Biology subjects

Neumann, C.

Publications and source records attributed to Neumann, C..

15 recordsLinked to original sources

bioRxiv2026

Proteolytic Remodeling of Cargo Receptor Networks by RHBDL4 Tunes Secretory Pathway Flux

Cargo receptors are central organizers of the secretory pathway, yet the mechanisms controlling their abundance remain poorly understood. The endoplasmic reticulum (ER)-resident intramembrane protease RHBDL4 promotes substrate turnover via a non-canonical branch of ER-associated degradation and has recently been implicated in regulating secretory pathway components. We previously identified the p24 cargo receptor TMED7 as an RHBDL4 substrate, suggesting that cargo receptor turnover contributes to secretory pathway regulation. Here, quantitative proteomics identify members of the ER-Golgi intermediate compartment (ERGIC) cargo receptor family as endogenous RHBDL4 substrates, demonstrating that RHBDL4 targets multiple cargo receptor families within the early secretory pathway. Accordingly, RHBDL4 modulates multiple ERGIC-dependent transport pathways. In addition, unbiased secretome analysis reveals increased secretion of lysosomal precursor proteins upon RHBDL4 ablation. Mechanistically, we show that this phenotype is mediated, at least in part, by RHBDL4-dependent cleavage of the lysosomal cargo receptor sortilin/SORT1. Together, these findings identify cargo receptors as a major class of RHBDL4 substrates and establish proteolytic remodeling of cargo receptor networks as a mechanism for regulating secretory pathway flux.

cell biology↗

bioRxiv2026

Copulation calls indicate fertility but do not reflect female mate competition in wild Guinea baboons

Across different modalities, signals play a core role in attracting mates and influencing mating success. In several non-human primate species, females produce calls during mating that are thought to promote male competition over receptive females. The extent to which social system characteristics modulate the function of copulation calls remains less clear. We studied copulation calls in wild Guinea baboons (Papio papio), who live in a multilevel society structured around units in which females associate and mate almost exclusively with a single male. We hypothesised that females use copulation calls as an indirect form of mate competition, with competition increasing in larger units. In addition, we hypothesised that females are more likely to mate again after calling. We analysed 6116 copulations between 2014 and 2025, involving 99 reproductively active females and 78 subadult and adult males. Females produced copulation calls in 72.7% of copulations, with large inter-individual variation. Neither unit size nor its interaction with the female's swelling size or the presence of simultaneously receptive females affected the probability of calling. A survival analysis with a subset of the data (2353 copulations) revealed no effect of calling on the latency to the next mating. Our results render the hypothesis that female Guinea baboons use calls in indirect mate competition unlikely. Yet, the probability of calling varied with sexual swelling size, suggesting that calls signal female fertility. Possibly, Guinea baboon copulation calls represent an evolutionary remnant, no longer under selective pressure, and can be considered index signals of female fertility.

animal behavior and cognition↗

bioRxiv2026

Senescence-associated loss of intestinal α1,2-fucose disrupts a modifiable host-microbiome homeostasis axis in people with HIV

BackgroundPeople with HIV (PWH), despite effective antiretroviral therapy (ART), experience disrupted intestinal homeostasis characterized by microbial dysbiosis and impaired intestinal barrier integrity, which contribute to chronic inflammation and aging-associated comorbidities. However, tractable mechanisms contributing to this dysfunction remain poorly defined. ObjectiveTo determine whether acquired loss of intestinal 1,2-fucose, a host-derived intrinsic prebiotic glycan that supports colonization by short-chain fatty acid (SCFA)-producing bacteria essential for intestinal barrier integrity, contributes to microbiome disruption, impaired epithelial resilience, inflammation, and biological aging in PWH. DesignIleal and colonic biopsies, isolated crypts, stool, and blood from PWH on ART and controls underwent multi-omic analyses. Findings were mechanistically interrogated using stool anaerobic fermentation assays and 3D intestinal organoid models of stress-mediated epithelial disruption. ResultsIn intestinal tissues, PWH exhibited reduced 1,2-fucosylation and increased senescence-associated expression of the fucose-degrading enzyme -L-fucosidase. Lower 1,2-fucose tracked with depletion of SCFA-producing bacteria, increased inflammation, and premature biological aging. In anaerobic fermentations, stool from PWH produced fewer SCFAs than controls, whereas supplementation with the human-milk-oligosaccharide-derived 1,2-fucose donor 2'-fucosyllactose restored SCFA production and improved intestinal organoid resilience to stress-mediated disruption. ConclusionThese findings identify acquired loss of intestinal 1,2-fucose as a modifiable host-microbiome mechanism linking epithelial senescence, microbial metabolic dysfunction, impaired barrier resilience, inflammation, and biological aging in treated HIV infection. SUMMARY BOXO_ST_ABSWhat is already known on this topicC_ST_ABSPeople with HIV on suppressive antiretroviral therapy frequently have persistent intestinal barrier dysfunction, microbial dysbiosis, chronic inflammation, and accelerated biological aging, but the host mechanisms that maintain this disrupted mucosal state remain incompletely defined. What this study addsThis study identifies acquired loss of intestinal 1,2-fucosylation as a feature of treated HIV infection and links this defect to a host fucosidase-high, senescence-enriched mucosal niche, depletion of SCFA-producing bacteria, impaired tight junction-associated barrier signatures, inflammation, and biological aging phenotypes. How this study might affect research, practice or policyThese findings support intestinal glycan ecology as a modifiable host-microbiome axis and provide a rationale for testing 1,2-fucose-replenishing strategies, such as 2'-fucosyllactose, to restore microbial metabolic output and improve epithelial resilience in people with HIV.

microbiology↗

bioRxiv2025

Nested Male Reproductive Strategies in a Tolerant Multilevel Primate Society

Male reproductive success varies within populations. Models explaining reproductive skew emphasise dominance, yet the determinants of male reproductive success in egalitarian societies remain poorly understood. Using nine years of behavioural and genetic data from five parties, we investigated male reproductive monopolisation in wild Guinea baboons (*Papio papio*), an egalitarian multilevel society with one-male "units" nested within "parties" and low male-male contest competition. Genetic analyses showed 93% of the 71 infants were sired by the female's "unit male", with extra-unit paternities consistent with limited control models. Reproduction was distributed among multiple unit males, resulting in low reproductive skew at the party level, with top males siring 23-40% of offspring, well below levels in despotic species. Female takeovers were rare, suggesting male restraint. Among prime-aged males, the number of unit females was only weakly positively associated with dominance ratings. Prime-age predicted reproductive success better than dominance. Non-prime-aged males had fewer females across dominance ratings. In conclusion, male Guinea baboons' reproductive potential is shaped less by dominance than by age and stable associations with females, who play an active role in inter-sexual relationships. These results emphasise the need to move beyond frameworks focused solely on dominance-based mechanisms and to consider species-specific social organisation.

animal behavior and cognition↗

bioRxiv2025

Aging-Associated Microbiota Drives Treg Dysfunction via TNF Signaling

Aging is associated with a chronic, low-grade inflammatory state referred to as inflammaging, which contributes to impaired immune regulation and increased susceptibility to disease. While regulatory T (Treg) cells are key mediators of immune homeostasis, their role in the context of age-related inflammation remains poorly understood. Here we demonstrate that age-related changes in the microbiota promote impaired Treg cell function, resulting in the differentiation of inflammatory T cells. In agreement, we find that aged germ-free (GF) mice exhibited a more balanced immune profile, where the Treg cells are functional and pro-inflammatory mediators are reduced, suggesting that microbial exposure is essential for the establishment of inflammaging. Furthermore, we show that the use of old microbiota in young animals was sufficient to induce pro-inflammatory T cell responses and impaired mucosal Treg cell proliferation, while young microbiota restored Treg cell function in old animals. Mechanistically, we show that exposure to aged microbiota was associated with sustained TNF signaling, elevated oxidative stress, DNA damage, and increased expression of senescence markers such as {gamma}H2AX and p16 in Treg cells. These findings uncover a microbiota-TNF-dependent mechanism by which age-associated microbial dysbiosis drives Treg cell dysfunction and promotes immune aging, highlighting the therapeutic potential of microbiota-targeted strategies to restore immune homeostasis in the elderly.

immunology↗

bioRxiv2025

The Lipid Hydrolase ABHD6 is a Therapeutic Target in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)-Related Hepatocellular Carcinoma

Primary liver cancer accounts for approximately 700,000 deaths worldwide annually ranking third in cancer-related mortality, with hepatocellular carcinoma (HCC) comprising the majority of these tumors. Metabolic dysfunction-associated steatotic liver disease (MASLD) is currently a leading cause of HCC in the United States. We previously identified the lipid hydrolase alpha/beta hydrolase domain 6 (ABHD6) as a key mediator of the development of metabolic syndrome and intimately involved in cell signaling, making it a prime target for investigation in MASLD-related HCC. ABHD6 displays higher expression within HCC tumor cores when compared to adjacent non-tumor liver tissue in human subjects. Using an in vivo antisense oligonucleotide (ASO)-driven knockdown approach, we have shown the inhibition of ABHD6 prevents the development and progression of HCC in an obesity/MASLD-driven mouse model. Additionally, a xenograft model using the human Huh7 cell line displayed reduced tumor engraftment and growth with ABHD6 genetic deletion and small molecule inhibition. ABHD6 knockout cells demonstrated increased levels of bis(monoacylglycerol)phosphates (BMPs), lipids relevant to high fat diet-induced lysosomal dysfunction, and knockout cells also demonstrated altered autophagy and lysosomal activity using in vitro model of saturated fatty acid-induced lipotoxicity. These studies reveal novel lipid signaling mechanisms by which MASLD progresses towards HCC and provide support for ABHD6 as a therapeutic target in HCC. SignificanceWe have identified that alpha/beta hydrolase domain 6 (ABHD6) plays a role in lysosomal membrane lipid remodeling pathways that are relevant in obesity/MASLD-driven HCC. Inhibitors targeting ABHD6 reorganize lysosomal lipid homeostasis to improve outcomes in HCC.

cancer biology↗

bioRxiv2024

Meat transfers follow social ties in the multi-level society of Guinea baboons but are not related to male reproductive success

In human foraging societies, hunting skill is often interpreted as a signal of male quality linked to his reproductive success through his ability to provision his family and community. Similarly, in some bird and insect species, males offer their mates food to indicate their quality as a provider. Among non-human primates, however, the relationship between meat sharing and reproductive success is underexplored, leaving the evolutionary origins of this phenomenon unresolved. Guinea baboons (Papio papio) are a promising model to investigate whether meat sharing signals male quality, since females choose their mates, have been shown to rely on males to catch and share prey, and are responsive to male foraging skill. We combined records of 109 meat-eating events with nine years of behavioural data to test whether males who more frequently acquired and shared meat with females had more females in their social units for longer. Contrary to our predictions, we found no evidence that females preferred males who acquired or shared meat more frequently, suggesting that meat acquisition does not function as a signal of male quality in Guinea baboons. One explanation may be the relatively low frequency of meat-eating events. Another is that females are less dependent on males for meat than previously reported. Our results revealed that nearly half (41%) of female meat intake originated from sources other than her unit male, including the first documented cases of female prey capture (11% of events). Thus, females likely apply other, more pertinent, criteria in mate choice.

animal behavior and cognition↗

bioRxiv2023

WCRC-25: A novel luminal Invasive Lobular Carcinoma cell line model

Breast cancer is categorized by the molecular and histologic presentation of the tumor, with the major histologic subtypes being No Special Type (NST) and Invasive Lobular Carcinoma (ILC). ILC are characterized by growth in a single file discohesive manner with stromal infiltration attributed to their hallmark pathognomonic loss of E-cadherin (CDH1). Few ILC cell line models are available to researchers. Here we report the successful establishment and characterization of a novel ILC cell line, WCRC-25, from a metastatic pleural effusion from a postmenopausal Caucasian woman with metastatic ILC. WCRC-25 is an ER-negative luminal epithelial ILC cell line with both luminal and Her2-like features. It exhibits anchorage independent growth and haptotactic migration towards Collagen I. Sequencing revealed a CDH1 Q706* truncating mutation, together with mutations in FOXA1, CTCF, BRCA2 and TP53, which were also seen in a series of metastatic lesions from the patient. Copy number analyses revealed amplification and deletion of genes frequently altered in ILC while optical genome mapping revealed novel structural rearrangements. RNA-seq analysis comparing the primary tumor, metastases and the cell line revealed signatures for cell cycle progression and receptor tyrosine kinase signaling. To assess targetability, we treated WCRC-25 with AZD5363 and Alpelisib confirming WCRC-25 as susceptible to PI3K/AKT signaling inhibition as predicted by our RNA sequencing analysis. In conclusion, we report WCRC-25 as a novel ILC cell line with promise as a valuable research tool to advance our understanding of ILC and its therapeutic vulnerabilities. Financial supportThe work was in part supported by a Susan G Komen Leadership Grant to SO (SAC160073) and NCI R01 CA252378 (SO/AVL). AVL and SO are Komen Scholars, Hillman Foundation Fellows and supported by BCRF. This project used the UPMC Hillman Cancer Center and Tissue and Research Pathology/Pitt Biospecimen Core shared resource which is supported in part by award P30CA047904. This research was also supported in part by the University of Pittsburgh Center for Research Computing, RRID:SCR_022735, through the resources provided. Specifically, this work used the HTC cluster, which is supported by NIH award number S10OD028483. Finally, partial support was provided by the Magee-Womens Research Institute and Foundation, The Shear Family Foundation, and The Metastatic Breast Cancer Network.

cancer biology↗

bioRxiv2023

MacaqueNet: big-team research into the biological drivers of social relationships

O_LIFor many animals, social relationships are a key determinant of fitness. However, major gaps remain in our understanding of the adaptive function, ontogeny, evolution, and mechanistic underpinnings of social relationships. There is a vast and ever-accumulating amount of social behavioural data on individually recognised animals, an incredible resource to shed light onto the biological basis of social relationships. Yet, the full potential of such data lies in comparative research across taxa with distinct life histories and ecologies. Substantial challenges impede systematic comparisons, one of which is the lack of persistent, accessible, and standardised databases. C_LIO_LIHere, we advocate for the creation of big-team collaborations and comparative databases to unlock the wealth of behavioural data for research on social relationships by introducing MacaqueNet (https://macaquenet.github.io/). C_LIO_LIAs a global collaboration of over 100 researchers, the MacaqueNet database encompasses data from 1981 to the present on 14 species and is the first publicly searchable and standardised database on affiliative and agonistic animal social networks. With substantial inter-specific variation in ecology and social structure and the first published record on macaque behaviour dating back to 1956, macaque research has already contributed to answering fundamental questions on the biological bases and evolution of social relationships. Building on these strong foundations, we believe that MacaqueNet can further promote collaborative and comparative research on social behaviour. C_LIO_LIWe believe that big-team approaches to building standardised databases, bringing together data contributors and researchers, will aid much-needed large-scale comparative research in behavioural ecology and beyond. We describe the establishment of MacaqueNet, from starting a large-scale collective to the creation of a cross-species collaborative database and the implementation of data entry and retrieval protocols. As such, we hope to provide a functional example for future endeavours of large-scale collaborative research into the biology of social behaviour. C_LI

animal behavior and cognition↗

bioRxiv2023

(De)composing sociality: disentangling individual-specific from dyad-specific propensities to interact

In group-living animals, relationships between group members are often highly differentiated. Some dyads can maintain strong and long-lasting relationships, while others are only connected by weak or fleeting ties. Evidence accumulates that aspects of social relationships are related to reproductive success and survival. Yet, few of these analyses have considered that frequent or prolonged affiliative interactions between two individuals can be principally driven by two distinct processes: namely, the overall gregariousness of individuals, and dyadic affinity, i.e., the preference the members of the dyad have to interact specifically with one another. Crucially, these two axes of sociality cannot be observed directly, although distinguishing them is essential for many research questions, for example, when estimating kin bias or when studying the link between sociality and fitness. We present a principled statistical framework to estimate the two underlying sociality axes using dyadic interaction data. We also provide a basic R package bamoso, which implements models based on the proposed framework and allows visual and numerical evaluation of the estimated sociality axes. We demonstrate critical features of the proposed modeling framework with simulated and empirical data: (1) the possibility of checking model fit against observed data, (2) the assessment of uncertainty in the estimated sociality parameters, and (3) the possibility to extend it to more complex models that use interaction data to estimate the relationship between individual-level social features and individual-level outcomes in a unified model. Our model provides a principled foundation to explain variation in dyadic interactions. This approach allows us to address questions about the relationship between variation in sociality characteristics and other features of interest, both within and across species.

animal behavior and cognition↗

bioRxiv2022

Extending Bayesian Elo-rating to quantify dominance hierarchy steepness

The steepness of dominance hierarchies provides information about the degree of competition within animal social groups and is thus an important concept in socioecology. The currently most widely-used metrics to quantify steepness are based on Davids scores (DS) derived from dominance interaction networks. One serious drawback of these DS-based metrics is that they are biased, i.e., network density systematically decreases steepness values. Here, we provide a novel approach to estimate steepness based on Elo-ratings, implemented in a Bayesian framework (STEER: Steepness estimation with Elo-rating). Our new metric has two key advantages. First, STEER is unbiased, precise and more robust to data density than DS-based steepness. Second, it provides explicit probability distributions of the estimated steepness coefficient, which allows uncertainty assessment. In addition, it relies on the same underlying concept and is on the same scale as the original measure, and thus allows comparison to existing published results. We evaluate and validate performance of STEER by means of experimentation on empirical and artificial data sets and compare its performance to that of several other steepness estimators. Our results suggest that STEER provides a considerable improvement over existing methods to estimate dominance hierarchy steepness. We provide an R package EloSteepness to calculate the new steepness measure, and also show an example of using steepness in a comparative analysis.

animal behavior and cognition↗

bioRxiv2022

Gut Microbial Trimethylamine is Elevated in Alcohol-Associated Hepatitis and Contributes to Ethanol-Induced Liver Injury in Mice

BACKGROUNDThere is mounting evidence that microbes resident in the human intestine contribute to diverse alcohol-associated liver diseases (ALD) including the most deadly form known as alcohol-associated hepatitis (AH). However, mechanisms by which gut microbes synergize with excessive alcohol intake to promote liver injury are poorly understood. Furthermore, whether drugs that selectively target gut microbial metabolism can improve ALD has never been tested. METHODSWe used liquid chromatography tandem mass spectrometry to quantify the levels of microbe and host choline co-metabolites in healthy controls and AH patients, finding elevated levels of the microbial metabolite trimethylamine (TMA) in AH. In subsequent studies, we treated mice with non-lethal bacterial choline TMA lyase (CutC/D) inhibitors to blunt gut microbe-dependent production of TMA in the context of chronic ethanol administration. Indices of liver injury were quantified by complementary RNA sequencing, biochemical, and histological approaches. In addition, we examined the impact of ethanol consumption and TMA lyase inhibition on gut microbiome structure via 16S rRNA sequencing. RESULTSWe show the gut microbial choline metabolite trimethylamine (TMA) is elevated in AH patients and correlates with reduced hepatic expression of the TMA oxygenase flavin-containing monooxygenase 3 (FMO3). Provocatively, we find that small molecule inhibition of gut microbial CutC/D activity protects mice from ethanol-induced liver injury. CutC/D inhibitor-driven improvement in ethanol-induced liver injury is associated with distinct reorganization of the gut microbiome and host liver transcriptome. CONCLUSIONSThe microbial metabolite TMA is elevated in patients with AH, and inhibition of TMA production from gut microbes can protect mice from ethanol-induced liver injury.

biochemistry↗

bioRxiv2020

Gut Microbe-Targeted Choline Trimethylamine Lyase Inhibition Improves Obesity Via Rewiring of Host Circadian Rhythms

Obesity has repeatedly been linked to reorganization of the gut microbiome, yet to this point obesity therapeutics have been targeted exclusively toward the human host. Here we show that gut microbe-targeted inhibition of the trimethylamine N-oxide (TMAO) pathway protects mice against the metabolic disturbances associated with diet-induced obesity (DIO) or leptin deficiency (ob/ob). Small molecule inhibition of the gut microbial enzyme choline TMA-lyase (CutC) does not reduce food intake, but is instead associated with beneficial remodeling of the gut microbiome, improvement in glucose tolerance, and enhanced energy expenditure. We also show that CutC inhibition is associated with reorganization of host circadian control of both phosphatidylcholine and energy metabolism. This study underscores the relationship between microbe and host metabolism, and provides evidence that gut microbe-derived trimethylamine (TMA) is a key regulator of the host circadian clock. This work also demonstrates that gut microbe-targeted enzyme inhibitors have untapped potential as anti-obesity therapeutics.

physiology↗

bioRxiv2020

SR-B1 uptake of HDL promotes prostate cancer proliferation and tumor progression

High density lipoprotein (HDL) metabolism, in part, is facilitated by scavenger receptor class B, type 1 (SR-B1) that mediates its uptake into cells. SR-B1 is upregulated in prostate cancer tissue. Here, we report that knockout (KO) of SR-B1 via CRISPR/Cas9 editing led to reduced HDL uptake into prostate cancer cells, and reduced their proliferation in response to HDL. In vivo studies using syngeneic SR-B1 wildtype (SR-B1+/+) and SR-B1 KO (SR-B1-/-) prostate cancer cells in WT and apolipoprotein-AI KO (apoA1-KO) C57BL/6J mice showed that WT hosts, containing higher levels of total and HDL-cholesterol, grew larger tumors than apoA1-KO hosts with lower levels of total and HDL-cholesterol. Furthermore, SR-B1-/- prostate cancer cells formed smaller tumors in WT hosts, than SR-B1+/+ cells in same host model. Tumor volume data was overall similar to survival data. We conclude that tumoral SR-B1 KO reduced HDL-mediated increases in prostate cancer cell proliferation and disease progression.

cancer biology↗

bioRxiv2019

First analysis of behavioural responses of humpback whales (Megaptera novaeangliae) to two acoustic alarms in a northern feeding ground off Iceland

Mitigating cetacean entanglement in fishing industries is of global interest. Strategies include the use of acoustic alarms to warn whales of fishing gear. For baleen whales, responses to acoustic alarms are poorly understood. This behavioural response study compared the behaviour of humpback whales (Megaptera novaeangliae) in their feeding grounds off Iceland prior to, during, and after exposure to a low-frequency whale pinger (Future Oceans) and a high-frequency seal scarer (Lofitech ltd.). Linear mixed effects models and binary generalized linear mixed effects models were used to analyze the effect of the alarms on surface feeding, swimming speed, breathing rate, directness and dive time. We observed a significant decrease in surface feeding and a significant increase in swimming speed during exposure to the whale pinger. Changes in dive time between the phases of a trial differed significantly between individuals indicating that responses may depend on individual or behavioural state. We did not find any significant reactions in response to the seal scarer. In addition to the experimental exposures, a trial of whale pingers on a capelin purse seine net was conducted. Results from this trial showed that whales entered the net from the bottom while the pingers were attached at the top, but the encircled whales were able to locate an opening free of pingers and escape without damaging the net. Our results suggest that whale pingers may be a useful entanglement mitigation tool in humpback whale feeding grounds given that a reduction in feeding around nets likely reduces the risk of whales swimming through them. Pingers may also minimize net damage if whales are encircled by aiding the whales in finding their way out. However, given the uncertain long-term consequences of the behavioural changes reported here, whale pingers are most advisable for short-term use in conjunction with other entanglement mitigation measures.

animal behavior and cognition↗