bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanical force regulates the inhibitory function of PD-1
Authors: Chen Hui , Zhang Yong , Cui Lei , Fan Juan , Wu Songfang , Zhou Hang , Zhang Yanruo , Song Guangtao , Jiang Ning , Zhu Mingzhao , Lou Changjie , Chen Wei , Lou Jizhong 
Published: December 2024

AbstractThe immune checkpoint molecule, programmed cell death 1 (PD-1), plays a pivotal role in regulating T-cell function. Upon binding to its ligands, PD-L1 or PD-L2, PD-1 suppresses T-cell receptor signaling, thereby preventing T-cell activation, making it a critical target in cancer immunotherapy. Although extensively studied, the molecular mechanism of PD-1’s inhibitory function is still not fully understood, especially at the atomic level. Using the biomembrane force probe (BFP), we discovered that interactions between PD-1 and PD-L1/PD-L2 exhibit catch-slip bond behavior under force. At lower forces, catch bonds are observed, transitioning to slip bond as the force increases. Steered molecular dynamics (SMD) simulations revealed a force-induced bond state between PD-1 and its ligands, distinct from the force-free state observed in solved complex structures. Disrupting interactions that stabilize either state weakens the catch bond and diminishes PD-1’s inhibitory function. Interestingly, soluble forms of PD-L1 and PD-L2 compete with their surface-bond counterparts, attenuating PD-1’s suppression of T-cell activation. This suggests that soluble PD-1 ligands could potentially serve as anti-PD-1 drugs. Tumor growth studies in mice confirmed the anti-cancer activity of soluble PD-L1. Our findings highlight the critical role of mechanical force in PD-1’s inhibitory function, suggesting that PD-1 may act as a mechanical sensor in suppressing T-cell activation. These insights indicate that mechanical regulation should be considered when designing PD-1 blocking inhibitors and other PD-1 related cancer immunotherapies.TeaserThis study shows that the interaction between PD-1 and its ligands is force-dependent, and soluble forms of PD-1 ligands can potentially serve as PD-1 blockers in cancer immunotherapy.
Genomic diversity of the African malaria vectorAnopheles funestus
Authors: Boddé Marilou , Nwezeobi Joachim , Korlević Petra , Makunin Alex , Akone-Ella Ousman , Barasa Sonia , Gadji Mahamat , Hart Lee , Kaindoa Emmanuel W. , Love Katie , Lucas Eric R. , Lujumba Ibra , Máquina Mara , Nagi Sanjay , Odero Joel O. , Polo Brian , Sangbakembi Claire , Dadzie Samuel , Koekemoer Lizette L. , Kwiatkowski Dominic , McAlister Erica , Ochomo Eric , Okumu Fredros , Paaijmans Krijn , Tchouassi David P. , Wondji Charles S. , Ayala Diego , Durbin Richard , Miles Alistair , Lawniczak Mara K. N. 
Published: December 2024

AbstractAnopheles funestuss.s. is a formidable human malaria vector across sub-Saharan Africa. To understand how the species is evolving, especially in response to malaria vector control, we sequenced 656 modern specimens (collected 2014-2018) and 45 historic specimens (collected 1927-1967) from 16 African countries. We find high levels of genetic variation with clear and stable continental patterns. Six segregating inversions might be involved in adaptation of local ecotypes. Strong recent signals of selection centred on canonical insecticide resistance genes are shared by multiple populations. A promising gene drive target inAn. gambiaeis highly conserved inAn. funestus. This work represents a significant advance in our understanding of the genetic diversity and population structure ofAn. funestusand will enable smarter targeted malaria control.
Surviving in the mountains: Temperature and elevation have contrasting physiological effects on the hoverflyEristalis tenaxin the Himalayas
Authors: Gharpure Gauri , Vedamurthy Jagath , Priya Sakshi , Thimmegowda Geetha G , Olsson Shannon B. 
Published: December 2024

ABSTRACTInsect populations are experiencing a global decline due to a variety of human-linked environmental changes. Among these changes, how insects’ physiology might be affected by predicted upslope migration due to climate change is unknown. Being ectotherms, insect physiology is impacted by abiotic factors like ambient temperature that change with elevation. Here, we performedin situexperiments to assess the sensory and cardiac physiology of an important generalist pollinating hoverflyEristalis tenax(Diptera: Syrphidae), across different elevations in the eco-sensitive and biodiverse Himalayan mountains. We built a portable physiology setup and measured hoverfly antennal responses towards common floral volatiles at 3600 masl and 4200 masl. We also recorded their heart rate at 3000 masl, 3500 masl and 4000 masl. We report the firstin situphysiology experiments performed in the high-altitude Himalayas. Our results show a contrasting impact of elevation and temperature on the sensory and cardiac physiology of hoverflies, with antennal sensitivity decreasing with increasing elevation, while average heart rate increased with temperature, independent of elevation. With upslope migration and climate warming, consequent sensory mismatches and cardiac stress could have deleterious effects on the health of both hoverflies and the vulnerable Himalayan ecosystem.
Chromosomal rearrangements and instability caused by the LINE-1 retrotransposon
Authors: Mendez-Dorantes Carlos , Zeng Xi , Karlow Jennifer A. , Schofield Phillip , Turner Serafina , Kalinowski Jupiter , Denisko Danielle , Lee Eunjung Alice , Burns Kathleen H. , Zhang Cheng-Zhong 
Published: December 2024

ABSTRACTLINE-1 (L1) retrotransposition is widespread in many cancers, especially those with a high burden of chromosomal rearrangements. However, whether and to what degree L1 activity directly impacts genome integrity is unclear. Here, we apply whole-genome sequencing to experimental models of L1 expression to comprehensively define the spectrum of genomic changes caused by L1. We provide definitive evidence that L1 expression frequently and directly causes both local and long-range chromosomal rearrangements, small and large segmental copy-number alterations, and subclonal copy-number heterogeneity due to ongoing chromosomal instability. Mechanistically, all these alterations arise from DNA double-strand breaks (DSBs) generated by L1-encoded ORF2p. The processing of ORF2p-generated DSB ends prior to their ligation can produce diverse rearrangements of the target sequences. Ligation between DSB ends generated at distal loci can generate either stable chromosomes or unstable dicentric, acentric, or ring chromosomes that undergo subsequent evolution through breakage-fusion bridge cycles or DNA fragmentation. Together, these findings suggest L1 is a potent mutagenic force capable of driving genome evolution beyond simple insertions.
Warm or bright – temperature and light microhabitat use in insect pollinators
Authors: Bartholomée Océane , Jie Vun Wen , Caplat Paul , Smith Henrik G. , Baird Emily 
Published: December 2024

AbstractEnvironmental heterogeneity in forest understories creates microhabitat niches that differ both spatially and temporally in light intensity and temperature. Do animal communities segregate in relation to these niche dimensions and can this be explained by functional traits? Answering these questions is particularly important for insect pollinators as they play a critical role in maintaining flowering plant biodiversity.Bumblebees are essential pollinators of high altitude/latitude ecosystems and are particularly sensitive to climate change. In early spring, they forage on bilberry, a keystone species in heterogeneous habitats – hemi- boreal forests. We capitalized on these conditions to study species-specific selection of foraging niches in relation to abiotic conditions.We combined full-day monitoring of bumblebee communities foraging in bilberry-dominated forests with joint species distribution modelling, which showed that temperature conditioned species occurrence, while light intensity explained species abundance. The inclusion of functional traits did not improve the overall explanatory and predictive power of the models.Our results suggest that temperature acts as a first filter of the local species pool and that species, once present, partition along a light intensity gradient. This study confirms and extends upon previous findings that microhabitat partitioning may act a mechanism underpinning bumblebee coexistence. It highlights the importance of focusing on micro-scales when studying how species interact with their environment, as this could, for example help improve our ability to predict consequences of global changes.
Precipitation tolerance determines elevational migration strategies of resident birds of the Western Ghats of India
Authors: Akshay V.A. , Campbell Caitlin J. , Loiselle Bette , Guralnick Robert 
Published: December 2024

AbstractAimAvian elevational migration is a common, but less studied form of short-distance migration. Numerous hypotheses have been proposed to explain this behavior, yet few studies have tested those comprehensively. We examine four non mutually exclusive hypotheses—climatic constraint, limited foraging opportunities, body size, and dispersal ability—using a comparative framework to evaluate their support in explaining avian elevational migration in the monsoon-dominant Western Ghats.Location:Western Ghats.Time period:2013 - 2023.Major taxa studied:Birds.MethodsWe used citizen science data from eBird to quantify elevational migration patterns of resident birds of the Western Ghats. Using robust data curation and new bias correction methods, we modeled migration patterns of 164 species across summer, monsoon and winter seasons. We built seasonal phylogenetic logistic regression models to test the effect of a species’ environmental tolerances, diet, body-size and dispersal ability on elevational migration likelihood.Results43% of resident birds exhibited elevational migration in at least one season. Most species migrated between winter and summer (57), followed by migrations between summer and monsoon (39) and then monsoon and winter (38). Species predominantly moved upslope in summer (82%) and downslope in monsoon (87%), with no discernible pattern in winter. Species with broader temperature tolerances were more likely to migrate across all seasons. Additionally, species associated with wetter environments were more likely to migrate in summer and winter. Lastly, species with narrower precipitation tolerances were more likely to migrate during the monsoon, influenced by diet.Main conclusionsWe find support for the climatic constraint and limited foraging opportunities hypotheses in explaining both the direction and likelihood of elevational migration. Precipitation is a particularly strong climatic driver for elevational migrants, especially under monsoon conditions. This suggests a complex relationship between precipitation tracking and the associated changes in resource availability determining elevational migration strategies in the region.
Functional characterization of the store-operated calcium entry pathway in naked mole-rat cells
Authors: Drugachenok Polina , Urriola-Muñoz Paulina , Qui Lanhui , Han Zhuang Zhuang , Smith Ewan St J , Rahman Taufiq 
Published: December 2024

ABSTRACTNaked mole-rats (NMRs,Heterocephalus glaber) are highly unusual rodents exhibiting remarkable adaptations to their subterranean habitat and resistance to developing various age-related diseases such as those related to abnormal cell proliferation or cancer, neurodegeneration and inflammation. In other rodents, as well as humans, a ubiquitous Ca2+influx pathway, namely the store-operated Ca2+entry (SOCE), has been implicated in all these diseases. SOCE is triggered by intracellular Ca2+store depletion resulting in interaction of Stim proteins with Orai proteins, the putative homologs of which appear be present in the NMR genome, but no characterisation of SOCE in NMRs has yet been conducted. In this study, we provide the first functional and pharmacological characterization of SOCE in NMR cells using both excitable and non-excitable cells.
Muscle-Specific ECM Fibers Made with Anchored Cell Sheet Engineering Support Tissue Regeneration in Rat Models of Volumetric Muscle Loss
Authors: Shahin-Shamsabadi Alireza , Cappuccitti John 
Published: December 2024

AbstractVolumetric muscle loss (VML) represents a critical unmet need in regenerative medicine, with no established standard of care. This study introduces a novel therapeutic strategy using tissue-specific skeletal muscle extracellular matrix (ECM) fibers fabricated using scaffold-free Anchored Cell Sheet Engineering technology. These engineered fibers replicate the native ECM composition and microarchitecture of skeletal muscle, incorporating essential structural and basement membrane proteins. In a rat VML model, engineered ECM fibers demonstrated a promising regenerative capacity compared to commercial porcine-derived small intestine submucosa (SIS) ECM. Over an 8-week period, the engineered fibers preserved muscle volume and weight, regulated inflammatory and fibrotic responses, and promoted vascularization. In contrast, SIS was rapidly degraded by week 4 and associated with excessive fibrotic response. Force recovery in the muscles treated with engineered ECM fibers was lower at the 8-week time point (77% compared to 91% in the control group), but histological and immunohistochemical analyses revealed newly formed, dispersed muscle fibers exclusively within the repaired muscle tissue treated with engineered ECM fibers. Importantly, only in cases where engineered ECM fibers were used, muscle weight was preserved, resulting in similar normalized force-to-weight recovery across all groups (87% in the test group vs. 88% in the control group). The histological analyses further demonstrated ongoing tissue remodeling, indicative of sustained regeneration, in contrast to the premature fibrotic healing observed in the other groups. A novel quantitative image analysis workflow using a custom Python script, enabled objective assessment of spatial tissue heterogeneity through histology and immunohistochemistry images, setting a new standard for tissue regeneration analysis. These findings establish engineered tissue-specific ECM fibers as a transformative approach for VML treatment and lay the groundwork for translation to clinical applications.
Trehalose dimycolate inhibits phagosome maturation and promotes intracellularM. tuberculosisgrowth via noncanonical SNARE interaction
Authors: Santamaria Carolina , Biegas Kyle J. , Kim Christi Y. , Cabral Jessica , Lee James R. , Swarts Benjamin M. , Siegrist M. Sloan 
Published: December 2024

AbstractMycobacterial cell envelopes are rich in unusual lipids and glycans that play key roles during infection and vaccination. The most abundant envelope glycolipid is trehalose dimycolate (TDM). TDM compromises the host response to mycobacterial species via multiple mechanisms, including inhibition of phagosome maturation. The molecular mechanism by which TDM inhibits phagosome maturation has been elusive. We find that a clickable, photoaffinity TDM probe phenocopies native TDM in macrophage host cells and binds several host SNARE proteins, including VTI1B, STX8, and VAMP2. VTI1B and STX8 normally promote endosome fusion by forming a complex with VAMP8. However in the presence of native TDM orMycobacterium tuberculosis, VTI1B and STX8 can complex with VAMP2, which in turn inhibits VAMP8 binding. VAMP2 inhibits phagosome maturation and promotes intracellularM. tuberculosisreplication. Thus one mechanism by which TDM constrains the innate immune response toM. tuberculosisis via non-canonical SNARE complexation.Significance StatementGlycolipids from theMycobacterium tuberculosiscell envelope, particularly trehalose dimycolate (TDM), play key roles in subverting the immune response to this intracellular pathogen. How subversion occurs is often unclear because glycans and lipids are technically challenging to study in cells. We discovered that a TDM-mimicking chemical probe interacts with three host SNARE proteins, including two that regulate endosome fusion and one that does not. The presence of TDM orM. tuberculosistriggers abnormal binding of these SNAREs, which in turn inhibits the fusion ofM. tuberculosis-containing phagosomes with lysosomes and promotesM. tuberculosisreplication. Our work provides an unusual example of a bacterial pathogen restricting the immune response via glycolipid-SNARE interactions.
The effect of HNF4α knockout in beta cells is age and gender dependent
Authors: Villaca Catharina B.P. , Oliveira Viviane R. , Santos Gustavo J. , Ortis Fernanda 
Published: December 2024

AbstractHNF4α is important for beta cells’ ability to adequately secrete insulin in response to glucose concentration and endoplasmic reticulum (ER) homeostasis. In humans, HNF4α mutation is responsible for Diabetesmellitussubtype MODY1, which has age determined onset. In addition, in other types of DM, there are evidences that gender can influence beta cell dysfunction, with possible involvement of ER stress pathways. Thus, we assessed the influence of gender and age on beta cell dysfunction induced by HNF4α absence. We used an animal model with specific beta cells KO for HNF4α, induced after birth (Ins. CRE HNF4αloxP/loxP). Glucose intolerance is observed after 10 days of KO induction, at 50 days of age, with KO males (MKO) showing greater glucose intolerance than KO females (FKO). Percentage of insulin-positive cells in KO mice islets is lower compared to Control at all ages evaluated, with MKO having a lower percentage at later ages compared to FKO. Both KO groups have reduced beta cell mass and increased α-cell mass, which is higher in MKO. ER stress is induced in both KO groups. However, ER stress-mediated apoptosis is observed only in MKO. FKO shows evidence of beta cell differentiated state loss. Thus, loss of beta cells in HNF4α KO is influenced by gender and age, involves induction of ER stress, and is more pronounced in males, where ER stress-induced beta cell death is observed. Partial protection observed in females seems to involve dedifferentiation of beta cells.
Predicting the impact of giant kelp restoration on food webs and fisheries production
Authors: O’Neill Tess , Bennett Scott , Brown Christopher J. 
Published: December 2024

Abstract1. Ecosystem restoration is gaining momentum as communities and policymakers increasingly appreciate the need to recover lost ecosystem services. However, more knowledge about the potential ecological outcomes of restoration for ecosystem services is needed to promote engagement of stakeholders with restoration targets. In Tasmania the giant kelp,Macrocystis pyrifera,is a productive canopy species that has declined by 95%.2. We aimed to predict the effects ofM. pyriferarestoration on foodwebs and fisheries production. The primary productivity multiple ofM. pyriferacompared to the dominant understory speciesEcklonia radiatawas quantified and then incorporated into an Ecopath with Ecosim (EwE) model of Tasmanian waters. The model was fitted to catch per unit effort data to estimate the predator/prey interactions. Several scenarios were then simulated, representing uncertainty in predator/prey interactions and different areas ofM. pyriferarestoration.3. Restoration of degraded reefs withM. pyriferawas predicted to increase primary productivity by about 40 times per unit area compared to the existing habitat.4. We predicted that restoring 30% of the degradedM. pyriferaarea would increase abalone and coastal demersal fish catch rates by ∼7%. Rock lobster and reef-associated fisheries catch rates were predicted to increase by 1-2% respectively.5. Model scale was hypothesized to underestimate the increases in biomass and catch. By modelling outcomes of ecological restoration, achievable targets can be set that are locally relevant and therefore more likely to attract support.
PPARδ restrains the suppression function of intra-tumoral Tregs by limiting CIITA-MHC II expression
Authors: Yang Qiyuan , Liang Yuqiong , Inoue-Hatanaka Tomoko , Koh Zhiqian , Ilkenhans Nadja , Suman Ethan , Yu Jingting , Zheng Ye 
Published: December 2024

AbstractRegulatory T cells (Tregcells) play a critical role in suppressing anti-tumor immunity, often resulting in unfavorable clinical outcomes across numerous cancers. However, systemic Tregdepletion, while augmenting anti-tumor responses, also triggers detrimental autoimmune disorders. Thus, dissecting the mechanisms by which Tregcells navigate and exert their functions within the tumor microenvironment (TME) is pivotal for devising innovative Treg-centric cancer therapies. Our study highlights the role of peroxisome proliferator-activated receptor β/δ (PPARδ), a nuclear hormone receptor involved in fatty acid metabolism. Remarkably, PPARδ ablation in Tregescalated tumor growth and augmented the immunosuppressive characteristics of the TME. This absence of PPARδ spurred an increased expression of genes central to antigen presentation, notably CIITA and MHC II. Our results showcase a novel association where the absence of CIITA in PPARδ-deficient Tregbolsters anti-tumor responses, casting CIITA as a pivotal downstream regulator of PPARδ within Treg.In vitroassays demonstrated that elevated CIITA levels enhance the suppressive capacity of Treg, facilitated by an antigen-independent interaction between Treg-MHC II and Tconv-TCR/CD4/Lag3. A significant revelation was the role of type 1 interferon as a TME signal that promotes the genesis of MHC II+Treg; PPARδ deficiency intensifies this phenomenon by amplifying type 1 interferon signaling, mediated by a notable upsurge in JAK3 transcription and an increase of pSTAT1-Y701. In conclusion, the co-regulation between TME cues and PPARδ signaling shapes the adaptive and suppressive roles of Tregcells through the CIITA-MHC II pathway. Strategically targeting the potent MHC II+Tregpopulation could open a new avenue for cancer therapies by boosting anti-tumor defenses while curbing autoimmune threats.HighlightsPPARδ Tregconditional knockout mice show accelerated tumor growth due to increased expression of CIITA-MHC II.Type I interferon signal regulates TregCIITA-MHC II axisin vitroandin vivo.PPARδ attenuates Type I interferon response and restrains CIITA-MHC II expression in Tregcells.Tregsuppressive function is enhanced by TregMHC II’s direct interaction with TCR/CD4/Lag3 on Teffcells.