A TNIP1-driven systemic autoimmune disorder with elevated IgG4.

Whole-exome sequencing of two unrelated kindreds with systemic autoimmune disease featuring antinuclear antibodies with IgG4 elevation uncovered an identical ultrarare heterozygous TNIP1Q333P variant segregating with disease. Mice with the orthologous Q346P variant developed antinuclear autoantibodies, salivary gland inflammation, elevated IgG2c, spontaneous germinal centers and expansion of age-associated B cells, plasma cells and follicular and extrafollicular helper T cells. B cell phenotypes were cell-autonomous and rescued by ablation of Toll-like receptor 7 (TLR7) or MyD88. The variant increased interferon-ß without altering nuclear factor kappa-light-chain-enhancer of activated B cells signaling, and impaired MyD88 and IRAK1 recruitment to autophagosomes. Additionally, the Q333P variant impaired TNIP1 localization to damaged mitochondria and mitophagosome formation. Damaged mitochondria were abundant in the salivary epithelial cells of Tnip1Q346P mice. These findings suggest that TNIP1-mediated autoimmunity may be a consequence of increased TLR7 signaling due to impaired recruitment of downstream signaling molecules and damaged mitochondria to autophagosomes and may thus respond to TLR7-targeted therapeutics.

Lymphoma Driver Mutations in the Pathogenic Evolution of an Iconic Human Autoantibody.

Pathogenic autoantibodies arise in many autoimmune diseases, but it is not understood how the cells making them evade immune checkpoints. Here, single-cell multi-omics analysis demonstrates a shared mechanism with lymphoid malignancy in the formation of public rheumatoid factor autoantibodies responsible for mixed cryoglobulinemic vasculitis. By combining single-cell DNA and RNA sequencing with serum antibody peptide sequencing and antibody synthesis, rare circulating B lymphocytes making pathogenic autoantibodies were found to comprise clonal trees accumulating mutations. Lymphoma driver mutations in genes regulating B cell proliferation and V(D)J mutation (CARD11, TNFAIP3, CCND3, ID3, BTG2, and KLHL6) were present in rogue B cells producing the pathogenic autoantibody. Antibody V(D)J mutations conferred pathogenicity by causing the antigen-bound autoantibodies to undergo phase transition to insoluble aggregates at lower temperatures. These results reveal a pre-neoplastic stage in human lymphomagenesis and a cascade of somatic mutations leading to an iconic pathogenic autoantibody.

TLR7 gain-of-function genetic variation causes human lupus.

Although circumstantial evidence supports enhanced Toll-like receptor 7 (TLR7) signalling as a mechanism of human systemic autoimmune disease1-7, evidence of lupus-causing TLR7 gene variants is lacking. Here we describe human systemic lupus erythematosus caused by a TLR7 gain-of-function variant. TLR7 is a sensor of viral RNA8,9 and binds to guanosine10-12. We identified a de novo, previously undescribed missense TLR7Y264H variant in a child with severe lupus and additional variants in other patients with lupus. The TLR7Y264H variant selectively increased sensing of guanosine and 2',3'-cGMP10-12, and was sufficient to cause lupus when introduced into mice. We show that enhanced TLR7 signalling drives aberrant survival of B cell receptor (BCR)-activated B cells, and in a cell-intrinsic manner, accumulation of CD11c+ age-associated B cells and germinal centre B cells. Follicular and extrafollicular helper T cells were also increased but these phenotypes were cell-extrinsic. Deficiency of MyD88 (an adaptor protein downstream of TLR7) rescued autoimmunity, aberrant B cell survival, and all cellular and serological phenotypes. Despite prominent spontaneous germinal-centre formation in Tlr7Y264H mice, autoimmunity was not ameliorated by germinal-centre deficiency, suggesting an extrafollicular origin of pathogenic B cells. We establish the importance of TLR7 and guanosine-containing self-ligands for human lupus pathogenesis, which paves the way for therapeutic TLR7 or MyD88 inhibition.

Novel antiinflammatory biologics shaped by parasite-host coevolution.

Parasitic helminth infections, while a major cause of neglected tropical disease burden, negatively correlate with the incidence of immune-mediated inflammatory diseases such as inflammatory bowel diseases (IBD). To evade expulsion, helminths have developed sophisticated mechanisms to regulate their host's immune responses. Controlled experimental human helminth infections have been assessed clinically for treating inflammatory conditions; however, such a radical therapeutic modality has challenges. An alternative approach is to harness the immunomodulatory properties within the worm's excretory-secretory (ES) complement, its secretome. Here, we report a biologics discovery and validation pipeline to generate and screen in vivo a recombinant cell-free secretome library of helminth-derived immunomodulatory proteins. We successfully expressed 78 recombinant ES proteins from gastrointestinal hookworms and screened the crude in vitro translation reactions for anti-IBD properties in a mouse model of acute colitis. After statistical filtering and ranking, 20 proteins conferred significant protection against various parameters of colitis. Lead candidates from distinct protein families, including annexins, transthyretins, nematode-specific retinol-binding proteins, and SCP/TAPS were identified. Representative proteins were produced in mammalian cells and further validated, including ex vivo suppression of inflammatory cytokine secretion by T cells from IBD patient colon biopsies. Proteins identified herein offer promise as novel, safe, and mechanistically differentiated biologics for treating the globally increasing burden of inflammatory diseases.

Chromosomal inversions harbour excess mutational load in the coral, Acropora kenti, on the Great Barrier Reef.

The future survival of coral reefs in the Anthropocene depends on the capacity of corals to adapt as oceans warm and extreme weather events become more frequent. Targeted interventions designed to assist evolutionary processes in corals require a comprehensive understanding of the distribution and structure of standing variation, however, efforts to map genomic variation in corals have so far focussed almost exclusively on SNPs, overlooking structural variants that have been shown to drive adaptive processes in other taxa. Here, we show that the reef-building coral, Acropora kenti, harbours at least five large, highly polymorphic structural variants, all of which exhibit signatures of strongly suppressed recombination in heterokaryotypes, a feature commonly associated with chromosomal inversions. Based on their high minor allele frequency, uniform distribution across habitats and elevated genetic load, we propose that these inversions in A. kenti are likely to be under balancing selection. An excess of SNPs with high impact on protein-coding genes within these loci elevates their importance both as potential targets for adaptive selection and as contributors to genetic decline if coral populations become fragmented or inbred in future.

A case-control comparison of acute-phase peripheral blood gene expression in participants diagnosed with minor ischaemic stroke or stroke mimics.

BACKGROUND: Past studies suggest that there are changes in peripheral blood cell gene expression in response to ischaemic stroke; however, the specific changes which occur during the acute phase are poorly characterised. The current study aimed to identify peripheral blood cell genes specifically associated with the early response to ischaemic stroke using whole blood samples collected from participants diagnosed with ischaemic stroke (n = 29) or stroke mimics (n = 27) following emergency presentation to hospital. Long non-coding RNA (lncRNA), mRNA and micro-RNA (miRNA) abundance was measured by RNA-seq, and the consensusDE package was used to identify genes which were differentially expressed between groups. A sensitivity analysis excluding two participants with metastatic disease was also conducted. RESULTS: The mean time from symptom onset to blood collection was 2.6 h. Most strokes were mild (median NIH stroke scale score 2.0). Ten mRNAs (all down-regulated in samples provided by patients experiencing ischaemic stroke) and 30 miRNAs (14 over-expressed and 16 under-expressed in participants with ischaemic stroke) were significantly different between groups in the whole cohort and sensitivity analyses. No significant over-representation of gene ontology categories by the differentially expressed genes was observed. Random forest analysis suggested a panel of differentially expressed genes (ADGRG7 and miRNAs 96, 532, 6766, 6798 and 6804) as potential ischaemic stroke biomarkers, although modelling analyses demonstrated that these genes had poor diagnostic performance. CONCLUSIONS: This study provides evidence suggesting that the early response to minor ischaemic stroke is predominantly reflected by changes in the expression of miRNAs in peripheral blood cells. Further work in independent cohorts particularly in patients with more severe stroke is needed to validate these findings and investigate their clinical relevance.

Evaluating the Acceptability of the Drink Less App and the National Health Service Alcohol Advice Web Page: Qualitative Interview Process Evaluation.

BACKGROUND: The extent to which interventions are perceived as acceptable to users impacts engagement and efficacy. OBJECTIVE: In this study, we evaluated the acceptability of (1) the smartphone app Drink Less (intervention) and (2) the National Health Service (NHS) alcohol advice web page (usual digital care and comparator) among adult drinkers in the United Kingdom participating in a randomized controlled trial evaluating the effectiveness of the Drink Less app. METHODS: A subsample of 26 increasing- and higher-risk drinkers (Alcohol Use Disorders Identification Test score≥8) assigned to the intervention group (Drink Less; n=14, 54%; female: n=10, 71%; age: 22-72 years; White: n=9, 64%) or usual digital care group (NHS alcohol advice web page; n=12, 46%; female: n=5, 42%; age: 23-68 years: White: n=9, 75%) took part in semistructured interviews. The interview questions were mapped on to the 7 facets of acceptability according to the Theoretical Framework of Acceptability: affective attitude, burden, perceived effectiveness, ethicality, intervention coherence, opportunity costs, and self-efficacy. Alongside these constructs, we also included a question on perceived personal relevance, which previous research has linked to acceptability and engagement. Framework and thematic analysis of data was undertaken. RESULTS: The Drink Less app was perceived as being ethical, easy, user-friendly, and effective for the period the app was used. Participants reported particularly liking the tracking and feedback sections of the app, which they reported increased personal relevance and which resulted in positive affect when achieving their goals. They reported no opportunity cost. Factors such as negative affect when not meeting goals and boredom led to disengagement in the longer term for some participants. The NHS alcohol advice web page was rated as being easy and user-friendly with no opportunity costs. However, the information presented was not perceived as being personally relevant or effective in changing drinking behavior. Most participants reported neutral or negative affect, most participants thought the alcohol advice web page was accessible, and some participants reported ethical concerns around the availability of suggested resources. Some participants reported that it had acted as a starting point or a signpost to other resources. Participants in both groups discussed motivation to change and contextual factors such as COVID-19 lockdowns, which influenced their perceived self-efficacy regardless of their assigned intervention. CONCLUSIONS: Drink Less appears to be an acceptable digital intervention among the recruited sample. The NHS alcohol advice web page was generally considered unacceptable as a stand-alone intervention among the recruited sample, although it may signpost and help people access other resources and interventions.

StabilitySort: assessment of protein stability changes on a genome-wide scale to prioritize potentially pathogenic genetic variation.

SUMMARY: Missense mutations that change protein stability are strongly associated with human genetic disease. With the recent availability of predicted structures for all human proteins generated using the AlphaFold2 prediction model, genome-wide assessment of the stability effects of genetic variation can, for the first time, be easily performed. This facilitates the interrogation of personal genetic variation for potentially pathogenic effects through the application of stability metrics. Here, we present a novel tool to prioritize variants predicted to cause strong instability in essential proteins. We show that by filtering by ΔΔG values and then prioritizing by StabilitySort Z-scores, we are able to more accurately discriminate pathogenic, protein-destabilizing mutations from population variation, compared with other mutation effect predictors. AVAILABILITY AND IMPLEMENTATION: StabilitySort is available as a web service (https://www.stabilitysort.org), as a data download for integration with other tools (https://www.stabilitysort.org/download) or can be deployed as a standalone system from source code (https://gitlab.com/baaron/StabilitySort). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Recovery From Nicotine Addiction: A Diffusion Model Decomposition of Value-Based Decision-Making in Current Smokers and Ex-smokers.

INTRODUCTION: A considerable number of people successfully give up tobacco smoking. In nicotine-dependent individuals, tobacco choice is determined by greater expected drug value; however, less is known about the underlying mechanisms through which people quit smoking. AIMS AND METHODS: This study aimed to explore whether computational parameters of value-based decision-making (VBDM) characterize recovery from nicotine addiction. Using a preregistered, between-subject design, current daily smokers (n = 51) and ex-smokers who used to smoke daily (n = 51) were recruited from the local community. Participants completed a two-alternative forced choice task in which they chose between either two tobacco-related images (in one block) or tobacco-unrelated images (in a different block). During each trial, participants pressed a computer key to select the image they rated most positively during a previous task block. To estimate evidence accumulation (EA) processes and response thresholds during the different blocks, a drift-diffusion model was fitted to the reaction time and error data. RESULTS: Ex-smokers had significantly higher response thresholds when making tobacco-related decisions (p = .01, d = 0.45) compared to current smokers, although there were no significant group differences during tobacco-unrelated decisions. Furthermore, there were no significant group differences in EA rates when making tobacco or tobacco-unrelated decisions. CONCLUSIONS: Greater cautiousness when making value-based decisions about tobacco-related cues characterized recovery from nicotine addiction. IMPLICATIONS: The number of people dependent on nicotine has decreased steadily during the past decade; however, the mechanisms that underlie recovery are currently less well understood. The present study applied advances in the measurement of value-based choice. The aim was to explore whether the internal processes that underpin VBDM discriminate current daily tobacco smokers from ex-tobacco smokers who used to smoke daily. Findings revealed that recovery from nicotine addiction was characterized by higher response thresholds when making value-based decisions about tobacco-related cues; this may serve as a novel target for treatment interventions that focus on helping people to stop smoking.

Mucosal delivery of ESX-1-expressing BCG strains provides superior immunity against tuberculosis in murine type 2 diabetes.

Tuberculosis (TB) claims 1.5 million lives per year. This situation is largely due to the low efficacy of the only licensed TB vaccine, Bacillus Calmette-Guérin (BCG) against pulmonary TB. The metabolic disease type 2 diabetes (T2D) is a risk factor for TB and the mechanisms underlying increased TB susceptibility in T2D are not well understood. Furthermore, it is unknown if new TB vaccines will provide protection in the context of T2D. Here we used a diet-induced murine model of T2D to investigate the underlying mechanisms of TB/T2D comorbidity and to evaluate the protective capacity of two experimental TB vaccines in comparison to conventional BCG. Our data reveal a distinct immune dysfunction that is associated with diminished recognition of mycobacterial antigens in T2D. More importantly, we provide compelling evidence that mucosal delivery of recombinant BCG strains expressing the Mycobacterium tuberculosis (Mtb) ESX-1 secretion system (BCG::RD1 and BCG::RD1 ESAT-6 ∆92-95) are safe and confer superior immunity against aerosol Mtb infection in the context of T2D. Our findings suggest that the remarkable anti-TB immunity by these recombinant BCG strains is achieved via augmenting the numbers and functional capacity of antigen presenting cells in the lungs of diabetic mice.

Bot or Not? Detecting and Managing Participant Deception When Conducting Digital Research Remotely: Case Study of a Randomized Controlled Trial.

BACKGROUND: Evaluating digital interventions using remote methods enables the recruitment of large numbers of participants relatively conveniently and cheaply compared with in-person methods. However, conducting research remotely based on participant self-report with little verification is open to automated "bots" and participant deception. OBJECTIVE: This paper uses a case study of a remotely conducted trial of an alcohol reduction app to highlight and discuss (1) the issues with participant deception affecting remote research trials with financial compensation; and (2) the importance of rigorous data management to detect and address these issues. METHODS: We recruited participants on the internet from July 2020 to March 2022 for a randomized controlled trial (n=5602) evaluating the effectiveness of an alcohol reduction app, Drink Less. Follow-up occurred at 3 time points, with financial compensation offered (up to £36 [US $39.23]). Address authentication and telephone verification were used to detect 2 kinds of deception: "bots," that is, automated responses generated in clusters; and manual participant deception, that is, participants providing false information. RESULTS: Of the 1142 participants who enrolled in the first 2 months of recruitment, 75.6% (n=863) of them were identified as bots during data screening. As a result, a CAPTCHA (Completely Automated Public Turing Test to Tell Computers and Humans Apart) was added, and after this, no more bots were identified. Manual participant deception occurred throughout the study. Of the 5956 participants (excluding bots) who enrolled in the study, 298 (5%) were identified as false participants. The extent of this decreased from 110 in November 2020, to a negligible level by February 2022 including a number of months with 0. The decline occurred after we added further screening questions such as attention checks, removed the prominence of financial compensation from social media advertising, and added an additional requirement to provide a mobile phone number for identity verification. CONCLUSIONS: Data management protocols are necessary to detect automated bots and manual participant deception in remotely conducted trials. Bots and manual deception can be minimized by adding a CAPTCHA, attention checks, a requirement to provide a phone number for identity verification, and not prominently advertising financial compensation on social media. TRIAL REGISTRATION: ISRCTN Number ISRCTN64052601; https://doi.org/10.1186/ISRCTN64052601.

Natural-Product-Based Solutions for Tropical Infectious Diseases.

About half of the world's population and 80% of the world's biodiversity can be found in the tropics. Many diseases are specific to the tropics, with at least 41 diseases caused by endemic bacteria, viruses, parasites, and fungi. Such diseases are of increasing concern, as the geographic range of tropical diseases is expanding due to climate change, urbanization, change in agricultural practices, deforestation, and loss of biodiversity. While traditional medicines have been used for centuries in the treatment of tropical diseases, the active natural compounds within these medicines remain largely unknown. In this review, we describe infectious diseases specific to the tropics, including their causative pathogens, modes of transmission, recent major outbreaks, and geographic locations. We further review current treatments for these tropical diseases, carefully consider the biodiscovery potential of the tropical biome, and discuss a range of technologies being used for drug development from natural resources. We provide a list of natural products with antimicrobial activity, detailing the source organisms and their effectiveness as treatment. We discuss how technological advancements, such as next-generation sequencing, are driving high-throughput natural product screening pipelines to identify compounds with therapeutic properties. This review demonstrates the impact natural products from the vast tropical biome have in the treatment of tropical infectious diseases and how high-throughput technical capacity will accelerate this discovery process.

Chromosome-length genome assembly and structural variations of the primal Basenji dog (Canis lupus familiaris) genome.

BACKGROUND: Basenjis are considered an ancient dog breed of central African origins that still live and hunt with tribesmen in the African Congo. Nicknamed the barkless dog, Basenjis possess unique phylogeny, geographical origins and traits, making their genome structure of great interest. The increasing number of available canid reference genomes allows us to examine the impact the choice of reference genome makes with regard to reference genome quality and breed relatedness. RESULTS: Here, we report two high quality de novo Basenji genome assemblies: a female, China (CanFam_Bas), and a male, Wags. We conduct pairwise comparisons and report structural variations between assembled genomes of three dog breeds: Basenji (CanFam_Bas), Boxer (CanFam3.1) and German Shepherd Dog (GSD) (CanFam_GSD). CanFam_Bas is superior to CanFam3.1 in terms of genome contiguity and comparable overall to the high quality CanFam_GSD assembly. By aligning short read data from 58 representative dog breeds to three reference genomes, we demonstrate how the choice of reference genome significantly impacts both read mapping and variant detection. CONCLUSIONS: The growing number of high-quality canid reference genomes means the choice of reference genome is an increasingly critical decision in subsequent canid variant analyses. The basal position of the Basenji makes it suitable for variant analysis for targeted applications of specific dog breeds. However, we believe more comprehensive analyses across the entire family of canids is more suited to a pangenome approach. Collectively this work highlights the importance the choice of reference genome makes in all variation studies.

A rare variant in EZH2 is associated with prostate cancer risk.

Prostate cancer (PrCa) is highly heritable, and although rare variants contribute significantly to PrCa risk, few have been identified to date. Herein, whole-genome sequencing was performed in a large PrCa family featuring multiple affected relatives spanning several generations. A rare, predicted splice site EZH2 variant, rs78589034 (G > A), was identified as segregating with disease in all but two individuals in the family, one of whom was affected with lymphoma and bowel cancer and a female relative. This variant was significantly associated with disease risk in combined familial and sporadic PrCa datasets (n = 1551; odds ratio [OR] = 3.55, P = 1.20 × 10-5 ). Transcriptome analysis was performed on prostate tumour needle biopsies available for two rare variant carriers and two wild-type cases. Although no allele-dependent differences were detected in EZH2 transcripts, a distinct differential gene expression signature was observed when comparing prostate tissue from the rare variant carriers with the wild-type samples. The gene expression signature comprised known downstream targets of EZH2 and included the top-ranked genes, DUSP1, FOS, JUNB and EGR1, which were subsequently validated by qPCR. These data provide evidence that rs78589034 is associated with increased PrCa risk in Tasmanian men and further, that this variant may be associated with perturbed EZH2 function in prostate tissue. Disrupted EZH2 function is a driver of tumourigenesis in several cancers, including prostate, and is of significant interest as a therapeutic target.

Detecting pathogenic variants in autoimmune diseases using high-throughput sequencing.

Sequencing the first human genome in 2003 took 15 years and cost $2.7 billion. Advances in sequencing technologies have since decreased costs to the point where it is now feasible to resequence a whole human genome for $1000 in a single day. These advances have allowed the generation of huge volumes of high-quality human sequence data used to construct increasingly large catalogs of both population-level and disease-causing variation. The existence of such databases, coupled with a high-quality human reference genome, means we are able to interrogate and annotate all types of genetic variation and identify pathogenic variants for many diseases. Increasingly, sequencing-based approaches are being used to elucidate the underlying genetic cause of autoimmune diseases, a group of roughly 80 polygenic diseases characterized by abnormal immune responses where healthy tissue is attacked. Although sequence data generation has become routine and affordable, significant challenges remain with no gold-standard methodology to identify pathogenic variants currently available. This review examines the latest methodologies used to identify pathogenic variants in autoimmune diseases and considers available sequencing options and subsequent bioinformatic methodologies and strategies. The development of reliable and robust sequencing and analytic workflows to detect pathogenic variants is critical to realize the potential of precision medicine programs where patient variant information is used to inform clinical practice.

Spatial population genomics of a recent mosquito invasion.

Population genomic approaches can characterize dispersal across a single generation through to many generations in the past, bridging the gap between individual movement and intergenerational gene flow. These approaches are particularly useful when investigating dispersal in recently altered systems, where they provide a way of inferring long-distance dispersal between newly established populations and their interactions with existing populations. Human-mediated biological invasions represent such altered systems which can be investigated with appropriate study designs and analyses. Here we apply temporally restricted sampling and a range of population genomic approaches to investigate dispersal in a 2004 invasion of Aedes albopictus (the Asian tiger mosquito) in the Torres Strait Islands (TSI) of Australia. We sampled mosquitoes from 13 TSI villages simultaneously and genotyped 373 mosquitoes at genome-wide single nucleotide polymorphisms (SNPs): 331 from the TSI, 36 from Papua New Guinea (PNG) and four incursive mosquitoes detected in uninvaded regions. Within villages, spatial genetic structure varied substantially but overall displayed isolation by distance and a neighbourhood size of 232-577. Close kin dyads revealed recent movement between islands 31-203 km apart, and deep learning inferences showed incursive Ae. albopictus had travelled to uninvaded regions from both adjacent and nonadjacent islands. Private alleles and a co-ancestry matrix indicated direct gene flow from PNG into nearby islands. Outlier analyses also detected four linked alleles introgressed from PNG, with the alleles surrounding 12 resistance-associated cytochrome P450 genes. By treating dispersal as both an intergenerational process and a set of discrete events, we describe a highly interconnected invasive system.

Infanticide vs. inherited cardiac arrhythmias.

AIMS: In 2003, an Australian woman was convicted by a jury of smothering and killing her four children over a 10-year period. Each child died suddenly and unexpectedly during a sleep period, at ages ranging from 19 days to 18 months. In 2019 we were asked to investigate if a genetic cause could explain the children's deaths as part of an inquiry into the mother's convictions. METHODS AND RESULTS: Whole genomes or exomes of the mother and her four children were sequenced. Functional analysis of a novel CALM2 variant was performed by measuring Ca2+-binding affinity, interaction with calcium channels and channel function. We found two children had a novel calmodulin variant (CALM2 G114R) that was inherited maternally. Three genes (CALM1-3) encode identical calmodulin proteins. A variant in the corresponding residue of CALM3 (G114W) was recently reported in a child who died suddenly at age 4 and a sibling who suffered a cardiac arrest at age 5. We show that CALM2 G114R impairs calmodulin's ability to bind calcium and regulate two pivotal calcium channels (CaV1.2 and RyR2) involved in cardiac excitation contraction coupling. The deleterious effects of G114R are similar to those produced by G114W and N98S, which are considered arrhythmogenic and cause sudden cardiac death in children. CONCLUSION: A novel functional calmodulin variant (G114R) predicted to cause idiopathic ventricular fibrillation, catecholaminergic polymorphic ventricular tachycardia, or mild long QT syndrome was present in two children. A fatal arrhythmic event may have been triggered by their intercurrent infections. Thus, calmodulinopathy emerges as a reasonable explanation for a natural cause of their deaths.

Food-related attentional bias and its associations with appetitive motivation and body weight: A systematic review and meta-analysis.

Theoretical models suggest that food-related visual attentional bias (AB) may be related to appetitive motivational states and individual differences in body weight; however, findings in this area are equivocal. We conducted a systematic review and series of meta-analyses to determine if there is a positive association between food-related AB and: (1.) body mass index (BMI) (number of effect sizes (k) = 110), (2.) hunger (k = 98), (3.) subjective craving for food (k = 35), and (4.) food intake (k = 44). Food-related AB was robustly associated with craving (r = 0.134 (95% CI 0.061, 0.208); p < .001), food intake (r = 0.085 (95% CI 0.038, 0.132); p < .001), and hunger (r = 0.048 (95% CI 0.016, 0.079); p = .003), but these correlations were small. Food-related AB was unrelated to BMI (r = 0.008 (95% CI -0.020, 0.035); p = .583) and this result was not moderated by type of food stimuli, method of AB assessment, or the subcomponent of AB that was examined. Furthermore, in a between-groups analysis (k = 22) which directly compared participants with overweight/obesity to healthy-weight control groups, there was no evidence for an effect of weight status on food-related AB (Hedge's g = 0.104, (95% CI -0.050, 0.258); p = .186). Taken together, these findings suggest that food-related AB is sensitive to changes in the motivational value of food, but is unrelated to individual differences in body weight. Our findings question the traditional view of AB as a trait-like index of preoccupation with food and have implications for novel theoretical perspectives on the role of food AB in appetite control and obesity.

Genetic Bias, Diversity Indices, Physiochemical Properties and CDR3 Motifs Divide Auto-Reactive from Allo-Reactive T-Cell Repertoires.

The distinct properties of allo-reactive T-cell repertoires are not well understood. To investigate whether auto-reactive and allo-reactive T-cell repertoires encoded distinct properties, we used dextramer enumeration, enrichment, single-cell T-cell receptor (TCR) sequencing and multiparameter analysis. We found auto-reactive and allo-reactive T-cells differed in mean ex vivo frequency which was antigen dependent. Allo-reactive T-cells showed clear differences in TCR architecture, with enriched usage of specific T-cell receptor variable (TRBJ) genes and broader use of T-cell receptor variable joining (TRBJ) genes. Auto-reactive T-cell repertoires exhibited complementary determining regions three (CDR3) lengths using a Gaussian distribution whereas allo-reactive T-cell repertoires exhibited distorted patterns in CDR3 length. CDR3 loops from allo-reactive T-cells showed distinct physical-chemical properties, tending to encode loops that were more acidic in charge. Allo-reactive T-cell repertoires differed in diversity metrics, tending to show increased overall diversity and increased homogeneity between repertoires. Motif analysis of CDR3 loops showed allo-reactive T-cell repertoires differed in motif preference which included broader motif use. Collectively, these data conclude that allo-reactive T-cell repertoires are indeed different to auto-reactive repertoires and provide tangible metrics for further investigations and validation. Given that the antigens studied here are overexpressed on multiple cancers and that allo-reactive TCRs often show increased ligand affinity, this new TCR bank also has translational potential for adoptive cell therapy, soluble TCR-based therapy and rational TCR design.

Isolating Proactive Slowing from Reactive Inhibitory Control in Heavy Drinkers.

Background: Impaired inhibitory control is thought to contribute to alcohol (mis)use. However, current definitions of inhibitory control are over-simplified by a failure to distinguish reactive inhibitory control from proactive slowing. Objectives: To distinguish "reactive" inhibitory control and proactive slowing in heavy drinkers, and characterize associations between both constructs and individual differences in alcohol consumption. Methods: Sixty heavy drinkers completed self-reported measures of alcohol consumption, followed by two modified Stop-Signal tasks and an AX-continuous performance task in a laboratory setting. Results: Heavy drinkers demonstrated proactive slowing when inhibition was more likely but individual differences in proactive slowing and reactive stopping were unrelated to individual differences in alcohol consumption. Conclusions/Importance: Within a sample of heavy drinkers, individual differences in reactive inhibitory control and proactive slowing are unrelated to individual differences in alcohol consumption.