bluuebunny/crossref_metadata_2025 huggingface dataset:
Fluoroscopic balloon dilation is effective for anastomotic leakage caused by compression due to intraperitoneal hematoma after ileostomy closure: A case report
Authors: Kamada Teppei , Ohdaira Hironori , Aida Takashi , Yamagishi Daisuke , Takahashi Junji , Nakashima Keigo , Ito Eisaku , Suzuki Norihiko , Hata Taigo , Yoshida Masashi , Yamanouchi Eigoro , Suzuki Yutaka
Published: January 2025

Rationale:

There have been no reports of delayed anastomotic leakage of the ileum caused by compression of an intra-abdominal hematoma due to postoperative bleeding after ileostomy closure.

Patient concerns:

We report the case of a 44-year-old man with delayed anastomotic leakage after ileostomy closure caused by the compression of an intra-abdominal hematoma that healed quickly after fluoroscopic balloon dilatation of the bowel stenosis area.

Diagnoses:

Postoperative bleeding and hemorrhagic shock occurred on postoperative day 1 after ileostomy closure. Vital signs stabilized after blood transfusion, and computerized tomography-guided drainage was successfully performed to reduce the hematoma volume. However, residual hematoma compressed the ileum on the anal side of the anastomosis, leading to delayed anastomotic leakage.

Interventions/outcomes:

Fluoroscopic balloon dilation of the stenotic area through the drain was successfully performed, and the anastomotic leakage healed quickly.

Lessons:

In cases of small intestinal anastomotic leakage after postoperative bleeding, compression of the intestinal tract due to a hematoma should be considered. Fluoroscopic balloon dilation through a drain is an effective procedure.
Role of Serpin B3 and LRG1 as biomarkers in cervical cancer diagnosis and progression
Authors: Dsouza Reshma Maria Cocess , G. Shyamala , Kudva Ranjini , A.M. Ciraj , P.Y. Prakash , Ummer V. Saleena
Published: January 2025

Cervical cancer is a significant health concern for women, yet it is largely preventable. Persistent infections with oncogenic human papilloma viruses (HPVs) are the predominant cause, with viral oncoproteins facilitating neoplastic growth. Acute HPV infections often result in low-grade precursor lesions that typically resolve on their own in over 90% of cases, with fewer than 10% advancing to high-grade or invasive malignancies. As a result, the implementation of Pap smear screening programs has significantly decreased the incidence and mortality associated with cervical cancer, but it still remains a global health concern. Challenges such as low sensitivity and the unavailability of tests in rural areas pose significant hurdles. Novel biomarkers that monitor critical molecular events in histological or cytological samples are expected to improve the detection of high-risk lesions in both primary screening and triage scenarios.
Building Health Policy Advocacy Expertise in Pediatric Nurse Practitioners Through Civic-Based Experiential Learning
Authors: Schindler Christine A. , Kuester Jill C. , Pfister Jennifer K. , McDermott Katie L.
Published: January 2025

Background:

Many nurses work largely as policy implementers rather than policy developers. The literature posits several multifaceted reasons for this lack of policy acumen including interprofessional power dynamics, marginalization of nurses in policy making, and lack of formal training in public policy advocacy.

Purpose:

To evaluate the impact of a targeted teaching strategy on increasing political astuteness, perceived skill, and comfort in health policy advocacy among a cohort of acute care pediatric nurse practitioner students.

Methods:

Curriculum assessment data were collected using the Political Astuteness Inventory, pre- and postclass discussions, and written reflections.

Results:

This curriculum evaluation suggests that specific policy and advocacy training coupled with civic-based experiential learning increased graduate nursing students’ political astuteness as well as increased their perceived skill and comfort with health policy advocacy.

Conclusions:

Targeted training is an important step in giving nurses the needed tools to work for equitable health care policies.
Textbook Selection in Nursing Education: An Updated Perspective
Authors: Anderson Judy K. , Downing Lucille , Heitman Susan , Heiser Vickie R. , Rauch Linda J.
Published: January 2025

Background:

Evidence-based guidelines about textbook selection for nursing didactic courses are lacking. Therefore, this study explored the priorities of faculty in baccalaureate nursing programs for selecting primary textbooks.

Purpose:

The study aimed to identify the ranking of essential characteristics in nursing textbooks, including content, general characteristics, supplemental resources, organization, and specific considerations about electronic textbooks.

Methods:

Using a cross-sectional design, a descriptive survey was conducted among faculty members across the United States.

Results:

Results from 59 faculty participants demonstrated a strong preference for textbooks emphasizing clinical judgment and application to practice, with content being the top priority. Additionally, instructor resources, such as test banks and teaching strategies, were prioritized within supplemental resources. Few participants reported formal training in textbook selection, indicating a potential area for nursing education improvement.

Conclusions:

The study found the need for further research and development of structured guidelines to aid in the textbook selection process.
Prevalence and incidence of HPV-related dysplasia of oropharyngeal, cervical, and anal mucosae in Spanish people living with HIV (PLHIV)
Authors: Hidalgo-Tenorio Carmen , Calle-Gómez Inmaculada , Moya Raquel , Omar Mohamed , Lopez-Hidalgo Javier , Rodriguez-Granges Javier , Muñoz Leopoldo , García-Martinez Carmen
Published: January 2025

Background:

Objectives were to determine the prevalence/incidence of HPV-related dysplasia and clearance/acquisition rates of high-risk HPV (HR-HPV) genotypes in genital mucosa of women-LHIV and oropharyngeal and anal mucosa of PLHIV and to evaluate factors related to HR-HPV infection in oropharyngeal mucosa at 12-months.

Material and methods:

Prospective, longitudinal study with 12-month follow-up, enrolled PLHIV between December 2022 and April 2023. At baseline and 12-months, HIV-related clinical and analytical variables were recorded, oropharyngeal mucosa exudates were taken for polymerase chain reaction (PCR) studies for HPV and other sexually transmitted infections, while anal and female genital samples were self-sampled for HPV detection and genotyping by PCR and thin-layer cytology.

Results:

276 PLHIV with mean age of 45.3 years, 79% male, 24.3% with history of AIDS, 100% under ART, and 30.1% with completed HPV vaccination. HPV infection prevalence in oropharyngeal mucosa was 11.6% at baseline, most frequently by genotype 16 (2.2%), without dysplasia. No oropharyngeal dysplasia was observed at 12 months, and HR-HPV clearance and acquisition rates were 5.5% and 4.4%, respectively. Incidence of anal HSIL was 1,811.6 casesx100,000 people-year, and HR-HPV clearance and acquisition rates were 16.2% and 25.6%, respectively. Incidence of CIN2/CIN3 or cervical cancer was zero, and HR-HPV clearance and acquisition rates were 11.3% and 7.5%. HIV-RNA viral load <50 cop/mL protected against HPV infection in oropharyngeal mucosa (97.2 vs. 87%, HR 0.044; 95%CI [0.042 – 0.956]).

Conclusions:

Among PLHIV, HSIL incidence and HR-HPV acquisition rate are higher in anal versus oropharyngeal and genital mucosae. Non-detectability protects against oropharyngeal HPV infection.
Draft genome sequence of Flavobacterium aquidurense strain, isolated from untreated wastewater
Authors: Kingdon Alexander D. H. , D’Arcy Kara , Breen Anya , McKeown Claudia , Allman Ellie , Sharma Priyanka , McLeman Amy , Roberts Adam P.
Published: January 2025

Here, we report the draft 5.8 Mb genome sequence of a Flavobacterium aquidurense isolate from untreated wastewater in Liverpool, UK. The reported isolate has the potential to produce both flexirubin and β-carotene, and contains an additional biosynthetic gene cluster for a putative novel beta-lactone. The genome also contains a gene for a putative beta-lactamase blaJOHN-1 analogue and putative novel insertion sequences of the IS3 family.
Modified multiplex PCR for serotyping and pathotyping of Streptococcus suis
Authors: Hatrongjit Rujirat , Sittichottumrong Kulsatri , Boueroy Parichart , Chopjitt Peechanika , Gottschalk Marcelo , Nuanualsuwan Suphachai , Kerdsin Anusak
Published: January 2025

Introduction.
Streptococcus suis is a zoonotic pathogen that causes invasive infections in humans who have been in close contact with infected pigs or contaminated pork-derived products. There is currently no consensus on the universal virulence factors or markers that can differentiate pathogenic from non-pathogenic or commensal S. suis isolates.

Gap statement. A diagnostic tool for serotyping and pathotyping of S. suis is required for active public health surveillance and the One-Health approach.

Aim. To improve the former multiplex PCR to serotyping all 29 recognized ‘true’ serotypes and distinguish pathogenic pathotypes using primers targeting the capsule and ROK pathogenic marker genes.

Methodology. Four sets of multiplex PCRs were modified and improved to detect all 29 recognized serotypes of S. suis and distinguish their pathogenic pathotypes using the ROK gene.

Results. This multiplex PCR allowed for the simultaneous amplification of S. suis-specific, serotype-specific and pathogenic pathotypes from the DNA of each serotype in each reaction. The accuracy, sensitivity, specificity, positive predictive value and negative predictive value of the pathogenic ROK marker genes were 84.7% (625/738), 96.4% (423/439), 67.6% (202/299), 81.4% (423/520) and 92.7% (202/218), respectively. There was a significant (P-value <0.001), high positive likelihood ratio [2.9 with 2.5–3.5 of 95% confidence interval (CI)] and a significant odds ratio (55.1 with 31.6–95.9 of 95 % CI), which indicated that the ROK gene could be used as the pathogenic pathotype marker. No cross-reactions were observed with other bacterial species.

Conclusion. This modified multiplex PCR was able to distinguish 29 well-known serotypes and predicted the pathogenic pathotypes of S. suis isolates from humans and pigs in a single assay. It is useful for One-Health surveillance of human and pig isolates of S. suis.
Multiple introductions of NRCS-A Staphylococcus capitis to the neonatal intensive care unit drive neonatal bloodstream infections: a case-control and environmental genomic survey
Authors: Lees Emily A. , Gentry Jessica , Webster Hermione , Sanderson Nicholas , Eyre David , Wilson Daniel , Lipworth Sam , Crook Derrick , Wong T.H. Nicholas , Mark Anthony , Jeffery Katie , Paulus Stéphane , Young Bernadette C.
Published: January 2025

Background. The Staphylococcus capitis NRCS-A strain has emerged as a global cause of late-onset sepsis associated with outbreaks in neonatal intensive care units (NICUs) whose transmission is incompletely understood.

Methods. Demographic and clinical data for 45 neonates with S. capitis and 90 with other coagulase-negative staphylococci (CoNS) isolated from sterile sites were reviewed, and clinical significance was determined. S. capitis isolated from 27 neonates at 2 hospitals between 2017 and 2022 underwent long-read (ONT) (n=27) and short-read (Illumina) sequencing (n=18). These sequences were compared with S. capitis sequenced from blood culture isolates from other adult and paediatric patients in the same hospitals (n=6), S. capitis isolated from surface swabs (found in 5/150 samples), rectal swabs (in 2/69 samples) in NICU patients and NICU environmental samples (in 5/114 samples). Reads from all samples were mapped to a hybrid assembly of a local sterile site strain, forming a complete UK NRCS-A reference genome, for outbreak analysis and comparison with 826 other S. capitis from the UK and Germany.

Results.
S. capitis bacteraemia was associated with increased length of NICU stay at sampling (median day 22 vs day 12 for other CoNS isolated; P=0.05). A phylogeny of sequenced S. capitis revealed a cluster comprised of 25/27 neonatal sterile site isolates and 3/5 superficial, 2/2 rectal and 1/5 environmental isolates. No isolates from other wards belonged to this cluster. Phylogenetic comparison with published sequences confirmed that the cluster was NRCS-A outbreak strain but found a relatively high genomic diversity (mean pairwise distance of 84.9 SNPs) and an estimated NRCS-A S. capitis molecular clock of 5.1 SNPs/genome/year (95% credibility interval 4.3–5.9). The presence of S. capitis in superficial cultures did not correlate with neonatal bacteraemia, but both neonates with rectal NRCS-A S. capitis carriage identified also experienced S. capitis bacteraemia.

Conclusions.
S. capitis bacteraemia occurred in patients with longer NICU admission than other CoNS. Genomic analysis confirms clinically significant infections with the NRCS-A S. capitis strain, distinct from non-NICU clinical samples. Multiple introductions of S. capitis, rather than prolonged environmental persistence, were seen over 5 years of infections.
Ultraviolet B Induces Cutaneous Lupus Erythematosus by Triggering a Ribotoxic-Stress-Response-Dependent MIF-p38 Feedback Loop in Keratinocytes
Authors: Guo Chipeng , Luo Siweier , Luo Jigang , Lv Haoran , Zhang Yating , Wang Le , Wang Liangchun , Liu Tao , Zhou Yiming
Published: January 2025

Ultraviolet B (UVB) is one of the most common triggers of cutaneous lupus erythematosus (CLE), but the mechanism is still unclear. Here, we discovered that the expression of macrophage migration inhibitory factor (MIF), a multipotent cytokine, was significantly increased in keratinocytes of lupus patients in scRNA-seq data and clinical samples. We further discovered that UVB exposure induced MIF releasing from lupus keratinocytes and contributed to the tissue remodeling and inflammation by regulating the expression of matrix metalloproteinases (MMPs) and pro-inflammatory cytokines in keratinocytes and fibroblasts. Mechanistically, UVB exposure triggered a ribotoxic stress response (RSR) in lupus keratinocytes, which was featured by the increased level of phospho-ZAKα. The RSR induced MIF releasing through the activation of p38 and GSDMD cleavage. The released MIF could further promote the activation of p38 through its receptor CD74, forming a positive feedback loop triggered by UVB exposure in lupus keratinocytes. Intradermal injection of a Mif-shRNA AAV significantly improved the skin lesions in lupus mice. To further investigate the potentials of MIF as a therapeutic target, we developed a microneedle patch capable of intradermal administration of a MIF inhibitor, which effectively protected lupus mice from skin lesions induced by UVB exposure. In conclusion, our findings suggest a novel mechanism by which UVB exposure contributes to the development of CLE by triggering a positive feedback loop of MIF-p38 in lupus keratinocytes. Our results also demonstrate the translational potentials of microneedle patch targeting MIF in the treatment of CLE.
Exploring new Bacteroidota strains: Functional Diversity and Probiotic Characteristics
Authors: Ladewig Lisa , Tufail Muhammad Aammar , Kinfu Birhanu M. , Fokt Hanna , Baines John F. , Schmitz Ruth A.
Published: January 2025

Bacteroidota, a diverse phylum of bacteria, are increasingly recognized for their significant contributions to host health, particularly through their antimicrobial and probiotic properties. This study investigates the functional diversity and probiotic potential of 42 new Bacteroidota strains enriched and identified from diverse hosts, including mouse ceca and human stool samples. Using 16S rRNA gene sequencing, we phylogenetically characterized the strains of the genera Bacteroides, Phocaeicola and Sphingobacterium and assessed their functional properties related to probiotic potential. The strains were evaluated concerning their ability to inhibit biofilm formation of WHO declared clinically significant pathogens, including gram-positiveStaphylococcus aureusandStaphylococcus epidermidis, gram-negativeKlebsiella oxytocaandPseudomonas aeruginosa, and the eukaryotic fungusCandida albicans.Additionally, we investigated bile salt hydrolase and quorum quenching activities of the strains, key traits associated with probiotic efficacy. Our findings demonstrate that all examined Bacteroidota strains consistently exhibit a capacity to inhibit biofilm formation but to different extent. Furthermore, 14 strains showed quorum quenching activity, and 39 bile salt hydrolase activity, highlighting their probiotic potential. High biofilm inhibition as well as quorum quenching activity against both autoinducers, AHL and AI-2, were predominantly observed inBacteroides caecimurisandBacteroides muris, making them attractive candidates for next-generation probiotics. Overall, this study advances the field of next-generation probiotics by identifying promising candidates for therapeutic applications potentially revolutionizing approaches to microbiome-based interventions and pathogen control in clinical settings.
An explainable artificial intelligence framework reveals mutations associated with drug resistance inMycobacterium tuberculosis
Authors: Cen Hui , Zhang Peng , Ling Yunchao , Zhao Guoping , Zhang Guoqing
Published: January 2025

Understanding the mechanisms of drug resistance inMycobacterium tuberculosis(MTB) is essential for the rapid detection of resistance and for guiding effective treatment, ultimately contributing to reducing the global burden of tuberculosis (TB). Under anti-TB drugs pressure, MTB continues to accumulate resistance loci. The current repertoire of known resistance-associated mutations requires further refinement, necessitating efficient methods for the timely identification of potential resistance sites. Here, we introduce xAI-MTBDR, an explainable artificial intelligence framework designed to identify new resistance-associated mutations and predict drug resistance in MTB. It outperforms state-of-the-art methods in predicting drug resistance for all first-line drugs, and scoring each mutation’s contribution to resistance. By leveraging public whole-genome sequencing data from nearly 40,000 MTB isolates, the framework identified 788 candidate resistance-related mutations and revealed 30 potential resistance markers, several of which are structurally located closer to their respective drugs compared to known resistance mutations. Furthermore, these scores enabled the framework to efficiently subgroup isolates with different resistance mechanisms and reflect varying levels of resistance. The framework serves as a valuable tool for accurate detection of drug-resistant MTB and offers new insights into its underlying mechanisms.
A novel human blood-brain barrier model reveals pericytes as critical regulators of viral neuroinvasion
Authors: Richards Alexsia , Khalil Andrew , Bisht Punam , Whitfield Troy W. , Gao Xinlei , Kamm Roger , Mooney David , Gehrke Lee , Jaenisch Rudolf
Published: January 2025

The blood-brain barrier (BBB) plays a vital role in regulating the passage of biomolecules between the bloodstream and the central nervous system (CNS) while also protecting the CNS from pathogens. Pericytes reside at the interface between the endothelial cells that form the vessel walls and the brain parenchyma. These cells are critical for maintaining BBB integrity and play key roles in regulating vessel permeability, blood flow, and immune cell migration. In this study, we developed a novel serum-free protocol to generate neural crest cell-derived pericytes (NCC-PCs) from human pluripotent stem cells (hPSCs). These NCC-PCs enhance BMEC barrier function and can be co-cultured with hPSC-derived brain microvascular endothelial cells (BMECs) in a contact co-culture BBB model that recapitulates thein vivocellular interactions at the BBB. We used this model to evaluate the pathological consequences of BBB cell infection by highly neuroinvasive flaviviruses. Our results identify a previously undescribed role for NCC-PCs in maintaining BMEC barrier integrity during infection and reducing the spread of viral infection to the CNS.
Visual experience contributes to separation of face and language responses in the ventral stream
Authors: Saccone Elizabeth J. , Akshi  , Murty N. Apurva Ratan , Kim Judy S. , Tian Mengyu , Kanwisher Nancy , Bedny Marina
Published: January 2025

Human ventral occipitotemporal cortex (vOTC) contains specialized regions that support visual recognition of behaviorally-relevant categories, including faces, written language and places (e.g.,1–4). An open question is how experience interacts with innate constraints to enable functional specialization. We investigate this question by comparing vOTC function across sighted and congenitally blind adults. In sighted adults, a region in lateral vOTC called the fusiform face area (FFA) responds preferentially to faces, whereas distinct left-lateralized portions of vOTC respond to written language1,2,5–12. In blind people, lateral vOTC responds to face touching, braille and speech, but their functional co-localization has not been tested13–16. The same group of congenitally blind adults (n=20) touched faces and spatial layouts (Experiment 1) and performed a reading (braille) and spoken language task (Experiment 2). Sighted adults performed analogous tasks in the visual modality (n=28). Using within subject analyses, we replicate the separation of faces and written language in sighted adults: written language responses are found only in left vOTC and within that hemisphere they are separate from faces. By contrast, left and right vOTC responds to language in people born blind and in the left hemisphere face and language responses overlap. These findings suggest that visual experience contributes to segregating responses to face and language in vOTC. Co-localization of face and language responses suggests an innate predisposition for communication-relevant processing in lateral vOTC.
Long-Term Seizure Reduction Associated with Vagal Nerve Stimulation in Dravet Syndrome
Authors: Bajaj Sunanjay , Ivaniuk Alina , Bruenger Tobias , Coelho Da Silva Émile Moura , Huth Emily , Montanucci Ludovica , Leu Costin , Taylor Gary , Sinha Mousumi , Tai Rahil A. , Shah Manish N. , Watkins Michael W. , Lankford Jeremy E. , Kommuru Indira M. , Pati Sandipan , Kotagal Prakash , Alexopoulos Andreas , Lhatoo Samden D. , Knight Elia Pestana , Von Allmen Gretchen , Lal Dennis
Published: January 2025

SCN1Avariants cause a range of epilepsy syndromes, including Dravet syndrome, leading to early cognitive and functional impairment. Despite advances in medical management, drug-resistant epilepsy remains common. Vagal nerve stimulation (VNS) has been suggested reducing seizure frequency in these patients but there is a lack of long-term follow-up, quantitative analysis that corrected for confounding factors such as antiseizure medications (ASMs) and the impact of VNS settings on response.

This two-center, retrospective cohort study analyzed 12-month and for the first time up to ten-year seizure outcomes in therapy-refractory epilepsy patients with loss-of-functionSCN1Avariants (93.75% Dravet Syndrome) who underwent VNS implantation. A ≥50% seizure frequency reduction was observed in 93.75% (15/16) of patients in the 12-month and 87.5% (14/15) in the ten-year period. Median seizure frequency was significantly lower in both follow-up periods than in the pre-implantation period. Linear mixed-effects regression showed that the reduction in seizure burden was independent of ASM use, and the VNS duty cycle was significantly associated with seizure reduction. Three individuals (18.8%) experienced minor side effects.

Our results highlight the benefits of genotype-driven therapeutic interventions such as VNS in patients withSCN1A-related epilepsy. This study emphasizes the need for further implementation of genotype-driven clinical decision-making.
The Dynamics of Cognitive Decline towards Alzheimer’s Disease Progression: Results from ADSP-PHC’s Harmonized Cognitive Composites
Authors: Kang Kaidi , Zhang Panpan , Dumitrescu Logan , Mukherjee Shubhabrata , Lee Michael L. , Choi Seo-Eun , Trittschuh Emily H. , Mez Jesse , Saykin Andrew J. , Gifford Katherine A. , Buckley Rachel F. , Gao Xiaoting , Di Jianing , Crane Paul K. , Hohman Timothy J. , Liu Dandan
Published: January 2025

INTRODUCTION

Accurately assessing temporal order of cognitive decline across multiple domains is critical in Alzheimer’s disease (AD). Existing literature presented controversial conclusions likely due to the use of a single cohort and different analytical strategies.

METHODS

Harmonized composite cognitive measures in memory, language and executive functions from 13 cohorts in the ADSP-PHC data are used. A novel double anchoring events-based sigmoidal mixed model was developed using time to the incident of AD diagnosis as the time scale.

RESULTS

Decline in memory occurred before decline in language which was followed by the decline in executive function. Throughout the entire AD continuum, APOE-ε4 non-carriers and non-Hispanic Whites showed better memory performance, respectively, in all three cognitive domains.

DISCUSSION

Using harmonized data across multiple cohorts is the key to accurately characterizing the temporal order of AD biomarkers. Time to incident AD diagnosis should be used as the time scale for reproducibility purposes.
ICU Readmission Prediction for Intracerebral Hemorrhage Patients using MIMIC III and MIMIC IV Databases
Authors: Li Hexin , Monger Rachel , Pishgar Elham , Pishgar Maryam
Published: January 2025

Background

Intracerebral hemorrhage (ICH) is a critical form of stroke resulting from bleeding within the brain, with a mortality rate of 40-50% within a few days and significant risk of long-term disability. Despite the high incidence of ICU readmissions among ICH patients, the specific factors contributing to these readmissions remain unclear. This study utilizes MIMIC-III and MIMIC-IV databases to develop machine learning models that predict ICU readmissions in ICH patients.

Methods

Data from 2,144 patients were extracted using ICD-9 and ICD-10 codes. Four machine learning models - AdaBoost, Random Forest, XGBoost, and LightGBM - were implemented. Recursive Feature Elimination with Cross-Validation reduced features from 50 to 18 key predictors. The RandomUnderSampler technique addressed class imbalance by reducing majority class samples to 60% of the minority class, while the Optuna framework with Tree-structured Parzen Estimator optimized model parameters. Performance was primarily evaluated using AUROC, which effectively handles class imbalance and provides threshold-independent assessment, complemented by accuracy, sensitivity, and specificity metrics.

Results

The AdaBoost model achieved an AUROC of 0.877 (95% CI: 0.815-0.913) and accuracy of 0.810, improving from the previous best AUROC of 0.736. Sensitivity notably increased from 22.6% to 84.0%, demonstrating substantial improvement in identifying high-risk patients. This enhancement resulted from effective class imbalance handling and AdaBoost’s adaptive weighting mechanism. Through comprehensive SHAP and ablation analyses, we identified oxygen saturation and cardiovascular disease as crucial predictive features for ICU readmission risk assessment, providing new insights into patient monitoring and care management.

Conclusions

Our preprocessing methodology and model selection strategy significantly improved high-risk ICH patient identification. Through comprehensive improvements combining advanced hyperparameter optimization, balanced sampling techniques, and dual feature importance analysis, we achieved a 19.2% AUROC improvement while reducing feature dimensionality from 51 to 18. This integrated approach demonstrates the potential of machine learning in enhancing clinical decision-making. The framework provides a promising foundation for developing clinical decision support tools in ICU settings, improving resource allocation and enabling more personalized patient care interventions.
Comprehensive cerebrospinal fluid analysis indicates key roles for B cells in multiple sclerosis
Authors: Fernández-Zapata Camila , Otto Carolin , Gallaccio Gerardina , Chen Qianlan , Wang Meng , Uluvar Burulça , Teves Matteo , Samol Claudia , Buthut Maria , Bösl Fabian R. , Dehlinger Adeline , Jang GueHo , Böttcher Christian , Radbruch Helena , Priller Josef , Schindler Patrick , Raposo Catarina , Shippling Sven , Pedotti Rosetta , Kunkel Desiree , Pietzner Maik , Franke Christiana , Oefner Peter J. , Gronwald Wolfram , Prüß Harald , Lohmeier Johannes , Paul Friedemann , Ruprecht Klemens , Böttcher Chotima
Published: January 2025

Multiple sclerosis (MS) is a complex inflammatory and neurodegenerative disease of the central nervous system (CNS) with a multifaceted pathophysiology, likely involving a variety of mechanisms and effectors. To characterize the spectrum of cellular and molecular factors involved in MS at an unprecedented level, we here performed a comprehensive analysis of cerebrospinal fluid (CSF) and peripheral blood using multiple high-dimensional technologies, including mass cytometry, metabolomics and proteomics (NULISA and Olink Explore®3072). Enriched B cells and proteins involved in B cell functions in the CSF separated MS patients from other neurological disease entities. Specific B cell subpopulations and molecular markers including gut-microbiota-derived metabolites and neurofilament light protein, a marker of neuroaxonal damage, in CSF correlated with clinical (acute vs. stable disease) and/or radiological (gadolinium enhancement) disease activity. Altogether, unbiased broad phenotyping suggests key roles of diverse B subpopulations and B cell related molecular markers in MS, which are associated with both, inflammatory and degenerative aspects of the disease and may serve as disease activity and treatment response biomarkers.
Actinobacteriophage Inteins: Host Diversity, Local Dissemination, and Non-Canonical Architecture
Authors: Gosselin Sophia P. , Arsenault Danielle , Gogarten Johann Peter
Published: January 2025

Intein presence within Actinobacteriophages (within PhagesDB) was last surveyed in 2016, and despite a 5-fold increase in the size of the database, has not been updated since. To address this, we present a modern survey of the current iteration of the PhagesDB database. We developed a new algorithm — Iterative Cluster Expansion BLAST (ICE-BLAST) — to expand our search to more divergent sequences. Nearly 800 inteins were retrieved through this process; the majority of which were previously unreported. We describe the nature of these inteins, their classes, integration target sites, distribution within phage clusters, and explore the geographical location of nearly identical intein sequences found in divergent exteins. Our findings suggest that these inteins recently invaded local phage populations. We also find two instances of a Cas4 exonuclease intein evolving from a terminase intein, and propose a model by which one of these inteins was able to utilize sequence similarity conferred by a shared nucleotide binding site to jump between genes. Additionally, we find inteins with never-before reported homing endonucleases, and inteins with homing endonucleases encoded in a reading frame separate from that which encodes the extein and the intein’s self-splicing domains. We provide predicted structures for these elements and hypothesize on their evolution and relation to free-standing homing endonucleases within phage genomes. Finally, we provide evidence that these “non-canonical” inteins are still transferring between host genomes, in a fashion similar to other inteins with canonical homing endonucleases within the dataset.
Computational Fluid Dynamics (CFD) Modeling of Ilamycin E Production inStreptomyces atratusSCSIO ZH16 Submerged Fermentation
Authors: Zhou Weiyan , Zheng Gaofan , Wang Jialuo , Xin Xiujuan , Zhuang Liwei , An Faliang
Published: January 2025

A computational fluid dynamics (CFD) model was developed and validated against experiments for a laboratory-scale 5-L bioreactor. Numerical simulation was performed to describe the bioreaction ofStreptomyces atratusSCSIO ZH16 fermentation for ilamycin E production with the dynamic changes in viscosity of the fermentation broth due to biomass growth and decay. This model can account for the two-way coupling between the fermentation environment and medium, which allowed for the elucidation of the impact of the flow field in the bioreactor on bacterial growth and production, as well as the influence of viscosity changes on the flow field. This work represents the first integration of Streptomyces fermentation with CFD, enabling the simulation of flow field and mass transfer under varying stirring speed, aeration rate, and viscosity duringStreptomycesfermentation. An optimum range of fermentation broth viscosity (10-30 mPa s) was identified for ilamycin E production byS.atratusSCSIO ZH16 fermentation. Furthermore, the addition of sorbitol to optimize the viscosity of the fermentation broth in the later stages of fermentation. The enhanced mass transfer efficiency strengthens the respiration, energy supply, and carbon source consumption inStreptomyces, thereby increasing the ilamycin E production. This research offers a practical strategy for the process intensification and industrial scale-up for such bioreactors.

Graphical abstract
NR6A1 is essential for neural crest cell specification, formation and survival
Authors: Moore Zajic Emma L. , Muñoz William A. , Dennis Jennifer F , Bhatt Shachi , Sakai Daisuke , Achilleos Annita , Zhao Ruonan , Lamb Maureen , Price Andrew J , Seidel Chris , Tiana María , Barral Antonio , Clawson Delaney , Manzanares Miguel , Trainor Paul A.
Published: January 2025

Neural crest cells (NCC) are a migratory progenitor cell population considered unique to vertebrates. Derived from the neuroepithelium during early embryogenesis, NCC contribute to nearly every tissue and organ system throughout the body, and disruptions in NCC development can result in congenital disorders, termed neurocristopathies. Despite decades of research, we have a poor understanding of the cellular mechanisms and signals that govern mammalian NCC formation. We discovered nuclear receptor superfamily 6 group member 1 (NR6A1/GCNF/RTR), is a novel, critical regulator of mammalian NCC specification, formation and survival.Nr6a1is expressed throughout the neuroepithelium in mouse embryos from E8.0 to E9.5 and briefly in newly delaminated NCC. Nr6a1 loss-of-function perturbs anterior cranial NCC formation and survival, and results in the complete agenesis of migratory NCC caudal to the first pharyngeal arch. Using mouse ESC and human iPSC differentiation into NCC, chromatin immunoprecipitation, and multiomic approaches, we demonstrate that these phenotypes are associated with perturbation of NCC specification (Foxd3, Sox9, Sox10) and epithelial-mesenchymal transition (EMT;Snail1, Zeb2), in concert with persistent expression of pluripotency-associated factors (Oct4andNanog) in the neuroepithelium. Conditional deletion revealed that Nr6a1 is required during mid-late gastrulation, demonstrating that murine NCC specification occurs earlier than previously thought. Consistent with these observations,in vivooverexpression ofOct4in gastrulating mouse embryos disrupts NCC specification and formation. Therefore, Nr6a1 is essential for mammalian NCC formation and moreover, may function as a bimodal switch repressing pluripotency-associated factors in the neuroepithelium, while concomitantly activating NCC specifiers and regulators of EMT.
Non-vectorial Integration of Intersectional Short-Pulse Stimulation Enables Enhanced Deep Brain Modulation and Effective Seizure Control
Authors: Földi Tamás , Szoboszlay Miklos , Chadaide Zoltán , Radics Bence , Horváth Bálint , Vecsernyés Endre , Langó István , Ráfi Péter , Pejin Andrea , Barcsai Lívia , Kozák Gábor , Forgó Nóra , Furuglyás Kristóf , Nagy Olivér , Nagy Anett J. , Laszlovszky Tamás , Somogyvári Zoltán , Lőrincz Magor L. , Devinsky Orrin , Berényi Antal
Published: January 2025

Transcranial electrical stimulation (TES) holds promise to treat neurological disorders, but its efficacy is limited by poor spatial focality and depth of penetration. Here, we examined the potential utility of Intersectional Short-Pulse (ISP) stimulation of deeper brain penetration. Using computational modeling andin vivopatch-clamp recordings in rats, we demonstrate that neurons integrate ISP-induced electric fields in a non-vectorial manner. This mechanism allows ISP to overcome some limits of conventional TES, achieving spatially limited stimulation across cortical and subcortical structures. In a rat model of temporal lobe epilepsy, closed-loop ISP stimulation significantly outperformed conventional TES in reducing seizure duration and severity. ISP reduced hippocampal seizure duration by 49% and 41% compared to sham stimulation and conventional TES and significantly reduced motor seizure severity. Our findings demonstrate that ISP stimulation can rapidly terminate hippocampal seizures, offering a potential new approach for non-invasive neuromodulation with applications across diverse neurologic and psychiatric disorders.
Sustained Isobutene Production bySynechocystissp. PCC 6803 Entrapped in Polyvinyl Alcohol Hydrogel Beads
Authors: Vajravel Sindhujaa , Aravind Sanjukta , Stensjö Karin
Published: January 2025

Cyanobacteria convert CO2into valuable compounds using solar energy, making them ideal for sustainable isobutene production, a key precursor for fuels and chemicals. This study aimed to enhance isobutene production in engineeredSynechocystissp. PCC 6803 strains: Syn-RnKICD, producing isobutene from α-ketoisocaproate (KIC) viaRattus norvegicusα- ketoisocaproate dioxygenase (RnKICD), and Syn-F336V, expressing a mutant variant ofRnKICD with improved KIC specificity. We investigated the effects of varying culture conditions, including light intensity, inorganic carbon, and nitrogen on isobutene production. Nitrogen limitation emerged as a critical factor, improving yields by reducing growth. This likely occurred due to decreased competition from branched-chain amino acid (BCAA) biosynthesis, redirecting carbon toward isobutene synthesis. However, prolonged nitrogen limitation ultimately reduced productivity due to impaired metabolic functions. To address this limitation, we employed a polyvinyl alcohol-sodium alginate (PVA-SA) hydrogel, crosslinked with B(OH)₄⁻ and Ca²⁺, to entrap cells. This approach restricted growth while maintaining cell viability and isobutene productivity. Optimizing crosslinking parameters such as time, pH, and the hydrogel-to-cell mass ratio improved bead stability under bicarbonate and nitrate supply. This strategy extended cell viability and isobutene productivity in Syn-RnKICD and Syn- F336V by nearly a month, increasing yields by 60% and 80%, respectively, compared to suspension cells, achieving a maximum yield of 94 mg/g DW. This study underscores the importance of optimizing environmental conditions for isobutene production inSynechocystisand highlights the effectiveness of PVA-SA cell entrapment as a biocatalyst platform for sustained chemical production.

Highlights

Optimized light, carbon, and nitrogen sources enhanced isobutene production.

Rate of isobutene production increased 10-fold compared to our previous report.

Nitrogen limitation improved isobutene yield by redirecting carbon from growth.

PVA-entrapped cells sustained isobutene productivity for nearly 31 days.
High-resolution digital dissociation of brain tumors with deep multimodal autoencoder
Authors: Sun Jiao , Pan Yue , Lin Tong , Smith Kyle , Onar-Thomas Arzu , Robinson Giles W. , Zhang Wei , Northcott Paul A. , Li Qian
Published: January 2025

Single-cell technologies enable high-resolution, multi-dimensional analysis of molecular profiles in cancer biology but face challenges related to low coverage and cell annotation. The inherent hetero-geneity and complexity of brain tumors may hinder large-scale single cell multi-omic profiling. An efficient alternative is digital dissociation, which involves quantifying cell abundance and purifying bulk samples at high resolution. However, most existing tools for resolving bulk transcriptomes using scRNA-seq as a reference are not easily transferred to other omics (e.g., chromatin accessibility, DNA methylation, protein) due to ambiguous cell markers. Here, we introduce MODE, a novel multimodal autoencoder neural network designed to jointly recover personalized multi-omic profiles and estimate multimodal cellular compositions. MODE is the first algorithm trained on large-scale pseudo-bulk multi-omics derived from an external scRNA-seq reference and an individualized non-RNA reference panel constructed from target tumors. The accuracy of MODE was evaluated through an extensive simulation study, which generated realistic multi-omic data from distinct tissue types. MODE outperformed existing deconvolution pipelines with superior generalizability. Additionally, the high-resolution multi-omic profiles purified by MODE showed strong fidelity and enhanced power to detect differentially expressed genes. We applied MODE to bulk methylome-transcriptome data from two independent brain tumor cohorts, revealing modality-specific cellular landscapes in pediatric medul-loblastoma (MB) and adult glioblastoma (GBM). In MB tumors, MODE accurately predicted the composition of embryonal lineage cells and their marker genes expression. In GBM, the deconvoluted cellular composition revealed an increased myeloid cell abundance associated with poorer event-free survival. Overall, MODE high-resolution multimodal dissociation unravels the origins, evolution, and prognosis of pediatric and adult brain tumors, offering a powerful tool for multi-omic analysis at cell state resolution without large-scale single cell sequencing. MODE is a pipeline freely available athttps://github.com/jsuncompubio/MODE.
A single-cell transcriptome atlas of adult male and female human hookwormAncylostoma ceylanicum
Authors: Bharti Suman , Rosa Bruce A , Martin John , Mitreva Makedonka
Published: January 2025

Hookworms infect over 500 million people globally and represent a major neglected tropical disease. The prevalence, high reinfection rate, limited drugs and emerging resistance underscore the need for new therapeutic or vaccine targets. To mitigate halted progress of discovering targets, we provide new molecular insights into sex-specific expression and cellular heterogeneity by generating the first single-cell atlas of male and female transcriptome for the human hookwormAncylostoma ceylanicum. We systemically annotated 10 transcriptionally distinct cell types in female and 13 in male hookworm by comparing marker genes with tissue-specific knowledge. Non-reproductive tissues included pharynx, intestine, cephalic and pharyngeal glands, muscle and hypodermis, complemented with female reproductive tissues (ovary, uterus, eggs, seminal receptacle), and male reproductive tissues (testis, seminal vesicle, cement gland, sperm). Anatomical confocal microscopy and fluorescence in situ hybridization assisted in visualizing these tissues and confirming marker genes. Functional comparisons revealed previously undescribed tissue pathways and molecular markers, providing previously unrecognized insights into hookworm biology, and new targets. Overall, this study presents a detailed cell-type atlas for adult stages of this important yet neglected metazoan parasite.

Graphical abstract
Facilitation of CaV3.2 channel gating in pain pathways reveals a novel mechanism of serum-induced hyperalgesia
Authors: Sanner Karolina , Kawell Sarah , Evans J. Grayson , Elekovic Vida , Walz MacKenzie , Joksimovic Sonja Lj. , Joksimovic Srdjan M. , Donald Rebecca R. , Tomic Maja , Orestes Peihan , Feseha Simon , Dedek Annemarie , Ghodsi Seyed Mohammadreza , Fallon Isabella P. , Lee Jeonghan , Hwang Sung Mi , Hong Sung Jun , Mayer John P. , Covey Douglas F. , Romano Carmelo , Timic Stamenic Tamara , Chemin Jean , Bourinet Emmanuel , Poulen Gaetan , Longon Nicolas , Vachiery-Lahaye Florence , Bauchet Lue , Zorumski Charles F. , Stowell Michael H. B. , Hildebrand Michael E. , Eisenmesser Elan Z. , Jevtovic-Todorovic Vesna , Todorovic Slobodan M.
Published: January 2025

The CaV3.2 isoform of T-type voltage-gated calcium channels plays a crucial role in regulating the excitability of nociceptive neurons; the endogenous molecules that modulate its activity, however, remain poorly understood. Here, we used serum proteomics and patch-clamp physiology to discover a novel peptide albumin (1-26) that facilitates channel gating by chelating trace metals that tonically inhibit CaV3.2viaH191 residue. Importantly, serum also potently modulated T-currents in human and rodent dorsal root ganglion (DRG) neurons.In vivopain studies revealed that injections of serum and albumin (1-26) peptide resulted in robust mechanical and heat hypersensitivity. This hypersensitivity was abolished with a T-channel inhibitor, in CaV3.2 null mice and in CaV3.2 H191Q knock-in mice. The discovery of endogenous chelators of trace metals in the serum deepens our understanding of the role of CaV3.2 channels in neuronal hyperexcitability and may facilitate the design of novel analgesics with unique mechanisms of action.
The WRC domain of GRF transcription factors. Structure and DNA recognition
Authors: Biglione Franco A. , Palatnik Javier F. , González Schain Nahuel D. , Rasia Rodolfo M.
Published: January 2025

Growth-regulating factors (GRFs) belong to a plant-specific family of transcription factors which display important roles in plant growth and development. GRF transcriptional activity is finely tuned by regulatory processes involving post-transcriptional silencing exerted by miRNA396, and protein-protein interactions involving a family of co-transcriptional regulators known as GRF-interacting factors (GIFs). In this way, expression of GRF target genes is modulated by a highly complex interplay between GRF/GIF isoform diversity and expression patterns along with miR396 and GIF gradients throughout plant tissues. At the protein level, GRFs are composed of two highly conserved domains known as QLQ and WRC and a less conserved C-terminal trans-activation domain. Whereas QLQ mediates GRF-GIF interaction by forming a complex with SNH domains found in GIFs, the WRC has been proposed as a putative zinc finger domain responsible for target DNA recognition and nuclear import. However, the structural aspects governing GRF transcriptional activity and target recognition remain unknown. In this work, we applied bioinformatic and biophysical analysis to comprehensively characterize the structural features that modulate the biological function of this protein family with a focus on the WRC domain. We provide insights into the structure of the WRC domain in GRFs and explore the WRC features driving GRFs:DNA complex formation. These findings offer new insights into how WRC domains modulate the biological functions of GRFs, laying the groundwork for future studies on their structure-function relationship in gene regulation and development of plants.