bluuebunny/crossref_metadata_2025 huggingface dataset:
Epidemiology of Chlamydia trachomatis and Repeat Positivity Following Detection in New York State
Authors: Currenti Salvatore , O’Grady Thomas , Bomma Srikanth , Gurram Namratha , Miranda Wilson , Hart-Malloy Rachel
Published: July 2024

Background:

In New York State, excluding New York City, chlamydia remains a persistent health concern. Our aim was to characterize chlamydia epidemiology and identify groups at higher risk of repeat positivity to inform targeted public health interventions.

Methods:

We analyzed demographic and clinical data of laboratory-confirmed chlamydia cases in New York State from 2015 to 2019. Repeat positivity was defined as a second positive chlamydia test within 31 to 365 days of the initial positive test. We compared characteristics of individuals with single and repeat positivity and evaluated associations with repeat positivity using multivariable logistic regression models.

Results:

During the study period, 176 273 individuals were diagnosed with chlamydia, with 17 253 experiencing repeat positivity. Repeat positivity was more common among individuals assigned female at birth. Key predictors of repeat positivity among females included non-Hispanic Black (adjusted odds ratio [aOR]: 1.33; 95% confidence interval [CI], 1.27-1.40) race/ethnicity, ages 13 to 19 (aOR: 1.62; 95% CI, 1.55-1.69), prior sexually transmitted infection (STI) diagnosis (aOR: 1.24; 95% CI, 1.18-1.31), symptomatic examination (aOR: 1.07; 95% CI, 1.02-1.13), and county/community (aOR: 1.10; 95% CI, 1.05-1.15) or private/public (aOR: 1.18; 95% CI, 1.11-1.25) provider. Among males, predictors included non-Hispanic Black (aOR: 1.57; 95% CI, 1.45-1.70) race/ethnicity, ages 13 to 19 (aOR: 1.27; 95% CI, 1.17-1.38), HIV coinfection (aOR: 1.30; 95% CI, 1.10-1.54), prior STI diagnosis (aOR: 1.31; 95% CI, 1.20-1.43), extragenital infection site (aOR: 2.59; 95% CI, 2.27-2.95), symptomatic examination (aOR: 1.21; 95% CI, 1.12-1.31), and county/community health (aOR: 1.09; 95% CI, 1.02-1.17) provider.

Conclusions:

Our findings provide valuable insights for sexual health interventions to prevent chlamydia transmission and recurrence. Prioritizing resources for prevention interventions and tailored sexual health promotion among non-Hispanic Black individuals is crucial. Additionally, targeted STI prevention efforts are needed for males who have sex with men and those initially diagnosed with extragenital infection. Research is warranted on STI prevention among people living with HIV or at high risk of HIV infection. Strengthening prevention strategies through Expedited Partner Therapy and sexual health education for individuals at risk of repeat positivity could enhance prevention efforts.
Number of Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) Treatments is Associated with Longer Survival
Authors: Orgad Ran , Bakrin Naoual , Bonnefoy Isabelle , Villeneuve Laurent , Alyami Mohamad , Alhadeedi Omar , Glehen Olivier , Kepenekian Vahan
Published: July 2024

Objective:

To analyze the reasons for stopping pressurized intraperitoneal aerosolized chemotherapy (PIPAC) delivered for unresectable peritoneal surface malignancies (PSM) and to determine survival in a large patient cohort of an experienced PIPAC center.

Background:

PIPAC alone or combined with systemic chemotherapy was developed to palliatively treat unresectable PSM. Safety, tolerance and promising survival results were already reported, but the reasons for stopping treatment remain unclear and the influence of the number of PIPAC procedures on prognosis has not been evaluated.

Methods:

A retrospective analysis of PIPAC procedures from a prospectively maintained single institution PSM database was conducted from January 2016 to January 2023.

Results:

A total of 346 patients underwent 1200 PIPAC treatments in the defined time period. Two-thirds of the patients completed 3 or more PIPAC procedures, and 2 patients had more than 15 treatment procedures. Reasons for PIPAC cessation were disease progression or complication (56%), reorientation to a potential curative procedure (19%), surgical complications of the procedure (13%), death between procedures (8%) and patient request (3%). PSM origin and receiving 3 or more PIPAC treatments were independently correlated with better survival in the overall population, in the group of ultimately unresectable PSM and after propensity score weighting.

Conclusion:

The main reason for stopping PIPAC treatment in palliative management of PSM is disease progression. When 3 or more PIPAC procedures can be delivered in combination to systemic chemotherapy, survival is significantly improved. Its use should be validated by prospective studies.
Simultaneous determination of diosmin and hesperidin in combined pharmaceutical preparation by synchronous fluorescence spectrofluorimetric method
Authors: Askar H. , Fathy M. E. , Tolba M. M. , Aly Fatma A. , Metwally Mohammed E.-S.
Published: July 2024

A sensitive, rapid and green synchronous spectrofluorimetric method was developed to simultaneously analyze a binary mixture of diosmin (DSM) and hesperidin (HSP). The RSFI of both medications was measured in methanol at Δ
λ
of 100 nm. The results indicated that specific experimental factors had an impact on these intensities. The optimization and thorough examination of these parameters were conducted. The plots of synchronous fluorescence intensity-concentration for DSM and HSP were found to be linear within the concentration ranges of 0.5–5.0 µg ml
−1
and 0.2–3.0 µg ml
−1
, respectively. The detection limits for DSM and HSP were 0.107 µg ml
−1
and 0.048 µg ml
−1
, respectively. The limits of quantification were 0.323 µg ml
−1
and 0.144 µg ml
−1
for DSM and HSP, respectively. The method outlined in this study was successfully used to determine the quantities of both drugs present in commercially available mixed tablets. The results obtained using this method were subsequently compared to those of a comparison method. Greenness assessment of the suggested procedure was accomplished by applying the GAPI method. Consequently, the recommended method can be used in the routine quality control analysis of the two cited drugs with minimum harmful effect on the environment as well as the individuals.
More diverse rhizobial communities can lead to higher symbiotic nitrogen fixation rates, even in nitrogen-rich soils
Authors: Taylor Benton N. , Komatsu Kimberly J.
Published: July 2024

Symbiotic nitrogen (N) fixation (SNF) by legumes and their rhizobial partners is one of the most important sources of bioavailable N to terrestrial ecosystems. While most work on the regulation of SNF has focussed on abiotic drivers such as light, water and soil nutrients, the diversity of rhizobia with which individual legume partners may play an important but under-recognized role in regulating N inputs from SNF. By experimentally manipulating the diversity of rhizobia available to legumes, we demonstrate that rhizobial diversity can increase average SNF rates by more than 90%, and that high rhizobial diversity can induce increased SNF even under conditions of high soil N fertilization. However, the effects of rhizobial diversity, the conditions under which diversity effects were the strongest, and the likely mechanisms driving these diversity effects differed between the two legume species we assessed. These results provide evidence that biodiversity–ecosystem function relationships can occur at the scales of an individual plant and that the effects of rhizobial diversity may be as important as long-established abiotic factors, such as N availability, in driving terrestrial N inputs via SNF.
Massive presence of the invasivePolydora websteri(Polychaeta: Spionidae) in the North Adriatic Sea (Mediterranean Sea)
Authors: Lezzi Marco , Mazziotti Cristina
Published: July 2024

In recent decades, the Mediterranean Sea has experienced a marked escalation in the introduction of non-native and invasive marine species.

The global expansion of aquaculture, coupled with the increased movement of commercial species, has raised concerns about the potential for introducing parasites into new environments, posing a growing threat to marine ecosystems.

Polydora websteriis a shell boring polydorin worm that induces the formation of mud-filled blisters within the shells of molluscs. The annelid is considered indigenous to the Asian coasts and has been documented in various locations across the globe. In the present work, we report a massive presence ofP. websteriin several sites of the North Adriatic costline and we provide some diagnostic features that are useful to identify the species.Polydora websterican be distinguished of a lateral flange on chaetiger 5. Moreover the palps are characterized by continuous black lines along the margins of the ciliated groove.

The combined findings of this study provide compelling evidence thatP. websteriis expanding its range within the Mediterranean coast. Given the potential for severe ecological and economic impacts associated with this invasive polychaete, this study serves as an urgent call to action for increased monitoring ofP. websteriin both farmed and wild Pacific oysters in the Mediterranean Sea. Identification key of MediterraneanPolydorais provided.
Unraveling thein plantagrowth of the plant pathogenRalstonia pseudosolanacearumby mathematical modeling
Authors: Baroukh Caroline , Gerlin Léo , Escourrou Antoine , Genin Stéphane
Published: July 2024

Ralstonia pseudosolanacearum, a plant pathogen responsible for bacterial wilt in numerous plant species, exhibits paradoxical growth in the host by achieving high bacterial densities in xylem sap, an environment traditionally considered nutrient-poor. This study combinedin vitroexperiments and mathematical modeling to elucidate the growth dynamics ofR. pseudosolanacearumstrain GMI1000 within plants. To simulate the xylem environment, a tomato xylem-mimicking medium containing amino acids and sugars was developed to monitor the growth kinetics ofR. pseudosolanacearum. Results indicated that glutamine is the primary metabolite driving bacterial growth, while putrescine is abundantly excreted, and acetate is transiently produced and subsequently consumed. A mathematical model was constructed and calibrated using thein vitrodata. This model was employed to simulate the evolution of bacterial density and xylem sap composition during plant infection. The model accurately reproducedin plantaexperimental observations, including high bacterial densities and the depletion of glutamine and asparagine. Additionally, the model estimated the minimal number of bacteria required to initiate infection, the timing of infection post-inoculation, the bacterial mortality rate within the plant, and the rate at which excreted putrescine is assimilated by the plant. The findings demonstrate that xylem sap is not as nutrient-poor and can sustain high bacterial densities. The study also provides an explanatory framework for the presence of acetate and putrescine in the sap of infected xylem and give clues as to the role of putrescine in the virulence ofR. pseudosolanacearum.
Multi-Omic Analysis Reveals Lipid Dysregulation Associated with Mitochondrial Dysfunction in Parkinson’s Disease Brain
Authors: Hällqvist Jenny , Toomey Christina E , Pinto Rui , Wernick Anna , Sharhani Mesfer Al , Heales Simon , Eaton Simon , Mills Kevin , Gandhi Sonia , Heywood Wendy E
Published: July 2024

Parkinson’s Disease (PD) is an increasingly prevalent condition within the aging population. PD can be attributed to rare genetic mutations, but most cases are sporadic where the gene-environment interactions are unknown/likely contributory. Age related dysregulation of the glycosphingolipid degradation pathway has been implicated in the development of PD, however, our understanding of how brain lipids vary across different regions of the brain, with age and in disease stages, remains limited.

In this study we profiled several phospho- and sphingolipid classes in eight distinct regions of the human brain and investigated the association of lipids with a spatio-temporal pathology gradient, utilising PD samples from early, mid, and late stages of the disease. We performed high-precision tissue sampling in conjunction with targeted LC-MS/MS and applied this to post-mortem samples from PD and control subjects. The lipids were analysed for correlations with untargeted proteomics and mitochondrial activity data, in a multi-omics approach. We concluded that the different brain regions demonstrated their own distinct profiles and also found that several lipids were correlated with age. The strongest differences between PD and controls were identified in ganglioside, sphingomyelin and n-hexosylceramides. Sphingomyelin was also found to correlate with several proteins implicated in Parkinson’s disease pathways. Mitochondrial activity was correlated with the levels of several lipids in the putamen region. Finally, we identified a gradient corresponding to Braak’s disease spread across the brain regions, where the areas closer to the brainstem/substantia nigra showed alterations in PC, LPC and glycosphingolipids, while the cortical regions showed changes in glycosphingolipids, specifically gangliosides, HexCer and Hex2Cer.

Graphical Abstract
Effectiveness and equity of vaccination strategies against Rift Valley fever in a heterogeneous landscape
Authors: Tennant Warren S. D. , Cardinale Eric , Moutroifi Youssouf , Spencer Simon E. F. , Charafouddine Onzade , Tildesley Mike J. , Métras Raphaëlle
Published: July 2024

Spatio-temporal variations in environment and socio-agricultural factors create heterogeneity in livestock disease transmission risk, raising challenges in identifying populations most at risk and how this risk changes over time. Consequently, prioritising control strategies, such as vaccination, to achieve optimal or equitable outcomes across regions impedes the design of an effective vaccination strategy. We developed a metapopulation model for Rift Valley fever transmission in livestock across the Comoros archipelago which incorporates livestock vaccination in addition to heterogeneity in viral transmission rates and animal movements. We used the model to evaluate three vaccine allocation strategies–proportional allocation, optimal allocation for maximising total infections averted across the archipelago, and optimal allocation for more equitable outcomes across islands—under different vaccination coverage levels and animal identification scenarios. We report that (i) both archipelago-wide and island-specific strategy effectiveness were impacted by vaccination rate, allocation strategy, and animal identification approach, (ii) optimally allocating vaccines improved strategy effectiveness compared with proportional allocation but resulted in inequitable outcomes between islands, and (iii) tagging animals post-vaccination boosted overall strategy effectiveness for all vaccination rates.
CoDIAC: A comprehensive approach for interaction analysis reveals novel insights into SH2 domain function and regulation
Authors: Kandoor Alekhya , Martinez Gabrielle , Hitchcock Julianna M. , Angel Savannah , Campbell Logan , Rizvi Saqib , Naegle Kristen M.
Published: July 2024

Protein domains are conserved structural and functional units and are the functional building blocks of proteins. Evolutionary expansion means that domain families are often represented by many members in a species, which are found in various configurations with other domains, which have evolved new specificity for interacting partners. Here, we develop a structure-based interface analysis to comprehensively map domain interfaces from available experimental and predicted structures, including interfaces with other macromolecules and intraprotein interfaces (such as might exist between domains in a protein). We hypothesized that a comprehensive approach to contact mapping of domains could yield new insights. Specifically, we use it to gain information about how domains selectivity interact with ligands, whether domain-domain interfaces of repeated domain partnerships are conserved across diverse proteins, and identify regions of conserved post-translational modifications, using relationship to interaction interfaces as a method to hypothesize the effect of post-translational modifications (and mutations). We applied this approach to the human SH2 domain family, an extensive modular unit that is the foundation of phosphotyrosine-mediated signaling, where we identified a novel approach to understanding the binding selectivity of SH2 domains and evidence that there is coordinated and conserved regulation of multiple SH2 domain binding interfaces by tyrosine and serine/threonine phosphorylation and acetylation, suggesting that multiple signaling systems can regulate protein activity and SH2 domain interactions in a regulated manner. We provide the extensive features of the human SH2 domain family and this modular approach, as an open source Python package for COmprehensive Domain Interface Analysis of Contacts (Co-DIAC).
TREM2 expression level is critical for microglial state, metabolic capacity and efficacy of TREM2 agonism
Authors: Feiten Astrid F , Dahm Kilian , van Lengerich Bettina , Suh Jung H , Reifschneider Anika , Wefers Benedikt , Bartos Laura M , Wind-Mark Karin , Schlepckow Kai , Ulas Thomas , De-Domenico Elena , Becker Matthias , Khalin Igor , Davis Sonnet S. , Wurst Wolfgang , Plesnila Nikolaus , Neher Jonas J , Brendel Matthias , Lewcock Joseph W , Di Paolo Gilbert , Capell Anja , Monroe Kathryn M , Schultze Joachim L , Haass Christian
Published: July 2024

Triggering receptor expressed on myeloid cells 2 (TREM2) is a central regulator of microglial activity and sequence variants are major risk factors for late onset Alzheimer’s disease (LOAD). To better understand the molecular and functional changes associated with TREM2 signalling, we generated a TREM2 reporter mouse model and observed a gradual upregulation of reporter expression with increasing plaque proximity. Isolated microglia were sorted based on reporter expression and their transcriptomic profiles acquired in both wildtype and APP transgenic animals, allowing us to disentangle TREM2 versus pathology-specific effects. Bulk RNA-sequencing highlighted TREM2 level-dependent changes in major immunometabolic pathways, with enrichment of genes in oxidative phosphorylation and cholesterol metabolism in microglia with increased TREM2 expression. To confirm these findings, we next analysed uptake of fluorodeoxyglucose (FDG) and examined metabolomic and lipidomic profiles. Again, independent of Aβ pathology, TREM2 expression correlated with uptake of FDG as well as increased cellular redox, energetics, and cholesterol homeostasis. Finally, we performed chronic treatment with a brain penetrant TREM2 agonist and identified a window of TREM2 expression where microglia are most responsive. Thus, our data provide novel insights into TREM2-mediated regulation of microglial metabolic function and informs current efforts to bring TREM2 agonists into clinical application.
Rapid and accurate genotype imputation from low coverage short read, long read, and cell free DNA sequence
Authors: Li Zilong , Albrechtsen Anders , Davies Robert William
Published: July 2024

Inexpensive and accurate genotyping methods are essential to modern genomics and health risk prediction. Here we introduce QUILT2, a scalable read-aware imputation method that can efficiently use biobank scale haplotype reference panels. This allows for fast and accurate imputation using short reads, as well as long reads (e.g. ONT 1X r2 = 0.937 at common SNPs), linked-reads and ancient DNA. In addition, QUILT2 contains a methodological innovation that enables imputation of the maternal and fetal genome using cell free non-invasive prenatal testing (NIPT) data. Using a UK Biobank reference panel, we see accurate imputation of both mother (r2 = 0.966) and fetus (r2 = 0.465) at 0.25X (fetal fraction of 10%, common SNPs). Imputation gets increasingly accurate as coverage increases, with r2 of around 0.90 or above for both mother and fetus at 4.0X (mother r2 = 0.996, fetal r2 = 0.894). We show that this imputation enables powerful GWAS and accurate PRS for both mother and fetus, which creates both clinical opportunities, and if phenotypes can be collected alongside clinical NIPT, the potential for large GWAS.
Network-based investigation of petroleum hydrocarbons-induced ecotoxicological effects and their risk assessment
Authors: Sahoo Ajaya Kumar , Madgaonkar Shreyes Rajan , Chivukula Nikhil , Karthikeyan Panneerselvam , Ramesh Kundhanathan , Marigoudar Shambanagouda Rudragouda , Sharma Krishna Venkatarama , Samal Areejit
Published: July 2024

Petroleum hydrocarbons (PHs) are compounds composed mostly of carbon and hydrogen, originating from crude oil and its derivatives. PHs are primarily released into the environment through the diffusion of oils, resulting from anthropogenic activities like transportation and offshore drilling, and accidental incidents such as oil spills. Once released, these PHs can persist in different ecosystems and cause long-term detrimental ecological impacts. While the hazards associated with such PH contaminations are often assessed by the concentrations of total petroleum hydrocarbons in the environment, studies focusing on the risks associated with individual PHs are limited. Here, we leveraged different network-based frameworks to explore and understand the adverse ecological effects associated with PH exposure. First, we systematically curated a list of 320 PHs from published reports. Next, we integrated biological endpoint data from toxicological databases, and constructed a stressor-centric adverse outcome pathway (AOP) network linking 75 PHs with 177 ecotoxicologically-relevant high confidence AOPs within AOP-Wiki. Further, we relied on stressor-species network constructions, based on reported toxicity concentrations and bioconcentration factors data for 80 PHs and 28 PHs, respectively, and found that crustaceans are documented to be affected by many of these PHs. Finally, we utilized the aquatic toxicity data within ECOTOX to construct species sensitivity distributions for polycyclic aromatic hydrocarbons (PAHs) prioritized by the US EPA, and derived their corresponding hazard concentrations (HC05) that protect 95% of species in the aquatic ecosystem. Overall, this study highlights the importance of using network-based approaches and risk assessment methods to understand the PH-induced toxicities effectively.
Oestrogen influences B cell class-switching in individuals with an XX sex chromosome complement
Authors: Peckham Hannah , Radziszewska Anna , de Gruijter Nina M , Restuadi Restuadi , Kartawinata Melissa , Robinson George A , Martin-Gutierrez Lucia , Deakin Claire T , Wedderburn Lucy R , Jury Elizabeth C , Butler Gary , Rosser Elizabeth C. , Ciurtin Coziana
Published: July 2024

Sex differences in humoral immunity are well-documented, though the mechanisms underpinning these differences remain ill-defined. Here, we demonstrate that post-pubertal cisgender females have higher levels of class-switched B cells compared to age-matched cisgender males. However, whilst sex chromosome-encoded genes characterise most of the differences in total B cell transcriptomes between cisgender-females and -males, sex differences in class-switched B cells are only observed post-pubertally. Accordingly, B cells express high levels of oestrogen receptor 2(ESR2)and genes known to regulate B cell class-switching are enriched forESR2-binding sites. Using a gender-diverse cohort of young people, we show that in transgender males (XX chromosomal background), blockade of natal oestrogen reduced the frequency of class-switched B cells, whilst gender-affirming oestradiol treatment in transgender females (XY chromosomal background), did not increase the frequency of class-switched B cells. These data demonstrate that sex hormones and chromosomes work in tandem to impact immune responses, with oestrogen only supporting B cell class-switching on an XX chromosomal background.

eTOC summary

Sex hormones and chromosomes work in tandem to impact immune responses, with oestrogen influencing B cell class-switching exclusively on an XX chromosomal background.
Tunable bicontinuous macroporous cell culture scaffolds via kinetically controlled phase separation
Authors: Dudaryeva Oksana Y. , Cousin Lucien , Krajnovic Leila , Gröbli Gian , Sapkota Virbin , Ritter Lauritz , Deshmukh Dhananjay , Style Robert W. , Levato Riccardo , Labouesse Céline , Tibbitt Mark W.
Published: July 2024

Three-dimensional (3D) scaffolds enable biological investigations with a more natural cell conformation. However, the porosity of synthetic hydrogels is often limited to the nanometer scale, which confines the movement of 3D encapsulated cells and restricts dynamic cell processes. Precise control of hydrogel porosity across length scales remains a challenge and the development of porous materials that allow cell infiltration, spreading, and migration in a manner more similar to natural ECM environments is desirable. Here, we present a straightforward and reliable method for generating kinetically-controlled macroporous systems using liquid–liquid phase separation between poly(ethylene glycol) (PEG) and dextran. Photopolymerization-induced phase separation resulted in macroporous hydrogels with tunable pore size. Varying light intensity and hydrogel composition controlled polymerization kinetics, time to percolation, and complete gelation, which defined the average pore diameter (Ø = 1– 300 μm) and final gel stiffness of the formed hydrogels. Critically, for biological applications, macroporous hydrogels were prepared from aqueous polymer solutions at physiological pH and temperature using visible light, allowing for direct cell encapsulation. We encapsulated human dermal fibroblasts in a range of macroporous gels with different pore sizes. Porosity improved cell spreading with respect to bulk gels and allowed migration in the porous systems.
MR Corge: Sensitivity analysis of Mendelian randomization based on the core gene hypothesis for polygenic exposures
Authors: Zhang Wenmin , Su Chen-Yang , Yoshiji Satoshi , Lu Tianyuan
Published: July 2024

Mendelian randomization is being utilized to assess causal effects of polygenic exposures, where many genetic instruments are subject to horizontal pleiotropy. Existing methods for detecting and correcting for horizontal pleiotropy have important assumptions that may not be fulfilled. Built upon the core gene hypothesis, we developed MR Corge for performing sensitivity analysis of Mendelian randomization. MR Corge identifies a small number of putative core instruments that are more likely to affect genes with a direct biological role in an exposure and obtains causal effect estimates based on these instruments, thereby reducing the risk of horizontal pleiotropy. Using positive and negative controls, we demonstrated that MR Corge estimates aligned with established biomedical knowledge and the results of randomized controlled trials. MR Corge may be widely applied to investigate polygenic exposure-outcome relationships.

Availability and Implementation

An open-sourced R package is available athttps://github.com/zhwm/MRCorge.
IL-4 receptor alpha blockade in mice reduces skin inflammation, systemic response and the atopic march
Authors: Leyva-Castillo Juan-Manuel , Wong Daniel Sen Hoi , Geha Raif S
Published: July 2024

Atopic dermatitis (AD) commonly precedes food allergy and asthma in the atopic march. Epicutaneous (EC) sensitization in mice with ovalbumin (OVA) results in allergic skin inflammation that mimics AD and promotes food anaphylaxis or asthma following a gastric or intranasal challenge with OVA, respectively. Using our mouse model of EC sensitization with OVA we evaluate whether anti-IL-4Rα blocking antibody improve allergic skin inflammation and impact the atopic march. IL-4Rα blockade at the end of EC sensitization decreased allergic skin inflammation in OVA-sensitized mice, evidenced by significantly decreased eosinophil infiltration, decrease production of IL-4, IL-13 by OVA- restimulated splenocytes and reduced serum levels OVA-specific IgE. However, late IL- 4Rα blockade did not affect food anaphylaxis or airway inflammation in EC sensitized mice following an oral or intranasal challenge with OVA. IL-4Rα blockade at the beginning of EC sensitization not only impact allergic skin inflammation and systemic response to the antigen, but also decreased food anaphylaxis or airway inflammation following OVA challenge. These results suggest that the blockade of sensitization through the skin by IL-4Rα blockade could impact the atopic march.
A pan-cancer gamma delta T cell repertoire
Authors: Yu Xiaoqing , Song Li , Cen Ling , Cao Biwei , Tao Ranran , Shen Yuanyuan , Daga Daniel Abate- , Rodriguez Paulo C. , Conejo-Garcia Jose R. , Wang Xuefeng
Published: July 2024

This report presents the largest collection of gamma-delta T cell receptor (γδ TCR) reads in human cancer to date, analyzing about 11,000 patient tumor samples across 33 cancer types using the TRUST4 algorithm. Despite γδ T cells being a small fraction of the T cell population, they play a key role in both innate and adaptive immunity. Our comprehensive analysis reveals their significant presence across all cancer types, specifically highlighting the diverse spectrum and clonality patterns of their γδ receptors. This research highlights the complex roles of γδ T cells in tumor tissues and their potential as prognostic biomarkers. We also demonstrate the utility of T cell receptor gamma (TRG) and delta (TRD) gene expression values from standard RNA-seq data. Ultimately, our work establishes a fundamental resource for future tumor-infiltrating γδ T cell research and may facilitate the development of novel γδ-T-cell-based therapeutic strategies. Together, we demonstrate the strong diversity and prognostic potential of γδ T cells in multiple cancer types.

Highlights

Comprehensive analysis of γδ TCRs from 11,473 tumor samples

Significant variability and overall consistency in γδ gene expression and clonotype

γδ TCR expression and diversity as prognostic biomarkers across multiple cancers

Centralized γδ TCR repertoire database for future therapeutic discovery
Effects of Age and Diet on Triglyceride Metabolism in Mice
Authors: Spitler Kathryn M. , Shetty Shwetha K. , Davies Brandon S.J.
Published: July 2024

Background

Both age and diet can contribute to alterations in triglyceride metabolism and subsequent metabolic disease. In humans, plasma triglyceride levels increase with age. Diets high in saturated fats can increase triglyceride levels while diets high in omega-3 fatty acids decrease triglyceride levels. Here we asked how age and long-term diet effected triglyceride metabolism in mice.

Methods

We fed male and female mice a low-fat diet, a western diet, or a diet high in polyunsaturated and omega-3 (n-3) fatty acids for up to 2 years. We measured survival, body composition, plasma triglyceride levels, chylomicron clearance, and oral fat, glucose, and insulin tolerance.

Results

Triglyceride levels in mice did not increase with age, regardless of diet. Oral fat tolerance increased with age, while chylomicron clearance remained unchanged. Mice fed western diet had decreased survival. Interestingly, mice fed the n-3 diet gained more lean mass, and had lower insulin levels than mice fed either low-fat or western diet. Moreover, triglyceride uptake into the hearts of mice fed the n-3 diet was strikingly higher than in other groups.

Conclusions

In mice, age-induced changes in triglyceride metabolism did not match those in humans. Our data suggested that mice, like humans, had decreased fat absorption with age, but plasma triglyceride clearance did not decrease with age in mice, resulting in lower plasma triglyceride levels and improved oral fat tolerance with age. A chronic diet high in n-3 fatty acids increased insulin sensitivity and uptake of triglycerides specifically into the heart but how these observations are connected is unclear.

Research Perspectives

The changes in triglyceride metabolism that occur with age in humans are not reflected in a mouse model, thus mice are likely not an ideal model for understanding how age impacts lipid metabolism and subsequent metabolic disease.

A fish-oil based high-fat diet high in omega-3 fatty acids significantly increases fatty acid uptake in the heart while at the same time decreases fasting insulin levels.

In future studies it will be important to understand how the omega-3 fatty acid induced increase in fatty acid uptake affects cardiac function and how it is related to other phenotypes induced by omega-3 fatty acids.
A Novel Whole Tissue Explant Model of Hidradenitis Suppurativa
Authors: Leboit PE , Patel DU , Cohen JN , Moss MI , Naik HB , Yates AE , Harris HW , Klufas DM , Kim EA , Neuhaus IM , Hansen SL , Kyle RL , Kelly M , Rosenblum MD , Lowe MM
Published: July 2024

Hidradenitis Suppurativa (HS) is a relatively common and highly morbid inflammatory skin disease. Due to our relatively limited understanding of HS’s pathogenesis, there are currently insufficient treatment options available, and many patients’ medical needs are not being met. This is partly due to a scarcity of ex vivo human assays and animal models that accurately recapitulate the disease. To address this deficit, we have developed a whole-tissue explant model of HS to examine its pathogenic mechanisms and the efficacy of potential treatments within intact human tissue. We measured cytokine protein and RNA within whole tissue maintained in an agar-media solution, finding that IL-6 and IL-8 concentrations trended upwards in both HS explants and healthy controls, while IL-17A, IL-1β, and TNF-α exhibited increases in HS tissue alone. We also show that the explants were responsive to treatment with both dexamethasone and IL-2. Not only do our results show that this model effectively delivers treatments throughout the explants, but they also elucidate which cytokines are related to the explant process regardless of tissue state and which are related to HS tissue specifically, laying the groundwork for future implementations of this model.
Uncovering the Neural Correlates of the Urge-to-Blink: A Study Utilising Subjective Urge Ratings and Paradigm Free Mapping
Authors: Houlgreave Mairi S. , Uruñuela Eneko , Caballero-Gaudes César , Gowland Penny , Dyke Katherine , Brandt Valerie , Mohammed Imaan , Panchuelo Rosa Sanchez , Jackson Stephen
Published: July 2024

Neuroimaging plays a significant role in understanding the neurophysiology of Tourette syndrome (TS), in particular the main symptom, tics, and the urges associated with them. Premonitory urge is thought to be a negative reinforcer of tic expression in TS. Tic expression during neuroimaging is most often required as an overt marker of increased urge-to-tic, which can lead to considerable head movement, and thus data loss. This study aims to identify the brain regions involved in urge in healthy subjects using multi-echo functional MRI and a timing- free approach to localise the BOLD response associated with the urge-to-act without information of when these events occur. Blink suppression is an analogous behaviour that can be expressed overtly in the MRI scanner which gives rise to an urge like those described by individuals with TS.

We examined the urge-to-blink in 20 healthy volunteers with an experimental paradigm including two conditions, “Okay to blink” and “Suppress blinking”, to identify brain regions involved in blink suppression. Multi-echo functional MRI data was analysed using a novel approach to investigate the BOLD signal correlated with the build-up of the urge-to-blink that participants continuously reported using a rollerball device. In addition, we used the method of multi-echo paradigm free mapping (MESPFM) to identify these regions without prior specification of task timings.

Subjective urge scores were correlated with activity in the right posterior and ventral-anterior insula as well as the mid-cingulate and occipital cortices. Furthermore, blink suppression was associated with activation in the dorsolateral prefrontal cortex, cerebellum, right dorsal-anterior insula, mid-cingulate cortex and thalamus. These findings illustrate that different insula subregions contribute to the urge-for-action and suppression networks. The MESPFM approach showed co-activation of the right insula and cingulate cortex. The MESPFM activation maps showed the highest overlap with activation associated with blink suppression, as identified using general linear model analysis, demonstrating that activity associated with suppression can be determined without prior knowledge of task timings.
A novel method (RIM-Deep) for enhancing imaging depth and resolution stability of deep cleared tissue in inverted confocal microscopy
Authors: Liu Yisi , Wang Pu , Zou Junjie , Zhou Hongwei
Published: July 2024

The increasing use of tissue clearing techniques underscores the urgent need for cost-effective and simplified deep imaging methods. While traditional inverted confocal microscopes excel in high-resolution imaging of tissue sections and cultured cells, they face limitations in deep imaging of cleared tissues due to refractive index mismatches between the immersion media of objectives and sample container. To overcome these challenges, the RIM-Deep was developed to significantly improve deep imaging capabilities without compromising the normal function of the confocal microscope. This system facilitates deep immunofluorescence imaging of the prefrontal cortex in cleared macaque tissue, extending imaging depth from 2 mm to 5 mm. Applied to an intact and cleared Thy1-EGFP mouse brain, the system allowed for clear axonal visualization at high imaging depth. Moreover, this advancement enables large-scale, deep 3D imaging of intact tissues. In principle, this concept can be extended to any imaging modality, including existing inverted wide-field, confocal, and two-photon microscopy. This would significantly upgrade traditional laboratory configurations and facilitate the study of connectomics in the brain and other tissues.
An application of the MR-Horse method to reduce selection bias in genome-wide association studies of disease progression
Authors: Donovan Killian , Torres Jason , Zhu Doreen , Herrington William G , Staplin Natalie
Published: July 2024

Genome-wide association studies (GWAS) of disease progression are vulnerable to collider bias caused by selection of participants with disease at study entry. This bias introduces spurious associations between disease progression and genetic variants that are truly only associated with disease incidence. Methods of statistical adjustment to reduce this bias have been published, but rely on assumptions regarding the genetic correlation of disease incidence and disease progression which are likely to be violated in many human diseases.

MR-Horse is a recently published Bayesian method to estimate the parameters of a general model of genetic pleiotropy in the setting of Mendelian Randomisation. We adapted this method to provide bias-reduced GWAS estimates of associations with disease progression, robust to the genetic correlation of disease incidence and disease progression and robust to the presence of pleiotropic variants with effects on both incidence and progression.

We applied this adapted method to simulated GWAS of disease incidence and progression with pleiotropic variants and varying degrees of genetic correlation. When significant genetic correlation was present, the MR-Horse method produced less biased estimates than unadjusted analyses or analyses adjusted using other existing methods. Type 1 error rates with the MR-Horse method were consistently below the nominal 5% level, at the expense of a modest reduction in power. We then applied this method to summary statistics from the CKDGen consortium GWAS of kidney function decline. MR-Horse attenuated the effects of variants with known likely biased effects in the CKDGen GWAS, whilst preserving effects at loci with likely true effects.
Cell cycle expression heterogeneity predicts degree of differentiation
Authors: Noller Kathleen , Cahan Patrick
Published: July 2024

Methods that predict fate potential or degree of differentiation from transcriptomic data have identified rare progenitor populations and uncovered developmental regulatory mechanisms. However, some state-of-the-art methods are too computationally burdensome for emerging large-scale data and all methods make inaccurate predictions in certain biological systems. We developed a method in R (stemFinder) that predicts single cell differentiation time based on heterogeneity in cell cycle gene expression. Our method is computationally tractable and is as good as or superior to competitors. As part of our benchmarking, we implemented four different performance metrics to assist potential users in selecting the tool that is most apt for their application. Finally, we explore the relationship between differentiation time and cell fate potential by analyzing a lineage tracing dataset with clonally labelled hematopoietic cells, revealing that metrics of differentiation time are correlated with the number of downstream lineages.
Structural diversity of mitochondria in the neuromuscular system across development
Authors: Bae J. Alexander , Choi Myung-kyu , Ahn Soungyub , Ko Gwanho , Choe Daniel T. , Yim Hyunsoo , Nguyen Ken C. , Kim Jinseop S. , Hall David H. , Lee Junho
Published: July 2024

As an animal matures, its neural circuit undergoes alterations, yet the developmental changes in intracellular organelles to facilitate these changes is less understood. Using 3D electron microscopy and deep learning, we developed semi-automated methods for reconstructing mitochondria inC.elegansand collected mitochondria reconstructions from normal reproductive stages and dauer, enabling comparative study on mitochondria structure within the neuromuscular system. We found that various mitochondria structural properties in neurons correlate with synaptic connections and these properties are preserved across development in different neural circuits. To test the necessity of these universal mitochondria properties, we examined the behavior indrp-1mutants with impaired mitochondria fission and discovered that it caused behavioral deficits. Moreover, we observed that dauer neurons display distinctive mitochondrial features, and mitochondria in dauer muscles exhibit unique reticulum-like structure. We propose that this specialized mitochondria structure may serve as an adaptive mechanism to support stage-specific behavioral and physiological needs.
Dads on duty: First account of nest sitting in barnacle ganders
Authors: Scheiber Isabella B. R. , Slettenhaar Annabel J. , Loonen M. J. J. E. , de Jong Margje E.
Published: July 2024

In most Anseriformes (ducks, geese and swans) only females are known to incubate. Here we scientifically describe, indicidents of male nest sitting in barnacle geese (Branta leucopsis) as a form of paternal care of nest attendance. Based on pictures from wildlife cameras we identified males, which sat on their nests when their mates took incubation recesses. Wildlife cameras were placed at nests of which either the male or female was fitted with a GPS neck collar in the year prior, which aided with identifying individual birds on the nest. To attach transmitters, some geese were caught while defending their nests, thus we may have unintentionally selected bolder males which defended their nests more aggressively and were easier to catch. Nest sitting occurred relatively frequent,i.e. in 6/15 individuals. Our results show that males with collars were more likely to nest sit, but this does not deflect from the fact this behaviour exists in geese. In the course of this finding we discuss several possible functions of this behaviour,i.e. against raiding of nests by aerial predators, thermal control of nest temperature, and intraspecific brood parasitism. At this time we cannot demonstrate a possible function, as chances of successful hatching were not increased in nest-sitting males and we lack sample size for more in depth analyses. Lastly, we argue that ‘male incubation’ is misleading in the waterfowl literature, as it is truly justified for only two species, the black swan (Cygnus atratus)and black-bellied whistling duck (Dendrocygna autumnalis).
Diversity and functional specialization of oyster immune cells uncovered by integrative single cell level investigations
Authors: Divonne Sébastien de La Forest , Pouzadoux Juliette , Romatif Océane , Montagnani Caroline , Mitta Guillaume , Destoumieux-Garzon Delphine , Gourbal Benjamin , Charrière Guillaume M. , Vignal Emmanuel
Published: July 2024

Mollusks are a major component of animal biodiversity and play a critical role in ecosystems and global food security. The Pacific oyster,Crassostrea (Magallana) gigas, is the most farmed bivalve mollusk in the world and is becoming a model species for invertebrate biology. Despite the extensive research on hemocytes, the immune cells of bivalves, their characterization remains elusive. Here we were able to extensively characterize the diverse hemocytes and identified at least seven functionally distinct cell types and three hematopoietic lineages. A combination of single-cell RNA sequencing, quantitative cytology, cell sorting, functional assays and pseudo-time analyses was used to deliver a comprehensive view of the distinct hemocyte types. This integrative analysis enabled us to reconcile molecular and cellular data and identify distinct cell types performing specialized immune functions, such as phagocytosis, reactive oxygen species production, copper accumulation, and expression of antimicrobial peptides. This study emphasized the need for more in depth studies of cellular immunity in mollusks and non-model invertebrates and set the ground for further comparative immunology studies at the cellular level.
Spiking neural network models of sound localisation via a massively collaborative process
Authors: Ghosh Marcus , Habashy Karim G. , De Santis Francesco , Fiers Tomas , Erçelik Dilay Fidan , Mészáros Balázs , Friedenberger Zachary , Béna Gabriel , Hong Mingxuan , Abubacar Umar , Byrne Rory T. , Riquelme Juan Luis , Liu Yuhan Helena , Aizenbud Ido , Bicknell Brendan A. , Bormuth Volker , Antonietti Alberto , Goodman Dan F. M.
Published: July 2024

Abstract

Neuroscientists are increasingly initiating large-scale collaborations which bring together tens to hundreds of researchers. However, while these projects represent a step-change in scale, they retain a traditional structure with centralised funding, participating laboratories and data sharing on publication. Inspired by an open-source project in pure mathematics, we set out to test the feasibility of an alternative structure by running a grassroots, massively collaborative project in computational neuroscience. To do so, we launched a public Git repository, with code for training spiking neural networks to solve a sound localisation task via surrogate gradient descent. We then invited anyone, anywhere to use this code as a springboard for exploring questions of interest to them, and encouraged participants to share their work both asynchro-nously through Git and synchronously at monthly online workshops. At a scientific level, our work investigated how a range of biologically-relevant parameters, from time delays to mem-brane time constants and levels of inhibition, could impact sound localisation in networks of spiking units. At a more macro-level, our project brought together 31 researchers from multiple countries, provided hands-on research experience to early career participants, and opportunities for supervision and teaching to later career participants. Looking ahead, our project provides a glimpse of what open, collaborative science could look like and provides a necessary, tentative step towards it.