bluuebunny/crossref_metadata_2025_split huggingface dataset:
Proteomic Biomarkers for the Prediction of Transition to Psychosis in Individuals at Clinical High Risk: A Multi-cohort Model Development Study
Authors: Byrne Jonah F , Healy Colm , Föcking Melanie , Susai Subash Raj , Mongan David , Wynne Kieran , Kodosaki Eleftheria , Heurich Meike , de Haan Lieuwe , Hickie Ian B , Smesny Stefan , Thompson Andrew , Markulev Connie , Young Alison Ruth , Schäfer Miriam R , Riecher-Rössler Anita , Mossaheb Nilufar , Berger Gregor , Schlögelhofer Monika , Nordentoft Merete , Chen Eric Y H , Verma Swapna , Nieman Dorien H , Woods Scott W , Cornblatt Barbara A , Stone William S , Mathalon Daniel H , Bearden Carrie E , Cadenhead Kristin S , Addington Jean , Walker Elaine F , Cannon Tyrone D , Cannon Mary , McGorry Pat , Amminger Paul , Cagney Gerard , Nelson Barnaby , Jeffries Clark , Perkins Diana , Cotter David R 
Published: January 2024

Abstract
Psychosis risk prediction is one of the leading challenges in psychiatry. Previous investigations have suggested that plasma proteomic data may be useful in accurately predicting transition to psychosis in individuals at clinical high risk (CHR). We hypothesized that an a priori-specified proteomic prediction model would have strong predictive accuracy for psychosis risk and aimed to replicate longitudinal associations between plasma proteins and transition to psychosis. This study used plasma samples from participants in 3 CHR cohorts: the North American Prodrome Longitudinal Studies 2 and 3, and the NEURAPRO randomized control trial (total n = 754). Plasma proteomic data were quantified using mass spectrometry. The primary outcome was transition to psychosis over the study follow-up period. Logistic regression models were internally validated, and optimism-corrected performance metrics derived with a bootstrap procedure. In the overall sample of CHR participants (age: 18.5, SD: 3.9; 51.9% male), 20.4% (n = 154) developed psychosis within 4.4 years. The a priori-specified model showed poor risk-prediction accuracy for the development of psychosis (C-statistic: 0.51 [95% CI: 0.50, 0.59], calibration slope: 0.45). At a group level, Complement C8B, C4B, C5, and leucine-rich α-2 glycoprotein 1 (LRG1) were associated with transition to psychosis but did not surpass correction for multiple comparisons. This study did not confirm the findings from a previous proteomic prediction model of transition from CHR to psychosis. Certain complement proteins may be weakly associated with transition at a group level. Previous findings, derived from small samples, should be interpreted with caution.
The chromatographic fingerprinting study and genotoxicity evaluation of aqueous extract from Cyclocarya paliurus leaves
Authors: Zhao Hongwei , Yang Xiaobing , Wang Lei , Huang Xianju 
Published: January 2024

Abstract
Cyclocarya paliurus leaf is a medicinal and edible homologous plant, which possess various bioactive components with significant health benefits. However, the quality and safety of the aqueous extract from Cyclocarya paliurus leaves (CPLAE) vary greatly due to the raw materials and preparation technology. At present, chromatographic fingerprinting has been widely used for qualitative and quantitative analysis of traditional Chinese medicine (TCM). In this study, a method combining high performance liquid chromatography (HPLC) fingerprint with quantitative analysis was established and successfully applied to the characterization and quality evaluation of the CPLAE. In addition, the genetic safety of the CPLAE was evaluated by genotoxicity tests, including Ames test, chromosomal aberration test of Chinese hamster lung (CHL) cell in vitro, and bone marrow micronucleus test in mice. The results showed that 10 batches of CPLAE samples were analyzed by high performance liquid chromatography coupled with mass spectrometry (HPLC-MS), and the similarity of chromatographic fingerprint of each batch was above 0.961, indicating good similarity. At the same time, the 6 compounds with high absorption strength in the chromatogram were quantitatively analyzed. The results showed that all 6 compounds had good regression (R2=1.000) in the test range, and the recoveries ranged from 96.25% to 102.46%. The results of the 3 genotoxicity tests showed that the highest dose of CPLAE had no genotoxicity. In conclusion, the newly established chromatographic fingerprint and multi-component quantitative analysis method is stable and accurate, and can be used for the identification and quality evaluation of the CPLAE. Moreover, the CPLAE has the characteristics of safety and high quality as functional materials in food.
The sphingosine‐1‐phosphate receptor 1 modulator ponesimod repairs cuprizone‐induced demyelination and induces oligodendrocyte differentiation
Authors: Willems Emily , Schepers Melissa , Piccart Elisabeth , Wolfs Esther , Hellings Niels , Ait‐Tihyaty Maria , Vanmierlo Tim 
Published: January 2024

AbstractSphingosine‐1‐phosphate receptor (S1PR) modulators are clinically used to treat relapse‐remitting multiple sclerosis (MS) and the early phase of progressive MS when inflammation still prevails. In the periphery, S1PR modulators prevent lymphocyte egress from lymph nodes, hence hampering neuroinflammation. Recent findings suggest a role for S1PR modulation in remyelination. As the Giα‐coupled S1P1 subtype is the most prominently expressed S1PR in oligodendrocyte precursor cells (OPCs), selective modulation (functional antagonism) of S1P1 may have direct effects on OPC functionality. We hypothesized that functional antagonism of S1P1 by ponesimod induces remyelination by boosting OPC differentiation. In the cuprizone mouse model of demyelination, we found ponesimod to decrease the latency time of visual evoked potentials compared to vehicle conditions, which is indicative of functional remyelination. In addition, the Y maze spontaneous alternations test revealed that ponesimod reversed cuprizone‐induced working memory deficits. Myelin basic protein (MBP) immunohistochemistry and transmission electron microscopy of the corpus callosum revealed an increase in myelination upon ponesimod treatment. Moreover, treatment with ponesimod alone or in combination with A971432, an S1P5 monoselective modulator, significantly increased primary mouse OPC differentiation based on O4 immunocytochemistry. In conclusion, S1P1 functional antagonism by ponesimod increases remyelination in the cuprizone model of demyelination and significantly increases OPC differentiation in vitro.
KAT8 functions in redox homeostasis and mitochondrial dynamics during mouse oocyte meiosis progression
Authors: Wu Xuan , Wang Shiwei , Guo Yajun , Song Shuang , Zeng Shenming 
Published: January 2024

AbstractAs a histone acetyltransferase, lysine acetyltransferase 8 (KAT8) participates in diverse biological processes. However, the effect of KAT8 on oocyte maturation in mice remains unclear. In this study, we found that mouse oocytes overexpressing Kat8‐OE induced maturation failure manifested reduced rates of GVBD and first polar body emission. In addition, immunostaining results revealed that Kat8 overexpressing oocytes showed inappropriate mitochondrial distribution patterns, overproduction of reactive oxygen species (ROS), accumulation of phosphorylated γH2AX, hyperacetylation of α‐tubulin, and severely disrupted spindle/chromosome organization. Moreover, we revealed that Kat8 overexpression induced a decline in SOD1 proteins and KAT8's interaction with SOD1 in mouse ovaries via immunoprecipitation. Western blotting data confirmed that Kat8‐OE induced downregulation of SOD1 expression, which is a key factor for the decline of oocyte quality in advanced maternal age. Also, the injection of Myc‐Sod1 cRNA could partially rescue maternal age‐induced meiotic defects in oocytes. In conclusion, our data demonstrated that high level of KAT8 inhibited SOD1 activity, which in turn induced defects of mitochondrial dynamics, imbalance of redox homeostasis, and spindle/chromosome disorganization during mouse oocyte maturation.
Development of a novel HER2-CAR monocyte cell therapy with controllable proliferation and enhanced anti-tumor efficacy
Authors: Yang Bing , Wang Xiaoxue , Wei Xundong , Ma Jie 
Published: January 2024

Abstract

Background:
One of the significant challenges for cell therapies, such as chimeric antigen receptor (CAR)-T cell therapy, is the poor infiltration of immune cells into tumor tissues. CAR-monocytes/macrophages (CAR-M) are promising therapies because of their enrichment in the tumor microenvironment. Thus, we constructed a novel CAR-M to facilitate the infiltration of T cells and other immune cells.

Methods:
The suicide gene inducible caspase-9 (iCasp9) and anti-erb-b2 receptor tyrosine kinase 2 (HER2) CAR elements were transfected into THP1 (an immortalized human monocyte cell line) by lentivirus. The suicide efficiency and specific anti-tumor efficacy were assessed using flow cytometry, inCucyte, and tumor-bearing BALB/c-nude mouse models. The activation of related signaling pathways in CAR-THP1 activation was explored by transcriptome sequencing. Finally, the synergistic therapeutic efficacy of CAR-THP1 combined with RAK cell treatment was demonstrated in tumor-bearing NOD.CB17-Prkdcscid Il2rgtm1/Bcgen mouse models.

Results:
We developed a novel CAR-THP1, which incorporated iCasp9, CD3ζ, and CD147 intracellular segments, based on the first-generation HER2-CAR backbone. By constructing and comparing a series of CARs with different permutations, CAR-CD3ζ-CD147-iCasp9-THP1 was selected as the optimal combination. CAR-CD3ζ-CD147-iCasp9-THP1 initiated suicide quickly and efficiently under the control of iCasp9 gene, which enabled us to achieve controlled proliferation of CAR-THP1. CAR-THP1 also exhibited robust specific anti-tumor efficacy independently of T cells in vitro and in vivo. Through transcriptional sequencing, we found that CAR-THP1 tended to differentiate into the M1 phenotype and bridged innate and adaptive immunity. A combination of CAR-THP1 and Retronectin actived killer cells (RAKs) showed better therapeutic efficiency, as the metalloproteinases (MMPs) secreted by CAR-THP1 facilitated the degradation of the dense tumor matrix. This further assisted intratumoral infiltration of T cells and augmented the anti-tumor immune response.

Conclusion:
CAR-THP1 might be effective against HER2-positive tumor cells and has great potential for combination therapy with other immune cells.
GRK2–YAP signaling is implicated in pulmonary arterial hypertension development
Authors: Ye Peng , Deng Yunfei , Gu Yue , Liu Pengfei , Luo Jie , Pu Jiangqin , Chen Jingyu , Huang Yu , Wang Nanping , Ji Yong , Chen Shaoliang 
Published: January 2024

Abstract

Background:
Pulmonary arterial hypertension (PAH) is characterized by excessive proliferation of small pulmonary arterial vascular smooth muscle cells (PASMCs), endothelial dysfunction, and extracellular matrix remodeling. G protein-coupled receptor kinase 2 (GRK2) plays an important role in the maintenance of vascular tone and blood flow. However, the role of GRK2 in the pathogenesis of PAH is unknown.

Methods:
GRK2 levels were detected in lung tissues from healthy people and PAH patients. C57BL/6 mice, vascular smooth muscle cell-specific Grk2-knockout mice (Grk2
Δ
SM22), and littermate controls (Grk2
flox/flox) were grouped into control and hypoxia mice (n = 8). Pulmonary hypertension (PH) was induced by exposure to chronic hypoxia (10%) combined with injection of the SU5416 (cHx/SU). The expression levels of GRK2 and Yes-associated protein (YAP) in pulmonary arteries and PASMCs were detected by Western blotting and immunofluorescence staining. The mRNA expression levels of Grk2 and Yes-associated protein (YAP) in PASMCs were quantified with real-time polymerase chain reaction (RT-PCR). Wound-healing assay, 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) assay, and 5-Ethynyl-2′-deoxyuridine (EdU) staining were performed to evaluate the proliferation and migration of PASMCs. Meanwhile, the interaction among proteins was detected by immunoprecipitation assays.

Results:
The expression levels of GRK2 were upregulated in the pulmonary arteries of patients with PAH and the lungs of PH mice. Moreover, cHx/SU-induced PH was attenuated in Grk2
Δ
SM22 mice compared with littermate controls. The amelioration of PH in Grk2
Δ
SM22 mice was accompanied by reduced pulmonary vascular remodeling. In vitro study further confirmed that GRK2 knock-down significantly altered hypoxia-induced PASMCs proliferation and migration, whereas this effect was severely intensified by overexpression of GRK2. We also identified that GRK2 promoted YAP expression and nuclear translocation in PASMCs, resulting in excessive PASMCs proliferation and migration. Furthermore, GRK2 is stabilized by inhibiting phosphorylating GRK2 on Tyr86 and subsequently activating ubiquitylation under hypoxic conditions.

Conclusion:
Our findings suggest that GRK2 plays a critical role in the pathogenesis of PAH, via regulating YAP expression and nuclear translocation. Therefore, GRK2 serves as a novel therapeutic target for PAH treatment.
Effects of the Need for Support From the Workplace and Resilience on Psychological Distress in Japanese Employees
Authors: Eguchi Hisashi , Inoue Akiomi , Mafune Kosuke , Tsuji Mayumi , Tateishi Seiichiro , Ikegami Kazunori , Nagata Tomohisa , Matsugaki Ryutaro , Fujino Yoshihisa ,   for the CORoNaWork project
Published: January 2024

Purpose
This study examines workplace support and resilience’s influence on psychological distress in Japanese employees.

Method
A 1-year prospective online cohort study was conducted. Logistic regression analyzed prevalence odds ratios and 95% confidence intervals for psychological distress. Participants were grouped based on their support and resilience levels.

Results
Prevalence odds ratios for psychological distress followed this pattern for low and high resilience groups: “necessary but not received” (prevalence odds ratio and 95% confidence interval for low/high resilience: 9.71, 6.88–13.69 and 4.72, 2.97–7.52, respectively), “received” (6.65, 4.29–10.29 and 2.27, 1.21–4.25), and “not necessary” (4.43, 3.30–5.95 and reference). Workplace support had a stronger impact on psychological distress in low-resilience employees.

Conclusions
We provided evidence that the combination of the need for support from the workplace and resilience affects psychological distress in employees.
Relationship Between Infection or Close Contact With COVID-19 and Workplace Mistreatment Among Japanese Workers
Authors: Sawamoto Naoya , Okawara Makoto , Muramatsu Keiji , Odagami Kiminori , Mafune Kosuke , Tateishi Seiichiro , Tsuji Mayumi , Ogami Akira , Fujino Yoshihisa 
Published: January 2024

ObjectiveDiscriminatory treatment against those with emerging infection is a long-standing problem. The present study investigates whether workers infected or in close contact with COVID-19 were susceptible to workplace mistreatment during the pandemic in Japan.MethodsThis Internet-based cross-sectional study analyzed a total of 18,170 workers aged 20 to 60 years in Japan in December 2020. Odds ratios (ORs) for workplace mistreatment were estimated.ResultsFor workers with close contact or infection, ORs for workplace mistreatment in a model adjusted for socioeconomic factors were 7.64 (95% CI: 5.52–10.6,P< 0.001) and 10.7 (95% CI: 8.44–13.6,P< 0.001), respectively.ConclusionsWorkers with infection or close contact were significantly more likely to experience workplace mistreatment. Actions against workplace mistreatment for workers with emerging infection are still required.
A bird’s-eye view: exploration of the flavin-containing monooxygenase (FMO) superfamily in common wheat
Authors: Sun Sherry , Bakkeren Guus 
Published: January 2024

AbstractThe Flavin Monooxygenase (FMO) gene superfamily in plants is involved in various processes most widely documented for its involvement in auxin biosynthesis, specialized metabolite biosynthesis, and plant microbial defense signalling. The roles of FMOs in defense signaling and disease resistance have recently come into focus as they may present opportunities to increase immune responses in plants including leading to systemic acquired resistance, but are not well characterized. We present a comprehensive catalogue ofFMOs found in genomes across vascular plants and explore, in depth, 170 wheatTaFMOgenes for sequence architecture,cis-acting regulatory elements, and changes due to Transposable Element insertions. A molecular phylogeny separates TaFMOs into three clades (A, B, and C) for which we further report gene duplication patterns, and differential rates of homoeologue expansion and retention among TaFMO subclades. We discuss Clade B TaFMOs where gene expansion is similarly seen in other cereal genomes. Transcriptome data from various studies point towards involvement of subclade B2TaFMOs in disease responses against both biotrophic and necrotrophic pathogens, substantiated by promoter element analysis. We hypothesize that certain TaFMOs are responsive to both abiotic and biotic stresses, providing potential targets for enhancing disease resistance, plant yield and other important agronomic traits. Altogether, FMOs in wheat and other crop plants present an untapped resource to be exploited for improving the quality of crops.
Neurophysiological Correlates of Phase-Specific Enhancement of Motor Memory Consolidation via Slow-Wave Closed-Loop Targeted Memory Reactivation
Authors: Nicolas Judith , King Bradley R. , Levesque David , Lazzouni Latifa , Wang David , Grossman Nir , Swinnen Stephan P. , Doyon Julien , Carrier Julie , Albouy Geneviève 
Published: January 2024

AbstractMemory consolidation can be enhanced during sleep using targeted memory reactivation (TMR) and closed-loop (CL) acoustic stimulation on the up-phase of slow oscillations (SOs). Here, we tested whether applying TMR at specific phases of the SOs (up vs. down vs. no reactivation) could influence the behavioral and neural correlates of motor memory consolidation in healthy young adults. Results showed that up- (as compared to down-) state cueing resulted in greater performance improvement. Sleep electrophysiological data indicated that up-stimulated SOs exhibited higher amplitude and greater peak-nested sigma power. Task-related functional magnetic resonance images revealed that up-state cueing strengthened activity in - and segregation of - striato-motor and hippocampal networks; and that these modulations were related to the beneficial effect of TMR on sleep features and performance. Overall, these findings highlight the potential of CL-TMR to induce phase-specific modulations of motor performance, sleep oscillations and brain responses during motor memory consolidation.
CXCR3-expressing myeloid cells recruited to the hypothalamus protect against diet-induced body mass gain and metabolic dysfunction
Authors: Mendes Natalia F. , Zanesco Ariane M. , Aguiar Cristhiane F. , Rodrigues-Luiz Gabriela F. , da Silva Dayana C. , Campos Jonathan F. , Câmara Niels O. S. , de Moraes-Vieira Pedro M. M. , de Araújo Eliana P. , Velloso Licio A. 
Published: January 2024

AbstractMicrogliosis is an important component of diet-induced hypothalamic inflammation in obesity. A few hours after the introduction of a high-fat diet, the mediobasal hypothalamus resident microglia undergo morphological and functional changes toward an inflammatory phenotype. If the consumption of large amounts of dietary fats persists for long periods, bone marrow- derived myeloid cells are recruited and integrated into a new landscape of hypothalamic microglia. However, it is currently unknown what are the transcriptional signatures and specific functions exerted by either resident or recruited subsets of hypothalamic microglia. Here, the elucidation of the transcriptional signatures revealed that resident microglia undergo only minor changes in response to dietary fats; however, under the consumption of a high-fat diet, there are major transcriptional differences between resident and recruited immune cells with major impact on chemotaxis. In addition, in CCR2+ recruited peripheral immune cells, there are major transcriptional differences between females and males with important impact on transcripts involved in neurodegeneration and thermogenesis. The chemokine receptor CXCR3 emerged as one of the components of chemotaxis with the greatest difference between recruited and resident microglia, and thus, was elected for further intervention. The hypothalamic immunoneutralization of CXCL10, one of the ligands for CXCR3, resulted in increased body mass gain and reduced energy expenditure, particularly in females. Furthermore, the chemical inhibition of CXCR3 resulted in a much greater change in phenotype with increased body mass gain, reduced energy expenditure, increased blood leptin, glucose intolerance, and reduced insulin. Thus, this study has elucidated the transcriptional differences between resident microglia and recruited immune cells in diet-induced obesity, identifying chemokines as a relevant subset of genes undergoing regulation. In addition, we showed that a subset of recruited immune cells expressing CXCR3 has a protective, rather than a detrimental role in the metabolic outcomes promoted by the consumption of a high-fat diet, thus, establishing a new concept in obesity-associated hypothalamic inflammation.
Advancing Transcription Factor Binding Site Prediction Using DNA Breathing Dynamics and Sequence Transformers via Cross Attention
Authors: Kabir Anowarul , Bhattarai Manish , Rasmussen Kim Ø. , Shehu Amarda , Bishop Alan R , Alexandrov Boian , Usheva Anny 
Published: January 2024

AbstractUnderstanding the impact of genomic variants on transcription factor binding and gene regulation remains a key area of research, with implications for unraveling the complex mechanisms underlying various functional effects. Our study delves into the role of DNA’s biophysical properties, including thermodynamic stability, shape, and flexibility in transcription factor (TF) binding. We developed a multi-modal deep learning model integrating these properties with DNA sequence data. Trained on ChIP-Seq (chromatin immunoprecipitation sequencing) datain vivoinvolving 690 TF-DNA binding events in human genome, our model significantly improves prediction performance in over 660 binding events, with up to 9.6% increase in AUROC metric compared to the baseline model when using no DNA biophysical properties explicitly. Further, we expanded our analysis toin vitrohigh-throughput Systematic Evolution of Ligands by Exponential enrichment (SELEX) and Protein Binding Microarray (PBM) datasets, comparing our model with established frameworks. The inclusion of DNA breathing features consistently improved TF binding predictions across different cell lines in these datasets. Notably, for complex ChIP-Seq datasets, integrating DNABERT2 with a cross-attention mechanism provided greater predictive capabilities and insights into the mechanisms of disease-related non-coding variants found in genome-wide association studies. This work highlights the importance of DNA biophysical characteristics in TF binding and the effectiveness of multi-modal deep learning models in gene regulation studies.