bluuebunny/crossref_metadata_2025 huggingface dataset:
In vivohuman neurite exchange imaging (NEXI) at 500 mT/m diffusion gradients
Authors: Chan Kwok-Shing , Ma Yixin , Lee Hansol , Marques José P. , Olesen Jonas , Coelho Santiago , Novikov Dmitry S , Jespersen Sune , Huang Susie Y. , Lee Hong-Hsi
Published: December 2024

Evaluating tissue microstructure and membrane integrity in the living human brain through diffusion-water exchange imaging is challenging due to requirements for a high signal-to-noise ratio and short diffusion times dictated by relatively fast exchange processes. The goal of this work was to demonstrate the feasibility ofin vivoimaging of tissue micro-geometries and water exchange within the brain gray matter using the state-of-the-art Connectome 2.0 scanner equipped with an ultra-high-performance gradient system (maximum gradient strength=500 mT/m, maximum slew rate=600 T/m/s). We performed diffusion MRI measurements in 15 healthy volunteers at multiple diffusion times (13-30 ms) andb-values up to 17.5 ms/μm2. The anisotropic Kärger model was applied to estimate the exchange time between intra-neurite and extracellular water in gray matter. The estimated exchange time across the cortical ribbon was around (median±interquartile range) 13±8 ms on Connectome 2.0, substantially faster than that measured using an imaging protocol compatible with Connectome 1.0-alike systems on the same cohort. Our investigation suggested that the NEXI exchange time estimation using a Connectome 1.0 compatible protocol was more prone to residual noise floor biases due to the small time-dependent signal contrasts across diffusion times when the exchange is fast (≤20 ms). Furthermore, spatial variation of exchange time was observed across the cortex, where the motor cortex, somatosensory cortex and visual cortex exhibit longer exchange times compared to other cortical regions. Non-linear fitting for the anisotropic Kärger model was accelerated 100 times using a GPU-based pipeline compared to the conventional CPU-based approach. This study highlighted the importance of the chosen diffusion times and measures to address Rician noise in dMRI data, which can have a substantial impact on the estimated NEXI exchange time and require extra attention when comparing NEXI results between various hardware setups.

Highlights

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The Connectome 2.0 scanner equipped with 500 mT/m gradients enables high-sensitivity diffusion MRI for imaging exchange timesin vivo

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The global exchange time across the living human cortex was estimated to be about 13 ms on Connectome 2.0, faster than measured using a protocol compatible to Connectome 1.0

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Spatially varying exchange times were observed across the cortex

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A GPU-accelerated tool was developed to speed up parameter estimation by 100 times

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The narrow pulse approximation used in neurite exchange imaging does not affect estimation performance in high gradient performance MRI systems
Neuroimmune mechanisms of a mouse model of chronic back pain
Authors: Goins Aleyah E. , Zurek Nesia A. , Holguin Cristian O. , Gravelle Alexis , Goyal Sachin , Noor Shahani , Demeter Jenna B. , Koch Maddy R. , de la Peña June Bryan I. , Westlund Karin N. , Alles Sascha R.A.
Published: December 2024

Chronic back pain (CBP) is the leading cause of disability affecting 1 in 10 people worldwide. Symptoms are marked by persistent lower back pain, reduced mobility, and heightened cold sensitivity. Here, we utilize a mouse model of CBP induced by injecting urokinase-type plasminogen activator (uPA), a proinflammatory agent in the fibrinolytic pathway, between the L2/L3 lumbar vertebrae. We identified neuroimmune interactions contributing to uPA-induced CBP (henceforth, uPA-CBP) in mouse dorsal root ganglia (DRG), where nociceptive neurons reside. Flow cytometric data reveal that uPA-CBP increases CD45+CD11b+ cells in the DRG, a population characteristically implicated in other chronic pain models1. Blocking colony stimulating factor 1 receptor (CSF1R) signaling using PLX5622 partially reduced pain, suggesting CD45+CD11b+ macrophage involvement. Whole-cell patch-clamp electrophysiology data indicated DRG neuron hyperexcitability in CBP mice compared to controls. RNA sequencing revealed upregulation of pain- and inflammation-related genes involved in leukocyte migration. Together, these findings underscore the importance of the DRG neuroimmune axis in mediating chronic back pain.

Highlights

uPA-CBP induces gait changes, mechanical and thermal sensitivity compared to shams

uPA-CBP mice show increased CD45+CD11b+ cells in DRG compared to shams

uPA-CBP mice show neuronal excitability in DRG neurons compared to shams

Pain behaviors are alleviated by pharmacologically blocking CSF1R signaling

Dysregulation of inflammation- and ion channel-related genes in uPA-CBP DRG
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

The 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.

Teaser

This 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

Anopheles 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

Insect 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

LINE-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

Environmental 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

Aim

Avian 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.

Methods

We 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.

Results

43% 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 conclusions

We 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

Naked 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

Volumetric 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

Mycobacterial 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 Statement

Glycolipids 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

HNF4α 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

1. 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

Regulatory 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.

Highlights

PPARδ 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.
A generalizable Hi-C foundation model for chromatin architecture, single-cell and multi-omics analysis across species
Authors: Wang Xiao , Zhang Yuanyuan , Ray Suhita , Jha Anupama , Fang Tangqi , Hang Shengqi , Doulatov Sergei , Noble William Stafford , Wang Sheng
Published: December 2024

Nuclear DNA is organized into a compact three-dimensional (3D) structure that impacts critical cellular processes. High-throughput chromosome conformation capture (Hi-C) is the most widely used method for measuring 3D genome architecture, while linear epigenomic assays, such as ATAC-seq, DNase-seq, and ChIP-seq, are extensively employed to characterize epigenomic regulation. However, the integrative analysis of chromatin interactions and associated epigenomic regulation remains challenging due to the pairwise nature of Hi-C data, mismatched resolution between Hi-C and epigenomic assays, and inconsistencies among analysis tools. Here we propose HiCFoundation, a Hi-C-based foundation model for integrative analysis linking chromatin structure to downstream regulatory function. HiCFoundation is trained from hundreds of Hi-C assays encompassing 118 million contact matrix submatrices. The model achieves state-of-the-art performance on multiple types of 3D genome analysis, including reproducibility analysis, resolution enhancement, and loop detection. We further demonstrate the model's generalizability through genome architecture analysis of 316 species. Notably, by enhancing low-coverage experimental Hi-C data, HiCFoundation reveals genome-wide loop loss during differentiation of hematopoietic stem and progenitor cells (HSPCs) to neutrophils. Additionally, HiCFoundation is able to predict multiple types of epigenomic activity from Hi-C input and further interprets the link between Hi-C input and epigenomic output to reveal the relationship between chromatin conformation and genome function. Finally, HiCFoundation can analyze single-cell Hi-C data, shedding light on genome structure at single-cell resolution. HiCFoundation thus provides a unified, efficient, generalizable, and interpretable foundation for genome architecture, single-cell and multi-omics analysis across species, paving the path for systematically studying genome 3D architecture and its regulatory mechanisms.
Ex Vivo Drug Responses and Molecular Profiles of 597 Pediatric Acute Lymphoblastic Leukemia Patients
Authors: Enblad Anna Pia , Krali Olga , Gezelius Henrik , Lundmark Anders , Blom Kristin , Andersson Claes , Palle Josefine , Frost Britt-Marie , Ryhänen Samppa , Flægstad Trond , Jónsson Ólafur G , Schmiegelow Kjeld , Heyman Mats , Harila Arja , Nygren Peter , Larsson Rolf , Lönnerholm Gudmar , Nordlund Jessica
Published: December 2024

Ex vivodrug response profiling is emerging as a valuable tool for identifying drug resistance mechanisms and advancing precision medicine in hematological cancers. However, the functional impact of dysregulation of the epigenome and transcriptome in this context remains poorly understood. In this study, we combinedex vivodrug sensitivity profiling with transcriptomic and epigenomic analyses in diagnostic samples from 597 pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) patients.Ex vivoresistance to antimetabolites (e.g., cytarabine, thioguanine), glucocorticoids (e.g., dexamethasone, prednisolone), and doxorubicin was independently associated with reduced relapse-free survival (RFS, p < 0.05). Molecular profiling identified pre-treatment DNA methylation and gene expression patterns distinguishing resistant from sensitive cases, revealing key drug resistance signatures. These included aberrant expression of genes related to heme metabolism (e.g.ATPV06A) andKRASsignaling (e.g.ABCB1). Notably, we also observed atypical expression of genes usually restricted to T-cells and other immune cells (e.g.,ITK) in resistant BCP-ALL cells. Our findings demonstrate thatex vivodrug response patterns are predictive of clinical outcomes and reflect intrinsic molecular states associated with drug tolerance. This integrative multi-omics approach highlights potential therapeutic targets and underscores the value of functional precision medicine in identifying treatment vulnerabilities in pediatric ALL.

Key points

Ex vivodrug response profiling provides predictors of outcome that complement standard clinical risk stratification, identifying high-risk phenotypes not captured by traditional methods.

Pre-treatment transcriptional and epigenetic profiles reveal resistance-primed molecular states detectable at diagnosis, mechanisms driving treatment resistance and offer potential therapeutic targets to counteract drug tolerance.
Unique nigral and cortical pathways implicated by epigenomic and transcriptional analyses in a rotenone rat model of Parkinson’s disease
Authors: Tsalenchuk Maria , Farmer Kyle , Castro Sandra , Scheirer Abigail , Ye Yuqian , Greenamyre J. Timothy , Rocha Emily M. , Marzi Sarah J.
Published: December 2024

Pesticide exposure is increasingly recognised as a potential environmental factor contributing to the onset of idiopathic Parkinson’s disease, yet the molecular mechanisms underlying this connection remain unclear. This study aims to explore how pesticide exposure disrupts key brain regions involved in Parkinson’s disease pathology by reshaping gene regulatory landscapes. Using the well-established rotenone rat model of the disease, we performed H3K27ac ChIP-sequencing to profile active regulatory elements in the substantia nigra and cortex. In this model, rotenone distributes uniformly throughout the brain, and the degree of complex I inhibition is equivalent in cortical and substantia nigra neurons. Despite the uniformity of complex I inhibition, we identified widespread epigenomic differences, with brain region specific acetylation patterns associated with rotenone exposure. We showed consistent changes in transcriptomic activity by RNA-sequencing. Our results indicate there is a strong immune response to rotenone localised to the substantia nigra and highlight an enrichment of immune-related motifs in this brain region, suggesting that the immune response is at least partially driven by gene regulatory mechanisms. We also noted an increase in C1q complement pathway activity in the substantia nigra. In contrast, we identified widespread dysregulation of synaptic function at the gene regulatory level in the cortex of these same rats. Our results highlight a role for gene regulatory mechanisms potentially mediating the effects of pesticide exposure, driving region-specific functional responses in the brain that may contribute to the pathology and selective vulnerability that characterise Parkinson’s disease.
cfos principal cells and interneurons are strongly reactivated by sharp wave ripples
Authors: Javed M. H. , Robles-Hernandez E. M. , Patel R. , Haberl M.G. , da Silva S. Viana
Published: December 2024

The hippocampal formation is central for the learning and consolidation of spatial memories. While it is known that the high-frequency oscillations, called sharp wave ripples, play a critical role for memory processes, it is unclear if they interact with the memory engram and spatial engram cells. Here we identify the effect of these oscillations on engram cells as mice explored two environments over several days. We found that both principal cells and interneurons are part of the cfos-tagged engram. cfos-tagged principal cells, place cells and interneurons are highly reactivated by SWRs, whereas none of the negatively SWR-modulated cells are part of the engram. Together, our findings reveal a critical link between cellular and network mechanisms for memory formation and imply that interneurons play a key role in it.
Single-particle analysis of small extracellular vesicles from the follicular fluid of women undergoing fertility treatments reveals distinct PD-L1+populations
Authors: Bortot Barbara , Di Florio Roberta , Zito Gabriella , Valle Francesco , Brucale Marco , Ricci Giuseppe , Viganò Paola , Biffi Stefania
Published: December 2024

In some cell systems, small extracellular vesicles bearing PD-L1 (PD-L1+sEVs) have been shown to be able to suppress T-cell immunity. We have herein investigated whether a distinct profile of PD-L1+ sEVs exists in human follicular fluid (FF). Single-particle interferometric reflectance imaging sensing combined with a single-particle antibody capture and immunofluorescence labelling were used to determine the expression and colocalization of CD63, CD81, CD9, and PD-L1 in sEVs derived from FF of women undergoing fertility treatments (n=10). In addition, the size distribution of sEVs was investigated via atomic force microscopy. Our data indicate that the bulk of tetraspanin-expressing EVs in human FF are less than 50 nm in size. Tetraspanins and PD-L1 exhibit distinct expression and colocalization profiles at sEV level across all cohort samples. A total of 42%, 46%, and 50% of all the particles captured by anti-CD63, anti-CD81, and anti-CD9 antibodies, respectively, were positive for CD81. PD-L1 was expressed at the highest level on CD9+ sEVs, with an average value of 5% within the cohort. The presence of distinct PD-L1+ sEV subpopulations suggests that they may play a role in regulating the immune response in the follicular microenvironment. Further research is needed to fully understand the functional significance of PD-L1+ sEVs in this context and their potential as biomarkers for predicting fertility outcomes.

Abstract Figure
Venomics AI: a computational exploration of global venoms for antibiotic discovery
Authors: Guan Changge , Torres Marcelo D. T. , Li Sufen , de la Fuente-Nunez Cesar
Published: December 2024

The relentless emergence of antibiotic-resistant pathogens, particularly Gram-negative bacteria, highlights the urgent need for novel therapeutic interventions. Drug-resistant infections account for approximately 5 million deaths annually, yet the antibiotic development pipeline has largely stagnated. Venoms, representing a remarkably diverse reservoir of bioactive molecules, remain an underexploited source of potential antimicrobials. Venom-derived peptides, in particular, hold promise for antibiotic discovery due to their evolutionary diversity and unique pharmacological profiles. In this study, we mined comprehensive global venomics datasets to identify new antimicrobial candidates. Using machine learning, we explored 16,123 venom proteins, generating 40,626,260 venom-encrypted peptides (VEPs). Using APEX, a deep learning model combining a peptide-sequence encoder with neural networks for antimicrobial activity prediction, we identified 386 VEPs structurally and functionally distinct from known antimicrobial peptides. Our analyses showed that these VEPs possess high net charge and elevated hydrophobicity, characteristics conducive to bacterial membrane disruption. Structural studies revealed considerable conformational flexibility, with many VEPs transitioning to α-helical conformations in membrane-mimicking environments, indicative of their antimicrobial potential. Of the 58 VEPs selected for experimental validation, 53 displayed potent antimicrobial activity. Mechanistic assays indicated that VEPs primarily exert their effects through bacterial membrane depolarization, mirroring AMP-like mechanisms.In vivostudies using a mouse model ofAcinetobacter baumanniiinfection demonstrated that lead VEPs significantly reduced bacterial burdens without notable toxicity. This study highlights the value of venoms as a resource for new antibiotics. By integrating computational approaches and experimental validation, venom-derived peptides emerge as promising candidates to combat the global challenge of antibiotic resistance.
Delineating sex-dependent and anatomic decline of motor functions in the SOD1G93A mouse model of amyotrophic lateral sclerosis
Authors: Shelest Oksana , Tindel Ian , Lauzon Marie , Dawson Ashley , Ho Ritchie
Published: December 2024

The transgenic SOD1G93A mouse model is the most widely used animal model of amyotrophic lateral sclerosis (ALS), a fatal disease of motor neuron degeneration. While genetic background influences onset and progression variability of motor dysfunction, the C57BL/6 background most reliably exhibits robust ALS phenotypes; thus, it is the most widely used strain in mechanistic studies. In this model, paresis begins in the hindlimbs and spreads rostrally to the forelimbs. Males experience earlier onset, greater disease severity, and shorter survival than females. However, the influence of sex on patterns of declining motor function between forelimbs and hindlimbs as well as among distinct, spinal-innervated muscle groups within each limb are not fully understood. To provide a higher resolution framework of degenerating motor function across the body, we conducted more comprehensive, limb-dependent and independent measures of motor decline over the course of disease. Subsequently, we compared the timing and intensity of these features across sex, and we consider to what extent these patterns are conserved in clinical observations from human ALS patients. We found male mice experienced earlier and less localized onset than females. We also report distinct motor features decline at different rates between sexes. Finally, mice showed differences in correlation between the decline of left- and right-side measures of the hindlimb. Consequently, our findings reinforce and refine the utility of the SOD1 mouse in modeling more highly resolved, sex-specific differences in ALS patient motor behavior. This may better guide preclinical studies in stratifying patients by sex and anatomical site of onset.
A bacterial NLR-related protein recognizes multiple unrelated phage triggers to sense infection
Authors: Kibby Emily M. , Robbins Laurel K. , Deep Amar , Min Nathan K. , Whalen Lindsay A. , Nagy Toni A. , Freeborn Layla , Corbett Kevin D. , Whiteley Aaron T.
Published: December 2024

Immune systems must rapidly sense viral infections to initiate antiviral signaling and protect the host. Bacteria encode >100 distinct viral (phage) defense systems and each has evolved to sense crucial components or activities associated with the viral lifecycle. Here we used a high-throughput AlphaFold-multimer screen to discover that a bacterial NLR-related protein directly senses multiple phage proteins, thereby limiting immune evasion. Phages encoded as many as 5 unrelated activators that were predicted to bind the same interface of a C-terminal sensor domain. Genetic and biochemical assays confirmed activators bound to the bacterial NLR-related protein at high affinity, induced oligomerization, and initiated signaling. This work highlights howin silicostrategies can identify complex protein interaction networks that regulate immune signaling across the tree of life.
Decoding pre-movement neural activity from thalamic LFPs for adaptive neurostimulation in tremor patients
Authors: Plazas Fernando Rodriguez , Simpson Thomas G. , Wehmeyer Laura , Shah Rahul S. , Brannigan Jamie , Hart Michael G. , Andrade Pablo , Morgante Francesca , Visser-Vandewalle Veerle , Pereira Erlick A. , Tan Huiling , He Shenghong
Published: December 2024

Objective

Understanding the neural mechanisms underlying movement initiation is crucial for advancing movement-driven adaptive deep brain stimulation therapies for tremor disorders. We investigated the feasibility of decoding pre-movement periods of upper limb movements by machine learning using thalamic local field potentials (LFPs) and scalp electroencephalography (EEG) signals.

Approach

Data were analysed from 11 patients undergoing deep brain stimulation surgery, employing machine learning models—including logistic regression, gradient-boosted decision trees, and convolutional neural networks—to distinguish rest periods from pre-movement periods.

Main results

Our results demonstrate that early neural correlates can predict movement onset, achieving above-chance decoding performance starting approximately 680 ms before movement execution using thalamic LFPs and 1.09 s using EEGs. Individualized, patient-specific decoders outperformed cross-patient models, reflecting substantial inter-patient variability in neural modulatory patterns. Additionally, multiple frequency bands contributed independently to decoding performance, emphasizing the importance of incorporating a broad spectrum of frequencies rather than relying solely on single canonical bands.

Significance

These findings underscore the value of personalized, multi-band machine learning approaches in capturing the neural correlates preceding movement. They support the development of adaptive neurostimulation therapies that enhance the effectiveness of clinical interventions through tailored models that account for patient-specific neural activity.
Theory of Mind Variability in Schizophrenia: A Neurodevelopmental Perspective through Neurological Soft Signs and Premorbid Adjustment
Authors: Giralt-López M. , Miret S. , Campanera S. , Moreira M. , Sotero-Moreno A. , Hostalet N. , Lázaro L. , Krebs MO. , Fañanás L. , Fatjó-Vilas M.
Published: December 2024

Background

Theory of Mind (ToM) is impaired in individuals with schizophrenia (SZ). Given the neurodevelopmental nature of both social cognition and SZ, variations in ToM abilities likely originate early in life. Thus, indirect markers of altered neurodevelopment, such as neurological soft signs (NSS) and premorbid adjustment (PA), may help explain these differences.

Methods

The study included 38 patients with schizophrenia-spectrum disorder (SSD), 26 healthy siblings and 47 controls. ToM was assessed using the Hinting Task (HT). NSS were evaluated with the Neurological Evaluation Scale (NES) and PA with the Premorbid Adjustment Scale (PAS), yielding Social and Academic scores. Intelligence Quotient (IQ) was estimated two subtests of the WAIS-III and Family History (FH) through the Family Interview for Genetic Studies (FIGS).

Results

First, patients presented more deficits in two subscales of the NES (motor coordination and sequencing of complex motor acts) than siblings and controls, with siblings performing intermediate in the sequencing subscale (linear mixed models, adjusted for age, sex and IQ). Patients showed worse social PA than siblings during childhood and late adolescence. Second, patients showed poorer HT performance than siblings and controls, but the neurodevelopmental markers did not modulate such differences. Third, within each group, neurodevelopmental vulnerability markers were not associated with ToM performance (linear regression analyses adjusted for age, sex, IQ and FH).

Conclusion

In our sample, while patients showed more evidence of neurodevelopmental deviances than siblings and controls, such differences did not contribute to ToM variability, suggesting that they may stem from different neurodevelopment-related pathways.
Intracerebral Hemorrhage Outcomes after Reversal of Subtherapeutic Warfarin: Analysis of Data from GWTG-Stroke
Authors: LacKamp Aaron N. , Weber Jeremy M. , Mac Grory Brian C. , Caye Adrien J. , Stenuf Chaeli , Smith Eric E. , Daniels Justin D. , Barkley Tiffany T , Messe Steven R. , Alhanti Brooke , Sheth Kevin N. , Blanco Rosalia G , Fonarow Gregg C. , Xian Ying , Mangat Halinder S.
Published: December 2024

Background

Current guidelines recommend reversal of warfarin anticoagulation with intracranial hemorrhages. The benefit of reversing subtherapeutic warfarin anticoagulation in acute spontaneous intracerebral hemorrhage (ICH) is uncertain.

Methods

An observational cohort used Get With The Guidelines® Stroke registry between January 2015 and January 2022 to determine association of reversal with outcomes for subtherapeutic anticoagulation (INR 1.5 to 1.9). Exclusions were thrombolytics, direct oral anticoagulants, transferring out, or leaving against medical advice.

Results

The primary outcome (mRS 0-3 at discharge) was assessed among 1868 patients (mean age 73 years, 42% female), which occurred in 188/894 (21.0%) with reversal and 225/974 (23.1%) without reversal (adjusted odds ratio (aOR) 0.80 [95% CI 0.63-1.005]). Ordinal analysis showed higher odds of mRS 0-4 vs. 5-6 with reversal {52.7% vs 42.5% (aOR 1.21 [1.001, 1.48])}. Outcomes not requiring mRS were analyzed among 2569 patients. Mortality or discharge to hospice was lower with reversal {30.6% vs 41.5% (aOR 0.75 [95% CI, 0.63, 0.89])}. Fewer were ambulatory at discharge {25.8% vs 35.7% (aOR 0.68 [0.54, 0.85])}, fewer discharged to home {18.4% vs 21.7% (aOR 0.79 [0.65, 0.97])}, more discharged to skilled nursing {21.0% vs 15.7% (aOR 1.33 [1.08, 1.65])}, and more discharged to rehabilitation {24.9% vs 18.9% (aOR 1.20 [0.98, 1.47])}. Hospital length of stay was longer {median 6 vs 4 days (adjusted risk ratio (aRR) 1.25 [95% CI, 1.13, 1.37]). There was no difference in venous thromboembolism {2.9% vs 2.3% (aOR 1.47 [0.88, 2.46])}.

Discussion

Reversal of subtherapeutic warfarin with acute spontaneous intracerebral hemorrhage and INR 1.5 - 1.9 was not associated with improvement in functional outcome based upon discharge mRS 0-3 vs 4-6. Patients that received a reversal agent had 25% lower odds of dying in the hospital or being discharged to hospice, but had a longer hospital stay and were less likely to be fully ambulatory at discharge.