bluuebunny/crossref_metadata_2025_split huggingface dataset:
Polygenic scores for tobacco use provide insights into systemic health risks in a diverse EHR-linked biobank in Los Angeles
Authors: Venkateswaran Vidhya , Boulier Kristin , Ding Yi , Johnson Ruth , Bhattacharya Arjun , Pasaniuc Bogdan 
Published: January 2024

AbstractTobacco use is a major risk factor for many diseases and is heavily influenced by environmental factors with significant underlying genetic contributions. Here, we evaluated the predictive performance, risk stratification, and potential systemic health effects of tobacco use disorder (TUD) predisposing germline variants using a European- ancestry-derived polygenic score (PGS) in 24,202 participants from the multi-ancestry, hospital-based UCLA ATLAS biobank. Among genetically inferred ancestry groups (GIAs), TUD-PGS was significantly associated with TUD in European American (EA) (OR: 1.20, CI: [1.16, 1.24]), Hispanic/Latin American (HL) (OR:1.19, CI: [1.11, 1.28]), and East Asian American (EAA) (OR: 1.18, CI: [1.06, 1.31]) GIAs but not in African American (AA) GIA (OR: 1.04, CI: [0.93, 1.17]). Similarly, TUD-PGS offered strong risk stratification across PGS quantiles in EA and HL GIAs and inconsistently in EAA and AA GIAs. In a cross-ancestry phenome-wide association meta-analysis, TUD-PGS was associated with cardiometabolic, respiratory, and psychiatric phecodes (17 phecodes at P < 2.7E-05). In individuals with no history of smoking, the top TUD-PGS associations with obesity and alcohol-related disorders (P = 3.54E-07, 1.61E-06) persist. Mendelian Randomization (MR) analysis provides evidence of a causal association between adiposity measures and tobacco use. Inconsistent predictive performance of the TUD-PGS across GIAs motivates the inclusion of multiple ancestry populations at all levels of genetic research of tobacco use for equitable clinical translation of TUD-PGS. Phenome associations suggest that TUD-predisposed individuals may require comprehensive tobacco use prevention and management approaches to address underlying addictive tendencies.
Diminished social motivation in early psychosis is associated with polygenic liability for low vitamin D
Authors: Hatzimanolis Alex , Tosato Sarah , Ruggeri Mirella , Cristofalo Doriana , Mantonakis Leonidas , Xenaki Lida-Alkisti , Dimitrakopoulos Stefanos , Selakovic Mirjana , Foteli Stefania , Kosteletos Ioannis , Vlachos Ilias , Soldatos Rigas-Filippos , Nianiakas Nikos , Ralli Irene , Kollias Konstantinos , Ntigrintaki Angeliki-Aikaterini , Stefanatou Pentagiotissa , Murray Robin M. , Vassos Evangelos , Stefanis Nikos C. 
Published: January 2024

AbstractInsufficiency of vitamin D levels often occur in individuals with schizophrenia and first-episode psychosis (FEP). However, it is unknown whether this represents a biological predisposition, or it is essentially driven by illness-related alterations in lifestyle habits. Lower vitamin D has also been associated with adverse neurodevelopmental outcomes and predominant negative psychotic symptoms. This study aimed to investigate the contribution of polygenic risk score for circulating 25-hydroxyvitamin D concentration (PRS-vitD) to symptom presentation among individuals with FEP enrolled in the Athens First-Episode Psychosis Research Study (AthensFEPn = 205) and the Psychosis Incident Cohort Outcome Study (PICOSn = 123). The severity of psychopathology was evaluated using the Positive and Negative Syndrome Scale at baseline and follow-up assessments (AthensFEP: 4-weeks follow-up, PICOS: 1-year follow-up). Premorbid intelligence and adjustment domains were also examined as proxy measures of neurodevelopmental deviations. An inverse association between PRS-vitD and severity of negative symptoms, in particular lack of social motivation, was detected in the AthensFEP at baseline (adjusted R2 = 0.04,p < 0.001) and follow-up (adjusted R2 = 0.03,p < 0.01). The above observation was independently validated in PICOS at follow-up (adjusted R2 = 0.06,p < 0.01). No evidence emerged for a relationship between PRS-vitD and premorbid measures of intelligence and adjustment, likely not supporting an impact of lower PRS-vitD on developmental trajectories related to psychotic illness. These findings suggest that polygenic vulnerability to reduced vitamin D impairs motivation and social interaction in individuals with FEP, thereby interventions that encourage outdoor activities and social engagement in this patient group might attenuate enduring negative symptoms.
Reconsidering repurposing: long-term metformin treatment impairs cognition in Alzheimer’s model mice
Authors: Cho So Yeon , Kim Eun Woo , Park Soo Jin , Phillips Benjamin U. , Jeong Jihyeon , Kim Hyunjeong , Heath Christopher J. , Kim Daehwan , Jang Yurim , López-Cruz Laura , Saksida Lisa M. , Bussey Timothy J. , Lee Do Yup , Kim Eosu 
Published: January 2024

AbstractMetformin, a primary anti-diabetic medication, has been anticipated to provide benefits for Alzheimer’s disease (AD), also known as “type 3 diabetes”. Nevertheless, some studies have demonstrated that metformin may trigger AD pathology and even elevate AD risk in humans. Despite this, limited research has elucidated the behavioral outcomes of metformin treatment, which would hold significant translational value. Thus, we aimed to perform thorough behavioral research on the prolonged administration of metformin to mice: We administered metformin (300 mg/kg/day) to transgenic 3xTg-AD and non-transgenic (NT) C57BL/6 mice over 1 and 2 years, respectively, and evaluated their behaviors across multiple domains via touchscreen operant chambers, including motivation, attention, memory, visual discrimination, and cognitive flexibility. We found metformin enhanced attention, inhibitory control, and associative learning in younger NT mice (≤16 months). However, chronic treatment led to impairments in memory retention and discrimination learning at older age. Furthermore, metformin caused learning and memory impairment and increased levels of AMPKα1-subunit, β-amyloid oligomers, plaques, phosphorylated tau, and GSK3β expression in AD mice. No changes in potential confounding factors on cognition, including levels of motivation, locomotion, appetite, body weight, blood glucose, and serum vitamin B12, were observed in metformin-treated AD mice. We also identified an enhanced amyloidogenic pathway in db/db mice, as well as in Neuro2a-APP695 cells and a decrease in synaptic markers, such as PSD-95 and synaptophysin in primary neurons, upon metformin treatment. Our findings collectively suggest that the repurposing of metformin should be carefully reconsidered when this drug is used for individuals with AD.
The constitutive activation of STAT3 gene and its mutations are at the crossroad between LGL leukemia and autoimmune disorders
Authors: Semenzato Gianpietro , Calabretto Giulia , Teramo Antonella , Gasparini Vanessa Rebecca , Rampazzo Elisa , Barilà Gregorio , Zambello Renato 
Published: January 2024

AbstractType T Large Granular Lymphocyte Leukemia (T-LGLL) is a chronic disorder characterized by the abnormal proliferation of clonal cytotoxic T cells. The intriguing association of T-LGLL with autoimmune and inflammatory diseases, the most prominent example being rheumatoid arthritis, raises questions about the underlying pathophysiologic relationships between these disorders which share several biological and clinical features, most notably neutropenia, which is considered as a clinical hallmark. Recent progress in molecular genetics has contributed to a better understanding of pathogenetic mechanisms, thus moving our knowledge in the field of LGL leukemias forward. Focusing on the constitutive activation of STAT3 pathway and the well-established role of STAT3 mutations in T-LGLL, we herein discuss whether the T cell clones occurring in comorbid conditions are the cause or the consequence of the immune-inflammatory associated events. Overall, this review sheds light on the intricate relationships between inflammation and cancer, emphasizing the importance of the STAT3 gene and its activation in the pathophysiology of these conditions. Gaining a deeper understanding of these underlying mechanisms seeks to pave the way for the development of novel targeted therapies for patients affected by inflammation-related cancers.
miR-277 targets the proapoptotic gene-hid to ameliorate Aβ42-mediated neurodegeneration in Alzheimer’s model
Authors: Deshpande Prajakta , Chen Chao-Yi , Chimata Anuradha Venkatakrishnan , Li Jian-Chiuan , Sarkar Ankita , Yeates Catherine , Chen Chun-Hong , Kango-Singh Madhuri , Singh Amit 
Published: January 2024

AbstractAlzheimer’s disease (AD), an age-related progressive neurodegenerative disorder, exhibits reduced cognitive function with no cure to date. One of the reasons for AD is the accumulation of Amyloid-beta 42 (Aβ42) plaque(s) that trigger aberrant gene expression and signaling, which results in neuronal cell death by an unknown mechanism(s). Misexpression of human Aβ42 in the developing retina of Drosophila exhibits AD-like neuropathology. Small non-coding RNAs, microRNAs (miRNAs), post-transcriptionally regulate the expression of their target genes and thereby regulate different signaling pathways. In a forward genetic screen, we identified miR-277 (human ortholog is hsa-miR-3660) as a genetic modifier of Aβ42-mediated neurodegeneration. Loss-of-function of miR-277 enhances the Aβ42-mediated neurodegeneration. Whereas gain-of-function of miR-277 in the GMR > Aβ42 background downregulates cell death to maintain the number of neurons and thereby restores the retinal axonal targeting defects indicating the functional rescue. In addition, gain-of-function of miR-277 rescues the eclosion- and climbing assays defects observed in GMR > Aβ42 background. Thus, gain-of-function of miR-277 rescues both structurally as well as functionally the Aβ42-mediated neurodegeneration. Furthermore, we identified head involution defective (hid), an evolutionarily conserved proapoptotic gene, as one of the targets of miR-277 and validated these results using luciferase- and qPCR -assays. In the GMR > Aβ42 background, the gain-of-function of miR-277 results in the reduction of hid transcript levels to one-third of its levels as compared to GMR > Aβ42 background alone. Here, we provide a novel molecular mechanism where miR-277 targets and downregulates proapoptotic gene, hid, transcript levels to rescue Aβ42-mediated neurodegeneration by blocking cell death. These studies shed light on molecular mechanism(s) that mediate cell death response following Aβ42 accumulation seen in neurodegenerative disorders in humans and provide new therapeutic targets for neurodegeneration.
Targeting PAK4 reverses cisplatin resistance in NSCLC by modulating ER stress
Authors: Liu Shixin , Yang Pingshan , Wang Lu , Zou Xiaofang , Zhang Dongdong , Chen Wenyou , Hu Chuang , Xiao Duqing , Ren Hongzheng , Zhang Hao , Cai Songwang 
Published: January 2024

AbstractChemoresistance poses a significant impediment to effective treatments for non-small-cell lung cancer (NSCLC). P21-activated kinase 4 (PAK4) has been implicated in NSCLC progression by invasion and migration. However, the involvement of PAK4 in cisplatin resistance is not clear. Here, we presented a comprehensive investigation into the involvement of PAK4 in cisplatin resistance within NSCLC. Our study revealed enhanced PAK4 expression in both cisplatin-resistant NSCLC tumors and cell lines. Notably, PAK4 silencing led to a remarkable enhancement in the chemosensitivity of cisplatin-resistant NSCLC cells. Cisplatin evoked endoplasmic reticulum stress in NSCLC. Furthermore, inhibition of PAK4 demonstrated the potential to sensitize resistant tumor cells through modulating endoplasmic reticulum stress. Mechanistically, we unveiled that the suppression of the MEK1-GRP78 signaling pathway results in the sensitization of NSCLC cells to cisplatin after PAK4 knockdown. Our findings establish PAK4 as a promising therapeutic target for addressing chemoresistance in NSCLC, potentially opening new avenues for enhancing treatment efficacy and patient outcomes.
Clinical application of tumour-in-normal contamination assessment from whole genome sequencing
Authors: Mitchell Jonathan , Milite Salvatore , Bartram Jack , Walker Susan , Volkova Nadezda , Yavorska Olena , Zarowiecki Magdalena , Chalker Jane , Thomas Rebecca , Vago Luca , Sosinsky Alona , Caravagna Giulio 
Published: January 2024

AbstractThe unexpected contamination of normal samples with tumour cells reduces variant detection sensitivity, compromising downstream analyses in canonical tumour-normal analyses. Leveraging whole-genome sequencing data available at Genomics England, we develop a tool for normal sample contamination assessment, which we validate in silico and against minimal residual disease testing. From a systematic review of $$771$$
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patients with haematological malignancies and sarcomas, we find contamination across a range of cancer clinical indications and DNA sources, with highest prevalence in saliva samples from acute myeloid leukaemia patients, and sorted CD3+ T-cells from myeloproliferative neoplasms. Further exploration reveals 108 hotspot mutations in genes associated with haematological cancers at risk of being subtracted by standard variant calling pipelines. Our work highlights the importance of contamination assessment for accurate somatic variants detection in research and clinical settings, especially with large-scale sequencing projects being utilised to deliver accurate data from which to make clinical decisions for patient care.
Altered DNA methylation within DNMT3A, AHRR, LTA/TNF loci mediates the effect of smoking on inflammatory bowel disease
Authors: Zhang Han , Kalla Rahul , Chen Jie , Zhao Jianhui , Zhou Xuan , Adams Alex , Noble Alexandra , Ventham Nicholas T. , Wellens Judith , Ho Gwo-Tzer , Dunlop Malcolm G. , Nowak Jan Krzysztof , Ding Yuan , Liu Zhanju , Satsangi Jack , Theodoratou Evropi , Li Xue 
Published: January 2024

AbstractThis work aims to investigate how smoking exerts effect on the development of inflammatory bowel disease (IBD). A prospective cohort study and a Mendelian randomization study are first conducted to evaluate the association between smoking behaviors, smoking-related DNA methylation and the risks of Crohn’s disease (CD) and ulcerative colitis (UC). We then perform both genome-wide methylation analysis and co-localization analysis to validate the observed associations. Compared to never smoking, current and previous smoking habits are associated with increased CD (P = 7.09 × 10−10) and UC (P < 2 × 10−16) risk, respectively. DNA methylation alteration at cg17742416 [DNMT3A] is linked to both CD (P = 7.30 × 10−8) and UC (P = 1.04 × 10−4) risk, while cg03599224 [LTA/TNF] is associated with CD risk (P = 1.91 × 10−6), and cg14647125 [AHRR] and cg23916896 [AHRR] are linked to UC risk (P = 0.001 and 0.002, respectively). Our study identifies biological mechanisms and pathways involved in the effects of smoking on the pathogenesis of IBD.
Benchmark for welding gun fault prediction with multivariate time series data
Authors: Wang Xiaoye , Zhang Changsheng , Wang Tao 
Published: January 2024

AbstractIn the automotive industry, machinery failures of the resistance spot welding (RSW) guns would interrupt the manufacturing lines and cause unplanned downtime, potentially resulting in a significant loss of production and reliability. Predicting the machinery failures of the RSW gun can provide more scientific strategies for predictive maintenance and decision-making. However, fault prediction of RSW guns has become increasingly challenging due to their complex behavior and data variability. In this paper, we created a benchmark dataset and proposed welding gun fault prediction benchmarks to aid in the development of machine learning approaches toward welding gun fault prediction. The dataset was collected at the Body-Shop (BS) of BMW Brilliance Automotive Ltd. from different components of hundreds of RSW guns to capture the patterns and trends before welding errors with historical data. Then we provide state-of-the-art machine learning (ML) benchmarks on time series forecasting methods in a welding gun fault prediction use case. This study will provide insights for time series forecasting while enabling ML researchers to contribute towards the fault prediction of the RSW guns.
A novel on design and implementation of hybrid MPPT controllers for solar PV systems under various partial shading conditions
Authors: Hussaian Basha Chakarajamula , Palati Madhu , Dhanamjayulu C. , Muyeen S. M. , Venkatareddy Prashanth 
Published: January 2024

AbstractAt present, fossil fuel-based power generation systems are reducing drastically because of their less availability in nature. In addition, it produces hazardous gasses and high environmental pollution. So, in this work, the solar natural source is selected for generating the electricity. Due to the nonlinear behavior of PV, achieving maximum voltage from the Photovoltaic (PV) system is a more tough job. In this work, various hybrid optimization controllers are studied for tracing the working power point of the PV under different Partial Shading Conditions. The studied hybrid optimization MPPT methods are equated in terms of oscillations across MPP, output power extraction, settling time of the MPP, dependency on the PV modeling, operating duty value of the converter, error finding accuracy of MPPT, algorithm complexity, tracking speed, periodic tuning required, and the number of sensing parameters utilized. Based on the simulative comparison results, it has been observed that the modified Grey Wolf Optimization based ANFIS hybrid MPPT method provides good results when equated with the other power point tracking techniques. Here, the conventional converter helps increase the PV source voltage from one level to another level. The proposed system is investigated by using the MATLAB/Simulink tool.
Identification of human skin microbiome odorants that manipulate mosquito landing behavior
Authors: Coutinho-Abreu Iliano V. , Jamshidi Omid , Raban Robyn , Atabakhsh Katayoon , Merriman Joseph A. , Akbari Omar S. 
Published: January 2024

AbstractThe resident human skin microbiome is responsible for the production of most of the human scents that are attractive to mosquitoes. Hence, engineering the human skin microbiome to synthesize less of mosquito attractants or produce repellents could potentially reduce bites and prevent the transmission of deadly mosquito-borne pathogens. In order to further characterize the human skin volatilome, we quantified the major volatiles of 39 strains of skin commensals (Staphylococci and Corynebacterium). Importantly, to validate the behavioral activity of these volatiles, we first assessed landing behavior triggered by human skin volatiles. We demonstrated that landing behavior is gated by the presence of carbon dioxide and L-(+)-lactic acid. This is similar to the combinatorial coding triggering mosquito short range attraction. Repellency behavior to selected skin volatiles and terpenes was tested in the presence of carbon dioxide and L-(+)-lactic acid. In a 2-choice landing behavior context, the skin volatiles 2- and 3-methyl butyric acids reduced mosquito landing by 62.0–81.6% and 87.1–99.6%, respectively. Similarly, the terpene geraniol was capable of reducing mosquito landing behavior by 74.9%. We also tested the potential repellency effects of terpenes in mosquitoes at short-range using a 4-port olfactometer. In these assays, geraniol reduced mosquito attraction (69–78%) to a mixture of key human kairomones carbon dioxide, L-(+)-lactic acid, and ammonia. These findings demonstrate that carbon dioxide and L-(+)-lactic acid change the valence of other skin volatiles towards mosquito landing behavior. Moreover, this study offers candidate odorants to be targeted in a novel strategy to reduce attractants or produce repellents by the human skin microbiota that may curtail mosquito bites, and subsequent mosquito-borne disease.
Broadband stripline Lenz lens achieves 11 × NMR signal enhancement
Authors: Liang Jianyi , Davoodi Hossein , Wadhwa Sagar , Badilita Vlad , Korvink Jan G. 
Published: January 2024

AbstractA Lenz lens is an electrically passive conductive element that, when placed in a time-varying magnetic field, acts as a magnetic flux concentrator or a magnetic lens. In the realm of nuclear magnetic resonance (NMR), Lenz lenses have been exploited as electrically passive metallic radiofrequency interposers placed between a sample and a tuned or untuned NMR detector in order to focus the $${B}_1$$

B
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-field of the detector onto a smaller sample space. Here we explore a novel embodiment of the Lenz lens, which acts as a non-resonant stripline interposer, i.e., the $${B}_1$$

B
1

-field acts along the longitudinal volume of a sample container, such as a capillary or other microfluidic channel that is coincident with the axis of the stripline. The almost vanishing self-resonance of the stripline Lenz lens, at frequencies relevant for NMR, leads to a desirable $${B}_1$$

B
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-field amplitude that is nearly perfectly uniform across the sample and hence lacking a characteristic sinusoidal modal shape. The action of Lenz’ law ensures that no stray $${B}_1$$

B
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-field is found outside of the stripline’s active volume. Because the stripline Lenz lens does not rely on its own geometry to achieve resonance, its frequency response is thus widely broadband for field enhancements up to a factor of 11, with only the external driving resonator properties governing the overall resonant behaviour. We explore the use of the stripline Lenz lens with a sub-nanolitre sample volume, readily detecting 4 isotopes with resonances ranging from 125.76 to 500 MHz. The concept holds potential for the NMR study of thin films, small biological samples, as well as the in situ study of battery materials.
Learning in hybrid classes: the role of off-task activities
Authors: Ochs Carli , Gahrmann Caroline , Sonderegger Andreas 
Published: January 2024

AbstractHybrid teaching (synchronous online and on-site teaching) offers many advantages (e.g., increased flexibility). However, previous research has suggested that students who join classes online suffer higher levels of distractibility, which might translate into students engaging in more off-task activities. This, in turn, can impair students’ learning performance. The following quasi-experimental field study investigated this specific link between teaching mode, engagement in off-task activities, and learning performance. We collected survey data from N = 690 students in six hybrid classes (N = 254 online, N = 436 on-site). Participants reported the amount of time they spent engaging in digital and non-digital off-task activities and responded to a quiz on the course material. Results revealed that online students spent more time engaging in off-task activities than on-site students. Further, results were consistent with our hypothesis that joining the class online is associated with lower learning performance via time spent on digital off-task activities.