bluuebunny/crossref_metadata_2025 huggingface dataset:
Is Zika virus re-emerging as a distinct genetic lineage in India?
Authors: N Pradeep Kumar , P M Ajith Lal , Saini Prasanta , S Aiswarya R , Suresh Abidha , Samuel Philip , R Balasubramaniam , Mathew Jessu , T Sonia , K P Amju , K H K Raju , A Veerapathiran , A Selvam , T Balaji , Kumar Ashwani
Published: January 2025

An outbreak of Zika fever occurred in Thiruvananthapuram City, Kerala, India during 2021. On request of the Kerala state health administration, we investigated the same, towards proposing requisite containment strategies of the disease outbreak. Epidemiological investigations indicated a clustering pattern of Zika fever cases with the presumed index case from a multi-speciality hospital in the city. Preliminary reports on the same had been already reported elsewhere during 2021. Further, entomological surveys carried out evinced the predominant mosquito species in the City viz., Aedes albopictus (65.55%), Aedes aegypti (22.0%) and Aedes vittatus (12.0%) were naturally infected with Zika virus (ZIKV), the Minimum Infection Rates (MIR) being 17.9, 7.8 and 3.6 respectively. Also, trans-ovarian transmission was recorded in Ae. albopictus. This is the first report on detection of ZIKV from Ae. albopictus in India. Analysis of phylogenetically informative genes of ZIKV genome indicated the emergence of a distinct lineage of the Asian strain of virus, with five unique non-synonymous mutations viz., “A22T” & “I160M” (pre-Membrane) and “D348N”, “T470A” & “V473L” (Envelope). was involved in the outbreak. The altered gene expression pattern and evolutionary implications of these unique mutations remain to be investigated. Genetic analysis of the virus isolates from this and other investigations carried out on sporadic outbreaks of ZIKV in the country subsequently, indicated ZIKV is reemerging as a distinct genetic lineage in India. These findings and other recent reports on ZIKV outbreaks warrant an urgent need for a systematic country-wide surveillance strategy, towards the prevention/ preparedness/ containment of a massive outbreak of this emerging neurovirulent arboviral disease.
The first comparative metagenomic analysis of diarrheal and non-diarrheal gut microbiome leading to the identification of prospective prognostic markers and probiotics to protect from diarrhea: A Brief Report
Authors: De Rituparna , Kanungo Suman , Mukhopadhyay Asish K. , Dutta Shanta
Published: January 2025

Introduction: Diarrhea is a leading contributor of mortality. Its disease burden can be assuaged using enhanced prognostics and therapeutics. A cross-sectional gut microbiome analysis  of  non-diarrheal  and   diarrheal  fecal  samples was conducted to meet the goals of the Global Action Plan for Pneumonia and Diarrhea.
Hypothesis: Next-generation Sequencing as a tool for epidemiological surveillance helps in the comparison of structural diversity of the gut microbiome of diarrheal and non-diarrheal samples and can identify prognostic and therapeutic candidates. Aim: The pilot study was designed to identify taxa that are enriched in non-diarrheal samples and to predict gut microbial interactions. Methodology: 16SrRNA amplicon sequencing  and  analysis  were deployed for taxonomic  profiling  and  abundance  interpretation  of  OTUs (Operational Taxonomic Units). Results: The findings suggested significant  differences  in structural composition between  the  two  groups. Firmicutes was the  most  abundant  phylum in most samples. B/F ratio was consistently <1 in all diarrheal samples. Proteobacteria  was    more  abundant  in    diarrheal  samples.  Prevotellaceae  was  the  most  abundant  family  in  non-diarrheal  samples.  Streptococcaceae  was  the  most  abundant  family  in  60%  diarrheal  samples.Where  Streptococcaceae  was  suppressed,  Bacteroideaceae  and  Nocardeaceae  were  the  most  abundant.    In  non-diarrheal  samples  where  Bifidobacteriaceae  was  the  most  abundant  other  families  were significantly low.  A  negative  correlation  was  observed  between  Prevotellaceae  and  Bacteroideaceae  in    non-diarrheal  samples.  Prevotella  copri  was  the  most  abundant  species  in  70%  non-diarrheal  samples  and  was  significantly  suppressed  in  diarrheal  samples.  Proteus  mirabilis  was  identified  in  all  the  non-diarrheal  samples  and  were  absent in  diarrheal  samples.  Conclusion: The OTUs  associated  with  diarrheal  dysbiosis  can  serve  as  prognostic  markers.  This is the first report on the comparative analysis of diarrheal and non-diarrheal microbiome.  The study addressed  gut microbiome dysbiosis from the context that can lead to the development of prognostic markers and probiotics for protecting the endemic population from diarrhea and help in reaching Sustainable Development Goals 2 and 3.
Regulating white blood cell activity through the novel Universal Receptive System
Authors: Tetz Victor , Kardava Kristina , Vecherkovskaya Maria , Khodadadi-Jamayran Alireza , Tsirigos Aristotelis , Tetz George
Published: January 2025

The understanding of the mechanisms that control key features of immune cells in various disease contexts remains limited, and few techniques are available for manipulating immune cells. Thus, discovering novel strategies for regulating immune cells is essential for gaining insight into their roles in health and disease. In this study, we investigated the potential of the recently described Universal Receptive System to regulate human immune cell functions. This was achieved for the first time by specifically targeting newly discovered surface-bound DNA and RNA-based receptors on leukocytes and generating “Leukocyte-Tells.” This approach upregulated numerous genes related to immune cell signaling, migration, endocytosis, and phagocytosis pathways. The antimicrobial and anticancer activities of Leukocyte-Tells exceeded the activity of control leukocytesin vitro. In some settings, such as in antibiofilm experiments, the Leukocyte-Tells showed up to 1,000,000-fold higher activities than control leukocytes. Our findings reveal, for the first time, that the Universal Receptive System can orchestrate fundamental properties of immune cells, including enhanced antimicrobial and anti-tumor activities. This novel approach offers a new avenue for understanding the biology and regulation of white blood cells.
Impact of selective digestive decontamination on the pangenome composition of ESBL-E. coli
Authors: Paganini Julian A. , Schürch A. C. , Scharringa Jelle , Bonten M. J. M. , Willems R. J. L. , Plantinga N. L.
Published: January 2025

In Dutch ICUs patients receive selective digestive decontamination (SDD) as a prophylactic antimicrobial treatment to prevent colonisation with potentially pathogenic microorganisms and subsequent infections, with a beneficial effect on 28-day mortality. In the R-GNOSIS ICU study, conducted outside of The Netherlands, SDD consisted of a mix of an oropharyngeal paste and a gastric suspension containing colistin, tobramycin and nystatin. These topical antimicrobial agents aim to target aerobic Gram-negative bacteria,S. aureusand yeast. SDD improves patient outcome, but its effects on the resistome and pangenome of potentially pathongenic microorganisms have not been extensively studied. In this work, we compared 129 genomes ofE. coliisolates from patients that received SDD and patients that did not receive SDD, but standard care only (baseline patients) in five ICUs located across three European countries (R-GNOSIS ICU study). We found that the overall pangenome compositions ofE. colirecovered from both patient groups were highly similar. Variations in the accessory genome were strongly associated with the phylogeny of isolates but not with the use of SDD. Similarly, the plasmidome variations were not explained by treatment, but rather by the interaction between ICU location and phylogroup. One antibiotic resistance gene, which confers resistance to tobramycin, was found to be more prevalent in SDD patients. This gene was flanked by IS26 elements and significantly co-occurred with blaCTX-M-15 in various plasmid backbones and chromosomal contexts. Notably, no mcr genes coding for colistin resistance were detected.
Occupational profile and prevalence of workplace accidents among beach workers
Authors: Cremonese Cleber , Awoniyi Adedayo Michael , dos Santos Mariela Sousa , Silva Jailma dos Santos , Nunes Thayane Silva , Dias Wiler de Paula , Rodrigues Joelma Marques , Soares Juliana Cristina dos Santos , Meyer Armando
Published: January 2025

Background

Workplace accidents (WAs) are acute, often preventable events that result in injuries or functional impairments, typically arising from occupation-related activities. In 2019, an estimated 395 million workers worldwide suffered non-fatal work-related injuries, with 330,000 fatalities, the majority occurring in low- and middle-income countries (LMICs) like Brazil. The true figures may be considerably higher due to underreporting, as many informal workers lack adequate social protection and may avoid reporting accidents for fear of jeopardizing their livelihood.

Objective

To assess the prevalence of WAs and their association with demographic and occupational determinants among beach workers in Salvador, Bahia, Brazil, between 2023 and 2024.

Methods

A cross-sectional epidemiological study was conducted with 579 urban beach workers in Salvador from November 2023 to March 2024. Following ethical approval and participants’ consent, questionnaires were administered to gather data on sociodemographic and occupational characteristics, workplace environments and processes, workplace-related injuries and illnesses, and history and characteristics of WA. WA prevalence and prevalence ratios were calculated, and associations were analyzed using a Poisson regression model with robust variance.

Results

Among the workers, 59.4% were males, 25% were aged ≤29 years and 11.4% were ≥60 years. Black and brown individuals represented 92.9% of the population. The most performed activities were street vendors (43.6%) and waiters (25%). Informal employment was reported by 72.3% of workers, 70.2% worked ≥9 hours per day, and 88% had no occupational training. The overall WA prevalence observed was 40.3%, with workers ≤29 years old having a 2.59 times higher likelihood of experiencing WA compared to those ≥60 years old. The most common WAs were punctures (42.7%), cuts (28.4%) and burns (12.1%).

Conclusions

The high prevalence of WA among beach workers, especially those ≤29 years old, may be associated with inadequate working conditions, including long working hours and lack of occupational training. These findings highlight the need for targeted interventions to improve working conditions and reduce WA risks.
Photosynthetic adjustments maintain lettuce growth under dynamically changing lighting in controlled indoor farming setups
Authors: Makinen Arttu , Ishihara Hirofumi , Poque Sylvain , Sipari Nina , Himanen Kristiina , Varjus Ilona , Heininen Juho , Pastell Matti , Elomaa Paula , Shapiguzov Alexey , Kotilainen Titta , Kangasjarvi Saijaliisa
Published: January 2025

Studies have uncovered delicate mechanisms that enable plant acclimation to fluctuating light. Translating the knowledge to controlled environment agriculture could advance the development of cost-effective dynamic lighting strategies, but the effects of varying light intensities on vegetable crops remain poorly understood. Here we recorded chlorophyll fluorescence, photosynthetic activity, metabolic responses, and growth of lettuce (Lactuca sativa L.) cv. Katusa under dynamic lighting. The light intensity was varied at different times of the photoperiod with uniform daily light integral. Three setups, including a plant phenotyping facility, a small-scale vertical farm testbed and a larger-scale vertical farm were utilized to address the physiological responses and scalability of lighting strategies. We found that dynamic lighting supported lettuce cv. Katusa growth in all three indoor cultivation setups, even under artificial split-night regimes where the photoperiod was interrupted by two periods of darkness. The lettuce plants displayed delicate adjustments in photosynthetic light reactions and carbon metabolism, the latter of which followed the cumulative daily light integral under different lighting regimes. However, the overall metabolic composition of lettuce leaves did not respond to the changing light intensities. Our findings support the conclusion that dynamic lighting enables cost-effective lighting via optimization of electricity use in indoor cultivation.
scTFBridge: A Disentangled Deep Generative Model Informed by TF-Motif Binding for Gene Regulation Inference in Single-Cell Multi-Omics
Authors: Wang Feng-ao , He Ruikun , Liu Junwei , Li Yixue
Published: January 2025

The interplay between transcription factors (TFs) and regulatory elements (REs) drives gene transcription, forming gene regulatory networks (GRNs). Advances in single-cell technologies now enable simultaneous measurement of RNA expression and chromatin accessibility, offering unprecedented opportunities for GRN inference at single-cell resolution. However, heterogeneity across omics layers complicates regulatory feature extraction. We present scTFBridge, a multi-omics deep generative model for GRN inference. scTFBridge disentangles latent spaces into shared and specific components across omics layers. By integrating TF-motif binding knowledge, scTFBridge aligns shared embeddings with specific TF regulatory activities, enhancing biological interpretability. Using explainability methods, scTFBridge computes regulatory scores for REs and TFs, enabling robust GRN inference. It consistently outperformed baseline methods in both cis- and trans-regulation inference tasks. Our results demonstrate that scTFBridge can uncover cell-type-specific susceptibility genes and distinct regulatory programs, offering new insights into gene regulation mechanisms at single-cell resolution.
A phylogenetic method identifies candidate drivers of the evolution of the SARS-CoV-2 mutation spectrum
Authors: Corbett-Detig Russ
Published: January 2025

The molecular processes that generate new mutations evolve, but the causal mechanisms are largely unknown. In particular, the relative rates of mutation types (e.g., C>T), the mutation spectrum, sometimes vary among closely related species and populations. I present an algorithm for subdividing a phylogeny into distinct mutation spectra. By applying this approach to a SARS-CoV-2 phylogeny comprising approximately eight million genome sequences, I identify 10 shifts in the mutation spectrum. I find strong enrichment consistent with candidate causal amino-acid substitutions in the SARS-CoV-2 polymerase, and strikingly three appearances of the same homoplasious substitution are each associated with decreased C>T relative mutation rates. With rapidly growing genomic datasets, this approach and future extensions promises new insights into the mechanisms of evolution of mutational processes.
Mechanism of chaperone recruitment and retention on mitochondrial precursors
Authors: Juszkiewicz Szymon , Peak-Chew Sew-Yeu , Hegde Ramanujan S.
Published: January 2025

Nearly all mitochondrial proteins are imported into mitochondria from the cytosol. How nascent mitochondrial precursors acquire and sustain import-competence in the cytosol under normal and stress conditions is incompletely understood. Here, we show that under normal conditions, the Hsc70 and Hsp90 systems interact with and redundantly minimize precursor degradation. During acute import stress, Hsp90 buffers precursor degradation, preserving proteins in an import-competent state until stress resolution. Unexpectedly, buffering by Hsp90 relies critically on a mitochondrial targeting signal (MTS), the absence of which greatly decreases precursor-Hsp90 interaction. Site-specific photo-crosslinking and biochemical reconstitution showed how the MTS directly engages co-chaperones of Hsc70 (St13 and Stip1) and Hsp90 (p23 and Cdc37) to facilitate chaperone retention on the mature domain. Thus, the MTS has a previously unappreciated role in regulating chaperone dynamics on mitochondrial precursors to buffer their degradation and maintain import competence, functions that may facilitate restoration of mitochondrial homeostasis after acute import stress.

Significance statement

Mitochondrial proteins encoded by the nuclear genome are synthesized in the cytosol before their subsequent import into mitochondria. The factors that recognize mitochondrial precursors in the cytosol to maintain their import-competence are incompletely defined.

Using a systematic site-specific photo-crosslinking strategy, the authors find that the mitochondrial targeting signal (MTS) is directly recognized by co-chaperones of Hsc70 and Hsp90. The co-chaperones facilitate recruitment, retention, and remodeling of these general chaperones on the nascent precursor protein.

Chaperone retention becomes particularly important during mitochondrial stress, when precursors must avoid degradation during a prolonged period in the cytosol.
Signal peptide-independent secretion of keratin-19 by pancreatic cancer cells
Authors: Moresco Philip , Kastan Jonathan P. , Yang Jung-in , Prabakar Rishvanth , Minicozzi Francesca , Adams Dexter W. , Cifani Paolo , Tuveson David A. , Fearon Douglas T.
Published: January 2025

The exclusion of T cells causes immune escape of pancreatic ductal adenocarcinoma (PDA). T cell exclusion is mediated by the interaction between CXCR4 on T cells and its ligand, CXCL12, which is complexed to keratin-19 (KRT19) on the surface of PDA cells. KRT19 secretion by PDA cells is essential to this process but is unusual because KRT19 lacks an endoplasmic reticulum (ER)-directing signal peptide (SP). By using biotinylation by an ER-restricted TurboID system and a split-GFP assay in PDA cells, we demonstrate that KRT19 enters the ER via its “head” domain. Additionally, KRT19 is shown to interact with the signal recognition particle and its secretion is sensitive to canonical protein secretion inhibitors. In vivo, mouse tumors formed with ER-TurboID-expressing PDA cells contain biotinylated KRT19. In contrast, keratin-8 (KRT8), which colocalizes with KRT19 on the surface of PDA cells, does not enter the ER. Rather, KRT8 is externalized via secretory autophagy possibly in a complex with KRT19. Thus, despite lacking a classical SP, PDA cells secrete KRT19 to capture CXCL12 and protect against immune attack.

Significance Statement

Pancreatic ductal adenocarcinoma (PDA) is resistant to immunotherapy because T cells are excluded from cancer cell nests. Cancer cells capture cancer associated fibroblast sourced CXCL12, which ligates T cell CXCR4, to exclude T cells from cancer cell nests. CXCL12 is captured by cancer cells via the externalization of the normally intracellular intermediate filament keratin-19 (KRT19). We studied the unconventional secretion of KRT19 and found it is secreted by signal peptide independent entry into the endoplasmic reticulum, as well as via secretory autophagy. Thus, PDA externalized immunosuppressive KRT19 through two unconventional means.
DNAHX: a novel, non-motile dynein heavy chain subfamily, identified by cryo-EM endogenously
Authors: Chai Pengxin , Loustaunau Diego Suchenski , Zheng Wan , Yang Jun , Zhang Kai(Jack)
Published: January 2025

Ciliogenesis and cilia motility rely on the coordinated actions of diverse dyneins, yet the complexity of these motor proteins in cilia has posed challenges for understanding their specific roles. Traditional evolutionary analyses often overlook key family members due to technical limitations. Here, we present a cryo-EM-based, bottom-up approach for large-scale, de novo protein identification and functional prediction of endogenous axonemal dynein complexes. This approach led to the identification of a novel dynein heavy chain subfamily (XP_041462850), designated as DNAHX, from sea urchin sperm. Phylogenetic analysis indicates that DNAHX branches from the outer-arm dynein alpha chain during evolution and is found in specific animal lineages with external fertilization. DNAHX contains multiple insertions throughout the protein, locking DNAHX permanently in a prepowerstroke state. The AAA1 site exhibits poor conservation of essential ATPase motifs, consistent with DNAHX's non-motile nature. DNAHX also forms a heterodimeric dynein complex, which we named dynein-X, with another dynein heavy chain and accessory chains. Furthermore, a subset of dynein-X displays an autoinhibited phi particle conformation, potentially facilitating the intraflagellar transport of axonemal dyneins. Our discovery of the novel, non-motile dynein heavy chain and the dynein-X complex provides valuable insights into the evolution of dyneins and potentially their diverse cellular functions.
Few-Shot Learning for Prostate Cancer Detection on MRI: Comparative Analysis with Radiologists’ Performance
Authors: Yamagishi Yosuke , Baba Yasutaka , Suzuki Jun , Okada Yoshitaka , Kanao Kent , Oyama Masafumi
Published: January 2025

Background

Deep-learning models for prostate cancer detection often require large datasets, which can be challenging to obtain and may lead to domain shift issues in various clinical settings.

Purpose

This study aimed to develop a deep-learning model for prostate cancer detection on magnetic resonance images using few-shot learning and compare its performance with radiologists.

Materials and Methods

This retrospective study used 99 cases (80 positive, 19 negative) of confirmed prostate cancer, diagnosed through needle biopsy from 2017 to 2022, with 20 cases for training, 5 for validation, and 74 for testing. The 2D transformer model was trained on T2-weighted, diffusion-weighted, and apparent diffusion coefficient map images. Model predictions were compared between the two radiologists using the Matthews correlation coefficient (MCC) and F1 score, and the bootstrap method was used to calculate 95% confidence intervals (CIs).

Results

Seventy-four patients (mean age, 71 years ± 8; 60 men) were included in the test set. The model achieved an MCC of 0.297 (95% CI: 0.095–0.474) and F1 score of 0.707 (95% CI: 0.598–0.847). Radiologist 1 had an MCC of 0.276 (95% CI: 0.054–0.484) and an F1 score of 0.741 (95% CI: 0.632–0.832), while Radiologist 2 had an MCC of 0.504 (95% CI: 0.289–0.703) and an F1 score of 0.871 (95% CI: 0.800–0.931). The performance of the model was not significantly different from that of Radiologist 1 (MCC difference: 0.021, 95% CI: −0.270–0.306; F1 score difference: −0.034, 95% CI: −0.153–0.078), but was lower than that of Radiologist 2 (F1 difference: −0.16, 95% CI: −0.287– - 0.061).

Conclusion

A deep-learning model trained on only 20 cases achieved a performance comparable to one radiologist in detecting prostate cancer on magnetic resonance images, demonstrating the potential of few-shot learning in addressing domain shift challenges.

Key Results

A deep learning model for prostate cancer detection on MRI was developed using only 20 training cases.

The model achieved performance comparable to one radiologist (MCC: 0.297 vs 0.276) but lower than another (F1: 0.707 vs 0.871).

Few-shot learning demonstrated potential for addressing domain shift challenges in medical imaging AI.

Summary Statement

Few-shot learning enables development of prostate cancer detection models on MRI with performance comparable to radiologists, using minimal training data.
BREATH-PATH – Protocol for lung cancer management in surgical patients through analysis of breath profiles
Authors: Barata Rita , Carvalheiro Catarina , Raimundo Bernardo S. , Pantarotto Marcos , Vaz Pedro D.
Published: January 2025

Background

Anatomical surgical resection is the treatment of choice for early-stage non–small cell lung cancer (NSCLC) and is a part of the multimodality treatment for resectable, locally advanced NSCLC. Local, regional and distant recurrence is the most common cause of treatment failure after resection. Multiple studies have recommended chest computed tomography (CT) for lung cancer (LC) patient’s follow-up. Even though adopting this strategy, the recurrence will only be detected months after the onset of the disease once imaging changes will only occur with a high tumor burden.

Methods

Breath analysis is a promising technology and useful addition to the currently available modalities to achieve lung cancer diagnosis and management. The volatile organic compounds (VOCs) produced as end-products of metabolism by the LC cells (and present on the exhaled breath of the patients) seem to have a unique pattern that can be used as a tool to detect lung cancer (VOC profile).

Discussion

The BREATH-PATH study aims to establish a VOC profile for all LC patients at diagnosis and understand its variations with the different implemented treatments in order to find response patterns. By understanding these patterns and identifying their deviations thereof with disease relapse supported by imaging methods we will be able to validate the breath analysis as a useful tool for LC recurrence detection.

This study intents not only to reiterate the methods’ efficacy but also to understand how high its sensitivity is in detecting a tumor recurrence, allowing breath analysis to be integrated into clinical decision algorithms.
Vestibulo-Ocular Reflex Function in Individuals with Car Sickness: A Cross-Sectional Study
Authors: Ambode Oluwaseun I. , Johnson Eric G. , Mleziva Pablo , San Lucas Summer , Daher Noha S.
Published: January 2025

Objective

To determine whether Vestibulo-ocular reflex (VOR) integrity is different between young adults with and without car sickness, To assess the effect of gender on VOR integrity in young adults with and without car sickness and To compare postural stability across different levels of physical activity in young adults with and without car sickness.

Design

Cross-sectional study

Setting

General community

Participants

Forty-six healthy young adult men and women (ages 20-40 years) with and without car sickness

Main Outcome measures

Bertec Vision Advantage (BVA) was used to assess VOR integrity, computerized dynamic posturography with immersion virtual reality(CDP-IVR) was used to assess postural stability and the International Physical Activity Questionnaire (IPAQ-SF) was used to assess physical activity.

Results

Among females, there was no significant difference in BVA outcomes between the car sickness and no car sickness groups (p>0.05, Table 2), In males, there was no significant difference in median (Inter quartile range (IQR) outcomes by study group except for DVA lines lost. Male participants in the car sickness group had more lines lost compared to males in the no car sickness group.

Conclusion

Our findings showed that male participants with car sickness appeared to have a weaker VOR compared to females. Also, we found no significant interaction between physical activity and postural stability in young adults with and without car sickness. Future studies should consider assessing postural stability in the sitting position to better replicate the functional position of driving.
Systematic druggable genome-wide Mendelian randomization identifies therapeutic target genes for chronic periodontitis
Authors: Cheng Zhongwei , Wang Fang , Ran Meimei , Liang Shenhu , Song Qinggao
Published: January 2025

Currently,the treatment of chronic periodontitis (CP) still has challenges. This study aimed to identify novel drug targets for the treatment of chronic periodontitis in the druggable genome using the Mendelian randomization (MR) method.In this study,based on the list of 4479 drug gene targets,overlapping genes were selected in blood expression Quantitative Trait Loci(eQTL), which were then subjected to Two-Sample MR(TSMR) and validated Fusion Transcriptome-Wide Association Study(TWAS) with data from the Genome-Wide Association Study(GWAS) of CP to confirm drug genes genetically associated with CP and tested for multiplicity of effects using Summary-data-based Mendelian randomization(SMR) analysis and colocalisation. Finally, Phenome-Wide association study(PheWAS) was executed on the identified drug targets.We applied SMR,TSMR,Fusion TWAS,and a series of manners of co-localisation to assess the genetic association between drugable targets and CP. In conclusion,Metalloproteinase 25(MMP25)was considered the most promising drug target,in addition to which we maintained some confidence in TNFRSF18,CDC25B,STK10 and ACVR2B.Finally,the PheWAS-MR results showed that the possible side effects of applying MMP25 inhibitors were Otitis externa as well as some metabolic disorders,among others.In summary,we identified five potential CP drug targets using TSMR,Fusion TWAS,SMR,and co-localisation a series of methods,of which MMP25 passed all the tests.Such discovery offered an academic basis for future CP drug development and reduce drug development time and economic costs to some extent.
Pregnancy-related risk and birth setting trends: Insights from Indonesian Demographic Health Survey data
Authors: Hodgkin Kai , Joshy Grace , Lokuge Kamalini
Published: January 2025

Background

Most maternal and neonatal deaths occur in low- and middle-income countries and are largely preventable with quality care. In Indonesia, 98% of pregnant people receive antenatal care and birth commonly occurs in community settings or hospitals. Outside of high-income countries, few studies identify where women with pregnancy-related risk factors give birth. Accurate identification of pregnancy risk factors and referral to an appropriate birth setting is considered an essential element of quality antenatal care, though its efficacy in Indonesia is unknown.

Methods

This study aimed to identify suitable indicators of pregnancy risk factors for Indonesia and examine population-level patterns in pregnancy-related risk, care and appropriateness of birth setting. Risk factors in pregnancy based on internationally relevant referral guidelines were identified from literature search and mapped to available indicators. Using self-reported data from three waves of the Indonesian Demographic Health Survey (2007, 2012, 2017), a representative survey of women aged 15-49 years, we examined receipt of maternity care, prevalence of pregnancy risk factors and time trends in birth setting, overall and by presence of risk factors.

Results

In the weighted sample (n=43,846), one quarter of women reported pregnancy risk factors. From 2002-2017, numbers of births in hospitals have doubled and births at home have halved. However, the proportions of women with pregnancy risk in each setting remains largely unchanged.

Discussion

These findings identify opportunities for shifting care in Indonesia to ensure women are receiving the appropriate level of care at birth.
Genetic markers of enhanced functional antibody responses to COVID-19 vaccination
Authors: Purcell Ruth A , Aurelia L Carissa , Allen Lilith F , Bond Katherine A , Williamson Deborah A , Trevillyan Janine M , Trubiano Jason A , Wines Bruce D , Hogarth P Mark , Juno Jennifer A , Wheatley Adam K , Nguyen Thi HO , Subbarao Kanta , Kedzierska Katherine , Kent Stephen J , Mahanty Siddhartha , John Selva Kevin , Chung Amy W
Published: January 2025

Introduction

Substantial population-level variation in vaccine-specific antibody responses has been observed following global coronavirus disease 2019 (COVID-19) vaccination efforts. Beyond the influence of clinical and demographic features, immunogenetic variation is suggested to underlie divergent serological responses following COVID-19 vaccination of distinct populations.

Methods

Immunoglobulin G1 (IgG1) allotypic markers (G1m) for 121 COVID-19 vaccinated healthy adults were genotyped via Sanger sequencing. Vaccine-specific IgG and Fc gamma receptor (FcγR) engagement were characterised via bead-based multiplex array.

Results

Following two COVID-19 vaccine doses, G1m1,17+/+compared to G1m-1,3+/+vaccinees had increased IgG and FcγR engagement specific for the antigenically conserved SARS-CoV-2 Spike 2 (S2) domain. IgG targeting antigenically novel SARS-CoV-2 receptor binding domain (RBD) trended higher in G1m1,17+/+vaccinees, facilitating increased RBD-specific FcγR2a-R131 and FcγR2b binding.

Conclusion

Primary COVID-19 vaccination induced increased S2-specific IgG in G1m1,17+/+vaccinees, potentially facilitating enhanced anti-viral FcγR activation. Validation in larger cohorts may inform optimisation of next-generation vaccination strategies.
Molecular characterization informs prognosis in patients with localized Ewing sarcoma: A report from the Children’s Oncology Group
Authors: Gillani Riaz , Shulman David S. , DelRocco Natalie J. , Klega Kelly , Han Ruxu , Krailo Mark D. , Slack Jonathan C. , Tanhaemami Mohammad , Ward Abigail , Bainer Victoria , Ricker Cora , Sparks Josee , Bailey Kelly M. , Reed Damon R. , DuBois Steven G. , Leavey Patrick , Mascarenhas Leo , Grohar Patrick J. , Church Alanna J. , Crompton Brian D. , Janeway Katherine A.
Published: January 2025

PURPOSE

Identification of discrete sub-groups associated with treatment response and resistance in localized Ewing sarcoma (EWS) remains a challenge. The primary objective of the Children’s Oncology Group biology study AEWS18B1-Q was to perform molecular characterization of a large cohort of patients with localized Ewing sarcoma treated on prospective trials with modern standard of care therapy.

METHODS

We analyzed clinical and molecular features from patients with localized EWS enrolled on AEWS0031, AEWS1031, or INT-0154 frontline trials. All patients had available FFPE tissue, frozen tissue, or whole-genome amplified material. Sequencing was performed for identification of canonical fusions, recurrent copy number alterations (CNAs), and alterations inTP53andSTAG2. Where available, tissue was analyzed for loss of STAG2 protein expression. Molecular features were evaluated for their association with cumulative incidence of relapse in univariate and multivariable analyses.

RESULTS

Three hundred and fifty-one cases had sufficient tissue, which in most cases was extracted from two FFPE slides. EWS canonical fusions were identified in 282 cases (80.3%). Pathogenic mutations inTP53andSTAG2were identified in 5.1% and 7.6% of cases, respectively and 63.1% of cases were found to have recurrent CNAs. In univariate analysis, there was an increased cumulative incidence of relapse in patients withTP53mutation (5-year cumulative incidence of relapse 43%, CI [17%, 67%] vs. 22%, CI [17%, 27%]; Gray’s testP= 0.039),STAG2mutation (53%, CI [29%, 73%] vs. 21%, CI [16%, 26%];P< 0.001), and recurrent CNAs (30%, CI [22%, 37%] vs. 16%, CI [9%, 24%];P= 0.005). In a multivariable analysis,STAG2mutation was the only molecular biomarker that remained prognostic.

CONCLUSION

This is a prospective validation of the molecular prognostic features of localized EWS receiving standard of care therapy on therapeutic clinical trials. Building on prior work, patients withSTAG2mutations were at high risk of relapse.

CONTEXT

Key Objective

To determine if molecular features can identify clinically relevant disease sub-groups applicable to frontline clinical trial design among patients with localized Ewing sarcoma.

Knowledge Generated

Among 351 patients with localized Ewing sarcoma treated on prospective trials, canonical fusions were identified in 80% of cases. In a multivariable analysis of patients with genomically defined Ewing sarcoma, the presence ofSTAG2mutations identified a high-risk population.

Relevance (added by Associate Editor)
A cholinergic spinal pathway for the adaptive control of breathing
Authors: Lin Minshan , Calabrese Giulia Benedetta , Incognito Anthony V. , Moore Matthew T. , Agarwal Aambar , Wilson Richard J.A. , Zagoraiou Laskaro , Sharples Simon A. , Miles Gareth B. , Philippidou Polyxeni
Published: January 2025

The ability to amplify motor neuron (MN) output is essential for generating high intensity motor actions. This is critical for breathing that must be rapidly adjusted to accommodate changing metabolic demands. While brainstem circuits generate the breathing rhythm, the pathways that directly augment respiratory MN output are not well understood. Here, we mapped first-order inputs to phrenic motor neurons (PMNs), a key respiratory MN population that initiates diaphragm contraction to drive breathing. We identified a predominant spinal input from a distinct subset of genetically-defined V0Ccholinergic interneurons. We found that these interneurons receive phasic excitation from brainstem respiratory centers, augment phrenic output through M2 muscarinic receptors, and are highly activated under a hypercapnia challenge. Specifically silencing cholinergic interneuron neurotransmission impairs the breathing response to hypercapnia. Collectively, our findings identify a novel spinal pathway that amplifies breathing, presenting a potential target for promoting recovery of breathing following spinal cord injury.
Multi-Region Brain Organoid –Fusion Organoid with Cerebral, Endothelial and Mid-Hindbrain Components
Authors: Kshirsagar Anannya , Mnatsakanyan Hayk , Kulkarni Sai , Guo John , Cheng Kai , Bohra Oce , Sagar Ram , Mahairaki Vasiliki , Badr Christian E , Kathuria Annie
Published: January 2025

Brain organoid technology has revolutionized our ability to model human neurodevelopment in vitro. However, current techniques remain limited by their reliance on simplified endothelial cell populations rather than a complete endothelial system. We engineered Multi-Region Brain Organoids (MRBOs) that integrate cerebral, mid/hindbrain, and complex endothelial organoids into one structure. Different from the earlier approaches based on isolated HUVECs, our endothelial organoids contain diverse vascular cell types, including vascular progenitors, mature endothelial cells, pericytes, proliferating angiogenic cells and stromal cells. Our strategy employs a sequential modulation of key developmental pathways to generate individual organoids, followed by optimized fusion conditions that maintain regional identities while supporting cellular integration. Single-nucleus RNA sequencing shows that MRBOs develop discrete neural populations specific to each brain region alongside specialized endothelial populations that establish paracrine signalling networks. Integration analysis with human fetal brain data shows that MRBOs contribute to 80% of cellular clusters found in human fetal brain tissue (Carnegie stages 12-16), whereas CellChat analysis identifies 13 previously uncharacterized endothelial-neural signalling interactions. Notably, we uncover endothelial-derived factors that support the persistence of intermediate progenitor populations during hindbrain development, but not during the cerebral one thereby revealing a new role for complex endothelial populations in regional brain patterning. This platform enables matching multiple developmental regions, fully incorporating the endothelial nature at the same time providing opportunities for studying neurodevelopmental disorders in which neural-endothelial interactions are disrupted. Our engineered MRBO system establishes a foundation for investigating complex neurodevelopmental processes, providing an enabling context closer to physiological relevance.
AI-driven discovery of host thioredoxin as a CRISPR enhancer of phage-encoded miniature Cas12 hacker nuclease
Authors: Wang Zhipeng , Wang Yujue , Gao Hui , Dai Jiani , Tang Na , Wang Yannan , Ji Quanjiang
Published: January 2025

The evolutionary arms race between bacteriophages and their bacterial hosts has driven the evolution of sophisticated adaptive immune systems, such as CRISPR-Cas, as a crucial defense mechanism. While bacteriophages have developed various anti-CRISPR strategies to counteract these immune systems, the role of bacterial host factors in enhancing CRISPR-Cas functions has been relatively unexplored. In this study, we employ an artificial intelligence (AI)-driven approach to systematically analyze potential interactions betweenEscherichia coli(E. coli) proteins and fifteen previously uncharacterized Cas12 proteins, generating 65,715 predicted binary complex structures. Our findings reveal a previously unknown dimension of CRISPR immunity, demonstrating that the host’s ubiquitous redox enzyme, thioredoxin (TrxA), significantly enhances the DNA cleavage efficiency of a phage-encoded, miniature Cas12 nuclease (termed ‘Cas12 hacker’). This synergistic relationship represents a strategic inversion, where a bacteriophage hijacks a host protein to reinforce its own genome degradation machinery, possibly targeting rival nucleic acids. Through comprehensive biochemical characterizations, structural analyses of the Cas12 hacker-TrxA-sgRNA-dsDNA quaternary complex, andin vivobacterial defense assays, we uncover an intricate association in which thioredoxin binds to and activates the Cas12 hacker nuclease, intensifying its DNA cleavage capacity and bolstering CRISPR immunity. Our findings expand the understanding of the molecular interactions underlying host-phage conflicts and highlight the potential for harnessing endogenous host factors to enhance the capabilities of CRISPR-based genetic engineering tools.
Evasion of serum antibodies and complement bySalmonellaTyphi and Paratyphi A
Authors: Guerra Fermin E. , Karlinsey Joyce E. , Libby Stephen J. , Fang Ferric C.
Published: January 2025

Nontyphoidal and enteric fever serovars ofSalmonella entericadisplay distinctive interactions with serum antibodies and the complement system, which initiate the host immune response to invading microbes. This study examines the contributions of lipopolysaccharide O-antigen and theS.Typhi Vi polysaccharide capsule to serum resistance, complement activation and deposition, and immunoglobulin (Ig) binding in nontyphoidalS. entericaserovar Typhimurium and the enteric fever serovarsS.Typhi andS.Paratyphi A. Although all three serovars are resistant to serum killing,S.Typhi andS.Paratyphi A exhibit lower levels of Ig binding, complement binding and complement activation compared toS.Typhimurium. InS.Typhimurium, WzzB-dependent long O-antigen production and FepE-dependent very long O-antigen production are required for serum resistance but do not prevent IgM binding or complement deposition.S.Typhi lacks very long O-antigen, but its production of Vi capsule inhibits IgM binding and complement deposition, while acting in concert with long O-antigen to resist serum killing. InS.Paratyphi A, long O-antigen production is deficient due to a hypofunctional WzzB protein, but this is compensated by greater quantities of very long O-antigen, which are required for serum resistance. Restoration of WzzB function by exchange with theS.Typhimurium orS.TyphiwzzBalleles can restore long O-antigen production inS.Paratyphi A but decreases very long O-antigen production, resulting in increased IgM binding. Replacement of theS.Paratyphi A O2-type polysaccharide with theS.Typhi O9 polysaccharide further increases IgM binding ofS.Paratyphi A, which enhances complement activation but not complement deposition. Lastly, a gene duplication ofrfbVinS.Paratyphi A is necessary for higher levels of very long O-antigen and resistance to complement deposition and antibody binding. Collectively, these observations demonstrate fundamental differences between nontyphoidal and enteric feverSalmonellaserovars in their interactions with innate immune effectors.

Author Summary

Enteric fever acquired by ingestion of food or water contaminated withSalmonellaTyphi or Paratyphi A is a significant cause of morbidity and mortality in low- and middle-income countries. In this study, we dissect the different mechanisms by which these bacteria avoid binding by serum proteins that are required for the initiation of protective immune responses. This is in contrast to the nontyphoidal serovarSalmonellaTyphimurium, a common cause of gastroenteritis, which does not avoid complement activation nor antibody binding but instead exploits host inflammation. Our observations provide new insights into the mechanisms responsible for the distinctive immunological features of human enteric fever and can inform the development ofSalmonellavaccines that target theSalmonellacell envelope.
The interplay between CB2and NMDA receptors in Parkinson’s disease
Authors: Lillo Jaume , Raïch Iu , Rebassa Joan Biel , Capó Toni , Badia Pau , Navarro Gemma , Reyes-Resina Irene
Published: January 2025

Parkinson’s disease (PD) is a progressive neurological disorder that affects movement, causing symptoms such as tremors, stiffness, slowness, and balance problems due to the degeneration of dopamine-producing neurons in the brain. Nowadays there is no cure for PD. Alpha synuclein (α-syn) aggregates, which are a hallmark of PD, are known to induce microglial activation, specifically the detrimental M1 microglial phenotype, which contributes to neuroinflammation and disease progression. Cannabinoid receptor 2 (CB2R) activation has been shown to counteract neuroinflammation. CB2R is able to interact with NMDA receptors (NMDAR), which has also attracted attention in PD research due to its role in excitotoxicity. Here we aimed to study the interaction between CB2R and NMDAR in a PD context. We observed that α-syn fibrils alter CB2R activation and CB2R-NMDAR heteromerization in a heterologous expression system. Furthermore, activation of CB2R counteracted NMDAR signaling. In neurons α-syn fibrils decreased CB2R-NMDAR heteromer expression, while increasing CB2R signaling. Importantly, CB2R activation counteracted the α-syn fibrils-induced increase in M1 activated microglia, while it favored the polarization of microglia to the beneficial M2 phenotype. These results reinforce the idea of using cannabinoids for treating PD, as they provide not only the anti-inflammatory effects of cannabinoids but also counteract the detrimental increase in NMDAR signaling present in this disease.
Characterisation of a touchscreen-based Go/No Go task for assessing cognitive judgement bias in mice: a new translational tool for affective state disorder drug screening
Authors: Lopez-Cruz L , Phillips BU , Saksida LM , Heath CJ , Bussey TJ
Published: January 2025

A major obstacle in the pre-clinical study of mood-related disorders and novel affective state therapeutic evaluation is the lack of animal models that fully recapitulate human symptomatology.

In this study, we developed a touchscreen-based Go/No Go cognitive judgement bias (CJB) task for mice. In this task, animals first learned to discriminate between two visual stimuli displayed on the touchscreen: one associated with a reward (S+) and one associated with a time-out and flashing house light (S−). Once mice learned to respond to the S+ and to withhold responding to the S− consistently, a set of four ambiguous stimuli ranging in visual similarity to the S+ and S− stimuli were randomly interspersed in the stimulus presentation sequence. Responses to these ambiguous stimuli were interpreted as a greater expectation of positive (‘optimistic bias’) or negative (‘pessimistic bias’) outcomes as a function of their similarity to the S+ or S− stimuli.

The acute administration of the SSRIs fluoxetine and citalopram and the 5HT-2C receptor antagonist SB204048 did not produce any effects on CJB task performance. However, the noradrenaline/dopamine reuptake inhibitor, bupropion, increased responses to the ambiguous stimuli consistent with induction of an ‘optimistic bias’ and the pro-depressant tetrabenazine yielded the opposite effect.

This study underscores the capacity of mice to respond to visually ambiguous stimuli in an ambiguity-dependent manner, a phenomenon observed across various species, including humans. Furthermore, it establishes and validates an operant behavioural task to assess CJB in mice delivered using the touchscreen platform which has significant intrinsic cross-species translational potential.