Structure, function and pharmacology of human itch GPCRs.

The MRGPRX family of receptors (MRGPRX1-4) is a family of mas-related G-protein-coupled receptors that have evolved relatively recently1. Of these, MRGPRX2 and MRGPRX4 are key physiological and pathological mediators of itch and related mast cell-mediated hypersensitivity reactions2-5. MRGPRX2 couples to both Gi and Gq in mast cells6. Here we describe agonist-stabilized structures of MRGPRX2 coupled to Gi1 and Gq in ternary complexes with the endogenous peptide cortistatin-14 and with a synthetic agonist probe, respectively, and the development of potent antagonist probes for MRGPRX2. We also describe a specific MRGPRX4 agonist and the structure of this agonist in a complex with MRGPRX4 and Gq. Together, these findings should accelerate the structure-guided discovery of therapeutic agents for pain, itch and mast cell-mediated hypersensitivity.

Low-frequency somatic copy number alterations in normal human lymphocytes revealed by large-scale single-cell whole-genome profiling.

Genomic-scale somatic copy number alterations in healthy humans are difficult to investigate because of low occurrence rates and the structural variations' stochastic natures. Using a Tn5-transposase-assisted single-cell whole-genome sequencing method, we sequenced over 20,000 single lymphocytes from 16 individuals. Then, with the scale increased to a few thousand single cells per individual, we found that about 7.5% of the cells had large-size copy number alterations. Trisomy 21 was the most prevalent aneuploid event among all autosomal copy number alterations, whereas monosomy X occurred most frequently in over-30-yr-old females. In the monosomy X single cells from individuals with phased genomes and identified X-inactivation ratios in bulk, the inactive X Chromosomes were lost more often than the active ones.

LSD1 in drug discovery: From biological function to clinical application.

Lysine-specific demethylase 1 (LSD1) is a flavin adenine dinucleotide (FAD) dependent monoamine oxidase (MAO) that erases the mono-, and dimethylation of histone 3 lysine 4 (H3K4), resulting in the suppression of target gene transcriptions. Besides, it can also demethylate some nonhistone substrates to regulate their biological functions. As reported, LSD1 is widely upregulated and plays a key role in several kinds of cancers, pharmacological or genetic ablation of LSD1 in cancer cells suppresses cell aggressiveness by several distinct mechanisms. Therefore, numerous LSD1 inhibitors, including covalent and noncovalent, have been developed and several of them have entered clinical trials. Herein, we systemically reviewed and discussed the biological function of LSD1 in tumors, lymphocytes as well as LSD1-targeting inhibitors in clinical trials, hoping to benefit the field of LSD1 and its inhibitors.

Comparative proximity biotinylation implicates the small GTPase RAB18 in sterol mobilization and biosynthesis.

Loss of functional RAB18 causes the autosomal recessive condition Warburg Micro syndrome. To better understand this disease, we used proximity biotinylation to generate an inventory of potential RAB18 effectors. A restricted set of 28 RAB18 interactions were dependent on the binary RAB3GAP1-RAB3GAP2 RAB18-guanine nucleotide exchange factor complex. Twelve of these 28 interactions are supported by prior reports, and we have directly validated novel interactions with SEC22A, TMCO4, and INPP5B. Consistent with a role for RAB18 in regulating membrane contact sites, interactors included groups of microtubule/membrane-remodeling proteins, membrane-tethering and docking proteins, and lipid-modifying/transporting proteins. Two of the putative interactors, EBP and OSBPL2/ORP2, have sterol substrates. EBP is a Δ8-Δ7 sterol isomerase, and ORP2 is a lipid transport protein. This prompted us to investigate a role for RAB18 in cholesterol biosynthesis. We found that the cholesterol precursor and EBP-product lathosterol accumulates in both RAB18-null HeLa cells and RAB3GAP1-null fibroblasts derived from an affected individual. Furthermore, de novo cholesterol biosynthesis is impaired in cells in which RAB18 is absent or dysregulated or in which ORP2 expression is disrupted. Our data demonstrate that guanine nucleotide exchange factor-dependent Rab interactions are highly amenable to interrogation by proximity biotinylation and may suggest that Micro syndrome is a cholesterol biosynthesis disorder.

Structurally Specific Z-DNA Proteolysis Targeting Chimera Enables Targeted Degradation of Adenosine Deaminase Acting on RNA 1.

Given the prevalent advancements in DNA- and RNA-based PROTACs, there remains a significant need for the exploration and expansion of more specific DNA-based tools, thus broadening the scope and repertoire of DNA-based PROTACs. Unlike conventional A- or B-form DNA, Z-form DNA is a configuration that exclusively manifests itself under specific stress conditions and with specific target sequences, which can be recognized by specific reader proteins, such as ADAR1 or ZBP1, to exert downstream biological functions. The core of our innovation lies in the strategic engagement of Z-form DNA with ADAR1 and its degradation is achieved by leveraging a VHL ligand conjugated to Z-form DNA to recruit the E3 ligase. This ingenious construct engendered a series of Z-PROTACs, which we utilized to selectively degrade the Z-DNA-binding protein ADAR1, a molecule that is frequently overexpressed in cancer cells. This meticulously orchestrated approach triggers a cascade of PANoptotic events, notably encompassing apoptosis and necroptosis, by mitigating the blocking effect of ADAR1 on ZBP1, particularly in cancer cells compared with normal cells. Moreover, the Z-PROTAC design exhibits a pronounced predilection for ADAR1, as opposed to other Z-DNA readers, such as ZBP1. As such, Z-PROTAC likely elicits a positive immunological response, subsequently leading to a synergistic augmentation of cancer cell death. In summary, the Z-DNA-based PROTAC (Z-PROTAC) approach introduces a modality generated by the conformational change from B- to Z-form DNA, which harnesses the structural specificity intrinsic to potentiate a selective degradation strategy. This methodology is an inspiring conduit for the advancement of PROTAC-based therapeutic modalities, underscoring its potential for selectivity within the therapeutic landscape of PROTACs to target undruggable proteins.

lncRNA799/TBL1XR1/ZEB1 Axis Forms a Feedback Loop to Promote the Epithelial-Mesenchymal Transition of Cervical Cancer Cells.

Cervical cancer is a common malignancy among women worldwide. Long non-coding RNAs (lncRNAs) are frequently involved in the pathogenesis of cervical cancer. Therefore, the present study aimed to investigate the potentials of lncRNA799 in cervical cancer. mRNA and protein expression were detected by reverse transcription-quantitative polymerase chain reaction and Western blot analysis, respectively. Cellular functions were assessed using CCK-8, wound healing and transwell analysis. The binding potential of zinc finger E-box-binding homeobox 1 (ZEB1) on the promoter of lncRNA799 was predicted utilizing the JASPAR database, and was then verified by luciferase and chromatin immunoprecipitation (ChIP) assays. Furthermore, the gene interactions were assessed using RNA immunoprecipitation and co-immunoprecipitation assays. The results demonstrated that lncRNA799 was upregulated in cervical cancer cells. However, lncRNA799 deficiency suppressed the proliferation and epithelial-mesenchymal transition of cervical cancer cells. Furthermore, lncRNA799 could interact with eukaryotic translation initiation factor 4A3 to maintain the mRNA stability of transducin (ß)-like 1 X-linked receptor 1 (TBL1XR1) and promote the interaction between ZEB1 and TBL1XR1. Additionally, the results showed that ZEB1 could transcriptionally activate lncRNA799. Taken together, the present study suggested that the lncRNA799/TBL1XR1/ZEB1 axis could form a positive feedback loop in cervical cancer and could be, therefore, considered as a potential therapeutic strategy for cervical cancer.

Microcrystalline Engineering of Anthracite-Based Carbon Via Salt-Assisted Ball Milling for Enhanced Sodium Storage Performance.

Coal-based carbon material, characterized by abundant resources and low cost, has gained considerable interests as a promising anode candidate for sodium-ion batteries (SIBs). However, the coal-based carbon generally shows inferior Na-storage performance due to its highly-ordered microstructure with narrow interlayer spacing. Herein, a salt-assisted mechanical ball-milling strategy is proposed to disrupt the polycyclic aromatic hydrocarbon structure in anthracite molecules, thereby reducing the microcrystalline regularity of the derived carbon during following pyrolysis process. In addition, the induced C─O─C bonds during ball-milling process can alter the pyrolysis behavior of anthracite and restrain the formation of surface defects. Consequently, in contrast to pristine anthracite-based pyrolytic carbon, which exhibits a Na-storage capacity of 198.4 mAh g-1 with a low initial Coulombic efficiency (ICE) of 65.1%, the ball-milling modified carbon assisted by NaCl salt (NAC), with enhanced structural disordering and reduced surface defects, demonstrate significantly improved Na-storage capacity of 332.1 mAh g-1 and ICE value of 82.0%. The NAC electrode also realizes excellent cycle and rate performance, retaining a capacity of 196.0 mAh g-1 at 1 C after 1000 cycles. Furthermore, when coupled with NaNi1/3Fe1/3Mn1/3O2 cathode, the assembled Na-ion full cell deliveres an exceptional electrochemical performance, highlighting its promising prospect as high-performance anode for SIBs.

PLAG1 dampens protein synthesis to promote human hematopoietic stem cell self-renewal.

Hematopoietic stem cell (HSC) dormancy is understood as supportive of HSC function and its long-term integrity. Although regulation of stress responses incurred as a result of HSC activation is recognized as important in maintaining stem cell function, little is understood of the preventive machinery present in human HSCs that may serve to resist their activation and promote HSC self-renewal. We demonstrate that the transcription factor PLAG1 is essential for long-term HSC function and, when overexpressed, endows a 15.6-fold enhancement in the frequency of functional HSCs in stimulatory conditions. Genome-wide measures of chromatin occupancy and PLAG1-directed gene expression changes combined with functional measures reveal that PLAG1 dampens protein synthesis, restrains cell growth and division, and enhances survival, with the primitive cell advantages it imparts being attenuated by addition of the potent translation activator, c-MYC. We find PLAG1 capitalizes on multiple regulatory factors to ensure protective diminished protein synthesis including 4EBP1 and translation-targeting miR-127 and does so independently of stress response signaling. Overall, our study identifies PLAG1 as an enforcer of human HSC dormancy and self-renewal through its highly context-specific regulation of protein biosynthesis and classifies PLAG1 among a rare set of bona fide regulators of messenger RNA translation in these cells. Our findings showcase the importance of regulated translation control underlying human HSC physiology, its dysregulation under activating demands, and the potential if its targeting for therapeutic benefit.

MSI2 regulates NLK-mediated EMT and PI3K/AKT/mTOR pathway to promote pancreatic cancer progression.

BACKGROUND: The incidence of pancreatic cancer is increasing by years, and the 5-year survival rate is very low. Our team have revealed that Musashi2 (MSI2) could promote aggressive behaviors in pancreatic cancer by downregulating Numb and p53. MSI2 also facilitates EMT in pancreatic cancer induced by EGF through the ZEB1-ERK/MAPK signaling pathway. This study aims to further explore the molecular mechanisms of MSI2-regulated downstream pathways in pancreatic cancer. METHODS: In vitro and in vivo experiments were conducted to investigate the role and mechanism of MSI2 in promoting malignant behaviors of pancreatic cancer through regulation of NLK. RESULTS: Genes closely related to MSI2 were screened from the GEPIA and TCGA databases. We found that NLK showed the most significant changes in mRNA levels with consistent changes following MSI2 interference and overexpression. The high correlation between MSI2 and NLK was also observed at the protein level. Multivariate analysis revealed that both MSI2 and NLK were independent adverse indicators of survival in pancreatic cancer patients, as well as join together. In vitro, silencing or overexpressing NLK altered cell invasion and migration, by regulating EMT and the PI3K-AKT-mTOR pathway. Silencing MSI2 reduced protein expression in the EMT and PI3K-AKT-mTOR pathways, leading to decreased cell invasion and migration abilities, while these effects could be reversed by overexpression of NLK. In vivo, MSI2 silencing inhibited liver metastasis, which could be reversed by overexpressing NLK. Mechanistically, MSI2 directly binds to the translation regulatory region of NLK mRNA at positions 79-87 nt, enhancing its transcriptional activity and exerting post-transcriptional regulatory roles. The analysis of molecular docking showed the close relationship between MSI2 and NLK in pancreatic cancer patients. CONCLUSIONS: Our findings elucidate the regulatory mechanisms of the MSI2-NLK axis in modulating aggressive behaviors of pancreatic cancer cells, which providing new evidence for therapeutic strategies in pancreatic cancer.

Cholesterol suppresses AMFR-mediated PDL1 ubiquitination and degradation in HCC.

The degradation of proteasomes or lysosomes is emerging as a principal determinant of programmed death ligand 1 (PDL1) expression, which affects the efficacy of immunotherapy in various malignancies. Intracellular cholesterol plays a central role in maintaining the expression of membrane receptors; however, the specific effect of cholesterol on PDL1 expression in cancer cells remains poorly understood. Cholesterol starvation and stimulation were used to modulate the cellular cholesterol levels. Immunohistochemistry and western blotting were used to analyze the protein levels in the samples and cells. Quantitative real-time PCR, co-immunoprecipitation, and confocal co-localization assays were used for mechanistic investigation. A xenograft tumor model was constructed to verify these results in vivo. Our results showed that cholesterol suppressed the ubiquitination and degradation of PDL1 in hepatocellular carcinoma (HCC) cells. Further mechanistic studies revealed that the autocrine motility factor receptor (AMFR) is an E3 ligase that mediated the ubiquitination and degradation of PDL1, which was regulated by the cholesterol/p38 mitogenic activated protein kinase axis. Moreover, lowering cholesterol levels using statins improved the efficacy of programmed death 1 (PD1) inhibition in vivo. Our findings indicate that cholesterol serves as a signal to inhibit AMFR-mediated ubiquitination and degradation of PDL1 and suggest that lowering cholesterol by statins may be a promising combination strategy to improve the efficiency of PD1 inhibition in HCC.

Group A Streptococcal meningitis in children: a short case series and systematic review.

BACKGROUND: Group A streptococcal(GAS) meningitis is a severe disease with a high case fatality rate. In the era of increasing GAS meningitis, our understanding about this disease is limited. PURPOSE: To gain a better understanding about GAS meningitis. METHODS: Five new cases with GAS meningitis were reported. GAS meningitis related literatures were searched for systematic review in PUBMED and EMBASE. Case reports and case series on paediatric cases were included. Information on demographics, risk factors, symptoms, treatments, outcomes, and emm types of GAS was summarized. RESULTS: Totally 263 cases were included. Among 100 individuals, 9.9% (8/81) had prior varicella, 11.1% (9/81) had anatomical factors, and 53.2% (42/79) had extracranial infections. Soft tissue infections were common among infants (10/29, 34.5%), while ear/sinus infections were more prevalent in children ≥ 3 years (21/42, 50.0%). The overall case fatality rate (CFR) was 16.2% (12/74). High risk of death was found in patients with shock or systemic complications, young children(< 3 years) and cases related to hematogenic spread. The predominate cause of death was shock(6/8). Among the 163 patients included in case series studies, ear/sinus infections ranged from 21.4 to 62.5%, while STSS/shock ranged from 12.5 to 35.7%, and the CFR ranged from 5.9 to 42.9%. CONCLUSIONS: A history of varicella, soft tissue infections, parameningeal infections and CSF leaks are important clinical clues to GAS in children with meningitis. Young children and hematogenic spread related cases need to be closely monitored for shock due to the high risk of death.

Linking tonic and phasic pupil responses to P300 amplitude in an emotional face-word Stroop task.

The locus coeruleus-norepinephrine (LC-NE) system, which regulates arousal levels, is important for cognitive control, including emotional conflict resolution. Additionally, the LC-NE system is implicated in P300 generation. If the P300 is mediated by the LC-NE system, and considering the established correlations between LC activity and pupil dilation, P300 amplitude should correlate with task-evoked (phasic) pupil dilation on a trial-by-trial basis. However, prior studies, predominantly utilizing oddball-type paradigms, have not demonstrated correlations between concurrently recorded task-evoked pupil dilation and P300 responses. Using a recently developed emotional face-word Stroop task that links pupil dilation to the LC-NE system, here, we examined both intra- and inter-individual correlations between task-evoked pupil dilation and P300 amplitude. We found that lower accuracy, slower reaction times, and larger task-evoked pupil dilation were obtained in the incongruent compared to the congruent condition. Furthermore, we observed intra-individual correlations between task-evoked pupil dilation and P300 amplitude, with larger pupil dilation correlating with a greater P300 amplitude. In contrast, pupil dilation did not exhibit consistent correlations with N450 and N170 amplitudes. Baseline (tonic) pupil size also showed correlations with P300 and N170 amplitudes, with smaller pupil size corresponding to larger amplitude. Moreover, inter-individual differences in task-evoked pupil dilation between the congruent and incongruent conditions correlated with differences in reaction time and P300 amplitude, though these effects only approached significance. To summarize, our study provides evidence for a connection between task-evoked pupil dilation and P300 amplitude at the single-trial level, suggesting the involvement of the LC-NE system in P300 generation.

Risk factors of low-level viremia in chronic hepatitis B patients receiving Entecavir monotherapy: a retrospective cohort study.

BACKGROUND AND AIM: Low-level viremia (LLV), a special case of poor response to antiviral therapy, has become a focus of liver disease research; however, most studies have focused on poor response to antiviral therapy, and little attention has been paid to LLV. Therefore, this study aimed to investigate the factors influencing LLV in patients with chronic hepatitis B (CHB) receiving entecavir (ETV) monotherapy. METHODS: Clinical data of CHB patients receiving ETV treatment for at least 1 year at the outpatient department of the Affiliated Hospital of Xuzhou Medical University from November 2018 to June 2020 were collected. Patients were divided into LLV (180 cases) and sustained virological response (SVR) groups (337 cases) according to the hepatitis B virus (HBV) DNA load at the end of the observation period. Demographic features and laboratory markers were also examined. Univariate and multivariate logistic regression analyses were performed to examine factors influencing LLV in patients receiving long-term ETV monotherapy. RESULTS: Significant differences were noted between the LLV and SVR groups in terms of age, sex, presence or absence of cirrhosis, HBeAg positivity rate, baseline HBV DNA load, and baseline HBsAg level before treatment. Multivariate logistic regression analysis showed that baseline HBeAg status, HBV DNA load, and HBsAg quantification were pretreatment risk factors for LLV in long-term ETV antiviral therapy. CONCLUSIONS: CHB patients with a high HBV DNA load, high HBsAg quantification, and positive HBeAg results tend to have a high risk of LLV despite long-term ETV antiviral treatment and should be dynamically monitored.

Efficacy of Citicoline Delivered via Brain Extracellular Space against Experimental Acute Ischemic Stroke in Rats.

Objective: Citicoline can be used to reduce acute ischemic stroke injury via venous infusion, however, its protective effects in the brain extracellular space remain largely unknown. Herein, we investigated the brain protective effects of citicoline administered via the brain extracellular space and sought precise effective dosage range that can protect against ischemic injury after experimental ischemic stroke in rats. Methods: Fifty-six Sprague-Dawley rats were randomly divided into control, intraperitoneal (IP), caudate-putamen (CPu)-25, CPu-40, CPu-50, CPu-60 and CPu-75 groups based on the infusion site and concentration of citicoline. Two hours after the administration of citicoline, the rats were subjected to a permanent middle cerebral artery occlusion to mimic acute ischemic stroke. Then, the brain infarct volume in rats after stroke was measured and their neurological deficiency was evaluated to explain the protective effects and effective dosage range of citicoline. Results: Compared to the control and IP groups, brain infarct volume of rats in CPu-40, CPu-50, and CPu-60 groups is significant smaller. Furthermore, the brain infarct volume of rats in CPu-50 is the least. Conclusions: Here, we showed that citicoline can decrease the brain infarct volume, thus protecting the brain from acute ischemic stroke injury. We also found that the appropriate effective citicoline dose delivered via the brain extracellular space is 50 mM. Our study provides novel insights into the precise treatment of acute ischemic stroke by citicoline via the brain extracellular space, further guiding the treatment of brain disease.

A multifunctional PEGylated liposomal-encapsulated sunitinib enhancing autophagy, immunomodulation, and safety in renal cell carcinoma.

BACKGROUND: Sunitinib is a multikinase inhibitor used to treat patients with advanced renal cell carcinoma (RCC). However, sunitinib toxicity makes it a double-edged sword. Potent immune modulation by sunitinib extends to nuclear interactions. To address these issues, there is an urgent need for delivery vectors suitable for sunitinib treatment. METHODS: We developed PEGylated liposomes as delivery vectors to precisely target sunitinib (lipo-sunitinib) to RCC tumors. Further investigations, including RNA sequencing (RNA-seq), were performed to evaluate transcriptomic changes in these pathways. DiI/DiR-labeled lipo-sunitinib was used for the biodistribution analysis. Flow cytometry and immunofluorescence (IF) were used to examine immune modulation in orthotopic RCC models. RESULTS: The evaluation of results indicated that lipo-sunitinib precisely targeted the tumor site to induce autophagy and was readily taken up by RCC tumor cells. In addition, transcriptomic assays revealed that following lipo-sunitinib treatment, autophagy, antigen presentation, cytokine, and chemokine production pathways were upregulated, whereas the epithelial-mesenchymal transition (EMT) pathway was downregulated. In vivo data provided evidence supporting the inhibitory effect of lipo-sunitinib on RCC tumor progression and metastasis. Flow cytometry further demonstrated that liposunitinib increased the infiltration of effector T cells (Teffs) and conventional type 1 dendritic cells (cDC1s) into the tumor. Furthermore, systemic immune organs such as the tumor-draining lymph nodes, spleen, and bone marrow exhibited upregulated anticancer immunity following lipo-sunitinib treatment. CONCLUSION: Our findings demonstrated that lipo-sunitinib is distributed at the RCC tumor site, concurrently inducing potent autophagy, elevating antigen presentation, activating cytokine and chemokine production pathways, and downregulating EMT in RCC cells. This comprehensive approach significantly enhanced tumor inhibition and promoted anticancer immune modulation.

Prediction models for retinopathy of prematurity occurrence based on artificial neural network.

INTRODUCTION: Early prediction and timely treatment are essential for minimizing the risk of visual loss or blindness of retinopathy of prematurity, emphasizing the importance of ROP screening in clinical routine. OBJECTIVE: To establish predictive models for ROP occurrence based on the risk factors using artificial neural network. METHODS: A cohort of 591 infants was recruited in this retrospective study. The association between ROP and perinatal factors was analyzed by univariate analysis and multivariable logistic regression. We developed predictive models for ROP screening using back propagation neural network, which was further optimized by applying genetic algorithm method. To assess the predictive performance of the models, the areas under the curve, sensitivity, specificity, negative predictive value, positive predictive value and accuracy were used to show the performances of the prediction models. RESULTS: ROP of any stage was found in 193 (32.7%) infants. Twelve risk factors of ROP were selected. Based on these factors, predictive models were built using BP neural network and genetic algorithm-back propagation (GA-BP) neural network. The areas under the curve for prediction models were 0.857, and 0.908 in test, respectively. CONCLUSIONS: We developed predictive models for ROP using artificial neural network. GA-BP neural network exhibited superior predictive ability for ROP when dealing with its non-linear clinical data.

Durable Effects of Acupuncture for Knee Osteoarthritis: A Systematic Review and Meta-analysis.

PURPOSE OF REVIEW: Knee osteoarthritis (KOA) is a degenerative joint disease which can result in chronic pain and disability. The current interventions available for KOA often fail to provide long-lasting effects, highlighting the need for new treatment options that can offer durable benefits. Previous studies have suggested the efficacy of acupuncture for knee osteoarthritis (KOA) with its durability remaining uncertain. In this review, we aimed to investigate the durability of the efficacy after completion of treatment. RECENT FINDINGS: We performed thorough searches of PubMed, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials from inception to November 4, 2023. The outcomes were assessed at all available time points after completion of treatment. Primary outcomes were changes from baseline in pain and function measured using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and function subscales. Secondary outcomes included response rate, overall pain, the WOMAC stiffness subscale, total WOMAC index, and physical and mental health components of 12/36-item Short-Form Health Survey. A total of 10 randomized controlled trials (RCTs) involving 3221 participants were included. Pooled estimates suggested that acupuncture may offer potential improvements in function and overall pain for 4.5 months post-treatment versus sham acupuncture (SA). Acupuncture may provide durable clinically important pain relief and functional improvement up to 5 months post-treatment versus usual care, and up to 6 months post-treatment versus diclofenac. For acupuncture versus no treatment, one trial with large sample size indicated that improvements in pain and function persisted for 3 months post-treatment, while the other trial reported that significant pain reduction and functional improvement were only observed at the end of the treatment, not at 9 months post-treatment. However, acupuncture as adjunct to exercise-based physical therapy (EPT) showed no superiority to SA as an adjunct to EPT or EPT alone up to 11.25 months after completion of treatment. Acupuncture may provide pain alleviation and functional improvements in KOA patients for 3 to 6 months after completion of treatment with a good safety profile.

Durable Effect of Acupuncture for Chronic Neck Pain: A Systematic Review and Meta-Analysis.

OBJECTIVE: Chronic neck pain, a prevalent health concern characterized by frequent recurrence, requires exploration of treatment modalities that provide sustained relief. This systematic review and meta-analysis aimed to evaluate the durable effects of acupuncture on chronic neck pain. METHODS: We conducted a literature search up to March 2024 in six databases, including PubMed, Embase, and the Cochrane Library, encompassing both English and Chinese language publications. The main focus of evaluation included pain severity, functional disability, and quality of life, assessed at least 3 months post-acupuncture treatment. The risk of bias assessment was conducted using the Cochrane Risk of Bias 2.0 tool, and meta-analyses were performed where applicable. RESULTS: Eighteen randomized controlled trials were included in the analysis. Acupuncture as an adjunct therapy could provide sustained pain relief at three (SMD: - 0.79; 95% CI - 1.13 to - 0.46; p < 0.01) and six (MD: - 18.13; 95% CI - 30.18 to - 6.07; p < 0.01) months post-treatment. Compared to sham acupuncture, acupuncture did not show a statistically significant difference in pain alleviation (MD: - 0.12; 95% CI - 0.06 to 0.36; p = 0.63). However, it significantly improved functional outcomes as evidenced by Northwick Park Neck Pain Questionnaire scores 3 months post-treatment (MD: - 6.06; 95% CI - 8.20 to - 3.92; p < 0.01). Although nine studies reported an 8.5%-13.8% probability of adverse events, these were mild and transitory adverse events. CONCLUSION: Acupuncture as an adjunct therapy may provide post-treatment pain relief lasting at least 3 months for patients with chronic neck pain, although it is not superior to sham acupuncture, shows sustained efficacy in improving functional impairment for over 3 months, with a good safety profile.

Advancements in Myopic Macular Foveoschisis Research.

BACKGROUND: Presently, the global prevalence of myopia and high myopia reaches approximately 1.95 billion and 277 million individuals, respectively. Projections suggest that by 2050, the number of people with myopia may rise to 4.758 billion and those with high myopia to 938 million. In highly myopic eyes, the occurrence of MF is reported to be as high as 8-33%. SUMMARY: This review comprehensively addresses the classification, pathogenesis, natural progression, concomitant pathologies, and therapeutic strategies for macular foveoschisis in highly myopic patients. KEY MESSAGES: In recent years, macular foveoschisis has emerged as a prevalent complication in individuals with high myopia, primarily resulting from the combination of inward traction by vitreoretinal adhesions and outward traction exerted by posterior scleral staphyloma on the retina. While some maintain partial visual stability over an extended period, others may progress to macular holes or even retinal detachment. For highly myopic patients with macular foveoschisis, the mainstay procedures are vitrectomy, macular buckle, and posterior scleral reinforcement. However, there is controversy about whether to perform inner limiting membrane peeling and gas filling.

PIEZO mediates a protective mechanism for nematode Caenorhabditis elegans in response to nanoplastics caused dopaminergic neurotoxicity at environmentally relevant concentrations.

Studies have probed nanoplastic toxicity on environmental organisms, but the regulatory role of animal PIEZO-type mechanosensitive ion channel component (PIEZO) remains unclear. Herein, we identified the sole PIEZO in Caenorhabditis elegans (C. elegans), utilizing amino acid homology analysis and Trans-Membrane prediction using Hidden Markov Models (TMHMM). In C. elegans, RNAi knockdown of pezo-1 had no impact on lifespan, body length, lethality, locomotion behaviors, or oxidative response (P > 0.05). However, exposure to 15 µg/L nanopolystyrene in the pezo-1 RNAi group resulted in severe locomotion changes: head trashes (P < 0.01), body bends (P < 0.05), forward turns (P < 0.05), backward turns (P < 0.01), and impaired sensory perception, including abnormal chemotaxis to NaCl (P < 0.01) and diacetyl (P < 0.01), as well as aversive responses (P < 0.05) to nanopolystyrene compared to the wild-type group. Dopaminergic neuron damage explains these behaviors, with GST-4 (P < 0.01) and SKN-1/Nrf2 (P < 0.01) activation mitigating nanoplastic-induced damage. Our results emphasize that even at the environmentally relevant concentrations (ERC), nanoplastics can impact neurotoxicity-related endpoints, with PIEZO mediating the regulation of oxidative and antioxidative systems in response to these effects. PIEZO may be applied for assessing the neurotoxicity or oxidative stress induced by other environmental toxicants besides nanoplastics.