bluuebunny/crossref_metadata_2025_split huggingface dataset:
Unlocking the potential of blood-stage vaccines for malaria elimination
Authors: Nema Shrikant , Rathore Sumit , Mohmmed Asif , Malhotra Pawan 
Published: February 2025

Abstract
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.
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

Abstract

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.
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

AbstractBackgroundNeonatal 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.MethodsThis 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.ResultsThe 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.ConclusionModified 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.
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

AbstractLong-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

AbstractMarteilia 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.HighlightsM. sydneyiinfection induces a large transcriptional response inS. glomerataUpregulation 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

AbstractHuman 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

AbstractDespite 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.COIC.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.FundingThis 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

AbstractMicrogels, 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

AbstractExperimental 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.
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

AbstractRecognition 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.