Carvedilol to prevent hepatic decompensation of cirrhosis in patients with clinically significant portal hypertension stratified by new non-invasive model (CHESS2306).

Background & Aims: Non-invasive models stratifying clinically significant portal hypertension (CSPH) are limited. Herein, we developed a new non-invasive model for predicting CSPH in patients with compensated cirrhosis and investigated whether carvedilol can prevent hepatic decompensation in patients with high-risk CSPH stratified using the new model. Methods: Non-invasive risk factors of CSPH were identified via systematic review and meta-analysis of studies involving patients with hepatic venous pressure gradient (HVPG). A new non-invasive model was validated for various performance aspects in three cohorts, i.e., a multicenter HVPG cohort, a follow-up cohort, and a carvedilol-treating cohort. Results: In the meta-analysis with six studies (n = 819), liver stiffness measurement and platelet count were identified as independent risk factors for CSPH and were used to develop the new "CSPH risk" model. In the HVPG cohort (n = 151), the new model accurately predicted CSPH with cutoff values of 0 and -0.68 for ruling in and out CSPH, respectively. In the follow-up cohort (n = 1,102), the cumulative incidences of decompensation events significantly differed using the cutoff values of <-0.68 (low-risk), -0.68 to 0 (medium-risk), and >0 (high-risk). In the carvedilol-treated cohort, patients with high-risk CSPH treated with carvedilol (n = 81) had lower rates of decompensation events than non-selective beta-blockers untreated patients with high-risk CSPH (n = 613 before propensity score matching [PSM], n = 162 after PSM). Conclusions: Treatment with carvedilol significantly reduces the risk of hepatic decompensation in patients with high-risk CSPH stratified by the new model.

Sex and Age Differences in Ontogeny of Alloparenting: A Relation to Forebrain DRD1, DRD2, and HTR2A mRNA Expression?

Alloparenting refers to the practice of caring for the young by individuals other than their biological parents. The relationship between the dynamic changes in psychological functions underlying alloparenting and the development of specific neuroreceptors remains unclear. Using a classic 10-day pup sensitization procedure, together with a pup preference and pup retrieval test on the EPM (elevated plus maze), we showed that both male and female adolescent rats (24 days old) had significantly shorter latency than adult rats (65 days old) to be alloparental, and their motivation levels for pups and objects were also significantly higher. In contrast, adult rats retrieved more pups than adolescent rats even though they appeared to be more anxious on the EPM. Analysis of mRNA expression using real-time-PCR revealed a higher dopamine D2 receptor (DRD2) receptor expression in adult hippocampus, amygdala, and ventral striatum, along with higher dopamine D1 receptor (DRD1) receptor expression in ventral striatum compared to adolescent rats. Adult rats also showed significantly higher levels of 5-hydroxytryptamine receptor 2A (HTR2A) receptor expression in the medial prefrontal cortex, amygdala, ventral striatum, and hypothalamus. These results suggest that the faster onset of alloparenting in adolescent rats compared to adult rats, along with the psychological functions involved, may be mediated by varying levels of dopamine DRD1, DRD2, and HTR2A in different forebrain regions.

Simultaneous Determination of Fragmentation Functions and Test on Momentum Sum Rule.

We perform a simultaneous global analysis of hadron fragmentation functions (FFs) to various charged hadrons (π^{±}, K^{±}, and p/p[over ¯]) at next-to-leading order in QCD. The world data include results from electron-positron single-inclusive annihilation, semi-inclusive deep inelastic scattering, as well as proton-proton collisions including jet fragmentation measurements for the first time, which lead to strong constraints on the gluon fragmentations. By carefully selecting hadron kinematics to ensure the validity of QCD factorization and the convergence of perturbative calculations, we achieve a satisfying best fit with χ^{2}/d.o.f.=0.90. The total momentum of u, d quarks and gluon carried by light charged hadrons have been determined precisely, urging precision determinations of FFs to neutral hadrons for a test of fundamental sum rules in QCD fragmentation.

A Bioinspired Membrane with Ultrahigh Li+/Na+ and Li+/K+ Separations Enables Direct Lithium Extraction from Brine.

Membranes with precise Li+/Na+ and Li+/K+ separations are imperative for lithium extraction from brine to address the lithium supply shortage. However, achieving this goal remains a daunting challenge due to the similar valence, chemical properties, and subtle atomic-scale distinctions among these monovalent cations. Herein, inspired by the strict size-sieving effect of biological ion channels, a membrane is presented based on nonporous crystalline materials featuring structurally rigid, dimensionally confined, and long-range ordered ion channels that exclusively permeate naked Li+ but block Na+ and K+. This naked-Li+-sieving behavior not only enables unprecedented Li+/Na+ and Li+/K+ selectivities up to 2707.4 and 5109.8, respectively, even surpassing the state-of-the-art membranes by at least two orders of magnitude, but also demonstrates impressive Li+/Mg2+ and Li+/Ca2+ separation capabilities. Moreover, this bioinspired membrane has to be utilized for creating a one-step lithium extraction strategy from natural brines rich in Na+, K+, and Mg2+ without utilizing chemicals or creating solid waste, and it simultaneously produces hydrogen. This research has proposed a new type of ion-sieving membrane and also provides an envisioning of the design paradigm and development of advanced membranes, ion separation, and lithium extraction.

[Micro-energy medicine in the treatment of erectile dysfunction: An update].

Erectile dysfunction (ED) is one of the most common sexual disorders in males, which seriously affects the health of the patient and well-being of the family. The therapeutic strategy of ED is an individualized comprehensive treatment based on phosphodiesterase inhibitors. At present, as a new option for the treatment of ED, micro-energy medicine has attracted more and more attention in its therapeutic effects and advantages. This article presents an overview of the progress in the studies of micro-energy medicine in the treatment of ED.

Deblurring masked image modeling for ultrasound image analysis.

Recently, large pretrained vision foundation models based on masked image modeling (MIM) have attracted unprecedented attention and achieved remarkable performance across various tasks. However, the study of MIM for ultrasound imaging remains relatively unexplored, and most importantly, current MIM approaches fail to account for the gap between natural images and ultrasound, as well as the intrinsic imaging characteristics of the ultrasound modality, such as the high noise-to-signal ratio. In this paper, motivated by the unique high noise-to-signal ratio property in ultrasound, we propose a deblurring MIM approach specialized to ultrasound, which incorporates a deblurring task into the pretraining proxy task. The incorporation of deblurring facilitates the pretraining to better recover the subtle details within ultrasound images that are vital for subsequent downstream analysis. Furthermore, we employ a multi-scale hierarchical encoder to extract both local and global contextual cues for improved performance, especially on pixel-wise tasks such as segmentation. We conduct extensive experiments involving 280,000 ultrasound images for the pretraining and evaluate the downstream transfer performance of the pretrained model on various disease diagnoses (nodule, Hashimoto's thyroiditis) and task types (classification, segmentation). The experimental results demonstrate the efficacy of the proposed deblurring MIM, achieving state-of-the-art performance across a wide range of downstream tasks and datasets. Overall, our work highlights the potential of deblurring MIM for ultrasound image analysis, presenting an ultrasound-specific vision foundation model.

Eukaryotic Pif1 helicase unwinds G-quadruplex and dsDNA using a conserved wedge.

G-quadruplexes (G4s) formed by guanine-rich nucleic acids induce genome instability through impeding DNA replication fork progression. G4s are stable DNA structures, the unfolding of which require the functions of DNA helicases. Pif1 helicase binds preferentially to G4 DNA and plays multiple roles in maintaining genome stability, but the mechanism by which Pif1 unfolds G4s is poorly understood. Here we report the co-crystal structure of Saccharomyces cerevisiae Pif1 (ScPif1) bound to a G4 DNA with a 5' single-stranded DNA (ssDNA) segment. Unlike the Thermus oshimai Pif1-G4 structure, in which the 1B and 2B domains confer G4 recognition, ScPif1 recognizes G4 mainly through the wedge region in the 1A domain that contacts the 5' most G-tetrad directly. A conserved Arg residue in the wedge is required for Okazaki fragment processing but not for mitochondrial function or for suppression of gross chromosomal rearrangements. Multiple substitutions at this position have similar effects on resolution of DNA duplexes and G4s, suggesting that ScPif1 may use the same wedge to unwind G4 and dsDNA. Our results reveal the mechanism governing dsDNA unwinding and G4 unfolding by ScPif1 helicase that can potentially be generalized to other eukaryotic Pif1 helicases and beyond.

Magnetic Resonance Imaging-Related Anatomic and Functional Parameters for the Diagnosis and Prognosis of Chiari Malformation Type I: A Systematic Review and Meta-analysis.

OBJECTIVE: Imaging parameters of Chiari malformation type I (CMI) development are not well established. This study aimed to collect evidence of general or specific imaging measurements in patients with CMI, analyze indicators that may assist in determining the severity of CMI, and guide its diagnosis and treatment. METHODS: A comprehensive search was conducted across various databases including the Cochrane Library, PubMed, MEDLINE, Scopus, and Embase, covering the period from January 2002 to October 2023, following predefined inclusion criteria. Meta-analyses were performed using RevMan (ver. 5.4). We performed a quantitative summary and systematic analysis of the included studies. This study was registered in the PROSPERO (International Prospective Register of Systematic Reviews) prior to initiation (CRD42023415454). RESULTS: Thirty-three studies met our inclusion criteria. The findings indicated that out of the 14 parameters examined, 6 (clivus length, basal angle, Boogard's angle, supraocciput lengths, posterior cranial fossa [PCF] height, and volume) exhibited significant differences between the CMI group and the control group. Furthermore, apart from certain anatomical parameters that hold prognostic value for CMI, functional parameters like tonsillar movement, obex displacement, and cerebrospinal fluid dynamics serve as valuable indicators for guiding the clinical management of the disease. CONCLUSION: We collated and established a set of linear, angular, and area measurements deemed essential for diagnosing CMI. However, more indicators can only be analyzed descriptively for various reasons, particularly in prognostic prediction. We posit that the systematic assessment of patients' PCF morphology, volume, and other parameters at a 3-dimensional level holds promising clinical application prospects.

Aronia Melanocarpa Elliot Anthocyanins Inhibits Alcoholic Liver Disease by Activation of α7nAChR.

The study wanted to explore the preventative effects of Aornia melanocarpa Elliot anthocyanins (AMA) to Alcoholic liver disease (ALD) by bioinformatics prediction and experimental verification. We founded 419 differentially expressed genes (DEGs) in GSE28619 related to ALD from GEO database, COL1A1 was selected by the core gene module construction and molecular docking. Mice were treated by intragastric administration of gradient 50% ethanol, AMA alleviated liver injury by ALD and ameliorated the model's body weight, lessened the liver inflammation according to histopathological evaluation, increased serum liver biochemical index (AST, ALT, TC, TG and LDL-C) and decreased HDL-C, reversed the expression of enzymes (ALDH and GSH-PX), decreased cytokines expression (Ki67, TNF-α and IL-6), reversed the expression of α7nAChR and collagen I, downregulated the PI3K-Akt pathway and Keap1/HO-1 pathway (p-PI3K, PI3K, p-Akt, Akt, Keap1, Nrf2, HO-1,GSK-3ß and Bcl-2), indicated that α7nAChR and collagen I may be the AMA action targets.

Dietary Supplementation with Rumen-Protected Arginine or N-Carbamylglutamate Enhances Fetal Liver Development in Nutrient-Restricted Pregnant Hu Ewes.

This study was conducted in nutrient-restricted pregnant Hu ewes to determine whether rumen-protected arginine (RP-Arg) or N-carbamylglutamate (NCG) supplementation affects fetal liver growth and development. From 35 d to 110 d of gestation, 32 Hu ewes were randomly divided into four groups: a control group (100% of the National Research Council (NRC) requirements), a nutrient-restricted group (50% of the NRC requirements), and two treatment groups (ARG and NCG, 50% of the NRC requirements, supplemented with 20 g/day RP-Arg or 5 g/day NCG, respectively). Fetal body weights, fetal liver growth performance, the capability of antioxidation, and the expression of the mRNA and proteins of apoptosis-related genes in the fetal liver were determined and analyzed at 110 d of gestation. The dry matter, water, fat, protein, and ash components of the fetal livers in the RG group were found to be lower than in the CG group, and these components were significantly higher in the NCG group than in the RG group (p < 0.05). A decrease in DNA, RNA, and protein concentrations and contents, as well as in protein/DNA ratios, was observed in the RG group in comparison to the CG group (p < 0.05). Compared with the RG group, the NCG group had higher concentrations of DNA, RNA, and protein, as well as higher protein/DNA ratios (p < 0.05). The RG group had lower concentrations of cholinesterase, nitric oxide, nitric oxide synthase, superoxide dismutase, alanine aminotransferase, and total protein than the CG group (p < 0.05). The RG group had higher levels of glutathione peroxidase, maleic dialdehyde, and aspartate aminotransferase than the CG group (p < 0.05). In the RG group, the mRNA and protein expression of p53 and Bax was significantly increased (p < 0.05) compared with the CG group, and the gene expression of FasL and Bcl-2, the ratio of Bcl-2 to Bax, and the protein expression of Bcl-2 in the RG group were lower (p < 0.05) than in the CG group. It appears that RP-Arg and NCG supplementation during pregnancy could influence fetal liver growth and development. A nutrition-based therapeutic intervention to alleviate reduced fetal growth can be developed based on this study, which has demonstrated that maternal undernutrition during pregnancy induces the maldevelopment of the fetal liver.

Fatty infiltration in paraspinal muscles: Predicting the outcome of lumbar surgery and postoperative complications.

Lumbar spine disorders often cause lower back pain, lower limb radiating pain, restricted movement, and neurological dysfunction, which seriously affect the quality of life of middle-aged and older people. It has been found that pathological changes in the spine often cause changes in the morphology and function of the paraspinal muscles (PSMs). Fatty infiltration (FI) in PSMs is closely associated with disc degeneration and Modic changes. And FI causes inflammatory responses that exacerbate the progression of lumbar spine disease and disrupt postoperative recovery. Magnetic resonance imaging (MRI) can better distinguish between fat and muscle tissue with the threshold technique. Three-dimensional-MRI multi-echo imaging techniques such as water-fat separation and proton density are currently popular for studying FI. Muscle fat content obtained based on these imaging sequences has greater accuracy, visualization, acquisition speed, and utility. The proton density fat fraction calculated from these techniques has been shown to evaluate more subtle changes in PSMs. Magnetic resonance spectroscopy can accurately reflect the relationship between FI and the degeneration of PSMs by measuring intracellular and extracellular lipid values to quantify muscle fat. We have pooled and analyzed published studies and found that patients with spinal disorders often exhibit FI in PSMs. Some studies suggest an association between FI and adverse surgical outcomes, although conflicting results exist. These suggests that clinicians should consider FI when assessing surgical risks and outcomes. Future studies should focus on understanding the biological mechanisms underlying FI and its predictive value in spinal surgery, providing valuable insights for clinical decision-making.

[Gene cloning and functional analysis of an iridoid oxidase gene in Rehmannia glutinosa].

Rehmannia glutinosa is one of the commonly used Chinese herbal medicines, which has activities of heat-clearing,blood-cooling, Yin-nourishing, and body fluid-promoting. Iridoid glycosides are the main bioactive in R. glutinosa. Iridoid oxidase is a key rate-limiting enzyme in the biosynthetic pathway of iridoid glycosides. In this study, an iridoid oxidase gene Rg IO was screened based on the transcriptome data, followed by bioinformatics analysis, expression characteristic detection, and subcellular localization analysis. The results show that the coding region of Rg IO is 1 536 bp, with 511 amino acids encoded, and the molecular weight is about 58 258. 01. The protein sequence of Rg IO contains the conserved domains and motifs of cytochrome P450 oxidases. Rg IO has the highest sequence identities with its ortholog proteins in Striga asiatica, Striga hermonthica, and Centranthera grandiflora and has good sequence identities(77. 28%) with Catharanthus roseus Cr IO. Rg IO shows specific expression in the leaf of R. glutinosa. In response to MeJA induction, the expression of MeJA in leaves and roots after treatment increases by 3. 15 and 1. 3 times at 3 h and 6 h,respectively. The result of subcellular localization shows that Rg IO is distributed in the endoplasmic reticulum. Agrobacterium-mediated transient expression of Rg IO gene in leaves of R. glutinosa makes the content of catalpol increase by 0. 82 times compared with the transient expression of the empty vector. This study provides a key target gene for the molecular regulation and biosynthesis of catalpol in R. glutinosa and lays a foundation for revealing the complete biosynthetic pathway of catalpol.

Fecal Microbiota Transfer from Young Mice Reverts Vascular Aging Hallmarks and Metabolic Impairments in Aged Mice.

As a major risk factor for cardiometabolic diseases, aging refers to a gradual decline in physiological function, characterized with 12 conspicuous hallmarks, like telomere attrition, chronic inflammation, and dysbiosis. Common vascular aging hallmarks include endothelial dysfunction, telomere dysfunction, and vascular inflammation. In this study, we sought to test the hypothesis that young-derived gut microbiota retards vascular aging hallmarks and metabolic impairments in aged hosts. We also aimed to study the therapeutic efficacy of young microbiota in hosts of different ages. Fecal microbiota transplantation (FMT) from young to aged or middle-aged C57BL/6 mice was conducted for 6 consecutive weeks after antibiotic pretreatment. Endothelium-dependent relaxations (EDRs) in mouse arteries were determined by wire myography. Inflammation and AMPK/SIRT1 signaling in mouse aortas and intestines were studied by biochemical assays. The telomere function of aortas and intestines, in terms of telomerase reverse transcriptase expression, telomerase activity, and relative telomere length, were also studied. FMT significantly reverted vascular dysfunction and metabolic impairments in middle-aged mice than in aged mice. Besides, FMT significantly reverted inflammation and telomere dysfunction in aortas and intestines of middle-aged mice. Improved intestinal barrier function and activated AMPK/SIRT1 signaling potentially underlie benefits of FMT. The findings imply gut-vascular connection as potential target against age-associated cardiometabolic disorders, highlight crosstalk among aging hallmarks, and suggest a critical timepoint for efficacy of anti-aging interventions.

Bariatric arterial embolization slows gastric emptying and improves postprandial glycaemia in obese dogs with impaired glucose tolerance.

AIM: To evaluate the effects of bariatric arterial embolization (BAE) on gastric emptying of, and the glycaemic response to, an oral glucose load in an obese canine model with impaired glucose tolerance. METHODS: Eleven male dogs were fed a high-fat, high-fructose diet for 7 weeks before receiving BAE, which involved selective embolization of the left gastric artery (n = 5; 14.9 ± 0.8 kg), or the sham (n = 6; 12.6 ± 0.8 kg) procedure. Postprocedural body weight was measured weekly for 4 weeks. Prior to and at 4 weeks postprocedure, a glucose solution containing 13C-acetate was administered orally for evaluation of the gastric half-emptying time (T50) and the glycaemic response. The relationship between the changes in the blood glucose area under the curve over the first 60 minutes (AUC0-60min) and the T50 was also assessed. RESULTS: At 4 weeks postprocedure, BAE reduced body weight (BAE vs. the sham procedure: -5.7% ± 0.9% vs. 3.5% ± 0.9%, P < .001), slowed gastric emptying (T50 at baseline vs. postprocedure: 75.5 ± 2.0 vs. 82.5 ± 1.8 minutes, P = .021 in the BAE group; 73.8 ± 1.8 vs. 74.3 ± 1.9 minutes in the sham group) and lowered the glycaemic response to oral glucose (AUC0-60min at baseline vs. postprocedure: 99.2 ± 13.7 vs. 67.6 ± 9.8 mmol·min/L, P = .043 in the BAE group; 100.2 ± 13.4 vs. 103.9 ± 14.6 mmol·min/L in the sham group). The change in the glucose AUC0-60min correlated inversely with that of the T50 (r = -0.711; P = .014). CONCLUSIONS: In a canine model with impaired glucose tolerance, BAE, while reducing body weight, slowed gastric emptying and attenuated the glycaemic response to an oral glucose load.

Fluorescence quenching of deprotonated phenylurea through twisting motion induced by an electron-donating substituent group.

The excited-state proton transfer (ESPT) reaction between anthracen-2-yl-3-phenylurea (PUA) derivatives and tetrabutylammonium acetate (TBAAc) in dimethyl sulfoxide (DMSO) solvent was theoretically investigated using time-dependent density functional theory. The electron-donating methoxy group (OMe) and electron-withdrawing trifluoromethyl group (CF3) were bonded to 2PUA to form OMe-2PUA and CF3-2PUA, respectively. Two hydrogen bonds formed in the 1 : 1 hydrogen-bonded complexes between the 2PUA derivative and acetate ion (AcO-), namely N1-H1⋯O1 and N2-H2⋯O2. Strong charge transfer (CT) due to the electron-donating OMe group led to H1 transfer in the S1 state for the OMe-2PUA:AcO- hydrogen-bonded complex. On the contrary, weak CT due to the electron-withdrawing CF3 group led to H2 transfer in the S1 state for CF3-2PUA. After the ESPT reaction, the binding energies of the hydrogen-bonded complexes strongly decreased in both cases, and this promoted the separation of contact-ion pairs (CIPs*) and formed different types of anionic species. CF3-2PUA- could keep its nearly planar structure in the S1 state and emit "abnormal" fluorescence. On the other hand, the anionic OMe-2PUA- underwent a twisting motion to form a twisted structure in the S1 state with very low energy, and this led to a rapid internal conversion (IC) to quench long-wave fluorescence in the emission spectra.

Computational Polarization Imaging In Vivo through Surgical Smoke Using Refined Polarization Difference.

In surgery, the surgical smoke generated during tissue dissection and hemostasis can degrade the image quality, affecting tissue visibility and interfering with the further image processing. Developing reliable and interpretable computational imaging methods for restoring smoke-affected surgical images is crucial, as typical image restoration methods relying on color-texture information are insufficient. Here a computational polarization imaging method through surgical smoke is demonstrated, including a refined polarization difference estimation based on the discrete electric field direction, and a corresponding prior-based estimation method, for better parameter estimation and image restoration performance. Results and analyses for ex vivo, the first in vivo animal experiments, and human oral cavity tests show that the proposed method achieves visibility restoration and color recovery of higher quality, and exhibits good generalization across diverse imaging scenarios with interpretability. The method is expected to enhance the precision, safety, and efficiency of advanced image-guided and robotic surgery.

Observation of reentrant metal-insulator transition in a random-dimer disordered SSH lattice.

The interrelationship between localization, quantum transport, and disorder has remained a fascinating focus in scientific research. Traditionally, it has been widely accepted in the physics community that in one-dimensional systems, as disorder increases, localization intensifies, triggering a metal-insulator transition. However, a recent theoretical investigation [Phys. Rev. Lett. 126, 106803] has revealed that the interplay between dimerization and disorder leads to a reentrant localization transition, constituting a remarkable theoretical advancement in the field. Here, we present the first experimental observation of reentrant localization using an experimentally friendly model, a photonic SSH lattice with random-dimer disorder, achieved by incrementally adjusting synthetic potentials. In the presence of correlated on-site potentials, certain eigenstates exhibit extended behavior following the localization transition as the disorder continues to increase. We directly probe the wave function in disordered lattices by exciting specific lattice sites and recording the light distribution. This reentrant phenomenon is further verified by observing an anomalous peak in the normalized participation ratio. Our study enriches the understanding of transport in disordered mediums and accentuates the substantial potential of integrated photonics for the simulation of intricate condensed matter physics phenomena.

Heterozygous variants in USP25 cause genetic generalized epilepsy.

USP25 encodes ubiquitin-specific proteases 25, a key member of deubiquitinating enzyme family and is involved in neural fate determination. Although abnormal expression in Down's syndrome was reported previously, the specific role of USP25 in human diseases has not been defined. In this study, we performed trio-based whole exome sequencing in a cohort of 319 cases (families) with generalized epilepsy of unknown etiology. Five heterozygous USP25 variants including two de novo and three co-segregated variants were determined in eight individuals affected by generalized seizures and/or febrile seizures from five unrelated families. The frequency of USP25 variants showed a significantly high aggregation in this cohort compared to the East Asian population and all populations in the gnomAD database. The mean onset ages of febrile and afebrile seizures were 10 months (infancy) and 11.8 years (juvenile), respectively. The patients achieved seizure freedom except one had occasional nocturnal seizures at the last follow-up. Two patients exhibited intellectual disability. Usp25 was ubiquitously expressed in mouse brain with two peaks on embryonic days (E14‒E16) and postnatal day 21, respectively. Similarly, USP25 expressed in fetus/early childhood stage with a second peak at approximately 12‒20 years old in human brain, consistent with the seizure onset age at infancy and juvenile in the patients. To investigate the functional impact of USP25 deficiency in vivo, we established Usp25 knock-out mice, which showed increased seizure susceptibility compared to wild-type mice in pentylenetetrazol-induced seizure test. To explore the impact of USP25 variants, we employed multiple functional detections. In HEK293T cells, the severe phenotype associated variant (p.Gln889Ter) led to a significant reduction of mRNA and protein expressions but formed a stable truncated dimers with increment of deubiquitinating enzyme activities and abnormal cellular aggregations, indicating a gain-of-function effect. The p.Gln889Ter and p.Leu1045del increased neuronal excitability in mice brain, with a higher firing ability in p.Gln889Ter. These functional impairments align with the severity of the observed phenotypes, suggesting a genotype-phenotype correlation. Hence, a moderate association between USP25 and epilepsy was noted, indicating USP25 is potentially a predisposing gene for epilepsy. Our results from Usp25 null mice and the patient-derived variants indicated that USP25 would play epileptogenic role via loss-of-function or gain-of-function effects. The truncated variant p.Gln889Ter would have profoundly different effect on epilepsy. Together, our results underscore the significance of USP25 heterozygous variants in epilepsy, thereby highlighting the critical role of USP25 in the brain.

Whole-exome sequencing-based mutational profiling of hepatocellular adenoma malignant transformation to hepatocellular carcinoma.

Hepatocellular adenoma (HCA) represents a rare benign hepatic neoplasm with potential for malignant transformation into hepatocellular carcinoma (HCC), yet the underlying mechanism remains elusive. In this study, we investigated the genomic landscape of this process to identify therapeutic strategies for blocking malignant transformation. Using micro-detection techniques, we obtained specimens of adenoma, cancerous neoplasm and adjacent normal liver from three patients undergoing hepatic resection surgery. Whole-exome sequencing (WES) was performed, and genomic interactions between HCA and HCC components within the same tumour were evaluated using somatic variant calling, copy number variation (CNV) analysis, clonality evaluation and mutational signature analysis. Our results revealed genomic heterogeneity among patient cases, yet within each sample, HCA and HCC tissues exhibited a similar mutational landscape, suggesting a high degree of homology. Using nonnegative matrix factorization and phylogenetic trees, we identified shared and distinct mutational characteristics and uncovering necessary pathways associated with HCA-HCC malignant transformation. Remarkably, we found that HCA and HCC shared a common monoclonal origin while displaying significant genetic diversity within HCA-HCC tumours, indicating fundamental genetic connections or evolutionary pathways between the two. Moreover, elevated immune therapy-related markers in these patients suggested heightened sensitivity to immune therapy, providing novel avenues for the treatment of hepatic malignancies. This study sheds light on the genetic mechanisms underlying HCA-HCC progression, offering potential targets for therapeutic intervention and highlighting the promise of immune-based therapies in managing hepatic malignancies.

Congener-welded crystalline carbon nitride membrane for robust and highly selective Li/Mg separation.

Extracting lithium from salt-lake brines critically relies on the separation of Li+ and Mg2+, which could combat the lithium shortage. However, designing robust sieving membrane with high Li+/Mg2+ selectivity in the long-time operation has remained highly challenging. Here, we demonstrate a bioinspired congener-welded crystalline carbon nitride membrane that can accomplish efficient and stable monovalent ion sieving over divalent Mg ion. The crystalline carbon nitrides have uniform and narrow pore size to reject the large hydrated Mg2+ and rich ligating sites to facilitate an almost barrierless Li+ transport as suggested by ab initio simulations. These crystals were then welded by vapor-deposited congeners, i.e., amorphous polymer carbon nitride, which have similar composition and chemistry with the crystals, forming intimate and compatible crystal/polymer interface. As a result, our membrane can sieve out highly dilute Li+ (0.002 M) from concentrated Mg2+ (1.0 M) with a high selectivity of 1708, and can be continuously operated for 10 days.