24, − 0.006) and verbal learning (β = − 0.14; 95% CI − 0.28, − 0.01) at the 50th percentile. After adjusting for IBD type and disease activity, higher FRS remained associated with lower information processing speed (β = − 0.14; 95% CI − 0.27, − 0.065). Vascular comorbidity is associated with lower cognitive functioning in persons with IBD, particularly in the area of information processing speed. These findings suggest that prevention, identification, and treatment of vascular comorbidity in IBD may play a critical role for improving functional outcomes in IBD.

Abstract Tyrosyl-DNA phosphodiesterase I (Tdp1) hydrolyzes phosphodiester-linked adducts from both ends of DNA. This includes the topoisomerase I (TOP1)-DNA covalent reaction intermediate that is the target of the camptothecin class of chemotherapeutics. Tdp1 two-step catalysis is centered on the formation of a Tdp1-DNA covalent complex (Tdp1cc) using two catalytic histidines. Here, we examined the role of the understudied, structurally undefined, and poorly conserved N-terminal domain (NTD) of Tdp1 in context of full-length protein in its ability to remove TOP1cc in cells. Using toxic Tdp1 mutants, we observed that the NTD is critical for Tdp1’s ability to remove TOP1-DNA adducts in yeast. Full-length and N-terminal truncated Tdp1 mutants showed similar expression levels and cellular distribution yet an inversed TOP1-dependent toxicity. Single turnover catalysis was significantly different between full-length and truncated catalytic mutants but not wild-type enzyme, suggesting that Tdp1 mutants depend on the NTD for catalysis. These observations suggest that the NTD plays a critical role in the regulation of Tdp1 activity and interaction with protein-DNA adducts such as TOP1cc in cells. We propose that the NTD is a regulatory domain and coordinates stabilization of the DNA-adducted end within the catalytic pocket to access the phosphodiester linkage for hydrolysis.

Abstract Adiponectin has been associated with cardiometabolic traits in observational studies across populations, yet it is unclear if these associations are causal. We performed Mendelian randomization (MR) analysis to assess the relationship between adiponectin and cardiometabolic traits in sub-Saharan Africans. We constructed a polygenic risk score (PRS) for adiponectin levels across 3354 unrelated sub-Saharan Africans. The PRS was used as the instrumental variable in two-stage least-squares MR analysis to assess its association with insulin resistance, HDL, LDL, total cholesterol, triglycerides, blood pressure, Type 2 Diabetes (T2D), and hypertension. The adiponectin PRS was causally related with LDL (β = 0.55, 95%CI 0.07–1.04, P-value = 0.024) but not the other traits. This association was observed in both overweight/obese and normal weight individuals, but only reached statistical significance among overweight/obese individuals (β = 0.55, 95%CI 0.01–1.08, P-value = 0.045). In normal weight individuals, the adiponectin PRS was associated with T2D (OR = 0.13, 95%CI 0.02–0.73, P-value = 0.021), and in men with HDL (β = 1.03, 95%CI 0.14–1.92, P-value = 0.023). The findings of this first MR study in sub-Saharan Africans support a causal relationship of adiponectin with LDL, with T2D in normal weight individuals only, and with HDL in men only. These observations add to the small but growing literature on adiponectin MR studies.

Abstract Many conjunctival inflammatory diseases differ between the sexes and altered conjunctival goblet cells (CGCs) response is often involved. Inflammation is initiated by the release of pro-inflammatory mediators and terminated by the biosynthesis of specialized pro-resolution mediators (SPMs). Herein, we determined the sex-based difference in the responses of CGCs to inflammatory stimuli or pro-resolving lipid SPMs and their interaction with sex hormones. GCs were cultured from pieces of human conjunctiva in RPMI media. CGCs were transferred 24 h before the start of experiments to phenol red-free and FBS-free media to minimize exogenous hormones. RT-PCR, immunofluorescence microscopy (IF), and Western Blot (WB) were performed to determine the presence of sex hormone receptors. Cellular response to pro-inflammatory stimuli or SPMs was studied by measuring the increase in intracellular [Ca2+] ([Ca2+]i) using fura 2/AM microscopy. Use of RT-PCR demonstrated estrogen receptor (ER) α in 4/5 males and 3/3 females; ERβ in 2/4 males and 2/3 females; and androgen receptors (AR) in 3/3 male and 3/3 female CGCs. Positive immunoreactivity by IF and protein expression by WB was detected using antibodies for the ERα and ERβ in 3/3 males and 3/3 females, while AR were only present in males. Significantly different Ca2+ responses between sexes were found with carbachol only at 10–3 M, but not with histamine or leukotriene (LT) B4 at any concentration used. Incubation with dihydrotestosterone (DHT), estrone (E1), or estradiol (E2) at 10–7 M for 30 min significantly inhibited the LTB4-stimulated [Ca2+]i increase in male and female CGCs. Incubation with DHT, E1, and E2 overnight significantly inhibited the LTB4 response in females, while DHT and E2 significantly inhibited the LTB4 response in males. The SPM lipoxin A4 (LXA4) (10–9–10−8 M), but not the resolvins D1 or D2, induced an [Ca2+]i increase that was significantly higher in males compared to females. We conclude that male and female CGCs showed differences in the expression of sex hormone receptors. Treatment with sex hormones altered pro-inflammatory mediator LTB4-induced response. Males compared to females have a higher response to the ω-6-fatty acid derived SPM LXA4, indicating males may terminate inflammation in conjunctival goblet cells faster than females.

Abstract Obesity can initiate, promote, and maintain systemic inflammation via metabolic reprogramming of macrophages that encircle adipocytes, termed crown-like structures (CLS). In breast cancer the presence of CLS has been correlated to high body mass index (BMI), larger mammary adipocyte size and postmenopausal status. However, the prognostic significance of CLS in HER2 + breast cancer is still unknown. We investigated the prognostic significance of CLS in a cohort of 69 trastuzumab-naïve and 117 adjuvant trastuzumab-treated patients with primary HER2 + breast cancer. Immunohistochemistry of tumour blocks was performed for CLS and correlated to clinical outcomes. CLS were more commonly found at the adipose-tumour border (B-CLS) (64.8% of patients). The presence of multiple B-CLS was associated with reduced time to metastatic disease (TMD) in trastuzumab treated patients with BMI ≥ 25 kg/m2 but not those with BMI

Abstract Convulxin (CVX), a C-type lectin-like protein isolated from the venom of the snake species, Crotalus durissus terrificus, stimulates platelet aggregation by acting as a collagen receptor agonist for glycoprotein VI found in the platelets. The effect of CVX on platelets has been studied, but its effect on human peripheral blood mononuclear cells (PBMCs) remains unclear. Given the significance of PBMCs in inflammation, this study explored the effect of CVX on PBMCs, specifically regarding NLRP3 inflammasome activation by assessing cell viability, ability to induce cell proliferation, reactive oxygen species (ROS) and nitric oxide production, interleukin (IL)-2 and IL-10 secretion, NLRP3 complex activation, and the role of C-type lectin-like receptors (CTLRs) in these. CVX was not toxic to PBMCs at the investigated concentrations and did not increase PBMC growth or IL-2 release; however, CVX induced IL-10 release and ROS generation via monocyte activation. It also activated the NLRP3 complex, resulting in IL-1β induction. Furthermore, the interaction between CVX and Dectin-2, a CTLR, induced IL-10 production. CVX interaction with CTLR has been demonstrated by laminarin therapy. Because of the involvement of residues near the Dectin-2 carbohydrate-recognition site, the generation of ROS resulted in inflammasome activation and IL-1β secretion. Overall, this work helps elucidate the function of CVX in immune system cells.

Abstract Pneumonia remains a major cause of mortality and morbidity. Most molecular diagnoses of viruses rely on polymerase chain reaction (PCR) assays that however can fail due to primer mismatch. We investigated the performance of routine virus diagnostics in Kilifi, Kenya, using random-primed viral next generation sequencing (viral NGS) on respiratory samples which tested negative for the common viral respiratory pathogens by a local standard diagnostic panel. Among 95 hospitalised pneumonia patients and 95 household-cohort individuals, analysis of viral NGS identified at least one respiratory-associated virus in 35 (37%) and 23 (24%) samples, respectively. The majority (66%; 42/64) belonged to the Picornaviridae family. The NGS data analysis identified a number of viruses that were missed by the diagnostic panel (rhinovirus, human metapneumovirus, respiratory syncytial virus and parainfluenza virus), and these failures could be attributed to PCR primer/probe binding site mismatches. Unexpected viruses identified included parvovirus B19, enterovirus D68, coxsackievirus A16 and A24 and rubella virus. The regular application of such viral NGS could help evaluate assay performance, identify molecular causes of missed diagnoses and reveal gaps in the respiratory virus set used for local screening assays. The results can provide actionable information to improve the local pneumonia diagnostics and reveal locally important viral pathogens.

Abstract Sulfotransferase 4A1 (SULT4A1) is an orphan member of the cytosolic SULT superfamily that contains enzymes that catalyze the sulfonation of hydrophobic drugs and hormones. SULT4A1 has been assessed through all classical SULT approaches yet no SULT activity has been reported. To ascertain SULT4A1 function and activity, we utilized Saccharomyces cerevisiae as a model system, which exhibits no endogenous SULT activity nor possesses SULT-related genes. We observed that ectopic SULT4A1 expression in yeast displays similar subcellular localization as reported in mouse neurons and observed that SULT4A1 is associated with the outer mitochondria membrane. SULT4A1 expression stimulates colony formation and protects these cells from hydrogen peroxide and metabolism-associated oxidative stress. These SULT4A1-mediated phenotypes are dependent on extracellular sulfate that is converted in yeast to PAPS, the universal sulfonate donor for SULT activity. Thus, heterologous SULT4A1 expression in yeast is correctly distributed and functional, and SULT4A1 antioxidant activity is sulfate dependent supporting the concept that SULT4A1 has sulfate-associated activity.

Abstract Axonal loss is the main determinant of disease progression in multiple sclerosis (MS). This study aimed to assess the utility of corneal confocal microscopy (CCM) in detecting corneal axonal loss in different courses of MS. The results were confirmed by two independent segmentation methods. 72 subjects (144 eyes) [(clinically isolated syndrome (n = 9); relapsing–remitting MS (n = 20); secondary-progressive MS (n = 22); and age-matched, healthy controls (n = 21)] underwent CCM and assessment of their disability status. Two independent algorithms (ACCMetrics; and Voxeleron deepNerve) were used to quantify corneal nerve fiber density (CNFD) (ACCMetrics only), corneal nerve fiber length (CNFL) and corneal nerve fractal dimension (CNFrD). Data are expressed as mean ± standard deviation with 95% confidence interval (CI). Compared to controls, patients with MS had significantly lower CNFD (34.76 ± 5.57 vs. 19.85 ± 6.75 fibers/mm2, 95% CI − 18.24 to − 11.59, P

Abstract The internal architecture of chambered ammonoid conchs profoundly increased in complexity through geologic time, but the adaptive value of these structures is disputed. Specifically, these cephalopods developed fractal-like folds along the edges of their internal divider walls (septa). Traditionally, functional explanations for septal complexity have largely focused on biomechanical stress resistance. However, the impact of these structures on buoyancy manipulation deserves fresh scrutiny. We propose increased septal complexity conveyed comparable shifts in fluid retention capacity within each chamber. We test this interpretation by measuring the liquid retained by septa, and within entire chambers, in several 3D-printed cephalopod shell archetypes, treated with (and without) biomimetic hydrophilic coatings. Results show that surface tension regulates water retention capacity in the chambers, which positively scales with septal complexity and membrane capillarity, and negatively scales with size. A greater capacity for liquid retention in ammonoids may have improved buoyancy regulation, or compensated for mass changes during life. Increased liquid retention in our experiments demonstrate an increase in areas of greater surface tension potential, supporting improved chamber refilling. These findings support interpretations that ammonoids with complex sutures may have had more active buoyancy regulation compared to other groups of ectocochleate cephalopods. Overall, the relationship between septal complexity and liquid retention capacity through surface tension presents a robust yet simple functional explanation for the mechanisms driving this global biotic pattern.

Abstract Genome-wide association studies (GWAS) have identified thousands of genetic loci associated with cross-sectional blood pressure (BP) traits; however, GWAS based on longitudinal BP have been underexplored. We performed ethnic-specific and trans-ethnic GWAS meta-analysis using longitudinal and cross-sectional BP data of 33,720 individuals from five cohorts in the US and one in Brazil. In addition to identifying several known loci, we identified thirteen novel loci with nine based on longitudinal and four on cross-sectional BP traits. Most of the novel loci were ethnic- or study-specific, with the majority identified in African Americans (AA). Four of these discoveries showed additional evidence of association in independent datasets, including an intergenic variant (rs4060030, p = 7.3 × 10–9) with reported regulatory function. We observed a high correlation between the meta-analysis results for baseline and longitudinal average BP (rho = 0.48). BP trajectory results were more correlated with those of average BP (rho = 0.35) than baseline BP(rho = 0.18). Heritability estimates trended higher for longitudinal traits than for cross-sectional traits, providing evidence for different genetic architectures. Furthermore, the longitudinal data identified up to 20% more BP known associations than did cross-sectional data. Our analyses of longitudinal BP data in diverse ethnic groups identified novel BP loci associated with BP trajectory, indicating a need for further longitudinal GWAS on BP and other age-related traits.

Abstract Respiratory syncytial virus (RSV) is responsible for a significant burden of severe acute lower respiratory tract illness in children under 5 years old; particularly infants. Prior to rolling out any vaccination program, identification of the source of infant infections could further guide vaccination strategies. We extended a dynamic model calibrated at the individual host level initially fit to social-temporal data on shedding patterns to include whole genome sequencing data available at a lower sampling intensity. The study population was 493 individuals (55 aged

Abstract Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease with limited therapeutic options and poor prognosis. IPF has been associated with aberrant vascular remodelling, however the role of vascular remodelling in pulmonary fibrosis is poorly understood. Here, we used a novel segmental challenge model of bleomycin-induced pulmonary fibrosis in sheep to evaluate the remodelling of the pulmonary vasculature, and to investigate the changes to this remodelling after the administration of the KCa3.1 channel inhibitor, senicapoc, compared to the FDA-approved drug pirfenidone. We demonstrate that in vehicle-treated sheep, bleomycin-infused lung segments had significantly higher blood vessel density when compared to saline-infused control segments in the same sheep. These microvascular density changes were significantly attenuated by senicapoc treatment. The increases in vascular endothelial growth factor (VEGF) expression and endothelial cell proliferation in bleomycin-infused lung segments were significantly reduced in sheep treated with the senicapoc, when compared to vehicle-treated controls. These parameters were not significantly suppressed with pirfenidone treatment. Senicapoc treatment attenuated vascular remodelling through inhibition of capillary endothelial cell proliferation and VEGF expression. These findings suggest a potential new mode of action for the novel drug senicapoc which may contribute to its efficacy in combatting pulmonary fibrosis.

Abstract Genetic and archaeological studies have established a sub-Saharan African origin for anatomically modern humans with subsequent migrations out of Africa. Using the largest multi-locus data set known to date, we investigated genetic differentiation of early modern humans, human admixture and migration events, and relationships among ancestries and language groups. We compiled publicly available genome-wide genotype data on 5,966 individuals from 282 global samples, representing 30 primary language families. The best evidence supports 21 ancestries that delineate genetic structure of present-day human populations. Independent of self-identified ethno-linguistic labels, the vast majority (97.3%) of individuals have mixed ancestry, with evidence of multiple ancestries in 96.8% of samples and on all continents. The data indicate that continents, ethno-linguistic groups, races, ethnicities, and individuals all show substantial ancestral heterogeneity. We estimated correlation coefficients ranging from 0.522 to 0.962 between ancestries and language families or branches. Ancestry data support the grouping of Kwadi-Khoe, Kx’a, and Tuu languages, support the exclusion of Omotic languages from the Afroasiatic language family, and do not support the proposed Dené-Yeniseian language family as a genetically valid grouping. Ancestry data yield insight into a deeper past than linguistic data can, while linguistic data provide clarity to ancestry data.

Abstract Genetics plays a central role in susceptibility to obesity and metabolic diseases. BALB/c mice are known to be resistant to high fat diet (HFD)-induced obesity, however the genetic cause remains unknown. We report that deletion of the innate immunity antibacterial gene Nod2 abolishes this resistance, as Nod2 −/− BALB/c mice developed HFD-dependent obesity and hallmark features of metabolic syndrome. Nod2 −/− HFD mice developed hyperlipidemia, hyperglycemia, glucose intolerance, increased adiposity, and steatosis, with large lipid droplets in their hepatocytes. These changes were accompanied by increased expression of immune genes in adipose tissue and differential expression of genes for lipid metabolism, signaling, stress, transport, cell cycle, and development in both adipose tissue and liver. Nod2 −/− HFD mice exhibited changes in the composition of the gut microbiota and long-term treatment with antibiotics abolished diet-dependent weight gain in Nod2 −/− mice, but not in wild type mice. Furthermore, microbiota from Nod2 −/− HFD mice transferred sensitivity to weight gain, steatosis, and hyperglycemia to wild type germ free mice. In summary, we have identified a novel role for Nod2 in obesity and demonstrate that Nod2 and Nod2-regulated microbiota protect BALB/c mice from diet-induced obesity and metabolic dysfunction.

Abstract Effective verification of soil organic carbon (SOC) improvement interventions through soil carbon sequestration (SCS) requires robust methodologies to measure, report, and verify changes in soil carbon (C) levels. Furthermore, soil C must be monitored over time to ensure that sequestered C is not being re-emitted, thus ensuring the permanence of C removals. The traditional methods for soil C measurement are time-consuming, labor-intensive, and energy-intensive, increasing analysis costs. In this article, we verify the use of a commercially available laser-induced breakdown spectroscopy analyzer, the LaserAg-Quantum, coupled with the recursive feature addition, the gradient-boosted decision trees regression model, and the novelty detection model to predict C in soils. The developed method shows promising performance with an average limit of quantification of 0.75% of C and a precision of 4.10%. Accuracy metrics, including R2, mean absolute error, and root mean square error, yielded values of 0.81, 0.27%, and 0.37% for the validation dataset. Additionally, around 10% of validation samples after the novelty detection model exhibited relative error greater than 30%. Finally, our findings demonstrate the potential of the LaserAg-Quantum process to support measuring SOC in agricultural soils on a large scale.