bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pre-clinical validation of an RNA-based precision oncology platform for patient-therapy alignment in a diverse set of human malignancies resistant to standard treatments
Authors: Mundi Prabhjot S. , Dela Cruz Filemon S. , Grunn Adina , Diolaiti Daniel , Mauguen Audrey , Rainey Allison R. , Guillan Kristina C. , Siddiquee Armaan , You Daoqi , Realubit Ronald , Karan Charles , Ortiz Michael V. , Accordino Melissa , Mistretta Suzanne , Brogan Frances , Bruce Jeffrey N. , Caescu Cristina I. , Carvajal Richard , Crew Katherine , Decastro Guarionex , Heaney Mark , Henick Brian , Hershman Dawn , Hou June , Iwamoto Fabio , Jurcic Joseph , Kiran Ravi P. , Kluger Michael , Kreisl Teri , Lamanna Nicole , Lassman Andrew , Lim Emerson , Manji Gulam A. , McKhann Guy , McKiernan James , Neugut Alfred , Olive Kenneth , Rosenblat Todd , Schwartz Gary K. , Shu Catherine , Sisti Michael , Tergas Ana , Vattakalam Reena , Welch Mary , Wenske Sven , Wright Jason D. , Hibshoosh Hanina , Kalinsky Kevin , Aburi Mahalaxmi , Sims Peter A. , Alvarez Mariano J. , Kung Andrew L. , Califano Andrea 
Published: October 2021

AbstractPredicting tumor sensitivity to antineoplastics remains an elusive challenge, with no methods demonstrating predictive power. Joint analysis of tumors—from patients with distinct malignancies who had progressed on multiple lines of therapy—and drug perturbation transcriptional profiles predicted sensitivity to 28 of 350 drugs, 26 of which (93%) were confirmed in low-passage, patient-derived xenograft (PDX) models. Drugs were prioritized based on their ability to either invert the activity of individual Master Regulator proteins, with available high-affinity inhibitors, or of the modules they comprise (Tumor-Checkpoints), based on de novo mechanism of action analysis. Of 138 PDX mice enrolled in 16 single and 18 multi-protein treatment arms, a disease control rate (DCR) of 68% and 91 %, and an objective response rate (ORR) of 12% and 17%, were achieved respectively, compared to 6% and 0% in the negative controls arm, with multi-protein drugs achieving significantly more durable responses. Thus, these approaches may effectively complement and expand current precision oncology approaches, as also illustrated by a case study.
Allometric scaling of RNA abundance from genes to communities
Authors: Lopez Mark Louie D. , Lin Ya-ying , Schneider Stephan Q. , Machida Ryuji J. 
Published: October 2021

AbstractThe metabolic theory of ecology (MTE) and growth rate hypothesis (GRH) help explain the mechanistic basis of size (allometry) and temperature dependence on growth rate and whole-body-RNA content in organisms. However, testing RNA allometric scaling with next-generation sequencing is yet to be done. Here, we validated the assumptions of GRH and MTE on messenger RNA and ribosome abundance using mock community metatranscriptome analysis. Our findings highlight that fast-growing smaller species harbor greater RNA abundance per mass of tissue compared with species having larger body sizes and slower growth rates, where allometric slopes for genomic and gene-level RNA abundance range from –⅓ to −1. We found that genome size and body size impose significant constraints in interspecific RNA abundance scaling, while the assumed temperature dependence appeared to be weak. Lastly, allometric scaling integration in community-level models may extend the use of metatranscriptomics as a reliable tool for estimating ecosystem processes.
COVID-19 aerosol transmission simulation-based risk analysis for in-person learning
Authors: Swanson Tessa , Guikema Seth , Bagian James , Schemanske Christopher , Payne Claire 
Published: October 2021

AbstractAs educational institutions begin a school year following a year and a half of disruption from the COVID-19 pandemic, risk analysis can help to support decision-making for resuming in-person instructional operation by providing estiamtes of the relative risk reduction due to different interventions. In particular, a simulation-based risk analysis approach enables scenario evaluation and comparison to guide decision making and action prioritization under uncertainty. We develop a simulation model to characterize the risks and uncertainties associated with infections resulting from aerosol exposure in in-person classes. We demonstrate this approach by applying it to model a semester of courses in a real college with approximately 11,000 students embedded within a larger university. To have practical impact, risk cannot focus on only infections as the end point of interest, we estimate the risks of infection, hospitalizations, and deaths of students and faculty in the college. We incorporate uncertainties in disease transmission, the impact of policies such as masking and facility interventions, and variables outside of the college’s control such as population-level disease and immunity prevalence. We show in our example application that universal use of masks that block 40% of aerosols and the installation of near-ceiling, fan-mounted UVC systems both have the potential to lead to substantial risk reductions and that these effects can be modeled at the individual room level. These results exemplify how such simulation-based risk analysis can inform decision making and prioritization under great uncertainty.
Impairment of CSF Egress through the Cribriform Plate plays an Apical role in Alzheimer’s disease Etiology
Authors: Zaragoza Ricardo , Miulli Daniel , Kashyap Samir , Carson Tyler A , Obenaus Andre , Siddiqi Javed , Ethell Douglas W 
Published: October 2021

AbstractCerebrospinal fluid (CSF) clears the brain’s interstitial spaces, and disruptions in CSF flow or egress impact homeostasis, contributing to various neurological conditions. Here, we recast the human cribriform plate from innocuous bony structure to complex regulator of CSF egress with an apical role in Alzheimer’s disease etiology. It includes the pathological evaluation of 70 post-mortem samples using high-resolution contrast-enhanced micro-CT and cutting-edge machine learning, a novel ferret model of neurodegeneration, and a clinical study with 560 volunteers, to provide conclusive evidence of a relationship between cribriform plate aging/pathology and cognitive impairment. Interstitial spaces within the medial temporal lobe and basal forebrain are cleared by CSF flow that drains through olfactory structures to the olfactory bulb—directly above the cribriform plate. We characterized CSF flow channels from subarachnoid spaces under the olfactory bulb to the nasal mucosa through subarachnoid evaginations that subdivide into tiny tubules that connect to an elaborate conduit system within the cribriform plate. These conduits form an internal watershed that runs from the crista galli’s vault to a bony manifold within the olfactory fossa’s back wall, connecting with large apertures in between. We found that the cross-sectional area of apertures limits CSF flux through the cribriform plate, which declines with increasing age. Subjects with a confirmed post-mortem diagnosis of Alzheimer’s disease had the smallest CSF flux capacity, which reduces CSF-mediated clearance in upstream areas and leads to the accumulation of toxic macromolecules that seen AD pathology. We surgically occluded apertures in adult ferrets and found that this manipulation induced progressive deficits in spatiotemporal memory and significant atrophy of the temporal lobe, olfactory bulbs, and lateral olfactory stria. Finally, we explored human cribriform plate aging/pathology and cognition in a clinical study with 560 participants (20-95y). We evaluated cribriform plate morphology with CT and Deep Learning, assessed memory with a novel touch screen platform, tested olfactory discrimination, and asked questions about family history and relevant life events, like broken noses. Deep learning algorithms effectively parsed subjects and established the feasibility of predicting Alzheimer’s disease years before a clinical presentation of cognitive impairment. This study provides a new perspective of the cribriform plate as a critical regulator of CSF egress and brain homeostasis.
Covariate clustering: women with breast cancer in southwestern Paraná, Brazil
Authors: Romeiro Neyva M. L. , Panis Carolina , dos Santos Mara C.T. , Rech Daniel , Natti Paulo L. , Cirilo Eliandro R. 
Published: October 2021

ABSTRACTDue to the high incidence and aggressiveness of breast cancer, the understanding of specific factors associated with the profile of the disease is necessary. In this context, the aim of the study was to analyze data from 155 patients with breast cancer, attended at a reference hospital for Oncology of the Unified Health System (SUS), in the period 2015-2020, in the southwest region of Paraná, Brazil. Using multivariate statistical analysis, sample data were divided into three clusters. The heterogeneity between clusters was obtained by Ward’s method. The clinical and pathological variables obtained from the patients’ medical records were: presence of intratumoral emboli, presence of lymph nodes, menopausal status, molecular subtype of breast cancer, histological grade, TNM staging of the disease, tumor size (cm), age at diagnosis (years), weight (kg), height (m2) and body mass index (BMI) (kg/m2). From the data of the total sample, it is observed that 70% of the patients were in menopause at diagnosis, 31.5% had tumors containing emboli, and 41% had positive lymph nodes. The prevalence of Luminal subtype B tumors, intermediate histological grade, and TNM staging II was verified. Furthermore, the prevalence of the disease was higher in women aged over 50 years, representing 66% of cases. The BMI of the patients ranged from 17.63 kg/m2to 51.26 kg/m2, with 26.45% of the patients with a BMI below 25 kg/m2, 40.65% with a BMI between 25 kg/m2and 30 kg/m2and 32.9% with BMI above 30 kg/m2. Cluster analysis, using the spatial distribution of patients, showed that the region of Vale do Iguaçu was the region with the worst averages for clinical-pathological variables, while the region of Vale do Marrecas had the highest number of breast cancer cases.
A randomized placebo-controlled clinical trial of Nicotinamide Riboside and Pterostilbene supplementation in experimental muscle injury in elderly subjects
Authors: Jensen Jonas Brorson , Dollerup Ole L. , Møller Andreas B. , Billeskov Tine B. , Dalbram Emilie , Chubanava Sabina , Dellinger Ryan W. , Trost Kajetan , Moritz Thomas , Ringgaard Steffen , Møller Niels , Treebak Jonas T. , Farup Jean , Jessen Niels 
Published: October 2021

AbstractBackgroundMaintenance and regeneration of functional skeletal muscle are dependent on a sufficient pool of muscle stem cells (MuSCs). During ageing there is a functional decline in this cellular pool which influences the regenerative capacity of skeletal muscle. Preclinical evidence have suggested that Nicotinamide Riboside (NR) and Pterostilbene (PT) can improve muscle regeneration e.g. by increasing MuSC function. The objective of the present study was to investigate if NRPT supplementation promotes skeletal muscle regeneration after muscle injury in elderly humans by improved recruitment of MuSCs.MethodsIn a randomized, double-blinded, placebo-controlled trial, 32 elderly men and women (55-80 yr) received daily supplementation with either NRPT (1000 mg NR + 200 mg PT) or matched placebo. Two weeks after initiation of supplementation, a skeletal muscle injury was applied in the vastus lateralis part of the quadriceps femoris muscle by electrically induced eccentric muscle work in a dynamometer. Skeletal muscle biopsies were obtained pre, 2h, 2, 8, and 30 days post injury. The main outcome of the study was change in MuSC content 8 days post injury.Results31 enrolled subjects completed the entire protocol. The muscle work induced a substantial skeletal muscle injury in the study participants and was associated with release of myoglobin and creatine kinase, muscle soreness, tissue edema, and a decrease in muscle strength. MuSC content increased by 107% 8 days post injury (p= 0.0002) but with no effect of NRPT supplementation (p=0.58 for supplementation effect). MuSC proliferation and cell size revealed a large demand for recruitment post injury but was not affected by NRPT. Furthermore, histological analyses of muscle fiber area, internal nuclei and embryonic Myosin Heavy Chain showed no effect of NRPT supplementation.ConclusionDaily supplementation with 1000 mg NR + 200 mg PT is safe but does not improve recruitment of the MuSC pool or other measures of muscle recovery in response to injury or subsequent regeneration in elderly subjects.
A randomized, double-blind phase I clinical trial of two recombinant dimeric RBD COVID-19 vaccine candidates: safety, reactogenicity and immunogenicity
Authors: Pérez-Rodríguez Sonia , de la Caridad Rodríguez-González Meiby , Ochoa-Azze Rolando , Climent-Ruiz Yanet , González-Delgado Carlos Alberto , Paredes-Moreno Beatriz , Valenzuela-Silva Carmen , Rodríguez-Noda Laura , Perez-Nicado Rocmira , González-Mugica Raúl , Martínez-Pérez Marisel , Sánchez-Ramírez Belinda , Hernández-García Tays , Díaz-Machado Alina , Tamayo-Rodríguez Maura , Martín-Trujillo Alis , Rubino-Moreno Jorman , Suárez-Batista Anamary , Dubed-Echevarría Marta , Pérez-Guevara María Teresa , Amoroto-Roig Mayté , Chappi-Estévez Yanet , Bergado-Báez Gretchen , Pi-Estopiñán Franciscary , Chen Guang-Wu , Valdés-Balbín Yuri , García-Rivera Dagmar , Vérez-Bencomo Vicente 
Published: October 2021

AbstractBackgroundThe Receptor Binding Domain (RBD) of the SARS-CoV-2 spike protein is the target for many COVID-19 vaccines. Here we report results for phase 1 clinical trial of two COVID-19 vaccine candidates based on recombinant dimeric RBD (d-RBD).MethodsWe performed a randomized, double-blind, phase I clinical trial in the National Centre of Toxicology in Havana. Sixty Cuban volunteers aged 19-59 years were randomized into three groups (20 subjects each): 1) FINLAY-FR-1 (50 mcg d-RBD plus outer membrane vesicles from N. meningitidis); 2) FINLAY-FR-1A-50 mcg d-RBD (three doses); 3) FINLAY-FR-1A-25 mcg d-RDB (three doses). The FINLAY-FR-1 group was randomly divided to receive a third dose of the same vaccine candidate (homologous schedule) or of FINLAY-FR-1A-50 (heterologous schedule). The primary outcomes were safety and reactogenicity. The secondary outcome was vaccine immunogenicity. Humoral response at baseline and following each vaccination was evaluated using live-virus neutralization test, anti-RBD IgG ELISA and in-vitro neutralization test of RBD:hACE2 interaction.ResultsMost adverse events were of mild intensity (63.5%), solicited (58.8%), and local (61.8%); 69.4% with causal association with vaccination. Serious adverse events were not found. The FINLAY-FR-1 group reported more adverse events than the other two groups. After the third dose, anti-RBD seroconversion was 100%, 94.4% and 90% for the FINLAY-FR-1, FINLAY-FR-1A-50 and FINLAY-FR-1A-25 respectively. The in-vitro inhibition of RBD:hACE2 interaction increased after the second dose in all formulations. The geometric mean neutralizing titres after the third dose rose significantly in the group vaccinated with FINLAY-FR-1 with respect to the other formulations and the COVID-19 Convalescent Serum Panel. No differences were found between FINLAY-FR-1 homologous or heterologous schedules.ConclusionsVaccine candidates were safe and immunogenic, and induced live-virus neutralizing antibodies against SARS-CoV-2. The highest values were obtained when outer membrane vesicles were used as adjuvant.Trial registryhttps://rpcec.sld.cu/en/trials/RPCEC00000338-En
Post-tuberculosis sequelae and their correlation with quality of life: An observational study at a tertiary care center of north India
Authors: Aggarwal Nishant , Ghosh Tamoghna , Bhan Munish , Dwarakanathan Vignesh , Sethi Prayas , Meena Ved Prakash , Sinha Sanjeev , Ray Animesh 
Published: October 2021

ABSTRACTBackgroundLung impairment is a frequently recognised outcome in patients treated for pulmonary tuberculosis (TB). The impact of post-TB sequelae is not only restricted to clinical outcomes but also includes the quality of life and psycho-social well-being. However the magnitude of involvement of quality of life and the likely factors determining it are not clear. In this study, we assess the degree of compromise of quality of life and its determinants in patients of post-TB sequelae.MethodsPatients >18 years of age with a history of pulmonary tuberculosis were included in the study. Clinical history, pulmonary function test (PFT) and chest radiographs were recorded. The severity of dyspnea was evaluated using mMRC; quality of life assessment (QoL) was done using two standardized questionnaires- St. George’s Respiratory Questionnaire (SGRQ) and Seattle Obstructive Lung Disease Questionnaire (SOLQ).ResultsA total of 90 participants (mean age 40.4±11.6 years; 60 [66.7%] males) were recruited in the study. Overall, 93.3% (95% CI: 86.1%-97.5%) were currently symptomatic. A total of 96.8% (61/63) patients had abnormal pulmonary function test results, out of which 61.9% (39/63) had a mixed type. Out of 65 patients with chest radiographs available, 60 (92.3%,95% CI:84.6-96.8) patients had abnormalities with 45 (69.2%,95% CI: 58.3-78.2) having bilateral chest radiographic abnormalities. On assessment of QoL by SGRQ, the average score obtained was 42.3±24.0 (95% CI:37.3-47.3), with ‘Symptoms’ being the most affected domain. On using SOLQ, ‘Treatment satisfaction’ (mean score 38.5±21.7, 95% CI:34-43) and ‘Physical function’ (mean score 66.6±23.7, 95% CI:61.6-71.6) were the most affected. Neither spirometry results nor chest radiograph severity score could significantly account for the reduction of QoL. There was also a significant correlation between most of the parameters of SGRQ and SOLQ questionnaires in these patients.ConclusionPersistent respiratory symptoms, radiographic and spirometric abnormalities, were present in most of the patients with post-tubercular sequelae. Quality of life, as measured by SGRQ and SOLQ, was found to be significantly impaired in the majority of patients.
Synergetic impacts of turbulence and fishing reduce ocean biomass
Authors: McKerral Jody C. , Seymour Justin R. , Lavery Trish J. , Rogers Paul J. , Jeffries Thomas C. , Paterson James S. , Roudnew Ben , Huveneers Charlie , Newton Kelly , van Dongen-Vogels Virginie , Cribb Nardi P. , Winn Karina M. , Smith Renee J. , Beckmann Crystal L. , Prime Eloise , Charlton Claire M. , Kleshnina Maria , Grigson Susanna R. , Takeuchi Marika , Seuront Laurent , Mitchell James G. 
Published: October 2021

AbstractA universal scaling relationship exists between organism abundance and body size1,2. Within ocean habitats this relationship deviates from that generally observed in terrestrial systems2–4, where marine macro-fauna display steeper size-abundance scaling than expected. This is indicative of a fundamental shift in food-web organization, yet a conclusive mechanism for this pattern has remained elusive. We demonstrate that while fishing has partially contributed to the reduced abundance of larger organisms, a larger effect comes from ocean turbulence: the energetic cost of movement within a turbulent environment induces additional biomass losses among the nekton. These results identify turbulence as a novel mechanism governing the marine size-abundance distribution, highlighting the complex interplay of biophysical forces that must be considered alongside anthropogenic impacts in processes governing marine ecosystems.
Extracellular release of mitochondrial DNA is triggered by cigarette smoke and is detected in COPD
Authors: Giordano Luca , Gregory Alyssa D. , Verdaguer Mireia Perez , Ware Sarah A. , Harvey Hayley , DeVallance Evan , Brzoska Tomasz , Sundd Prithu , Zhang Yingze , Sciurba Frank C. , Shapiro Steven D. , Kaufman Brett A. 
Published: October 2021

AbstractChronic obstructive pulmonary disease (COPD) is characterized by continuous and irreversible inflammation frequently caused by persistent exposure to toxic inhalants such as cigarette smoke (CS). CS may trigger mitochondrial DNA (mtDNA) extrusion into the cytosol, extracellular space, or foster its transfer by extracellular vesicles (EVs). The present study aimed to elucidate whether mtDNA is released upon CS exposure and in COPD. We measured cell-free mtDNA (cf-mtDNA) in the plasma of former smokers affected by COPD, in the serum of mice that developed CS-induced emphysema, and in the extracellular milieu of human bronchial epithelial cells exposed to cigarette smoke extract (CSE). Further, we characterized cells exposed to sublethal and lethal doses of CSE by measuring mitochondrial membrane potential and dynamics, superoxide production and oxidative stress, cell cycle progression, and cytokine expression. Patients with COPD and mice that developed emphysema showed increased levels of cf-mtDNA. In cell culture, exposure to a sublethal dose of CSE decreased mitochondrial membrane potential, increased superoxide production and oxidative damage, dysregulated mitochondrial dynamics, and triggered mtDNA release in extracellular vesicles. The release of mtDNA into the extracellular milieu occurred concomitantly with increased expression of DNase III, DNA-sensing receptors (cGAS, NLRP3), proinflammatory cytokines (IL-1β, IL-6, IL-8, IL-18, CXCL2), and markers of senescence (p16, p21). Exposure to a lethal dose of CSE preferentially induced mtDNA and nuclear DNA release in cell debris. Our findings demonstrate that CS-induced stress triggers mtDNA release and is associated with COPD, supporting cf-mtDNA as a novel signaling response to CS exposure.
Genomic architecture and sexually dimorphic expression underlying immunity in the red mason bee, Osmia bicornis
Authors: Möllmann Jannik S. , Colgan Thomas J. 
Published: October 2021

AbstractInsect pollinators provide crucial ecosystem services yet face increasing environmental pressures. The challenges posed by novel and reemerging pathogens on bee health means we need to improve our understanding of the immune system, an important barrier to infections and disease. Despite its importance, for certain ecologically important species, such as solitary bees, our understanding of the genomic basis and molecular mechanisms underlying immune potential, and how intrinsic and extrinsic factors may influence immune gene expression is lacking. Here, to improve our understanding of the genomic architecture underlying immunity of a key solitary bee pollinator, we characterised putative immune genes of the red mason bee, Osmia bicornis. In addition, we used publicly available RNA-seq datasets to determine how sexes differ in immune gene expression and splicing but also how pesticide exposure may affect immune gene expression in females. Through comparative genomics, we reveal an evolutionary conserved set of more than 500 putative immune-related genes. We found genome-wide patterns of sex-biased gene expression, including immune genes involved in antiviral-defence. Interestingly, the expression of certain immune genes were also affected by exposure to common neonicotinoids, particularly genes related to haemocyte proliferation. Collectively, our study provides important insights into the gene repertoire, regulation and expression differences in the sexes of O. bicornis, as well as providing additional support for how neonicotinoids can affect immune gene expression, which may affect the capacity of solitary bees to respond to pathogenic threats.