bluuebunny/crossref_metadata_2025 huggingface dataset:
Investigating Neural Processing of Color in Normal and Impaired Vision
Authors: Rina Andriani
Published: January 2025

This study examines cortical responses to chromatic and luminance stimuli in individuals with normal trichromatic vision, Daltonism, and achromatopsia. Functional magnetic resonance imaging (fMRI) data were collected using stimuli modeled after Wade et al. (2008) to evaluate the differential activation of visual cortical areas. In normal trichromats, hV4 demonstrated the highest chromatic sensitivity, while ventral areas showed stronger responses to color compared to dorsal regions. In Daltonic and achromatopsia participants, cortical activation was observed under combined chromatic and luminance conditions; however, no significant color-specific activity was detected, even in hV4.

This work establishes a baseline for understanding cortical responses in color vision deficiencies and preceded gene therapy studies in the same achromatopsia patients (Fischer et al., 2020; Seitz et al., 2022). These findings contribute to ongoing research into neural plasticity and targeted therapeutic interventions.
Molecular analyses of individual variation in honey bee sociability
Authors: Traniello Ian M. , Avalos Arian , Gachomba Michael J. M. , Gernat Tim , Chen Zhenqing , Cash-Ahmed Amy C. , Hamilton Adam R. , Cook Jennifer L. , Robinson Gene E.
Published: January 2025

Individual variation in sociability is a central feature of every society. This includes honey bees, with some individuals well-connected and sociable, and others at the periphery of their colony’s social network. However, the genetic and molecular bases of sociability are poorly understood. Trophallaxis – a behavior involving sharing liquid with nutritional and signaling properties - comprises a social interaction and a proxy for sociability in honey bee colonies: more sociable bees engage in more trophallaxis. Here we identify genetic and molecular mechanisms of trophallaxis-based sociability by combining genome sequencing, brain transcriptomics, and automated behavioral tracking. A genome-wide association study (GWAS) identified 18 single-nucleotide polymorphisms (SNPs) associated with variation in sociability. Several SNPs were localized to genes previously associated with sociability in other species, including in the context of human autism, suggesting shared molecular mechanisms of sociability. Variation in sociability also was linked to differential brain gene expression, particularly genes associated with neural signaling and development. Using comparative genomic and transcriptomic approaches, we also detected evidence for divergent mechanisms underpinning sociability across species, including those related to reward sensitivity and encounter probability. These results highlight both potential evolutionary conservation of the molecular roots of sociability and points of divergence.
Critical Scaling of Novelty in the Cortex
Authors: Ribeiro Tiago L. , Vakili Ali , Gifford Bridgette , Siddiqui Raiyyan , Sinfuego Vincent , Pajevic Sinisa , Plenz Dietmar
Published: January 2025

The ability to detect unanticipated, novel events and rapidly relay this information across neural networks is fundamental to brain function, enabling the selection of appropriate behavioral responses. Here, we examine the transmission of holographically triggered action potentials in primary visual cortex of quietly resting mice, focusing on the dynamics of communication from pyramidal neurons. We demonstrate that these novel action potentials, which are uncorrelated with preceding activity, exert a disproportionally large influence on neighboring neurons. Their influence scales robustly to an exponent between 0.2 and 0.3 relative to their number. Remarkably, even a small number of novel action potentials can engage a majority of the local network, achieving high decoding accuracy of the perturbation origin in the face of high trial-by-trial variability and ongoing activity characterized by scale-invariant, parabolic neuronal avalanches. This heightened susceptibility to small, local perturbations aligns with the behavior of complex systems exhibiting critical dynamics. Our findings reveal that scaling underpins the efficient communication of unanticipated action potentials, suggesting it is a fundamental mechanism for detecting and processing novel events in the brain. These results provide new insights into the neural basis of novelty detection and highlight the importance of critical dynamics in cortical network function.
The cytosolic cysteinyl-tRNA synthetase is capable of regulating ATF4 translation independent of eIF2α phosphorylation state
Authors: Xu Acer E. , Weissman Jonathan S.
Published: January 2025

In mammalian cells, the integrated stress response (ISR) triggers ATF4 translation under general conditions of cell stress. Mammalian target of rapamycin (mTOR) signaling also triggers ATF4 translation under general pro-growth conditions. While the transcriptomic changes of these two contradictory pathways are have been studied, a full understanding of all pathways capable of increasing ATF4 translation and how these pathways are regulated and interact with each other remains unknown. In a genome-wide CRISPRi screen, we found that loss of CARS is sufficient to activate ATF4 translation independent of canonical ISR signaling. This ATF4 translation does not require eIF2α phosphorylation and does not require MTOR kinase activity. In a genome-wide epistasis CRISPRi screen using a staggered sgRNA infection strategy, we identified METAP2 and OGT as potential downstream factors in this pathway. This represents a novel pathway for activation of ATF4 translation that may enable targeted manipulation of ATF4 for beneficial therapeutic outcomes.
Correlation between DNA double strand breaks and cell death in peripheral blood lymphocytes from breast cancer patients
Authors: Solana-Peña Ángela , Pujol-Canadell Monica , López Juan-Sebastián , Macià Miquel , Martínez Pérez Evelyn , Linares Isabel , Stefanovic Milica , Pérez-Montero Héctor , González-Viguera Javier , Arangüena Peñacoba Marina , Ventura Montse , de Miguel-Garcia Gisela , Guedea Ferran , Erill Nadina , González-Rumayor Victor , Armengol Gemma , Barquinero Joan Francesc
Published: January 2025

Radiotherapy is an effective treatment to fight cancer. However, it not only affects cancer cells but also healthy tissues, causing side effects. Different factors can influence the appearance of radiotoxicity, like total dose administered or patient individual characteristics, such as genetic variability. Several biomarkers have been proposed to predict radiotoxicity, especially those based on apoptosis or DNA damage, for example γ-H2AX, which correlates with DNA double strand breaks. Our purpose is to analyze how apoptosis and γ-H2AX correlate to each other and to link these results with selected SNPs associated with apoptosis. Blood samples from 60 breast cancer patients in remission were recruited. After mononucleated cells isolation, samples were irradiated. Then, we assessed induction and kinetics of disappearance of γ-H2AX at different times after 2-Gy irradiation and apoptosis induced 24 and 48 h after 8-Gy irradiation. A negative correlation was observed between basal and residual γ-H2AX and apoptosis at 48 h post-irradiation. This result supports previous studies with cancer patients showing a negative correlation between these two biomarkers. Considering the high variability of radio-induced apoptosis, we performed a genotyping study. Two SNPs located atTP53andFASgenes were associated with apoptosis. Overall, our results indicate that individuals with less efficiency in removing damaged cells, probably due to genetic polymorphisms, presented more basal and residual levels of DNA damage.
C. elegansLET-381/FoxF and DMD-4/DMRT control development of the mesodermal HMC endothelial cell
Authors: Stefanakis Nikolaos , Xi Jasmine , Jiang Jessica , Shaham Shai
Published: January 2025

Endothelial cells form the inner layer of blood vessels and play key roles in circulatory system development and function. A variety of endothelial cell types have been described through gene expression and transcriptome studies; nonetheless, the transcriptional programs that specify endothelial cell fate and maintenance are not well understood. To uncover such regulatory programs, we studied theC. elegansHead Mesodermal Cell (HMC), a non-contractile mesodermal cell bearing molecular and functional similarities to vertebrate endothelial cells. Here, we demonstrate that a Forkhead transcription factor, LET-381/FoxF, is required for HMC fate specification and maintenance of HMC gene expression. DMD-4, a Dmrt transcription factor, acts downstream of and in conjunction with LET-381 to mediate HMC fate specification and gene expression maintenance. DMD-4, independently of LET-381, also represses the expression of genes associated with a different, non-HMC, mesodermal fate. Our studies uncover essential roles for FoxF transcriptional regulators in endothelial cell development, and suggest that the identity of FoxF co-functioning target transcription factors promotes specific non-contractile mesodermal fates.
Primary healthcare providers’ perspectives on six-month dispensing of HIV medication in South Africa: a cross-sectional survey
Authors: Ntjikelane Vinolia , Huber Amy , Morgan Allison , Pascoe Sophie , Manganye Musa , Malala Lufuno , Rosen Sydney
Published: January 2025

Background

In many African countries the dispensing duration for antiretroviral therapy (ART) medication for HIV treatment has increased from 3 months to 6 months for stable clients. To help inform a decision about whether to move from three-month dispensing (3MMD) to six-month dispensing (6MMD) in South Africa, we surveyed healthcare providers about their perspectives on dispensing and scripting durations.

Methods

We conducted a cross-sectional survey of healthcare providers (nurses, managers, pharmacists) at 24 primary healthcare clinics in South Africa from May to September 2024, asking closed- and open-ended questions. Results are reported as frequencies.

Results

182 providers were enrolled from four provinces (median age 44, 88% female). Most (>70%) respondents said that the 3MMD guideline offered multiple benefits for providers and patients, compared to the previous two-month dispensing rule; most (64%) also said there were no challenges in implementing 3MMD. >80% of respondents across all cadres reported that they would be comfortable dispensing 6 months of ART at a time, believing that it would reduce facility overcrowding, lighten staff workloads, and be advantageous to clients by decreasing their visit burden and travel costs. Two thirds (63%) of participating nurses, who provide the largest share of direct ART care, were also in favour of resuming 12-month scripting for ART; the remaining 37% expressed concerns about decreases in treatment adherence and clinical monitoring of clients.

Conclusion

Most healthcare providers at primary healthcare clinics in South Africa are in favour of allowing six-month dispensing and 12-month prescriptions as options for established ART clients.
Single-Cell Temporal Atlas of Myeloid Cells in the Live Haemorrhagic Brain
Authors: Kawamura Yuki , Johnson Conor W. , DeLong Jonathan , de Lima Camillo Lucas Paulo , Takahashi Munetomo , Beatty Hannah E. , Herbert Ryan , Cord Branden J. , Matouk Charles , Askenase Michael , Sansing Lauren H.
Published: January 2025

CNS-resident microglia and recruited myeloid cells populate the haematoma in intracerebral haemorrhage (ICH), but the contribution of these cell populations to injury and repair has been controversial. To better characterise myeloid cell changes over time, we employed single-cell RNA sequencing to generate a unique paired dataset of live haematoma and peripheral blood samples from 10 ICH patients. This work presents a temporal atlas of ICH myeloid populations and identifies population-specificin-situtranscriptional drivers. In addition to distinct populations of activated microglia and TNF-low microglia, we found a unique and highly activated population of CD14+monocytes in the haematoma. Perturbation analysis comparing haematoma-associated monocytes to shared populations in blood and haematomas identified TNF signalling as the primary driver of their activation. Employing a custom temporal trajectory analysis based on the embeddings of a single-cell foundation model, we found that this TNF response in monocytes was transient, peaking early after haemorrhage and decreasing over the ensuing 48 hours. Our analysis further identified a transient population of highly activated microglia as the likely source of TNF during the acute stage of ICH. Acute TNF signalling in CD14+monocytes associated with better adjusted outcomes both in our and external cohorts. Overall, our results suggest that acute TNF signalling between transient populations of activated microglia and unique haematoma-associated monocytes could potentially be beneficial in recovery after ICH.

One sentence summary

We present a single-cell temporal atlas of myeloid cells in intracerebral haemorrhage and identify TNF signalling as a driver of haematoma dynamics.
Cardiometabolic biomarkers and systemic inflammation in US adolescents and young adults with latent tuberculosis infection: a population-based cohort study
Authors: Magodoro IM , Ntusi NAB , Jao J , Heather JZ , Claggett BL , Siedner MJ , Wilkinson KA , Wilkinson RJ
Published: January 2025

Background

Mycobacterium tuberculosis(M.tb) infection in adults increases incident type 2 diabetes and atherosclerotic cardiovascular disease risk, but it is unknown if this cardiometabolic detriment occurs in the young. We sought to determine if young persons with latent tuberculosis infection (LTBI) have worse cardiometabolic health than their tuberculosis (TB) uninfected peers.

Methods

Peripubescent adolescents (12-15 years old) and older adolescents and young adults (16-30 years old) (older participants) were cross-sectionally surveyed. LTBI was assessed by tuberculin skin testing (induration ≥10mm). Fasting plasma glucose (FPG), HbA1c, c-peptide, NTproBNP, hs-Troponin T, c-reactive protein (CRP), ferritin, diabetes/prediabetes (FPG ≥5.6 mmol/L and/or HbA1c ≥5.7%) and homeostatic model of insulin resistance (IR) (HOMA2-IR) were measured as study outcomes. LTBI cases were propensity score matched 1:4 on sociodemographic and lifestyle indicators with TB uninfected controls to estimate adjusted median (adjMedian), mean differences (adjMD), and odds ratios (adjOR) of cardiometabolic indices.

Results

Seventy-five young persons with LTBI were matched with 300 TB uninfected peers of similar age [mean (SD): 18.3 (5.5) vs. 18.0 (5.5) years], race [Hispanic: 74.7% vs. 76.7%], and sedentary time [3.5 (1.5%) vs. 3.5 (1.6) hours/day]. LTBI was associated with higher inflammation [adjMedian (IQR) CRP: 0.22 (0.05, 0.34) vs. 0.11 (0.04, 0.35) mg/dL; p=0.027; ferritin: 55.0 (25.1, 90.3) vs. 41.1 (29.5, 136.2) ng/mL; p=0.047] among older participants, but not peripubescent adolescents [CRP: 0.08 (0.04, 0.36) vs. 0.05 (0.02, 0.17) mg/dL; p=0.42; ferritin: 23.0 (18.5, 33.5) vs. 32.7 (21.5, 48.2) ng/mL; p=0.011]. By contrast, there were no meaningful differences in FPG [adjMD (95%CI): −0.05 (−0.22, 0.12) mmol/L; p=0.57], HbA1c [0.0 (−0.17, 0.17) %; p=0.98] or diabetes/prediabetes prevalence [adjOR (95%CI): 0.9 (0.29, 2.29); p=0.85] by LTBI status. Insulin secretion and resistance, NTproBNP and hs-Troponin T were also similar.

Conclusion

Older adolescents and young adults with LTBI had greater markers of inflammation than those without LTBI while cardiometabolic profiles were similar across TB and/or age strata. Unlike in adults,M.tbinfection in young persons does not appear associated with cardiometabolic derangement, although longterm consequences of chronic inflammation requires further study.
Cytotoxic activity against human leukemia cells of Kaempferol-3-O-rhamnoside from VietnameseSchima wallichii(DC.) Korth: A combination ofin vitroandin silicoinsights
Authors: Tran Manh Hung , Nguyen Yen Nhi , Pham Lam Thuy Mi , Tran Thuy Linh Thi , Nguyen Tan Khanh , Le Tuan Anh , Bich Van Ngo Thai , Truong Hieu Phu Chi , Tran Vinh Pham Phu
Published: January 2025

In the investigation of the cytotoxic activity against leukemia cells of Vietnamese medicinal plants, we identified the extract ofSchima wallichii(DC.) Korth as capable of inhibiting several leukemia cell lines. In this study, we isolated a main compound as kaempferol-3-O-rhamnoside, marking the first report of this compound being isolated from the stem ofSchima wallichiicollected in Vietnam. Inin vitroexperiments, kaempferol-3-O-rhamnoside exhibited cytotoxic effects on three leukemia cell lines, HL-60 and KG-1. Regarding its mechanism of action, the compound effectively inhibited growth of HL-60 and KG-1 leukemia cell lines by activating caspase-3 and caspase-9 in both cell lines. Additionally, kaempferol-3-O-rhamnoside upregulated the pro-apoptotic protein Bax while downregulating the anti-apoptotic protein Bcl-2 in these cell lines.In silicoexperiments revealed that docking simulations showed kaempferol-3-O-rhamnoside binds to both the allosteric site of procaspase-3 and the active site of PARP1, with binding energies of -7.36 and -10.76 kcal/mol, respectively. Kaempferol-3-O-rhamnoside demonstrated stable binding affinity with PARP1, characterized by significant hydrogen bonding, hydrophobic interactions, and pi-stacking in the molecular dynamic simulations. These results suggest that kaempferol-3-O-rhamnoside has the potential PARP1 inhibitor, making it a promising candidate for targeting leukemia cells. Moreover, it provides evidence for considering this compound in drug discovery and development targeting PARP1-related pathways.
A 3D ovarian cancer metastasis model using a decellularized peritoneal matrix to study therapy response
Authors: Gjerde Christiane Helgestad , Kleinmanns Katrin , Langer Anika , Ponce Gorka Ruiz de Garibay , Rozmus Ezekiel , Stangeland Gina Nyhus , Leitch Calum , Elnour Rammah , Dongre Harsh Nitin , Berger Constantin , Gultekin Okan , Forcados Christopher , Stensland Maria , Nyman Tuula A. , Lehti Kaisa , Davidson Ben , Wälchli Sébastien , Gelebart Pascal , Costea Daniela Elena , Kotopoulis Spiros , Bjørge Line , McCormack Emmet
Published: January 2025

High-grade serous ovarian carcinoma (HGSOC) presents a significant therapeutic challenge. Late-stage disease is frequently associated with peritoneal carcinomatosis. The peritoneal metastases exhibit a unique tumor microenvironment (TME) distinct from the primary tumors and other metastatic sites. Understanding the critical influence of the extracellular matrix (ECM) in shaping the tumor phenotype is essential for the development of effective new therapies. This study introduces a novel three-dimensional (3D) model of HGSOC peritoneal metastases using a porcine decellularized peritoneal-derived ECM scaffold, referred to as peritoneal matrix (PerMa). We show that the decellularization maintains the structural integrity and composition of ECM molecules. Comparative analysis reveals structural, compositional, and mechanical similarities between porcine and human peritoneal matrices, underscoring the porcine model’s translational relevance for modeling human peritoneum physiology. The PerMa supports the 3D growth of HGSOC cell lines. The model enables the assessment of sensitivity to traditional chemotherapy and novel cell-based immunotherapy through confocal imaging and quantification of cell volume. Our model offers a valuable platform for investigating peritoneal carcinomatosis in HGSOC, with the potential to contribute significantly to the development of novel therapeutic approaches.
Optimal Graph Representations and Neural Networks for Seizure Detection Using Intracranial EEG Data
Authors: Díaz-Montiel Alan A. , Zhang Richard , Lankarany Milad
Published: January 2025

In recent years, several machine-learning (ML) solutions have been proposed to solve the problems of seizure detection, seizure characterization, seizure prediction, and seizure onset zone (SOZ) localization, achieving excellent performance with accuracy levels above 95%. However, none of these solutions has been fully deployed in clinical settings. The primary reason has been a lack of trust from clinicians towards the so-called black-box decision-making operability of ML. More recently, research efforts have focused on explainability frameworks of ML models that are clinician-friendly. In this paper, we conducted an analysis of graph neural networks (GNN), a paradigm of artificial neural networks optimized to operate on graph-structured data, as a framework to detect seizures from intracranial electroencephalographic (iEEG) data. We employed two multi-center international datasets, comprising 23 and 16 patients and 5 and 7 hours of iEEG recordings. We evaluated four GNN models, with the highest performance achieving a seizure detection accuracy of 97%, demonstrating its potential for clinical application.
Evolutionary conserved reciprocal senescence and tumor suppressor signals limit lifetime cancer
Authors: Liu Liqiong , Davis Stephani , Yusuff Shamila , Strange Ann , Zhuang Yonghua , Vaddi Prasanna , Flaherty Kathleen , Jara Kelly , Kramer Joseph , Archer Christine , Lee Schuyler , Gao Bifeng , Van Bokhoven Adrie , Wang Wei , Pine Sharon R. , Nakamura Tetsuya , Sabaawy Hatim E.
Published: January 2025

Cellular senescence features a durable exit from the cell cycle triggered by stress or carcinogens. The INK4 locus is inactivated in various cancers, yet in senescence, p16Ink4ais activated. Whether senescence is tumor-suppressing or -promoting remains a conundrum. We discovered an evolutionally-conserved Vertebrata INK4-homolog. Thisink4abtriggers senescence upon oxidative- and/or carcinogenic-stress. Adult Ink4ab-deficient animals failed to activate senescence and developed spontaneous cancers. Combined Ink4ab and Tp53 deficiency revealed a reciprocal senescence and apoptosis regulation, controlling tumorigenesis, including retinoblastoma. INK4-hematopoietic-deficient mice exhibited p19Arf-dependent enhanced senescence-like phenotypes, uncontrolled cell proliferation, defective stem cell differentiation, and splenomegaly, with single-splenocytes spatially-enriched in senescence-associated secretory profiles. Our studies reveal the evolutionary origin of paradigms co-regulating senescence and tumor suppression and offer strategies to exploit these reciprocal pathways for cancer prevention and therapy.
Patient Adapted Paternalism for Endomyocardial Biopsy Policy Changes in Heart Transplant Patients: A Mixed-Methods Study
Authors: Kim Hyoungmin , Cusi Vincenzo , McLenon Melissa , Fielding-Miller Rebecca , Cruz Rodriguez Jose Benjamin , Chak Jennifer , Urey Marcus Anthony , Kim Paul J.
Published: January 2025

Endomyocardial biopsies (EMB) are invasive procedures performed in heart transplant (HTx) patients for surveillance of acute rejection. However, patient preferences for replacing EMBs with noninvasive assays in the context of potential institutional policy changes are unknown. A mixed-methods design was used with 28 semi-structured patient interviews and 123 self-administered online survey questionnaires in English and Spanish between January to June 2023. Additionally, we performed semi-structured interviews with 18 HTx team members. Three dominant themes were identified: alleviating patient anxiety and distress, consistent patient-provider communication, and strong interpersonal trust with the HTx team. We found that strong interpersonal trust with the HTx team by the patients was more highly prioritized than their own opinions on whether to replace EMBs with noninvasive assays. Thus, HTx patients often considered surveillance EMBs important to their care (93%), based on the recommendations provided by their HTx team. HTx faculty physicians stated that more multicenter trials are needed prior to replacing EMBs with noninvasive assays. In conclusion, patients identified strong interpersonal trust with HTx team members to justify patient adapted paternalism, where the provider decides in accordance with the patient’s situation, as their preferred shared decision-making paradigm when considering institutional policy on surveillance EMBs.
High Pathogenicity Avian Influenza Virus (HPAIV) H5N1 clade 2.3.4.4b recovered from a kelp gull (Larus dominicanus) in the South Shetland Islands, Antarctica
Authors: Ogrzewalska Maria , Pereira Elisa Cavalcante , Vanstreels Ralph Eric Thijl , Campista Emandi , Correa Junior Leonardo , Macedo Larissa , Appolinario Luciana Reis , Brandão Martha Lima , Vilela Roberto , Degrave Wim , Motta Fernando Couto , Siqueira Marilda Mendonca , Resende Paola Cristina
Published: January 2025

Whole-genome analysis of the earliest-detected High Pathogenicity Avian Influenza Virus (HPAIV) H5N1 clade 2.3.4.4b detected in Hannah Point, Antarctica (January 2024) reveals close relatedness to strains that circulated in pinnipeds and seabirds along the Atlantic coast of South America during the second half of 2023.
CLCNet: a contrastive learning and chromosome-aware network for genomic prediction in plants
Authors: Huang Jiangwei , Yang Zhihan , Yin Mou , Li Chao , Li Jinmin , Wang Yu , Huang Lu , He Fei , Liang Chengzhi , Li Miaomiao , Han Rongchen , Jiang Yuqiang
Published: January 2025

Genomic selection (GS) is a sophisticated breeding technology that utilizes genomic markers in conjunction with phenotypic data to predict breeding values and phenotypes of candidate populations. The foundation of GS is the construction of precise genomic prediction (GP) models. Traditional GP models, which are typically linear in nature, encounter difficulties in capturing non-linear relationships within genetic data, thereby constraining their capacity to adequately characterize complex genetic architectures. To address this limitation, we have developed a novel deep learning framework, namely contrastive learning and chromosome-aware network (CLCNet), which has been specifically tailored for plant GP. The architecture of CLCNet comprises two key modules: a contrastive learning module designed to capture phenotypic variations, and a chromosome-aware module that accounts for the effects of linkage, as well as local and global epistasis. The performance of CLCNet was evaluated across eight datasets representing seven plant species: maize (Zea mays), rice (Oryza sativa), cotton (Gossypium hirsutum), millet (Setaria italica), chickpea (Cicer arietinum), rapeseed (Brassica napus), and soybean (Glycine max). In comparative assessments against three classical models (rrBLUP, Bayesian Ridge, Bayesian Lasso), two machine learning approaches (LightGBM, SVR), and two other deep learning models (DNNGP, DeepGS), CLCNet exhibited superior performance, achieving higher Pearson correlation coefficients (PCC) and lower root mean squared errors (RMSE). Due to its superior prediction accuracy, generalization capability and scalability in high-dimensional datasets, CLCNet is expected to be a powerful tool for future GS applications in the field of plant breeding.
Antimicrobial resistance, pathogenicity and virulence patterns ofEscherichia coliisolated from cockroaches (Blattella germanica) across diverse environments: a public health concern
Authors: Sigma Sanzila Hossain , Ashraf Md. Nahid , Karmakar Susmita , Rimi Sabrina Sultana , Chakraborty Sourav , Siddique Mahbubul Pratik , Hassan Jayedul , Islam Md. Alimul , Rahman Md. Tanvir , Islam Md. Safiqul , Hossain Muhammad Tofazzal
Published: January 2025

This investigation explores the prevalence and antimicrobial resistance (AMR) ofEscherichia coliisolated fromBlattella germanica(cockroaches) from diverse locations, including homes, kitchens, and laboratories, over the course of six months, from August 2022 to January 2023. A total of 125 cockroaches were analyzed, yielding 67 (53%) of positiveE. coliisolates, with kitchen environments having the highest incidence (57.77%). The existence of virulence genes (stx1,stx2, andrfbO157) was confirmed by pathogenicity assessments carried out on mouse model, which led to a considerable increase in morbidity and mortality. 82.08% of isolates showed evidence of resistance to at least one antibiotic, according to the antimicrobial susceptibility test with β-lactams displaying the highest rates of resistance. Remarkably, complex resistance patterns were observed in 77.61% of the isolates, which were categorized as multidrug-resistant. Multiple antibiotic resistance genes (ARGs) were found by molecular analysis, particularlyblaTEMandtetAas well as virulence-associated genes (VAGs) linked to extraintestinal pathogenicE. coli. Phylogenetic grouping indicated that 90.38% of the MDR isolates belonged to virulent groups B2 and D. These findings highlight the role of cockroaches as potential reservoirs for pathogenicE. coli, raising significant public health concerns regarding AMR. The study underscores the imperative need for thorough investigation and feasible control strategies to ease the dissemination of AMR in diverse contexts.
Mutual information of high-dimensional random variables: estimation by frontier mutual information
Authors: Mori Tsutomu , Kawamura Takashi
Published: January 2025

Many natural sources of information, including genes, yield intricate datasets characterized by high-dimensional random variables. However, the computational constraints and information loss have often limited the accuracy of mutual information (MI) computations in such datasets. To address these limitations, we introduce a novel metric, micromutual information, which measures the information exchange at each cell level within high-dimensional contingency tables. This methodology represents an extension of our previous techniques and employs a linear index approach. The method simplifies complex, high-dimensional genetic data into a one-dimensional format, thereby improving computational efficiency while preserving the intricate structure of gene interactions. Theorems are developed which demonstrate how the sum of micromutual information asymptotically converges to the total MI for multidimensional variables. Our findings indicate that the maximum value of micromutual information, termedMIfront, adheres to an extreme value distribution. The observation ofMIfrontprovides a streamlined approach to estimating the total MI, due to the simplicity of measuring the micromutual information of just one cell. This approach has the potential to improve data analysis in genomics and other fields that deal with multidimensional information.
Hydrogen sulfide (H2S) coordinates redox balance, carbon metabolism, and mitochondrial bioenergetics to suppress SARS-CoV-2 infection
Authors: Agrawal Ragini , Pal Virender Kumar , Suhas KS , Menon Gopika Jayan , Singh Inder Raj , Malhotra Nitish , Naren CS , Ganesh Kailash , Rajmani Raju S , Narain Seshasayee Aswin Sai , Chandra Nagasuma , Joshi Manjunath B , Singh Amit
Published: January 2025

Viruses exploit host metabolism for replication and immune-regulation. Understanding how SARS-CoV-2 alters the host metabolism may lead to treatments for COVID-19. We report that a ubiquitous gaseous molecule, hydrogen sulfide (H2S), regulates redox, metabolism, and mitochondrial bioenergetics to control SARS-CoV-2. Virus replication is associated with down-regulation of the H2S-producing enzymes cystathionine-β-synthase (CBS), cystathionine-γ-lyase (CTH), and 3-mercaptopyruvate sulfurtransferase(3-MST), resulting in diminished endogenous H2S levels. Inhibition of CTH resulted in SARS-CoV-2 proliferation. A slow-releasing H2S donor, GYY4137, diminished virus replication by inducing Nrf2/Keap1 pathway, restoring redox balance and mitochondrial bioenergetics. Treatment of SARS-CoV-2-infected animals with GYY4137 suppressed viral replication, ameliorated respiratory pathology, and restored antioxidant gene expression. Notably, whole-body plethysmography showed improved pulmonary function variables, including pulmonary obstruction and end-expiratory pause upon GYY4137 treatmentin vivo. Data extend our understanding of H2S-mediated regulation of viral-infections, and open new avenues for investigating the pathogenic mechanisms and therapeutic opportunities for coronavirus-associated disorders.
Intrahepatic crystals from elevated dietary cholesterol are sufficient to stiffen the liver
Authors: Li David , Loneker Abigail E. , Safraou Yasmine , Ford Jamie , Mihelc Elaine , Levental Kandice R. , Levental Ilya , Sack Ingolf , Janmey Paul A. , Wells Rebecca G.
Published: January 2025

Chronic lipid accumulation is a hallmark of metabolic dysfunction-associated steatotic liver disease (MASLD), and dyslipidemia is associated with disease progression and poorer patient outcomes. Tissue stiffening is an established fibrogenic cue, but how changes in lipid accumulation affect tissue mechanics is not fully understood. Here we show that cholesterol-containing lipid crystals stiffen steatotic liver tissue. We show that rats fed elevated dietary cholesterol develop both liquid and solid cholesterol-containing lipid crystals in the liver. While steatotic livers without crystals are softer than control livers, livers with lipid crystals show increased baseline stiffness and compression stiffening as well as increased progression to fibrosis. Lipid extracts from livers containing crystals stiffen fibrous tissue mimics, while depletion of cholesterol using methyl-ꞵ-cyclodextrin reduces both crystal abundance and tissue stiffness. Our results demonstrate in a rat model that a high cholesterol diet leads to formation of liquid and solid crystals and that cholesterol-containing crystals stiffen tissues. This work implicates lipid crystals arising from dyslipidemia as a key driver of MASLD progression. The presence of cholesterol crystals could lead to new diagnostic tools for progressive MASLD and could be a therapeutic target.
Plasma Proteomic Profiles Predict the Risk of Coronary Artery Disease in the UK Biobank Cohort
Authors: Zhang Chenhao , Ji Xiangwen , Cui Chunmei , Bai Xueke , He Guangda , Chen Liang , Cui Qinghua
Published: January 2025

Coronary artery disease (CAD) is a complex, multifactorial, and serious condition influenced by genetic, environmental, and lifestyle factors. Thus, it is crucial to develop strategies to predict the risk of CAD for individuals. Plasma proteomics provides a powerful framework for identifying novel biomarkers, discovering potential therapeutic targets, and further improving risk stratification. Here, we examined the association between 2,919 plasma proteins and incident CAD in the UK Biobank cohort (n=35,778). As a result, we identified 576 proteins significantly associated with CAD and found significant alterations in key biological pathways, including signal transduction, immune regulation, and chemotaxis, before CAD onset. Subsequently, we developed machine learning models to predict CAD onset at different time intervals (5 years, 10 years, over 10 years, and entire cohort), demonstrating superior performance over models based on polygenic risk scores (ΔAUC = 0.052), and Pooled Cohort Equations (ΔAUC = 0.049). Notably, the integration of PRS with proteomic data resulted in a marked enhancement in predictive accuracy (AUC = 0.779), comparable to the full model (AUC = 0.780). Key plasma protein predictors, including MMP12, GDF15, and EDA2R, showed sustained importance across models predicting CAD onset at multiple time points. Additionally, Mendelian randomization analysis provided robust evidence for a causal relationship between six plasma proteins and CAD, including MMP12, LPA and PLA2G7, highlighting their potential as therapeutic targets. In conclusion, our study elucidates the plasma proteome associated with CAD, reveals underlying pathogenic mechanisms, and provides valuable insights for identifying high-risk individuals and advancing precision medicine.
Interactions of sequence diverse effector proteins of wheat powdery mildew control recognition specificity by the corresponding immune receptor
Authors: Isaksson Jonatan , Heuberger Matthias , Amhof Milena , Kunz Lukas , Bourras Salim , Keller Beat
Published: January 2025

To successfully colonize the living tissue of its host, the fungal wheat powdery mildew pathogen produces diverse effector proteins that are suggested to reprogram host defense responses and physiology. When recognized by host immune receptors, these proteins become avirulence (AVR) effectors. Several sequence-diverse AVRPM3 effectors and the suppressor of AVRPM3-PM3 recognition (SVRPM3a1/f1) are involved in triggering allele-specific, Pm3-mediated resistance, but the molecular mechanisms controlling their function in the host cell remain unknown. Here, we describe that AVRPM3b2/c2, AVRPM3a2/f2and SVRPM3a1/f1form homo- and heteromeric complexes with each other, suggesting they are present as dimers in the host cell. Alphafold2 modelling substantiated previous predictions that AVRPM3b2/c2, AVRPM3a2/f2and SVRPM3a1/f1all adopt a core RNase-like fold. We found that a single amino acid mutation in a predicted surface exposed region of AVRPM3a2/f2resulted in recognition by the PM3b immune receptor, which does not recognize wildtype AVRPM3a2/f2. This indicates that differential AVRPM3 recognition by variants of the highly related PM3 immune receptors is due to subtle differences in similar protein surfaces of sequence-diverse AVRs. Based on our findings, we propose a model in which homodimers of AVRPM3s are recognized by their corresponding PM3 variants and that heterodimer formation with SVRPM3a1/f1allows for evasion of recognition.
Rewiring oncogenic signaling to RNA vector replication for the treatment of metastatic cancer
Authors: Zou Xinzhi , Zhao Cynthia , Beier Kevin T. , Kang Chil-Yong , Lin Michael Z.
Published: January 2025

Despite recent advances, improvements to long-term survival in metastatic carcinomas, such as pancreatic or ovarian cancer, remain limited. Current therapies suppress growth-promoting biochemical signals, ablate cells expressing tumor-associated antigens, or promote adaptive immunity to tumor neoantigens. However, these approaches are limited by toxicity to normal cells using the same signaling pathways or expressing the same antigens, or by the low frequency of neoantigens in most carcinomas. Here, we report a fundamentally different strategy for designing safer and more effective anti-cancer therapies through the sensing of cancer-driving biochemical signals and their rewiring to virotherapeutic activation. Specifically, we rationally engineer a RNA vector to self-replicate and cause cytotoxicity in cancer cells exhibiting hyperactive HER2 (ErbB2), but not in normal cells with normal HER2 signaling. Compared to a widely tested virotherapeutic from the same vector family, our hyperactive ErbB2-restricted RNA vector (HERV) exhibits lower toxicity and greater activity against metastatic HER2-positive ovarian cancer in mice, extending survival independently of tumor antigenicity. Most importantly, HERV synergizes with standard-of-care chemotherapy against ovarian cancer metastases in vivo, with 43% of combination-treated subjects surviving for months beyond subjects treated with either therapy alone. Taken together, these results introduce rewiring of cancer-driving signaling pathways to virotherapeutic activation as a strategy for more specific and effective cancer treatment.
Targeting GSK-beta with Peptide Inhibitors: A Rational Computational Strategy for Alzheimer's Disease Intervention
Authors: Zareei Sara , Pourmand Saeed , Rahimi Negin , Massahi Shokoufeh
Published: January 2025

Abstract Glycogen synthase kinase-3 beta is a pivotal serine/threonine kinase implicated in Alzheimers disease (AD) pathogenesis, particularly through the hyperphosphorylation of tau protein and increased production of amyloid-beta (Abeta) peptides. This study investigates kappa casein-derived peptides as potential inhibitors of GSK-3beta. A peptide library of 42 sequences was generated from kappa casein and docking studies identified IP8 (LRFFVAPFPE) as the top candidate for binging to the previously approved inhibition site of GSK-3beta. Molecular dynamics (MD) simulations revealed that IP8 first three residues contributed unfavorably to binding, promoting the design of mutated peptides (MPs) MP27, MP31, and MP39. Of these, MP31 (HPDFVAPFPE) demonstrated the most stable interaction with GSK-3beta, exhibiting the most favorable binding score (-96.6) and interacting with 19 residues of the ATP-binding pocket of the enzyme. Structural analyses confirmed MP31 superior stability, with minimal RMSD deviations, and stable hydrogen bond formation. The results showed that peptide binding stabilizes GSK-3beta by reducing both domain-level dynamics and local side-chain flexibility, leading to a more structurally constrained enzyme. This dual stabilization of the backbone and side chains underscores the critical role of peptide interactions in modulating the conformational landscape of GSK-3beta and potentially obstructing substrate access or product release, which are crucial for enzyme activity. These results suggest that kappa casein-derived peptides, particularly MP31, could be promising therapeutic candidates for inhibiting GSK-3beta in AD.
TCPGdb: A comprehensive T cell perturbation genomics database for identification of critical T cell regulators
Authors: Dong Chuanpeng , Zhang Feifei , Tang Kaiyuan , Verma Nipun , Zhu Xinxin , Feng Di , Cai James , Zhao Hongyu , Chen Sidi
Published: January 2025

CAR-T therapies utilizing T cells engineered with chimeric antigen receptors (CARs) have revolutionized the treatment of hematologic and immune-related malignancies. However, the anti-tumor capability of engineered CAR-T cells are often not persistent, which greatly dampen its clinical efficacy. To address this limitation, massive parallel genetic screens were widely used to identified novel targets and regulators that enhance T cell anti-tumor capability and persistence in tumor microenvironment. We hypothesized that by combining the pooled screen data from multiple independent genetic screens we could provide a systematic, comprehensive, and robust analysis of the effect of gene perturbation on T-cell based immunotherapies. After collecting data from previously published T cell screens, including CRISPR-based and ORF-based screens, through Gene Expression Omnibus (GEO), we reprocessed the gene hits summary and conducting a pathway enrichment analysis. A T cell screen perturbation score (TPS) was employed to quantifies the impact of the gene on T cell function. Additionally, gene expression data (both bulk RNA level and single-cell RNA level) from autoimmune disease and T cell-derived cancers were analyzed to pick up gene perturbations that potentially augment T cell proliferation. We integrated all data and analysis on 27 T-cells screens into our state-of-the-art T cell perturbation genomics database (TCPGdb), which is made easily accessible through our webserver and allows users to interactively explore the impact of query genes on T cell function based on prior screen data and our TPS scoring module. TCPGdb is publicly accessible athttp://tcpgdb.sidichenlab.org/.
40S ribosomal subunits scan mRNA for the start codon by one-dimensional diffusion
Authors: Wakabayashi Hironao , Zhu Mingyi , Grayhack Elizabeth J. , Mathews David H. , Ermolenko Dmitri N.
Published: January 2025

During eukaryotic translation initiation, the small (40S) ribosomal subunit is recruited to the 5′ cap and subsequently scans the 5′ untranslated region (5′ UTR) of mRNA in search of the start codon. The molecular mechanism of mRNA scanning remains unclear. Here, using GFP reporters inSaccharomyces cerevisiaecells, we show that order-of-magnitude variations in the lengths of unstructured 5′ UTRs have a modest effect on protein synthesis. These observations indicate that mRNA scanning is not rate limiting in yeast cells. Conversely, the presence of secondary structures in the 5′ UTR strongly inhibits translation. Loss-of-function mutations in translational RNA helicases eIF4A and Ded1, as well as mutations in other initiation factors implicated in mRNA scanning, namely eIF4G, eIF4B, eIF3g and eIF3i, produced a similar decrease in translation of GFP reporters with short and long unstructured 5′ UTRs. As expected, mutations in Ded1, eIF4B and eIF3i severely diminished translation of the reporters with structured 5′ UTRs. Evidently, while RNA helicases eIF4A and Ded1 facilitate 40S recruitment and secondary structure unwinding, they are not rate-limiting for the 40S movement along the 5′ UTR. Hence, our data indicate that, instead of helicase-driven translocation, one-dimensional diffusion predominately drives mRNA scanning by the 40S subunits in yeast cells.
Mean gene conversion tract length in humans estimated to be 459 bp from UK Biobank sequence data
Authors: Masaki Nobuaki , Browning Sharon R.
Published: January 2025

Non-crossover gene conversion is a type of meiotic recombination characterized by the non-reciprocal transfer of genetic material between homologous chromosomes. Gene conversions are thought to occur within relatively short tracts of DNA, estimated to be in the order of 100-1,000 bp in humans. However, the number of observable gene conversion tracts per study has so far been limited by the use of pedigree or sperm-typing data to detect gene conversion events. In this study, we propose a statistical method to estimate the mean length of gene conversion tracts in humans. Our method can handle a large number of gene conversion tracts, leading to more precise estimates of the mean tract length. We apply our method to gene conversion tracts detected in whole autosome sequence data from the UK Biobank using clusters of identity-by-descent segments. From this dataset, we estimate the mean gene conversion tract length in humans to be 459 bp (95% CI: [457, 461]). Stratifying detected gene conversion tracts by whether they overlapped with a recombination hotspot, we estimate the mean gene conversion tract length to be 418 bp (95% CI: [416, 420]) and 492 bp (95% CI: [489, 494]) respectively, for tracts that overlap and do not overlap with a recombination hotspot.