bluuebunny/crossref_metadata_2025_split huggingface dataset:
Brain morphometry and psychomotor development in children with PCH2A
Authors: Pretzel Pablo , Herrmann Antonia , Kuhn Alice , Klauser Anna-Lena , Matilainen Julia , Kellner Elias , Hackenberg Maren , Mayer Simone , Laugwitz Lucia , Uhl Markus , Groeschel Samuel , Janzarik Wibke 
Published: December 2024

AbstractIntroductionPontocerebellar hypoplasia type 2A (PCH2A) is a rare neurogenetic disease causing severe cognitive and motor impairment. We report on brain morphometry and psychomotor development of affected children.Materials and MethodsWe analyzed 78 cerebral MRI datasets of 57 patients with genetically proven PCH2A. Volumetry and in-plane measurements were performed in cerebellum, neocortex and pons. Supratentorial width and width of the anterior horns of the lateral ventricles was used to calculate the Evans index.Caregivers of 65 patients with PCH2A (7 months to 33 years) filled in a survey assessing motor and cognitive development. Developmental status was compared to MRI measurements.ResultsIn children with PCH2A, cerebellar volume was markedly smaller than in healthy children at birth, with slower increase and stagnation at around 12 months. No cerebellar growth was observed in the cranio-caudal axis. Long-term data did not show a decrease in cerebellar volume or in-plane measurements. Supratentorial measurements showed progressive microcephaly and a continuous increase of the Evans index, indicating progressive cerebral atrophy. Patients showed severely impaired cognitive and motor development. Developmental regression was reported only for a minority. No statistical relationship between brain measurements and cognitive or motor development was observed.ConclusionMRI of patients with PCH2A shows limited cerebellar growth during infancy, especially restricted along the cranio-caudal axis. After infancy, cerebellar volume remains relatively stable. Supratentorial measurements indicate slowly progressive atrophy. Psychomotor development is severely impaired, but regression is rare.Highlights-MRI (57 patients) and developmental data (65 patients) of children with PCH2A-Cerebellar growth is affected in a spatial manner, resulting in the dragonfly sign-Ongoing supratentorial atrophy, potentially secondary to cerebellar pathology-Psychomotor development is delayed, but takes place and regression is rare-No relation between brain measurements and developmental trajectories
Mammalian heat shock protein A4 family orthologHsc70Cbis required for two phases of spermatogenesis inD. melanogaster
Authors: Houston Brendan J. , Nguyen Joseph , Burke Richard , Alves Andre N. , Hime Gary , O’Bryan Moira K. 
Published: December 2024

AbstractHeat shock proteins play essential roles as molecular chaperones, enacting protein folding and preventing of protein aggregation. In a previous study, a predicted damaging homozygous non-synonymous genetic variant was detected in the heat shock protein geneHSPA4L. Here, we used RNA interference inDrosophila melanogasterto explore the role of the heat shock protein A member 4 family (HSPA4) family in male fertility. Expression of the fly orthologue of the mammalianHSPA4andHSPA4Lgenes,Hsc70Cb, was ablated in the male germline using two RNAi lines and the Nanos-Gal4 driver. Strong knockdown ofHsc70Cbin male germ cells resulted in male sterility, characterised by the absence of germ cells in testes and the over-proliferation of the testis soma. A less robust knockdown ofHsc70Cbin the male germline resulted in a sperm individualisation defect and a failure of sperm release into the seminal vesicle (analogous to the epididymis). When humanHSPA4orHSPA4LcDNA was introduced into infertileHsc70Cbmutant flies, a partial rescue was observed, whereby in the robustHsc70Cbknockdown setting germ cells progressed to the spermatocyte stage before undergoing cell death. Collectively, the absence of sperm in theHsc70Cb(line 1) is consistent with the infertile man harbouring a homozygousHSPA4Lgenetic variant, supporting the hypothesis thatHSPA4Lis required for male fertility in humans and flies and highlighting the utility of the fly as a model of human spermatogenesis.In briefHsc70Cbis essential for spermatogonia survival and sperm individualisation inDrosophila. This study highlights the conserved roles of the HSPA4 family across animals and the utility of flies as a model organism for male fertility research.
Divergent regulatory element programs steer sex-specific supporting cell differentiation along mouse gonadal development
Authors: Stévant Isabelle , Abberbock Elisheva , Ridnik Meshi , Weiss Roni , Swisa Linoy , Futtner Christopher R , Maatouk Danielle , Lovell-Badge Robin , Malysheva Valeriya , Gonen Nitzan 
Published: December 2024

AbstractGonadal sex determination relies on tipping a delicate balance involving the activation and repression of several transcription factors and signalling pathways. This is likely mediated by numerous non-coding regulatory elements that shape sex-specific transcriptomic programs. To explore the dynamics of these in detail, we performed paired time-series of transcriptomic and chromatin accessibility assays on pre-granulosa and Sertoli cells throughout their development in the embryo, making use of new and existing mouse reporter lines. Regulatory elements were associated with their putative target genes by linkage analysis, and this was complemented and verified experimentally using promoter capture Hi-C. We identified the transcription factor motifs enriched in these regulatory elements along with their occupancy, pinpointing LHX9/EMX2 as potentially critical regulators of ovarian development. Variations in the DNA sequence of these regulatory elements are likely to be responsible for many of the unexplained cases of individuals with Differences of Sex Development.TeaserMultiomics analysis revealed the regulatory elements and transcription factors responsible for gonadal sex determination.
Development of intimin-enriched outer membrane vesicles (OMVs) as a vaccine to control intestinal carriage of EnterohemorrhagicEscherichia coli
Authors: Garling Asja , Goursat Cécile , Seguy Carine , Martin Patricia , Goman Audrey , Nougayrède Jean-Philippe , Oswald Éric , Auvray Frédéric , Branchu Priscilla 
Published: December 2024

EnterohemorrhagicEscherichia coli(EHEC) are foodborne pathogens causing severe human infections including hemorrhagic colitis and hemolytic uremic syndrome (HUS), particularly in children. Ruminants are the main reservoir of EHEC which colonize their intestinal tract through a mechanism involving the bacterial outer membrane adhesin intimin. Vaccination of cattle has shown efficacy in reducing EHEC O157:H7 shedding in feces. However, most of these vaccines are based on purified proteins and/or require the addition of adjuvants, resulting in expensive vaccines that are not used by breeders. This study introduces the development of a new type of vaccine based on Outer Membrane Vesicles (OMVs) carrying the C-terminal domain of intimin (Int280). A vaccine which combines OMVs carrying luminal Int280 and OMVs displaying surface-exposed Int280 was produced using two addressing systems based on PelB peptide signal and Lpp-OmpA hybrid protein, respectively. This mixed vaccine was tested in a mouse model as a proof of concept using the murine host-specific intestinal pathogenCitrobacter rodentiumwhich shares a similar intimin-based adhesion mechanism with EHEC. Vaccination of mice with OMV-Int280 elicited a strong anti-intimin IgG response. Interestingly, we observed a shortenedC. rodentiumfecal shedding duration in immunized mice compared to the control group. This OMVs-intimin vaccine therefore represents a promising candidate for the control of EHEC intestinal carriage and fecal shedding in ruminants.IMPORTANCEEnterohemorrhagicEscherichia coli(EHEC) are foodborne pathogenic bacteria causing intestinal infection that may lead to hemorrhagic colitis and hemolytic uremic syndrome (HUS) particularly in young children. There is no effective treatment, and antibiotics are contraindicated because they promote the development of HUS. Vaccination of ruminants, the main reservoir of EHEC, has been proposed as an important strategy to reduce the fecal shedding of EHEC to reduce transmission to humans. Outer Membrane Vesicles (OMVs) derived fromE. coliare a highly attractive vaccine platform. Here, we produced OMVs enriched with the C-terminal part of the intimin (Int280). As a proof of concept, we used a mice model ofCitrobacter rodentiumcolonization as a surrogate for EHEC intestinal colonization. Vaccination elicited antibodies against intimin and decreased the duration of fecal shedding ofC. rodentium. Therefore, this OMV-Int280 vaccine is a promising candidate to control EHEC intestinal carriage and fecal shedding in ruminants.
Intestinal fibroblast heterogeneity: unifying RNA-seq studies and introducing consensus-driven nomenclature
Authors: Glisovic Neda , Chikina Aleksandra , Robil Noémie , Lameiras Sonia , Vignjevic Danijela Matic 
Published: December 2024

AbstractAbstract FigureGraphical abstractIn the colon, single-layered epithelium lines the crypts, which descend into the underlying mucosa. Colonic crypts are surrounded by a network of fibroblasts essential for various functions, including the production and remodeling of the extracellular matrix (ECM), supporting the epithelial stem cell niche, and promoting the differentiation of epithelial cells. Recent studies indicate that fibroblasts are not a homogeneous cell population. However, differences in nomenclature and a lack of exact markers hindered their classification and functional understanding. Here, we used single-cell RNA-sequencing (scRNA-seq) to identify six distinct fibroblast subpopulations in mouse colonic mucosa, each with unique molecular signatures and functional specialization. Our analysis reveals that some fibroblasts are primarily involved in ECM production and remodeling, while others exhibit high contractility. Additionally, a subset of fibroblasts produces cytokines that promote epithelial cell differentiation, whereas another group secrete cytokines essential for maintaining the epithelial stem cell niche. We also map the spatial distribution of these fibroblast subpopulations within the colonic mucosa. Differentiation trajectory analysis suggests distinct pathways for fibroblast differentiation, while cell cycle scoring reveals that fibroblasts do not proliferate under homeostatic conditions. Furthermore, we integrated our scRNA-seq data with previously published datasets to identify common fibroblast populations and propose a standardized nomenclature for intestinal fibroblasts. This unified framework aims to improve communication within the research community and enhance understanding of fibroblast roles in gut homeostasis and gastrointestinal diseases.
The kinesin KIF3AC recycles endocytosed integrin to polarize adhesion formation towards the leading edge
Authors: Rockenbach Johnny A. Z. , Nader Guilherme P. F. , Antoku Susumu , Gundersen Gregg G. 
Published: December 2024

AbstractThe recycling of integrin endocytosed during focal adhesion (FA) disassembly is critical for cell migration and contributes to the polarized formation of new FAs toward the leading edge. How this occurs is unclear. Here, we sought to identify the kinesin motor protein(s) that is involved in recycling endocytosed integrin back to the plasma membrane. We show that the kinesin-2 heterodimer, KIF3AC and the Rab11 adaptor protein RCP are required for FA reformation after the disassembly of FAs in mouse and human fibroblasts. In the absence of KIF3AC, integrin does not return to the cell surface after FA disassembly and is found in the Rab11 endocytic recycling compartment. Biochemical pulldowns revealed that KIF3C associated with β1 integrin in an RCP dependent fashion, but only after FA disassembly. KIF3AC knockdown inhibited cell migration, trafficking of RCP toward the leading edge, and polarized formation of FAs at the leading edge. These results show that KIF3AC promotes cell migration by recycling integrin so that it generates new FAs in a polarized fashion.SummaryThe study reveals that the heterodimeric kinesin-2 motor KIF3AC and its adaptor RCP are crucial for polarized formation of focal adhesions at the front of migrating fibroblasts. KIF3AC and RCP associate with intracellularly recycling integrin to promote its return to the cell surface after its endocytosis from disassembled focal adhesions.
Programmed death ligand-1 and Programmed cell death protein-1 expression across the anal disease continuum and association with improved survival in anal cancer
Authors: Chowdhury S. , Gasper C. , Lazar A. A. , Allaire K. , Darragh T. M. , Fong L. , Palefsky J. M. 
Published: December 2024

AbstractHigh-risk human papillomavirus is associated with anal high-grade intraepithelial lesion (aHSIL) and anal squamous cell carcinoma (aSCC). The prognostic significance of PD-L1 expression in aSCC and its impact on overall survival (OS) is controversial. ASCC can evade immune surveillance by co-opting the PD-L1/PD-1 immune checkpoint pathway, enhancing tumorigenesis. To assess the potential role of the PD-L1/PD-1 axis on tumor progression, we assessed PD-L1 and PD-1 expression on epithelial cells (ECs) and immune cells (ICs) by immunohistochemistry in benign anal tissue (n=22), aHSIL (n=22), and aSCC (n=52) from HIV-negative participants and people living with HIV. PD-L1 expression on EC was restricted to tumor cells with no expression in benign and HSIL tissues. PD-1 expression on ICs increased along the disease continuum from benign to SCC. The combined PD-L1 expression score on ECs and ICs showed a substantial increase from benign to aHSIL to aSCC. The combined positive score (CPS) for aSCC was 8.2. PD-L1 expression on IC in aSCC was more prominent than in tumor cells which correlated with increased IC infiltration and interferon-gamma secretion. 92% of aSCC demonstrated an adaptive PD-L1 expression pattern. HIV status did not affect PD-L1/PD-1 expression in benign, aHSIL or aSCC. PD-L1 expression in treatment naïve aSCC was associated with improved OS. Those with CPS of 0 had a higher risk of death [Hazard ratio 15.2 (95% CI: 3.3-69, p=0.0004; log-rank p<0.0001)] compared to those with CPS > 0. CPS may indicate the presence of immune activation and serve as a potential prognostic marker.SignificancePD-L1 expression becomes more prominent as HPV-infected anal epithelial tissues progress from pre-cancer to cancer. ASCCs with high PD-L1/PD-1 expression indicates a reactive tumor microenvironment, making them promising candidates for immunotherapy.
Utilizing Deep Learning to Improve Diagnostic Accuracy in Glioma, Pituitary Tumors, and Meningiomas
Authors: Gorenshtein Alon , Liba Tom , Goren Avner 
Published: December 2024

AbstractBackgroundGlioma, pituitary tumors, and meningiomas constitute the major types of primary brain tumors. The challenge in achieving a definitive diagnosis stems from the brain’s complex structure, limited accessibility for precise imaging, and the resemblance between different types of tumors. An alternative and promising solution is the application of artificial intelligence (AI), specifically through deep learning models.MethodsThis study developed a brain tumor detection model using a comprehensive dataset of 7,023 MRI images. Included 1,621 images for glioma, 1,645 for meningioma, 1,757 for pituitary tumors, and 2,000 for non-tumor magnetic resonance imaging (MRI) images. We employed deep learning, specifically convolutional neural network (CNN). We utilized the ResNet-18 architecture, a widely used pre-trained model. We fine-tuned the pre-trained ResNet-18 on our dataset, which included MRI images classified into glioma, pituitary, and meningioma tumors. The fine-tuning was conducted over 10 epochs. After fine-tuning, the model that demonstrated the highest performance on validation data was selected as the best modelResultsThe deep learning model demonstrated exceptional performance across all diagnostic categories, with the training accuracy stabilizing at nearly 100% and validation accuracy closely mirroring this trend. The model achieved an AUC of 1.00 across all categories, with sensitivities of 95% for glioma, 98% for meningoma, 99% for pituitary tumors, and 100% for non-tumor MRI images.ConclusionOur study utilized a fine-tuned Residual Network 18 layers (ResNet-18) model in PyTorch to significantly enhance the diagnostic accuracy of primary brain tumors, specifically gliomas, meningiomas, and pituitary tumors. The model demonstrated high accuracy, indicating its potential to improve early diagnosis and patient outcomes. These findings suggest that integrating AI models like ResNet-18 into clinical workflows could lead to earlier detection and more precise prognostic evaluations, ultimately enhancing patient care and survival rates.
The role of the components of PM2.5in the incidence of Alzheimer’s disease and related disorders
Authors: Zhang Haisu , Wang Yifan , Li Haomin , Zhu Qiao , Ma Tszshan , Liu Yang , Steenland Kyle 
Published: December 2024

AbstractBackgroundThe associations of PM2.5mass and various adverse health outcomes have been widely investigated. However, fewer studies focused on the potential health impacts of PM2.5components, especially for dementia and Alzheimer’s diseases (AD).MethodsWe constructed a nationwide population-based open cohort study among Medicare beneficiaries aged 65 or older during 2000-2018. This dataset was linked with the predicted levels of 15 PM2.5components, including 5 major mass contributors (EC, OC, NH4+, NO3-, SO42-) and 10 trace elements (Br, Ca, Cu, Fe, K, Ni, Pb, Si, V, Zn) across contiguous US territory. Data were aggregated by ZIP code, calendar year and individual level demographics. Two mixture analysis methods, weighted quantile sum regression (WQS) and quantile g-computation (qgcomp), were used with quasi-Poisson models to analyze the health effects of the total mixture of PM2.5components on dementia and AD, as well as the relative contribution of individual components.ResultsExposure to PM2.5components over the previous 5 years was significantly associated with increased risks of both dementia and AD, with stronger associations observed for AD. SO42-, OC, Cu were identified with large contributions to the combined positive association of the mixture from both WQS and qgcomp models.ConclusionWe found positive associations between the 15 PM2.5components and the incidence of dementia and AD. Our findings suggest that reducing PM2.5emissions from traffic and fossil fuel combustion could help mitigate the growing burden of dementia and Alzheimer’s disease.
Multidisciplinary stepwise treatments for lumbar disc herniation: a retrospective study
Authors: Zeng Shaoting , Weng Yan , Ye Ling 
Published: December 2024

AbstractObjectiveThe study was aimed to compare the efficacy of the treatment for lumbar disc herniation (LDH) in the pain management department, orthopedics department and rehabilitation department, and to explore the multidisciplinary stepwise treatments style.MethodsThis single-center retrospective study analyzed the clinical data from 1397 patients with LDH between June 2015 and July 2019 in the hospital. The patients were divided into three groups: Pain Management Department (P), Orthopedics Department (O), and Rehabilitation Department (R). Propensity score matching (PSM) was used to adjust for imbalanced confounding variables among the three groups. Patients’ general information, different style of treatments, visual analogue scale (VAS), duration of hospitalization, and hospitalization costs were recorded. Follow-up information of patients was obtained through the telephone, including: Oswestry dysfunction index (ODI), remission rate at discharge, the rate of three months revisit after the discharge. The independent student’s t test and chi-square test were applied to compare the differences among groups.ResultsAfter PSM, 144 patients from each group were included in the study and all covariates were well balanced among the three groups. In the matched patients, the order of remission rate at discharge was O>P>R(P<0.05), the rate of three months revisit after discharge was R (17.36%)> P (6.94%)>R (4.86%) (P <0.05). There was no significant difference in ODI index at discharge and follow-up between group O and group P(P> 0.05), while group R was higher than the other two groups (P <0.05). Patients in Group R had a longer length of hospital stay (P <0.05), while the hospitalization costs were ranked as O>P>R (P <0.05).ConclusionsIn the treatment of LDH, orthopedics department, pain management department and rehabilitation department could all achieve the relief of clinical symptoms, and the long-term efficacy was not stable. Patients presenting to the orthopedic department had the highest pain relief rate at discharge, low rate of the revisit at three months after discharge, followed by the pain management department and third by the rehabilitation department. We proposed that the treatment of LDH should be based on stepwise treatment and multidisciplinary treatment (MDT) model.
Comparative Effectiveness of Rituximab and Cladribine in Relapsing-Remitting Multiple Sclerosis: A Target Trial Emulation
Authors: Rød Brit Ellen , Høgestøl Einar A. , Torkildsen Øivind , Bjørnevik Kjetil , Gran Jon Michael , Øverås Mathias H. , König Marton , Celius Elisabeth G. , Myhr Kjell-Morten , Wergeland Stig , Nygaard Gro O. 
Published: December 2024

BackgroundHead-to-head comparisons of high-efficacy therapies for relapsing-remitting multiple sclerosis (RRMS) are lacking. We emulated a target trial to compare the long-term effectiveness of rituximab and cladribine.MethodsWe estimated the effect of initiating treatment with rituximab or cladribine by emulating a target trial using data from the Norwegian MS Registry and Biobank at two university hospitals with different treatment strategies. Cumulative incidence and risk differences after 4 years were estimated using a weighted Kaplan-Meier estimator, adjusted for baseline covariates. The primary outcome was MRI disease activity, with the secondary outcomes including relapses and safety.ResultsThe study included 285 patients, 159 receiving rituximab and 126 receiving cladribine, with a median follow-up of 4.5 years (IQR 4.0 to 5.0). Rituximab-treated patients had a lower risk of new MRI disease activity compared to cladribine-treated patients (p< 0.0001). The 4-year risk was 18% (95% CI 11 to 23) for the rituximab-treated patients and 57% (95% CI 48 to 65) for cladribine-treated patients, yielding a risk difference (RD) of 38 percentage-points (95% CI 29 to 51). The 4-year RD for relapse was 11.2 percentage-points (95% CI 3 to 18) and the RD for discontinuation or a third dose of cladribine was 13.7 percentage-points (95% CI 9 to 25). The incidence of hospitalizations related to potential adverse events was 6.0 per 100 person-years for rituximab and 4.1 per 100 person-years for cladribine.ConclusionsThese findings suggest that rituximab has superior effectiveness compared to cladribine during a median follow-up of 4.5 years.