Direct and indirect regulation of ß-glucocerebrosidase by the transcription factors USF2 and ONECUT2.

Mutations in GBA1 encoding the lysosomal enzyme ß-glucocerebrosidase (GCase) are among the most prevalent genetic susceptibility factors for Parkinson's disease (PD), with 10-30% of carriers developing the disease. To identify genetic modifiers contributing to the incomplete penetrance, we examined the effect of 1634 human transcription factors (TFs) on GCase activity in lysates of an engineered human glioblastoma line homozygous for the pathogenic GBA1 L444P variant. Using an arrayed CRISPR activation library, we uncovered 11 TFs as regulators of GCase activity. Among these, activation of MITF and TFEC increased lysosomal GCase activity in live cells, while activation of ONECUT2 and USF2 decreased it. While MITF, TFEC, and USF2 affected GBA1 transcription, ONECUT2 might control GCase trafficking. The effects of MITF, TFEC, and USF2 on lysosomal GCase activity were reproducible in iPSC-derived neurons from PD patients. Our study provides a systematic approach to identifying modulators of GCase activity and deepens our understanding of the mechanisms regulating GCase.

METTL5-mediated 18S rRNA m6A modification promotes corticospinal tract sprouting after unilateral traumatic brain injury.

The key to improving function of an impaired limb after unilateral brain injury is promotion of corticospinal tract (CST) sprouting across the midline into the denervated hemicord. Previous studies have unveiled specific genes that regulate CST sprouting. CST sprouting may also be regulated by RNA modification. We examined METTL5, the methyltransferase for 18S rRNA m6A modification, as a regulator of CST sprouting in mice. Overexpression of METTL5 in contralesional corticospinal neurons promoted CST sprouting after unilateral traumatic brain injury. Mechanically, METTL5-mediated 18S rRNA m6A modification promoted the translation efficiency (TE) of various genes. Notably, the upregulation of TE in the gene Cfl1, which encodes cofilin, led to an increase in its expression. Additionally, the upregulation of TE in the gene Inpp5k led to the activation of cofilin. Active cofilin stimulates actin polymerization and facilitates protrusion and bundling of microtubules, thus promoting axon outgrowth. These findings offer valuable insights for developing novel strategies to promote CST sprouting.

Effect of chitosan on thermal gelling properties of pork myofibrillar protein and its mechanism.

BACKGROUND: Previous studies have demonstrated that the addition of chitosan can improve the quality and functional properties of meat products. However, the underlying mechanism remains unclear. In this study, the effect and mechanism of the addition of chitosan on the gel properties of myofibrillar protein (MP) were investigated. RESULTS: The results indicated that the gel strength and the water-holding capacity of MP-chitosan gel increased significantly when chitosan was added at 2.5-10 mg mL-1. Myofibrillar protein samples with 10 mg mL-1 added chitosan exhibited the highest elasticity and viscosity during gel formation and strengthening. The addition of chitosan also caused a modification in both the secondary and tertiary structure of MP, resulting in an enhanced exposure of hydrophobic and sulfhydryl groups in comparison with the control. Chitosan inhibited the conversion of immobilized water into free water and the formation of water channels during the thermal gelation process of MP. The denaturation enthalpy (ΔH) of myosin decreased as the concentration of chitosan exceeded 5 mg mL-1. The microstructure showed that the incorporation of chitosan (5-10 mg mL-1) facilitated the formation of compact and well organized MP gel networks. CONCLUSION: The addition of chitosan can enhance the functional properties of meat protein and facilitate heat-induced gelation, making it a promising ingredient for improving the quality of processed meat products. © 2024 Society of Chemical Industry.

Exploring the impact of coffee consumption on liver health: A comprehensive bibliometric analysis.

The study indicates that while research has demonstrated the potential of coffee to mitigate liver damage, a comprehensive quantitative analysis of its effects has yet to be conducted. This study seeks to explore the current landscape and focal points of research on coffee consumption's impact on the liver from 2013 to 2023. Articles published within this timeframe were retrieved from the Web of Science database and subjected to analysis using R software, VOSviewer, and CiteSpace software. A total of 1106 articles primarily focused on coffee's impact on liver health were analyzed. The frequency of publication exhibited a significant increase from 2013 to 2023. The United States emerged as the leading contributor in publications and international collaborations, particularly with institutions such as Harvard Medical School and Harvard T.H. Chan School of Public Health. Noteworthy journals in this domain included "Nutrients" and "Hepatology" Commonly occurring keywords encompassed components, chlorogenic acids, oxidative stress, and liver. The study highlighted coffee's potential benefits in preventing cardiovascular and liver diseases, attributed to mechanisms such as antioxidant activity and modulation of hepatic cells. Through bibliometric analysis, this study offers valuable insights into the research status and emphasis on coffee's effects on liver health, serving as a significant reference for future investigations in this area.

Exploring the roles and potential therapeutic strategies of inflammation and metabolism in the pathogenesis of vitiligo: a mendelian randomization and bioinformatics-based investigation.

Introduction: Vitiligo, a common autoimmune acquired pigmentary skin disorder, poses challenges due to its unclear pathogenesis. Evidence suggests inflammation and metabolism's pivotal roles in its onset and progression. This study aims to elucidate the causal relationships between vitiligo and inflammatory proteins, immune cells, and metabolites, exploring bidirectional associations and potential drug targets. Methods: Mendelian Randomization (MR) analysis encompassed 4,907 plasma proteins, 91 inflammatory proteins, 731 immune cell features, and 1400 metabolites. Bioinformatics analysis included Protein-Protein Interaction (PPI) network construction, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Subnetwork discovery and hub protein identification utilized the Molecular Complex Detection (MCODE) plugin. Colocalization analysis and drug target exploration, including molecular docking validation, were performed. Results: MR analysis identified 49 proteins, 39 immune cell features, and 59 metabolites causally related to vitiligo. Bioinformatics analysis revealed significant involvement in PPI, GO enrichment, and KEGG pathways. Subnetwork analysis identified six central proteins, with Interferon Regulatory Factor 3 (IRF3) exhibiting strong colocalization evidence. Molecular docking validated Piceatannol's binding to IRF3, indicating a stable interaction. Conclusion: This study comprehensively elucidates inflammation, immune response, and metabolism's intricate involvement in vitiligo pathogenesis. Identified proteins and pathways offer potential therapeutic targets, with IRF3 emerging as a promising candidate. These findings deepen our understanding of vitiligo's etiology, informing future research and drug development endeavors.

Haplotype-resolved 3D chromatin architecture of the hybrid pig.

In diploid mammals, allele-specific three-dimensional (3D) genome architecture may lead to imbalanced gene expression. Through ultradeep in situ Hi-C sequencing of three representative somatic tissues (liver, skeletal muscle, and brain) from hybrid pigs generated by reciprocal crosses of phenotypically and physiologically divergent Berkshire and Tibetan pigs, we uncover extensive chromatin reorganization between homologous chromosomes across multiple scales. Haplotype-based interrogation of multi-omic data revealed the tissue dependence of 3D chromatin conformation, suggesting that parent-of-origin-specific conformation may drive gene imprinting. We quantify the effects of genetic variations and histone modifications on allelic differences of long-range promoter-enhancer contacts, which likely contribute to the phenotypic differences between the parental pig breeds. We also observe the fine structure of somatically paired homologous chromosomes in the pig genome, which has a functional implication genome-wide. This work illustrates how allele-specific chromatin architecture facilitates concomitant shifts in allele-biased gene expression, as well as the possible consequential phenotypic changes in mammals.

Temporospatial hierarchy and allele-specific expression of zygotic genome activation revealed by distant interspecific urochordate hybrids.

Zygotic genome activation (ZGA) is a universal process in early embryogenesis of metazoan, when the quiescent zygotic nucleus initiates global transcription. However, the mechanisms related to massive genome activation and allele-specific expression (ASE) remain not well understood. Here, we develop hybrids from two deeply diverged (120 Mya) ascidian species to symmetrically document the dynamics of ZGA. We identify two coordinated ZGA waves represent early developmental and housekeeping gene reactivation, respectively. Single-cell RNA sequencing reveals that the major expression wave exhibits spatial heterogeneity and significantly correlates with cell fate. Moreover, allele-specific expression occurs in a species- rather than parent-related manner, demonstrating the divergence of cis-regulatory elements between the two species. These findings provide insights into ZGA in chordates.

Spatially resolved single-cell atlas of ascidian endostyle provides insight into the origin of vertebrate pharyngeal organs.

The pharyngeal endoderm, an innovation of deuterostome ancestors, contributes to pharyngeal development by influencing the patterning and differentiation of pharyngeal structures in vertebrates; however, the evolutionary origin of the pharyngeal organs in vertebrates is largely unknown. The endostyle, a distinct pharyngeal organ exclusively present in basal chordates, represents a good model for understanding pharyngeal organ origins. Using Stereo-seq and single-cell RNA sequencing, we constructed aspatially resolved single-cell atlas for the endostyle of the ascidian Styela clava. We determined the cell composition of the hemolymphoid region, which illuminates a mixed ancestral structure for the blood and lymphoid system. In addition, we discovered a cluster of hair cell-like cells in zone 3, which has transcriptomic similarity with the hair cells of the vertebrate acoustico-lateralis system. These findings reshape our understanding of the pharynx of the basal chordate and provide insights into the evolutionary origin of multiplexed pharyngeal organs.

Logical design of synthetic cis-regulatory DNA for genetic tracing of cell identities and state changes.

Descriptive data are rapidly expanding in biomedical research. Instead, functional validation methods with sufficient complexity remain underdeveloped. Transcriptional reporters allow experimental characterization and manipulation of developmental and disease cell states, but their design lacks flexibility. Here, we report logical design of synthetic cis-regulatory DNA (LSD), a computational framework leveraging phenotypic biomarkers and trans-regulatory networks as input to design reporters marking the activity of selected cellular states and pathways. LSD uses bulk or single-cell biomarkers and a reference genome or custom cis-regulatory DNA datasets with user-defined boundary regions. By benchmarking validated reporters, we integrate LSD with a computational ranking of phenotypic specificity of putative cis-regulatory DNA. Experimentally, LSD-designed reporters targeting a wide range of cell states are functional without minimal promoters. Applied to broadly expressed genes from human and mouse tissues, LSD generates functional housekeeper-like sLCRs compatible with size constraints of AAV vectors for gene therapy applications. A mesenchymal glioblastoma reporter designed by LSD outperforms previously validated ones and canonical cell surface markers. In genome-scale CRISPRa screens, LSD facilitates the discovery of known and novel bona fide cell-state drivers. Thus, LSD captures core principles of cis-regulation and is broadly applicable to studying complex cell states and mechanisms of transcriptional regulation.

Relationship between bullous pemphigoid and malignancy: A Mendelian randomization study.

Bullous pemphigoid (BP) is the most common autoimmune blistering disease, which primarily affects the elderly. However, the relationship between BP and malignancy remains controversial in traditional observational studies. The aim of this study, which included only European populations, was to assess the potential causative link between BP and 13 types of malignant tumors in a two-sample Mendelian randomization (MR) study. BP was not associated with an increased risk of developing 13 types of malignant tumors. This study did not find a causal relationship between BP and malignant tumors. However, further research is warranted to examine the generalizability of this conclusion in non-European populations.

Chain mediations of perceived social support and emotional regulation efficacy between role stress and compassion fatigue: insights from the COVID-19 pandemic.

Background: Nurses at the frontline faced high risks of the COVID-19 infection, undertook heavy workloads of patient care, and experienced tremendous stress that often led to compassion fatigue. Aim: This study was to explore the role of positive psychosocial resources (i.e., perceived social support and emotional regulation efficacy) in the relationship between role stress and compassion fatigue. Methods: A cross-sectional design was conducted in Hubei Province, China between May and September 2021. The Role Stress Questionnaire, the Perceived Social Support Scale, the Emotional Regulation Efficacy Scale, and the Professional Quality of Life Scale were used to measure key variables of interest. Nurse socio-demographic data were also collected. Structural equation modeling was used to explore the relationships, including potential mediating effect, among role stress, perceived social support, emotional regulation efficacy, and compassion fatigue. Results: A total of 542 nurses participated in this investigation, and 500 were eventually enrolled in the analysis. The incidence of compassion fatigue among nurses was 94.2%, including 65.8% of nurses reporting at least moderate compassion fatigue. Univariate analysis showed that educational level, marital status, hospital rank, sleep time were the factors affecting compassion fatigue of the nurses. The structural equation modeling revealed that: Role stress had a direct positive effect on compassion fatigue; Perceived social support and emotional regulation efficacy partially mediated the link between role stress and compassion fatigue respectively; And there was a chain mediating role of perceived social support and emotional regulation efficacy between role stress and compassion fatigue. Conclusion: The incidence of compassion fatigue was high during the COVID-19 pandemic among bedside nurses in China. Improving social support and enhancing the efficacy of emotion regulation may help alleviate compassion fatigue directly and/or via buffering the impact of role stress.

An Improved Toeplitz Approximation Method for Coherent DOA Estimation in Impulsive Noise Environments.

Direction of arrival (DOA) estimation is an important research topic in array signal processing and widely applied in practical engineering. However, when signal sources are highly correlated or coherent, conventional subspace-based DOA estimation algorithms will perform poorly due to the rank deficiency in the received data covariance matrix. Moreover, conventional DOA estimation algorithms are usually developed under Gaussian-distributed background noise, which will deteriorate significantly in impulsive noise environments. In this paper, a novel method is presented to estimate the DOA of coherent signals in impulsive noise environments. A novel correntropy-based generalized covariance (CEGC) operator is defined and proof of boundedness is given to ensure the effectiveness of the proposed method in impulsive noise environments. Furthermore, an improved Toeplitz approximation method combined CEGC operator is proposed to estimate the DOA of coherent sources. Compared to other existing algorithms, the proposed method can avoid array aperture loss and perform more effectively, even in cases of intense impulsive noise and low snapshot numbers. Finally, comprehensive Monte-Carlo simulations are performed to verify the superiority of the proposed method under various impulsive noise conditions.

Conservative Management of Varus/Valgus Stable Tibial Plateau Fractures in Osteoporotic Bone - Preliminary Results and Considerations.

Objectives: While operative fixation is the current recommendation for treating significantly displaced tibial plateau fractures (DTPFs) in elderly patients, our research suggests that non-operative management may also be a viable option as the primary treatment for these individuals. Our study aimed to evaluate the clinical outcomes of patients with complex DTPFs who received non-operative management as their primary management. Methods: Our study involved a retrospective analysis of non-operatively treated DTPFs during the period of 2019 to 2020. We included all patients for the evaluation of fracture healing and range of motion (ROM). Additionally, we conducted functional outcome assessments on all patients, utilizing the Oxford Knee Score (OKS) both before their injury and at the 10-month mark after their injury. Results: The study included 10 patients, comprising two males and eight females, with a mean age of 62.9 years (range: 46-74). Among them, four patients had Schatzker Type III DTPFs, two had Type V, and four had Type VI. Non-operative management was administered using hinged-knee braces, and patients progressed to weight-bearing gradually, with a minimum follow-up period of 10 months. The average time to bone union was 4.3 months (range: 2-7). The mean Oxford Knee Score (OKS) after the injury was 38.8 (range: 23-45), with an average reduction of 16.9% (p = 0.003). The average fracture depression was 11.41 mm (range: 4.2-29), and the average fracture split was 14.03 mm (range: 5.5-44). Conclusion: Based on our study, it appears that elderly patients with significantly displaced tibial plateau fractures (DTPFs) can be treated non-operatively as their primary management, despite the current consensus suggesting otherwise.

Comparative Transcriptomic Analysis Reveals the Functionally Segmented Intestine in Tunicate Ascidian.

The vertebrate intestinal system consists of separate segments that remarkably differ in morphology and function. However, the origin of intestinal segmentation remains unclear. In this study, we investigated the segmentation of the intestine in a tunicate ascidian species, Ciona savignyi, by performing RNA sequencing. The gene expression profiles showed that the whole intestine was separated into three segments. Digestion, ion transport and signal transduction, and immune-related pathway genes were enriched in the proximal, middle, and distal parts of the intestine, respectively, implying that digestion, absorption, and immune function appear to be regional specializations in the ascidian intestine. We further performed a multi-species comparison analysis and found that the Ciona intestine showed a similar gene expression pattern to vertebrates, indicating tunicates and vertebrates might share the conserved intestinal functions. Intriguingly, vertebrate pancreatic homologous genes were expressed in the digestive segment of the Ciona intestine, suggesting that the proximal intestine might play the part of pancreatic functions in C. savignyi. Our results demonstrate that the tunicate intestine can be functionally separated into three distinct segments, which are comparable to the corresponding regions of the vertebrate intestinal system, offering insights into the functional evolution of the digestive system in chordates.

Mitochondria-derived H2O2 triggers liver regeneration via FoxO3a signaling pathway after partial hepatectomy in mice.

Reactive oxygen species (ROS) can induce oxidative injury and are generally regarded as toxic byproducts, although they are increasingly recognized for their signaling functions. Increased ROS often accompanies liver regeneration (LR) after liver injuries, however, their role in LR and the underlying mechanism remains unclear. Here, by employing a mouse LR model of partial hepatectomy (PHx), we found that PHx induced rapid increases of mitochondrial hydrogen peroxide (H2O2) and intracellular H2O2 at an early stage, using a mitochondria-specific probe. Scavenging mitochondrial H2O2 in mice with liver-specific overexpression of mitochondria-targeted catalase (mCAT) decreased intracellular H2O2 and compromised LR, while NADPH oxidases (NOXs) inhibition did not affect intracellular H2O2 or LR, indicating that mitochondria-derived H2O2 played an essential role in LR after PHx. Furthermore, pharmacological activation of FoxO3a impaired the H2O2-triggered LR, while liver-specific knockdown of FoxO3a by CRISPR-Cas9 technology almost abolished the inhibition of LR by overexpression of mCAT, demonstrating that FoxO3a signaling pathway mediated mitochondria-derived H2O2 triggered LR after PHx. Our findings uncover the beneficial roles of mitochondrial H2O2 and the redox-regulated underlying mechanisms during LR, which shed light on potential therapeutic interventions for LR-related liver injury. Importantly, these findings also indicate that improper antioxidative intervention might impair LR and delay the recovery of LR-related diseases in clinics.

Transcriptional Analysis of the Endostyle Reveals Pharyngeal Organ Functions in Ascidian.

The endostyle is a pharyngeal organ with an opening groove and cilia in invertebrate chordates (amphioxus and ascidian) and cyclostomate (lamprey), serving as a filter-feeding tract and thyroid-secreting location. Emerging evidence implies its complex cellular composition and potentially versatile functions. Multiple cell types in the endostyle have been thought to be progenitors of complex organs in advanced vertebrates. To describe the expression profile and the potential functions, bulk RNA sequencing on the endostyle in ascidian Styela clava was conducted and distinct markers were selected by multileveled comparative analysis. Transcriptional data assay and qRT-PCR-verified results showed the regional expression patterns of Hox genes in the longitudinal axis. Organ-specific markers of the endostyle was proposed by comparing expression with the main organs of the ascidian. A cross-species transcriptional profile projection between the endostyle and organs from Danio rerio and Homo sapiens indicates a robust homogenous relationship to the thyroid and digestive system of the endostyle. The high similarity between the endostyle and the head kidney in zebrafish/the bone marrow in human implies uniquely profound functions of the pharyngeal organ in proto-vertebrates. Our result revealed that the transcriptional profile of the human parathyroid gland was similar to the ascidian endostyle, indicating the evolutionary origin of vertebrate hormone secretion organs.

Proteomic identification of intracellular vesicle trafficking and protein glycosylation requirements for lumen inflation in Ciona notochord.

Lumen formation and inflation are crucial steps for tubular organ morphogenesis, yet the underling mechanism remains largely unrevealed. Here, we applied 4D proteomics to screen the lumenogenesis-related proteins and revealed the biological pathways potentially that are involved in lumen inflation during notochord lumen formation in the ascidian Ciona savignyi. In total, 910 differentiated expressed proteins (DEPs) were identified before and after notochord lumen formation utilizing Mfuzz analysis. Those DEPs were grouped into four upregulated clusters based on their quantitative expression patterns; the functions of these proteins were enriched in protein metabolic and biosynthetic process, the establishment of localization, and vesicle-mediated transport. We analyzed the vesicle trafficking cluster and focused on several vesicle transport hub proteins. In vivo function-deficient experiments showed that mutation of vesicle transport proteins resulted in an abnormal lumen in notochord development, demonstrating the crucial role of intracellular trafficking for lumen formation. Moreover, abundant extracellular matrix proteins were identified, the majority of which were predicted to be glycosylated proteins. Inhibition of glycosylation markedly reduced the lumen expansion rate in notochord cells, suggesting that protein glycosylation is essential for lumenogenesis. Overall, our study provides an invaluable resource and reveals the crucial mechanisms in lumen formation and expansion.

Efficient Whole-Cell Biotransformation for α-Arbutin Production through the Engineering of Sucrose Phosphorylase Combined with Engineered Cell Modification.

α-Arbutin is extensively used in cosmetic industries. The lack of highly active enzymes and the cytotoxicity of hydroquinone limit the biosynthesis of α-arbutin. In this study, a whole-cell biocatalytic approach based on enzyme engineering and engineered cell modification was identified as effective in enhancing α-arbutin production. First, a sucrose phosphorylase (SPase) mutant with higher enzyme activity was obtained by experimental screening. Next, to avoid the oxidation of hydroquinone, we established an anaerobic process to improve the robustness of the cells by knocking out lytC, sdpC, and skfA in Bacillus subtilis and overcoming the inhibitory effect of a high concentration of hydroquinone. Finally, the engineered strain was used for biotransformation in a 5 L fermenter with batch feeding for 24 h. The final yield of α-arbutin achieved was 129.6 g/L, which may provide a basis for the large-scale industrial production of α-arbutin.

EDomics: a comprehensive and comparative multi-omics database for animal evo-devo.

Evolutionary developmental biology (evo-devo) has been among the most fascinating interdisciplinary fields for decades, which aims to elucidate the origin and evolution of diverse developmental processes. The rapid accumulation of omics data provides unprecedented opportunities to answer many interesting but unresolved evo-devo questions. However, the access and utilization of these resources are hindered by challenges particularly in non-model animals. Here, we establish a comparative multi-omics database for animal evo-devo (EDomics, http://edomics.qnlm.ac) containing comprehensive genomes, bulk transcriptomes, and single-cell data across 40 representative species, many of which are generally used as model organisms for animal evo-devo study. EDomics provides a systematic view of genomic/transcriptomic information from various aspects, including genome assembly statistics, gene features and families, transcription factors, transposable elements, and gene expressional profiles/networks. It also exhibits spatiotemporal gene expression profiles at a single-cell level, such as cell atlas, cell markers, and spatial-map information. Moreover, EDomics provides highly valuable, customized datasets/resources for evo-devo research, including gene family expansion/contraction, inferred core gene repertoires, macrosynteny analysis for karyotype evolution, and cell type evolution analysis. EDomics presents a comprehensive and comparative multi-omics platform for animal evo-devo community to decipher the whole history of developmental evolution across the tree of life.

The Importance of Fracture Liaison Services to the Healthcare System: A Review.

Osteoporosis is an important public health concern, with secondary fragility fractures carrying a poor prognosis. The role of a Fracture Liaison Service (FLS) is to identify fragility fracture patients via investigation and risk assessment. This serves to address the osteoporosis treatment care gap that exists where the majority of patients with a new fragility fracture over 50-years-old fail to receive a bone mass density (BMD) scan and osteoporosis treatment, ultimately receiving inadequate care. Osteoporosis medication is effective in reducing secondary fragility fractures. However, treatment adherence poses a problem. The FLS serves to prevent more serious secondary fragility fractures such as hip fractures. This minimises operative costs and the cost of postoperative care and results in fewer secondary care and care home admissions, increasing healthcare savings. Implementation of the FLS is effective in increasing investigation, treatment initiation, and adherence, with a corresponding decrease in refracture rate and mortality. This paper aims to evaluate the previous osteoporosis treatment care gap, the effectiveness of osteoporosis medications currently available, and finally, the cost and clinical effectiveness of the FLS serving as a secondary prevention tool.