bluuebunny/crossref_metadata_2025 huggingface dataset:
Historical biogeography of North American killifishes (Cyprinodontiformes) recapitulates geographical history in the Gulf of México watershed
Authors: Hernández-Ávila Sonia Gabriela , Hoagstrom Christopher W , Matamoros Wilfredo A
Published: October 2024

We analysed phylogenetic relationships within a major clade of Cyprinodontiformes (Teleostei) that includes five families of North American killifishes. We used DNA sequences from five genes for 130 species, with four fossil calibrations and three secondary calibrations, to generate a time-calibrated phylogeny. We estimated diversification rates, ancestral areas, and ancestral habitats for each node. Findings were interpreted within a detailed biogeographical synthesis. The results indicate that the clade arose in the Eocene along the Gulf of México coast. The speciation rate was uniform through time, except for acceleration in Cyprinodontidae after ~10.9 Mya. In other families, neither viviparity nor marine-to-freshwater transition was associated with accelerated speciation. Sea-level fluctuations might have created a speciation pump by stimulating cycles of dispersal and vicariance along the coast. Diversification also included many cases of inland immigration from coastal ancestors. For upland lineages, ancient river drainages accord with lineage distributions, including enigmatic disjunctions in Goodeidae and Fundulus. Diversification in uplands occurred via barrier displacement within alluvial or tectonically active landscapes. Killifishes also display high environmental tolerance and persist within harsh, peripheral environments unsuitable for most other fishes. Hence, a combination of clade antiquity, adaptability, dynamic geography, and persistence can explain the living diversity of New World killifishes.
Molecular phylogenetic relationships among lineages in the genus Carabus (Coleoptera: Carabidae) and radiation of the subgenus Apotomopterus
Authors: Sota Teiji , Liang Hongbin , Pham Hong Thai , Lin Chung-Ping , Hori Michio , Takami Yasuoki , Ikeda Hiroshi
Published: October 2024

The genus Carabus (Coleoptera: Carabidae: Carabinae) is a group of predacious ground beetles found throughout Holarctic temperate zones. The diversification of this group is attributed not only to allopatric speciation but also to diversification in life-history traits and morphological traits that are involved in ecological adaptation and reproductive isolation. Precise phylogenetic reconstruction of Carabus is important to understanding the factors associated with species’ divergence in relation to such character divergence. Here, we analyse the phylogeny of Carabus among higher taxonomic groups and among species of the subgenus Apotomopterus, a hyper-diverse group endemic to East Asia. We used genome-wide sequence data from ultraconserved elements for phylogenetic reconstruction via maximum-likelihood and species-tree reconstruction methods. With regard to the relationships among higher taxonomic groups, the obtained phylogenetic trees resolved two structures with previously unresolved divergence. The subgenus Apotomopterus contained three lineages, i.e. the Vitalisi, Prodigus, and Sauteri groups. It showed diversification of the spinula, a sclerotized male genital structure, and variation in the female elytral notch (preapical emargination). These morphological traits may be involved in copulatory behaviour and potentially affect reproductive isolation, and their character state divergence may have facilitated species divergence of Apotomopterus.
Genetic associations of neuropathic pain and sensory profile in a deeply phenotyped neuropathy cohort
Authors: Åkerlund Mikael , Baskozos Georgios , Li Wenqianglong , Themistocleous Andreas C. , Pascal Mathilde M.V. , Rayner N. William , Attal Nadine , Baron Ralf , Baudic Sophie , Bennedsgaard Kristine , Bouhassira Didier , Comini Maddalena , Crombez Geert , Faber Catharina G. , Finnerup Nanna B. , Gierthmühlen Janne , Granovsky Yelena , Gylfadottir Sandra Sif , Hébert Harry L. , Jensen Troels S. , John Jishi , Kemp Harriet I. , Lauria Giuseppe , Laycock Helen , Meng Weihua , Nilsen Kristian Bernhard , Palmer Colin , Rice Andrew S.C. , Serra Jordi , Smith Blair H. , Tesfaye Solomon , Topaz Leah Shafran , Veluchamy Abirami , Vollert Jan , Yarnitsky David , van Zuydam Natalie , Zwart John Anker , McCarthy Mark I. , Lyssenko Valeriya , Bennett David L.
Published: October 2024

We aimed to investigate the genetic associations of neuropathic pain in a deeply phenotyped cohort. Participants with neuropathic pain were cases and compared with those exposed to injury or disease but without neuropathic pain as control subjects. Diabetic polyneuropathy was the most common aetiology of neuropathic pain. A standardised quantitative sensory testing protocol was used to categorize participants based on sensory profile. We performed genome-wide association study, and in a subset of participants, we undertook whole-exome sequencing targeting analyses of 45 known pain-related genes. In the genome-wide association study of diabetic neuropathy (N = 1541), a top significant association was found at the KCNT2 locus linked with pain intensity (rs114159097, P = 3.55 × 10−8). Gene-based analysis revealed significant associations between LHX8 and TCF7L2 and neuropathic pain. Polygenic risk score for depression was associated with neuropathic pain in all participants. Polygenic risk score for C-reactive protein showed a positive association, while that for fasting insulin showed a negative association with neuropathic pain, in individuals with diabetic polyneuropathy. Gene burden analysis of candidate pain genes supported significant associations between rare variants in SCN9A and OPRM1 and neuropathic pain. Comparison of individuals with the “irritable” nociceptor profile to those with a “nonirritable” nociceptor profile identified a significantly associated variant (rs72669682, P = 4.39 × 10−8) within the ANK2 gene. Our study on a deeply phenotyped cohort with neuropathic pain has confirmed genetic associations with the known pain-related genes KCNT2, OPRM1, and SCN9A and identified novel associations with LHX8 and ANK2, genes not previously linked to pain and sensory profiles, respectively.
Effect of traditional Chinese medicine therapy on labor pain in patients with natural childbirth: A network meta-analysis
Authors: Yi Yangyang , Ju Wenxuan , Fu Danni , Chen Rui , Bai Xue , Zhang Song
Published: October 2024

Background:

This systematic review compared the efficacy of traditional Chinese medicine (TCM) treatments for outcomes of different stages and labor pain among pregnant women.

Methods:

Eight databases were electronically searched for TCM on labor pain between January 2012 and January 2022. The studies were recorded and screened according to inclusion criteria and subsequently entered in Note Express. The quality of the included studies was evaluated using the Cochrane risk of bias tool, and network meta-analysis was conducted with Stata 16.0. Forest plots and league tables were used to compare different treatment modalities’ effect sizes. Additionally, the probabilities of various treatment modalities for each outcome under the cumulative ranking curve were determined. The protocol was registered in PROSPERO (CRD42022336091). This study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines.

Results:

Thirty articles encompassing 3277 participants were included in the network meta-analysis with 9 different treatment modalities. In terms of pain of labor at 30 minutes, acupuncture + autonomic nerve block was the most effective treatment modality. With regard to the 60-minute pain and the first stage of labor, acupressure + acupuncture therapy was most effective.

Conclusion:

In general, a combined treatment with acupressure and acupuncture is the most effective approach for relieving labor pain and shortening the duration of labor. Based on these data, we intend to explore further clinical TCM therapy for relieving maternal pain.
Robot-assisted congenital diaphragmatic hernia repair in adults: A case series
Authors: Huang Yu-Jen , Fang Yue-Lin
Published: October 2024

Rationale:

Congenital diaphragmatic hernia (CDH) is a rare condition predominantly affecting neonates, with only a few cases remaining undetected until adulthood. Surgical repair is the primary treatment approach for adults with confirmed CDH. Traditionally, these procedures include laparotomy, thoracotomy, and minimally invasive techniques such as thoracoscopy and laparoscopy. However, only a few cases of robotic diaphragmatic hernia repair have been reported in recent decades.

Patient concerns:

The patients, aged 31 and 71 years, presented with atypical symptoms of chest tightness and fever. Imaging studies revealed a left-sided Bochdalek CDH in 1 patient and a right-sided Morgagni CDH in the other.

Diagnoses:

The patients were diagnosed as CDH in adult with different symptoms.

Interventions:

Both patients received robot-assisted diaphragmatic hernia repair at our institution.

Outcomes:

The patients received robotic-assisted diaphragmatic hernia repair with acceptable surgery outcome and safety. There was no complication or recurrence.

Lessons:

This case series indicates that the robotic transabdominal approach for CDH repair in adults can be an optimal minimally invasive approach for selected patients, demonstrating adequate surgical safety and favorable outcomes.
Performance verification of Siemens Atellica DL IM1600 automatic immune analyzer detection system: A-TPO and A-TG
Authors: Huang Zhen , He Min , Wang Xiuyin
Published: October 2024

To study the performance of the Siemens Atellica DL IM1600 automatic immune analyzer detection system for thyroid peroxidase antibodies (A-TPO) and anti-thyroglobulin antibodies (A-TG). Perform performance verification based on CNAS and CLSI related documents, including precision, accuracy, reference interval, and linearity. In precision validation, intra-batch imprecision coefficient of variation values of A-TG and A-TPO were 3.60%, 5.40%, and 3.20%, 2.20%, inter-batch imprecision coefficient of variation values were 5.40%, 4.40%, and 5.00%, 2.50%, all within the specified range. In the accuracy verification, the A-TG comparison values were −10.94%, −1.49%, −1.14%, −7.78%, −3.28%, and the A-TPO values were 21.20%, 6.42%, 14.63%, 12.40%, and 6.55%, The absolute values were all lower than the comparison requirements. The reference interval verifies that the A-TG and A-TPO test results of health patients were within the normal reference interval of 0 to 60 U/mL. In the linear range validation, A-TG linear regression y = 1.0145x − 10.093, correlation coefficient R
2 = 0.9963 > 0.95, A-TPO linear regression y = 0.9985x − 18.172, correlation coefficient R
2 = 0.9954 > 0.95, indicating linear linearity. The performance verification of Siemens Atellica DL IM1600 automatic immune analyzer detection system for A-TPO and A-TG was satisfactory, suitable for clinical application.
The rate of change in clinical indicators can predict the progression of hepatitis B virus-related acute-on-chronic preliver failure
Authors: Lu Jun , Tu Zhihui , Zhang Zhen , Wang Shumei , Liu Zhuoqi , Lu Xiaohui , Zhang Jun , Luo Daya
Published: October 2024

The objective of this study was to investigate the predictors and predictive model construction of the progression of HBV-Pre.Acute-on-chronic liver failure (ACLF), a total of 133 patients with HBV-Pre.ACLF was divided into the progressive group (52 patients) and the recovery group (81 patients) according to whether they progressed to ACLF or not. The clinical parameters N%, L%, PLT, ALT, TBiL, ALB, Cre, Na, NH3, CRP, AFP, prothrombin time (PT), international normalized ratio (INR), FIB, and their rate of change at baseline were analyzed in the 2 groups. The independent risk factors for HBV-Pre.ACLF progression was found by univariate and multivariate analyses, and a predictive model was constructed. The clinical parameters ALB, FIB, Na, combined alprostadil treatment and MELD, and MELD-Na scores at baseline were significantly different between the 2 groups (P <.05), while ALT, TBiL, Cre, CHE, NH3, N%, L%, PLT, INR, and PT were not significantly different (P >.05). The change rates of Na, CHE, PT, FIB, CRP, Cre, PLT, and the ratio after to before of N% were significantly different between the 2 groups (P <.05), while the change rates of ALT, TBIL, NH3, AFP, L%, and the ratio after to before of INR were not significantly different between the 2 groups (P >.05). Univariate and multivariate analyses showed that baseline ALB, Na, FIB, combined alprostadil therapy and the rate of change of Na and PLT were protective factors for disease progression, and the rate of change of PT, CRP, and the ratio after to before of N% were independent risk factors for disease progression. The novel model was LogitP = −6.051 + 4.049×ΔPT + 0.626×ΔCRP + 4.527×the ratio after to before N% and its area under the curve was 0.944 (95% confidence interval: 0.900–0.988) predicting progression of HBV-Pre.ACLF, and the best cutoff value was −0.22. The patients with a higher logitP score (> −0.22) had an increased risk for progression to ACLF (P <.05). The novel model logitP shows good predictive value for the disease progression of HBV-Pre.ACLF.
Adult-onset neuronal ceroid lipofuscinosis misdiagnosed as autoimmune encephalitis and normal-pressure hydrocephalus: A 10-year case report and case-based review
Authors: Huang Huasheng , Liao Yuqi , Yu Yanni , Qin HuiHui , Wei Yi Zhi , Cao Liming
Published: October 2024

Rationale:

Neuronal ceroid lipofuscinoses (NCLs) are rare, fatal, inherited neurodegenerative disorders characterized by myoclonic epilepsy, cognitive decline, brain atrophy, and retinopathy. The pathogenesis and clinical manifestations of NCL are not well understood and frequently result in misdiagnosis and overtreatment. The aim of this case report and review is to improve our understanding of the clinical features and management of NCL.

Patient concerns:

A 36-year-old woman initially presented with refractory epilepsy.

Diagnoses:

Initially diagnosed with autoimmune encephalitis, the patient was later diagnosed with normal-pressure hydrocephalus. A definitive diagnosis of adult-onset neuronal ceroid lipofuscinosis (ANCL) was established after 10 years of observation, utilizing biopsy and genetic testing.

Interventions:

High-dose intravenous immunoglobulin and methylprednisolone were administered, along with the insertion of a ventriculoperitoneal shunt.

Outcomes:

Despite various treatments, the patient’s condition did not improve.

Lessons:

ANCL typically presents with the clinical triad of refractory seizures, progressive cognitive decline, and movement disorders. Neuroimaging often reveals progressive brain atrophy on magnetic resonance imaging, while electroencephalograms frequently show epileptiform discharges. The prognosis is generally poor. Improved understanding of ANCL from both clinical and radiological perspectives, coupled with early consideration of differential diagnoses, could minimize unnecessary interventions and optimize patient care.
The relationship between health literacy and healthy lifestyle behaviors: A meta-analysis
Authors: Elkin Nurten
Published: October 2024

Background:

Health literacy and healthy lifestyle behaviors are both pivotal elements for public health improvement. This meta-analysis aims to scrutinize studies investigating the nexus between health literacy and healthy lifestyle behaviors and to examine the correlation between health literacy and such behaviors.

Methods:

Studies conducted from 2013 to 2023 exploring the association between health literacy and healthy lifestyle behaviors, as well as the impact of gender and chronic disease status on health literacy, were included. The selection criteria for the meta-analysis involved a literature search utilizing databases such as PubMed, Google Academic, Web of Science, and the National Thesis Center. The keywords “health literacy” and “healthy lifestyle behaviors” were employed, identifying 206 studies. Subsequently, 53 studies meeting predetermined criteria were deemed suitable for inclusion in the meta-analysis.

Results:

The analysis of the relationship between health literacy and healthy lifestyle behaviors revealed no publication bias. Despite heterogeneity among the studies, the correlation effect size was determined to be 0.278 using the random effect model. In the meta-analysis examining the effect of gender on health literacy, no publication bias was detected. Since there was heterogeneity among the studies, the average effect size was calculated as 0.078 according to the random effect model. Regarding the meta-analysis on the effect of chronic disease status on health literacy, no publication bias was observed, and due to homogeneity between the studies, the average effect size was determined to be −0.098 using the fixed effect model.

Conclusion:

A positive yet weak relationship was identified between health literacy and healthy lifestyle behaviors. Notably, gender was a significant sociodemographic factor affecting health literacy, with higher levels observed in women. Moreover, individuals without chronic diseases exhibited higher mean health literacy scores than those with chronic diseases.
Study on correlation between CXCL13 and prognosis and immune characteristics of ovarian cancer
Authors: Wang Yaru , Cheng Xin , Li Wan , Zhang Hongmei
Published: October 2024

Ovarian cancer (OC) has a limited immunotherapeutic response; hence, this study aimed to investigate the relationship between CXC-chemokine ligand 13 (CXCL13) expression and overall survival (OS) rate, key immune pathways, degree of immune cell infiltration, and progressive disease (PD)-1 checkpoint blockade. A total of 703 differentially expressed genes were obtained from “The Cancer Genome Atlas” (TCGA) database based on the immune and stromal scores of 379 OC patients for getting the targeted gene CXCL13. The association between CXCL13 and OS in OC patients, biological function annotation of CXCL13, and its correlation with immune components were assessed. The results indicated that upregulated CXCL13 expression was positively correlated with better OC patient prognosis. CXCL13 expression was associated with 6 immune-related pathways, 10 immune cells, and PD-1 expression of OC micro-environment. Moreover, high expression of CXCL13 was related to a better tumor response and more extended tumor-stable stage after PD-1 blocking therapy in IMvigor210. The study concluded that CXCL13 could be a prognostic marker and a potential immunotherapy target for OC patients, especially PD-1 checkpoint blockade.
Pediatric Plasmablastic Lymphoma in the Setting of CD70 Deficiency
Authors: Baskin Kubra , Vural Ozge , Haskologlu Sule , Erman Baran , Uyar Gocun Pinar , Okur Arzu , Dogu Figen , Pinarli Faruk Guclu , Ikinciogullari Aydan
Published: October 2024

Combined immunodeficiency due to CD70 deficiency is characterized by increased susceptibility to infections, hypogammaglobulinemia, and malignancy. These patients typically present with chronic Epstein Barr virus (EBV) viremia, severe EBV-related hemophagocytic lymphohistiocytosis, lymphoproliferation, and Hodgkin and non-Hodgkin lymphomas. Plasmablastic lymphoma (PBL) is an extremely rare malignancy in all ages and is predominantly seen in male adults with human immunodeficiency virus infection. EBV infection, immunosuppression, solid organ transplantation, and age-related immune deterioration are also suspected causes of PBL. Nevertheless, there is scarce data about its association with primary immunodeficiencies in the literature. Here, we present the first case of a CD70-deficient pediatric patient with PBL.
Closing the Theory-to-Practice Gap
Authors: Halm Margo A. , Beebe Scott , Dicker Rachel , Hirsch Malka , Robertson Bethany , Troy David
Published: October 2024

This article presents a program evaluation study involving 18 health system leaders who use Ovid Synthesis, a web-based workflow solution for evidence-based practice, quality improvement, and research initiatives. The findings demonstrate the critical prioritization of standardization, collaboration, dissemination, and patient outcomes in order to successfully implement evidence-based practice (EBP) and how Ovid Synthesis successfully supports these priorities. Significant interest in measuring return on investment underscores the importance of demonstrating the value of EBP, in order to support continued investments in EBP practices.
Efficacy of complete versus culprit-lesion only revascularization in patients with diabetes undergoing percutaneous coronary intervention: a pilot meta-analysis
Authors: Goyal Aman , Tariq Muhammad Daoud , Hurjkaliani Sonia , Zahra Rubab , Jain Hritvik , Daoud Mohamed , Belur Agastya D.
Published: October 2024

Diabetes is a strong independent predictor of unfavorable cardiovascular outcomes in patients with coronary artery disease, and diabetic patients have a higher prevalence of multivessel disease. The impact of diabetes status on outcomes in patients undergoing complete versus culprit-only revascularization during percutaneous coronary intervention remains unexplored. A comprehensive literature search was conducted using MEDLINE, EMBASE, and SCOPUS. Pooled risk ratios (RRs) with 95% confidence intervals (CIs) were calculated using a random-effects model in Review Manager (version 5.4), with a P-value of <0.05 considered significant. Five studies comprising a total of 4686 patients met our inclusion criteria. No statistically significant differences were observed between the two groups in terms of all-cause mortality (RR: 0.79; 95% CI: 0.56–1.12; P = 0.19; I
2 = 66%), cardiovascular-related death (RR: 1.12; 95% CI: 0.74–1.69; P = 0.60; I
2 = 29%), myocardial infarction (RR: 0.78; 95% CI: 0.57–1.08; P = 0.13; I
2 = 12%), and stroke (RR: 1.06; 95% CI: 0.52–2.16; P = 0.88; I
2 = 0%).
H2-driven xylitol production inCupriavidus necatorH16
Authors: Jämsä Tytti , Claassens Nico J. , Salusjärvi Laura , Nyyssölä Antti
Published: October 2024

Background

Biocatalysis offers a potentially greener alternative to chemical processes. For biocatalytic systems requiring cofactor recycling, hydrogen emerges as an attractive reducing agent. Hydrogen is attractive because all the electrons can be fully transferred to the product, and it can be efficiently produced from water using renewable electricity. In this article, resting cells ofCupriavidus necatorH16 harboring a NAD-dependent hydrogenase were employed for cofactor recycling to reduce D-xylose to xylitol, a commonly used sweetener. To enable this bioconversion, D-xylose reductase fromScheffersomyces stipitiswas heterologously expressed inC. necator.

Results

D-xylose reductase was successfully expressed inC. necator, enabling almost complete bioconversion of 30 g/L of D-xylose into xylitol. It was found that over 90% of the energy and protons derived from hydrogen were spent for the bioconversion, demonstrating the efficiency of the system. The highest xylitol productivity reached was 0.7 g L-1h-1. Additionally, the same chassis efficiently produced L-arabitol and D-ribitol from L-arabinose and D-ribose, respectively.

Conclusions

This study highlights the efficient utilization of renewable hydrogen as a reducing agent to power cofactor recycling. Hydrogen-oxidizing bacteria, such asC. necator, can be promising hosts for performing hydrogen-driven biocatalysis.
Three-spined sticklebacks recognise familiar individuals by facial recognition
Authors: Sogawa Shumpei , Inoue Izumi , Awata Satoshi , Ikeya Koki , Kawasaka Kento , Kohda Masanori
Published: October 2024

Social vertebrates often recognise familiar individuals by facial recognition, a basal cognitive ability by which animals establish stable sociality, including territoriality. The three-spined stickleback (Gasterosteus aculeatus), a model species for behavioural studies, is territorial; its ability to visually recognise familiar individuals remains unclear. Here, we report that this species has individual-specific facial colour morph features and can recognise familiar individuals by facial recognition. Territorial neighbours of the same sex established a “dear enemy relationship” with each other. These focal fish were exposed to composite photographic models of four combinations of faces and bodies of familiar neighbours and unknown strangers of the same sex. Focal fish of both sexes frequently attacked photographs of strangers (stranger-face/stranger-body) more frequently than familiar neighbours (neighbour-face/neighbour-body). Furthermore, they attacked composite photographs of stranger-face/neighbour-body more frequently (similar to the stranger model) but less frequently attacked photographs of neighbour-face/stranger-body (similar to the neighbour model). These results suggest that the three-spined stickleback distinguishes familiar neighbours from unknown fish exclusively via facial recognition. The aggressiveness of males was independent of the presence of red nuptial colour on photograph-models. Our findings suggest that this fish controls its aggressiveness against opponent conspecifics in the context of social relationships independent of the sign-stimulus.
Sequence-dependent scale for translocon-mediated insertion of interfacial helices in membranes
Authors: Grau Brayan , Kormos Rian , Bañó-Polo Manuel , Chen Kehan , García-Murria María J. , Hajredini Fatlum , Sánchez del Pino Manuel M. , Jo Hyunil , Martínez-Gil Luis , von Heijne Gunnar , DeGrado William F. , Mingarro Ismael
Published: October 2024

Biological membranes consist of a lipid bilayer studded with integral and peripheral membrane proteins. Most α-helical membrane proteins require protein-conducting insertases known as translocons to assist in their membrane insertion and folding. While the sequence-dependent propensities for a helix to either translocate through the translocon or insert into the membrane have been codified into numerical hydrophobicity scales, the corresponding propensity to partition into the membrane interface remains unraveled. By engineering diagnostic glycosylation sites around test peptide sequences inserted into a host protein, we devised a system that can differentiate between water-soluble, surface-bound, and transmembrane (TM) states of the sequence based on its glycosylation pattern. Using this system, we determined the sequence-dependent propensities for transfer from the translocon to a TM, interfacial or extramembrane space. UMAP analysis of a large collection of TM and water-soluble helices provide useful embeddings for analysis of these propensities and aid in understanding the physical properties and functions of antimicrobial, lytic, and fusogenic peptides.
A Genomic Language Model for Chimera Artifact Detection in Nanopore Direct RNA Sequencing
Authors: Li Yangyang , Wang Ting-You , Guo Qingxiang , Ren Yanan , Lu Xiaotong , Cao Qi , Yang Rendong
Published: October 2024

Chimera artifacts in nanopore direct RNA sequencing (dRNA-seq) can significantly distort transcriptome analyses, yet their detection and removal remain challenging due to limitations in existing basecalling models. We present Deep-Chopper, a genomic language model that precisely identifies and removes adapter sequences from base-called dRNA-seq long reads at single-base resolution, operating independently of raw signal or alignment information to effectively eliminate chimeric read artifacts. By removing these artifacts, DeepChopper substantially improves the accuracy of critical downstream analyses, such as transcript annotation and gene fusion detection, thereby enhancing the reliability and utility of nanopore dRNA-seq for transcriptomics research.
CHK1-mediated regulation of TOP1 catalytic activity suppresses replication and transcription-associated genomic instability
Authors: Majumdar Ananda Guha , Chauhan Nitish , Gupta Pooja , Subramanian Mahesh , Patro Birija Sankar
Published: October 2024

The Topoisomerase 1 (TOP1) catalytic cycle involves a TOP1-DNA-covalent-complex (TOP1cc), which, if stabilized, can induce rapid accumulation of potentially lethal DNA double strand breaks (DSBs). Although TOP1cc are critically associated with genome instability, it is not yet precisely known how cells regulate TOP1cc level, under unperturbed physiological-condition, to prevent its accumulation and lethal consequences. We discovered a key role of CHK1 in phosphorylating TOP1 at Serine-320 and stimulating TOP1-catalytic cycle to minimise genome wide accumulation of TOP1cc in cancers. Pharmacological or genetic ablation of CHK1-mediated TOP1-phosphorylation leads to stalled replication forks and generates copious amounts of replication/transcription-associated DSBs, R-loops and transcription-replication collisions, eventually leading to chromosomal instability. Further, TOP1ccs stabilized due to CHK1 inhibition are not efficiently targeted by cellular TOP1cc-removal machineries. Since multiple patient clinical trials are ongoing with TOP1- and CHK1-targeting drugs, current finding of CHK1-mediated regulation of TOP1cc may help in better understanding the therapeutic outcomes.
Abl kinases regulate FGF signaling independent of Crk phosphorylation to prevent Peters anomaly
Authors: Wu Hao , Mao Yingyu , Wang Qian , Yu Honglian , Bouaziz Michael , Makrides Neoklis , Koleske Anthony J. , Radice Glenn L. , Zhang Xin
Published: October 2024

Peters anomaly, the most common cause of congenital corneal opacity, stems from corneal-lenticular adhesion. Despite numerous identified mutations, a cohesive molecular framework of the disease’s etiology remains elusive. Here, we identified Abl kinases as pivotal regulators of FGF signaling, as genetic ablation of Abl kinases restores lens induction even in the absence of FGF signaling. Intriguingly, bothAblkinase deficiency and increased FGF-Ras activity result in Peters anomaly independent of ERK signaling, which can be rescued by allelic deletion of Abl substrate, Crk. However, contrary to the prevailing belief that Abl kinases regulate Crk proteins by direct phosphorylation, mutations at Abl kinase phosphorylation sites on Crk and CrkL did not yield any observable effects. Instead, our findings reveal that Abl kinases phosphorylate Ptpn12, which in turn inhibits p130Cas phosphorylation and Crk recruitment, crucial for Rho GTPases activation and cytoskeletal dynamics. Consequently, Abl kinase deficiency reduces actomyosin contractility within the lens vesicle and genetically interacts with RhoA inhibition. Conversely,Rac1deletion mitigates Peters anomaly in models with aberrant FGF, Abl kinase and RhoA signaling. Our results demonstrate that Abl kinases regulate FGF signaling to balance RhoA and Rac1 activity via the Ptpn12-p130Cas pathway, suggesting that targeting tension-mediated lens vesicle separation could be a therapeutic strategy for Peters anomaly.
Inhibition ofCandida albicansvirulence factor by cyclic dipeptides derived fromAeromonas veroniiV03
Authors: Sekar Jinendiran , Parasuraman Gokul , Dharumadurai Dhanasekaran , Dileep Kumar B.S. , Natesan Sivakumar
Published: October 2024

Candida albicansis the most common human fungal pathogen with high mortality rates and limited antifungal treatments. Inhibition ofC. albicanspathogenesis by targeting virulence factors provides a promising strategy for the development of novel antifungal drugs and overcoming drug resistance. In this study, four structurally different cyclic dipeptides (or diketopiperazine(DKP) were isolated and identified as cyclo(L-Pro-L-Leu), cyclo(L-Pro-L-Val), cyclo(D-Pro-L-Phe), and cyclo(L-Pro-D-Tyr) fromAeromonas veroniiV03 and their antimicrobial potentials were evaluated. Results revealed that identified DKPs exhibited antibacterial activity against bacterial pathogens, such asStaphylococcus aureus, Proteus mirabilis,Pseudomonas aeruginosa,andAeromonas hydrophila. Importantly, cyclo(D-Pro-L-Phe) lacking hydroxyl groups showed potent inhibitory effects againstC. albicansand non-albicans species with low concentrations. Moreover, identified DKPs inhibited the virulence traits ofC. albicans,including yeast-to-hyphae transition, secreted hydrolases (aspartic proteases and phospholipase) and biofilm formation in a dose-dependent manner. Collectively, our findings suggest that cyclic dipeptides from DKPs derived fromA. veroniiV03 could potentially be developed as antivirulence agents againstC. albicansinfection.
Sphingolipid imbalance aggravates fibrillar Tau-induced endomembrane rigidification and rupture
Authors: Tittelmeier Jessica , Sandhof Carl Alexander , Martin Nicole , El-Kabarity Deike , Ngonza-Nito Soki-Bradel , Melki Ronald , Nussbaum-Krammer Carmen
Published: October 2024

Numerous studies have implicated endolysosomal dysfunction in Alzheimer’s disease (AD) and related tauopathies. However, the mechanisms driving these disturbances remain poorly understood. UsingC. elegans, we recently identified genes involved in sphingolipid metabolism as crucial for the maintenance of endolysosomal integrity. Abnormal sphingolipid metabolism is increasingly reported in AD, but its impact on Tau pathology remains unclear. Here, we investigated the role of sphingolipid metabolism in endolysosomal membrane homeostasis and its effect on Tau aggregation and toxicity inC. elegansand human cell culture models. Fluorescence recovery after photobleaching (FRAP) analysis and C-Laurdan dye imaging revealed that silencing of sphingolipid metabolism genes reduced the fluidity of endolysosomal vesicle membranes, and increased their susceptibility to rupture. The accumulation of aggregated Tau in endolysosomal vesicles further exacerbated endomembrane rigidification and damage. Moreover, enhanced membrane rigidity facilitated seeded Tau aggregation in a biosensor cell line. Restoring membrane fluidity by supplementation with the polyunsaturated omega-3 fatty acid alpha-linoleic acid suppressed endomembrane rupture and seeded Tau aggregation in cell models and neurotoxicity inC. elegans. This study provides mechanistic insights into how impaired sphingolipid homeostasis leads to endolysosomal membrane damage and how this might contribute to the progression of tau pathology.
Population genomics and molecular epidemiology of wheat powdery mildew in Europe
Authors: Jigisha Jigisha , Ly Jeanine , Minadakis Nikolaos , Freund Fabian , Kunz Lukas , Piechota Urszula , Akin Beyhan , Balmas Virgilio , Ben-David Roi , Bencze Szilvia , Bourras Salim , Bozzoli Matteo , Cotuna Otilia , Couleaud Gilles , Cséplő Mónika , Czembor Paweł , Desiderio Francesca , Dörnte Jost , Dreiseitl Antonín , Feechan Angela , Gadaleta Agata , Gauthier Kevin , Giancaspro Angelica , Giove Stefania Lucia , Handley-Cornillet Alain , Hubbard Amelia , Karaoglanidis George , Kildea Steven , Koc Emrah , Liatukas Žilvinas , Lopes Marta S. , Mascher Fabio , McCabe Cathal , Miedaner Thomas , Martìnez-Moreno Fernando , Nellist Charlotte F. , Okoń Sylwia , Praz Coraline , Sánchez-Martín Javier , Sărăţeanu Veronica , Schulz Philipp , Schwartz Nathalie , Seghetta Daniele , Solís Martel Ignacio , Švarta Agrita , Testempasis Stefanos , Villegas Dolors , Widrig Victoria , Menardo Fabrizio
Published: October 2024

Agricultural diseases are a major threat to sustainable food production. Yet, for many pathogens we know exceptionally little about their epidemiological and population dynamics, and this knowledge gap is slowing the development of efficient control strategies. Here we study the population genomics and molecular epidemiology of wheat powdery mildew, a disease caused by the biotrophic fungusBlumeria graminis forma specialis tritici(Bgt). We sampled Bgt for two consecutive years, 2022 and 2023, from 22 countries in Europe and surrounding regions, and compiled a genomic dataset of 415 Bgt isolates. We found one single epidemic unit in the north of Europe, consisting of a highly homogeneous population. Conversely, the south of Europe hosts smaller local populations which are less interconnected. In addition, we show that the population structure can be largely predicted by the prevalent wind patterns. We identified several loci that were under selection in the recent past, including fungicide targets and avirulence genes. Some of these loci are common between populations, while others are not, suggesting different local selective pressures. We reconstructed the evolutionary history of one of these loci,AvrPm17, coding for an effector recognized by the wheat receptor Pm17. We found evidence for a soft sweep on standing genetic variation. MultipleAvrPm17haplotypes, which can partially escape recognition by Pm17, spread rapidly throughout the continent upon its introduction in the early 2000s. We also identified a new virulent variant, which emerged more recently and can evadePm17resistance altogether. Overall, we highlight the potential of genomic surveillance in resolving the evolutionary and epidemiological dynamics of agricultural pathogens, as well as in guiding control strategies.
DrosophilaTrus, the orthologue of mammalian PDCD2L, is required for proper cell proliferation, larval developmental timing, and oogenesis
Authors: Takada Saeko , Bolkan Bonnie J. , O’Connor MaryJane , Goldberg Michael , O’Connor Michael B.
Published: October 2024

Toys are us (Trus) is theDrosophila melanogasterortholog of mammalian Programmed Cell Death 2-Like (PDCD2L), a protein that has been implicated in ribosome biogenesis, cell cycle regulation, and oncogenesis. In this study, we examined the function of Trus duringDrosophiladevelopment. CRISPR/Cas9 generated null mutations intruslead to partial embryonic lethality, significant larval developmental delay, and complete pre-pupal lethality. In mutant larvae, we found decreased cell proliferation and growth defects in the brain and imaginal discs. Mapping relevant tissues for Trus function usingtrus RNAiandtrusmutant rescue experiments revealed that imaginal disc defects are primarily responsible for the developmental delay, while the pre-pupal lethality is likely associated with faulty central nervous system (CNS) development. Examination of the molecular mechanism behind the developmental delay phenotype revealed thattrusmutations induce the Xrp1-Dilp8 ribosomal stress-response in growth-impaired imaginal discs, and this signaling pathway attenuates production of the hormone ecdysone in the prothoracic gland. Additional Tap-tagging and mass spectrometry of components in Trus complexes isolated fromDrosophilaKc cells identified Ribosomal protein subunit 2 (RpS2), which is coded bystring of pearls (sop)inDrosophila,and Eukaryotic translation elongation factor 1 alpha 1 (eEF1α1) as interacting factors. We discuss the implication of these findings with respect to the similarity and differences intrusgenetic null mutant phenotypes compared to the haplo-insufficiency phenotypes produced by heterozygosity for mutants in Minute genes and other genes involved in ribosome biogenesis.

Authors Summary

Ribosomes are essential macromolecular machines required for decoding mRNA to make proteins, the major biomolecules that carry out all central cellular functions. As such, their structural and operational integrity is critical to organismal survival, and mutations that disrupt proper stoichiometry or assembly of ribosomes produce serious pathological consequences during an organism’s development and/or adult life. The ribosome assembly factor PDCD2L is highly conserved from yeast to man, yet its overall function and requirement during development is poorly understood. By examining the developmental consequences of null mutations intrus, which encodes theDrosophilaPDCD2L homolog, we demonstrate an essential role for this factor in cell-cycle regulation. Furthermore, disruption of Trus function in mitotically dividing imaginal tissue activates the Xrp1-dilp8 stress response pathway which limits production of ecdysone, the major arthropod molting hormone, leading to severe developmental delay during larval stages. These studies provide new insights on the requirements of this highly conserved ribosome assemble factor during development.
Inhibiting the cholesterol storage enzyme ACAT1/SOAT1 in aging Apolipoprotein E4 mice alter their brains inflammatory profiles
Authors: Huynh Thao N. , Fikse Emma N. , Havrda Matthew C. , Chang Catherine C.Y. , Chang Ta Yuan
Published: October 2024

Aging and Apolipoprotein E4 (APOE4) are the two most significant risk factors for late-onset Alzheimer’s disease (LOAD). Compared to APOE3, APOE4 disrupts cholesterol homeostasis, increases cholesteryl esters (CEs), and exacerbates neuroinflammation in brain cells including microglia. Targeting CEs and neuroinflammation could be a novel strategy to ameliorate APOE4 dependent phenotypes. Toll-like receptor 4 (TLR4) is a key player in inflammation, its regulation is associated with cholesterol content of lipid rafts in cell membranes. We previously demonstrated that in normal microglia expressing APOE3, inhibiting the cholesterol storage enzyme acylCoA:cholesterol acyltransferase 1 (ACAT1/SOAT1) reduces CEs, dampened neuroinflammation via modulating the fate of TLR4. We also showed that treating myelin debris-loaded normal microglia with ACAT inhibitor F12511 reduced cellular CEs and activated ABC transporter 1 (ABCA1) for cholesterol efflux. In this study, we found that treating primary microglia expressing APOE4 with F12511 also reduces CEs, activated ABCA1, and dampened LPS dependent NFkB activation. In vivo, a two-week injections of nanoparticle F12511, which consists of DSPE-PEG2000, phosphatidylcholine, and F12511, to aged female APOE4 mice reduced TLR4 protein content and decreased proinflammatory cytokines including IL-1β in APOE4 mice brains. Overall, our work suggests nanoparticle F12511 is a novel agent to ameliorate LOAD.
Functional organization and natural scene responses across mouse visual cortical areas revealed with encoding manifolds
Authors: Dyballa Luciano , Field Greg D. , Stryker Michael P. , Zucker Steven W.
Published: October 2024

A challenge in sensory neuroscience is understanding how populations of neurons operate in concert to represent diverse stimuli. To meet this challenge, we have created “encoding manifolds” that reveal the overall responses of brain areas to diverse stimuli with the resolution of individual neurons and their response dynamics. Here we use encoding manifold to compare the population-level encoding of primary visual cortex (VISp) with five higher visual areas (VISam, VISal, VISpm, VISlm, and VISrl). We used data from the Allen Institute Visual Coding–Neuropixels dataset from the mouse. We show that the encoding manifold topology computed only from responses to grating stimuli is continuous, for V1 and for higher visual areas, with smooth coordinates spanning it that include orientation selectivity and firing-rate magnitude. Surprisingly, the manifolds for each visual area revealed novel relationships between how natural scenes are encoded relative to static gratings—a relationship that was conserved across visual areas. Namely, neurons preferring natural scenes preferred either low or high spatial frequency gratings, but not intermediate ones. Analyzing responses by cortical layer reveals a preference for gratings concentrated in layer 6, whereas preferences for natural scenes tended to be higher in layers 2/3 and 4. The results reveal how machine learning approaches can be used to organize and visualize the structure of sensory coding, thereby revealing novel relationships within and across brain areas and sensory stimuli.

Significance Statement

Manifolds have become a commonplace for analyzing and visualizing neural responses. However, prior work has focused on building manifolds that organize diverse stimuli in neural response coordinates. Here, we demonstrate the utility of an alternative approach: building manifolds to represent neurons in stimulus/response coordinates, which we term ‘encoding manifolds’. This approach has several advantages, such as being able to directly visualize and compare how different brain areas encode diverse stimulus ensembles. We use the approach to reveal novel relationships between layer-specific responses and the encoding of natural versus artificial stimuli.
Uterine stromal but not epithelial PTGS2 is critical for murine pregnancy success
Authors: Massri Noura , Arora Ripla
Published: October 2024

Use of non-steroidal anti-inflammatory drugs that target prostaglandin synthase (PTGS) enzymes have been implicated in miscarriage. Further, PTGS2-derived prostaglandins are reduced in the endometrium of patients with a history of implantation failure. However, in the mouse model of pregnancy, peri-implantation PTGS2 function is controversial. Some studies suggest thatPtgs2-/-mice display deficits in ovulation, fertilization, and implantation, while other studies suggest a role for PTGS2 only in ovulation but not implantation. Further, the uterine cell type responsible for PTGS2 function and role of PTGS2 in regulating implantation chamber formation is not known. To address this we generated tissue-specific deletion models ofPtgs2. We observed that PTGS2 ablation from the epithelium alone inLtfcre/+; Ptgs2f/fmice and in both the epithelium and endothelium of thePax2cre/+; Ptgs2f/fmice does not affect embryo implantation. Further, deletion of PTGS2 in the ovary, oviduct, and the uterus usingPgrcre/+; Ptgs2f/fdoes not disrupt pre-implantation events but instead interferes with post-implantation chamber formation, vascular remodeling and decidualization. While all embryos initiate chamber formation, more than half of the embryos fail to transition from blastocyst to epiblast stage, resulting in embryo death and resorbing decidual sites at mid-gestation. Thus, our results suggest no role for uterine epithelial PTGS2 in early pregnancy but instead highlight a role for uterine stromal PTGS2 in modulating post-implantation embryo and implantation chamber growth. Overall, our study provides clarity on the compartment-specific role of PTGS2 and provides a valuable model for further investigating the role of stromal PTGS2 in post-implantation embryo development.