Status and trends in the international wildlife trade in Chameleons with a focus on Tanzania.

Chameleons (family Chamaeleonidae) are a distinctive group of reptiles, mainly found in Africa, which have high local endemism and face significant threats from the international wildlife trade. We review the scale and structure of international chameleon trade, with a focus on collection in and exports from Tanzania; a hotspot of chameleon diversity. Analysis used data from the CITES Trade Database 2000-2019, combined with assessment of online trade, and on-the-ground surveys in Tanzania in 2019. Between 2000 and 2019, 1,128,776 live chameleons from 108 species were reported as exported globally, with 193,093 of these (from 32 species) exported by Tanzania. Both global and Tanzanian chameleon exports declined across the study period, driven by decreased trade in generalist genera. Whilst the proportion of captive-bred individuals increased across time for the generalist taxa, the majority of range-restricted taxa in trade remained largely wild-sourced. For Tanzanian exports, 41% of chameleons were from one of the 23 endemic species, and 10 of the 12 Tanzanian endemic species in trade are categorised as threatened with extinction by IUCN. In terms of online trade, of the 42 Tanzanian species assessed, there was evidence of online sale for 83.3% species, and 69% were actively for sale with prices listed. Prices were on average highest for Trioceros species, followed by Kinyongia, Rieppeleon, Rhampholeon, and Chameleo. Field work in Tanzania provided evidence that the historic harvest of endemic chameleon species has been higher than the quantities of these species reported as exported by Tanzania in their annual trade reports to CITES. However, we found no field evidence for trade in 2020 and 2021, in line with Tanzanian regulations that applied a blanket ban on all exports of live wild animals. Literature evidence, however, suggests that illegal trade continued to Europe from seizures of Tanzanian chameleon species in Austria in 2021.

Cardiomyopathy associated 5 (CMYA5) implicated as a genetic risk factor for radial hemimelia in Siamese cats.

OBJECTIVES: The present study aimed to determine the inheritance pattern and genetic cause of congenital radial hemimelia (RH) in cats. METHODS: Clinical and genetic analyses were conducted on a Siamese cat family (n = 18), including two siblings with RH. Radiographs were obtained for the affected kittens and echocardiograms of an affected kitten and sire. Whole genome sequencing was completed on the two cases and the parents. Genomic data were compared with the 99 Lives Cat Genome data set of 420 additional domestic cats with whole genome and whole exome sequencing data. Variants were considered as homozygous in the two cases of the siblings with RH and heterozygous in the parents. Candidate variants were genotyped by Sanger sequencing in the extended pedigree. RESULTS: Radiographs of the female kitten revealed bilateral absence of the radii and bowing of the humeri, while the male kitten showed a dysplastic right radius. Echocardiography suggested the female kitten had restrictive cardiomyopathy with a positive left atrial-to-aortic root ratio (LA:Ao = 1.83 cm), whereas hypertrophic cardiomyopathy was more likely in the sire, showing diastolic dysfunction using tissue Doppler imaging (59.06 cm/s). Twenty-two DNA variants were unique and homozygous in the affected kittens and heterozygous in the parents. Seven variants clustered in one chromosomal region, including two frameshift variants in cardiomyopathy associated 5 (CMYA5) and five variants in junction mediating and regulatory protein, P53 cofactor (JMY ), including a missense and an in-frame deletion. CONCLUSIONS AND RELEVANCE: The present study suggested an autosomal recessive mode of inheritance with variable expression for RH in the Siamese cat family. Candidate variants for the phenotype were identified, implicating their roles in bone development. These genes should be considered as potentially causal for other cats with RH. Siamese cat breeders should consider genetically testing their cats for these variants to prevent further dissemination of the suspected variants within the breed.

Genome sequencing of 2000 canids by the Dog10K consortium advances the understanding of demography, genome function and architecture.

BACKGROUND: The international Dog10K project aims to sequence and analyze several thousand canine genomes. Incorporating 20 × data from 1987 individuals, including 1611 dogs (321 breeds), 309 village dogs, 63 wolves, and four coyotes, we identify genomic variation across the canid family, setting the stage for detailed studies of domestication, behavior, morphology, disease susceptibility, and genome architecture and function. RESULTS: We report the analysis of > 48 M single-nucleotide, indel, and structural variants spanning the autosomes, X chromosome, and mitochondria. We discover more than 75% of variation for 239 sampled breeds. Allele sharing analysis indicates that 94.9% of breeds form monophyletic clusters and 25 major clades. German Shepherd Dogs and related breeds show the highest allele sharing with independent breeds from multiple clades. On average, each breed dog differs from the UU_Cfam_GSD_1.0 reference at 26,960 deletions and 14,034 insertions greater than 50 bp, with wolves having 14% more variants. Discovered variants include retrogene insertions from 926 parent genes. To aid functional prioritization, single-nucleotide variants were annotated with SnpEff and Zoonomia phyloP constraint scores. Constrained positions were negatively correlated with allele frequency. Finally, the utility of the Dog10K data as an imputation reference panel is assessed, generating high-confidence calls across varied genotyping platform densities including for breeds not included in the Dog10K collection. CONCLUSIONS: We have developed a dense dataset of 1987 sequenced canids that reveals patterns of allele sharing, identifies likely functional variants, informs breed structure, and enables accurate imputation. Dog10K data are publicly available.

Spontaneous EBV-Reactivation during B Cell Differentiation as a Model for Polymorphic EBV-Driven Lymphoproliferation.

Epstein-Barr virus (EBV)-driven B cell neoplasms arise from the reactivation of latently infected B cells. In a subset of patients, EBV was seen to drive a polymorphous lymphoproliferative disorder (LPD) in which B cell differentiation was retained. In this work, spontaneous EBV reactivation following B cell mitogen stimulation was shown to provide a potential model of polymorphic EBV-driven LPD. Here, we developed an in vitro model of plasma cell (PC) differentiation from peripheral blood memory B cells. To assess the frequency and phenotypes of EBV-associated populations derived during differentiation, we analysed eight differentiations during the PC stage with a targeted single-cell gene expression panel. We identified subpopulations of EBV-gene expressing cells with PC and/or B cell expression features in differentiations from all tested donors. EBV-associated cells varied in frequency, ranging from 3-28% of cells. Most EBV-associated cells expressed PC genes such as XBP1 or MZB1, and in all samples these included a quiescent PC fraction that lacked cell a cycle gene expression. With increasing EBV-associated cells, populations with B cell features became prominent, co-expressing a germinal centre (GC) and activating B cell gene patterns. The presence of highly proliferative EBV-associated cells was linked to retained MS4A1/CD20 expression and IGHM and IGHD co-expression, while IGHM class-switched cells were enriched in quiescent PC fractions. Thus, patterns of gene expression in primary EBV reactivation were shown to include features related to GC B cells, which was also observed in EBV-transformed lymphoblastoid cell lines. This suggests a particular association between spontaneously developing EBV-expansions and IgM+ IgD+ non-switched B cells.

Genetic Diversity and Population Structure of Sorghum (Sorghum bicolor (L.) Moench) Landraces Using DArTseq-Derived Single-Nucleotide Polymorphism (SNP) Markers.

Genetic integrity of an accession should be preserved in the conservation of germplasm. Characterization of diverse germplasm based on a molecular basis enhances its conservation and use in breeding programs. The aim of this study was to assess the genetic diversity of 169 sorghum accessions using a total of 6977 SNP markers. The polymorphic information content of the markers was 0.31 which is considered to be moderately high. Structure analysis using ADMIXTURE program revealed a total of 10 subpopulations. Neighbor-joining tree revealed the presence of six main clusters among these subpopulations whereas in principal component analysis, seven clusters were identified. Cluster analysis grouped most populations depending on source of collection although other accessions originating from the same source were grouped under different clusters. Analysis of molecular variance (AMOVA) revealed 30% and 70% of the variation occurred within and among accessions, respectively. Gene flow within the populations was, however, limited indicating high differentiation within the subpopulation. Observed heterozygosity among accessions varied from 0.03 to 0.06 with a mean of 0.05 since sorghum is a self-pollinating crop. High genetic diversity among the subpopulations can be further explored for superior genes to develop new sorghum varieties.

Cytokine receptor IL27RA is an NF-κB-responsive gene involved in CD38 upregulation in multiple myeloma.

Multiple myeloma (MM) shows constitutive activation of canonical and noncanonical nuclear factor κB (NF-κB) signaling via genetic mutations or tumor microenvironment (TME) stimulations. A subset of MM cell lines showed dependency for cell growth and survival on the canonical NF-κB transcription factor RELA alone, suggesting a critical role for a RELA-mediated biological program in MM pathogenesis. Here, we determined the RELA-dependent transcriptional program in MM cell lines and found the expression of the cell surface molecules interleukin-27 receptor-α (IL-27Rα) and the adhesion molecule JAM2 to be responsive to RELA at the messenger RNA and protein levels. IL-27Rα and JAM2 were expressed on primary MM cells at higher levels than on healthy long-lived plasma cells (PCs) in the bone marrow. IL-27 activated STAT1, and to a lesser extent STAT3, in MM cell lines and in PCs generated from memory B cells in an IL-21-dependent in vitro PC differentiation assay. Concomitant activity of IL-21 and IL-27 enhanced differentiation into PCs and increased the cell-surface expression of the known STAT target gene CD38. In accordance, a subset of MM cell lines and primary MM cells cultured with IL-27 upregulated CD38 cell-surface expression, a finding with potential implications for enhancing the efficacy of CD38-directed monoclonal antibody therapies by increasing CD38 expression on tumor cells. The elevated expression of IL-27Rα and JAM2 on MM cells compared with that on healthy PCs may be exploited for the development of targeted therapeutic strategies that modulate the interaction of MM cells with the TME.

The dogs of Chernobyl: Demographic insights into populations inhabiting the nuclear exclusion zone.

The 1986 Chernobyl nuclear disaster initiated a series of catastrophic events resulting in long-term and widespread environmental contamination. We characterize the genetic structure of 302 dogs representing three free-roaming dog populations living within the power plant itself, as well as those 15 to 45 kilometers from the disaster site. Genome-wide profiles from Chernobyl, purebred and free-breeding dogs, worldwide reveal that the individuals from the power plant and Chernobyl City are genetically distinct, with the former displaying increased intrapopulation genetic similarity and differentiation. Analysis of shared ancestral genome segments highlights differences in the extent and timing of western breed introgression. Kinship analysis reveals 15 families, with the largest spanning all collection sites within the radioactive exclusion zone, reflecting migration of dogs between the power plant and Chernobyl City. This study presents the first characterization of a domestic species in Chernobyl, establishing their importance for genetic studies into the effects of exposure to long-term, low-dose ionizing radiation.

Evaluating the Contribution of Complex International Research-for-Development Programmes to the Sustainable Development Goals.

While evaluation of research-to-policy projects is a fundamental aspect of measuring the impact of new knowledge, limited studies have examined evaluation methods in such projects, as well as how the evaluation can generate learning to facilitate the progress towards the Sustainable Development Goals (SDGs). This study conducted a systematic literature review and found that the most commonly used methods for SDG contribution evaluation were Analytical Hierarchy Process (40.4%), Fuzzy TOPSIS (13.2%) and ELECTRE and SPADE Methodology (3.5% each). Ranking analysis was undertaken to determine priorities among the six "Big Wins" as defined for the UKRI-GCRF Trade Hub Project, as a case, where the ranking was exercised by the project partners across the globe. Results revealed that "nature and social factors" was better considered in international trade agreements as the priority (36.4%) among others. Moreover, among the four "mechanisms" of the project, "knowledge, networks, and connectivity" was ranked as the top priority (56.9%), followed by "capacity building" (28.5%), "metrics, tools and models" (7.2%), and "improving the knowledge base" (4.6%). Mapping and evaluation revealed that the Big Wins of the Trade Hub contributed to ten out of the 17 SDGs. The most fulfilled goals were SDG 12 (Sustainable Consumption and Production), SDG 15 (Life on Land), and SDG 2 (Zero Hunger) in descending order. Furthermore, interaction analysis of the core SDGs revealed both synergy and tradeoff between different outputs. The research articles reviewed for this paper showed no gold standard framework for assessing international development projects against the SDGs. Further research should develop a tool to capture holistic and synergistic contributions of the target outcomes of projects to sustainable development.

Bien que l'évaluation des projets sur le lien entre recherche et politique soit un aspect fondamental de la mesure de l'impact des nouvelles connaissances, peu d'études ont examiné les méthodes d'évaluation de tels projets, ainsi que la manière dont l'évaluation peut générer un apprentissage pour faciliter la progression vers les objectifs de développement durable (ODD). Cette étude a mené une revue systématique de la littérature et a constaté que les méthodes les plus couramment utilisées pour l'évaluation de la contribution aux ODD étaient le processus d'analyse hiérarchique (40,4%), la méthode TOPSIS floue (13,2%), et les méthodes ELECTRE et SPADE (3,5% chacune). Une analyse par classement a été entreprise pour déterminer les priorités parmi les six « Grands Succès¼ tels que définis pour le projet UKRI-GCRF Trade Hub, par exemple, où le classement a été réalisé par les partenaires du projet à travers le monde. Les résultats ont révélé que les « facteurs naturels et sociaux¼ étaient mieux considérés dans les accords commerciaux internationaux comme la priorité (36,4%), parmi d'autres. De plus, parmi les quatre « mécanismes¼ du projet, « les connaissances, les réseaux et la connectivité¼ ont été classés comme la première priorité (56,9%), suivis du « renforcement des capacités¼ (28,5%), « les mesures, les outils et les modèles¼ (7,2%) et « améliorer la base de connaissances¼ (4,6%). La cartographie et l'évaluation ont révélé que les Grands Succès du projet Trade Hub ont contribué à dix des 17 ODD. La contribution aux objectifs était la plus importante, par ordre décroissant, pour l'ODD 12 (Consommation et production durables), l'ODD 15 (Vie terrestre) et l'ODD 2 (Faim zéro). En outre, l'analyse des interactions des principaux ODD a révélé à la fois une synergie et un compromis entre les différents produits. Les études examinées pour cet article n'ont montré aucun cadre de référence pour évaluer les projets de développement international par rapport aux ODD. Des études supplémentaires devraient être conduites pour développer un outil permettant de mesurer les contributions holistiques et synergiques des résultats cibles des projets au développement durable.

Cardiometabolic disease in Black African and Caribbean populations: an ethnic divergence in pathophysiology?

In the UK, populations of Black African and Caribbean (BAC) ethnicity suffer higher rates of cardiometabolic disease than White Europeans (WE). Obesity, leading to increased visceral adipose tissue (VAT) and intrahepatic lipid (IHL), has long been associated with cardiometabolic risk, driving insulin resistance and defective fatty acid/lipoprotein metabolism. These defects are compounded by a state of chronic low-grade inflammation, driven by dysfunctional adipose tissue. Emerging evidence has highlighted associations between central complement system components and adipose tissue, fatty acid metabolism and inflammation; it may therefore sit at the intersection of various cardiometabolic disease risk factors. However, increasing evidence suggests an ethnic divergence in pathophysiology, whereby current theories fail to explain the high rates of cardiometabolic disease in BAC populations. Lower fasting and postprandial TAG has been reported in BAC, alongside lower VAT and IHL deposition, which are paradoxical to the high rates of cardiometabolic disease exhibited by this ethnic group. Furthermore, BAC have been shown to exhibit a more anti-inflammatory profile, with lower TNF-α and greater IL-10. In contrast, recent evidence has revealed greater complement activation in BAC compared to WE, suggesting its dysregulation may play a greater role in the high rates of cardiometabolic disease experienced by this population. This review outlines the current theories of how obesity is proposed to drive cardiometabolic disease, before discussing evidence for ethnic differences in disease pathophysiology between BAC and WE populations.

CTSK variant implicated in suspected pyknodysostosis in a domestic cat.

Case summary: A 9-month-old entire male domestic longhair cat presented with a history of pathological fractures, chronic musculoskeletal pain and poor growth. Multiple facial and skeletal abnormalities were identified on physical examination and advanced imaging (CT and radiographs). A variant in CTSK was identified in the affected cat following whole-exome sequencing (WES). The cat was managed symptomatically with diet, environmental modifications and analgesia. Relevance and novel information: This is the first report of a cat with a similar clinical presentation and genetic variant to the hereditary human genetic disorder pyknodysostosis. In this case, WES was performed, which often facilitates the diagnosis of various hereditary disorders (ie, a conceptual framework for practicing feline genomic medicine). Despite the severe skeletal and appendicular abnormalities described, the cat was alive more than 2 years after its initial presentation.

APRIL Drives a Coordinated but Diverse Response as a Foundation for Plasma Cell Longevity.

Ab-secreting cells survive in niche microenvironments, but cellular responses driven by particular niche signals are incompletely defined. The TNF superfamily member a proliferation-inducing ligand (APRIL) can support the maturation of transitory plasmablasts into long-lived plasma cells. In this study, we explore the biological programs established by APRIL in human plasmablasts. Under conditions allowing the maturation of ex vivo- or in vitro-generated plasmablasts, we find that APRIL drives activation of ERK, p38, and JNK, accompanied by a classical NF-κB response and activation of the AKT/FOXO1 pathway. Time-course gene expression data resolve coordinated transcriptional responses propagated via immediate early genes and NF-κB targets and converging onto modules of genes enriched for MYC targets and metabolism/cell growth-related pathways. This response is shared between APRIL and an alternate TNF superfamily member CD40L but is not a feature of alternative niche signals delivered by IFN-α or SDF1. However, APRIL and CD40L responses also diverge. CD40L drives expression of genes related to the activated B cell state whereas APRIL does not. Thus, APRIL establishes a broad foundation for plasma cell longevity with features of cellular refueling while being uncoupled from support of the B cell state.

The effects of feeding and transport length on the welfare of white rhinoceroses (Ceratotherium simum simum) during long-distance translocations: a preliminary study.

Translocation is a valuable conservation tool, but poses significant risks for the transported rhinoceroses. Interventions reducing these risks are required to ensure positive welfare during transportation. The aim of this study was to evaluate the effect of journey duration and feeding during the transport of white rhinoceroses (Ceratotherium simum simum). A total of 32 animals were transported by road during two events, five days apart. Fifteen rhinoceroses in the first transport event (37.0 ± 2.4 hr duration) were not fed, while 17 rhinoceroses in the second event (32.2 ± 1.5 hr duration) were offered lucerne. Blood samples were collected at capture and after transport for the evaluation of changes in serum clinical chemistry analytes. The Wilcoxon rank-sum test was used to compare differences between the groups. In all rhinoceroses, transport resulted in changes in serum electrolyte, metabolite and enzyme concentrations, indicating a loss in total body water, nutritional shifts, stress and fatigue. Fed rhinoceroses, transported over a shorter time, displayed greater changes in osmolality (p < 0.006), serum sodium and chloride concentrations (p = 0.005 and = 0.001, respectively) indicating a greater degree of total body water loss than non-fed rhinoceroses. Feeding and a shorter transport duration reduced, but did not prevent, nutritional challenges. A greater increase in the muscle enzymes CK and AST (p = 0.027 and = 0.001, respectively), indicated greater fatigue in non-fed rhinoceroses transported over a longer time. Further work to distinguish the effects of feeding and journey duration is required to better understand the role feeding may play in mitigating welfare challenges during rhinoceros translocation.

MR1-dependence of unmetabolized folic acid side-effects.

The fortification of flour with folic acid for the prevention of neural tube defects (NTD) is currently mandated in over eighty countries worldwide, hence compelling its consumption by the greater part of the world's population. Notwithstanding its beneficial impact on rates of NTD, pervasive folic acid supplementation has invariably led to additive daily intakes reaching well beyond their original target, resulting in the circulation of unmetabolized folic acid. Associated idiopathic side-effects ranging from allergies to cancer have been suggested, albeit inconclusively. Herein, we hypothesize that their inconsistent detection and elusive etiology are linked to the in vivo generation of the immunosuppressive folic acid metabolite 6-formylpterin, which interferes with the still emerging and varied functions of Major Histocompatibility Complex-related molecule 1 (MR1)-restricted T cells. Accordingly, we predict that fortification-related adverse health outcomes can be eliminated by substituting folic acid with the bioequivalent folate vitamer 5-methyltetrahydrofolate, which does not break down into 6-formylpterin.

X-linked myotubular myopathy associated with an MTM1 variant in a Maine coon cat.

OBJECTIVE: Describe the clinical course and diagnostic and genetic findings in a cat with X-linked myotubular myopathy. CASE SUMMARY: A 7-month-old male Maine coon was evaluated for progressively worsening gait abnormalities and generalized weakness. Neurolocalization was to the neuromuscular system. Genetic testing for spinal muscular atrophy (LIX1) was negative. Given the progressive nature and suspected poor long-term prognosis, the owners elected euthanasia. Histopathology of skeletal muscle obtained post-mortem disclosed numerous rounded atrophic or hypotrophic fibers with internal nuclei or central basophilic staining. Using oxidative reactions mediated by cytochrome C oxidase and succinic dehydrogenase, scattered myofibers were observed to have central dark staining structures and a "ring-like" appearance. Given the cat's age and clinical history, a congenital myopathy was considered most likely, with the central nuclei and "ring-like" changes consistent with either centronuclear or myotubular myopathy. Whole genome sequencing identified an underlying missense variant in myotubularin 1 (MTM1), a known candidate gene for X-linked myotubular myopathy. NEW OR UNIQUE INFORMATION PROVIDED: This case is the first report of X-linked myotubular myopathy in a cat with an MTM1 missense mutation. Maine coon cat breeders may consider screening for this variant to prevent production of affected cats and to eradicate the variant from the breeding population.

Genomic and microenvironmental landscape of stage I follicular lymphoma, compared with stage III/IV.

Although the genomic and immune microenvironmental landscape of follicular lymphoma (FL) has been extensively investigated, little is known about the potential biological differences between stage I and stage III/IV disease. Using next-generation sequencing and immunohistochemistry, 82 FL nodal stage I cases were analyzed and compared with 139 FL stage III/IV nodal cases. Many similarities in mutations, chromosomal copy number aberrations, and microenvironmental cell populations were detected. However, there were also significant differences in microenvironmental and genomic features. CD8+ T cells (P = .02) and STAT6 mutations (false discovery rate [FDR] <0.001) were more frequent in stage I FL. In contrast, programmed cell death protein 1-positive T cells, CD68+/CD163+ macrophages (P < .001), BCL2 translocation (BCL2trl+) (P < .0001), and KMT2D (FDR = 0.003) and CREBBP (FDR = 0.04) mutations were found more frequently in stage III/IV FL. Using clustering, we identified 3 clusters within stage I, and 2 clusters within stage III/IV. The BLC2trl+ stage I cluster was comparable to the BCL2trl+ cluster in stage III/IV. The two BCL2trl- stage I clusters were unique for stage I. One was enriched for CREBBP (95%) and STAT6 (64%) mutations, without BLC6 translocation (BCL6trl), whereas the BCL2trl- stage III/IV cluster contained BCL6trl (64%) with fewer CREBBP (45%) and STAT6 (9%) mutations. The other BCL2trl- stage I cluster was relatively heterogeneous with more copy number aberrations and linker histone mutations. This exploratory study shows that stage I FL is genetically heterogeneous with different underlying oncogenic pathways. Stage I FL BCL2trl- is likely STAT6 driven, whereas BCL2trl- stage III/IV appears to be more BCL6trl driven.

Genetic Origins of the Two Canis lupus familiaris (Dog) Freight Dog Populations.

Despite periodic drops in popularity, Arctic sled dogs continue to play a vital role in northern societies, providing both freight transit and recreational race activities. In this study, we selected the Mackenzie River Husky, a freight dog of complex history, and the Chinook, an American Kennel Club recognized freight dog breed whose heritage reportedly overlaps that of the MKRH, for detailed population analysis. We tested each to determine their component breeds and used admixture analysis to ascertain their population structure. We utilized haplotype analysis to identify genomic regions shared between each population and their founding breeds. Our data show that the Alaskan Malamutes and modern Greenland sled dog contributed to both populations, but there are also unexpected contributions from the German Shepherd dog and Collie. We used haplotype analysis to identify genomic regions nearing fixation in population type and identify provocative genes in each region. Finally, in response to recent reports regarding the importance of dietary lipid genes in Arctic dogs, we analyzed 8 such genes in a targeted analysis observing signatures of selection in both populations at the MLXIPL gene loci. These data highlight the genetic routes that breeds of similar function have taken toward their occupation as successful sled dogs.

Molecular subclusters of follicular lymphoma: a report from the United Kingdom's Haematological Malignancy Research Network.

Follicular lymphoma (FL) is morphologically and clinically diverse, with mutations in epigenetic regulators alongside t(14;18) identified as disease-initiating events. Identification of additional mutational entities confirms this cancer's heterogeneity, but whether mutational data can be resolved into mechanistically distinct subsets remains an open question. Targeted sequencing was applied to an unselected population-based FL cohort (n = 548) with full clinical follow-up (n = 538), which included 96 diffuse large B-cell lymphoma (DLBCL) transformations. We investigated whether molecular subclusters of FL can be identified and whether mutational data provide predictive information relating to transformation. DNA extracted from FL samples was sequenced with a 293-gene panel representing genes frequently mutated in DLBCL and FL. Three clusters were resolved using mutational data alone, independent of translocation status: FL_aSHM, with high burden of aberrant somatic hypermutation (aSHM) targets; FL_STAT6, with high STAT6 & CREBBP mutation and low aSHM; and FL_Com, with the absence of features of other subtypes and enriched KMT2D mutation. Analysis of mutation signatures demonstrated differential enrichment of predicted mutation signatures between subgroups and a dominant preference in the FL_aSHM subgroup for G(C>T)T and G(C>T)C transitions consistent with previously defined aSHM-like patterns. Of transformed cases with paired samples, 17 of 26 had evidence of branching evolution. Poorer overall survival (OS) in the aSHM group (P = .04) was associated with older age; however, overall tumor genetics provided limited information to predict individual patient risk. Our approach identifies 3 molecular subclusters of FL linked to differences in underlying mechanistic pathways. These clusters, which may be further resolved by the inclusion of translocation status and wider mutation profiles, have implications for understanding pathogenesis as well as improving treatment strategies in the future.

Ectopic fat deposition in populations of black African ancestry: A systematic review and meta-analysis.

AIMS: In populations of black African ancestry (BA), a paradox exists whereby lower visceral adipose tissue is found despite their high risk for type 2 diabetes (T2D). This systematic review investigates ethnic differences in other ectopic fat depots (intrahepatic lipid: IHL; intramyocellular lipid: IMCL and intrapancreatic lipid; IPL) to help contextualise their potential contribution to T2D risk. METHODS: A systematic literature search was performed in December 2020 to identify studies reporting at least one ectopic fat comparison between BA and one/more other ethnicity. For IHL, a meta-analysis was carried out with studies considered comparable based on the method of measurement. RESULTS: Twenty-eight studies were included (IHL: n = 20; IMCL: n = 8; IPL: n = 4). Meta-analysis of 11 studies investigating IHL revealed that it was lower in BA populations vs pooled ethnic comparators (MD -1.35%, 95% CI -1.55 to -1.16, I2 = 85%, P < 0.00001), white European ancestry (MD -0.94%, 95% CI -1.17 to -0.70, I2 = 79%, P < 0.00001), Hispanic ancestry (MD -2.06%, 95% CI -2.49 to -1.63, I2 = 81%, P < 0.00001) and South Asian ancestry comparators (MD -1.92%, 95% CI -3.26 to -0.57, I2 = 78%, P = 0.005). However, heterogeneity was high in all analyses. Most studies found no significant differences in IMCL between BA and WE. Few studies investigated IPL, however, indicated that IPL is lower in BA compared to WE and HIS. CONCLUSION: The discordance between ectopic fat and greater risk for T2D in BA populations raises questions around its contribution to T2D pathophysiology in BA.