bluuebunny/crossref_metadata_2025_split huggingface dataset:
Disentangling heterogeneity in substance use disorder: Insights from genome-wide polygenic scores
Authors: Vilar-Ribó Laura , Cabana-Domínguez Judit , Alemany Silvia , Llonga Natalia , Arribas Lorena , Grau-López Lara , Daigre Constanza , Cormand Bru , Fernàndez-Castillo Noèlia , Ramos-Quiroga Josep Antoni , Soler Artigas María , Ribasés Marta 
Published: May 2024

AbstractSubstance use disorder (SUD) is a global health problem with a significant impact on individuals and society. The presentation of SUD is diverse, involving various substances, ages at onset, comorbid conditions, and disease trajectories. Current treatments for SUD struggle to address this heterogeneity, resulting in high relapse rates. SUD often co-occurs with other psychiatric and mental health-related conditions that contribute to the heterogeneity of the disorder and predispose to adverse disease trajectories. Family and genetic studies highlight the role of genetic and environmental factors in the course of SUD, and point to a shared genetic liability between SUDs and comorbid psychopathology. In this study, we aimed to disentangle SUD heterogeneity using a deeply phenotyped SUD cohort and polygenic scores (PGSs) for psychiatric disorders and related traits. We explored associations between PGSs and various SUD-related phenotypes, as well as PGS-environment interactions using information on lifetime emotional, physical, and/or sexual abuse. Our results identify clusters of individuals who exhibit differences in their phenotypic profile and reveal different patterns of associations between SUD-related phenotypes and the genetic liability for mental health-related traits, which may help explain part of the heterogeneity observed in SUD. In our SUD sample, we found associations linking the genetic liability for attention-deficit hyperactivity disorder (ADHD) with lower educational attainment, the genetic liability for post-traumatic stress disorder (PTSD) with higher rates of unemployment, the genetic liability for educational attainment with lower rates of criminal records and unemployment, and the genetic liability for well-being with lower rates of outpatient treatments and fewer problems related to family and social relationships. We also found evidence of PGS-environment interactions showing that genetic liability for suicide attempts worsened the psychiatric status in SUD individuals with a history of emotional physical and/or sexual abuse. Collectively, these data contribute to a better understanding of the role of genetic liability for mental health-related conditions and adverse life experiences in SUD heterogeneity.
The enhanced energy metabolism in the tumor margin mediated by RRAD promotes the progression of oral squamous cell carcinoma
Authors: Cheng Aoming , Xu Qiaoshi , Li Bo , Zhang Lirui , Wang Hao , Liu Chang , Han Zhengxue , Feng Zhien 
Published: May 2024

AbstractThe tumor margin as the invasive front has been proven to be closely related to the progression and metastasis of oral squamous cell carcinoma (OSCC). However, how tumor cells in the marginal region obtain the extra energy needed for tumor progression is still unknown. Here, we used spatial metabolomics and the spatial transcriptome to identify enhanced energy metabolism in the tumor margin of OSCC and identified that the downregulation of Ras-related glycolysis inhibitor and calcium channel regulator (RRAD) in tumor cells mediated this process. The absence of RRAD enhanced the ingestion of glucose and malignant behaviors of tumor cells both in vivo and in vitro. Mechanically, the downregulation of RRAD promoted the internal flow of Ca2+ and elevated its concentration in the nucleus, which resulted in the activation of the CAMKIV-CREB1 axis to induce the transcription of the glucose transporter GLUT3. GLUT inhibitor-1, as an inhibitor of GLUT3, could suppress this vigorous energy metabolism and malignant behaviors caused by the downregulation of RRAD. Taken together, our study revealed that enhanced energy metabolism in the tumor margin mediated by RRAD promotes the progression of OSCC and proved that GLUT3 is a potential target for future treatment of OSCC.
HAX-1 interferes in assembly of NLRP3-ASC to block microglial pyroptosis in cerebral I/R injury
Authors: Guo Xin-bin , Deng Xin , Wang Jingjing , Qi Yuruo , Zhao Wen , Guan Sheng 
Published: May 2024

AbstractAcute cerebral ischemia has a high rate of disability and death. Although timely recanalization therapy may rescue the ischemic brain tissue, cerebral ischemia-reperfusion injury has been shown to limit the therapeutic effects of vascular recanalization. Protein HAX-1 has been reported as a pro-survival protein that plays an important role in various disorders, particularly in association with the nervous system. However, the effects and mechanisms of HAX-1 in cerebral IR injury have yet to be elucidated. So, we aimed to investigate the effect of HAX-1 on microglial pyroptosis and explore its potential neuroprotective effects in ischemia-reperfusion injury. Our results show that the expression of HAX-1 decreased after cerebral IR injury, accompanied by an increase in pyroptosis pathway activation. In addition, HAX-1 could inhibit microglial pyroptosis both in vivo and in vitro and reduce the release of inflammatory mediators. The above neuroprotective effects might be partially mediated by inhibiting of interaction of NLRP3 and ASC through competitive binding, followed by the attenuation of NLRP3 inflammasome formation. In conclusion, Our findings support that HAX-1 exhibits a protective role in cerebral I/R injury, and further study on HAX-1 expression regulation will contribute to cerebral infarction therapy.
Upregulation of rate-limiting enzymes in cholesterol metabolism by PKCδ mediates endothelial apoptosis in diabetic wound healing
Authors: Qin Peiliang , Zhou Peng , Huang Yating , Long Binbin , Gao Ruikang , Zhang Shan , Zhu Bingjie , Li Yi-Qing , Li Qin 
Published: May 2024

AbstractDiabetic foot ulcer (DFU) is a prevalent complication of diabetes that poses significant challenges in terms of treatment and management. It is characterized by heightened endothelial apoptosis and impaired angiogenesis. In this study, we aimed to investigate the role of protein kinase Cδ (PKCδ) in regulating endothelial apoptosis in diabetic wounds by promoting cholesterol biosynthesis. The expression of PKCδ was increased in human umbilical vascular endothelial cells (HUVECs) cultivated in high glucose medium and skin tissue isolated from diabetic mice. High glucose-induced HUVECs apoptosis was reduced by PKCδ inhibition with siRNA or rottlerin. RNA-seq identified two enzymes, 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), as the downstream of PKCδ. PKCδ knockdown or inhibition suppressed the expression of HMGCS1 and HMGCR and lowered free cholesterol (FC) levels. Cholesterol restored high glucose-induced apoptosis in siRNA- or rottlerin-treated HUVECs. In vivo use of rosuvastatin calcium, an inhibitor of HMGCR, downregulated free cholesterol levels and accelerated the wound healing process. In conclusion, PKCδ expression in endothelial cells was activated by high glucose, which subsequently upregulates the expression of two enzymes catalyzing cholesterol biosynthesis, HMGCS1 and HMGCR. Enhanced cholesterol biosynthesis raises free cholesterol levels, promotes endothelial apoptosis, and finally delays wound healing.
Hypoxia-induced epigenetic regulation of miR-485-3p promotes stemness and chemoresistance in pancreatic ductal adenocarcinoma via SLC7A11-mediated ferroptosis
Authors: Liu Xinxin , Huang Zhihua , Chen Qiuzheng , Chen Kai , Liu Weikang , Liu Guangnian , Chu Xiangyu , Li Dongqi , Ma Yongsu , Tian Xiaodong , Yang Yinmo 
Published: May 2024

AbstractThe mechanism of hypoxia in chemoresistance of pancreatic ductal adenocarcinoma (PDAC) remains elusive. In this study, we revealed the essential role of miR-485-3p in PDAC, particularly its impact on cancer stemness and gemcitabine resistance under hypoxic conditions. We found substantial downregulation of miR-485-3p in PDAC tissues, with lower expression correlating to poor patient outcomes. Mechanistically, miR-485-3p influenced stemness characteristics, as evidenced by reduced tumor-sphere formation and increased sensitivity to gemcitabine upon overexpression. Moreover, we identified SOX9 and SLC7A11 as two targets of miR-485-3p, which play a vital role in stemness and ferroptosis. Under the hypoxic condition, DNMT3B expression was upregulated, leading to hypermethylation of the miR-485-3p promoter region. The reduced miR-485-3p expression promoted stemness and chemoresistance of PDAC. In conclusion, our findings elucidate the intricate interplay of hypoxia, epigenetic modifications, and ferroptosis in PDAC and shed light on potential avenues for targeted interventions that modulate cancer stemness and chemosensitivity, offering prospects for improved therapeutic strategies for PDAC.
Remote sensing of emperor penguin abundance and breeding success
Authors: Winterl Alexander , Richter Sebastian , Houstin Aymeric , Barracho Téo , Boureau Matthieu , Cornec Clément , Couet Douglas , Cristofari Robin , Eiselt Claire , Fabry Ben , Krellenstein Adélie , Mark Christoph , Mainka Astrid , Ménard Delphine , Morinay Jennifer , Pottier Susie , Schloesing Elodie , Le Bohec Céline , Zitterbart Daniel P. 
Published: May 2024

AbstractEmperor penguins (Aptenodytes forsteri) are under increasing environmental pressure. Monitoring colony size and population trends of this Antarctic seabird relies primarily on satellite imagery recorded near the end of the breeding season, when light conditions levels are sufficient to capture images, but colony occupancy is highly variable. To correct population estimates for this variability, we develop a phenological model that can predict the number of breeding pairs and fledging chicks, as well as key phenological events such as arrival, hatching and foraging times, from as few as six data points from a single season. The ability to extrapolate occupancy from sparse data makes the model particularly useful for monitoring remotely sensed animal colonies where ground-based population estimates are rare or unavailable.
Photo-cycloaddition reactions of vinyldiazo compounds
Authors: Bao Ming , Łuczak Klaudia , Chaładaj Wojciech , Baird Marriah , Gryko Dorota , Doyle Michael P. 
Published: May 2024

AbstractHeterocyclic rings are important structural scaffolds encountered in both natural and synthetic compounds, and their biological activity often depends on these motifs. They are predominantly accessible via cycloaddition reactions, realized by either thermal, photochemical, or catalytic means. Various starting materials are utilized for this purpose, and, among them, diazo compounds are often encountered, especially vinyldiazo compounds that give access to donor-acceptor cyclopropenes which engage in [2+n] cycloaddition reactions. Herein, we describe the development of photochemical processes that produce diverse heterocyclic scaffolds from multisubstituted oximidovinyldiazo compounds. High chemoselectivity, good functional group tolerance, and excellent scalability characterize this methodology, thus predisposing it for broader applications. Experimental and computational studies reveal that under light irradiation these diazo reagents selectively transform into cyclopropenes which engage in cycloaddition reactions with various dipoles, while under thermal conditions the formation of pyrazole from vinyldiazo compounds is favored.
PIF transcriptional regulators are required for rhythmic stomatal movements
Authors: Rovira Arnau , Veciana Nil , Basté-Miquel Aina , Quevedo Martí , Locascio Antonella , Yenush Lynne , Toledo-Ortiz Gabriela , Leivar Pablo , Monte Elena 
Published: May 2024

AbstractStomata govern the gaseous exchange between the leaf and the external atmosphere, and their function is essential for photosynthesis and the global carbon and oxygen cycles. Rhythmic stomata movements in daily dark/light cycles prevent water loss at night and allow CO2 uptake during the day. How the actors involved are transcriptionally regulated and how this might contribute to rhythmicity is largely unknown. Here, we show that morning stomata opening depends on the previous night period. The transcription factors PHYTOCHROME-INTERACTING FACTORS (PIFs) accumulate at the end of the night and directly induce the guard cell-specific K+ channel KAT1. Remarkably, PIFs and KAT1 are required for blue light-induced stomata opening. Together, our data establish a molecular framework for daily rhythmic stomatal movements under well-watered conditions, whereby PIFs are required for accumulation of KAT1 at night, which upon activation by blue light in the morning leads to the K+ intake driving stomata opening.
Organic and inorganic sublattice coupling in two-dimensional lead halide perovskites
Authors: Fu Jianhui , Bian Tieyuan , Yin Jun , Feng Minjun , Xu Qiang , Wang Yue , Sum Tze Chien 
Published: May 2024

AbstractTwo-dimensional layered organic-inorganic halide perovskites have successfully spread to diverse optoelectronic applications. Nevertheless, there remain gaps in our understanding of the interactions between organic and inorganic sublattices that form the foundation of their remarkable properties. Here, we examine these interactions using pump-probe spectroscopy and ab initio molecular dynamics simulations. Unlike off-resonant pumping, resonant excitation of the organic sublattice alters both the electronic and lattice degrees of freedom within the inorganic sublattice, indicating the existence of electronic coupling. Theoretical simulations verify that the reduced bandgap is likely due to the enhanced distortion index of the inorganic octahedra. Further evidence of the mechanical coupling between these two sublattices is revealed through the slow heat transfer process, where the resultant lattice tensile strain launches coherent longitudinal acoustic phonons. Our findings explicate the intimate electronic and mechanical couplings between the organic and inorganic sublattices, crucial for tailoring the optoelectronic properties of two-dimensional halide perovskites.
Glucocorticoids paradoxically promote steroid resistance in B cell acute lymphoblastic leukemia through CXCR4/PLC signaling
Authors: Abdoul-Azize Souleymane , Hami Rihab , Riou Gaetan , Derambure Céline , Charbonnier Camille , Vannier Jean-Pierre , Guzman Monica L. , Schneider Pascale , Boyer Olivier 
Published: May 2024

AbstractGlucocorticoid (GC) resistance in childhood relapsed B-cell acute lymphoblastic leukemia (B-ALL) represents an important challenge. Despite decades of clinical use, the mechanisms underlying resistance remain poorly understood. Here, we report that in B-ALL, GC paradoxically induce their own resistance by activating a phospholipase C (PLC)-mediated cell survival pathway through the chemokine receptor, CXCR4. We identify PLC as aberrantly activated in GC-resistant B-ALL and its inhibition is able to induce cell death by compromising several transcriptional programs. Mechanistically, dexamethasone (Dex) provokes CXCR4 signaling, resulting in the activation of PLC-dependent Ca2+ and protein kinase C signaling pathways, which curtail anticancer activity. Treatment with a CXCR4 antagonist or a PLC inhibitor improves survival of Dex-treated NSG mice in vivo. CXCR4/PLC axis inhibition significantly reverses Dex resistance in B-ALL cell lines (in vitro and in vivo) and cells from Dex resistant ALL patients. Our study identifies how activation of the PLC signalosome in B-ALL by Dex limits the upfront efficacy of this chemotherapeutic agent.
Germline Cas9 promoters with improved performance for homing gene drive
Authors: Du Jie , Chen Weizhe , Jia Xihua , Xu Xuejiao , Yang Emily , Zhou Ruizhi , Zhang Yuqi , Metzloff Matt , Messer Philipp W. , Champer Jackson 
Published: May 2024

AbstractGene drive systems could be a viable strategy to prevent pathogen transmission or suppress vector populations by propagating drive alleles with super-Mendelian inheritance. CRISPR-based homing gene drives convert wild type alleles into drive alleles in heterozygotes with Cas9 and gRNA. It is thus desirable to identify Cas9 promoters that yield high drive conversion rates, minimize the formation rate of resistance alleles in both the germline and the early embryo, and limit somatic Cas9 expression. In Drosophila, the nanos promoter avoids leaky somatic expression, but at the cost of high embryo resistance from maternally deposited Cas9. To improve drive efficiency, we test eleven Drosophila melanogaster germline promoters. Some achieve higher drive conversion efficiency with minimal embryo resistance, but none completely avoid somatic expression. However, such somatic expression often does not carry detectable fitness costs for a rescue homing drive targeting a haplolethal gene, suggesting somatic drive conversion. Supporting a 4-gRNA suppression drive, one promoter leads to a low drive equilibrium frequency due to fitness costs from somatic expression, but the other outperforms nanos, resulting in successful suppression of the cage population. Overall, these Cas9 promoters hold advantages for homing drives in Drosophila species and may possess valuable homologs in other organisms.
Reversible flexoelectric domain engineering at the nanoscale in van der Waals ferroelectrics
Authors: Liu Heng , Lai Qinglin , Fu Jun , Zhang Shijie , Fu Zhaoming , Zeng Hualing 
Published: May 2024

AbstractThe universal flexoelectric effect in solids provides a mechanical pathway for controlling electric polarization in ultrathin ferroelectrics, eliminating potential material breakdown from a giant electric field at the nanoscale. One challenge of this approach is arbitrary implementation, which is strongly hindered by one-way switching capability. Here, utilizing the innate flexibility of van der Waals materials, we demonstrate that ferroelectric polarization and domain structures can be mechanically, reversibly, and arbitrarily switched in two-dimensional CuInP2S6 via the nano-tip imprinting technique. The bidirectional flexoelectric control is attributed to the extended tip-induced deformation in two-dimensional systems with innate flexibility at the atomic scale. By employing an elastic substrate, artificial ferroelectric nanodomains with lateral sizes as small as ~80 nm are noninvasively generated in an area of 1 μm2, equal to a density of 31.4 Gbit/in2. Our results highlight the potential applications of van der Waals ferroelectrics in data storage and flexoelectronics.
The applications of flexible electronics in dental, oral, and craniofacial medicine
Authors: Wang Kang-Ning , Li Zi-Zhan , Cai Ze-Min , Cao Lei-Ming , Zhong Nian-Nian , Liu Bing , Zhou Kan , Huo Fang-Yi , Cai Bo , Bu Lin-Lin 
Published: May 2024

AbstractDental, oral, and craniofacial diseases jeopardize health and reduce the quality of life. Accessing disease-related signals in advance is beneficial to prevent the occurrence or progression of those diseases. However, the inconvenience of periodical in-hospital examinations and the difficulty of sustaining daily health monitoring challenge personal compliance and possibly lead to limited prevention or treatment. Medical flexible electronics are electric devices fabricated on soft and extensible substrates to fit the human skin and enable non-invasive continuous monitoring of biophysical/biochemical signals. They provide the possibility of long-term, continuous, comfortable, and wireless healthcare monitoring and are expected to alleviate time and economic consumption by avoiding in-hospital examinations and treatment. Therefore, flexible electronics have emerged for early diagnosis and disease monitoring in stomatology. It is noteworthy that special biophysical/biochemical characteristics and the environment of dental, oral, and craniofacial areas bring distinct challenges that flexible electronics need to address ingeniously to ensure their stability, selectivity, and sensitivity. This review summaries flexible electronics and their specificity when used in dental, oral, and craniofacial applications, including monitoring saliva or cavity-gas related biosignals, sensing the mechanical fluctuation from facial muscle/respiratory activities or orthodontic forces, and executing special functions in the prevention or postoperative recovery of relevant diseases. Furthermore, after analyzing current challenges and proposing potential solutions, the “5I” principles of imperceptibility, intelligence, individualization, integration, and inexpensiveness are presented to help guide the future development of flexible electronics and promote their commercialization for dental, oral, and craniofacial medicine.
Inferring upstream regulatory genes of FOXP3 in human regulatory T cells from time-series transcriptomic data
Authors: Magni Stefano , Sawlekar Rucha , Capelle Christophe M. , Tslaf Vera , Baron Alexandre , Zeng Ni , Mombaerts Laurent , Yue Zuogong , Yuan Ye , Hefeng Feng Q. , Gonçalves Jorge 
Published: May 2024

AbstractThe discovery of upstream regulatory genes of a gene of interest still remains challenging. Here we applied a scalable computational method to unbiasedly predict candidate regulatory genes of critical transcription factors by searching the whole genome. We illustrated our approach with a case study on the master regulator FOXP3 of human primary regulatory T cells (Tregs). While target genes of FOXP3 have been identified, its upstream regulatory machinery still remains elusive. Our methodology selected five top-ranked candidates that were tested via proof-of-concept experiments. Following knockdown, three out of five candidates showed significant effects on the mRNA expression of FOXP3 across multiple donors. This provides insights into the regulatory mechanisms modulating FOXP3 transcriptional expression in Tregs. Overall, at the genome level this represents a high level of accuracy in predicting upstream regulatory genes of key genes of interest.
A narrative review of norovirus epidemiology, biology, and challenges to vaccine development
Authors: Carlson Katherine B. , Dilley Anne , O’Grady Thomas , Johnson Jordan A. , Lopman Ben , Viscidi Emma 
Published: May 2024

AbstractNorovirus is a leading cause of acute gastroenteritis (AGE) globally. AGE resulting from norovirus causes significant morbidity and mortality in countries of all income levels, particularly among young children and older adults. Prevention of norovirus AGE represents a unique challenge as the virus is genetically diverse with multiple genogroups and genotypes cocirculating globally and causing disease in humans. Variants of the GII.4 genotype are typically the most common genotype, and other genotypes cause varying amounts of disease year-to-year, with GII.2, GII.3, and GII.6 most prevalent in recent years. Noroviruses are primarily transmitted via the fecal-oral route and only a very small number of virions are required for infection, which makes outbreaks of norovirus extremely difficult to control when they occur. Settings like long-term care facilities, daycares, and hospitals are at high risk of outbreaks and can have very high attack rates resulting in substantial costs and disease burden. Severe cases of norovirus AGE are most common in vulnerable patient populations, such as infants, the elderly, and immunocompromised individuals, with available treatments limited to rehydration therapies and supportive care. To date, there are no FDA-approved norovirus vaccines; however, several candidates are currently in development. Given the substantial human and economic burden associated with norovirus AGE, a vaccine to prevent morbidity and mortality and protect vulnerable populations could have a significant impact on global public health.