bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neurofilament light chain reference values in serum and cerebrospinal fluid: a bi-compartmental analysis in neurological diseases
Authors: Halbgebauer Steffen , Klose Veronika , Fazeli Badrieh , Klassen Paula , Alexudis Christoforos , Nagel Gabriele , Rosenbohm Angela , Rothenbacher Dietrich , de San Jose Nerea Gomez , Witzel Simon , Elmas Zeynep , Wiesenfarth Maximilian , Schuster Joachim , Dorst Johannes , Huss Andre , Bachhuber Franziska , Otto Markus , Landwehrmeyer G. Bernhard , Ludolph Albert C. , Tumani Hayrettin ,   the ALS Registry Swabia study group
Published: November 2024

AbstractBackgroundConcentrations of neurofilament light chain (NfL), a neuroaxonal damage marker, increase with age. Therefore, age-dependent reference values are important in clinical practice. However, so far these have only been established with a bead based system and age-dependent z-scores for CSF are missing. In addition, we here propose how the combined analysis of CSF and serum NfL could help in the discrimination between central (CNS) and peripheral nervous system (PNS) axonal degeneration.MethodsFor the calculation of age-reference values for serum and CSF 1514 NfL concentrations of control subjects determined with the microfluidic Ella system, were applied.ResultsAge-dependent NfL levels were calculated with additive quantile regression and presented with percentiles and z-scores. We observed a non-linear increase of NfL in serum and CSF. The spearman r of the association with age was 0.81 (95% CI: 0.78-0.83), p<0.0001 and 0.82 (95% CI: 0.79-0.85), p<0.0001 for serum and CSF NfL, respectively. Serum and CSF NfL levels were also associated with each other (r=0.68 (95%CI: 0.62-0.73), p<0.0001). Furthermore, we used this association to establish a bi-compartmental CSF and serum NfL model allowing to differentiate between peripheral or central origin of neurodegeneration.ConclusionsThe age-reference curves corroborate findings of an exponential elevation of NfL in serum and CSF with increasing age. As NfL values from different platforms are not interchangeable this is of additional high relevance. Moreover, the association between CSF and serum NfL values could be applied for clinical use regarding overlapping symptoms of CNS and PNS based neurological diseases.What is already known on this topicNeurofilament light chain levels in cerebrospinal fluid (CSF) and blood are widely accepted neuroaxonal damage markers which strongly correlate with age.What this study addsAge-dependent reference values and z-scores for both serum and CSF for the neurofilament light chain protein (NfL) using the microfluidic ELLA analysis platform. Novel approach for the discrimination between central and peripheral axonal damage using a bi-compartmental NfL model.How this study might affect research, practice or policyEasier and age-corrected interpretation of NfL values in clinical practice. Possibility to distinguish central from peripheral damage by analyzing both blood and CSF NfL.
Reassessing the link between adiposity and head and neck cancer: a Mendelian randomization study
Authors: Morales-Berstein Fernanda , Khouja Jasmine , Gormley Mark , Ebrahimi Elmira , Virani Shama , McKay James , Brennan Paul , Richardson Tom G , Relton Caroline L , Davey Smith George , Borges M Carolina , Dudding Tom , Richmond Rebecca C 
Published: November 2024

AbstractBackgroundAdiposity has been associated with an increased risk of head and neck cancer (HNC). Although body mass index (BMI) has been inversely associated with HNC risk among smokers, this is likely due to confounding. Previous Mendelian randomization (MR) studies could not fully discount causality between adiposity and HNC due to limited statistical power. Hence, we aimed to revisit this using the largest genome-wide association study (GWAS) of HNC available, which has more granular data on HNC subsites.MethodsWe assessed the genetically predicted effects of BMI (N=806,834), waist-to-hip ratio (WHR; N=697,734) and waist circumference (N=462,166) on the risk of HNC (N=12,264 cases and 19,259 controls) and its subsites (oral, laryngeal, hypopharyngeal and oropharyngeal cancers) using a two-sample MR framework. We used the inverse variance weighted (IVW) MR approach and multiple sensitivity analyses including the weighted median, weighted mode, MR-Egger, MR-PRESSO, and CAUSE approaches. We also used multivariable MR (MVMR) to explore the direct effects of the adiposity measures on HNC, while accounting for smoking behaviour, a well-known HNC risk factor.ResultsIn univariable MR, higher genetically predicted BMI increased the risk of overall HNC (IVW OR=1.17 per 1 standard deviation [1-SD] higher BMI, 95% CI 1.02–1.34, p=0.03), with no heterogeneity across subsites (Q p=0.78). However, the effect was not consistent in sensitivity analyses. The IVW effect was attenuated when smoking was included in the MVMR model (OR accounting for comprehensive smoking index=0.96 per 1-SD higher BMI, 95% CI 0.80–1.15, p=0.64) and CAUSE indicated the IVW results could be biased by correlated pleiotropy. Furthermore, we did not find a link between genetically predicted WHR (IVW OR=1.05 per 1-SD higher WHR, 95% CI 0.89–1.24, p=0.53) or waist circumference and HNC risk (IVW OR=1.01 per 1-SD higher waist circumference, 95% CI 0.85–1.21, p=0.87).ConclusionsOur findings suggest that adiposity does not play a role in HNC risk.
Evaluating the Efficacy of Miglustat and Ambroxol Combination Therapy in a Phase 1b/2 Virtual Drug Trial for Type 1 Tay-Sachs Disease Using aiHumanoid Simulations
Authors: Danter WR 
Published: November 2024

Abstract (Draft1)Type 1 Tay-Sachs Disease (TSD) is a rare and severe neurodegenerative disorder caused by HEXA Loss of Function (LOF) gene mutations, leading to the accumulation of lysosomal GM2 gangliosides and progressive neurological decline, with high lethality before age 10. Current treatments are primarily palliative, focusing on symptom management. This study investigates the therapeutic potential of Miglustat and Ambroxol, individually and combined, in slowing neurodegeneration and cognitive decline in Type 1 TSD, leveraging aiHumanoid virtual simulations. Miglustat, a substrate reduction therapy, and Ambroxol, a pharmacological chaperone, offer complementary mechanisms that may enhance lysosomal function and reduce ganglioside accumulation. In a virtual Phase 1b/2 trial, simulated cohorts of children received these treatments across four dose levels (10%, 20%, 33.3%, and 50% of maximum tolerated dose [MTD]), with outcomes assessed at intervals from birth to 10 years. Key metrics included cognitive and motor function, quality of life, and lysosomal enzyme activity. Results indicated that combination therapy significantly reduced neurodegenerative symptoms and improved cognitive and motor outcomes, particularly at intermediate dose levels. Findings suggest that Miglustat and Ambroxol may provide a beneficial intervention strategy, warranting further clinical evaluation. These results also provide important potential insights into dose optimization and therapeutic synergies, offering a basis for real-world trials in Type 1 Tay-Sachs Disease. The use of aiHumanoid simulations demonstrates a novel approach for drug testing in rare diseases, enabling detailed assessment of efficacy and safety profiles across developmental stages. The trial’s findings are based on virtual simulations rather than traditional clinical trials.
The Role of Birth Companionship in Women’s Experiences of Mistreatment during Childbirth and Postpartum Depression
Authors: Hameed Waqas , Khan Bushra , Avan Bilal Iqbal 
Published: November 2024

AbstractIntroductionBirth companionship during facility-based childbirth has been recommended by the World Health Organization to improve maternal and newborn outcomes. However, limited evidence exists on how companionship affects women’s experiences of mistreatment during childbirth and their mental health.ObjectivesTo assess the characteristics of birth companionship during intrapartum care and examine its associations with women’s experiences of mistreatment and postpartum anxiety and depression.MethodsWe analysed cross-sectional data on 314 women who gave birth in six public health facilities in rural Sindh, Pakistan. Women were interviewed 42 days postpartum about their childbirth experiences and postpartum anxiety and depression. Multivariable regression models were used to examine associations between birth companionship, mistreatment, and postpartum anxiety/depression. Path analysis explored whether mistreatment mediated the relationship between companionship and postpartum anxiety and depression.ResultsMost women (83.1%) had a full-time companion in the labor room, with in-laws (44.6%) being the most common, followed by family members (26.1%) and friends (15.0%). Higher levels of companion support were associated with lower levels of mistreatment, particularly regarding non-confidential care, lack of supportive care, and ineffective communication. Women receiving low companion support were 2.86 times more likely to experience postpartum anxiety and depression compared to those receiving high support. Informational support emerged as the strongest protective factor against both mistreatment and postpartum anxiety/depression. Path analysis revealed that the effect of companion support on postpartum mental health was mediated by experiences of mistreatment during childbirth.ConclusionBirth companionship, especially informational support, plays a crucial role in reducing mistreatment during childbirth and improving maternal mental health outcomes. These findings underscore the need for supportive policies and health system interventions that actively encourage the engagement of companions from a woman’s personal network during labor and childbirth. Future research should explore strategies to optimize the role of birth companions in promoting respectful maternity care and maternal well-being.
Molnupiravir clinical trial simulation suggests that polymerase chain reaction underestimates antiviral potency against SARS-CoV-2
Authors: Esmaeili Shadisadat , Owens Katherine , Standing Joseph F. , Lowe David M. , Zhang Shengyuan , Watson James A. , Schilling William H. K. , Wagoner Jessica , Polyak Stephen J. , Schiffer Joshua T. 
Published: November 2024

AbstractMolnupiravir is an antiviral medicine that induces lethal copying errors during SARS-CoV-2 RNA replication. Molnupiravir reduced hospitalization in one pivotal trial by 50% and had variable effects on reducing viral RNA levels in three separate trials. We used mathematical models to simulate these trials and closely recapitulated their virologic outcomes. Model simulations suggest lower antiviral potency against pre-omicron SARS-CoV-2 variants than against omicron. We estimate that in vitro assays underestimate in vivo potency 7-8 fold against omicron variants. Our model suggests that because polymerase chain reaction detects molnupiravir mutated variants, the true reduction in non-mutated viral RNA is underestimated by ∼0.5 log10in the two trials conducted while omicron variants dominated. Viral area under the curve estimates differ significantly between non-mutated and mutated viral RNA. Our results reinforce past work suggesting that in vitro assays are unreliable for estimating in vivo antiviral drug potency and suggest that virologic endpoints for respiratory virus clinical trials should be catered to the drug mechanism of action.
Transcriptome-wide analyses delineate the genetic architecture of expression variation in atopic dermatitis
Authors: Antonatos Charalabos , Mitsoudi Dimitra , Pontikas Alexandros , Akritidis Adam , Xiropotamos Panagiotis , Georgakilas Georgios K. , Georgiou Sophia , Tsiogka Aikaterini , Gregoriou Stamatis , Grafanaki Katerina , Vasilopoulos Yiannis 
Published: November 2024

AbstractGenome-wide association studies (GWASs) for atopic dermatitis (AD) have uncovered 81 risk loci in European participants, however translating these findings into functional and therapeutic insights remains challenging. We conducted a transcriptome-wide association study (TWAS) in AD leveragingcis-eQTL data from 3 central AD tissues and the latest GWAS of AD in Europeans. We implemented the OTTERS pipeline that combines polygenic risk score (PRS) techniques accommodating diverse assumptions in the architecture of gene regulation. We also used differential expression datasets and co-expression networks to characterize the transcriptomic landscape of AD. We identified 176 gene-tissue associations covering 126 unique genes (53 novel). Most TWAS risk genes were identified by adaptive PRS frameworks, with non-significant differences compared to clumping and thresholding approaches. The novel TWAS risk genes were enriched in allergic reactions (e.g.,AQP7,AFF4), skin barrier integrity (e.g.,ACER3) and inflammatory pathways (e.g.,TAPBPL). By integrating co-expression networks of lesional AD skin, we identified 16 hub genes previously identified as TWAS risk genes (6 novel) that orchestrate inflammatory responses (e.g.,HSPA4) and keratinization (e.g.,LCE3E,LCE3D), serving as potential drug targets through drug-gene interactions. Collectively, our findings provide additional risk genes for AD with potential implications in therapeutic approaches.
Mobilizing community-driven public health response: increasing access to diagnostic testing for underserved and uninsured individuals in Connecticut through lab-in-a-van partnerships
Authors: Choate Brittany , Sardana Ruhani , Mathews Acsah , Weirsman Stephanie , Fajardo Katherine , Ali Yasmine , Liu Chen , Hui Pei , Schofield Kevin , Wyllie Anne L. , Levi Angelique W. 
Published: November 2024

ABSTRACTBackgroundPartnering with community leaders, we sought to address ongoing diagnostic testing needs in underserved neighborhoods and evaluate whether a saliva-based mobile testing program could help overcome barriers to testing for uninsured and low-income individuals. This is critical as many lack a primary care provider, cannot access reliable health information, or have limited financial resources.MethodsFree saliva-based, SARS-CoV-2 diagnostic testing was offered at 123 local community events in Connecticut, between June 2023 to July 2024. The SalivaDirect extraction-free RT-qPCR protocol was run on a CLIA licensed van operated by Yale Pathology Labs under FDA Emergency Use Authorization. Testing locations were identified and advertised in partnership with the community. Patient perspectives on approachability, convenience, and usefulness of mobile testing were recorded via REDcap.ResultsApproximately 100 local contacts informed the mobile testing model. Overall, 1,428 individuals participated, with 838 completing a testing experience survey. Of these, 54% identified as Black, Indigenous, People of Color; 59% reported annual household income less than $25,000; 31% were uninsured. Test results were reported in an average 3.1 hours, 48 positive samples were identified. Test takers agreed it was easy to access the van (74%) and felt comfortable (75%); 29% received their first COVID-19 test at the van; 48% were unaware of alternate testing; 44% reported difficulty accessing health care; and 49% identified transportation as a challenge.ConclusionsThis study demonstrated the positive impact mobile testing could have for overcoming barriers to accessing healthcare, and its potential to serve as a framework for managing and responding to future public health needs.
Coordinated protein modules define DNA damage responses to carboplatin at single cell resolution in human ovarian carcinoma models
Authors: Bedia Jacob S. , Huang Ying-Wen , Gonzalez Antonio Delgado , Gonzalez Veronica D. , Funingana Ionut-Gabriel , Rahil Zainab , Mike Alyssa , Lowber Alexis , Vias Maria , Ashworth Alan , Brenton James D. , Fantl Wendy J. 
Published: November 2024

AbstractTubo-ovarian high-grade serous carcinoma (HGSC) is the most lethal gynecological malignancy and frequently responds to platinum-based chemotherapy because of common genetic and somatic impairment of DNA damage repair (DDR) pathways. The mechanisms of clinical platinum resistance are diverse and poorly molecularly defined. Consequently, there are no biomarkers or medicines that improve patient outcomes. Herein we use single cell mass cytometry (CyTOF) to systematically evaluate the phosphorylation and abundance of proteins known to participate in the DNA damage response (DDR). Single cell analyses of highly characterized HGSC cell lines that phenocopy human patients show that cells with comparable levels of intranuclear platinum, a proxy for carboplatin uptake, undergo different cell fates. Unsupervised analyses revealed a continuum of DDR responses. Decompositional methods were used to identify eight distinct protein modules of carboplatin resistance and sensitivity at single cell resolution. CyTOF profiling of primary and secondary platinum-resistance patient models shows that a complex DDR sensitivity module is strongly associated with response, suggesting it as a potential tool to clinically characterize complex drug resistance phenotypes.
Cardiolipin-mimic lipid nanoparticles without antibody modification delivered senolytic in-vivo CAR-T therapy for inflamm-aging
Authors: Zhang Zihan , Ma Bin , Li Buyao , Li Zhiwei , Gao Min , Zhao Hailong , Peng Rui , Hu Jiang , Wang Yu , You Wei , Gui Xun , Wang Rui , Hu Xiaoqing , Chen Beidi , Zhang Yuanjie , Hao Yanyun , Zhou Demin , Yang Yun , Deng Mi , Miao Lei 
Published: November 2024

AbstractmRNA-based in vivo CAR T cell engineering offers advantages over ex vivo therapies, including streamlined manufacturing and transient expression. However, current delivery requires antibody-modified vehicles with manufacturing challenges. In this study, inspired by cardiolipin, we identified a cardiolipin-like di-phosphoramide lipid that improved T cell transfection without targeting ligands, both in vivo and in vitro. The T cell-favored tropism is likely due to the lipid’s packing, shape, and rigidity. Encapsulating circular RNA further prolonged mRNA expression in the spleen and T cells. Using PL40 lipid nanoparticles, we delivered mRNA encoding a CAR targeting the senolytic and inflammatory antigen urokinase-type plasminogen activator receptor (uPAR), alleviating uPAR-related liver fibrosis and rheumatoid arthritis (RA). Single cell sequencing in humans confirmed uPAR’s relevance to senescence and inflammation in RA. To further enhance clinical translation, we screened and humanized scFvs against uPAR, establishing PL40 mRNA encoding a circular human uPAR CAR, with potential for treating aging-inflamed disorders.One Sentence SummaryWe’ve developed a unique class of Cardiolipin-mimic lipids that facilitate mRNA delivery to T cells in vivo without the need for antibody modification, enhancing the treatment of liver fibrosis and rheumatoid arthritis through circular CAR uPAR RNA and propelling the clinical application of humanized CAR against human uPAR.
Sustained non-photochemical quenching and regulation of PSII repair cycle during combined low temperature and high light stress in lettuce
Authors: Lempiäinen Tapio , Muth-Pawlak Dorota , Vainonen Julia P. , Rintamäki Eevi , Tikkanen Mikko , Aro Eva-Mari 
Published: November 2024

AbstractIn nature, light and other environmental conditions are constantly changing, requiring plants to have several overlapping regulatory mechanisms to keep light reactions and metabolism in balance. Here, we show that high light (HL) induces a much stronger down-regulation of light reactions when lettuce plants are exposed to 1500 µmol photons m−2s−1for 4 h at 13°C (low temperature, LT) compared to 23°C (growth temperature, GT). GT/HL treatment induced non-photochemical quenching (NPQ), which relaxed during 1 h recovery in darkness. In contrast, LT/HL treatment induced an exceptionally high NPQ that only partially relaxed during 1 h in darkness at GT. Such a high sustained NPQ (sNPQ) cannot be explained by canonical NPQ mechanism(s). Instead, sNPQ was associated with partial disassembly of PSII-LHCII complexes and a transient increase in phosphorylation of the minor antenna proteins LHCB4.1/LHCB4.2. This coincided with increased expression of the light-harvesting-like proteins SEP2 and ELIP1.2, the PSII assembly proteins HCF173 and LPA3, and accumulation of the pre-D1 protein. These results lead us to propose that LHCB4.1/LHCB4.2 phosphorylation- dependent disassembly of PSII-LHCII supercomplexes allows SEP2 to bind to CP47 and hypothetically quenches the inner PSII core antenna, while free CP43 released during PSII repair is proposed to be protected by LPA3.
Impact of Acute Endurance Exercise on Alternative Splicing in Skeletal Muscle
Authors: Ahn Alexander , Kim Jeongjin J. , Slusher Aaron L. , Ying Jeffrey Y. , Zhang Eric Y. , Ludlow Andrew T. 
Published: November 2024

ABSTRACTPurposeAlternative RNA splicing (AS) is a highly conserved post-transcriptional mechanism, generating mRNA variants to diversify the proteome. Acute endurance exercise appears to transiently perturb AS in skeletal muscle, but transcriptome-wide responses are not well-defined. We aimed to better understand differential AS (DAS) in skeletal muscle by comparing short-read RNA sequencing (SRS) and long-read RNA sequencing (LRS) data.MethodsPublicly accessible SRS of clinical exercise studies were extracted from the Gene Expression Omnibus. Oxford Nanopore LRS was performed on mouse gastrocnemius before and following treadmill exercise. Differential gene expression (DGE), DAS, and isoform switching were analyzed. Western blots were performed to validate expression changes of candidate genes.ResultsBoth SRS and LRS illustrated significant DGE in skeletal muscle post-exercise, whereby 57 and 15 RNA-binding proteins (RBPs) were up-/down-regulated, respectively. rMATS analysis of SRS data revealed that exon-skipping and intron-retaining splicing events were the most common. Swan analysis of LRS data revealed 38 RBPs with significant isoform switching: one of these RBPs,Hnrnpa3, underwent a significant intron-retained to protein-coding switch. HnRNP-A3 protein levels validated nearly two-fold increases at 1 hour (p=.0043) and 24 hours (p=.0103) post-exercise.ConclusionsThis study illustrates that acute endurance exercise can elicit changes in AS-related responses and RBP expression in skeletal muscle. SRS is certainly a powerful tool for analyzing DGE but lacks AS detection. As such, “hidden” genes with no transcriptional changes but significant DAS and protein expression changes pose a major gap in knowledge. Our work highlights how LRS can uncover previously unknown transcript diversity and mechanisms influencing endurance exercise adaptations and responses.