bluuebunny/crossref_metadata_2025 huggingface dataset:
Age and symptoms at onset of ankylosing spondylitis in Japanese patients
Authors: Kishimoto Kenji , Asai Shuji , Suzuki Mochihito , Takahashi Nobunori , Terabe Kenya , Ohashi Yoshifumi , Hattori Kyosuke , Kojima Toshihisa , Imagama Shiro
Published: August 2022

Objectives

To examine the age at onset and initial symptoms as clinical features of ankylosing spondylitis in Japanese patients.

Methods

This retrospective study included 60 Japanese patients diagnosed with ankylosing spondylitis at our institute between January 2004 and June 2021. Initial symptoms were considered pain in axial joints and/or extra-axial joints. If a patient had initial symptoms at multiple sites, each site was counted. We assessed trends for the number of patients and sites of initial symptoms according to age at onset.

Results

Mean age (± standard deviation) at onset was 28.9 (± 14.3) years. Approximately one-third of patients experienced onset before age 20. The back was the most common site of initial symptoms (36.7%), followed by the hip (26.7%), knee (15%), buttocks (15%), neck (10%), finger (6.7%), shoulder (3.3%), and others (including overlapping sites). Thirty-two (53.3%) and 25 (41.7%) patients had initial symptoms only in axial joints and only in extra-axial joints, respectively. The proportion of patients with initial symptoms only in extra-axial joints significantly decreased with increasing age (p = .024).

Conclusions

Sites of initial symptoms were frequently the back, hip, knee, and buttocks, and 41.7% had initial symptoms only in extra-axial joints. Younger onset patients frequently had extra-axial involvement.
Notifiable Infectious Diseases Among Organ Transplant Recipients: A Data-Linked Cohort Study, 2000–2015
Authors: Waller Karen M J , De La Mata Nicole L , Wyburn Kate R , Hedley James A , Rosales Brenda M , Kelly Patrick J , Ramachandran Vidiya , Shah Karan K , Morton Rachael L , Rawlinson William D , Webster Angela C
Published: August 2022

Background

Infections, including common communicable infections such as influenza, frequently cause disease after organ transplantation, although the quantitative extent of infection and disease remains uncertain.

Methods

A cohort study was conducted to define the burden of notifiable infectious diseases among all solid organ recipients transplanted in New South Wales, Australia, 2000–2015. Data linkage was used to connect transplant registers to hospital admissions, notifiable diseases, and the death register. Standardized incidence ratios (SIRs) were calculated relative to general population notification rates, accounting for age, sex, and calendar year. Infection-related hospitalizations and deaths were identified.

Results

Among 4858 solid organ recipients followed for 39 183 person-years (PY), there were 792 notifications. Influenza was the most common infection (532 cases; incidence, 1358 [95% CI, 1247–1478] per 100 000 PY), highest within 3 months posttransplant. Next most common was salmonellosis (46 cases; incidence, 117 [95% CI, 87–156] per 100 000 PY), then pertussis (38 cases; incidence, 97 [95% CI, 71–133] per 100 000 PY). Influenza and invasive pneumococcal disease (IPD) showed significant excess cases compared with the general population (influenza SIR, 8.5 [95% CI, 7.8–9.2]; IPD SIR, 9.8 [95% CI, 6.9–13.9]), with high hospitalization rates (47% influenza cases, 68% IPD cases) and some mortality (4 influenza and 1 IPD deaths). By 10 years posttransplant, cumulative incidence of any vaccine-preventable disease was 12%, generally similar by transplanted organ, except higher among lung recipients. Gastrointestinal diseases, tuberculosis, and legionellosis had excess cases among transplant recipients, although there were few sexually transmitted infections and vector-borne diseases.

Conclusions

There is potential to avoid preventable infections among transplant recipients with improved vaccination programs, health education, and pretransplant donor and recipient screening.
Dominant Negative TRAF3 Variant With Recurrent Mycobacterium abscessus Infection and Bronchiectasis
Authors: Liew Mei Fong , Lim Hui Fang , Liang Mui Cheng , Lim Ives , Tan Zhaohong , Tan Rachel Ying Min , Sam Qi Hui , Soe Win Mar , Tay Sen Hee , Xu Shengli , Chang Matthew Wook , Foo Roger , Soong Tuck Wah , Ravikumar Sharada , Chai Louis Yi Ann
Published: August 2022

Host factors leading to pulmonary nontuberculous mycobacteria (PNTM) disease are poorly understood compared with disseminated NTM disease, which is linked to the interleukin 12–interferon gamma signaling pathway. We investigated the tumor necrosis factor receptor associated factor 3 (TRAF3) R338W variant in a patient with recurrent PNTM infection, demonstrating TRAF3- and TNF-α-deficient phenotypes via ex vivo immune and cloning-transfection cellular studies.
High-risk US International Travelers Seeking Pretravel Consultation During the COVID-19 Pandemic
Authors: Hyle Emily P , Le Mylinh H , Rao Sowmya R , Mulroy Nora M , Walker Allison T , Ryan Edward T , LaRocque Regina C
Published: August 2022

Background

To assess the implications of coronavirus disease 2019 (COVID-19)–related travel disruptions, we compared demographics and travel-related circumstances of US travelers seeking pretravel consultation regarding international travel at US Global TravEpiNet (GTEN) sites before and after the initiation of COVID-19 travel warnings.

Methods

We analyzed data in the GTEN database regarding traveler demographics and travel-related circumstances with standard questionnaires in the pre-COVID-19 period (January–December 2019) and the COVID-19 period (April 2020–March 2021), excluding travelers from January to March 2020. We conducted descriptive analyses of differences in demographics, travel-related circumstances, routine and travel-related vaccinations, and medications.

Results

Compared with 16 903 consultations in the pre-COVID-19 period, only 1564 consultations were recorded at GTEN sites during the COVID-19 period (90% reduction), with a greater proportion of travelers visiting friends and relatives (501/1564 [32%] vs 1525/16 903 [9%]), individuals traveling for >28 days (824/1564 [53%] vs 2522/16 903 [15%]), young children (6 mo–<6 y: 168/1564 [11%] vs 500/16 903 [3%]), and individuals traveling to Africa (1084/1564 [69%] vs 8049/16 903 [48%]). A smaller percentage of vaccine-eligible travelers received vaccines at pretravel consultations during the COVID-19 period than before, except for yellow fever and Japanese encephalitis vaccinations.

Conclusions

Compared with the pre-COVID-19 period, a greater proportion of travelers during the COVID-19 period were young children, were planning to visit friends and relatives, were traveling for >28 days, or were traveling to Africa, which are circumstances that contribute to high risk for travel-related infections. Fewer vaccine-eligible travelers were administered travel-related vaccines at pretravel consultations. Counseling and vaccination focused on high-risk international travelers must be prioritized during the COVID-19 pandemic.
Machine Learning in Infectious Disease for Risk Factor Identification and Hypothesis Generation: Proof of Concept Using Invasive Candidiasis
Authors: Mayer Lisa M , Strich Jeffrey R , Kadri Sameer S , Lionakis Michail S , Evans Nicholas G , Prevots D Rebecca , Ricotta Emily E
Published: August 2022

Background

Machine learning (ML) models can handle large data sets without assuming underlying relationships and can be useful for evaluating disease characteristics, yet they are more commonly used for predicting individual disease risk than for identifying factors at the population level. We offer a proof of concept applying random forest (RF) algorithms to Candida-positive hospital encounters in an electronic health record database of patients in the United States.

Methods

Candida-positive encounters were extracted from the Cerner HealthFacts database; invasive infections were laboratory-positive sterile site Candida infections. Features included demographics, admission source, care setting, physician specialty, diagnostic and procedure codes, and medications received before the first positive Candida culture. We used RF to assess risk factors for 3 outcomes: any invasive candidiasis (IC) vs non-IC, within-species IC vs non-IC (eg, invasive C. glabrata vs noninvasive C. glabrata), and between-species IC (eg, invasive C. glabrata vs all other IC).

Results

Fourteen of 169 (8%) variables were consistently identified as important features in the ML models. When evaluating within-species IC, for example, invasive C. glabrata vs non-invasive C. glabrata, we identified known features like central venous catheters, intensive care unit stay, and gastrointestinal operations. In contrast, important variables for invasive C. glabrata vs all other IC included renal disease and medications like diabetes therapeutics, cholesterol medications, and antiarrhythmics.

Conclusions

Known and novel risk factors for IC were identified using ML, demonstrating the hypothesis-generating utility of this approach for infectious disease conditions about which less is known, specifically at the species level or for rarer diseases.
Assessing the Language Skills of African American English Child Speakers
Authors: Wyatt Toya A.
Published: August 2022

The purpose of this chapter is to provide an overview of current as well as past special education regulations, litigation, professional association guidelines, clinical models, and best practice approaches for the clinical speech and language skills of African American English (AAE) for zero-three, preschool and school-age child speakers. It also provides a summary of current AAE child language research within the field of Communication Sciences and Disorders that has implications for: a) the selection of appropriate formal and informal speech-language assessment procedures, b) accurate differential diagnosis of disorder vs. normal dialect difference in children with suspected language impairment and c) the identification of appropriate therapy goals when relevant. Implications for the development of future theoretical frameworks and standardized assessments that help to minimize the historical misdiagnosis and disproportionate over-identification of African American students for speech-language and other special education placements is also addressed.
The RNA helicase UAP56 and the E3 ubiquitin ligase COP1 coordinately regulate alternative splicing to repress photomorphogenesis in Arabidopsis
Authors: Li Yang , Du Yanxin , Huai Junling , Jing Yanjun , Lin Rongcheng
Published: August 2022

Light is a key environmental signal that regulates plant growth and development. While posttranscriptional regulatory mechanisms of gene expression include alternative splicing (AS) of pre-messenger RNA (mRNA) in both plants and animals, how light signaling affects AS in plants is largely unknown. Here, we identify DExD/H RNA helicase U2AF65-associated protein (UAP56) as a negative regulator of photomorphogenesis in Arabidopsis thaliana. UAP56 is encoded by the homologs UAP56a and UAP56b. Knockdown of UAP56 led to enhanced photomorphogenic responses and diverse developmental defects during vegetative and reproductive growth. UAP56 physically interacts with the central light signaling repressor constitutive photomorphogenic 1 (COP1) and U2AF65. Global transcriptome analysis revealed that UAP56 and COP1 co-regulate the transcription of a subset of genes. Furthermore, deep RNA-sequencing analysis showed that UAP56 and COP1 control pre-mRNA AS in both overlapping and distinct manners. Ribonucleic acid immunoprecipitation assays showed that UAP56 and COP1 bind to common small nuclear RNAs and mRNAs of downstream targets. Our study reveals that both UAP56 and COP1 function as splicing factors that coordinately regulate AS during light-regulated plant growth and development.
Notch1 and Notch2 Signaling Exclusively but Cooperatively Maintain Fetal Myogenic Progenitors
Authors: Jo Young-Woo , Park Inkuk , Yoo Kyusang , Woo Hyun-Young , Kim Ye Lynne , Kim Yea-Eun , Kim Ji-Hoon , Kong Young-Yun
Published: August 2022

Myogenic progenitors (MPs) generate myocytes that fuse to form myofibers during skeletal muscle development while maintaining the progenitor pool, which is crucial for generating sufficient muscle. Notch signaling has been known to reserve a population of embryonic MPs during primary myogenesis by promoting cell cycle exit and suppressing premature differentiation. However, the roles of individual Notch receptors (Notch1-4) during embryonic/fetal myogenesis are still elusive. In this study, we found that Notch1 and Notch2, which exhibit the highest structural similarity among Notch receptors, maintain the MP population by distinct mechanisms: Notch1 induces cell cycle exit and Notch2 suppresses premature differentiation. Moreover, genetic and cell culture studies showed that Notch1 and Notch2 signaling in MPs are distinctively activated by interacting with Notch ligand-expressing myofibers and MP-lineage cells, respectively. These results suggest that through different activation modes, Notch1 and Notch2 distinctively and cooperatively maintain MP population during fetal myogenesis for proper muscle development.
Liquid biopsies for early diagnosis of brain tumours:
in
silico
mathematical biomarker modelling
Authors: Blee Johanna A. , Liu Xia , Harland Abigail J. , Fatania Kavi , Currie Stuart , Kurian Kathreena M. , Hauert Sabine
Published: August 2022

Brain tumours are the biggest cancer killer in those under 40 and reduce life expectancy more than any other cancer. Blood-based liquid biopsies may aid early diagnosis, prediction and prognosis for brain tumours. It remains unclear whether known blood-based biomarkers, such as glial fibrillary acidic protein (GFAP), have the required sensitivity and selectivity. We have developed a novel
in
silico
model which can be used to assess and compare blood-based liquid biopsies. We focused on GFAP, a putative biomarker for astrocytic tumours and glioblastoma multi-formes (GBMs).
In silico
modelling was paired with experimental measurement of cell GFAP concentrations and used to predict the tumour volumes and identify key parameters which limit detection. The average GBM volumes of 449 patients at Leeds Teaching Hospitals NHS Trust were also measured and used as a benchmark. Our model predicts that the currently proposed GFAP threshold of 0.12 ng ml
−1
may not be suitable for early detection of GBMs, but that lower thresholds may be used. We found that the levels of GFAP in the blood are related to tumour characteristics, such as vasculature damage and rate of necrosis, which are biological markers of tumour aggressiveness. We also demonstrate how these models could be used to provide clinical insight.
Effect of cilia-induced surface velocity on cerebrospinal fluid exchange in the lateral ventricles
Authors: Yoshida Haruki , Ishida Shunichi , Yamamoto Taiki , Ishikawa Takayuki , Nagata Yuichi , Takeuchi Kazuhito , Ueno Hironori , Imai Yohsuke
Published: August 2022

Ciliary motility disorders are known to cause hydrocephalus. The instantaneous velocity of cerebrospinal fluid (CSF) flow is dominated by artery pulsation, and it remains unclear why ciliary dysfunction results in hydrocephalus. In this study, we investigated the effects of cilia-induced surface velocity on CSF flow using computational fluid dynamics. A geometric model of the human ventricles was constructed using medical imaging data. The CSF produced by the choroid plexus and cilia-induced surface velocity were given as the velocity boundary conditions at the ventricular walls. We developed healthy and reduced cilia motility models based on experimental data of cilia-induced velocity in healthy wild-type and Dpcd-knockout mice. The results indicate that there is almost no difference in intraventricular pressure between healthy and reduced cilia motility models. Additionally, it was found that newly produced CSF from the choroid plexus did not spread to the anterior and inferior horns of the lateral ventricles in the reduced cilia motility model. These findings suggest that a ciliary motility disorder could delay CSF exchange in the anterior and inferior horns of the lateral ventricles.
Enlightened female networks: gendered ways of producing knowledge (1720–1830)
Authors: Maerker Anna , Serrano Elena , Werrett Simon
Published: August 2022

This special issue investigates women's scientific networks in Europe roughly between 1720 and 1830, an interesting period from a gender point of view. The articles analyse the role that networks played in enabling, shaping and circumscribing women in their intellectual pursuits, social aspirations and ideals. They also focus on the nature of the members' relationships, how women negotiated their scientific identities and how often women could use their femininity to create new social spaces for themselves and their families. We traced different types of networks such as ‘paper’, ‘technical’, ‘distant’ (in its special and temporal sense), ‘moral’ and ‘mixed’, as well as how many of these networks were characterized by broad intellectual engagement that was never exclusively scientific, but also literary, poetic, educational and philosophical.
Does competitive winning increase subsequent cheating?
Authors: Colman Andrew M. , Pulford Briony D. , Frosch Caren A. , Mangiarulo Marta , Miles Jeremy N. V.
Published: August 2022

In this preregistered study, we attempted to replicate and substantially extend a frequently cited experiment by Schurr and Ritov, published in 2016, suggesting that winners of pairwise competitions are more likely than others to steal money in subsequent games of chance against different opponents, possibly because of an enhanced sense of entitlement among competition winners. A replication seemed desirable because of the relevance of the effect to dishonesty in everyday life, the apparent counterintuitivity of the effect, possible problems and anomalies in the original study, and above all the fact that the researchers investigated only one potential explanation for the effect. Our results failed to replicate Schurr and Ritov's basic finding: we found no evidence to support the hypotheses that either winning or losing is associated with subsequent cheating. A second online study also failed to replicate Schurr and Ritov's basic finding. We used structural equation modelling to test four possible explanations for cheating—sense of entitlement, self-confidence, feeling lucky and inequality aversion. Only inequality aversion turned out to be significantly associated with cheating.
On quantum states over time
Authors: Fullwood James , Parzygnat Arthur J.
Published: August 2022

In 2017, D. Horsman, C. Heunen, M. Pusey, J. Barrett and R. Spekkens proved that there is no physically reasonable assignment that takes a quantum channel and an initial state and produces a joint state on the tensor product of the input and output spaces. The interpretation was that there is a clear distinction between space and time in the quantum setting that is not visible classically, where in the latter, one can freely use Bayes’ theorem to go between joint states and marginals with noisy channels. In this paper, we prove that there actually is such a physically reasonable assignment, bypassing the no-go result of Horsman
et al.
, and we illustrate that this is achievable by restricting the domain of their assignment to a domain which represents the given data more faithfully.
The ontogeny of asymmetry in echolocating whales
Authors: Lanzetti Agnese , Coombs Ellen J. , Portela Miguez Roberto , Fernandez Vincent , Goswami Anjali
Published: August 2022

Extreme asymmetry of the skull is one of the most distinctive traits that characterizes toothed whales (Odontoceti, Cetacea). The origin and function of cranial asymmetry are connected to the evolution of echolocation, the ability to use high-frequency sounds to navigate the surrounding environment. Although this novel phenotype must arise through changes in cranial development, the ontogeny of cetacean asymmetry has never been investigated. Here we use three-dimensional geometric morphometrics to quantify the changes in degree of asymmetry and skull shape during prenatal and postnatal ontogeny for five genera spanning odontocete diversity (oceanic dolphins, porpoises and beluga). Asymmetry in early ontogeny starts low and tracks phylogenetic relatedness of taxa. Distantly related taxa that share aspects of their ecology overwrite these initial differences via heterochronic shifts, ultimately converging on comparable high levels of skull asymmetry. Porpoises maintain low levels of asymmetry into maturity and present a decelerated rate of growth, probably retained from the ancestral condition. Ancestral state reconstruction of allometric trajectories demonstrates that both paedomorphism and peramorphism contribute to cranial shape diversity across odontocetes. This study provides a striking example of how divergent developmental pathways can produce convergent ecological adaptations, even for some of the most unusual phenotypes exhibited among vertebrates.
Transcriptome Response of Cannabis (Cannabis sativa L.) to the Pathogenic fungus Golovinomyces ambrosiae
Authors: Adhikary Dinesh , El-Mezawy Aliaa , Khatri-Chhetri Upama , Wu Limin , Smith Stephen W. , Zhang Jian , Slaski Jan J. , Kav Nat N.V. , Deyholos Michael K.
Published: August 2022

Powdery mildew (PM), caused by the obligate biotrophic fungus Golovinomyces ambrosiae, is an economically important fungal disease of hemp - and marijuana–type cannabis. While the PM disease can be managed effectively by cultivating resistant hosts, there is no known PM-resistant genetic variant. This is the first report of transcript level responses of the hemp cultivar ‘X59’ to G. ambrosiae. Transcript level changes at 5-, 8-, and 11-days post-inoculation (DPI) of C. sativa were evaluated against uninoculated control. Our analysis revealed that 1,898 genes were significantly (q-value < 0.05) differentially expressed (DE) following the pathogen challenge. Among these, 910 and 988 genes were upregulated and downregulated, respectively as the infection progressed to 11 DPI. Genes related to salicylic acid (SA), (LOC115715124 and LOC115711424) and WRKY transcription factor (LOC115707546, LOC115715968, and LOC115707511) were highly upregulated. There were 45 DEGs that were homologous to PM-related genes, including chitin elicitor receptor kinase 1 (CERK 1), enhanced disease resistance 2, (EDR2), and powdery mildew resistance (PMR) genes. Moreover, the genes related to glycosyl hydrolases, particularly LOC115699396, LOC115708023, LOC115710105, and LOC115710100, were highly upregulated and potentially important in mediating pathogen responses. Collectively, this study has contributed to an enhanced understanding of the molecular mechanisms that are involved in cannabis and PM disease interaction and has identified several gene candidates that can be further investigated for their role in defence mechanisms.
A Web-scraped Skin Image Database of Monkeypox, Chickenpox, Smallpox, Cowpox, and Measles
Authors: Islam Towhidul , Hussain Mohammad Arafat , Chowdhury Forhad Uddin Hasan , Islam B. M. Riazul
Published: August 2022

Monkeypox has emerged as a fast-spreading disease around the world and an outbreak has been reported in 75 countries so far. Although the clinical attributes of Monkeypox are similar to those of Smallpox, skin lesions and rashes caused by Monkeypox often resemble those of other types of pox, for example, chickenpox and cowpox. This scenario makes an early diagnosis of Monkeypox challenging for the healthcare professional just by observing the visual appearance of lesions and rashes. The rarity of Monkeypox before the current outbreak further created a knowledge gap among healthcare professionals around the world. To tackle this challenging situation, scientists are taking motivation from the success of supervised machine learning in COVID-19 detection. However, the lack of Monkeypox skin image data is making the bottleneck of using machine learning in Monkeypox detection from patient skin images. Therefore, in this project, we introduce the Monkeypox Skin Image Dataset 2022, the largest of its kind so far. We used web-scraping to collect Monkeypox, Chickenpox, Smallpox, Cowpox, and Measles infected skin as well as healthy skin images to build a comprehensive image database and make it publicly available. We believe that our database will facilitate the development of baseline machine learning algorithms for early detection of Monkeypox in clinical settings. Our dataset is available at the following Kaggle link: https://www.kaggle.com/datasets/arafathussain/monkeypox-skin-image-dataset-2022.
Prosperity of the commons: Generalist mycorrhizal species dominate a mixed forest and may promote forest diversity by mediating resource sharing among trees
Authors: Rog Ido , Lewin-Epstein Ohad , Livne-Luzon Stav , Hadany Lilach , Klein Tamir
Published: August 2022

Mechanisms of host–microbe interactions and their direct impact on both parties have been extensively researched, however, much less is known on the effect of these interactions on the ecology of the host-community. Here we investigate tree-fungi mycorrhizal interactions, focusing on mycorrhizal-mediated resource sharing among trees, while examining the dynamics between specialist and generalist fungi and their implications on the forest ecology. Using genetic meta-barcoding, we identified the fungal community colonizing different trees in a mixed forest, and generated an extensive mapping connecting fungal sequences to their tree hosts. The mycorrhizal fungal community diverged between ectomycorrhizal and arbuscular host trees, but, unexpectedly, multiple ectomycorrhizal species colonized roots of non-ectomycorrhizal host trees. We complemented these findings by a novel computational framework, modeling competition between generalist and specialist mycorrhizal fungi, accounting for fungal-mediated resource sharing among neighboring trees. The analysis of the model revealed that generalist mycorrhizal networks may affect the entire tree community, and contribute to the maintenance of forest diversity in the long run. Furthermore, higher initial spatial mixing of trees can promote the evolution of generalist mycorrhizal species. These novel belowground interactions among trees and fungi may significantly impact forest biodiversity.
Geographic variability of hybridization between Red-breasted and Red-naped Sapsuckers
Authors: Natola Libby , Billerman Shawn M. , Carling Matthew D. , Seneviratne Sampath S. , Irwin Darren
Published: August 2022

Hybrid zones reveal the strength of reproductive isolation between populations undergoing speciation and are thus a key tool used in evolutionary biology research. Multiple replicate transects across the same hybrid zone offer further insight into the dynamics of hybridization in different environments, clarifying the role of extrinsic forces on the speciation process. Red-breasted and Red-naped Sapsuckers (Sphyrapicus ruber and S. nuchalis) have a long zone of contact over approximately 1,600 km from central British Columbia, Canada to central California, USA. We compared Genotyping-by-Sequencing data from three independent sapsucker hybrid zone transects to compare hybridization dynamics between the same species under variable geoclimatic conditions. We then generated geographic clines of the genomic data to compare hybrid zone widths and used Random Forest models and linear regression to assess the relationship between climate and sapsucker ancestry along each transect. Our results show variation in symmetry and directionality of back crossing, patterns often indicative of moving hybrid zones. We note variable cline widths among transects, indicating differences in the selection maintaining hybrid zone dynamics. Furthermore, Random Forest models identified different variables in close association with sapsucker ancestry across each transect. These results indicate a lack of repeatability across replicate transects and a strong influence of the local environment on hybrid zone dynamics.
Being noisy in a crowd: differential selective pressure on gene expression noise in model gene regulatory networks
Authors: Puzović Nataša , Madaan Tanvi , Dutheil Julien Y.
Published: August 2022

Expression noise, the variability of the amount of gene product among isogenic cells grown in identical conditions, originates from the inherent stochasticity of diffusion and binding of the molecular players involved in transcription and translation. It has been shown that expression noise is an evolvable trait and that central genes exhibit less noise than peripheral genes in gene networks. A possible explanation for this pattern is increased selective pressure on central genes since they propagate their noise to downstream targets, leading to noise amplification. To test this hypothesis, we developed a new gene regulatory network model with inheritable stochastic gene expression and simulated the evolution of gene-specific expression noise under constraint at the network level. Stabilizing selection was imposed on the expression level of all genes in the network and rounds of mutation, selection, replication and recombination were performed. We observed that local network features affect both the probability to respond to selection, and the strength of the selective pressure acting on individual genes. In particular, the reduction of gene-specific expression noise as a response to stabilizing selection on the mean expression is higher in genes with higher centrality metrics. Furthermore, global topological structures such as network diameter, centralization and average degree affect the average expression variance and average selective pressure acting on constituent genes. Our results demonstrate that selection at the network level leads to differential selective pressure at the gene level, and local and global network characteristics are an essential component of gene-specific expression noise evolution.
Differences in molecular sampling and data processing explain variation among single-cell and single-nucleus RNA-seq experiments
Authors: Chamberlin John T. , Lee Younghee , Marth Gabor T. , Quinlan Aaron R.
Published: August 2022

A mechanistic understanding of the biological and technical factors that impact cell and nuclear transcript measurements is essential to designing, analyzing, and interpreting single-cell and single-nucleus RNA sequencing experiments. RNA sampling in nuclei and cells is fundamentally different as nuclei contain the same pre-mRNA population as cells, yet contain a small subset of the largely-cytoplasmic mRNAs. Nonetheless, early studies argued that including pre-mRNA in single-nucleus analysis led to results comparable to cellular samples. However, typical bioinformatic workflows do not distinguish between pre-mRNA and mRNA when analyzing gene expression, and variation in the relative abundance of pre-mRNA and mRNA across cell types has received limited attention. These gaps are especially important given that incorporating pre-mRNA in routine gene expression analysis is now commonplace for both assays, despite known gene length bias in pre-mRNA capture. Here, we reanalyze public datasets from mouse and human to describe the mechanisms and contrasting effects of mRNA and pre-mRNA sampling in single-cell and nucleus RNA-seq. We disentangle the roles of bioinformatic processing, assay choice, and biological variability on measured gene expression and marker gene selection. We show that pre-mRNA levels vary considerably among cell types, which mediates the degree of gene length bias within and between assays and limits the generalizability of a recently-published normalization method intended to correct for this bias. As an alternative solution, we demonstrate the applicability of an existing post hoc gene length-based correction method developed for conventional RNA-seq gene set enrichment analysis. Finally, we show that the inclusion of pre-mRNA in bioinformatic processing can impart a larger effect on gene expression estimates than the choice of cell versus nuclear assay, which is pivotal to the effective reuse of existing data. Broadly, these analyses advance our understanding of the biological and technical factors underlying variation in single-cell and single-nucleus RNA-seq experiments to promote more informed choices in experimental design, data analysis, and data sharing and reuse.
ioSearch: a tool for searching disease-associated interacting omics; application on breast cancer data
Authors: Das Sarmistha , Srivastava Deo Kumar
Published: August 2022

Biomarkers identification is difficult for cancer and other polygenic traits because such complicated diseases occur due to an intricate interplay of various genetic materials. Although high-throughput data from recent technolo-gies provide access to a tremendous amount of information still there is a huge gap in harnessing knowledge from the generated multi-omics data. It is evident from the availability of subject-specific multi-omics data from large consortiums that there is a growing need for appropriate tools to analyze such data. Traditional single-omics association tests more often identify strong signals but fail to explore the between-omics relationship and find moderately weak signals due to multiple testing burdens. Multi-omics data integration intuitively provides a clear advantage in understanding the genetic architecture of disease a little better by imparting complementary information. But the construction of such methods is challenging because of the diversity in the nature of multiple omics and the sample size which is much less than the number of omics variables. It is important to consider factors such as data diversity and prior biological knowledge to make meaningful and better predictions. Dimension reduction techniques such as feature selection are used to circumvent the sample size issue in general but treating all the omics variables similarly might be an oversimplification of the complex biological interactions. The lack of appropriate approaches for biomarker identification from complex multi-omics data led us to develop this method. ioSearch is a tool for integrating two omics assays with continuous measurements. Based on a two-step model, ioSearch explores the inter-relationship of the omics in a principal regression framework and selects features using sparse principal component analysis to provide easily interpretable inference in terms of p-values. Also, it uses prior biological information to reduce multiple testing burdens. Extensive simulation results show that our method is statistically powerful with a controlled type I error rate. Application of ioSearch to two publicly available breast cancer datasets identified relevant genes and proteins in important pathways.
Is there a trade-off between host generalism and aggressiveness across pathogen populations? A synthesis of the global potato and tomato blight lesion growth data
Authors: Wan Justin SH
Published: August 2022

Phytophthora infestanspopulations and lineages vary widely in host specificity from specialisation to generalism among potato and tomato. However, generalists that displace others and became dominant on both hosts are relatively uncommon. Generalists may have lower fitness compared to specialists on the host of the latter, which could explain their coexistence at many locations. Lesion size is an aggressiveness metric closely related to fitness inP. infestans. A trade-off between generalism and lesion growth rate on the original host can explain the variation among blight populations. I collated the data from cross-inoculation trials on potato and tomato isolates to test for the trade-off. In addition, other metrics related to disease symptoms were included to test whether the degree of specificity is different between populations from potato and tomato, and to explore whether specificity had changed over time. The results indicate a trade-off between generalism and lesion growth rate where higher specificity was associated with significantly faster lesion growth on the original host at the population-level, but not at the lineage-level. Potato and tomato isolates were overall not significantly different in specificity, but tomato isolates tended towards generalism with time. These findings indicate that specialists may avoid displacement on their host by generalists through faster lesion growth, and help explain the common co-occurrence of generalists and specialists. However, a few invasive generalists can rapidly displace competitors and became dominant on both hosts across a broader region. It is likely that important exceptions exist to this trade-off.
A greenhouse-based high-throughput phenotyping platform for identification and genetic dissection of resistance to Aphanomyces root rot in field pea
Authors: Al Bari Md. Abdullah , Fonseka Dimitri , Stenger John , Zitnick-Anderson Kimberly , Atanda Sikiru Adeniyi , Worral Hannah , Piche Lisa , Kim Jeonghwa , Morales Mario , Johnson Josephine , Saludares Rica Amor , Flores Paulo , Pasche Julie , Bandillo Nonoy
Published: August 2022

Aphanomyces root rot (ARR) is a devastating disease in field pea(Pisum sativumL.) that can cause up to 100% crop failure. Assessment of ARR resistance can be a rigorous, costly, time-demanding activity that is relatively low-throughput and prone to human errors. These limits the ability to effectively and efficiently phenotype the disease symptoms arising from ARR infection, which remains a perennial bottleneck to the successful evaluation and incorporation of disease resistance into new cultivars. In this study, we developed a greenhouse-based high throughput phenotyping (HTP) platform that moves along the rails above the greenhouse benches and captures the visual symptoms caused byAphanomyces euteichesin field pea. We pilot tested this platform alongside with conventional visual scoring in five experimental trials under greenhouse conditions, assaying over 12,600 single plants. Precision estimated through broad-sense heritability (H2) was consistently higher for the HTP-indices (H2Exg =0.86) than the traditional visual scores (H2DSI=0.59), potentially increasing the power of genetic mapping. We genetically dissected variation for ARR resistance using the HTP-indices, and identified a total of 260 associated single nucleotide polymorphism (SNP) through genome-wide association (GWA) mapping. The number of associated SNP for HTP-indices was consistently higher with some SNP overlapped to the associated SNP identified using the visual scores. We identified numerous small-effect QTLs, with the most significant SNP explaining about 5 to 9% of the phenotypic variance per index, and identified previously mapped genes known to be involved in the biological pathways that trigger immunity against ARR, including Psat5g280480, Psat5g282800, Psat5g282880, and Psat2g167800. We also identified a few novel QTLs with small-effect sizes that may be worthy of validation in the future. The newly identified QTLs and underlying genes, along with genotypes with promising resistance identified in this study, can be useful for improving a long-term, durable resistance to ARR.
Rapid and accurate assembly of large DNA assisted by in vitro packaging of bacteriophage
Authors: Nozaki Shingo
Published: August 2022

Development of DNA assembly methods made it possible to construct large DNA. However, achieving the large DNA assembly easily, accurately, and at low cost remains a challenge. This study shows that DNA assembled only by annealing of overlapping single-stranded DNA ends, which are generated by exonuclease treatment, without ligation can be packaged in phage particles and can also be transduced into bacterial cells. Based on this, I developed a simple method to construct long DNA of about 40 - 50 kb from multiple PCR fragments using the bacteriophage in vitro packaging system. This method, named iPac (in vitroPackaging-assisted DNA assembly), allowed accurate and rapid construction of large plasmids and phage genomes. This simple method will accelerate research in molecular and synthetic biology, including the construction of gene circuits or the engineering of metabolic pathways.

Abstract Figure
Left anterior fascicular block is associated with non-ischemic myocardial scar and proportionately decreased ejection fraction
Authors: Scheele Johan von , Atwater Brett D , Klem Igor , Engblom Henrik , Loewenstein Daniel E , Wieslander Björn , Ugander Martin
Published: August 2022

Background

Left anterior fascicular block (LAFB) has been associated with increased mortality, but the underlying causes are unknown.

Objectives

To determine whether LAFB is associated with increased left ventricular (LV) scar burden and reduced LV ejection fraction (LVEF).

Methods

LAFB patients (n=51) and matched control patients (n=600) were retrospectively enrolled. Both groups had been referred for cardiovascular magnetic resonance imaging (CMR) and electrocardiography (ECG). They were compared regarding size and location of LV scar, LVEF, and a dysfunction index describing the difference between measured LVEF and expected LVEF based on scar size.

Results

Patients with LAFB had on average a larger LV scar (median [interquartile range] 0.7 [0.0-6.6] vs 0.0 [0.0-1.5] % LV mass, p<0.001). LAFB was associated with a higher prevalence of any scar (59% vs 33%, p<0.001). The groups had similar prevalence of ischemic scar (29% vs 23%, p=0.40) but LAFB patients a higher prevalence of non-ischemic scar (29% vs 10%, p=0.001) most frequently located in the basal and mid inferoseptal segments and the anterior and lateral apical LV segments. LVEF was lower in LAFB than in controls (58 [43-60] vs 60 [55-60] %, p=0.02). There was no difference in dysfunction index (24.0 [17.8-25.5] vs 24.0 [19.0-27.8] %-points of LVEF, p=0.32).

Conclusions

In a matched cohort, LAFB was associated with a small decrease in LVEF that was proportionate to the increased LV scar burden, which was more commonly of non-ischemic etiology and not infarction, and not more commonly located near the expected course of the left anterior fascicle.
Abnormal spirometric patterns and respiratory symptoms in HIV patients with no recent pulmonary infection in a periurban hospital in Ghana
Authors: Yeboah Kwame , Musa Latif , Bedu-Addo Kweku
Published: August 2022

Background

Human immunodeficiency virus (HIV) infection is associated with chronic pulmonary diseases, even in those with viral suppression by highly active antiretroviral treatment (HAART). Spirometry is an accurate method of diagnosing pulmonary dysfunction in people living with HIV (PLWH).

Aim

To compare the prevalence of spirometric abnormalities among HAART-treated HIV patients and HAART naïve HIV patients with non-HIV controls with no recent history of pulmonary infection in a peri-urban hospital in Ghana.

Methods

In a case-control design, we recruited 158 HAART-treated HIV patients, 150 HAART-naïve HIV patients and 156 non-HIV controls for the study. Clinical, sociodemographic data and respiratory symptoms were collected using a structured questionnaire. Spirometry was performed in all participants and abnormalities were categorised as obstructive (OSP) or restrictive (RSP) spirometric patterns based on the GLI definition.

Results

The prevalence of OSP was similar among the HAART treated, HAART naïve HIV patients and non-HIV controls (10.1% vs 9.3% vs 9% respectively, p=0.994), whereas that of RSP was higher in HAART-treated HIV patients compared to HAART-naïve HIV patients and non-HIV controls (51.9% vs 32.1% vs 32% respectively, p=0.013). Respiratory symptoms were common among HAART-treated and HAART-naïve HIV patients compared to non-HIV controls (48.1% vs 40% vs 19.2% respectively, p<0.001). The major determinants of OSP were female gender, exposure to medium-to-high levels of biomass, presence of a respiratory symptom, unemployment and underweight, and that of RSP were age, female gender, being unmarried, medium-to-high biomass exposure and being self-employed or unemployed.

Conclusion

In HIV patients without any recent pulmonary infection in a peri-urban area of Ghana, there was no difference in the prevalence of OSP among HAART-treated and HAART naïve HIV patients compared to the non-HIV control. However, the prevalence of RSP was higher in HAART-treated HIV patients compared to the other groups.
Geospatial disparities in federal COVID-19 test-to-treat program
Authors: Smith Emily R. , Oakley Erin M.
Published: August 2022

Background

Paxlovid is authorized for the treatment of COVID-19 and must be used within the first 5 days of symptom onset. This limited window for initiating treatment makes rapid access critical. Federal Test-to-Treat programs provide tests, prescriptions, and medication in one visit3.

Objective

The objective of this study was to map the location of and identify disparities in access to Test-to-Treat programs in the United States (U.S.).

Methods

We obtained location data for public providers of Paxlovid and Test-to-Treat programs in the contiguous U.S. and examined their spatial distribution at the zip code tabulation area level. We defined zip codes as underserved if there was no Test-to-Treat program located within the zip code or within 20 miles of its boundaries.

Results

More than 52,000,000 people—representing 16% of the continental U.S. population—do not have access to a Test-to-Treat program in their zip code or within 20 miles. The majority of zip codes representing metropolitan areas have a Test-to-Treat program within 20 miles (77%). In contrast, only 30% of small towns and 23% of rural areas have nearby access. Zip codes with a high proportion of Hispanic and Black residents were likely to have access to nearby Test-to-Treat programs (72%, 70%). In contrast, zip codes with a high proportion of Native American residents were likely to be underserved (70%). About half of high-poverty zip codes do not have access to a Test-to-Treat program within 20 miles.

Discussion

Disparities in outcomes related to COVID-19 have been apparent since the beginning of the pandemic and continue to grow. While the multi-dimensional measure of social vulnerability was used to expand the federal Test-to-Treat program, some populations remain without access.
Estimating temporally variable selection intensity from ancient DNA data with the flexibility of modelling linkage and epistasis
Authors: He Zhangyi , Dai Xiaoyang , Lyu Wenyang , Beaumont Mark , Yu Feng
Published: August 2022

Innovations in ancient DNA (aDNA) preparation and sequencing technologies have exponentially increased the quality and quantity of aDNA data extracted from ancient biological materials. The additional temporal component from the incoming aDNA data can provide improved power to address fundamental evolutionary questions like characterising selection processes that shape the phenotypes and genotypes of contemporary populations or species. However, utilising aDNA to study past selection processes still involves considerable hurdles like how to eliminate the confounding factor of genetic interactions in the inference of selection. To address this issue, we extend the approach of He et al. (2022) to infer temporally variable selection from the aDNA data in the form of genotype likelihoods with the flexibility of modelling linkage and epistasis in this work. Our posterior computation is carried out by a robust adaptive version of the particle marginal Metropolis-Hastings algorithm with a coerced acceptance rate. Our extension inherits the desirable features of He et al. (2022) such as modelling sample uncertainty resulting from the damage and fragmentation of aDNA molecules and reconstructing underlying gamete frequency trajectories of the population. We evaluate its performance through extensive simulations and show its utility with an application to the aDNA data from pigmentation loci in horses.