bluuebunny/crossref_metadata_2025_split huggingface dataset:
Translating pharmacogenomic sequencing data into drug response predictions—How to interpret variants of unknown significance
Authors: Tremmel Roman , Pirmann Sebastian , Zhou Yitian , Lauschke Volker M. 
Published: September 2023

AbstractThe rapid development of sequencing technologies during the past 20 years has provided a variety of methods and tools to interrogate human genomic variations at the population level. Pharmacogenes are well known to be highly polymorphic and a plethora of pharmacogenomic variants has been identified in population sequencing data. However, so far only a small number of these variants have been functionally characterized regarding their impact on drug efficacy and toxicity and the significance of the vast majority remains unknown. It is therefore of high importance to develop tools and frameworks to accurately infer the effects of pharmacogenomic variants and, eventually, aggregate the effect of individual variations into personalized drug response predictions. To address this challenge, we here first describe the technological advances, including sequencing methods and accompanying bioinformatic processing pipelines that have enabled reliable variant identification. Subsequently, we highlight advances in computational algorithms for pharmacogenomic variant interpretation and discuss the added value of emerging strategies, such as machine learning and the integrative use of omics techniques that have the potential to further contribute to the refinement of personalized pharmacological response predictions. Lastly, we provide an overview of experimental and clinical approaches to validate in silico predictions. We conclude that the iterative feedback between computational predictions and experimental validations is likely to rapidly improve the accuracy of pharmacogenomic prediction models, which might soon allow for an incorporation of the entire pharmacogenetic profile into personalized response predictions.
Individualized treatment with voriconazole in the Chinese population: Inflammation level as a novel marker for dose optimization
Authors: Hao Xu , Li Yuanyuan , Zhang Ying , Bian Jialu , Zhao Jinxia , Zhao Yinyu , Hu Lei , Luo Xingxian , Yang Changqing , Feng Yufei , Huang Lin 
Published: September 2023

AbstractAimsThe aim of this study was to explore the influence and possible mechanisms of pharmacokinetics‐related gene polymorphisms, especially CYP2C19 polymorphisms, and non‐genetic factors combined with the inflammatory status on the voriconazole (VRC) metabolism of the Chinese population.MethodsClinical studies were performed by collecting more than one VRC trough concentration and C‐reactive protein (CRP) level. A total of 265 blood samples were collected from 120 patients.ResultsResults of multiple regression analyses demonstrated that CYP2C19 genotypes and albumin (Alb) level remained predictors of Cminss/D in patients with no to mild inflammation (R2 = 0.12, P < .001). In addition, in patients with moderate to severe inflammation, it resulted in a significant model containing factors of CRP and total bilirubin (T‐Bil) levels (R2 = 0.19, P < .001). In non‐clinical studies, 32 rats were divided into control and inflammatory groups, and it was found that the mean residence time (MRT(0–t)) of VRC in the inflammatory group was significantly longer than that in the control group (P < .001), which may be due to down‐regulation of mRNA and protein expression of CYP2C19 (CYP2C6 in rats) through interleukin (IL)‐6/signal transducer and activator of transcription (STAT) 3 pathway.ConclusionsTherefore, the effect of CYP2C19 polymorphisms on VRC metabolism may be masked by inflammatory status, which should be of more concern than CYP2C19 polymorphisms in patients with moderate to severe inflammation. Additionally, the impact of Alb and T‐Bil on VRC metabolism should not be disregarded.
DADLE promotes motor function recovery by inhibiting cytosolic phospholipase A2 mediated lysosomal membrane permeabilization after spinal cord injury
Authors: Chen Yituo , Zhang Haojie , Jiang Liting , Cai Wanta , Kuang Jiaxuan , Geng Yibo , Xu Hui , Li Yao , Yang Liangliang , Cai Yuepiao , Wang Xiangyang , Xiao Jian , Ni Wenfei , Zhou Kailiang 
Published: September 2023

AbstractBackground and PurposeAutophagy is a protective factor for controlling neuronal damage, while necroptosis promotes neuroinflammation after spinal cord injury (SCI). DADLE (D‐Ala2, D‐Leu5]‐enkephalin) is a selective agonist for delta (δ) opioid receptor and has been identified as a promising drug for neuroprotection. The aim of this study was to investigate the mechanism/s by which DADLE causes locomotor recovery following SCI.Experimental approachSpinal cord contusion model was used and DADLE was given by i.p. (16 mg·kg−1) in mice for following experiments. Motor function was assessed by footprint and Basso mouse scale (BMS) score analysis. Western blotting used to evaluate related protein expression. Immunofluorescence showed the protein expression in each cell and its distribution. Network pharmacology analysis was used to find the related signalling pathways.Key ResultsDADLE promoted functional recovery after SCI. In SCI model of mice, DADLE significantly increased autophagic flux and inhibited necroptosis. Concurrently, DADLE restored autophagic flux by decreasing lysosomal membrane permeabilization (LMP). Additionally, chloroquine administration reversed the protective effect of DADLE to inhibit necroptosis. Further analysis showed that DADLE decreased phosphorylated cPLA2, overexpression of cPLA2 partially reversed DADLE inhibitory effect on LMP and necroptosis, as well as the promotion autophagy. Finally, AMPK/SIRT1/p38 pathway regulating cPLA2 is involved in the action DADLE on SCI and naltrindole inhibited DADLE action on δ receptor and on AMPK signalling pathway.Conclusion and ImplicationDADLE causes its neuroprotective effects on SCI by promoting autophagic flux and inhibiting necroptosis by decreasing LMP via activating δ receptor/AMPK/SIRT1/p38/cPLA2 pathway.
The impact of a community‐based music program during infancy on the quality of parent–child language interactions
Authors: Smith Amy R. , Salley Brenda , Hanson‐Abromeit Deanna , Paluch Rocco A. , Engel Hideko , Piazza Jacqueline , Kong Kai Ling 
Published: September 2023

AbstractThe early language environment, especially high‐quality, contingent parent–child language interactions, is crucial for a child's language development and later academic success. In this secondary analysis study, 89 parent–child dyads were randomly assigned to either the Music Together® (music) or play date (control) classes. Children were 9‐ to 15‐month old at baseline, primarily white (86.7%) and female (52%). Measures of conversational turns (CTs) and parental verbal quality were coded from parent–child free play episodes at baseline, mid‐intervention (month 6), and post‐intervention (month 12). Results show that participants in the music group had a significantly greater increase in CT measures and quality of parent verbalization post‐intervention. Music enrichment programs may be a strategy to enhance parent–child language interactions during early childhood.
Effects of climate on the distribution and conservation of commonly observed European earthworms
Authors: Zeiss Romy , Briones Maria J. I. , Mathieu Jérome , Lomba Angela , Dahlke Jessica , Heptner Laura‐Fiona , Salako Gabriel , Eisenhauer Nico , Guerra Carlos A. 
Published: September 2023

AbstractBelowground biodiversity distribution does not necessarily reflect aboveground biodiversity patterns, but maps of soil biodiversity remain scarce because of limited data availability. Earthworms belong to the most thoroughly studied soil organisms and—in their role as ecosystem engineers—have a significant impact on ecosystem functioning. We used species distribution modeling (SDMs) and available data sets to map the spatial distribution of commonly observed (i.e., frequently recorded) earthworm species (Annelida, Oligochaeta) across Europe under current and future climate conditions. First, we predicted potential species distributions with commonly used models (i.e., MaxEnt and Biomod) and estimated total species richness (i.e., number of species in a 5 × 5 km grid cell). Second, we determined how much the different types of protected areas covered predicted earthworm richness and species ranges (i.e., distributions) by estimating the respective proportion of the range area. Earthworm species richness was high in central western Europe and low in northeastern Europe. This pattern was mainly associated with annual mean temperature and precipitation seasonality, but the importance of predictor variables to species occurrences varied among species. The geographical ranges of the majority of the earthworm species were predicted to shift to eastern Europe and partly decrease under future climate scenarios. Predicted current and future ranges were only poorly covered by protected areas, such as national parks. More than 80% of future earthworm ranges were on average not protected at all (mean [SD] = 82.6% [0.04]). Overall, our results emphasize the urgency of considering especially vulnerable earthworm species, as well as other soil organisms, in the design of nature conservation measures.
High‐resolution single‐cell transcriptomic survey of cardiomyocytes from patients with hypertrophic cardiomyopathy
Authors: Lu Jiansen , Ren Jie , Liu Jie , Lu Minjie , Cui Yueli , Liao Yuhan , Zhou Yuan , Gao Yun , Tang Fuchou , Wang Jizheng , Wang Shuiyun , Wen Lu , Song Lei 
Published: September 2023

AbstractHypertrophic cardiomyopathy (HCM) is a common inherited cardiovascular disease, which can cause heart failure and lead to death. In this study, we performed high‐resolution single‐cell RNA‐sequencing of 2115 individual cardiomyocytes obtained from HCM patients and normal controls. Signature up‐ and down‐regulated genes in HCM were identified by integrative analysis across 37 patients and 41 controls from our data and published human single‐cell and single‐nucleus RNA‐seq datasets, which were further classified into gene modules by single‐cell co‐expression analysis. Using our high‐resolution dataset, we also investigated the heterogeneity among individual cardiomyocytes and revealed five distinct clusters within HCM cardiomyocytes. Interestingly, we showed that some extracellular matrix (ECM) genes were up‐regulated in the HCM cardiomyocytes, suggesting that they play a role in cardiac remodelling. Taken together, our study comprehensively profiled the transcriptomic programs of HCM cardiomyocytes and provided insights into molecular mechanisms underlying the pathogenesis of HCM.
Ghana's Debt Crisis and the Political Economy of Financial Dependence in Africa: History Repeating Itself?
Authors: Abotebuno Akolgo Isaac 
Published: September 2023

ABSTRACTRecent accounts of the re‐emergence of debt distress in Africa, while offering significant insights, fail to provide the historical political‐economic context within which African indebtedness is set. On the surface, spending induced by the COVID‐19 pandemic, economic fallout from the Russia–Ukraine war, and repeated examples of fiscal indiscipline by African governments appear to be the causes of the current wave of debt crises. Beyond these factors, however, this article argues that the present indebtedness, like previous episodes, is rooted in the economic and financial subordination of African economies. Specifically, the article places Ghana's extensive debt within the country's post‐independence political‐economic context, and thus traces the structural factors and external constraints that underlie its economic vulnerability and financial dependence. These include the collapse of developmentalism in the 1970s, the Structural Adjustment Programmes of the 1980s, and an exploitative transnational lending system dominated by Western commercial creditors. Internally, recent fiscal mistakes by the government, within its limited policy space, have exacerbated Ghana's indebtedness. The Ghanaian experience shows that unconditional debt cancellation, widely called for, is a necessary but insufficient measure to address the recurring cycles of indebtedness. Debt cancellation should be followed by broader economic and financial reforms, globally and domestically.
Political hierarchy spillovers: Evidence from China
Authors: Chen Meng‐Ting , Zhang Jiakai 
Published: September 2023

AbstractThis paper explores the impact of the political hierarchies of cities in China from different perspectives. First, we examine the economic disparities between prefectural cities and municipalities. Furthermore, this paper draws upon a quasi‐ experiment to analyze the impact of upgrading Chongqing to a municipality in 1997 using the synthetic control method. The city‐upgrading policy significantly increased Chongqing's gross domestic product (GDP) in the following 4 years. Finally, we find that the policy increased GDP in treated cities within 1200 km of Chongqing by about 10%–13% relative to the control cities.
Recent advances in understanding the role of the skin microbiome in the treatment of atopic dermatitis
Authors: Kim Kyunghee , Jang Hyeji , Kim Eunyul , Kim Hyeju , Sung Gun Yong 
Published: September 2023

AbstractThe skin is the largest organ in the human body, and histologically consists of the epidermis, dermis and subcutaneous tissue. Humans maintain a cooperative symbiotic relationship with their skin microbiota, a complex community of bacteria, fungi and viruses that live on the surface of the skin, and which act as a barrier to protect the body from the inside and outside. The skin is a ‘habitat’ and vast ‘ecosystem’ inhabited by countless microbes; as such, relationships have been forged through millions of years of coevolution. It is not surprising then that microbes are key participants in shaping and maintaining essential physiological processes. In addition to maintaining barrier function, the unique symbiotic microbiota that colonizes the skin increases the immune response and provides protection against pathogenic microbes. This review examines our current understanding of skin microbes in shaping and enhancing the skin barrier, as well as skin microbiome–host interactions and their roles in skin diseases, such as atopic dermatitis (AD). We also report on the current status of AD therapeutic drugs that target the skin microbiome, related research on current therapeutic strategies, and the limitations and future considerations of skin microbiome research. In particular, as a future strategy, we discuss the need for a skin‐on‐a‐chip‐based microphysiological system research model amenable to biomimetic in vitro studies and human skin equivalent models, including skin appendages.
Epiphanes brachionus spinosa from a temporary habitat in the Chihuahuan Desert: Morphological response to Asplanchna and control of sexual reproduction
Authors: Gilbert John J. 
Published: September 2023

Abstract

The rotifer Epiphanes brachionus spinosa occurs in shallow temporary waters with hydroperiods up to several months in the Chihuahuan Desert (U.S.A. and Mexico). Clonal populations from one such habitat were initiated from stem females hatched from fertilised resting eggs in flooded dried sediment, and cultured with the alga Cryptomonas erosa at 19°C in a photoperiod (L:D 16:8). Experiments show that the rotifer has: (1) a morphological response to the predatory rotifer Asplanchna, with which it can co‐occur; and (2) an early and constant propensity for sex and resting‐egg production during population development.

Stem females, and females from later generations, have two posterior spines. Measurements of live juveniles and adults indicate that spine length increases isometrically during postnatal growth.

Presence of live Asplanchna brightwellii, or its kairomone in Asplanchna‐conditioned medium, significantly increase spine length. In one clone, spine lengths of juvenile Epiphanes from cultures with or without live Asplanchna were, respectively, c. 40 and c. 27 μm. In that clone, spine lengths of adult Epiphanes in cultures with or without Asplanchna kairomone were, respectively, c. 54 and c. 37 μm. In another clone, these spine lengths were, respectively, c. 44 and c. 36 μm. Asplanchna‐induced spine elongation may act as a mechanical defence against capture and ingestion by the predator.

Sexual reproduction in E. brachionus spinosa populations is initiated soon after populations develop from stem females and then continues at a rate allowing both population growth by female parthenogenesis and production of resting eggs. Resting eggs hatched after 6–12 days at 19°C. Stem females were amictic (producing daughters parthenogenetically) but produced some daughters that were mictic (producing haploid males parthenogenetically or fertilised resting eggs). In subsequent generations tested 2–7 weeks after hatching of stem females, amictic females from three clonal populations produced similar proportions of mictic daughters (mean c. 0.25) when cultured singly in large volumes (15 and 40 ml) or a small one (1.5 ml).

Mictic‐female production is probably automatic and controlled by an endogenous mechanism, rather than specifically induced by crowding or some other environmental factor. Early and continuous sexual reproduction assures production of resting eggs throughout short and unpredictable hydroperiods.
Weighted thyroid‐stimulating hormone disturbance in prognosis of hepatitis B virus‐related acute‐on‐chronic liver failure
Authors: Tu Yasi , Ji Feiyang , Yang Jing , Rao Qunfang , Wu Haiquan , Xie Zhongyang , Zhang Sainan , Hou Zhouhua , Wu Daxian 
Published: September 2023

AbstractAimTo weight the prognostic value of thyroid hormones in catastrophic acute‐on‐chronic liver failure (ACLF).MethodsA retrospective cohort (n = 635) and two prospective cohorts (n = 353, and 198) were enrolled in this study. The performance of a novel developed prognostic score was assessed from aspects of reliability, discrimination, and clinical net benefit.ResultsThyroid‐stimulating hormone (TSH) was identified to have the most potential as a prognostic predictor for hepatitis B virus‐related ACLF among thyroid hormones. The novel score (modified chronic liver failure–organ failure score [mCLIF‐OFs]) was developed with weighted TSH and other scored organs in the CLIF‐OFs using the retrospective cohort (n = 635). The predicted risk and observed probabilities of death were comparable across the deciles of mCLIF‐OFs (Hosmer–Lemeshow χ2 = 4.28, p = 0.83; Brier scaled = 11.9). The C‐index of mCLIF‐OFs (0.885 [0.883–0.887]) for 30‐day mortality was significantly higher than that of the CLIF‐OFs, chronic liver failure–sequential organ failure assessment score (CLIF‐SOFAs), CLIF‐C ACLFs, Model of End‐stage Liver Disease (MELD), and Child–Pugh (all p < 0.001). The absolute improvements of prediction error rates of the mCLIF‐OFs compared to the above five scores were from 19.0% to 61.1%. After the analysis of probability density function, the mCLIF‐OFs showed the least overlapping coefficients (27.9%) among the above prognostic scores. Additionally, the mCLIF‐OFs showed greater net benefit than the above five prognostic scores over a wide range of risk threshold of death. Similar results were validated in two prospective ACLF cohorts with HBV and non‐HBV etiologies.ConclusionWeighted TSH portended the outcome of ACLF patients, which could be treated as a “damaged organ” of the hypothalamic–pituitary–thyroid axis. The novel mCLIF‐OFs is a reliable prognostic score with better discrimination power and clinical net benefit than CLIF‐OFs, CLIF‐SOFAs, CLIF‐C ACLFs, MELD, and Child–Pugh.
Frailty in people 50 years or older living with HIV: A sex perspective
Authors: Wiechmann Susana Lilian , Tejo Alexandre Mestre , Inácio Manuel Victor Silva , Mesas Arthur Eumann , Martínez‐Vizcaíno Vicente , Cabrera Marcos Aparecido Sarria 
Published: September 2023

AbstractObjectiveTo estimate prefrailty and frailty prevalence and associated factors in people living with HIV (PLHIV) from a sex perspective.MethodsCross‐sectional study on PLHIV at specialized public health centres in Brazil. Data were obtained from individuals aged ≥50 years using antiretroviral therapy (ART) and with an undetectable viral load through personal interviews, clinical evaluations and medical records. Frailty and prefrailty were characterized using the Fried Frailty Phenotype tool. Multinomial regression models were performed, and the associated factors were selected through the backward stepwise method.ResultsAmong 670 patients, 373 men and 297 women were included. The prevalence of frailty and prefrailty was significantly higher for women (16.2% and 56.2%, respectively) than for men (11.5% and 46.4%, respectively). Low socioeconomic and educational level, multimorbidity, depression, subjective cognitive complaints, and low scores on the Mini‐Mental State Exam (MMSE) were associated (P < 0.05) with frailty for both sexes. However, in the sex‐specific analysis, while smoking (OR = 3.66, 95% CI: 1.58–8.48) and a history of low adherence to ART (OR = 3.10, 95% CI: 1.33–7.23) were associated with frailty in men, depression (OR = 3.39, 95% CI: 1.36– 8.44) and the absence of functional dentition (OR = 3.77, 95% CI: 1.36– 10.43) were associated with frailty in women.ConclusionsThis study adds self‐reported cognitive complaints as a potential predictor of frailty in both sexes and supports the known deleterious effect of multimorbidity on frailty in adults living with HIV. Furthermore, it suggests that other possible predictors, such as depression, oral health status and adherence to ART, may be sex‐specific.
Family, friends, school and nation: Socio‐ecological determinants of mental health among Filipino college students post‐lockdown
Authors: Cleofas Jerome V. 
Published: September 2023

AbstractAs societies recover from the systemic socio‐economic impacts of the 2019 novel coronavirus disease pandemic, the mental health of the youth must be monitored as they transition back to on‐campus learning. This study sought to determine the socio‐ecological determinants of mental health among Filipino college students after a 2‐year lockdown (i.e., community quarantine). A total of 1204 students aged 18–24 participated in this cross‐sectional online survey research. Multi‐level socio‐ecological determinants were measured, such as individual (age, gender), micro/mesosystem (family, friends and school), exo/macrosystem (national resilience) and chronosystem (life satisfaction change over time). Findings suggest that male students who identify as cisheterosexual (cisgender, which refers to gender identity that aligns with biological sex, and heterosexual, which refers to sexual attraction exclusively for the opposite sex), with higher ratings for family, school community, national identity, trust in public institutions and improvements in life satisfaction post‐lockdown, demonstrated higher mental well‐being. Meanwhile, female, gender and sexual minorities, with lower ratings for family, respect for diversity in school and decline in life satisfaction post‐lockdown, reported higher psychological distress.