bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association between thyroid hormone levels and frailty in the community-dwelling oldest-old: a cross-sectional study
Authors: Guan Bo , Luo Jiakun , Huang Xin , Tian Fan , Sun Shasha , Ma Yufei , Yu Yan , Liu Ruihan , Cao Jian , Fan Li 
Published: November 2022

Abstract

Background:
Changes in thyroid hormone levels are commonly recognized characters among the elderly, which were reported to potentially influence incident frailty. Therefore, we examined the cross-sectional associations of thyroid hormones (THs) with frailty as well as the five components characterizing frailty (fatigue, resistance, ambulation, number of illnesses, and loss of weight) among the oldest-old.

Methods:
Four hundred and eighty-seven community-dwelling oldest-old from a local community in Haidian District, Beijing, participated in our recruitment campaign between April 2019 and May 2020. The primary outcomes were a definitive diagnosis of frailty according to the FRAIL scale (Fatigue, Resistance, Ambulation, Illnesses, Loss of weight) and a positive score for each frailty subdomain. Demographic information (age, sex, marital status, and educational status), comorbidities, and details on the participants’ lifestyles were recorded. Serum THs including free triiodothyronin (fT3), triiodothyronine (T3), free thyroxine (fT4), and thyroxine (T4) and thyroid stimulating hormone (TSH) levels were also measured at the beginning of our study. Logistic regressions were conducted to screen for potential risk factors for frailty and its subdomains.

Results:
Among the total 487 subjects at enrollment, 60 (12.23%) of them were diagnosed with subclinical hypothyroidism and 110 (22.59%) of the total population scored positive for frailty. Logistic regression analyses adjusted for all potential confounders, showed that frailty was significantly associated with the serum TSH concentration (odds ratio [OR]: 1.06), fT3 concentration (OR: 0.54), and subclinical hypothyroidism score (OR: 2.18). The association between fT4 and frailty was absent in our observational study. The fT3/fT4 ratio characterizing peripheral hormone conversion was also tested to be correlated with frailty.

Conclusion:
Subclinical hypothyroidism, higher TSH level, lower fT3 level, and decreased fT3/fT4 ratio were all associated with frailty assessed by the FRAIL scale among the community-dwelling oldest-old, suggesting a relevant role of thyroid function in aging. Future longitudinal studies are warranted to determine the casual relationship between thyroid dysfunction and frailty in the oldest-old.
Resident involvement in cataract surgery at the Veterans Health Administration: complications, case complexity, and the role of experience
Authors: Aggarwal Sahil , Wisely C. Ellis , Pepin Marc J. , Bryan William , Raghunathan Karthik , Challa Pratap 
Published: November 2022

Purpose:
To characterize intraoperative complications, case complexity, and changes in complication rates with surgical experience for cataract surgeries involving residents at the Veterans Health Administration (VHA).

Setting:
All VHA facilities where cataract surgery was performed.

Design:
Multicenter, retrospective cohort study.

Methods:
A retrospective review of all cataract surgeries within the VHA between July 2010 and June 2021 was conducted. Several parameters, including resident involvement, intraoperative complications, and case complexity as determined by Current Procedural Terminology codes, and use of pupil expansion or capsular support devices, were collected. Complication rates were compared between residents and attendings.

Results:
Of 392 428 cataract surgeries completed across 108 VHA facilities, 90 504 were performed by attendings alone, while 301 924 involved a resident. Of these, 10 244 (11.3%) of attending cases were complex compared with 32 446 (10.7%) of resident cases. Pupil expansion devices were required in 8191 of attending cases (9.05%) and 31 659 (10.5%) of cases involving residents (P < .001). Similarly, cases involving residents were more likely than attending-only cases to require a capsular support device (0.835% vs 0.586%, P < .001). Cases involving residents were more likely to have posterior capsular rupture (4.75% vs 2.58%, P < .001) and dropped nucleus (0.338% vs 0.198%, P < .001). Higher resident case volumes were associated with significantly lower complication rates for posterior capsular rupture, dropped nucleus, zonular loss, and suprachoroidal hemorrhage.

Conclusions:
Although residents had higher intraoperative complication rates than attendings, these rates were reduced with surgical experience. Residents were involved in a similar number of complex surgical cases as attendings.
The contribution of endocytosis to sensitization of nociceptors and synaptic transmission in nociceptive circuits
Authors: Tonello Raquel , Anderson Wayne B. , Davidson Steve , Escriou Virginie , Yang Lei , Schmidt Brian L. , Imlach Wendy L. , Bunnett Nigel W. 
Published: November 2022

Abstract
Chronic pain involves sensitization of nociceptors and synaptic transmission of painful signals in nociceptive circuits in the dorsal horn of the spinal cord. We investigated the contribution of clathrin-dependent endocytosis to sensitization of nociceptors by G protein–coupled receptors (GPCRs) and to synaptic transmission in spinal nociceptive circuits. We determined whether therapeutic targeting of endocytosis could ameliorate pain. mRNA encoding dynamin (Dnm) 1 to 3 and adaptor-associated protein kinase 1 (AAK1), which mediate clathrin-dependent endocytosis, were localized to primary sensory neurons of dorsal root ganglia of mouse and human and to spinal neurons in the dorsal horn of the mouse spinal cord by RNAScope. When injected intrathecally to mice, Dnm and AAK1 siRNA or shRNA knocked down Dnm and AAK1 mRNA in dorsal root ganglia neurons, reversed mechanical and thermal allodynia and hyperalgesia, and normalized nonevoked behavior in preclinical models of inflammatory and neuropathic pain. Intrathecally administered inhibitors of clathrin, Dnm, and AAK1 also reversed allodynia and hyperalgesia. Disruption of clathrin, Dnm, and AAK1 did not affect normal motor functions of behaviors. Patch clamp recordings of dorsal horn neurons revealed that Dnm1 and AAK1 disruption inhibited synaptic transmission between primary sensory neurons and neurons in lamina I/II of the spinal cord dorsal horn by suppressing release of synaptic vesicles from presynaptic primary afferent neurons. Patch clamp recordings from dorsal root ganglion nociceptors indicated that Dnm siRNA prevented sustained GPCR-mediated sensitization of nociceptors. By disrupting synaptic transmission in the spinal cord and blunting sensitization of nociceptors, endocytosis inhibitors offer a therapeutic approach for pain treatment.
Antibody Drug Conjugates in Lung Cancer
Authors: Merle Geoffrey , Friedlaender Alex , Desai Aakash , Addeo Alfredo 
Published: November 2022

Abstract
An antibody-drug conjugate (ADC) comprises a monoclonal antibody that is specific to a tumor cell protein, bound to a cytotoxic agent, known as the payload. The use of ADCs is already common practice in several cancers, thanks to their efficacy and potentially more manageable toxicity profile, resulting from the release of the cytostatic payload directly in the tumors. Currently, early-phase trials of ADCs in non–small cell lung cancer are rapidly gaining ground, with promising results targeting HER2 (human epidermal growth factor 2), HER3, TROP2 (trophoblast cell surface antigen 2), MET, CEACAM5 (carcinoembryonic antigen–related cell adhesion molecule 5), and PTK7 (tyrosine protein kinase–like 7). Unfortunately, in small cell lung cancer, trials targeting the ubiquitous DLL3 (delta-like ligand 3) protein have failed to show clinically relevant results, despite significant toxicity.
TRAUMA INDUCES INTRAVASCULAR HEMOLYSIS, EXACERBATED BY RED BLOOD CELL TRANSFUSION AND ASSOCIATED WITH DISRUPTED ARGININE–NITRIC OXIDE METABOLISM
Authors: Schaid Terry R. , Cohen Mitchell J. , D’Alessandro Angelo , Silliman Christopher C. , Moore Ernest E. , Sauaia Angela , Dzieciatkowska Monika , Hallas William , Thielen Otto , DeBot Margot , Cralley Alexis , LaCroix Ian , Erickson Christopher , Mitra Sanchayita , Banerjee Anirban , Jones Kenneth , Hansen Kirk C. 
Published: November 2022

ABSTRACT

Background: Severe injury can provoke systemic processes that lead to organ dysfunction, and hemolysis of both native and transfused red blood cells (RBCs) may contribute. Hemolysis can release erythrocyte proteins, such as hemoglobin and arginase-1, the latter with the potential to disrupt arginine metabolism and limit physiologic NO production. We aimed to quantify hemolysis and arginine metabolism in trauma patients and measure association with injury severity, transfusions, and outcomes. Methods: Blood was collected from injured patients at a level I trauma center enrolled in the COMBAT (Control of Major Bleeding After Trauma) trial. Proteomics and metabolomics were performed on plasma fractions through liquid chromatography coupled with mass spectrometry. Abundances of erythrocyte proteins comprising a hemolytic profile as well as haptoglobin, l-arginine, ornithine, and l-citrulline (NO surrogate marker) were analyzed at different timepoints and correlated with transfusions and adverse outcomes. Results: More critically injured patients, nonsurvivors, and those with longer ventilator requirement had higher levels of hemolysis markers with reduced l-arginine and l-citrulline. In logistic regression, elevated hemolysis markers, reduced l-arginine, and reduced l-citrulline were significantly associated with these adverse outcomes. An increased number of blood transfusions were significantly associated with elevated hemolysis markers and reduced l-arginine and l-citrulline independently of New Injury Severity Score and arterial base excess. Conclusions: Severe injury induces intravascular hemolysis, which may mediate postinjury organ dysfunction. In addition to native RBCs, transfused RBCs can lyse and may exacerbate trauma-induced hemolysis. Arginase-1 released from RBCs may contribute to the depletion of l-arginine and the subsequent reduction in the NO necessary to maintain organ perfusion.
Customized genomes for human and mouse ribosomal DNA mapping
Authors: George Subin S. , Pimkin Maxim , Paralkar Vikram R. 
Published: November 2022

ABSTRACTRibosomal RNAs (rRNAs) are transcribed from rDNA repeats, the most intensively transcribed loci in the genome. Due to their repetitive nature, there is a lack of genome assemblies suitable for rDNA mapping, creating a vacuum in our understanding of how the most abundant RNA in the cell is regulated. Our recent work1revealed binding of numerous mammalian transcription and chromatin factors to rDNA. Several of these factors were known to play critical roles in development, tissue function, and malignancy, but their potential rDNA roles had remained unexplored. Our work demonstrated the blind spot into which rDNA has fallen in genetic and epigenetic studies, and highlighted an unmet need for public rDNA-optimized genome assemblies.We customized five commonly used human and mouse assemblies - hg19 (GRCh37), hg38 (GRCh38), hs1 (T2T-CHM13), mm10 (GRCm38), mm39 (GRCm39) - to render them suitable for rDNA mapping. The standard builds of these genomes contain numerous fragmented or repetitive rDNA loci. We identified and masked all rDNA-like regions, added a single rDNA reference sequence of the appropriate species as a ∼45kb chromosome R, and created annotation files to aid visualization of rDNA features in browser tracks. We validated these customized genomes for mapping of known rDNA binding proteins, and present in this paper a simple workflow for mapping ChIP-seq datasets. These resources make rDNA mapping and visualization readily accessible to a broad audience.Customized genome assemblies, annotation files, positive and negative control tracks, and Snapgene files of standard rDNA reference sequence are deposited to GitHub.
Comparison of machine learning to deep learning for automated annotation of Gleason patterns in whole mount prostate cancer histology
Authors: Duenweg Savannah R. , Brehler Michael , Bobholz Samuel A. , Lowman Allison K. , Winiarz Aleksandra , Kyereme Fitzgerald , Nencka Andrew , Iczkowski Kenneth A. , LaViolette Peter S. 
Published: November 2022

AbstractBackgroundOne in eight men will be affected by prostate cancer (PCa) in their lives. While the current clinical standard prognostic marker for PCa is the Gleason score, it is subject to interreviewer variability. This study compares two machine learning methods for discriminating between high- and low-grade PCa on histology from 47 PCa patients.MethodsDigitized slides were annotated by a GU fellowship-trained pathologist. High-resolution tiles were extracted from annotated and unlabeled tissue. Glands were segmented and pathomic features were calculated and averaged across each patient. Patients were separated into a training set of 31 patients (Cohort A, n=9345 tiles) and a testing cohort of 16 patients (Cohort B, n=4375 tiles). Tiles from Cohort A were used to train a compact classification ensemble model and a ResNet model to discriminate tumor and were compared to pathologist annotations.ResultsThe ensemble and ResNet models had overall accuracies of 89% and 88%, respectively. The ResNet model was additionally able to differentiate Gleason patterns on data from Cohort B while the ensemble model was not.ConclusionsOur results suggest that quantitative pathomic features calculated from PCa histology can distinguish regions of cancer; how-ever, texture features captured by deep learning frameworks better differentiate unique Gleason patterns.
Turnover number predictions for kinetically uncharacterized enzymes using machine and deep learning
Authors: Kroll Alexander , Hu Xiao-Pan , Liebrand Nina A. , Lercher Martin J. 
Published: November 2022

ABSTRACTThe turnover numberkcat, a measure of enzyme efficiency, is central to understanding cellular physiology and resource allocation. As experimentalkcatestimates are unavailable for the vast majority of enzymatic reactions, the development of accurate computational prediction methods is highly desirable. However, existing machine learning models are limited to a single, well-studied organism, or they provide inaccurate predictions except for enzymes that are highly similar to proteins in the training set. Here, we present TurNuP, a general and organism-independent model that successfully predicts turnover numbers for natural reactions of wild-type enzymes. We constructed model inputs by representing complete chemical reactions through difference fingerprints and by representing enzymes through a modified and re-trained Transformer Network model for protein sequences. TurNuP outperforms previous models and generalizes well even to enzymes that are not similar to proteins in the training set. Parameterizing metabolic models with TurNuP-predictedkcat values leads to improved proteome allocation predictions. To provide a powerful and convenient tool for the study of molecular biochemistry and physiology, we implemented a TurNuP web server athttps://turnup.cs.hhu.de.
Interpreting phytoliths assemblages at chimpanzee (Pan troglodytes verus) nut-cracking sites in Bossou Forest, Guinea
Authors: Phillips C , Almeida-Warren K , Bamford MK 
Published: November 2022

AbstractThe nut-cracking behaviour of the chimpanzees of Bossou Forest has been long documented and studied in order to understand ultimate drivers for this form of durophagy by these apes. At sites in which they break open the nuts of the oil palm (Elaeis guineaeensis) on stone anvils with stone hammers, fragments of the tools as well as remnants of the nuts may be deposited into local sediments; however, they may become less visible at the macroscopic level as these sites are no longer used (become dormant). We build upon work that has been done to document this unique cultural heritage in West African chimpanzees by interpreting phytolith assemblages in sediments at active nut-cracking sites (used within the last two months). We compare these assemblages with those found in sediments of sites that have been dormant for ~10 years and sites where chimpanzees have not been observed to access and crack open oil palm nuts with stone tools. We predicted that larger assemblages of spheroid echinates, a phytolith associated with palms, would be found at active nut-cracking sites, however we found no statistical difference between total spheroid echinates (measured as total number found per gram of dry sediment) assemblages produced across active nut-cracking, dormant, or non-nut-cracking sites. This may have been due to small sample size (N≤6 sediment samples for each of the three sites) and so further sample collection and analyses are needed for inter-site comparisons. We also measured 2D area (μm2), perimeter and maximum diameter of spheroid echinates found in nut endocarps (shells) and leaflets from an oil palm frond. Intra-specific differences from all three measurements were found with these phytoliths being larger in the nut endocarp than the leaflet. This has implications for (re)interpreting the assemblages of spheroid echinate phytoliths at the three sites to determine if there is a greater productivity larger-sized spheroid echinates that fall within the size range of those measured for the nut endocarp (mean maximum diameter of 14.9 μmversus7.8 μm for those found in oil palm leaflet). Finally, we argue for the importance of initialising and continuing the interpretation of phytolith assemblages in local sediments that are located near sites where directed plant input by non-human taxa has occurred, in this case, chimpanzees cracking open oil palm nuts using stone tools. This is important to refine our interpretation of phytolith assemblages where human and non-human taxa who use complex foraging strategies share ecological spaces.
FINDEL: A Deep Learning Approach to Efficient Artifact Removal From Cancer Genomes
Authors: Tan Denis , Zhou Pengfei , Zhang Shaoting , Wong VicPearly , Zhang Jie , Long Edwin 
Published: November 2022

AbstractNext-generation sequencing technologies have increased sequencing throughput by 100-1000 folds and subsequently reduced the cost of sequencing a human genome to approximately US$1,000. However, the existence of sequencing artifacts can cause erroneous identification of variants and adversely impact the downstream analyses. Currently, the manual inspection of variants for additional refinement is still necessary for high-quality variant calls. The inspection is usually done on large binary alignment map (BAM) files which consume a huge amount of labor and time. It also suffers from a lack of standardization and reproducibility. Here we show that the use of mutational signatures coupled with deep learning can replace the current standards in the bioinformatics workflow. This software, called FINDEL, can efficiently remove sequencing artifacts from cancer samples. It queries the variant call format file which is much more compact than BAM files. The software automates the variant refinement process and produces high-quality variant calls.
3D Bioprinting of Stem Cell-Derived Central Nervous System Cells Enables Astrocyte Growth, Vasculogenesis and Enhances Neural Differentiation/Function
Authors: Sullivan Michael A. , Lane Samuel D. , Volkerling Alexander , Engel Martin , Werry Eryn L. , Kassiou Michael 
Published: November 2022

AbstractCurrent research tools for pre-clinical drug development such as rodent models and 2D immortalised monocultures have failed to serve as effective translational models for human CNS disorders. Recent advancements in the development of iPSCs and 3D culturing can improve thein vivo-relevanceof pre-clinical models, while generating 3D cultures though novel bioprinting technologies can offer increased scalability and replicability. As such, there is a need to develop platforms that combine iPSC-derived cells with 3D bioprinting to produce scalable, tunable and biomimetic cultures for preclinical drug discovery applications. We report a biocompatible PEG-based matrix which incorporates RGD and YIGSR peptide motifs and full length collagen IV at a stiffness similar to the human brain (1.5 kPa). Using a high-throughput commercial bioprinter we report the viable culture and morphological development of iPSC-derived astrocytes, brain microvascular endothelial cells, neural progenitors and neurons in our novel matrix. We also show that this system supports endothelial vasculogenesis and enhances neural differentiation and spontaneous activity. This platform forms a foundation for more complex, multicellular models to facilitate high-throughput translational drug discovery for CNS disorders.
Vitamin D and changes in cognitive performance in mid and later life: findings from the English Longitudinal Study of Ageing (ELSA)
Authors: Grajdean Sergiu , de Oliveira Cesar , Cadar Dorina 
Published: November 2022

AbstractBackgroundVitamin D has been found to be protective against biological processes associated with Alzheimer’s disease and cognition, including amyloid-β deposition, but the evidence in relation to cognitive decline is scarce.ObjectiveThis study aims to investigate the relationship between 25(OH)D serum levels and changes in cognitive performance over time in middle-aged and older English adults.Research Design and MethodsAn observational study design. We analyzed data collected biannually over a 6-year follow-up from a prospective cohort, the English Longitudinal Study of Ageing (ELSA). Mixed Linear Models analyses were conducted. The analytical sample consisted of 5,365 participants aged 50 and older without a diagnosis of dementia at baseline. Cognitive performance was ascertained with memory and orientation. Both tests were administered at every ELSA wave from Wave 6 (2012-2013) to Wave 9 (2018-2019). The values of blood levels of 25(OH)D and all covariates were considered at Wave 6 since this was the first time 25(OH)D was assessed. Blood levels of 25(OH)D were dichotomized in high versus low using the common threshold of 31nmol/l.ResultsA significant positive association was found between low serum levels of 25(OH)D and baseline memory scores (β= -0.28, SE=0.05, p≤0.001), but not with changes in memory over time. Furthermore, baseline blood levels of 25(OH)D were not associated with baseline orientation or changes in orientation over time.DiscussionIn this representative sample of the English population, we found that lower 25(OH)D serum levels were associated with a lower baseline memory but did not influence the change in cognitive functioning over time.ImplicationsThis study provides further clarification in understanding the deficient role of 25(OH)D on cognitive performance and the change in cognitive functioning over time.