bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cell Layers: uncovering clustering structure in unsupervised single-cell transcriptomic analysis
Authors: Blair Andrew P , Hu Robert K , Farah Elie N , Chi Neil C , Pollard Katherine S , Przytycki Pawel F , Kathiriya Irfan S , Bruneau Benoit G 
Published: August 2022

Abstract

Motivation
Unsupervised clustering of single-cell transcriptomics is a powerful method for identifying cell populations. Static visualization techniques for single-cell clustering only display results for a single resolution parameter. Analysts will often evaluate more than one resolution parameter but then only report one.

Results
We developed Cell Layers, an interactive Sankey tool for the quantitative investigation of gene expression, co-expression, biological processes and cluster integrity across clustering resolutions. Cell Layers enhances the interpretability of single-cell clustering by linking molecular data and cluster evaluation metrics, providing novel insight into cell populations.

Availability and implementation
https://github.com/apblair/CellLayers.
3D GAN image synthesis and dataset quality assessment for bacterial biofilm
Authors: Wang Jie , Tabassum Nazia , Toma Tanjin T , Wang Yibo , Gahlmann Andreas , Acton Scott T 
Published: August 2022

AbstractMotivationData-driven deep learning techniques usually require a large quantity of labeled training data to achieve reliable solutions in bioimage analysis. However, noisy image conditions and high cell density in bacterial biofilm images make 3D cell annotations difficult to obtain. Alternatively, data augmentation via synthetic data generation is attempted, but current methods fail to produce realistic images.ResultsThis article presents a bioimage synthesis and assessment workflow with application to augment bacterial biofilm images. 3D cyclic generative adversarial networks (GAN) with unbalanced cycle consistency loss functions are exploited in order to synthesize 3D biofilm images from binary cell labels. Then, a stochastic synthetic dataset quality assessment (SSQA) measure that compares statistical appearance similarity between random patches from random images in two datasets is proposed. Both SSQA scores and other existing image quality measures indicate that the proposed 3D Cyclic GAN, along with the unbalanced loss function, provides a reliably realistic (as measured by mean opinion score) 3D synthetic biofilm image. In 3D cell segmentation experiments, a GAN-augmented training model also presents more realistic signal-to-background intensity ratio and improved cell counting accuracy.Availability and implementationhttps://github.com/jwang-c/DeepBiofilm.Supplementary informationSupplementary data are available at Bioinformatics online.
ASURAT: functional annotation-driven unsupervised clustering of single-cell transcriptomes
Authors: Iida Keita , Kondo Jumpei , Wibisana Johannes Nicolaus , Inoue Masahiro , Okada Mariko 
Published: August 2022

AbstractMotivationSingle-cell RNA sequencing (scRNA-seq) analysis reveals heterogeneity and dynamic cell transitions. However, conventional gene-based analyses require intensive manual curation to interpret biological implications of computational results. Hence, a theory for efficiently annotating individual cells remains warranted.ResultsWe present ASURAT, a computational tool for simultaneously performing unsupervised clustering and functional annotation of disease, cell type, biological process and signaling pathway activity for single-cell transcriptomic data, using a correlation graph decomposition for genes in database-derived functional terms. We validated the usability and clustering performance of ASURAT using scRNA-seq datasets for human peripheral blood mononuclear cells, which required fewer manual curations than existing methods. Moreover, we applied ASURAT to scRNA-seq and spatial transcriptome datasets for human small cell lung cancer and pancreatic ductal adenocarcinoma, respectively, identifying previously overlooked subpopulations and differentially expressed genes. ASURAT is a powerful tool for dissecting cell subpopulations and improving biological interpretability of complex and noisy transcriptomic data.Availability and implementationASURAT is published on Bioconductor (https://doi.org/10.18129/B9.bioc.ASURAT). The codes for analyzing data in this article are available at Github (https://github.com/keita-iida/ASURATBI) and figshare (https://doi.org/10.6084/m9.figshare.19200254.v4).Supplementary informationSupplementary data are available at Bioinformatics online.
Design-based theory for cluster rerandomization
Authors: Lu Xin , Liu Tianle , Liu Hanzhong , Ding Peng 
Published: August 2022

Summary
Complete randomization balances covariates on average, but covariate imbalance often exists in finite samples. Rerandomization can ensure covariate balance in the realized experiment by discarding the undesired treatment assignments. Many field experiments in public health and social sciences assign the treatment at the cluster level due to logistical constraints or policy considerations. Moreover, they are frequently combined with re-randomization in the design stage. We define cluster rerandomization as a cluster-randomized experiment compounded with rerandomization to balance covariates at the individual or cluster level. Existing asymptotic theory can only deal with rerandomization with treatments assigned at the individual level, leaving that for cluster rerandomization an open problem. To fill the gap, we provide a design-based theory for cluster rerandomization. Moreover, we compare two cluster rerandomization schemes that use prior information on the importance of the covariates: one based on the weighted Euclidean distance and the other based on the Mahalanobis distance with tiers of covariates. We demonstrate that the former dominates the latter with optimal weights and orthogonalized covariates. Last but not least, we discuss the role of covariate adjustment in the analysis stage, and recommend covariate-adjusted procedures that can be conveniently implemented by least squares with the associated robust standard errors.
Electrophysiological biomarkers of brain function in CDKL5 deficiency disorder
Authors: Saby Joni N , Mulcahey Patrick J , Zavez Alexis E , Peters Sarika U , Standridge Shannon M , Swanson Lindsay C , Lieberman David N , Olson Heather E , Key Alexandra P , Percy Alan K , Neul Jeffrey L , Nelson Charles A , Roberts Timothy P L , Benke Timothy A , Marsh Eric D 
Published: August 2022

Abstract
CDKL5 deficiency disorder is a debilitating developmental and epileptic encephalopathy for which no targeted treatment exists. A number of promising therapeutics are under development for CDKL5 deficiency disorder but a lack of validated biomarkers of brain function and clinical severity may limit the ability to objectively assess the efficacy of new treatments as they become available. To address this need, the current study quantified electrophysiological measures in individuals with CDKL5 deficiency disorder and the association between these parameters and clinical severity. Visual and auditory evoked potentials, as well as resting EEG, were acquired across 5 clinical sites from 26 individuals with CDKL5 deficiency disorder. Evoked potential and quantitative EEG features were calculated and compared with typically developing individuals in an age- and sex-matched cohort. Baseline and Year 1 data, when available, were analysed and the repeatability of the results was tested. Two clinician-completed severity scales were used for evaluating the clinical relevance of the electrophysiological parameters. Group-level comparisons revealed reduced visual evoked potential amplitude in CDKL5 deficiency disorder individuals versus typically developing individuals. There were no group differences in the latency of the visual evoked potentials or in the latency or amplitude of the auditory evoked potentials. Within the CDKL5 deficiency disorder group, auditory evoked potential amplitude correlated with disease severity at baseline as well as Year 1. Multiple quantitative EEG features differed between CDKL5 deficiency disorder and typically developing participants, including amplitude standard deviation, 1/f slope and global delta, theta, alpha and beta power. Several quantitative EEG features correlated with clinical severity, including amplitude skewness, theta/delta ratio and alpha/delta ratio. The theta/delta ratio was the overall strongest predictor of severity and also among the most repeatable qEEG measures from baseline to Year 1.
Together, the present findings point to the utility of evoked potentials and quantitative EEG parameters as objective measures of brain function and disease severity in future clinical trials for CDKL5 deficiency disorder. The results also underscore the utility of the current methods, which could be similarly applied to the identification and validation of electrophysiological biomarkers of brain function for other developmental encephalopathies.
Guest Editor Introduction to Special Issue “(Ir)Religion in Clinical Ethics Consultation Methodology and Competencies”
Authors: Mason Jordan , Bishop Jeffrey 
Published: August 2022

AbstractThe push by some bioethicists to excise religion from the clinical ethics consultative process has received institutional support from the American Society for Bioethics and the Humanities (ASBH). Their certification program, Healthcare Ethics Consultant-Certified (HEC-C), is intended to identify and assess “a national standard for the professional practice of clinical healthcare ethics consulting” devoid of religious content. As Christian ethicists who wish to preserve the morally evaluative nature of healthcare ethics, we must pause and theologically reflect on the meaning of such a program. The five articles in this issue offer rich theological responses to the religion-free standardized methodology endorsed by the ASBH and reified in the HEC-C certification program. They offer a depth of theological reflection we see previously lacking in the literature, attending to the real possibilities of a “terraformed bioethics” effecting metaphysical harm, severing of clinical ethics from its sources, eliminating possibilities for conversion, and confusing the meaning of moral expertise.
A Cohort Study of the Age at Menopause in Female Patients With and Without Inflammatory Bowel Disease
Authors: Moktan Varun P , Daoud Nader D , Tremaine William J , Loftus Edward V , Kane Sunanda V , Hochwald Alexander P , Hodge David O , Hashash Jana G , Faubion Stephanie S , Farraye Francis A 
Published: August 2022

Abstract

Background
Menopause, defined by the complete cessation of menstrual cycles for 12 consecutive months, may occur at a younger age in women who have concomitant immune dysregulation. Our aim was to determine whether women with inflammatory bowel disease (IBD) experience an earlier onset of menopause compared to women without IBD.

Methods
This was a retrospective cohort study using resources of the Rochester Epidemiology Project, a collaboration between clinics, hospitals, and medical facilities in Olmsted County, Minnesota. From these people, women who were diagnosed with IBD between 1970 and 2010 comprised the case cohort while the reference cohort included women with no diagnosis of IBD. Data including age, body mass index (BMI), ethnicity, smoking status, age at onset of menopause, and current use of hormone therapy were collected. Patients with history of hysterectomy or oophorectomy were excluded. Wilcoxon rank-sum test for numeric variables and Fisher’s exact test for categorical variables were used to analyze the data.

Results
A total of 171 women met criteria for inclusion (83 cases and 88 controls). Mean age of menopause in women with IBD was 50.0 years compared to 51.5 years in women with no IBD (P = .006). There was no difference in BMI of women with and without IBD (28.7 versus 28.2 kg m−2; P = .9), respectively. There were more former smokers (33.7%) and current (6%) smokers in the IBD group (P = .009) compared to the non-IBD group.

Conclusions
IBD is associated with an earlier onset of menopause. Although it is unclear if this mean difference of 1.5 years is clinically relevant, it is known that early menopause is associated with an increased risk of osteoporosis and cardiovascular disease. Further research on the possible mechanisms is needed.
De novovariants cause complex symptoms in HSP-ATL1(SPG3A) and uncover genotype–phenotype correlations
Authors: Alecu Julian E , Saffari Afshin , Jordan Catherine , Srivastava Siddharth , Blackstone Craig , Ebrahimi-Fakhari Darius 
Published: August 2022

AbstractPathogenic variants in ATL1 are a known cause of autosomal-dominantly inherited hereditary spastic paraplegia (HSP-ATL1, SPG3A) with a predominantly ‘pure’ HSP phenotype. Although a relatively large number of patients have been reported, no genotype–phenotype correlations have been established for specific ATL1 variants. Confronted with five children carrying de novo ATL1 variants showing early, complex and severe symptoms, we systematically investigated the molecular and phenotypic spectrum of HSP-ATL1. Through a cross-sectional analysis of 537 published and novel cases, we delineate a distinct phenotype observed in patients with de novo variants. Guided by this systematic phenotyping approach and structural modelling of disease-associated variants in atlastin-1, we demonstrate that this distinct phenotypic signature is also prevalent in a subgroup of patients with inherited ATL1 variants and is largely explained by variant localization within a three-dimensional mutational cluster. Establishing genotype–phenotype correlations, we find that symptoms that extend well beyond the typical pure HSP phenotype (i.e. neurodevelopmental abnormalities, upper limb spasticity, bulbar symptoms, peripheral neuropathy and brain imaging abnormalities) are prevalent in patients with variants located within this mutational cluster.
A genome-wide association and fine-mapping study of white rust resistance in hexaploid chrysanthemum cultivars with a wild diploid reference genome
Authors: Sumitomo Katsuhiko , Shirasawa Kenta , Isobe Sachiko , Hirakawa Hideki , Harata Akiho , Nakano Michiharu , Nakano Yoshihiro , Yagi Masafumi , Hisamatsu Tamotsu , Yamaguchi Hiroyasu , Taniguchi Fumiya 
Published: August 2022

AbstractWhite rust caused by Puccinia horiana is one of the most serious diseases of chrysanthemum (Chrysanthemum × morifolium). In this study, we report the DNA markers associated with resistance against P. horiana via a simple approach using the genome of a wild diploid relative, Chrysanthemum seticuspe. First, we identified the important region of the genome in the resistant cultivar “Ariesu” via a genome-wide association study. Simplex single nucleotide polymorphism (SNP) markers mined from ddRAD-Seq were used in a biparental population originating from crosses between resistant “Ariesu” and susceptible “Yellow Queen”. The C. seticuspe genome was used as a reference. For the fine mapping of P. horiana resistance locus 2 (Phr2), a comparative whole genome sequencing study was conducted. Although the genome sequences of chrysanthemum cultivars assembled via the short-read approach were fragmented, reliable genome alignments were reconstructed by mapping onto the chromosome level of the C. seticuspe pseudomolecule. Base variants were then identified by comparing the assembled genome sequences of resistant “Ariesu” and susceptible “Yellow Queen”. Consequently, SNP markers that were closer to Phr2 compared with ddRAD-Seq markers were obtained. These SNP markers co-segregated with resistance in F1 progenies originating from resistant “Ariesu” and showed robust transferability for detecting Phr2-conferring resistance among chrysanthemum genetic resources. The wild C. seticuspe pseudomolecule, a de facto monoploid genome used for ddRAD-Seq analysis and assembled genome sequence comparison, demonstrated this method’s utility as a model for developing DNA markers in hexaploid chrysanthemum cultivars.
Apple U-box-type E3 ubiquitin ligase MdPUB23 reduces cold-stress tolerance by degrading the cold-stress regulatory protein MdICE1
Authors: Wang Da-Ru , Zhang Xiao-Wei , Xu Rui-Rui , Wang Gui-Luan , You Chun-Xiang , An Jian-Ping 
Published: August 2022

Abstract
Cold stress limits plant growth, geographical distribution, and crop yield. The MYC-type bHLH transcription factor ICE1 is recognized as the core positive regulator of the cold-stress response. However, how ICE1 protein levels are regulated remains to be further studied. In this study, we observed that a U-box-type E3 ubiquitin ligase, MdPUB23, positively regulated the cold-stress response in apple. The expression of MdPUB23 increased at both the transcriptional and post-translational levels in response to cold stress. Overexpression of MdPUB23 in transgenic apple enhanced sensitivity to cold stress. Further study showed that MdPUB23 directly interacted with MdICE1, promoting the ubiquitination-mediated degradation of the MdICE1 protein through the 26S-proteasome pathway and reducing the MdICE1-improved cold-stress tolerance in apple. Our results reveal that MdPUB23 regulates the cold-stress response by directly mediating the stability of the positive regulator MdICE1. The PUB23–ICE1 ubiquitination module may play a role in maintaining ICE1 protein homeostasis and preventing overreactions from causing damage to plants. The discovery of the ubiquitination regulatory pathway of ICE1 provides insights for the further exploration of plant cold-stress-response mechanisms.
Jackfruit genome and population genomics provide insights into fruit evolution and domestication history in China
Authors: Lin Xinggu , Feng Chao , Lin Tao , Harris A J , Li Yingzhi , Kang Ming 
Published: August 2022

Abstract
As the largest known tree-borne fruit in the world, jackfruit (Artocarpus heterophyllus) is an important cultivated crop in tropical regions of South and Southeast Asia. The species has been cultivated in China for more than 1000 years, but the history of its introduction to the country remains unclear. We assembled a high-quality chromosome-level genome of jackfruit into 985.63 Mb with scaffold N50 of 32.81 Mb. We analyzed whole-genome resequencing data of 295 landraces to investigate the domestication history in China and agronomic trait evolution of jackfruit. Population structure analysis revealed that jackfruits of China could be traced back to originate from Southeast Asia and South Asia independently. Selection signals between jackfruit and its edible congener, cempedak (Artocarpus integer), revealed several important candidate genes associated with fruit development and ripening. Moreover, analyses of selective sweeps and gene expression revealed that the AhePG1 gene may be the major factor in determining fruit texture. This study not only resolves the origins of jackfruit of China, but also provides valuable genomic resources for jackfruit breeding improvement and offers insights into fruit size evolution and fruit texture changes.
Toward ECG-based analysis of hypertrophic cardiomyopathy: a novel ECG segmentation method for handling abnormalities
Authors: Nezamabadi Kasra , Mayfield Jacob , Li Pengyuan , Greenland Gabriela V , Rodriguez Sebastian , Simsek Bahadir , Mousavi Parvin , Shatkay Hagit , Abraham M Roselle 
Published: August 2022

Abstract

Objective
Abnormalities in impulse propagation and cardiac repolarization are frequent in hypertrophic cardiomyopathy (HCM), leading to abnormalities in 12-lead electrocardiograms (ECGs). Computational ECG analysis can identify electrophysiological and structural remodeling and predict arrhythmias. This requires accurate ECG segmentation. It is unknown whether current segmentation methods developed using datasets containing annotations for mostly normal heartbeats perform well in HCM. Here, we present a segmentation method to effectively identify ECG waves across 12-lead HCM ECGs.

Methods
We develop (1) a web-based tool that permits manual annotations of P, P′, QRS, R′, S′, T, T′, U, J, epsilon waves, QRS complex slurring, and atrial fibrillation by 3 experts and (2) an easy-to-implement segmentation method that effectively identifies ECG waves in normal and abnormal heartbeats. Our method was tested on 131 12-lead HCM ECGs and 2 public ECG sets to evaluate its performance in non-HCM ECGs.

Results
Over the HCM dataset, our method obtained a sensitivity of 99.2% and 98.1% and a positive predictive value of 92% and 95.3% when detecting QRS complex and T-offset, respectively, significantly outperforming a state-of-the-art segmentation method previously employed for HCM analysis. Over public ECG sets, it significantly outperformed 3 state-of-the-art methods when detecting P-onset and peak, T-offset, and QRS-onset and peak regarding the positive predictive value and segmentation error. It performed at a level similar to other methods in other tasks.

Conclusion
Our method accurately identified ECG waves in the HCM dataset, outperforming a state-of-the-art method, and demonstrated similar good performance as other methods in normal/non-HCM ECG sets.
Malakoplakia of the appendix in a young healthy adult: a case report and literature review
Authors: Pastena Dario , Giambusso Mauro , Castri Federica , Potenza Angelo Eugenio , Caprino Paola , Sacchetti Franco , Sofo Luigi 
Published: August 2022

Abstract
Malakoplakia is a rare entity on inflammatory base that mostly occurs in immunocompromised individuals which is thought to be secondary to a bactericidal defect in macrophages. The genitourinary tract is typically affected. The appendix is a very rare localization. We report a case of malakoplakia in the appendix of a young healthy patient with a recent history of abdominal pain associated with diarrhea and nausea. The colonscopy and CT scan showed an extramucosal bumping mass pressing on the cecum and covered by normal mucosa. The patient underwent to laparoscopic appendectomy. The histology showed a malakoplakia of the appendix. Gastrointestinal localization of malakoplakia is often associated with preexisting diseases, which are probably responsible for an immune disorder underlying the etiopathogenesis of the disease. However, in our case, the patient had no comorbidities. Probably, a clinically unknown immune predisposition plays an important role. Further studies are needed to clarify this nexus.
A Call to Action: Integration of Buprenorphine Prescribing Into the Care of Persons With Human Immunodeficiency Virus and Opioid Use Disorder
Authors: Fujita A Wendy , Wilson J Deanna , Kennedy Amy J 
Published: August 2022

Abstract
During the coronavirus disease 2019 (COVID-19) pandemic, we also experienced a worsening opioid overdose epidemic. Untreated opioid use disorder (OUD) in persons with human immunodeficiency virus (HIV) is associated with worse HIV-related outcomes. Buprenorphine is a safe, evidence-based medication for OUD and is effective in reducing opioid craving and overdose and improving outcomes along the HIV care continuum. Despite the longstanding evidence supporting the benefits of buprenorphine, there remains an implementation gap in the uptake of buprenorphine prescribing in HIV care settings. To improve integration of OUD care and HIV primary care, we recommend (1) all HIV clinicians obtain a buprenorphine waiver, (2) teaching on OUD should be integrated into infectious diseases and HIV continuing medical education, and (3) previously validated models of integrated care should be leveraged to urgently expand access to buprenorphine for persons with HIV and OUD.