bluuebunny/crossref_metadata_2025_split huggingface dataset:
Next-generation sequencing-based bulked segregant analysis without sequencing the parental genomes
Authors: Zhang Jianbo , Panthee Dilip R 
Published: December 2021

Abstract
Genomic regions that control traits of interest can be rapidly identified using BSA-Seq, a technology in which next-generation sequencing is applied to bulked segregant analysis (BSA). We recently developed the significant structural variant method for BSA-Seq data analysis that exhibits higher detection power than standard BSA-Seq analysis methods. Our original algorithm was developed to analyze BSA-Seq data in which genome sequences of one parent served as the reference sequences in genotype calling and, thus, required the availability of high-quality assembled parental genome sequences. Here, we modified the original script to effectively detect the genomic region–trait associations using only bulk genome sequences. We analyzed two public BSA-Seq datasets using our modified method and the standard allele frequency and G-statistic methods with and without the aid of the parental genome sequences. Our results demonstrate that the genomic region(s) associated with the trait of interest could be reliably identified via the significant structural variant method without using the parental genome sequences.
Stage-specific disruption of X chromosome expression during spermatogenesis in sterile house mouse hybrids
Authors: Larson Erica L , Kopania Emily E K , Hunnicutt Kelsie E , Vanderpool Dan , Keeble Sara , Good Jeffrey M 
Published: December 2021

AbstractHybrid sterility is a complex phenotype that can result from the breakdown of spermatogenesis at multiple developmental stages. Here, we disentangle two proposed hybrid male sterility mechanisms in the house mice, Mus musculus domesticus and M. m. musculus, by comparing patterns of gene expression in sterile F1 hybrids from a reciprocal cross. We found that hybrid males from both cross directions showed disrupted X chromosome expression during prophase of meiosis I consistent with a loss of meiotic sex chromosome inactivation (MSCI) and Prdm9-associated sterility, but that the degree of disruption was greater in mice with an M. m. musculus X chromosome consistent with previous studies. During postmeiotic development, gene expression on the X chromosome was only disrupted in one cross direction, suggesting that misexpression at this later stage was genotype-specific and not a simple downstream consequence of MSCI disruption which was observed in both reciprocal crosses. Instead, disrupted postmeiotic expression may depend on the magnitude of earlier disrupted MSCI, or the disruption of particular X-linked genes or gene networks. Alternatively, only hybrids with a potential deficit of Sly copies, a Y-linked ampliconic gene family, showed overexpression in postmeiotic cells, consistent with a previously proposed model of antagonistic coevolution between the X- and Y-linked ampliconic genes contributing to disrupted expression late in spermatogenesis. The relative contributions of these two regulatory mechanisms and their impact on sterility phenotypes await further study. Our results further support the hypothesis that X-linked hybrid sterility in house mice has a variable genetic basis, and that genotype-specific disruption of gene regulation contributes to overexpression of the X chromosome at different stages of development. Overall, these findings underscore the critical role of epigenetic regulation of the X chromosome during spermatogenesis and suggest that these processes are prone to disruption in hybrids.
Restricted maximum-likelihood method for learning latent variance components in gene expression data with known and unknown confounders
Authors: Malik Muhammad Ammar , Michoel Tom 
Published: December 2021

Abstract
Random effects models are popular statistical models for detecting and correcting spurious sample correlations due to hidden confounders in genome-wide gene expression data. In applications where some confounding factors are known, estimating simultaneously the contribution of known and latent variance components in random effects models is a challenge that has so far relied on numerical gradient-based optimizers to maximize the likelihood function. This is unsatisfactory because the resulting solution is poorly characterized and the efficiency of the method may be suboptimal. Here, we prove analytically that maximum-likelihood latent variables can always be chosen orthogonal to the known confounding factors, in other words, that maximum-likelihood latent variables explain sample covariances not already explained by known factors. Based on this result, we propose a restricted maximum-likelihood (REML) method that estimates the latent variables by maximizing the likelihood on the restricted subspace orthogonal to the known confounding factors and show that this reduces to probabilistic principal component analysis on that subspace. The method then estimates the variance–covariance parameters by maximizing the remaining terms in the likelihood function given the latent variables, using a newly derived analytic solution for this problem. Compared to gradient-based optimizers, our method attains greater or equal likelihood values, can be computed using standard matrix operations, results in latent factors that do not overlap with any known factors, and has a runtime reduced by several orders of magnitude. Hence, the REML method facilitates the application of random effects modeling strategies for learning latent variance components to much larger gene expression datasets than possible with current methods.
The relative impact of evolving pleiotropy and mutational correlation on trait divergence
Authors: Chebib Jobran , Guillaume Frédéric 
Published: December 2021

Abstract
Both pleiotropic connectivity and mutational correlations can restrict the decoupling of traits under divergent selection, but it is unknown which is more important in trait evolution. To address this question, we create a model that permits within-population variation in both pleiotropic connectivity and mutational correlation, and compare their relative importance to trait evolution. Specifically, we developed an individual-based stochastic model where mutations can affect whether a locus affects a trait and the extent of mutational correlations in a population. We find that traits can decouple whether there is evolution in pleiotropic connectivity or mutational correlation, but when both can evolve, then evolution in pleiotropic connectivity is more likely to allow for decoupling to occur. The most common genotype found in this case is characterized by having one locus that maintains connectivity to all traits and another that loses connectivity to the traits under stabilizing selection (subfunctionalization). This genotype is favored because it allows the subfunctionalized locus to accumulate greater effect size alleles, contributing to increasingly divergent trait values in the traits under divergent selection without changing the trait values of the other traits (genetic modularization). These results provide evidence that partial subfunctionalization of pleiotropic loci may be a common mechanism of trait decoupling under regimes of corridor selection.
Skulls and Stories: Creating the Value of Bones in Johann Friedrich Blumenbach’s Collection
Authors: Schober Sarah-Maria 
Published: December 2021

Abstract
This article focuses on the famous skull collection of the German naturalist Johann Friedrich Blumenbach (1752–1840) to demonstrate that human remains in early modern scientific collections possessed an important but often underestimated economic value in addition to their well-known scientific and social worth. Blumenbach’s skulls are thus presented as a part of a vigorous early modern ‘necro-economy’ and as a product of its networks. The article highlights three strategies of enrichment which were used to create the value of these bones: reference to scientific values, the use of emotions and story-telling. The last two strategies in particular are relevant to present-day debates concerning the restitution of musealized human remains, for their analysis helps us deconstruct a perceptual bias that tends to contrast a Western and predominantly ‘scientific’ (and thus seemingly universal) value of collected human remains with theoretically ‘softer’ cultural values allegedly attributed to them in their countries of origin.
Reduced Electroencephalogram Complexity in Postoperative Delirium
Authors: Tanabe Sean , Parker Maggie , Lennertz Richard , Pearce Robert A , Banks Matthew I , Sanders Robert D 
Published: December 2021

Abstract
Delirium is associated with electroencephalogram (EEG) slowing and impairments in connectivity. We hypothesized that delirium would be accompanied by a reduction in the available cortical information (ie, there is less information processing occurring), as measured by a surrogate, Lempil-Ziv Complexity (LZC), a measure of time-domain complexity. Two ongoing perioperative cohort studies (NCT03124303, NCT02926417) contributed EEG data from 91 patients before and after surgery; 89 participants were used in the analyses. After cleaning and filtering (0.1–50Hz), the perioperative change in LZC and LZC normalized (LZCn) to a phase-shuffled distribution were calculated. The primary outcome was the correlation of within-patient paired changes in delirium severity (Delirium Rating Scale-98 [DRS]) and LZC. Scalp-wide threshold-free cluster enhancement was employed for multiple comparison correction. LZC negatively correlated with DRS in a scalp-wide manner (peak channel r2 = .199, p &lt; .001). This whole brain effect remained for LZCn, though the correlations were weaker (peak channel r2 = .076, p = .010). Delirium diagnosis was similarly associated with decreases in LZC (peak channel p &lt; .001). For LZCn, the topological significance was constrained to the midline posterior regions (peak channel p = .006). We found a negative correlation of LZC in the posterior and temporal regions with monocyte chemoattractant protein-1 (peak channel r2 = .264, p &lt; .001, n = 47) but not for LZCn. Complexity of the EEG signal fades proportionately to delirium severity implying reduced cortical information. Peripheral inflammation, as assessed by monocyte chemoattractant protein-1, does not entirely account for this effect, suggesting that additional pathogenic mechanisms are involved.
Loss of Natriuretic Peptide Receptor C Enhances Sinoatrial Node Dysfunction in Aging and Frail Mice
Authors: Jansen Hailey J , Moghtadaei Motahareh , Rafferty Sara A , Belke Darrell D , Rose Robert A 
Published: December 2021

Abstract
Heart rate (HR) is controlled by the sinoatrial node (SAN). SAN dysfunction is highly prevalent in aging; however, not all individuals age at the same rate. Rather, health status during aging is affected by frailty. Natriuretic peptides regulate SAN function in part by activating natriuretic peptide receptor C (NPR-C). The impacts of NPR-C on HR and SAN function in aging and as a function of frailty are unknown. Frailty was measured in aging wild-type and NPR-C knockout (NPR-C−/−) mice using a mouse clinical frailty index (FI). HR and SAN structure and function were investigated using intracardiac electrophysiology in anesthetized mice, high-resolution optical mapping in intact atrial preparations, histology, and molecular biology. NPR-C−/− mice rapidly became frail leading to shortened life span. HR was reduced and SAN recovery time was increased in older versus younger mice, and these changes were exacerbated in NPR-C−/− mice; however, there was substantial variability among age groups and genotypes. HR and SAN recovery time were correlated with FI score and fell along a continuum regardless of age or genotype. Optical mapping demonstrates impairments in SAN function that were also correlated with FI score. SAN fibrosis was increased in aged and NPR-C−/− mice and was graded by FI score. Loss of NPR-C results in accelerated aging and rapid decline in health status in association with impairments in HR and SAN function. Frailty assessment was effective and better able to distinguish aging-dependent changes in SAN function in the setting of shortened life span due to loss of NPR-C.
Antecedent Metabolic Health and Metformin (ANTHEM) Aging Study: Rationale and Study Design for a Randomized Controlled Trial
Authors: Kumari Santosh , Bubak Matthew T , Schoenberg Hayden M , Davidyan Arik , Elliehausen Christian J , Kuhn Katrin G , VanWagoner Timothy M , Karaman Rowan , Scofield Robert Hal , Miller Benjamin F , Konopka Adam R 
Published: December 2021

Abstract
The antidiabetic medication metformin has been proposed to be the first drug tested to target aging and extend healthspan in humans. While there is extensive epidemiological support for the health benefits of metformin in patient populations, it is not clear if these protective effects apply to those free of age-related disease. Our previous data in older adults without diabetes suggest a dichotomous change in insulin sensitivity and skeletal muscle mitochondrial adaptations after metformin treatment when co-prescribed with exercise. Those who entered the study as insulin-sensitive had no change to detrimental effects while those who were insulin-resistant had positive changes. The objective of this clinical trial is to determine if (a) antecedent metabolic health and (b) skeletal muscle mitochondrial remodeling and function mediate the positive or detrimental effects of metformin monotherapy, independent of exercise, on the metabolism and biology of aging. In a randomized, double-blind clinical trial, adults free of chronic disease (n = 148, 40–75 years old) are stratified as either insulin-sensitive or resistant based on homeostatic model assessment of insulin resistance (≤2.2 or ≥2.5) and take 1 500 mg/day of metformin or placebo for 12 weeks. Hyperinsulinemic-euglycemic clamps and skeletal muscle biopsies are performed before and after 12 weeks to assess primary outcomes of peripheral insulin sensitivity and mitochondrial remodeling and function. Findings from this trial will identify clinical characteristics and cellular mechanisms involved in modulating the effectiveness of metformin treatment to target aging that could inform larger Phase 3 clinical trials aimed at testing aging as a treatment indication for metformin.
Clinical Trials Registration Number: NCT04264897.
Effects of Stress Exposure Versus Appraisal on Episodic Memory Trajectories: Evidence for Risk and Resilience Among Black Older Adults
Authors: Morris Emily P , Brown Lauren L , Zaheed Afsara B , Palms Jordan D , Sol Ketlyne , Martino Alexa , Zahodne Laura B 
Published: December 2021

AbstractObjectivesChronic stressors, experienced disproportionately by Black older adults, are a risk factor for memory impairment. Racially patterned stress exposure may contribute to higher rates of Alzheimer’s disease and related dementias (ADRD) among Black older adults compared with Whites, but less is known about the role of stress appraisal. This study examined whether chronic stress exposure mediates racial disparities in memory and whether stress appraisal moderates these associations.MethodsParticipants included 16,924 older adults (Mage = 67.39, 21% Black) from the 2010 and 2012 waves of the Health and Retirement Study who completed measures of chronic stress exposure (health, financial, housing, relationships, and caregiving) and appraisal. Latent growth curves modeled longitudinal performance on a word list memory task over 6 years.ResultsBlack older adults reported greater stress exposure than Whites, and greater stress exposure partially mediated Black–White disparities in initial memory (standardized indirect effect = −0.002, p = .009). However, Black older adults appraised stressors as less upsetting than Whites. While stress appraisal did not moderate links between stress exposure and memory, appraising stressors as less upsetting was independently associated with better initial memory. Thus, Black–White disparities in initial memory was partially offset by Black participants’ appraisal of stressors as less upsetting (standardized indirect effect = 0.002, p = .016).DiscussionReducing chronic stress exposure may reduce racial disparities in ADRD risk. The counteractive effect of stress appraisal on Black–White disparities in episodic memory highlights resilience factors among Black older adults that should be characterized in future research to move beyond deficit models of ADRD inequality.
Toward Responsible Artificial Intelligence in Long-Term Care: A Scoping Review on Practical Approaches
Authors: Lukkien Dirk R M , Nap Henk Herman , Buimer Hendrik P , Peine Alexander , Boon Wouter P C , Ket Johannes C F , Minkman Mirella M N , Moors Ellen H M 
Published: December 2021

AbstractBackground and ObjectivesArtificial intelligence (AI) is widely positioned to become a key element of intelligent technologies used in the long-term care (LTC) for older adults. The increasing relevance and adoption of AI has encouraged debate over the societal and ethical implications of introducing and scaling AI. This scoping review investigates how the design and implementation of AI technologies in LTC is addressed responsibly: so-called responsible innovation (RI).Research Design and MethodsWe conducted a systematic literature search in 5 electronic databases using concepts related to LTC, AI, and RI. We then performed a descriptive and thematic analysis to map the key concepts, types of evidence, and gaps in the literature.ResultsAfter reviewing 3,339 papers, 25 papers were identified that met our inclusion criteria. From this literature, we extracted 3 overarching themes: user-oriented AI innovation; framing AI as a solution to RI issues; and context-sensitivity. Our results provide an overview of measures taken and recommendations provided to address responsible AI innovation in LTC.Discussion and ImplicationsThe review underlines the importance of the context of use when addressing responsible AI innovation in LTC. However, limited empirical evidence actually details how responsible AI innovation is addressed in context. Therefore, we recommend expanding empirical studies on RI at the level of specific AI technologies and their local contexts of use. Also, we call for more specific frameworks for responsible AI innovation in LTC to flexibly guide researchers and innovators. Future frameworks should clearly distinguish between RI processes and outcomes.
Profile of the current psychiatrist workforce in South Africa: establishing a baseline for human resource planning and strategy
Authors: Janse van Rensburg Bernard , Kotzé Carla , Moxley Karis , Subramaney Ugasvaree , Zingela Zukiswa , Seedat Soraya 
Published: December 2021

Abstract
The World Health Organization Global Health Observatory Data Repository reports South Africa with 1.52 psychiatrists per 100 000 of the population among other countries in Africa with 0.01 psychiatrists per 100 000 (Chad, Burundi and Niger) to more than 30 per 100 000 for some countries in Europe. The overall situation, while being cognizant that mental health care is not only provided by specialist psychiatrists and that the current treatment gap may have to be addressed by strategies such as appropriate task sharing, suggests that there are actually too few psychiatrists to meet the country’s mental health care needs. To address the need to develop a strategy to increase the local specialist training and examination capacity, a situational review of currently practicing psychiatrists was undertaken by the [BLINDED] and the [BLINDED] using the South African Society of Psychiatrists membership database. The number, distribution and attributes of practicing psychiatrists were compared with international figures on the ratio of psychiatrists per 100 000 population. In April 2019, there were 850 qualified psychiatrists actively practicing in the country and based on the national population figure of 55.6 million people (2016 Census), the psychiatrists per 100 000 ratio was 1.53. This indicates no improvement between 2016 to 2019. From the South African Society of Psychiatrists database, we determined that about 80% of psychiatrists are working in the private sector—a much higher proportion than is usually quoted. As the vast majority of psychiatrists are practicing in urban areas in two provinces, Gauteng (n = 350) and Western Cape (n = 292), the ratio of psychiatrists per 100 000 in these areas is relatively higher at 2.6 and 5.0, respectively, whereas rural areas in South Africa are largely without specialist mental health expertise at a rate of 0.03 per 100 000 population. This investigation provides a discipline-specific situational review of the attributes and distribution of the current workforce of specialists in the country.
A “Priesthood of Knowledge”: The International Thought of Henri de Saint-Simon
Authors: Eijking Jan 
Published: December 2021

Abstract
The French political theorist Henri de Saint-Simon is largely absent from historical International Relations (IR). This article shows why this is unwarranted and introduces him as an international thinker who made lasting contributions to IR's modern conceptual imagination. Largely responding to the French Revolution Saint-Simon rethought the parameters of international order, imagining the international as a realm separable from national politics and conformable to human agency. International order, on his account, could be actively created. This could take the shape of legislation, trade, or large-scale engineering projects: of new methods of governance. Based on a close reading of texts rarely brought into IR’s focus, this article introduces Saint-Simon as a thinker who cut across traditional IR divides and developed a central actor category of international order: impartial, knowledge-based agents of change. His understanding of international reform not only made it possible to theorize and experiment with a role in global governance for technical experts but also masked the imperial underpinnings of the international projects these experts facilitated. The article makes the case that Saint-Simon deserves a firm place in historical IR, that his thought presents an opportunity for revisiting widely held assumptions about international authority, and that a discernible Saint-Simonian strand of international thought puts typically liberal histories of global governance in question.
Development of a repository of computable phenotype definitions using the clinical quality language
Authors: Brandt Pascal S , Pacheco Jennifer A , Rasmussen Luke V 
Published: December 2021

Abstract

Objective
The objective of this study is to create a repository of computable, technology-agnostic phenotype definitions for the purposes of analysis and automatic cohort identification.

Materials and Methods
We selected phenotype definitions from PheKB and excluded definitions that did not use structured data or were not used in published research. We translated these definitions into the Clinical Quality Language (CQL) and Fast Healthcare Interoperability Resources (FHIR) and validated them using code review and automated tests.

Results
A total of 33 phenotype definitions met our inclusion criteria. We developed 40 CQL libraries, 231 value sets, and 347 test cases. To support these test cases, a total of 1624 FHIR resources were created as test data.

Discussion and Conclusion
Although a number of challenges were encountered while translating the phenotypes into structured form, such as requiring specialized knowledge, or imprecise, ambiguous, and conflicting language, we have created a repository and a development environment that can be used for future research on computable phenotypes.