bluuebunny/crossref_metadata_2025_split huggingface dataset:
Detecting Full-Length EccDNA with FLED and long-reads sequencing
Authors: Li Fuyu , Ming Wenlong , Lu Wenxiang , Wang Ying , Li Xiaohan , Dong Xianjun , Bai Yunfei 
Published: June 2023

AbstractReconstructing the full-length sequence of extrachromosomal circular DNA (eccDNA) from short sequencing reads has proved challenging given the similarity of eccDNAs and their corresponding linear DNAs. Previous sequencing methods were unable to achieve high-throughput detection of full-length eccDNAs. Here we describe a new strategy that combined rolling circle amplification (RCA) and nanopore long-reads sequencing technology to generate full-length eccDNAs. We further developed a novel algorithm, called Full-Length eccDNA Detection (FLED), to reconstruct the sequence of eccDNAs. We used FLED to analyze seven human epithelial and cancer cell line samples and identified over 5,000 full-length eccDNAs per sample. The structures of identified eccDNAs were validated by both PCR and Sanger sequencing. Compared to other published nanopore-based eccDNA detectors, FLED exhibited higher sensitivity. In cancer cell lines, the genes overlapped with eccDNA regions were enriched in cancer-related pathways andcis-regulatory elements can be predicted in the up-stream or downstream of intact genes on eccDNA molecules, and the expressions of these cancer-related genes were dysregulated in tumor cell lines, indicating the regulatory potency of eccDNAs in biological processes. Our method takes advantage of nanopore long reads and enables unbiased reconstruction of full-length eccDNA sequences. FLED is imple-mented using Python3 which is freely available on GitHub (https://github.com/FuyuLi/FLED).
Calcineurin inhibition enhancesCaenorhabditis eleganslifespan by defecation defects-mediated calorie restriction and nuclear hormone signaling
Authors: Das Priyanka , Aballay Alejandro , Singh Jogender 
Published: June 2023

AbstractCalcineurin is a highly conserved calcium/calmodulin-dependent serine/threonine protein phosphatase with diverse functions. Inhibition of calcineurin is known to enhance the lifespan ofCaenorhabditis elegansthrough multiple signaling pathways. Aiming to study the role of calcineurin in regulating innate immunity, we discover that calcineurin is required for the rhythmic defecation motor program (DMP) inC. elegans. Calcineurin inhibition leads to defects in the DMP, resulting in intestinal bloating, rapid colonization of the gut by bacteria, and increased susceptibility to bacterial infection. We demonstrate that intestinal bloating caused by calcineurin inhibition mimics the effects of calorie restriction, resulting in enhanced lifespan. The TFEB ortholog, HLH-30, is required for lifespan extension mediated by calcineurin inhibition. Finally, we show that the nuclear hormone receptor, NHR-8, is upregulated by calcineurin inhibition and is necessary for the increased lifespan. Our studies uncover a role for calcineurin in theC. elegansDMP and provide a new mechanism for calcineurin inhibition-mediated longevity extension.
SARS-CoV-2 virologic rebound with nirmatrelvir-ritonavir therapy
Authors: Edelstein Gregory E. , Boucau Julie , Uddin Rockib , Marino Caitlin , Liew May Y. , Barry Mamadou , Choudhary Manish C. , Gilbert Rebecca F. , Reynolds Zahra , Li Yijia , Tien Dessie , Sagar Shruti , Vyas Tammy D. , Kawano Yumeko , Sparks Jeffrey A. , Hammond Sarah P. , Wallace Zachary , Vyas Jatin M. , Barczak Amy K. , Lemieux Jacob E. , Li Jonathan Z. , Siedner Mark J. 
Published: June 2023

AbstractObjectiveTo compare the frequency of replication-competent virologic rebound with and without nirmatrelvir-ritonavir treatment for acute COVID-19. Secondary aims were to estimate the validity of symptoms to detect rebound and the incidence of emergent nirmatrelvir-resistance mutations after rebound.DesignObservational cohort study.SettingMulticenter healthcare system in Boston, Massachusetts.ParticipantsWe enrolled ambulatory adults with a positive COVID-19 test and/or a prescription for nirmatrelvir-ritonavir.ExposuresReceipt of 5 days of nirmatrelvir-ritonavir treatment versus no COVID-19 therapy.Main Outcome and MeasuresThe primary outcome was COVID-19 virologic rebound, defined as either (1) a positive SARS-CoV-2 viral culture following a prior negative culture or (2) two consecutive viral loads ≥4.0 log10copies/milliliter after a prior reduction in viral load to <4.0 log10copies/milliliter.ResultsCompared with untreated individuals (n=55), those taking nirmatrelvir-ritonavir (n=72) were older, received more COVID-19 vaccinations, and were more commonly immunosuppressed. Fifteen individuals (20.8%) taking nirmatrelvir-ritonavir experienced virologic rebound versus one (1.8%) of the untreated (absolute difference 19.0% [95%CI 9.0-29.0%], P=0.001). In multivariable models, only N-R was associated with VR (AOR 10.02, 95%CI 1.13-88.74). VR occurred more commonly among those with earlier nirmatrelvirritonavir initiation (29.0%, 16.7% and 0% when initiated days 0, 1, and ≥2 after diagnosis, respectively, P=0.089). Among participants on N-R, those experiencing rebound had prolonged shedding of replication-competent virus compared to those that did not rebound (median: 14 vs 3 days). Only 8/16 with virologic rebound reported worsening symptoms (50%, 95%CI 25%-75%); 2 were completely asymptomatic. We detected no post-rebound nirmatrelvir-resistance mutations in the NSP5 protease gene.Conclusions and RelevanceVirologic rebound occurred in approximately one in five people taking nirmatrelvir-ritonavir and often occurred without worsening symptoms. Because it is associated with replication-competent viral shedding, close monitoring and potential isolation of those who rebound should be considered.
Healthy adults possess cross-reactive neuraminidase inhibition antibodies to an A(H5N1) clade 2.3.4.4b avian influenza virus A/Black Faced Spoonbill/Hong Kong/AFCD-HKU-22-21429-01012/2022
Authors: Daulagala Pavithra , Cheng Samuel M. S. , Chin Alex W. H. , Luk Leo L. H. , Leung Kathy , Wu Joseph T. , Poon Leo L. M. , Peiris Malik , Yen Hui-Ling 
Published: June 2023

AbstractHemagglutination inhibition (HI) and neuraminidase inhibition (NI) antibodies to a clade 2.3.4.4b A(H5N1) highly pathogenic avian influenza virus were measured in 63 age-stratified healthy adults in Hong Kong. No HI antibody was detected; 61 subjects had detectable NI antibodies to A(H5N1). NI titers to A(H5N1) and A(H1N1)pdm09 viruses were correlated.
ecode: An R package to investigate community dynamics in ordinary differential equation systems
Authors: Wu Haoran 
Published: June 2023

AbstractPopulation dynamical modelling plays a crucial role in understanding ecological populations and making informed decisions for environmental management. However, existing software packages for dynamical system modelling often lack comprehensive integration of techniques and guidelines, limiting their practical usability. This paper introduces ecode, a novel package for modelling ecological populations and communities using ordinary differential equation systems, designed with a user-friendly framework. By following a three-cycle procedure, users can easily construct ecological models and explore their behaviours through a wide range of graphical, analytical, and numerical techniques. The package incorporates advanced techniques such as grid search methods and simulated annealing algorithms, enabling users to iteratively refine their models and achieve accurate predictions. Notably, ecode minimises external dependencies, ensuring robustness and reducing the risk of package failure caused by updates in dependencies. Overall, ecode serves as a valuable tool for ecological modelling, facilitating the exploration of complex ecological systems and the generation of informed predictions and management recommendations.
Q-BioLiP: A Comprehensive Resource for Quaternary Structure-based Protein–ligand Interactions
Authors: Wei Hong , Wang Wenkai , Peng Zhenling , Yang Jianyi 
Published: June 2023

AbstractSince its establishment in 2013, BioLiP has become one of the widely used resources for protein–ligand interactions. Nevertheless, several known issues occurred with it over the past decade. For example, the protein–ligand interactions are represented in the form of single chain-based tertiary structures, which may be inappropriate as many interactions involve multiple protein chains (known as quaternary structures). We sought to address these issues, resulting in Q-BioLiP, a comprehensive resource for quaternary structure-based protein–ligand interactions. The major features of Q-BioLiP include: (1) representing protein structures in the form of quaternary structures rather than single chain-based tertiary structures; (2) pairing DNA/RNA chains properly rather than separation; (3) providing both experimental and predicted binding affinities; (4) retaining both biologically relevant and irrelevant interactions to alleviate the problem of the wrong justification of ligands’ biological relevance; and (5) developing a new quaternary structure-based algorithm for the modelling of protein–ligand complex structure. With these new features, Q-BioLiP is expected to be a valuable resource for studying biomolecule interactions, including protein–small molecule, protein–peptide, protein–protein, and protein–DNA/RNA. Q-BioLiP is freely available athttps://yanglab.qd.sdu.edu.cn/Q-BioLiP/.
Follow-Up In Patients With Respiratory Disability After ARDS Related To COVID-19: A Systematic Review
Authors: Triantafyllaki Panagiota , Charalampopoulos Marios , Sampani Christina-Athanasia , Triantafyllou Christos , Papageorgiou Dimitrios 
Published: June 2023

AbstractIntroductionAcute Respiratory Distress Syndrome (ARDS) is an acute inflammatory pulmonary process that leads to protein-rich, non-hydrostatic pulmonary edema, undesirable hypoxemia, and lung stiffness. Due to COVID-19, a significant proportion of people who will require hospitalization to treat COVID-19, between 15%-30%, will develop severe respiratory failure, ARDS, and an increased likelihood of intubation for mechanical respiratory support.AimTo investigate the pulmonary function in COVID-19-related ARDS survivors after hospitalization.MethodsA search was performed on the Greek and international literature, as well as at the online Databases PubMed, Cochrane, Embase, and Google Scholar. Exclusion and integration criteria were set for the studies found, and a flow chart was created for the studies included.ResultsThrough the search, 352 articles were found matching the subject under study, and after further evaluation, four articles were included. The majority of the articles highlight that after ARDS occurs due to COVID-19, patients face impaired pulmonary function in combination with other physical and psychological symptoms like weakness, anxiety, depression, and generalized functional disability.ConclusionsIt is a fact that COVID-19 disease, in severe form and following the need for hospitalization due to the development of ARDS, results in an increased likelihood of prolonged occurrence of some symptoms of impaired respiratory function. Impaired CO2 diffusion is observed in the majority of studies as well as impaired respiratory function regarding prolonged imaging findings and impaired physical function.
Lysosomal mitochondrial interaction promotes tumor growth in squamous cell carcinoma of the head and neck
Authors: Gopalkrishnan Avani , Wang Nathaniel , Cruz-Rangel Silvia , Kassab Abdul Yassin- , Shiva Sruti , Kurukulasuriya Chareeni , Monga Satdarshan P. , DeBerardinis Ralph J , Kiselyov Kirill , Duvvuri Umamaheswar 
Published: June 2023

AbstractTumor growth and proliferation are regulated by numerous mechanisms. Communication between intracellular organelles has recently been shown to regulate cellular proliferation and fitness. The way lysosomes and mitochondria communicate with each other (lysosomal/mitochondrial interaction) is emerging as a major determinant of tumor proliferation and growth. About 30% of squamous carcinomas (including squamous cell carcinoma of the head and neck, SCCHN) overexpress TMEM16A, a calcium-activated chloride channel, which promotes cellular growth and negatively correlates with patient survival. TMEM16A has recently been shown to drive lysosomal biogenesis, but its impact on mitochondrial function is unclear. Here, we show that (1) patients with high TMEM16A SCCHN display increased mitochondrial content specifically complex I; (2)In vitroandin vivomodels uniquely depend on mitochondrial complex I activity for growth and survival; (3) β-catenin/NRF2 signaling is a critical linchpin that drives mitochondrial biogenesis, and (4) mitochondrial complex I and lysosomal function are codependent for proliferation. Taken together, our data demonstrate that LMI drives tumor proliferation and facilitates a functional interaction between lysosomes and mitochondria. Therefore, inhibition of LMI may serve as a therapeutic strategy for patients with SCCHN.
On the pH-dependence of α-synuclein amyloid polymorphism and the role of secondary nucleation in seed-based amyloid propagation
Authors: Frey Lukas , Ghosh Dhiman , Qureshi Bilal M. , Rhyner David , Guerrero-Ferreira Ricardo , Pokharna Aditya , Kwiatkowski Witek , Serdiuk Tetiana , Picotti Paola , Riek Roland , Greenwald Jason 
Published: June 2023

AbstractThe aggregation of the protein α-synuclein is closely associated with several neurodegenerative disorders and as such the structures of the amyloid fibril aggregates have high scientific and medical significance. However, there are dozens of unique atomic-resolution structures of these aggregates, and such a highly polymorphic nature of the α-synuclein fibrils hampers efforts in disease-relevantin vitrostudies on α-synuclein amyloid aggregation. In order to better understand the factors that affect polymorph selection, we studied the structures of α-synuclein fibrilsin vitroas a function of pH and buffer using cryo-EM helical reconstruction. We find that in the physiological range of pH 5.8-7.4 a pH- dependent selection between Types 1, 2 and 3 polymorphs occurs. Our results indicate that even in the presence of seeds, the polymorph selection during aggregation is highly dependent on the buffer conditions, attributed to the non-polymorph-specific nature of secondary nucleation. We also uncovered two new polymorphs that occur at pH 7.0 in phosphate-buffered saline. The first is a monofilament Type 1 fibril that highly resembles the structure of the juvenile-onset synucleinopathy polymorph found in patient-derived material. The second is a new Type 5 polymorph that resembles a polymorph that has been recently reported in a study that used diseased tissues to seed aggregation. Taken together, our results highlight the shallow amyloid energy hypersurface that can be altered by subtle changes in the environment, including the pH which is shown to play a major role in polymorph selection and in many cases appears to be the determining factor in seeded aggregation. The results also suggest the possibility of producing disease-relevant structurein vitro.
A monocarboxylate transporter rescues frontotemporal dementia and Alzheimer’s disease models
Authors: Xu Dongwei , Vincent Alec , González-Gutiérrez Andrés , Aleyakpo Benjamin , Anoar Sharifah , Giblin Ashling , Atilano Magda L , Adams Mirjam , Shen Dunxin , Thoeng Annora , Tsintzas Elli , Maeland Marie , Isaacs Adrian M , Sierralta Jimena , Niccoli Teresa 
Published: June 2023

AbstractBrains are highly metabolically active organs, consuming 20% of an organisms’ energy at resting state. A decline in glucose metabolism is a common feature across a number of neurodegenerative diseases. Another common feature is the progressive accumulation of insoluble protein deposits, it’s unclear if the two are linked.Glucose metabolism in the brain is highly coupled between neurons and glia, with glucose taken up by glia and metabolised to lactate, which is then shuttled via transporters to neurons, where it is converted back to pyruvate and fed into the TCA cycle for ATP production. Monocarboxylates are also involved in signalling, and play broad ranging roles in brain homeostasis and metabolic reprogramming. However, the role of monocarboxylates in dementia has not been tested.Here, we find that increasing pyruvate import inDrosophilaneurons by over-expression of the transporterbumpel, leads to a rescue of lifespan and behavioural phenotypes in fly models of both frontotemporal dementia and Alzheimer’s disease. The rescue is linked to a clearance of late stage autolysosomes, leading to degradation of toxic peptides associated with disease. We propose upregulation of pyruvate import into neurons as potentially a broad-scope therapeutic approach to increase neuronal autophagy, which could be beneficial for multiple dementias.
Severe fire regimes decrease resilience of ectothermic populations
Authors: de Sousa Heitor Campos , Malvasio Adriana , Colli Guarino Rinaldi , Salguero-Gómez Roberto 
Published: June 2023

AbstractUnderstanding populations’ responses to environmental change is crucial for mitigating human-induced disturbances.Here, we test hypotheses regarding how three essential components of demographic resilience (resistance, compensation, and recovery) co-vary along the distinct life histories of three lizard species exposed to variable, prescribed fire regimes.Using a Bayesian hierarchical framework, we estimate vital rates (survival, growth, and reproduction) with 14 years of monthly individual-level data and mark-recapture models to parameterize stochastic Integral Projection Models from five sites in Brazilian savannas, each historically subjected to different fire regimes. With these models, we investigate how weather, microclimate, and ecophysiological traits of each species influence their vital rates, emergent life history traits, and demographic resilience components in varying fire regimes.Overall, weather and microclimate are better predictors of the species’ vital rates, rather than their ecophysiological traits. Our findings reveal that severe fire regimes increase populations’ resistance, but decrease compensation or recovery abilities. Instead, populations have higher compensatory and recovery abilities at intermediate degrees of fire severity. Additionally, we identify generation time and reproductive output as predictors of resilience trends across fire regimes and climate. Our analyses demonstrate that the probability and quantity of monthly reproduction are the proximal drivers of demographic resilience across the three species.Our findings suggest that populations surpass a tipping point in severe fire regimes and achieve an alternative stable state to persist. Thus, higher heterogeneity in fire regimes can increase the reproductive aspects and resilience of different populations and avoid high-severity regimes that homogenize the environment. Despite being more resistant, species with long generation times and low reproductive output take longer to recover and cannot compensate as much as species with faster paces of life. We emphasize how reproductive constraints, such as viviparity and fixed clutch sizes, impact the ability of ectothermic populations to benefit and recover from disturbances, underscoring their relevance in conservation assessments.
Development and validation of NAD+metabolism-related gene signature in prognosis prediction of hepatocellular carcinoma
Authors: Du Yiheng 
Published: June 2023

AbstractLiver cancer is a prevalent and deadly malignancy worldwide, with a rising incidence rate. In this study, we focused on the role of NAD+metabolism-related genes in liver cancer prognosis prediction. We identified key genes among NAD+metabolism-related genes and explored their relationship with cancer staging and prognosis using gene expression data. A risk score model was constructed to assess cancer risk and survival status. The model demonstrated significant predictive potential for survival outcomes. Furthermore, we analyzed the risk scores in different populations and performed functional enrichment analyses to gain insights into the biological processes involved. Our study highlights the clinical value and significance of NAD+metabolism-related genes in liver cancer. The findings provide a foundation for personalized treatment strategies and open new avenues for further research in liver cancer management.
Development and validation of a population pharmacokinetic model to guide perioperative tacrolimus dosing after lung transplantation
Authors: Miano Todd A. , Feng Rui , Griffiths Stephen , Kalman Laurel , Oyster Michelle , Cantu Edward , Yang Wei , Diamond Joshua M. , Christie Jason D. , Scheetz Marc H. , Shashaty Michael G. S. 
Published: June 2023

AbstractBackgroundTacrolimus therapy is standard of care for immunosuppression after lung transplantation. However, tacrolimus exposure variability during the early postoperative period may contribute to poor outcomes in this population. Few studies have examined tacrolimus pharmacokinetics (PK) during this high-risk time period.MethodsWe conducted a retrospective pharmacokinetic study in lung transplant recipients at the University of Pennsylvania who were enrolled in the Lung Transplant Outcomes Group (LTOG) cohort. We derived a model in 270 patients using NONMEM (version 7.5.1) and examined validity in a separate cohort of 114 patients. Covariates were examined with univariate analysis and multivariable analysis was developed using forward and backward stepwise selection. Performance of the final model in the validation cohort was examined with calculation of mean prediction error (PE).ResultsWe developed a one-compartment base model with a fixed rate absorption constant. Significant covariates in multivariable analysis were postoperative day, hematocrit, transplant type,CYP3A5genotype, total body weight, and time-varying postoperative day, hematocrit, and CYP inhibitor drugs. The strongest predictor of tacrolimus clearance was postoperative day, with median predicted clearance increasing more than threefold over the 14 day study period. In the validation cohort, the final model showed a mean PE of 36.4% (95%CI 30.8%-41.9%) and a median PE of 7.2% (IQR −29.3%−70.53%).ConclusionPostoperative day was the strongest predictor of tacrolimus exposure in the early post-lung transplant period. Future multicenter studies employing intensive sampling to examine a broad set of variables related to critical illness physiology are needed to understand determinants of clearance, volume of distribution and absorption in this population.