bluuebunny/crossref_metadata_2025 huggingface dataset:
Mapping fine-scale socioeconomic inequality using machine learning and remotely sensed data
Authors: Pradhan Nabin , Agrawal Arun
Published: February 2025

Limited and missing socioeconomic data have made it nearly impossible to measure or estimate inequality consistently at fine spatiotemporal and jurisdictional scales, especially for lower- and middle-income countries. We deploy a novel data harmonization method that combines existing household survey data with freely available remotely sensed data and machine learning techniques to generate fine-scale socioeconomic inequality estimates across spatial and temporal scales for India. Our manuscript makes three important contributions. First, it identifies key remote sensing datasets that, in combination with nighttime luminosity, improve its predictive power to estimate measures of socioeconomic inequality. Second, it offers an analytical approach that reliably estimates the uneven distribution of socioeconomic conditions by harmonizing household assets and sociodemographic information that remotely sensed data at the village or similar geographic levels represent—the results achieve >84% prediction accuracy. Finally, it leverages a spatially cross-validated machine learning model with training and test datasets from two successive Demographic and Health Surveys to demonstrate how data gaps in socioeconomic inequality at subnational levels can be addressed. Our replicable approach has the potential to improve global inequality data, thereby supporting research and applications aiming to reduce socioeconomic inequality in the context of the Sustainable Development Goals.
Motivational Interviewing in Patients with Acute Psychosis:A Feasibility Study
Authors: Panchalingam Janani , Horisberger Rahel , Corda Claudio , Kleisner Nicolas , Krasnoff Julia , Burrer Achim , Spiller Tobias , Edkins Victoria , Seifritz Erich , Homan Philipp
Published: February 2025

Background and Hypothesis

Psychotic disorders are among the top causes of disability worldwide. Guidelines emphasize the need for psychotherapeutic approaches in the acute phase of this illness. Motivational interviewing (MI) is highly suitable for establishing a therapeutic alliance wherein the patient’s intrinsic motivation can be strengthened to adhere to therapy. This pilot study investigated the feasibility and impact of MI for patients with acute psychosis.

Study Design

A feasibility study was conducted, comparing MI and supportive counseling. The sample included 20 inpatients, who all received four therapy sessions. In line with CONSORT guidelines for pilot and feasibility studies, we measured various feasibility outcomes. Clinical outcomes were assessed using linear regression models, with baseline values used as covariates.

Study Results

The recruitment target (N = 24) was achieved at 83% in a reasonable timeframe (8 months), with a retention rate of 83% and completion rate at 71%. Eligibility rate (82 %) was high, consent rate (48%) was moderate, and both the dropout rate 17% and missing data rate (0.3%) were low. Regarding the clinical outcomes, a group difference was found for the severity of psychotic symptoms, with an advantage for MI (b = -12.0, 95% CI: [-18.7, -5.2], p < 0.01), although the small sample size must be kept in mind.

Conclusions

The study demonstrated the feasibility and acceptability of a clinical trial with MI for patients with psychosis in an inpatient setting. MI could offer benefits, particularly in terms of reducing psychotic symptoms.
Unlocking the potential of blood-stage vaccines for malaria elimination
Authors: Nema Shrikant , Rathore Sumit , Mohmmed Asif , Malhotra Pawan
Published: February 2025

Malaria vaccines are crucial for advancing public health and achieving malaria elimination. Currently, pre-erythrocytic vaccines like RTS, S/AS01 and R21/Matrix-M are in use, but their effectiveness is limited. Ongoing research on blood-stage vaccine candidates such as RH5, MSP1 and MSP3 has shown promising results. Incorporating a blood-stage vaccine could greatly enhance malaria control by targeting the symptomatic phase of the infection, providing additional protection alongside pre-erythrocytic vaccines and other control methods. Understanding the structural biology and immunological interactions of blood-stage antigens is essential for developing effective vaccines. Combining pre-erythrocytic and erythrocytic-stage vaccines could lead to better protection, improved public health outcomes and significant progress toward malaria elimination.
Host Resistance Screening of Baby Kale Against Downy Mildew Isolates Across the Central Coast of California
Authors: Locke-Paddon Emily Mae , Fernandez Marco Antonio , Das Kallol , Brasier Kyle , Dowling Charlie , Ding Shunping
Published: February 2025

Hyaloperonospora brassicae, the causal pathogen of downy mildew, presents significant challenges to spring mix greens production in California. Genetic resistance provides a strategy for sustainable management to reduce downy mildew infections and pesticide use in organic and conventional production systems. This study aimed to identify sources of downy mildew resistance to facilitate resistance breeding in baby kale. To achieve this, three host resistance screenings were conducted to assess the resistance of baby kale accessions against eight downy mildew isolates collected from eight distinct locations on the Central Coast of California. Artificial inoculation was performed by spraying a sporangia suspension onto baby kale plants, which were then incubated in a humidity chamber. Disease severity was assessed by examining both surfaces of each leaf for chlorotic and necrotic symptoms and sporulation and then quantified using an established rating scale. Screening of all 212 accessions revealed an average disease severity of 28%, with severities ranging from 0 to 100%. The initial subset screening showed average disease severities ranging from 2.2 to 9.4% depending on the isolate. The final subset screening demonstrated a range of 0.003 to 0.072% average disease severity among the four isolates, with 13 accessions exhibiting 100% estimated resistance probability, 11 accessions between 99.0 and 99.9%, and one accession below 99.0%. These results suggested that downy mildew could be effectively managed in baby kale through resistant varieties.
Mycotoxin contamination of hazelnut grown in Azerbaijan and Aspergillus communities associated with the crop
Authors: Aghayev Fagan , Bandyopadhyay Ranajit , Battilani Paola , Ortega-Beltran Alejandro
Published: February 2025

In Azerbaijan, hazelnut (Corylus avellana L.) is a crop of economical and nutritional importance. However, recent aflatoxin contamination events in hazelnut produced in Azerbaijan are posing health risks to consumers and reduce marketability. Aflatoxin and fumonisin levels were examined in hazelnuts collected at 33 farmers’ stores, one month after the 2022 harvest under various storage conditions, from two regions in Azerbaijan. All hazelnut samples were contaminated both with aflatoxins (range = 1.1 to 7.2 µg/kg) and fumonisins (range = 0.12 to 0.30 mg/kg). Aspergillus section Flavi fungi were isolated and both aflatoxin producers and atoxigenic (incapable of producing aflatoxins) isolates were identified. Several members of vegetative compatibility group IT006, to which the Italian aflatoxin biocontrol isolate MUCL54911 belongs, were found to be native to Azerbaijan. In laboratory competition assays, MUCL54911 reduced aflatoxin produced by three types of Aspergillus fungi by 97.5 to 100%, which indicates that biocontrol could be an option to reduce aflatoxin in hazelnut. Future research efforts should be geared toward detecting and characterizing additional atoxigenic isolates, optimizing biocontrol application for hazelnut, and implementing agronomic and post-harvest practices to manage aflatoxin throughout the value chain. For effective implementation of integrated mycotoxin strategies, coalitions composed of farmers, research institutions, non-governmental organizations, private sector, and government agencies are needed.
Qi-Huang-Yi-Shen Formula Alleviate Tubular Epithelial-Mesenchymal Transition in Diabetic Kidney Disease Through HIF-1a/snail Signaling Pathway
Authors: Yang Ronglu , Ren Qiuyue , Yuan Lisha , Liu Wu , Shi Kaifeng , Zhou Yi , Zhang Ning
Published: February 2025

Background:

Renal tubule hypoxia injury plays a pivotal role in the development of renal fibrosis in diabetic kidney disease (DKD). The Qi-Huang-Yi-Shen formula (QHYS) is a traditional Chinese medicine compound used for treating DKD. Nevertheless, the underlying mechanism remains unclear. Therefore, this study aimed to investigate whether QHYS could inhibit renal tubular epithelial-mesenchymal transition (EMT) through the hypoxia-inducible factor-1 alpha (HIF-1α) /snail pathway, thereby conferring renal protection.

Methods:

A rat model of diabetic nephropathy (DN) was established using a high-fat and high-sucrose diet in combination with an intraperitoneal streptozocin injection. An in vitro EMT model of human kidney-2 (HK-2) cells was induced by high glucose combined with cobalt chloride treatment. Various parameters were measured, including body weight, glucose/lipid metabolism, markers of renal tubule injury, proteinuria, renal function, and renal histological changes. The expressions of the HIF-1α/snail signaling pathway, EMT-related proteins, extracellular matrix (ECM), and matrix metalloproteinases in renal tissue and HK-2 cells were assessed using western blot, immunofluorescence, and enzyme linked immunosorbent assay (ELISA) techniques.

Results:

In vivo, QHYS decreased the 24-hour urinary protein quantity (24hUTP), kidney injury molecule 1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), fasting blood glucose, glycated hemoglobin, creatinine, and urea nitrogen levels in DN rats. Moreover, QHYS alleviated renal histopathological lesions, down-regulated the expression of HIF-1α, snail, N-cadherin, and α-smooth muscle actin (α-SMA), and up-regulated the expression of zonula occludens 1 (ZO-1) and E-cadherin. In vitro, QHYS treatment inhibited the HIF-1α/snail signaling pathway, reduced ECM deposition and cell migration, and delayed the occurrence of EMT in HK-2 cells.

Conclusion:

QHYS inhibits renal tubular EMT through the HIF-1α/snail pathway, thereby attenuating DKD-associated renal damage induced by hyperglycemic hypoxia.
Clinical Management of Designer Benzodiazepine Intoxication
Authors: Noe Gregory , McDuffee Nicholas , Li Katelyn , Munjal Sahil
Published: February 2025

Background

A subset of novel psychoactive substances (NPS), designer benzodiazepines, are rising in popularity. These compounds are more potent derivatives of prescription benzodiazepines and can lead to profound sedation. Therefore, clinicians are challenged with caring for patients who present with designer benzodiazepine intoxication or withdrawal. We conducted a systematic review of the literature for designer benzodiazepine overdoses with a focus on patient presentation and clinical management.

Methods

We conducted a systematic literature search in multiple databases using Medical Subject Headings (MeSH) terms “designer benzodiazepine(s)” and “case report” along with additional permutations of search terms. We used the PICOS search algorithm to enhance reporting of systematic reviews' findings.

Results

A total of 27 articles were selected for inclusion in our systematic review, comprising 35 patient cases. The average patient age was 27.14 years (SD = 9.86), and the male-to-female ratio was 3.38:1. More than half (54.29%) of cases involved designer benzodiazepines alone, whereas 45.71% of cases involved co-ingestions. The most frequent presenting sign was altered mental status. The most frequent abnormal vital sign was tachycardia.

Discussion

Management of patients presenting with acute designer benzodiazepine intoxication was highly variable, depending on the severity. We include practical clinical management guidance based on 3 designer benzodiazepine toxidromes including sedation-predominant, withdrawal-predominant, or mixed-sedation with rebound agitation.

Conclusion

Designer benzodiazepines are highly potent compounds that present a significant risk to patients and pose a clinical management challenge to clinicians. More research is needed to fully understand the effects of designer benzodiazepines in humans.
Laboratory adaptive evolution of thermotolerance is linked to the evolution of a robust proteostasis in S. cerevisiae
Authors: Dash Devi Prasanna , Zaidi Zainab , Sharma Akanksha , Dholakia Dhwani , Rai Manish , Dash Debasish , Chakraborty Kausik
Published: February 2025

Thermophilic organisms have evolved a proteome that resists thermal denaturation. While the evolution of their complete proteome would require multiple generations, early on, organisms would need to develop strategies to survive at high temperatures despite their thermolabile proteome. We hypothesized that the organisms would do this by reinforcing their proteostasis capacity. We tested this hypothesis using adaptive laboratory evolution of thermotolerance in Saccharomyces cerevisiae and found that the cells reproducibly evolved better proteostasis capacity in short-term evolution experiments. However, rather than improving the global proteostasis capacity, most of the evolved strains demonstrated enhanced capacity to tackle misfolding in the Endoplasmic Reticulum (ER), specifically by increasing their capacity for ER-associated degradation (ERAD). Given the strong selective advantage of these strains, we posit that protein folding in the ER may be exquisitely sensitive to chronic thermal stress and may act as an early indicator for adaptation to higher temperatures.
Evaluation Of Modified Hematological Sepsis Scoring System In Early Diagnosis Of Neonatal Sepsis
Authors: Baruwal Sishir , Karki Smriti , Gyawali Isha , Khadka Smriti , Yogi Tek Nath , Maharjan Santosh
Published: February 2025

Background

Neonatal sepsis, a significant cause of morbidity and mortality, is a systemic response to infection in the first month of life. Its early diagnosis is challenging due to nonspecific clinical manifestations and the time-intensive nature of blood cultures, the diagnostic gold standard. The Hematological Sepsis Scoring (HSS) system, introduced in 1988, offers a rapid diagnostic alternative using hematological parameters. To enhance diagnostic accuracy, the Modified HSS incorporates additional parameters, such as nucleated RBC, and assigns higher weightage to neutropenia. This study evaluates the utility of the Modified HSS in the early diagnosis of neonatal sepsis, aiming to facilitate prompt treatment and reduce neonatal mortality.

Methods

This descriptive analytical study was conducted over a year at B.P. Koirala Institute of Health Sciences, involving neonates >34 weeks of gestation within four weeks of birth, clinically suspected of sepsis. Blood samples were analyzed using Modified Hematological Sepsis Scoring (HSS) and BacT/ALERT for culture. Purposive sampling selected 147 cases. Ethical clearance was obtained, and informed consent secured. Hematological parameters, including TLC, ANC, IT ratio, and nucleated RBC, were assessed, and cultures were processed for microbial identification and susceptibility.

Results

The study included 147 neonates with suspected sepsis (male:female ratio 1.33). Blood cultures were positive in 21 cases, with early-onset sepsis predominant (81%). Modified Hematological Sepsis Scoring (HSS) showed high diagnostic accuracy: sensitivity (90.48%), specificity (96.83%), and accuracy (95.91%) for HSS ≥4. Among hematological parameters, degenerative changes had the highest sensitivity (95.23%), and nucleated RBC showed the highest accuracy (91.15%). Staphylococcus aureus (52.3%) was the most common pathogen. Modified HSS proved effective for early sepsis diagnosis.

Conclusion

Modified HSS is an effective and accurate tool for early neonatal sepsis diagnosis, with high sensitivity, especially when using a score ≥4 as the cutoff. The inclusion of nucleated RBC enhances sensitivity, while the system’s diagnostic accuracy is improved by recalibrating parameters. Modified HSS, utilizing common hematological parameters, shows significant potential for clinical application.
Unifying Genetic and Chemical Perturbagen Representation through a Hybrid Deep Learning Framework
Authors: Li Yiming , Zhu Jun , Liu Linjing , Wang Fang , Zeng Min , Huang Longkai , Yang Fan , Li Min , Yao Jianhua
Published: February 2025

The integration of genetic and chemical perturbations has driven transformative advances in elucidating cellular mechanisms and accelerating drug discovery. However, the lack of a unified representation for diverse perturbagen types limits comprehensive analysis and joint modeling of multi-domain perturbation agents (molecular cause space) and their resulting phenotypes (phenotypic effect spaces). Here, we present UniPert, a hybrid deep learning framework that encodes genetic and chemical perturbagens into a shared semantic representation space. UniPert employs tailored encoders to address the inherent molecular-scale differences across perturbagen types and leverages contrastive learning with experiment-driven compound-target interactions to bridge these domains. Extensive experiments validate UniPert’s versatility across diverse application. The generated representations effectively capture hierarchical pharmacological relationships of perturbagens, facilitating annotations of understudied targets and compounds. UniPert can be plugged in advanced frameworks to enhance performance in both genetic and chemical perturbation outcome prediction tasks. Notably, UniPert paves the way for cross-domain perturbation modeling, driving a novelgenetic-to-chemicalperturbation transfer learning paradigm, boosting context-specificin silicodrug screening efficiency and accelerating the development of personalized therapies.
Towards accurate, reference-free differential expression: A comprehensive evaluation of long-readde novotranscriptome assembly
Authors: Yan Feng , Baldoni Pedro L. , Lancaster James , Ritchie Matthew E. , Lewsey Mathew G. , Gouil Quentin , Davidson Nadia M.
Published: February 2025

Long-read RNA sequencing has significantly advanced transcriptomics by enabling the full length of transcripts to be assessed. However, current analysis methods often depend on a high-quality reference genome and gene annotation. Recently,de novoassembly methods have been developed to utilise long-read data in cases where a reference genome is unavailable, such as in non-model organisms. Despite the potential of these tools, there remains a lack of benchmarking and established protocols for optimal reference-free, long-read transcriptome assembly and differential expression analysis.

Here, we comprehensively evaluate the current state-of-the-art long-readde novotranscriptome assembly tools, RATTLE, RNA-Bloom2 and isONform, and compare their performance to one of the leading short-read assemblers, Trinity. We assess various metrics, including assembly quality and computational efficiency, across a range of datasets, which include simulated data and spike-in sequin transcripts, where ground truth is known, and real data from human cell lines and pea (Pisum sativum) samples, using the reference-guided assembler Bambu to define truth. To represent contemporary analysis scenarios, the datasets cover depths from 6 million to 60 million reads, Oxford Nanopore Technologies (ONT) cDNA and direct RNA sequencing, and critically, we assessed the downstream impact of assembly choice on the detection of differential gene and transcript expression.

Our results confirm that long reads generate longer assembled transcripts than short-reads for reference-free analysis, though limitations remain compared to reference-guided approaches, and suggest scope for improved accuracy and redundancy. Of thede novopipelines, RNA-Bloom2, coupled with Corset for transcript clustering, was the best performing in both accuracy and computational efficiency. Our findings offer guidance when selecting the most effective strategy for long-read differential expression analysis, when a high-quality reference genome is unavailable.
Transcriptomic responses toMarteilia sydneyiinfection in the Sydney rock oysterSaccostrea glomerata
Authors: Nenadic Nikolina , Bar Ido , McDougall Carmel
Published: February 2025

Marteilia sydneyi, an ascetosporean parasite, is the causative agent of Queensland Unknown (QX) disease inSaccostrea glomerata. QX disease outbreaks often lead to high mortality rates and considerable population losses. Investigating host/parasite interactions at a molecular level is imperative to better understand howS. glomeratamounts immune defences, and to explore whetherM. sydneyievades host responses. This study aims to investigateS. glomerata’sresponse toM. sydneyiinfection through differential gene expression analysis to uncover immune mechanisms and potential markers for resistance. RNA sequencing and differential gene expression analysis revealed widespread transcriptional changes between infected and non-infected oysters. Genes encoding proteins involved in pathogen recognition and immune response signalling, such as galectin-4-like and G-protein coupled receptors, were significantly differentially expressed inS. glomeratainfected withM. sydneyi, suggesting involvement in the host’s immune responses. Moreover, the upregulation of cytochrome P450 family genes indicate increases in the host’s detoxification processes and metabolic pathways, a possible response to infection-induced stress. However, extracellular superoxide dismutase, a gene previously implicated in the oxidative stress response to pathogens, was significantly downregulated, suggesting potential suppression of oxidative burst defence mechanisms. These results reveal the complex nature ofS. glomerata’sresponse toM. sydneyiinfection, and possible suppression or evasion of host defences by the parasite. The study also identifies multiple genes that likely play crucial roles in the molecular responses and defence mechanisms ofS. glomeratatoM. sydneyiinfection. The identification of these genes provides potential target genes for future studies and possible biomarkers for breeding QX-resistant oyster lines.

Highlights

M. sydneyiinfection induces a large transcriptional response inS. glomerata

Upregulation of pathogen recognition genes, including galectins, occurs in infected tissues.

Lack of differential expression of apoptosis genes suggests other immune strategies.

G-protein coupled receptor pathways were upregulated, indicating species-specific responses.

Results suggest possible suppression of host immune responses by the parasite.
Active site tyrosine residues in human NQO1 homodimer are critical for non-synchronous enzyme catalysis at the two active sites
Authors: Rivero Maribel , Pacheco-Garcia Juan Luis , Vankova Pavla , Loginov Dmitry S , Quereda-Moraleda Isabel , Martin-Garcia Jose Manuel , Man Petr , Medina Milagros , Pey Angel Luis
Published: February 2025

Abstract

Human NQO1 is a flavoenzyme essential for the redox metabolization of many substances and associated with wide-impacting diseases such as cancer and Alzheimeŕs. Recent X-ray crystallographic studies have proposed that a few residues at the active site of NQO1 (including Tyr126 and Tyr128) may control enzyme catalysis and functional negative cooperativity. In this work, we use rapid mixing pre-steady state kinetics and hydrogen-deuterium exchange followed by mass spectrometry (HDX-MS) to evaluate experimentally the role of Tyr126 and Tyr128 in NQO1 functionality by generating mutants to Phe, Ala and Glu. Mutations to Phe caused mild effects, whereas those to Ala significantly decreased hydride transfer efficiency and those to Glu virtually abolished NQO1 activity. Interestingly, structural stability studies by HDX-MS showed significant perturbations particularly affecting the binding site of NADH/NAD+in the less conservative mutations (particularly to Glu). Mutations of Tyr126 and Tyr128 seem to also modulate the non-synchronous catalysis in the two active sites (negative cooperativity) as well as the selectivity for NADH/NADPH as coenzymes. Our work experimentally demonstrates the critical role of Tyr126 and Tyr128 in the flavin reductive half-reaction of the catalytic cycle of NQO1 in the negative cooperativity, and also suggests that phosphorylation of these two Tyr residues might shut down NQO1 activity reversibly.
RAS pathway activation drives clonal selection and monocytic differentiation in FLT3 and BCL2 inhibitor resistance
Authors: Kennedy Vanessa E. , Peretz Cheryl A. C. , Walia Anushka , Chyla Brenda , Sun Yan , Hill Jason , Tran Elaine , Koh Andrew , Ferng Timothy , Pintar Samantha , Jones Matthew , Popescu Bogdan , Murad Natalia , Roy Ritu , Olshen Adam , Joshi Sunil , Traer Elie , Dail Monique , Hamidi Habib , Altman Jessica , Daver Naval , Levis Mark , McCloskey James , Perl Alexander , Smith Catherine C.
Published: February 2025

Despite efficacy of FLT3 and BCL2 inhibition in acute myeloid leukemia (AML), relapse limits survival. Mutation status and AML monocytic differentiation are implicated in resistance. On-treatment tumor evolution may select for genetically distinct clones or shifts in differentiation not resolvable by bulk sequencing. We performed multiomic single cell (SC) DNA/protein and RNA/protein profiling of patients treated on a clinical trial of the BCL2 inhibitor venetoclax and the FLT3 inhibitor gilteritinib (Ven/Git) to characterize immunophenotypic, transcriptional, and genetic clonal evolution on therapy. We found that while Ven/Gilt effectively eliminated FLT3 mutant clones, it selected for RAS mutations, RAS pathway activation and RAS-associated monocytic differentiation. In anin vitromodel of monocytic differentiation associated with heightened RAS pathway activation, we demonstrated that MEK inhibition re-sensitized to Ven/Gilt. These data indicate RAS signaling is central to FLT3 and BCL2 inhibitor resistance, is tightly coupled to monocytic differentiation and can be overcome by RAS pathway inhibition.

COI

C.C.S. has provided educational talks for Astellas Pharma, served on advisory boards for Genentech/Abbvie and received research funding from Abbvie. B.C., Y.S. and J.H. are employees of Abbvie. M.S. and H.H. are or were previously employees of Genentech.

Funding

This work was supported in part by Abbvie. C.C.S. is a Leukemia & Lymphoma Society Scholar in Clinical Research and a Damon Runyon-Richard Lumsden Foundation Clinical Investigator supported (in part) by the Damon Runyon Cancer Research Foundation (CI-99–18).

Statement of Significance:

Mutational and non-mutational RAS signaling activation drives clonal selection, monocytic differentiation and treatment resistance to FLT3 and BCL2 inhibition in AML. MEK inhibition can resensitize resistant AML cells, suggesting therapeutic potential for combined FLT3, BCL2 and RAS pathway inhibition in AML.
Evaluating Flow-Focused Microfluidic Device Fabrication Techniques for Silk Fibroin Microgel Production
Authors: Haghighattalab Mahsa , Karimi Fatemeh , Farbehi Nona , Rnjak-Kovacina Jelena
Published: February 2025

Microgels, or micro-scale hydrogels, are versatile emerging biomaterials. They absorb large amounts of water and facilitate molecule transfer. Their tunable size and shape and the capacity to form 3D scaffolds with microscale porosity offer significant advantages over traditional bulk hydrogels. Various strategies exist for fabricating microgels with microfluidic techniques offering the most control of microgel properties. This study compares three microfluidic device fabrication techniques—maskless photolithography, laser engraving, and 3D printing—for making photo-crosslinked silk fibroin microgels. Silk microgels were fabricated via water-in-oil microfluidics and crosslinked through di-tyrosine bonds between native tyrosine residues in silk. Microfluidic devices with target channel depths of 50, 100, or 400 µm were successfully fabricated, with each technique offering unique advantages and limitations. Maskless photolithography provided the highest channel patterning accuracy and smoothest profiles but was costly and required specialized facilities. Laser engraving was affordable but labor-intensive, with lower accuracy in the X-Y plane for deeper channels. 3D printing was user-friendly and affordable but resulted in low accuracy for 50 µm channels and rougher channel profiles, leading to larger microgels and less efficient microgel formation than the other techniques. Spherical silk microgels with diameters between 50 µm and > 400 µm were produced by modulating channel depth and flow rates, while rod-shaped microgels were made by crosslinking in the outlet tubing. Silk molecular weight was adjusted to control surface porosity and compressive modulus, with lower molecular weight silk resulting in higher porosity and softer microgels (modulated between ∼ 40 kPa and ∼ 590 kPa) while maintaining consistent size.

This study demonstrates the versatility and effectiveness of different microfluidic device fabrication techniques for producing photo-crosslinked silk microgels with tunable properties for biomedical applications.
Accelerating Antibody Development: Sequence and Structure-Based Models for Predicting Developability Properties through Size Exclusion Chromatography
Authors: Abeer A N M Nafiz , Boroumand Mehdi , Sermadiras Isabelle , Caldwell Jenna G , Stanev Valentin , Mody Neil , Kaplan Gilad , Savery James , Croasdale-Wood Rebecca , Pouryahya Maryam
Published: February 2025

Experimental screening for biopharmaceutical developability properties typically relies on resource-intensive, and time-consuming assays such as size exclusion chromatography (SEC). This study highlights the potential of in silico models to accelerate the screening process by exploring sequence and structure-based machine learning techniques. Specifically, we compared surrogate models based on pre-computed features extracted from sequence and predicted structure with sequence-based approaches using protein language models (PLMs) like ESM-2. In addition to different end-to-end fine-tuning strategies for PLM, we have also investigated the integration of the structural information of the antibodies into the prediction pipeline through graph neural networks (GNN). We applied these different methods for predicting protein aggregation propensity using a dataset of approximately 1200 Immunoglobulin G (IgG1) molecules. Through this empirical evaluation, our study identifies the most effective in silico approach for predicting developability properties for SEC assays, thereby adding insights to existing screening efforts for accelerating the antibody development process.
GPR182 is a lipoprotein receptor for dietary fat absorption
Authors: Sun Zhiwei , Torphy Robert J , Miller Emily N , Darehshouri Anza , Vigil Isaac , Terai Taichi , Eck Eleanor , Sun Yi , Guo Yujie , Yee Elliott J , Hu Junyi , Kedl Ross M , Lasda Erika L , Hesselberth Jay R , MacLean Paul , Bruce Kimberley D , Randolph Gwendalyn J , Schulick Richard D , Zhu Yuwen
Published: February 2025

The lymphatic system plays a central role in lipid absorption, which transports chylomicrons from the small intestine to the circulation. However, the molecular mechanism by which chylomicrons get into the intestinal lymphatics is unknown. Here we demonstrated that GPR182, a receptor in lymphatic endothelial cells (LECs), mediates dietary fat absorption. GPR182 knockout mice are resistant to dietary-induced obesity. GPR182 ablation in mice leads to poor lipid absorption and thereby a delay in growth during development. GPR182 binds and endocytoses lipoproteins broadly. Mechanistically, loss of GPR182 prevents chylomicrons from entering the lacteal lumen of the small intestine. GPR182 blockage with a monoclonal antibody (mAb) protects mice from dietary induced obesity. Together, our study identifies GPR182 as a lipoprotein receptor that mediates dietary fat absorption.
Microbiota Dynamics in Lionfish (Pterois): Insights into Invasion and Establishment in the Mediterranean Sea
Authors: Meron Dalit , Lalzar Maya , Rothman Shevy Bat-Sheva , Kroin Yael , Kaufman Elizabeth , Kitson-Walters Kimani , Zvi-Kedem Tal , Shemesh Eli , Tsadok Rami , Nativ Hagai , Einbinder Shai , Tchernov Dan
Published: February 2025

Abstract Lionfishes (Pterois spp.), originally native to the Indo-Pacific and Red Sea, have become one of the most invasive marine species globally, including the recent establishment in the Mediterranean Sea. This study investigates the microbiota of lionfish to explore its potential role in their invasion success and establishment. Using high-throughput sequencing and microbiota analyses, we characterized the species-specific core microbiome and identified habitat-specific markers across different regions (Red Sea, Mediterranean Sea, Caribbean, and aquarium populations) and organs. Focusing on the Mediterranean invasion, we tracked lionfish distribution and population dynamics along the Israeli coastline from 2017 to 2023, monitoring size, seasonal trends, and depth preferences. Our findings reveal that lionfish initially established themselves in deeper waters before expanding to shallower habitats, with a gradual increase in population size and body length over time. From a microbial aspect, we compared the microbiota of lionfish organs and identified a similar pattern (Photobacterium), to Earlier Lessepsian migrants fish species. This study provides novel insights into the interactions between microbiota and host ecology, shedding light on the mechanisms that may support the successful invasion. This study contributes to the understanding of lionfish invasion dynamics in the Mediterranean. It highlights the microbiota as an integral component for studying the ecological and biological mechanisms underpinning invasive species' success and establishment of lionfish.
Molecular investigation ofRlm3from rapeseed as a broad-spectrum resistance gene against fungal pathogens producing structurally conserved effectors
Authors: Talbi Nacera , Pakzad Simine , Blaise Françoise , Ollivier Bénédicte , Rouxel Thierry , Balesdent Marie-Hélène , Blondeau Karine , Lazar Noureddine , van Tilbeurgh Herman , Mesarich Carl H. , Fudal Isabelle
Published: February 2025

Recognition of a pathogen avirulence (AVR) effector protein by its cognate plant resistance (R) protein triggers immune responses that render the plant resistant, representing an efficient disease control strategy. While (AVR) effectors have long been considered species- or genotype-specific, based on a lack of homology in sequence databases, a growing number of studies have now shown that these proteins belong to a limited set of structural families. This is an important finding because it paves the way for the identification or engineering of broad- spectrum R proteins capable of recognizing several members of the same structural family. In theLeptosphaeria maculans/ rapeseed (Brassica napus) pathosystem, 13AVRgenes have been cloned, of which four encode effectors belonging to the LARS (LeptosphaeriaAviRulence and Supressing) structural family that has also been found in thirteen other phytopathogenic fungi. Homologues of theL. maculansAvrLm3 AVR protein, a LARS family member, have been identified in other fungal species, including an AVR protein fromFulvia fulvacalled Ecp11-1. We have previously shown that Ecp11-1 is recognized by rapeseed varieties carrying theRlm3 Rgene, and that this recognition is masked by the presence of another LARSAVRgene,AvrLm4-7. In this study, we expanded our characterization of the Rlm3 resistance spectrum to putative effectors fromFusarium oxysporumandZymoseptoria ardabiliaeand showed that one effector fromF. oxysporumf. sp.narcissibehaves like Ecp11-1, being recognized by Rlm3, and this recognition also being masked by the presence ofAvrLm4-7. We finally investigated which protein regions and amino acids were necessary for the recognition of AvrLm3 and Ecp11-1 by Rlm3. This analysis is a first step towards the identification or engineering of broad- spectrum R proteins that confer protection against multiple phytopathogens through the recognition of structural effector families.
Genetically induced mouse model for colon-specific epithelial cell tumorigenesis driven by loss of K8 and Apc
Authors: Tayyab Mina , Minkkinen Mira M. E. , Stenvall Carl-Gustaf A. , Polari Lauri , Shah Yatrik M. , Toivola Diana M.
Published: February 2025

Loss of keratin 8 (K8) has been shown to increase susceptibility towards colonocyte hyperproliferation and tumorigenesis. However, most colorectal cancer (CRC) mouse models require carcinogen, develop small intestinal tumors or have long latency period. The aim was to establish a genetic, colon-specific and more human like CRC model driven by loss of K8 and Apc. Colon epithelium specific targeting using the CDX2P-CreERT2mice was used to generate K8flox/flox; CDX2P-CreERT2and K8flox/flox; CDX2P-CreERT2; Apcflox/+mice. Body weight and stool consistency were monitored, and colon was analyzed for tumor burden and histopathology. Keratin expression, inflammation, and proliferation were assessed using immunoblotting and immunofluorescence analysis. This data was compared to K8 expression analysis in patients with CRC using UALCAN database. K8 downregulation in adult K8flox/flox; CDX2P-CreERT2mice triggers mild diarrhea and leads to loss of K8 and reduced partner keratin levels in a mosaic pattern in the colonic epithelium, while ileal K8 protein levels are unchanged. K8-negative colon areas display increased crypt loss and more MPO+ cells predominantly in the proximal colon. Increased colonocyte proliferation is observed as increased percentage of Ki67+ cells and lower IL-22BP protein levels throughout the colon. These mice with additional monoallelic Apc inactivation show increased colon tumor formation. In colon adenocarcinoma patients, K8 expression is decreased independent of disease type and stage, age or gender. New genetic and colon-specific mouse model with loss of K8 and Apc adequately resembles human CRC. This study also highlights a role of colonocyte K8 in maintaining colon epithelial integrity and protecting against colon tumorigenesis.
Hypoalbuminemia Increases Fibrin Clot Density and Impairs Fibrinolysis
Authors: Waller Amanda P. , Wolfgang Katelyn J. , Stevenson Zachary S. , Holle Lori A. , Wolberg Alisa S. , Kerlin Bryce A.
Published: February 2025

Background

Hypoalbuminemia is a thrombotic disease risk biomarker. Albumin is a negative acute phase reactant and may thus be an indirect biomarker of thromboinflammation. However, nephrotic syndrome (resulting from non-inflammatory proteinuric glomerular disease) causes both hypoalbuminemia and elevated thrombotic risk. Hypofibrinolysis has been observed in nephrotic syndrome and published data suggest that albumin may directly enhance fibrinolysis. These observations suggest that albumin may directly influence thrombotic risk.

Objective

To test the hypothesis that hypoalbuminemia impairs fibrinolysis.

Methods

Hypoalbuminemic blood and plasma from nephrotic syndrome rat models and nephrotic patients were analyzed by thromboelastometry, clot lysis assays, fibrin clot turbidity, confocal microscopy, and immunoblotting. Some studies were conducted without vs. with albumin repletion. Plasma from an analbuminemic mutant rat model was used to confirm albumin-dependent observations.

Results

Hypoalbuminemia was associated with hypofibrinolysis in nephrotic whole blood. Albumin levels were positively associated with fibrinolysis in both nephrotic rat and patient plasma. Hypoalbuminemia accelerated fibrin clot formation in nephrotic rat plasma. Dense fibrin clots are known to be resistant to fibrinolysis and fibrin clot network density was increased in hypoalbuminemic plasma clots from both nephrotic rats and patients. Clots formed from hypoalbuminemic plasma contained less albumin than controls, and repletion with recombinant albumin to healthy control levels corrected both fibrin network density and fibrinolysis in nephrotic and analbuminemic rat plasma.

Conclusion

These data show that albumin directly increases fibrin network porosity and enhances fibrinolysis. Hypoalbuminemia may mechanistically contribute to nephrotic syndrome thrombotic complications and may similarly increase thrombotic risk in other hypoalbuminemic conditions.
Investigating the impact of carbamazepine on tomato plant metabolism using genome-scale metabolic modelling
Authors: Srinivasan Samyuktha , Raman Karthik , Srivastava Smita
Published: February 2025

A comprehensive mechanistic analysis of emerging pharmaceutical pollutants’ stress response in plants is needed to understand its chronic impact on food-chain contamination and agricultural productivity. To unravel this at systems-level, the current study employs insights from green-liver concept and establishes the utility of constraint-based modelling approach for elucidating perturbations in a plant’s metabolism due to pharmaceutical stress.

In this study, the stress response of an emerging recalcitrant anticonvulsant pollutant, carbamazepine (CBZ), was simulated in tomato crop under phototrophic conditions. For this, an updated genome-scale metabolic model of tomato leaf (CBZ_iSL3433) was developed and augmented with CBZ transformation reactions based on the green-liver concept. The model was able to capture energy and co-factor competition-induced biomass reduction in presence of CBZ stress. Further, the study provides anin silicomechanistic proof for abiotic stress response induced by CBZ in tomato with altered flux states in nutrient assimilation, synthesis of key precursors of leaf biomass and secondary metabolites. Additionally, to extend the applicability of model, potential ameliorative effects of biostimulants such as proline, spermine, glycerol, and ethanol were investigated through model predictions. Through systematic computational analysis, 154 significantly altered reactions were identified in the presence of CBZ stress, of which 92 % of reactions were ameliorated with biostimulants. Amino acid biosynthesis was found to be the most significantly altered pathway under CBZ stress in the presence of biostimulants.

Overall, the proposed framework can aid in screening and developing rational strategies to maintain agricultural yields amid rising plant stress due to such anthropogenic pollutants.
Experimental Kinetic Mechanism of P53 Condensation-Amyloid Aggregation
Authors: Borkosky Silvia S. , Peralta-Martinez Ramon , Armella-Sierra Alicia , Esperante Sebastián A. , Lizárraga Leonardo , García-Pardo Javier , Ventura Salvador , Sanchez Ignacio E. , de Prat-Gay Gonzalo
Published: February 2025

The tumor suppressor p53 modulates the transcription of a variety of genes constituting a protective barrier against anomalous cellular proliferation. High frequency “hot-spot” mutations result in loss-of-function by the formation of amyloid-like aggregates that correlate with cancerous progression. We show that full-length p53 undergoes spontaneous homotypic condensation at sub-micromolar concentrations and in the absence of crowders, to yield dynamic coacervates that are stoichiometrically dissolved by DNA. These coacervates fuse and evolve into hydrogel-like clusters with strong thioflavin-T binding capacity, which further evolve into fibrillar species with a clearcut branching growth pattern. The amyloid-like coacervates can be rescued by the HPV master regulator E2 protein to yield large regular droplets. Furthermore, we kinetically dissected an overall condensation mechanism which consists of a nucleation-growth process by sequential addition of p53 tetramers, leading to discretely-sized and monodisperse early condensates followed by coalescence into bead-like coacervates that slowly evolve to the fibrillar species. Our results suggest strong similarities to condensation-to-amyloid transitions observed in neurological aggregopathies. Mechanistic insights uncover novel key early and intermediate stages of condensation that can be targeted for p53 rescuing drug discovery.

SIGNIFICANT STATEMENT

Known as “the guardian of the genome”, the tumor suppressor protein p53 becomes activated by injuries to the DNA genome, and determines whether the cell must undergo self-destruction to avoid cancerous proliferation. P53 is in fact inactivated by mutations in over 50% of all cancers, and restoring its function is recognized as a therapeutic cancer target. A recent biochemical revolution in cell physiology and pathology are liquid entities known as biomolecular condensates. We show that p53 form condensates en route to pathological forms in a surprisingly similar manner to neurological amyloid diseases such as Alzheimeŕs and Parkinsońs. We uncover the sequence of steps in the reaction, exposing flanks for a novel drug development platform based on the condensates paradigm.
Modelling and simulation of the interactions between the cardiovascular system, VA ECMO and IABP: when is it an appropriate combination?
Authors: De Lazzari Beatrice , Capoccia Massimo , Badagliacca Roberto , Maybauer Marc O , De Lazzari Claudio
Published: February 2025

Veno-arterial extracorporeal membrane oxygenation (VA ECMO) for the management of refractory cardiogenic shock (CS) has been widely used in recent years. Increased left ventricular (LV) afterload induced by retrograde flow remains a limiting factor, which is particularly evident during peripheral VA ECMO support. The concomitant use of the intra-aortic balloon pump (IABP) is an established strategy to achieve LV unloading during VA ECMO support. Nevertheless, there remains controversy about the combined use of IABP during central or peripheral VA ECMO in terms of beneficial effects and outcome. We developed a simulation setting to study left ventricular unloading with IABP during peripheral and central VA ECMO using CARDIOSIM©, an established software simulator of the cardiovascular system. The aim was to quantitatively evaluate potential differences between the two VA ECMO configurations and ascertain the true beneficial effects compared to VA ECMO alone.
sCIN: A Contrastive Learning Framework for Single-Cell Multi-omics Data Integration
Authors: Ebrahimi Amir , Siahpirani Alireza Fotuhi , Montazeri Hesam
Published: February 2025

The rapid advancement of single-cell omics technologies such as scRNA-seq and scATAC-seq has transformed our understanding of cellular heterogeneity and regulatory mechanisms. However, integrating these data types remains challenging due to distributional discrepancies and distinct feature spaces. To address this, we present a novel single-cell Contrastive INtegration framework (sCIN), that integrates different omics modalities into a shared low-dimensional latent space. sCIN uses modality-specific encoders and contrastive learning to generate latent representations for each modality, aligning cells across modalities and removing technology-specific biases. The framework was designed to rigorously prevent data leakage between training and testing, and was extensively evaluated on three real-world paired datasets including SHARE-seq, 10X PBMC (10k version), and CITE-seq. Paired datasets refer to multi-omics data generated using technologies capable of capturing different omics features from the same cell population. Results on paired datasets show that sCIN outperforms alternative models, including Con-AAE, Harmony, and MOFA across multiple metrics: Average Silhouette Width (ASW) for clustering quality, Recall@k, Cell type accuracy, and Median Rank for integration quality. Moreover, sCIN was evaluated on simulated unpaired datasets derived from paired data, demonstrating its ability to leverage available biological information for effective multimodal integration. In summary, sCIN reliably integrates omics modalities while preserving biological meaning in both paired and unpaired settings.