Functional Mechanism Research Articles

Temporal hydrogeochemical evolution of surface water and groundwater in a karst system discharging into a continental-type Ramsar site in the Huasteca Potosina, Mexico.

Ecosystems such as wetlands have karst groundwater as their primary source of preserving their services and functions. Karst systems are complex hydrogeological systems that are difficult to study because of their complicated functioning mechanism, which requires an interdisciplinary effort based on hydrodynamic assessment and characterization of the hydrogeology of the system. The study area is the Ramsar wetland Ciénaga de Tamasopo (Mexico), which is dependent on the discharge of karst groundwater that is affected by water extraction of extensive sugarcane agriculture and is also the main water source for the rural towns. Hydrogeochemical and isotopic tools further suggest that at least two distinct sources contribute to the groundwater composition in the Ciénaga de Tamasopo basin. One corresponds to meteoric water recharging the aquifer through karst structures of the El Abra Fm. and Tamasopo Fm. inferring a local flow with an isotopic composition of δ18O (- 4.75 to - 4.20‰) and δ2H (- 29.12 to - 23.86‰). The second is associated with regional-intermediate flow, indicating that the water has an enrichment of heavy δ18O (- 6.90 to - 6.65‰) and δ2H (- 41.37 to - 40.41‰) isotopes circulating in the Guaxcamá Fm. EC and temperature variations were evaluated, determining that the EC tends to increase in the rainy season because of the mixing of local and intermediate flows and that there is evidence of temperature increase. The chemical analysis identified the dominant processes in this karst system as dissolution-precipitation of calcite, dolomite, and gypsum by water-rock interaction, mixing, and evaporation. This study facilitated the development of a conceptual model for understanding groundwater movement in warm and sub-humid climate karst systems.

Insights into the functional mechanisms of the sesquiterpene synthase GEAS and GERDS in lavender.

Lavenders are economically significant plants cultivated worldwide for their essential oils (EOs) containing sesquiterpenes. These EOs contribute to the cosmetic, personal hygiene, and pharmaceutical industries. The biosynthesis of lavender sesquiterpenes involves enzymes like sesquiterpene synthases GEAS and GERDS. The structure and functional mechanism of these sesquiterpene synthases (GEAS or GERDS) are not fully understood. Here, we achieved the successful expression and purification of monomeric proteins at high purity. The results of the molecular docking revealed that negatively charged residues interact electrostatically with magnesium ions (Mg2+), thereby stabilizing and neutralizing negatively charged phosphate groups on the substrate. Notably, deletion of the N-terminus (∆N-terminus) significantly increased the enzymatic activity compared to the wild-type protein. These findings offer insights into the regulatory mechanisms underlying sesquiterpene biosynthesis in lavender, and suggest potential avenues for improving essential oils through genetic engineering and developing cosmetic and personal care products and alternative medicines.

Network pharmacology alliance with experimental validation unveils the anti-colorectal cancer mechanism of Xianlian Jiedu decoction.

The Xianlian Jiedu Decoction (XLJDD), a traditional Chinese medicine (TCM) decoction, which is effective in clinical treatment of colorectal cancer (CRC). Nevertheless, the pharmacodynamic material basis and mechanism of its action have not been explored yet. To investigate the potential functional components and possible mechanism of XLJDD in anti-CRC. The UPLC-Q-TOF-MS method was applied to the qualification of absorbed phytochemical compounds in the plasma of rats administrated with XLJDD. Network pharmacology approach was used to create the compound-target network, GO and KEGG enrichment resolution was used to predict the potential biological mechanism of XLJDD anti-CRC. The binding of potential active ingredients to their targets was demonstrated using AutoDock Tools. And the anti-CRC efficacy of XLJDD was investigated through in vitro and in vivo experiments. Furthermore, the mechanism of XLJDD anti-CRC was validated by Western blot. 14 compounds from XLJDD were detected in the plasma of rats administrated with XLJDD. The results of network pharmacology analysis shown that PI3K/AKT and chemokine signaling pathways were strongly linked to XLJDD against CRC. The potential active compounds berberine, 7-methoxycoumarin and 13-methylberberubine may target PRKACA, PIK3CB, and EGFR to regulate PI3K/AKT signaling pathway, which plays a crucial role in cancer cell proliferation. In vitro experimental results revealed that XLJDD apparently inhibits the cell viability and proliferation of HCT116cells. In vivo experimental results found that in contrast to the model group, the XLJDD treatment obviously cut down the size and weight of tumor. Further, Western blot results demonstrated that XLJDD significantly inhibited the CXCR2/PI3K/AKT signaling axis. The therapeutic mechanism of XLJDD against CRC involves inhibiting CRC cells proliferation via modulating the CXCR2/PI3K/AKT signaling pathway.

The Evolution of Ventriculoperitoneal Shunt Valves and Why They Fail.

This article reviews the historical progression of ventriculoperitoneal shunt valve designs with the goal of providing an understanding of their functionality and failure mechanisms. While shunting is the predominant treatment for hydrocephalus, the statistics of overall shunt failure remain high, and valve failure is responsible for a significant percentage of revision surgeries. Therefore, this review spans valve evolution from an engineering perspective with an emphasis on discussing potential failure mechanisms and patient-specific valve selection. Information is provided on the importance of valves in hydrocephalus treatment with discussion on each class of valves and their advantages and shortcomings. Substantial development over decades has significantly improved valve functionality, and ongoing research continues to provide more robust valves and shunt systems for hydrocephalus management.

Youthful Stem Cell Microenvironments: Rejuvenating Aged Bone Repair Through Mitochondrial Homeostasis Remodeling.

Extracellularmatrix (ECM) derived from mesenchymal stem cells regulates antioxidant properties and bone metabolism by providing a favorable extracellular microenvironment. However, its functional role and molecular mechanism in mitochondrial function regulation and aged bone regeneration remain insufficiently elucidated. This proteomic analysis has revealed a greater abundance of proteins supporting mitochondrial function in the young ECM (Y-ECM) secreted by young bone marrow-derived mesenchymal stem cells (BMMSCs) compared to the aged ECM (A-ECM). Further studies demonstrate that Y-ECM significantly rejuvenates mitochondrial energy metabolism in adult BMMSCs (A-BMMSCs) through the promotion of mitochondrial respiratory functions and amelioration of oxidative stress. A-BMMSCs cultured on Y-ECM exhibited enhanced multi-lineage differentiation potentials in vitro and ectopic bone formation in vivo. Mechanistically, silencing of silent information regulator type 3 (SIRT3) gene abolished the protective impact of Y-ECM on A-BMMSCs. Notably, a novel composite biomaterial combining hyaluronic acid methacrylate hydrogel microspheres with Y-ECM is developed, which yielded substantial improvements in the healing of bone defects in an aged rat model. Collectively, these findings underscore the pivotal role of Y-ECM in maintaining mitochondrial redox homeostasis and present a promising therapeutic strategy for the repair of aged bone defects.

Biofunctionalized patterned platform as microarray biochip to supervise delivery and expression of pDNA nanolipoplexes in stem cells via mechanotransduction

Biochips are widely applied to manipulate the geometrical morphology of stem cells in recent years. Patterned antenna-like pseudopodia are also probed to explore the influence of pseudopodia formation on gene delivery and expression on biochips. However, how the antenna-like pseudopodia affect gene transfection is unsettled and the underlying trafficking mechanism of exogenous genes in engineered single cells is not announced. Therefore, the engineered microarray biochips were conceptualized and prepared by the synthesized photointelligent biopolymer to precisely manage geometric topological structures (cell size and antenna-like protrusion) of stem cells on biochips. The cytoskeleton could be regulated in engineered cells and large cells with more antennas assembled well-organized actin filaments to affect cell tension distribution. The stiffness and adhesion force were measured by atomic force microscope to reveal cell nanomechanics on microarray biochips. Cytoskeleton-mediated nanomechanics could be adjusted by actin filaments. Gene transfection efficiency was enhanced with increasing cell nanomechanics, which was also confirmed by the evaluation of cell internalization capacity of nanoparticles and DNA synthesis ability. This work will provide a new strategy to study functional biomaterials, microarray chips and internal mechanism of gene transfection in patterned stem cells on biochips.Graphical abstract

Integrated Solution Combining Low-Frequency Forced Oscillation Technique and Continuous Equivital Sensor Monitoring for Assessment of Non-Invasive Ambulatory Respiratory Mechanics

Early assessment of respiratory mechanics is crucial for early-stage diagnosing and managing lung diseases, leading to greater patient outcomes. Traditional methods like spirometry are limited in continuous monitoring and patient compliance as they require forced maneuvers with significant patient cooperation, which may not be available in fragile individuals. The Forced Oscillation Technique (FOT) is a non-invasive measurement method, only based on the tidal breathing at rest from the patient for a limited time period. The proposed solution integrates low-frequency FOT with continuous monitoring using Equivital (EQV) sensors to enhance respiratory mechanics information with heart rate variability. Data were collected over a two-hour period from six healthy volunteers, measuring respiratory impedance every 7 min and continuously recording physiological parameters. The best-fitting fractional-order models for impedance data were identified using genetic algorithms. This study also explores the correlation between impedance model parameters and EQV data, discussing the potential of AI tools for forecasting respiratory properties. Our findings indicate that combined monitoring techniques and AI analysis provides additional complementary information, subsequently aiding the improved evaluation of respiratory function and tissue mechanics. The proposed protocol allows for ambulatory assessment and can be easily performed in normal breathing conditions.

MMFuncPhos: A Multi-Modal Learning Framework for Identifying Functional Phosphorylation Sites and Their Regulatory Types.

Protein phosphorylation plays a crucial role in regulating a wide range of biological processes, and its dysregulation is strongly linked to various diseases. While many phosphorylation sites have been identified so far, their functionality and regulatory effects are largely unknown. Here, a deep learning model MMFuncPhos, based on a multi-modal deep learning framework, is developed to predict functional phosphorylation sites. MMFuncPhos outperforms existing functional phosphorylation site prediction approaches. EFuncType is further developed based on transfer learning to predict whether phosphorylation of a residue upregulates or downregulates enzyme activity for the first time. The functional phosphorylation sites predicted by MMFuncPhos and the regulatory types predicted by EFuncType align with experimental findings from several newly reported protein phosphorylation studies. The study contributes to the understanding of the functional regulatory mechanism of phosphorylation and provides valuable tools for precision medicine, enzyme engineering, and drug discovery. For user convenience, these two prediction models are integrated into a web server which can be accessed at http://pkumdl.cn:8000/mmfuncphos.

Cloning and functional verification of Geraniol-10-Hydroxylase gene in Lonicera japonica.

Geraniol 10-hydroxylase (G10H) is a cytochrome P450 monooxygenase involved in regulation, which is involved in the biosynthesis of monoterpene. However, G10H is not characterized at the enzymatic mechanism and regulatory function in Lonicera japonica. A gene related to the biosynthesis of monoterpenoid, geraniol 10-hydroxylase, has been cloned from the medicinal plant Lonicera japonica. The gene, LjG10H, encodes a peptide of 498 amino acids with a predicted molecular weight of 54.45 kDa. LjG10H shares a homology of 72.93-83.90% with G10H from other plants. Phylogenetic analysis suggests that the protein encoded by this gene belongs to the cytochrome P450 monooxygenase family. Tissue-specific expression analysis revealed that LjG10H is most highly expressed in flowers. Through heterologous expression in E. coli, the LjG10H protein was purified and its catalytic activity was studied. The results show that the enzyme can catalyze the hydroxylation of geraniol to 10-hydroxygeraniol. Additionally, analysis of Lonicera japonica seedlings with silenced LjG10H revealed a reduction in monoterpenoid content. This study demonstrates that LjG10H plays an important role in the biosynthetic pathway of iridoids. This is the first article that ascribes G10H to be associated with the biosynthetic pathway of iridoid. This study provides a theoretical basis for the functional mechanism of LjG10H in regulating iridoid synthesis and provides a valuable resource for molecular breeding studies.

Efficacy of the Bushen Jianpi Huoxue Formula on Beclin-1/Bcl-2-mediated autophagy and apoptosis in osteoblasts.

The Beclin-1/Bcl-2 complex plays a pivotal role in regulating both autophagy and apoptosis in osteoblasts affected by osteoporosis. This study first investigates whether the Bushen Jianpi Huoxue Formula can enhance the cellular function of osteoblasts. Additionally, it initially explores the functional mechanism of Beclin-1/Bcl-2-related apoptosis. Osteoblasts were isolated from the calvaria of three-day-old Sprague-Dawley female rats. The lyophilized power of the Bushen Jianpi Huoxue Formula was prepared from the following ingredients: Fructus Psoraleae, Epimedii Folium, Desertliving Cistanche, Prepared Rehmannia Radix, Radix paeoniae alba, Astragali Radix, Semen Cuscuta, Radix Salviae miltiorrhizae, Angelica sinensis, and Jujube. The primary components were detected by HPLC-MS. Beclin-1 overexpressed osteoblasts were constructed by transfection. Gene expression and protein level were examined by qRT-PCR and immunoblotting assay. Cell viability, apoptosis, and autophagy were assayed with CCK-8, flow cytometer, MDC staining, and Lyso-Tracker staining, respectively. Osteogenic differentiation was assayed by ALP staining, and mineralization by ARS staining. The complex of Beclin-1/Bcl-2 was detected by immunoprecipitation. The results of this study indicated that the Bushen Jianpi Huoxue Formula could enhance both the proliferative activity, differentiation and mineralization of osteoblasts induced by Beclin-1 overexpression. This may be related to its role in activation of the WNT/β-CATENIN by increasing protein expression of WNT1 and β-CATENIN more than 1-fold. The formula effectively inhibited autophagy rate and apoptosis rate of osteoblasts by 50%. Furthermore, the formula was effective in attenuating endoplasmic reticulum stress by decreasing protein expression of AFT4, CHOP, eIF2α, and GRP78 more than 50%, which may play functions by suppressing the PERK signaling pathway. However, Mif treatment significantly weakened the effects of the formula. Bushen Jianpi Huoxue Formula effectively enhanced the osteogenic activity by inhibiting Beclin-1-induced autophagy instead of the binding of Beclin-1 and Bcl-2. This underscores the formula's multifaceted role in promoting bone health and managing cellular stress, and offers novel insights into its therapeutic potential against osteoporosis.

CAVIN2 attenuates ventilator-induced lung injury in rats by MAPK/ERK1/2 signaling pathway.

Mechanical ventilation is an important treatment in medical treatment, but it may cause or aggravate lung injury, which is called ventilator-induced lung injury (VILI). Studies have shown that CAVIN2 plays an important role in regulating inflammatory responses and cell death. However, its functional mechanism in VILI remains unclear. This study explores the potential role and mechanisms of CAVIN2 in the pathogenesis of VILI. We constructed rat and cell models of VILI. Real-time quantitative polymerase chain reactions (qRT-PCR), Western blot (WB), immunohistochemistry (IHC) and immunofluorescence (IF) were used to detect CAVIN2, ERK1/2, p-ERK1/2, autophagy-associated marker proteins LC3II/I, Beclin1 and P62, and the expression level of pro-inflammatory factors IL-1β and IL-6. Hematoxylin and eosin (H&E) staining were used to evaluate the degree of pathological injury of lung tissue, and the lung permeability was evaluated by measuring the wet-dry ratio of lung tissue and the total protein content in bronchoalveolar lavage fluid (BALF). Molecular docking, co-immunoprecipitation and immunofluorescence were used to verify the binding of CAVIN2 and ERK1/2, and the regulatory mechanisms of both were investigated by rescue experiments. CAVIN2 expression was downregulated in VILI rat lung tissues and ATII cells, whereas p-ERK1/2 expression was up-regulated. Overexpressing CAVIN2 alleviated pathological damage in VILI rat lung tissues and reduced the expression of pro-inflammatory factors and autophagy-related marker proteins in both lung tissues and ATII cells. Conversely, knockdown of CAVIN2 led to increased expression of pro-inflammatory factors and autophagy-related marker proteins in ATII cells. Further mechanism studies showed that CAVIN2 binds to ERK1/2 and inhibits ERK1/2 phosphorylation. Conversely when treated with the p-ERK1/2 agonist Ro67-7476, the protective, anti-inflammatory, and anti-autophagic effects of overexpressing CAVIN2 in VILI rats and ATII cells were reversed. CAVIN2 can bind to ERK1/2 and inhibit the activation of MAPK/ERK1/2 signaling pathway to reduce inflammatory response and autophagy in VILI, thereby reducing lung injury. Therefore, CAVIN2 may be a potential intervention target to provide a new strategy for the treatment of VILI.

Molecular mechanisms of the GABA type A receptor function.

The GABA type A receptor (GABAAR) belongs to the family of pentameric ligand-gated ion channels and plays a key role in inhibition in adult mammalian brains. Dysfunction of this macromolecule may lead to epilepsy, anxiety disorders, autism, depression, and schizophrenia. GABAAR is also a target for multiple physiologically and clinically relevant modulators, such as benzodiazepines (BDZs), general anesthetics, and neurosteroids. The first GABAAR structure appeared in 2014, but the past years have brought a particularly abundant surge in structural data for these receptors with various ligands and modulators. Although the open conformation remains elusive, this novel information has pushed the structure-function studies to an unprecedented level. Electrophysiology, mutagenesis, photolabeling, and in silico simulations, guided by novel structural information, shed new light on the molecular mechanisms of receptor functioning. The main goal of this review is to present the current knowledge of GABAAR functional and structural properties. The review begins with an outline of the functional and structural studies of GABAAR, accompanied by some methodological considerations, especially biophysical methods, enabling the reader to follow how major breakthroughs in characterizing GABAAR features have been achieved. The main section provides a comprehensive analysis of the functional significance of specific structural elements in GABAARs. We additionally summarize the current knowledge on the binding sites for major GABAAR modulators, referring to the molecular underpinnings of their action. The final chapter of the review moves beyond examining GABAAR as an isolated macromolecule and describes the interactions of the receptor with other proteins in a broader context of inhibitory plasticity. In the final section, we propose a general conclusion that agonist binding to the orthosteric binding sites appears to rely on local interactions, whereas conformational transitions of bound macromolecule (gating) and allosteric modulation seem to reflect more global phenomena involving vast portions of the macromolecule.

Nb-FAR-1: A key developmental protein affects lipid droplet accumulation and cuticle formation in Nippostrongylus brasiliensis.

Fatty acid and retinol binding proteins (FARs) are lipid-binding protein that may be associated with modulating nematode pathogenicity to their hosts. However, the functional mechanism of FARs remains elusive. We attempt to study the function of a certain FAR that may be important in the development of Nippostrongylus brasiliensis. Nb-FAR-1 was highly expressed throughout developmental stages by RNA-seq data and qPCR analyses, and Nb-FAR-1 was a secretory protein and abundant in the excretory-secretory products. Nb-FAR-1 could bind fatty acids and retinol. Fatty acid pattern of parasitic adults was more similar to rat intestine than to free-living L3s, indicating that N. brasiliensis may be dependent on the host to obtain fatty acids. Lentivirus-mediated RNAi was performed on L3s, resulting in a reduction in the expression of Nb-far-1 gene. Furthermore, these RNAi effects could be maintained in several generations. The offspring L3s in Nb-far-1 RNAi group had a reduction in lipid droplets within the subcuticle and the swelling of the perioral epidermis, accompanied with down-regulated expression of enzymes in amino acid and glycerolipid metabolism and glycometabolism for growth by RNA-seq data. Adults in Nb-far-1 RNAi group had the crumpled epidermis loosely attached to the basal membrane of body surface and the breakage of mouth epidermis, accompanied with a decrease in adult egg-shedding and an appearance of abnormal eggs. In vitro culture of eggs showed decreased efficiency of egg hatchability and larval development in the Nb-far-1 RNAi group. Transcriptomic analysis showed that interference with Nb-far-1 expression induced downregulated expression of major sperm protein and serpin for reproduction, and collagen for epidermis formation in adults, most of which were relatively high expression in adults but low expression in L3s in the WT group. Thus, Nb-FAR-1 may affect the reproduction, growth, and development of N. brasiliensis by regulating the level of lipids.

Genome-wide analysis of Class III peroxidase (PRX) family core genes and functional mechanism of GhPRXR1-A for seed development in Gossypium hirsutum.

Class III peroxidases (PRXs) play critical roles in plant growth and development by oxidizing various substrates with H2O2. Although many PRXs have been identified and their roles in biotic and abiotic stress responses have extensively investigated in plants. However, functional mechanisms of PRXs in seed development remain poorly understood. In this study, 14, 17, 9, and 13 PRX core genes were identified in Gossypium hirsutum, Gossypium barbadense, Gossypium arboreum, and Gossypium raimondii, respectively. Phylogenetic analysis categorized PRXs core genes of cotton into five groups. Six of the GhPRX genes co-localized with quantitative trait loci (QTLs) associated with oil or seed size, and GhPRXR1-A showed significant high expression levels in developing ovules. Heterologous overexpression of GhPRXR1-A in Arabidopsis thaliana resulted in a significant increase in thousand seed weight (Col-0: 0.015±0.00085g vs. OE-GhPRXR1-A: 0.022±0.0019g). In addition, molecular mechanism assays revealed that GhPRXR1-A is directly activated by GhGATA1 and interacts with GhNFYC4, a transcription factor of the nuclear factor Y, C subunit family that has previously been reported to mediate seed development. Collectively, these findings suggest that GhPRXR1-A is a regulator of seed development in Arabidopsis and may have similar functional role in cotton seed contributing traits.

Legal Consciousness as a Philosophical and Legal Category: Historical and Contemporary Interpretations

The relevance of this study stems from the need to develop a comprehensive understanding of legal consciousness as a multidimensional phenomenon, to create a theoretical foundation for effective practices in legal education and legal socialization, and to deepen knowledge of the mechanisms of formation and functioning of the legal system. Despite a significant number of studies dedicated to legal consciousness, there is still no unified, comprehensive model in the scholarly discourse that adequately describes this multifaceted phenomenon. The absence of such a model complicates further development in the theory of law and philosophy of law. Modern studies increasingly demonstrate that legal consciousness is an integrated socio-legal category. That is, it is not confined solely to philosophical and legal discourse but also encompasses psychological and social aspects. This broad scope presents challenges for research while simultaneously opening new perspectives for scholarly analysis. The aim of this work is to identify and describe the evolution of scholarly approaches to understanding legal consciousness. Such an analysis allows for identifying key stages in the development of the concept of «legal consciousness», determining dominant paradigms and concepts, analyzing the interconnection of philosophical, psychological, and sociological aspects of legal consciousness, and revealing unresolved issues and prospects for further research. The methodological aspects of the study include: historical analysis (examining the evolution of the concept of legal consciousness in the context of the development of philosophy, law, and society), comparative analysis (comparing various theoretical approaches to understanding legal consciousness), and an interdisciplinary approach (integrating philosophical, legal, psychological, and sociological research methods). This enables an analysis of the dynamic evolution of the concept, from ancient philosophical concepts to contemporary sociocultural interpretations; an understanding of shifting emphases, from moral and philosophical aspects to psychological, sociological, and cultural dimensions; and an examination of the influence of historical contexts – how the understanding of legal consciousness has changed in various sociocultural conditions. The research results identify the following key trends: interpretive pluralism – the absence of a single definition and the diversity of approaches to analyzing legal consciousness; interdisciplinarity in research – the interaction of philosophy of law, sociology, psychology, and other sciences in the study of this phenomenon; and problematization – growing interest in studying the distortions of legal consciousness in the context of modern social transformations. The conclusions of the study can be used as a theoretical basis for developing effective mechanisms to form society’s legal consciousness.

Nascency of Physiopathological Activation by The Effect of Genomic Single Nucleotide Exchange Factor in The PNPLA3 rs738409 Genotype of Patients with Hepatocellular Carcinoma

Background Patatin-like Phospholipase Domain-Containing 3 (PNPLA3) rs738409 is a genetic variant that is associated with an increased risk of developing hepatocellular carcinoma (HCC) in patients with chronic liver disease. This functional mechanism may cause liver cancer by altering protein function without affecting gene expression. Our aim in this study is to investigate the potential effect of PNPLA3 polymorphism on HCC development and to report its results. Material and Methodology A case-control study was designed involving 224 diagnosed and pathologically confirmed patients with HCC. Four groups were formed as ([HBV] n = 110, [HCV] n = 38, [other etiologies] n = 76) and 62 healthy controls. PNPLA3 genotyping in patients diagnosed with HCC was concluded by DNA isolation from blood samples. PNPLA3 rs738409 variant was genotyped in RT PCR device with Taq Man allelic separation test designed by the manufacturers according to protocols. The C nucleotide and G nucleotide were detected in VIC; FAM hydrolysis probes were used for genotyping and binding. SPSS program was used for statistical analysis. Results The PNPLA3 genotypes were determined for the groups of HBV-related HCC, HCV-related HCC, other etiologies-related HCC, and control. The HBV-related HCC group had CC (n = 58), CG (n = 36), and GG (n = 16) genotypes. The HCV-related HCC group had CC (n = 22), CG (n = 9), and GG (n = 7) genotypes. The other etiologies-related HCC group had CC (n = 35), CG (n = 26), and GG (n = 15) genotypes. The control group had CC (n = 36), CG (n = 13), and GG (n = 13) genotypes. Conclusions PNPLA3 rs738409 is an inherited risk factor for HCC development in chronic liver disease. Our study found that the GG genotype can directly activate liver cancer in other etiology groups. According to our findings, we think that PNPLA3 polymorphism can be used as a biomarker in the development of HCC due to other etiologies group.

Photosynthetic response of Solidago gigantea Aition and Calamagrostis epigejos L. (Roth) to complex environmental stress on heavy metal contaminated sites

Studies of in situ plant response and adaptation to complex environmental stresses, are crucial for understanding the mechanisms of formation and functioning of ecosystems of anthropogenically transformed habitats. We study short- and long-term responses of photosynthetic apparatus (PSA) and anti-oxidant capacity to complex abiotic stresses of common plants Calamagrostis epigejos and Solidago gigantea in semi-natural (C) and heavy metal contaminated habitats (LZ). We found significant differences in leaf pigment content between both plant species growing on LZ plots and their respective C populations. The average values of leaf chlorophyll indexes were 27% lower in the LZ populations of both species and significantly lower in Sg plants in comparison to Ce ones. The average values of the anthocyanin index in CeLZ and SgLZ populations were significantly higher (by 18%) than in their respective controls. In both Ce and Sg plants occurring on LZ plots, the average leaf flavonol indexes were higher than on their controls by 31% and 15% and this index was significantly higher in SgLZ population than CeLZ and CeC plants (by 34% and 54%, respectively). Both Ce and Sg populations growing on LZ plots showed significantly lower photosynthetic rate (A), transpiration rate (E) and stomatal conductance (gs) in comparison to controls. On the other hand, a significantly higher photosynthetic rate was detected in SgLZ than in CeLZ populations. The catalase activities were significantly higher than recorded in Sg than in Ce tissues, irrespective of the plot type. They were also higher in LZ populations than those in controls for both species. Moreover, the H2O2 content in Sg tissues was significantly higher than those in Ce. Hydrogen peroxide content in CeLZ and SgLZ were respectively 39% (non-significant) and 57% higher, compared to their controls. The reverse pattern was found in the case of MDA, whose concentration was significantly higher in the leaves of Ce population compared to the control population. The average MDA concentration in CeLZ populations was 17% higher than in the CeC. In the case of Sg no significant differences were found. Mechanisms of plant species adaptation to industrial areas are crucial for species selection and planning effective reclamation of them. The analysis of chlorophyll fluorescence induction curves as well as well as the results of JIP test revealed the decreased of Fj value despite positive ΔK–band in SgLZ and CeLZ plants suggesting the increased rate of electron transfer from QA to QB at the acceptor side of PSII, thus a high quantity of P680+ and/or effective quenching by exogenous molecules. The increase in the I–P part of the induction curve typically attributed to the reduction of electron transporters (ferredoxin, intermediary acceptors, and NADP) of the PSI acceptor side was observed in both SgC and SgLZ but not in CeLZ populations. These changes demonstrate species-specific effects on electron transport during the light phase of photosynthesis under complex environmental stress. Our results show that Sg and Ce individuals developed a range of structural and functional adaptations to protect PSA against complex environmental stresses (possible combination of heavy metals, water deficiency, temperature, nutrient deficiency and salinity). Both species from LZ plots could tolerate high levels of Cd, Zn and Pb in leaf tissues. Therefore they can be potential candidates for use in phytoremediation of HM contaminated areas. However, further long-term field and experimental research on plant traits response and adaptation to complex environmental stresses on industrial habitats are needed.

Human umbilical cord mesenchymal stem cells improve the ovarian function through oxidative stress-mediated PERK/eIF-2α/ATF4/CHOP signaling in premature ovarian insufficiency mice.

Premature ovarian insufficiency (POI) is a refractory disease that severely affects female fertility. The PERK/eIF-2α/ATF4/CHOP pathway is one of the classical pathways involved in the unfolded protein response to endoplasmic reticulum stress by regulating protein synthesis and promoting apoptosis. This study aimed to investigate the functional role and mechanism of human umbilical cord mesenchymal stem cells (hUCMSCs) in the POI animal model through the PERK/eIF-2α/ATF4/CHOP pathway. Forty-five sexually mature female C57 mice were divided into a blank control group, POI model group, and hUCMSCs intervention group. To establish the POI model, mice received intraperitoneal injections of cyclophosphamide (CTX) (70mg/kg) daily for 14 consecutive days, while the control group received saline only. In the hUCMSC intervention group, mice were given hUCMSCs on days 14 and 28, based on CTX modeling in the POI model group. The hUCMSCs were isolated, labeled with 1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine iodide (DiR) fluorescent dye, and tail vein-injected, and the distribution of the DiR signal was monitored in the mice using a fluorescence imaging detection method. The ovarian tissues were hematoxylin and eosin stained to observe the ovarian structure, and the number of primordial follicles were counted. An enzyme-linked immunosorbent assay was used to detect the serum levels of estradiol, anti-mullerian hormone, and follicle-stimulating hormone. Terminal deoxynucleotidyl transferase dUTP nick end labeling was used to detect the apoptosis of granulosa cells (GCs). The reactive oxygen species (ROS) content of ovarian tissue was detected by flow cytometry assay. The RNA expression of PERK, eIF-2α, ATF4, and CHOP was determined by quantitative real-time polymerase chain reaction, and protein levels of the targets were determined by western blot and immunohistochemistry. We identified hUCMSCs using surface antigenic markers (CD90, CD44, CD105, and CD73), and osteoblasts and chondroplast differentiation assays. Our studies demonstrated that hUCMSC intervention significantly restored ovarian function by improving the irregular estrous cycle, increasing the number of follicles, decreasing ROS, and inhibiting GC apoptosis in POI mice. Moreover, hUCMSCs suppressed CTX-induced PERK/eIF-2a/ATF4/CHOP pathway activation. HUCMSCs can migrate to the damaged ovaries of POI mice, and improve the ovarian function of POI mice by inhibiting oxidative stress, down-regulating the expression of the PERK/eIF-2α/ATF4/CHOP pathway, and reducing the apoptosis of GCs.

Topological functional network analysis of cortical blood flow in hyperacute ischemic rats

Acute cerebral ischemia alters brain network connectivity, leading to notable increases in both anatomical and functional connectivity while observing a reduction in metabolic connectivity. However, alterations of the cerebral blood flow (CBF) based functional connectivity remain unclear. We collected continuous CBF images using laser speckle contrast imaging (LSCI) technology to monitor ischemic occlusion-reperfusion progression through occlusion of the left carotid artery. We also used a dense cortical grid atlas to construct CBF-based functional connectivity networks for hyperacute ischemic rodents. Graph theoretical analysis was used to measure network topological characteristics and construct topological connection graphs. Coactivation pattern (CAP) analysis was utilized to examine the spatiotemporal characteristics of the global network. Additionally, we measured evoked functional hyperemia and correlated it with network topologies. Network analysis indicated a significant increase in functional connectivity, global efficiency, local efficiency, small-worldness, clustering coefficient, and regional degree centrality primarily within the left ischemic intra-hemisphere, accompanied by weaker changes in the right intra-hemisphere. Inter-hemisphere networks exhibited reduced homologous connections, global efficiency, and small-worldness. CAP analysis revealed increased strength of the left negative activation brain network's state fraction of time and transition probability from equilibrium-to-imbalance states. Left network metrics declined following blood flow reperfusion. Furthermore, positive/negative correlations between barrel-evoked intensity and regional network topologies were reversed as negative/positive correlations after cerebral ischemia. These findings suggest a damaged CBF functional network mechanism following acute cerebral ischemia and a disrupted association between resting state and evoked hyperemia.

Life-course perspective on the causal mechanism of social functioning in schizophrenia spectrum disorder.

Due to prior emphasis on clinical recovery in Schizophrenia Spectrum Disorder (SSD), improving social functioning (SF) was oftentimes neglected, with ⩽15% of patients achieving social recovery. Priorly, we and others have shown that life-course factors, including childhood adversities, play a role in the occurrence and severity of postmorbid SF impairments, highlighting the need to understand these factors for effective interventions. This study investigates the mechanisms influencing SF in SSD and examines the causal roles of childhood trauma, premorbid adjustment, perceived stigma, self-esteem, and quality of life. This longitudinal study utilized data of 1,057 SSD patients, with measures at baseline, 3 and 6-year follow-up, from the Genetic Risk and Outcome of Psychosis cohort, to unravel the causal mechanism underlying SF utilizing Structural Equation Modeling. Determinants were assessed using validated retrospective and self-report questionnaires. Model development and testing involved a multistage process, encompassing relationships exploration, fit evaluation and model comparison. We developed a probable causal model. Impaired premorbid adjustment emerged as a crucial factor, exerting negative influence on long-term SF, with a direct effect of β = -.252, p < .001 on SF at 3-year follow-up and β = -.056, p = .073 at 6-year follow-up. Childhood trauma exhibited a negative direct effect on SF at 3-year follow-up (β = -.087, p = .039), while demonstrating a substantial carry-over, indirect effect. Elevated perceived stigma negatively affected SF at 3-year follow-up (β = -.112, p = .008). The model explained 9.9% of SF variation at the 3-year follow-up and 54.3% at the 6-year follow-up. While validation is necessary, we found a foundational basis for causal interpretation. Premorbid adjustment, childhood trauma, and perceived stigma are essential life-course factors shaping postmorbid SF in SSD. We recommend interventions covering both prevention and treatment for individuals with established symptoms-addressing childhood trauma, premorbid adjustment, and perceived stigma-to enhance long-term social outcomes and offer actionable insights for clinicians.