bluuebunny/crossref_metadata_2025 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

Introduction

Pontocerebellar 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 Methods

We 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.

Results

In 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.

Conclusion

MRI 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

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MRI (57 patients) and developmental data (65 patients) of children with PCH2A

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Cerebellar growth is affected in a spatial manner, resulting in the dragonfly sign

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Ongoing supratentorial atrophy, potentially secondary to cerebellar pathology

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Psychomotor development is delayed, but takes place and regression is rare

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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

Heat 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 brief

Hsc70Cbis 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.
Benchmarking deep learning methods for biologically conserved single-cell integration
Authors: Yi Chenxin , Cheng Jinyu , Liu Wanquan , Liu Junwei , Li Yixue
Published: December 2024

Advancements in single-cell RNA sequencing (scRNA-seq) have enabled the analysis of millions of cells, but integrating such data across samples and methods while mitigating batch effects remains challenging. Deep learning approaches address this by learning biologically conserved gene expression representations, yet systematic benchmarking of loss functions and integration performance is lacking. This study evaluated 16 integration methods using a unified variational autoencoder framework, incorporating batch and cell-type information. Results revealed limitations in the single-cell integration benchmarking index (scIB) for preserving intra-cell-type information. To address this, we introduced a correlation-based loss function and enhanced benchmarking metrics to better capture biological conservation. Using annotations from the Human Lung Cell Atlas and Human Fetal Lung Cell Atlas, our approach improved biological signal preservation. This work highlights the need for biologically informed metrics in scRNA-seq integration and offers guidance for future deep learning developments.
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

Gonadal 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.

Teaser

Multiomics 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.

IMPORTANCE

EnterohemorrhagicEscherichia 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

Abstract Figure

Graphical abstract

In 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

The 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.

The 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

High-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.

Significance

PD-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

Background

Glioma, 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.

Methods

This 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 model

Results

The 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.

Conclusion

Our 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

Background

The 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).

Methods

We 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.

Results

Exposure 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.

Conclusion

We 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

Abstract

Objective

The 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.

Methods

This 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.

Results

After 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).

Conclusions

In 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

Background

Head-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.

Methods

We 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.

Results

The 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.

Conclusions

These findings suggest that rituximab has superior effectiveness compared to cladribine during a median follow-up of 4.5 years.
Reimagining the serocatalytic model for infectious diseases: a case study of common coronaviruses
Authors: Larsen Sophie L. , Yang Junke , Lv Huibin , Huan Yang Wei , Teo Qiwen , Pholcharee Tossapol , Lei Ruipeng , Gopal Akshita B , Shao Evan K. , Talmage Logan , Mok Chris K. P. , Takahashi Saki , Kraay Alicia N. M. , Wu Nicholas C. , Martinez Pamela P.
Published: December 2024

Despite the increased availability of serological data, understanding serodynamics remains challenging. Serocatalytic models, which describe the rate of seroconversion (gain of antibodies) and serore-version (loss of antibodies) within a population, have traditionally been fit to cross-sectional serological data to capture long-term transmission dynamics. However, a key limitation is their binary assumption on serological status, ignoring heterogeneity in optical density levels, antibody titers, and/or exposure history. Here, we implemented Gaussian mixture models - an established statistical tool - to cross-sectional data in order to characterize serological diversity of seasonal human coronaviruses (sHCoVs) throughout the lifespan. These methods identified four (NL63, 229E, OC43) to five (HKU1) distinct seropositive levels, suggesting that among seropositive individuals, the number of prior exposures or response to infection may vary. For each sHCoV, we fit adapted, multi-compartment serocatalytic models across 10 scenarios with different assumptions on exposure history and waning of antibodies. The best fit model for each sHCoV was always one that accounted for a gradient of seropositivity as well as host variation in the scale of serological response to infection. These models allowed us to estimate the strength and frequency of serological responses across sHCoVs, finding that the time for a seronegative individual to become seropositive ranges from 2.33-4.07 years across sHCoVs, and most individuals mount a strong antibody response reflected in high optical density values, skipping lower levels of seropositivity. We also find that despite frequent infection and strong serological responses, it is rare for an individual to remain seropositive throughout the lifetime. Crucially, our reimagined serocatalytic methods can be flexibly adapted across pathogens, having the potential to be broadly applied beyond this work.
Association between afterload-related cardiac performance and acute kidney injury in patients with sepsis: a retrospective cohort study
Authors: Zheng Jie-zhao , Guo Ze-bin , Li Li , Zhou Hong-xuan , Huang Jun-yu , Luo Min , Huang Min-xuan , Huo Jia-xian , Huang Wen-xing , Yuan Hao-ran , Chen Hong-xi , Jiang Zi-xin , Chen Wei-yan
Published: December 2024

Background

It is believed that there is a complex bidirectional causal and pathophysiological relationship between heart and kidney in sepsis. Afterload-related cardiac performance (ACP) has been found to have a close association with cardiac function and prognosis in sepsis. The aim of this study was to explore its correlation with sepsis-associated acute kidney injury (SA-AKI).

Methods

150 patients with sepsis who underwent PiCCO were included. Restricted cubic spline (RCS) and Cox proportional hazards regression were used to describe the relationship between ACP and SA-AKI. The receiver operating characteristic curve (AUROC) analysis was used to evaluate the predictive value of ACP for SA-AKI. A prediction model of SA-AKI occurrence probability within 7 days was presented by nomogram.

Results

67.3% patients developed SA-AKI within 7 days. The RCS model demonstrated that the risk of SA-AKI increased with the decrease of ACP. Cox regression analyses also found an independent inverse association between them (HR 0.974, 95%CI 0.963 - 0.985, p < 0.001). ACP showed significantly greater discrimination for SA-AKI than CI (p= 0.004). Independent risk factors for SA-AKI within 7 days were history of hypertension, type of pathogens, SOFA score, serum potassium and ACP. The AUROC of the nomogram established by age and the above factors was 0.865 (95%CI 0.808 – 0.923,p< 0.001) and the C-index was 0.800 (95%CI 0.753 - 0.847).

Conclusions

Low ACP was associated with an increased risk of SA-AKI within 7 days. ACP, which might be superior to CI, had the potential for early prediction of SA-AKI.
Crops under continuous cultivation exhibit less plasticity than those under interrupted cultivation
Authors: Alagarasan Ganesh , Varshney Rajeev K. , Ramireddy Eswarayya
Published: December 2024

Evolutionary studies indicate that species in stable environments often evolve with reduced plasticity, whereas those in variable environments tend to maintain higher plasticity to adapt to changing conditions. Our study explores whether this evolutionary principle extends to cultivated crops. In crop science, phenotypic plasticity is generally understood as a short-term response to environmental factors. Yet, the long-term evolutionary changes in both plastic and non-plastic traits under different cultivation regimes remain largely unexamined. Herein, we developed a novel mechanistic crop growth model, collectively termed the Trait-Environment Fitness Interaction (TEFI) Model, to study if and how trait plasticity varies among crops under different cultivation regimes. Our results, based on the TEFI Model, show higher trade-offs between fitness and plasticity. Specifically, we observed the evolution of higher plasticity in crops subjected to intermittent cultivation, which experienced more variable environments. However, this higher plasticity does not compensate for fitness losses due to the high rate of environmental unpredictability. Conversely, species under relatively stable conditions tend to evolve with reduced plasticity. Using real-world crop datasets, we validated the theoretical predictions of the TEFI Model, which suggest that the longer the interruption, the higher the plasticity. Our results highlight the evolutionary impact of cultivation patterns on trait plasticity and its importance in crop fitness. Ultimately, our findings illustrate how evolutionary principles of plasticity, as captured by the TEFI Model, can inform sustainable crop improvement strategies.
Targeting terrestrial vertebrates with eDNA: Trends, perspectives, and considerations for sampling
Authors: Newton Joshua P , Allentoft Morten E , Bateman Philip W , van der Heyde Mieke , Nevill Paul
Published: December 2024

Terrestrial vertebrates are experiencing worldwide population declines and species extinctions. To effectively conserve remaining populations and species, rapid, cost effective and scalable methods are needed to complement longstanding monitoring methods. Increasingly, environmental DNA (eDNA) based approaches are being used for terrestrial vertebrate biomonitoring within a range of environments. However, as we move eDNA biomonitoring onto land, we are presented with a new set of challenges. This necessitates the development of best-practice eDNA sample collection guidelines for terrestrial systems with the purpose of detecting terrestrial vertebrates. To address these needs we conducted a systematic literature review of 143 peer-reviewed papers applying eDNA to terrestrial vertebrate monitoring (excluding Lissamphibia) that were published between 2012 and 2023. We summarize the use of eDNA for terrestrial vertebrate biomonitoring, focusing on study design and field techniques. Over the decade we observe a steady growth in the annual number of publications, with 3 in 2012 and 33 in 2023. The majority of the reviewed studies targeted terrestrial mammals within temperate forest regions. While an equal number of studies focused on a metabarcoding approach to assess community taxon composition and/or species-specific eDNA detection methods, novel uses are increasingly published. These include studies of animal behaviour and population genetics. We record three types of sampling strategies, eight different substrate types and seven different preservation methods, suggesting there is no one size fits all eDNA based sampling methodology when detecting terrestrial vertebrates. With a multitude of study aims, across different environments, and target organisms with different ecologies, the standardization of eDNA sampling approaches in terrestrial systems is extremely challenging. We summarize in a table known factors influencing eDNA detection within terrestrial environments. Furthermore, we identify five key considerations to be addressed when sampling for eDNA studies targeting terrestrial vertebrate species, with the aim of guiding decision making.
Inhibition of DKK-1 by WAY262611 Inhibits Osteosarcoma Metastasis
Authors: Tal Adit , Gunawardana-Zeigler Shimara , Peng Da , Tan Yuqi , Perez Natalia Munoz , Offenbacher Rachel , Kastner Laurel , Ciero Paul , Randolph Matthew E. , Gong Yun , Deng Hong-Wen , Cahan Patrick , Loeb David M.
Published: December 2024

Osteosarcoma (OS) is the most common primary malignant bone tumor in childhood. Patients who present with metastatic disease at diagnosis or relapse have a very poor prognosis, and this has not changed over the past four decades. The Wnt signaling pathway plays a role in regulating osteogenesis and is implicated in OS pathogenesis. DKK-1 inhibits the canonical Wnt signaling pathway, causing inhibition of osteoblast differentiation and disordered bone repair. Our lab previously demonstrated that a monoclonal antibody against DKK-1 prevented metastatic disease in a mouse model. This study expands upon those findings by demonstrating similar results with a small molecule inhibitor of DKK-1, WAY262611, bothin vitroandin vivo. WAY262611 was evaluatedin vitroon osteosarcoma cell lines, including proliferation, caspase activation, cell cycle analysis, and signaling pathway activation. We utilized our orthotopic implantation-amputation model of osteosarcoma metastasisin vivoto determine the impact of WAY262611 on primary tumor progression and metastatic outgrowth of disseminated tumor cells. Differentiation status was determined using single cell RNA sequencing. We show here that WAY262611 activates canonical Wnt signaling, enhances nuclear localization and transcriptional activity of beta-catenin, and slows proliferation of OS cell lines. We also show that WAY262611 induces osteoblastic differentiation of an OS patient-derived xenograftin vivo, as well as inhibiting metastasis. This work credentials DKK-1 as a therapeutic target in OS, allowing for manipulation of the Wnt signaling pathway and providing preclinical justification for the development of new biologics for prevention of osteosarcoma metastasis.
THE FAM53C/DYRK1A axis regulates the G1/S transition of the cell cycle
Authors: Hammond Taylar , Choi Jong Bin , Membreño Miles W. , Demeter Janos , Ng Roy , Bhattacharya Debadrita , Nguyen Thuyen N. , Hartmann Griffin G. , Bossard Carine , Skotheim Jan M. , Jackson Peter K. , Pasca Anca , Rubin Seth M. , Sage Julien
Published: December 2024

A growing number of therapies are being developed to target the cell cycle machinery for the treatment of cancer and other human diseases. Consequently, a greater understanding of the factors regulating cell cycle progression becomes essential to help enhance the response to these new therapies. Here, using data from the Cancer Dependency Map, we identified the poorly-studied factor FAM53C as a new regulator of cell cycle progression. We found that FAM53C is critical for this cell cycle transition and that it acts upstream of the CyclinD-CDK4/6-RB axis in the regulation of the G1/S transition. By mass spectrometry, biochemical, and cellular assays, we identified and validated DYRK1A as a cell cycle kinase that is inhibited by and directly interacts with FAM53C. DYRK1A kinase inhibition rescues the G1 arrest induced by FAM53C knock-down. Consistent with the role for FAM53C identified in cells in culture,FAM53Cknockout human cortical organoids display increased cell cycle arrest and growth defects. In addition,Fam53Cknockout mice show defects in body growth and behavioral phenotypes. Because DYRK1A dysregulation contributes to developmental disorders such as Down syndrome as well as tumorigenesis, future strategies aiming at regulating FAM53C activity may benefit a broad range of patients.
Complex opioid driven modulation of glutamatergic and cholinergic neurotransmission in a GABAergic brain nucleus associated with emotion, reward and addiction
Authors: Chittajallu R. , Vlachos A. , Yuan X.Q. , Hunt S. , Abebe D. , London E. , Pelkey KA. , McBain C.J.
Published: December 2024

The medial habenula (mHb)/interpeduncular nucleus (IPN) circuitry is resident to divergent molecular, neurochemical and cellular components which, in concert, perform computations to drive emotion, reward and addiction behaviors. Although housing one of the most prominent mu opioid receptor (mOR) expression levels in the brain, remarkably little is known as to how they impact mHb/IPN circuit function at the granular level. In this study, our systematic functional and pharmacogenetic analyses demonstrate that mOR activation attenuates glutamatergic signaling whilst producing an opposing potentiation of glutamatergic/cholinergic co-transmission mediated by mHb substance P and cholinergic neurons, respectively. Intriguingly, this latter non-canonical augmentation is developmentally regulated only emerging during later postnatal stages. Further, specific potassium channels act as a molecular brake on nicotinic receptor signaling in the IPN with the opioid mediated potentiation of this arm of neurotransmission being operational only following attenuation of Kv1 function. Thus, mORs play a remarkably complex role in modulating the salience of distinct afferent inputs and transmitter modalities that ultimately influences synaptic recruitment of common downstream GABAergic IPN neurons. Together, these observations provide a framework for future investigations aimed at identifying the neural underpinnings of maladaptive behaviors that can emerge when endogenous or exogenous opioids, including potent synthetic analogs such as fentanyl, modulate or hijack this circuitry during the vulnerable stages of adolescence and in adulthood.
The Role of BAZ2-dependent Chromatin Remodeling in Suppressing G4 DNA Structures and Associated Genomic Instability
Authors: Vandeuren Adrianna L. , O’Dare Kierney , Wilson Rosemary H. C. , van Eijk Patrick , Julio Lindsay R. , MacLeod Shannon G. , Chee Ella , Salpukas Annika , Kriz Emma M. , Lantz George A. , Gordon Shellaina , Elsässer Simon J. , Reed Simon H. , Day Tovah A.
Published: December 2024

DNA G-quadruplexes (G4s) are secondary structures with significant roles in regulating genome function and stability. Dysregulation of the dynamic formation of G4s is linked to genomic instability and disease, but the underlying mechanisms are not fully understood. In this study, we conducted a screen of chromatin-modifying enzymes and identified nine potential inhibitors of G4 formation, including seven that were not previously characterized. Among these, we highlight the role of BAZ2 chromatin remodelers as key suppressors of G4 DNA and G4-related genome instability. Depletion of BAZ2 subunits led to increased G4 formation, especially at transcriptional regulatory elements. BAZ2B was found to associate with G4 loci, suggesting that it plays a direct role in suppressing G4s. While BAZ2-deficient cells exhibited modest genomic instability, treatment with the G4-stabilizing ligand BRACO19 exacerbated double-strand breaks (DSBs), highlighting its utility as a tool to study G4-dependent genome instability. DSB profiling using INDUCE-seq uncovered distinct breakage patterns around G4s, further underscoring the impact of G4s on genome integrity. Notably, we found that within G4s, G repeats were more susceptible to DSBs than loops. These results establish BAZ2 chromatin remodeling complexes as direct regulators of G4 dynamics and provide new insights into G4-dependent genome instability.
StarPhase: Comprehensive Phase-Aware Pharmacogenomic Diplotyper for Long-Read Sequencing Data
Authors: Holt James M. , Harting John , Chen Xiao , Baker Daniel , Saunders Christopher T. , Kronenberg Zev , Gonzaludo Nina , Yoo Byunggil , Hudjashov Georgi , Joeloo Maarja , Lawlor James M.J. , Lim Weng Khong ,   Estonian Biobank Research Team, Jamuar Saumya S. , Cooper Gregory M. , Milani Lili , Pastinen Tomi , Eberle Michael A.
Published: December 2024

Pharmacogenomics is central to precision medicine, informing medication safety and efficacy. Pharmacogenomic diplotyping of complex genes requires full-length DNA sequences and detection of structural rearrangements. We introduce StarPhase, a tool that leverages PacBio HiFi sequence data to diplotype 21 CPIC Level A pharmacogenes and provides detailed haplotypes and supporting visualizations for HLA-A, HLA-B, and CYP2D6. StarPhase diplotypes have high concordance with benchmarks where 99.5% are either exact matches or minor discrepancies. Manual inspection of the 0.5% mismatches indicates they were correctly called by StarPhase. With StarPhase, we update or correct 26.2% of GeT-RM pharmacogenomic diplotypes. Population distributions from StarPhase mostly reflect those of the All of Us cohort, while also highlighting gaps in existing pharmacogenomic databases that long-read sequencing can fill. With a single HiFi whole genome sequencing assay, StarPhase enables robust PGx diplotyping even as additional pharmacogenes and haplotypes are discovered.
Monoclonal antibodies targeting the FimH adhesin protect against uropathogenicE. coliUTI
Authors: Lopatto Edward D. B. , Santiago-Borges Jesús M. , Sanick Denise A. , Malladi Sameer Kumar , Azimzadeh Philippe N. , Timm Morgan W. , Fox Isabella F. , Schmitz Aaron J. , Turner Jackson S. , Ahmed Shaza Sayed , Ortinau Lillian , Gualberto Nathaniel C. , Pinkner Jerome S. , Dodson Karen W. , Ellebedy Ali H. , Kau Andrew L. , Hultgren Scott J.
Published: December 2024

As antimicrobial resistance increases, urinary tract infections (UTIs) are expected to pose an increased burden in morbidity and expense on the healthcare system, increasing the need for alternative antibiotic-sparing treatments. Most UTIs are caused by uropathogenicEscherichia coli(UPEC), whileKlebsiella pneumoniaecauses a significant portion of non-UPEC UTIs. Both bacteria express type 1 pili tipped with the mannose-binding FimH adhesin critical for UTI pathogenesis. We generated and biochemically characterized 33 murine monoclonal antibodies (mAbs) to FimH. Two mAbs protected mice fromE. coliUTI. Mechanistically, we show that this protection is Fc-independent and mediated by the ability of these mAbs to sterically block FimH function. Our data reveals that FimH mAbs hold promise as an antibiotic-sparing treatment strategy.
Relationship between concentration of cytokinin for efficient shoot regeneration and seed coat color in leaf lettuce
Authors: Kimura Mitsuhiro , Yoshizumi Takeshi
Published: December 2024

Lettuce (Lactuca sativaL.) is an economically important leafy vegetable crop around the world. Recently, transgenic lettuce has been developed to improve agronomic traits. Although plant regeneration is a key step in plant genetic transformation, it depends strongly on the cultivar. In this study, shoot regeneration efficiency was measured by using two leaf lettuce cultivars, ‘Chima-sanchi’, white seed cultivar, and ‘Chirimen-chisya’, brown seed cultivar, a basal salt mixture, and a combination of the cytokinin, 6-benzylaminopurine (BAP), and an auxin, 1- naphthaleneacetic acid (NAA). Efficient shoot regeneration in ‘Chima-sanchi’ was thus obtained on 1 x Murashige and Skoog medium (MS) with 0.05 mg L-1BAP and 0.1 mg L-1NAA. However, the highest efficiency was obtained in ‘Chirimen-chisya’ on 1 x MS with 0.5 mg L-1BAP and 0.1 mg L-1NAA. Therefore, the BAP concentration for efficient shoot regeneration differs significantly between the two cultivars. These cultivars also have different seed coat colors. Due to the similar results obtained from analyzing 4 additional cultivars, 2 white seed cultivars and 2 brown seed cultivars, we demonstrated a strong correlation between the BAP concentration for efficient shoot regeneration and the seed coat color in leaf lettuce.
Pex3 promotes formation of peroxisome-peroxisome and peroxisome-lipid droplet contact sites
Authors: Amado Lucía , Franzkoch Rico , Percifull Louis , Flatemersch Vico , Brüggermann Eleni Joana , Psathaki Olympia Ekaterini , Schuldiner Maya , Bohnert Maria , Bülow Margret , Montoro Ayelén González
Published: December 2024

Peroxisomes are ubiquitous organelles that mediate central metabolic functions, such as fatty acid β-oxidation, as well as diverse tissue- and organism-specific processes. Membrane contact sites, regions of close apposition with other organelles for direct communication, are central to several aspects of their life cycle. Pex3 is a conserved multifunctional peroxisomal transmembrane protein involved in the insertion of peroxisomal membrane proteins, in pexophagy, and in the formation of membrane contact sites. Here, we show that elevated Pex3 levels inSaccharomyces cerevisiaeinduce the formation of peroxisome clusters surrounded by lipid droplets, mediated by peroxisome-peroxisome and peroxisome-lipid droplet contact sites. This clustering occurs independently of Pex3 partners in other processes, Pex19, Inp1, and Atg36. The cytosolic domain of Pex3 binds peroxisomes, suggesting a direct role in homotypic contact site formation. Lipid droplet-peroxisome contact sites require the lipid droplet-localized triacylglycerol lipase Tgl4, which is enriched along with other lipases at this interface. Pex3 overexpression inDrosophila melanogaster similarly alters peroxisome and lipid droplet morphology and promotes contact site formation. Together, our results offer novel molecular insights into homotypic peroxisome contact sites and peroxisome-lipid droplet contact sites across species.
Resolving the design principles that control postnatal vascular growth and scaling
Authors: Pi Danielle , Braun Jonas , Dutta Sayantan , Patra Debabrata , Bougaran Pauline , Mompeón Ana , Ma Feiyang , Stock Stuart R , Choi Sharon , García-Ortega Lourdes , Pratama Muhammad Yogi , Pichardo Diomarys , Ramkhelawon Bhama , Benedito Rui , Bautch Victoria L , Ornitz David M , Goyal Yogesh , Iruela-Arispe M. Luisa
Published: December 2024

After birth, tissues grow continuously until reaching adult size, with each organ exhibiting unique cellular dynamics, growth patterns, and (stem or non-stem) cell sources. Using a suite of experimental and computational multiscale approaches, we found that aortic expansion is guided by specific biological principles and scales with the vertebral column rather than animal body weight. Expansion proceeds via two distinct waves of arterial cell proliferation along blood flow that are spatially stochastic, yet temporally coordinated. Each wave exhibits unique cell cycle kinetics and properties, with the first wave exhibiting cell cycle durations as fast as 6 hours. Single-cell RNA sequencing showed changes in fatty acid metabolism concomitant with an increase in cell size. Mathematical modeling and experiments indicated endothelial cell extrusion is essential for homeostatic aortic growth and balancing excess proliferation. In a genetic model of achondroplasia, the aorta achieves proper scaling through enhanced cell extrusion while maintaining normal proliferation dynamics. Collectively, these results provide a blueprint of the principles that orchestrate aortic growth which depends entirely on differentiated cell proliferation rather than resident stem cells.