Two laser-assisted hatching methods of embryos in ART: a systematic review and meta-analysis.

BACKGROUND: Laser-assisted hatching (LAH) stands as the predominant technique for removing the zona pellucida (ZP) in embryos, primarily consisting of two methods: drilling laser-assisted hatching (D-LAH) and thinning laser-assisted hatching (T-LAH). Presently, both methods have limitations, and their comparative efficacy for embryo implantation and clinical pregnancy remains uncertain. AIM: Evaluate the impact of D-LAH and T-LAH on clinical pregnancy rates within assisted reproductive technology (ART). METHODS: We systematically searched electronic databases including PubMed, Web of Science, and Cochrane Library until July 20, 2022. This study encompassed observational studies and randomized controlled trials (RCTs). A 95% confidence interval (CI) was utilized for assessing the risk ratio (RR) of pregnancy outcomes. The level of heterogeneity was measured using I2 statistics, considering a value exceeding 50% as indicative of substantial heterogeneity. RESULTS: The meta-analysis scrutinized 9 studies involving 2405 clinical pregnancies from D-LAH and 2239 from T-LAH. Findings suggested no considerable variation in the clinical pregnancy rates between the two techniques (RR = 0.93, 95% CI: 0.79-1.10, I2 = 71%, P = 0.41). Subgroup analyses also revealed no substantial differences. However, D-LAH exhibited a notably higher occurrence of singleton pregnancies compared to T-LAH (RR = 2.28, 95% CI: 1.08-4.82, I2 = 89%, P = 0.03). There were no noteworthy distinctions observed in other secondary outcomes encompassing implantation rate, multiple pregnancies, ongoing pregnancy, miscarriage, premature birth, and live birth. CONCLUSION: Both the primary findings and subgroup analyses showed no marked variance in clinical pregnancy rates between D-LAH and T-LAH. Therefore, patients with varying conditions should select their preferred LAH technique after assessing their individual situation. However, due to the restricted number of studies involved, accurately gauging the influence of these laser techniques on clinical outcomes is challenging, necessitating further RCTs and high-quality studies to enhance the success rate of ART. TRIAL REGISTRATION: PROSPERO: CRD42022347066.

Preclinical and phase I studies of an antisense oligonucleotide drug targeting IGF-1R in liver cancer.

Aim: To evaluate a novel antisense oligonucleotide drug targeting human IGF-1R in preclinical and phase I studies of liver cancer. Materials & methods: The tolerability and safety of an investigational new drug were evaluated in a dose-escalation trial involving 17 patients with advanced liver cancer after preclinical assessment of pharmacokinetics and pharmacodynamics. Results: The drug exposure levels in the phase I trial were determined by the in vivo efficacy with pharmacokinetics evaluation in rats and rhesus monkeys. This clinical study showed that the maximum tolerated dose was 3.96 mg/kg, and the dose-limiting toxicity dose was 4.4 mg/kg. Conclusion: The drug was safe and tolerable in patients with advanced liver cancer. Clinical Trial Registration: ChiCTR2100044235 (www.chictr.org.cn).

CT102 is a potential new drug for liver cancer treatment. It belongs to a new form of medicine using gene therapy technology called antisense oligonucleotides. There are some antisense oligonucleotides approved for treating rare diseases. This study evaluated the antitumor effect, metabolism and safety of CT102 in preclinical and clinical trials. The results showed that CT102 could inhibit tumor growth in mice with liver cancer and maintain high levels in the liver. It was found that CT102 was safe and tolerable in patients with advanced liver cancer. This suggests that CT102 has therapeutic potential for liver cancer treatment. The good tolerability and safety of CT102 in patients supports further studies on liver cancer treatment.

Effects of different oxidants on the behaviour of microplastic hetero-aggregates.

Microplastic hetero-aggregates are stable forms of microplastics in the aqueous environment. However, when disinfecting water containing microplastic hetero-aggregates, the response of them in water to different oxidizing agents and the effect on water quality have not been reported. Our results showed that Ca(ClO)2, K2S2O8, and sodium percarbonate (SPC) treatment could lead to the disaggregation of microplastic hetero-aggregates as well as a rise in cell membrane permeability, which caused a large amount of organic matter to be released. When the amount of oxidant dosing is insufficient, the oxidant cannot completely degrade the released organic matter, resulting in DOC, DTN, DTP and other indicators being higher than before oxidation, thus causing secondary pollution of the water body. In comparison, K2FeO4 can purify the water body stably without destroying the microplastic hetero-aggregates, but it only weakly inhibits the toxic cyanobacteria Microcystis and Pseudanabaena, which may cause cyanobacterial bloom as well as algal toxin and odorant contamination in practical application. Compared with the other oxidizers, K2S2O8 provides better inhibition of toxic cyanobacteria and has better ecological safety. Therefore, when treating microplastic-containing water bodies, we should consider both water purification and ecological safety, and select appropriate oxidant types and dosages to optimize the water treatment.

A preliminary study on the normal value of the thoracic haller index in children.

BACKGROUND AND OBJECTIVE: The Haller index (HI) is widely utilized as a quantitative indicator to assess the extent of pectus excavatum (PE) deformity, which is the most common chest wall abnormality in children. Both preoperative correction planning and postoperative follow-up need to be based on the standard of normal thoracic growth and development. However, there is currently no established reference range for the HI in children. Consequently, the aim of this study was to conduct a preliminary investigation of normal HI values among children to understand thoracic developmental characteristics. METHODS: Chest CT images obtained from January 2012 to March 2022 were randomly selected from the imaging system of the Children's Hospital of Chongqing Medical University. We divided the images of children into a total of 19 groups: aged 0-3 months (1 group), 4-12 months (1 group), and 1 year to 17 years (17 groups), with 50 males and 50 females, totaling 100 children in each group. HI was measured in the plane where the lowest point of the anterior thoracic wall was located and statistically analyzed using SPSS 26.0 software. RESULTS: A total of 1900 patients were included in the study. Our results showed that HI, transverse diameter, and anterior-posterior diameter were positively correlated with age (P < 0.05). Using age as the independent variable and HI as the dependent variable, the best-fit regression equations were HI-male = 2.047 * Age0.054(R2 = 0.276, P＜0.0001), HI-female = 2.045 * Age0.067(R2 = 0.398, P＜0.0001). Males had significantly larger thoracic diameters than females, and there was little difference in the HI between the two sexes. CONCLUSIONS: The HI rapidly increases during the neonatal period, slowly increases during infancy, and stops increasing during puberty, with no significant differences between sexes.

No Difference in Bone Tunnel Enlargement and Clinical Outcome between Cortical Suspension and Hybrid Femoral Fixation in Hamstring Anterior Cruciate Ligament Reconstruction.

OBJECTIVE: The best method for femoral fixation in anterior cruciate ligament reconstruction (ACLR) remains controversial. The study assesses the bone tunnel enlargement and clinical outcome in hamstring ACLR using cortical suspension or hybrid (cortical suspension and compression) femoral fixation. METHODS: From January 2010 to December 2021, 102 patients who underwent quadruple hamstring ACLR using cortical suspension (39 patients) or hybrid (63 patients) fixation on the femoral side were retrospectively analyzed. Clinical evaluation was conducted using the international knee documentation committee score, the Lysholm score, the Tegner activity level scale, the knee injury and osteoarthritis outcome score (quality of life score), the Lachman test, and the side-to-side difference by the KT-1000 arthrometer. The complications after the surgery were also evaluated. These data were compared at baseline and last follow-up. The diameters of the femoral tunnel were calculated at three sites: the width of the entrance of the femoral tunnel, 1 cm proximal to the entrance of the femoral tunnel and the largest diameter of the femoral tunnel on magnetic resonance imaging (MRI) coronal images. Bone tunnel widening data were contrasted between MRI images conducted at least 2 years and within 2 weeks after surgery. The morphology of bone tunnel enlargement was also observed and recorded. The categorical parameters were analyzed using the χ2-test and Fisher's exact test. The continuous variables conforming to a normal distribution were analyzed using Student's t-test, and the Mann-Whitney U-test was undertaken between the two groups without normal distribution. RESULTS: Both cortical suspension and hybrid femoral fixation in quadruple hamstring ACLR achieved significantly improved patient-reported outcome scores and knee stability compared to preoperative data. However, no significant differences were found between these two methods in clinical evaluations, postoperative complications, and patient-reported outcome scores. Although the mean diameter of the enlarged bone tunnel was lowered by an additional bioabsorbable interference screw fixation near the joint line, a statistically insignificant difference was found between the hybrid and cortical suspension fixation on the femoral side. There was no statistical difference in the distribution of enlarged bone tunnel morphology between groups. CONCLUSIONS: No significant difference was found in the bone tunnel enlargement and clinical outcome between cortical suspension and hybrid femoral fixation in ACLR using hamstring autograft.

Advances in Metabolism and Metabolic Toxicology of Quinoxaline 1,4-Di-N-oxides.

Quinoxaline 1,4-di-N-Oxides (QdNOs) have been used as synthetic antimicrobial agents in animal husbandry and aquaculture. The metabolism and potential toxicity have been also concerns in recently years. The metabolism investigations showed that there were 8 metabolites of Carbadox (CBX), 34 metabolites of Cyadox (CYA), 33 metabolites of Mequindox (MEQ), 35 metabolites of Olaquindox (OLA), and 56 metabolites of Quinocetone (QCT) in different animals. Among them, Cb3 and Cb8, M6, and O9 are metabolic residual markers of CBX, MEQ and OLA, which are associated with N → O reduction. Toxicity studies revealed that QdNOs exhibited severe tumorigenicity, cytotoxicity, and adrenal toxicity. Metabolic toxicology showed that toxicity of QdNOs metabolites might be related to the N → O group reduction, and some metabolites exhibited higher toxic effects than the precursor, which could provide guidance for further research on the metabolic toxicology of QdNOs and provide a wealth of information for food safety evaluation.

Suitable Isolation Side Chains: A Simple Strategy for Simultaneously Improving the Phototherapy Efficacy and Biodegradation Capacities of Conjugated Polymer Nanoparticles.

Utilizing one molecule to realize combinational photodynamic and photothermal therapy upon single-wavelength laser excitation, which relies on a multifunctional phototherapy agent, is one of the most cutting-edge research directions in tumor therapy owing to the high efficacy achieved over a short course of treatment. Herein, a simple strategy of "suitable isolation side chains" is proposed to collectively improve the fluorescence intensity, reactive oxygen species production, photothermal conversion efficiency, and biodegradation capacity. Both in vitro and in vivo results reveal the practical value and huge potential of the designed biodegradable conjugated polymer PTD-C16 with suitable isolation side chains in fluorescence image-guided combinational photodynamic and photothermal therapy. These improvements are achieved through manipulation of aggregated states by only side chain modification without changing any conjugated structure, providing new insight into the design of biodegradable high-performance phototherapy agents.

Sustained AhR activity programs memory fate of early effector CD8+ T cells.

Identification of mechanisms that program early effector T cells to either terminal effector T (Teff) or memory T (Tm) cells has important implications for protective immunity against infections and cancers. Here, we show that the cytosolic transcription factor aryl hydrocarbon receptor (AhR) is used by early Teff cells to program memory fate. Upon antigen engagement, AhR is rapidly up-regulated via reactive oxygen species signaling in early CD8+ Teff cells, which does not affect the effector response, but is required for memory formation. Mechanistically, activated CD8+ T cells up-regulate HIF-1α to compete with AhR for HIF-1ß, leading to the loss of AhR activity in HIF-1αhigh short-lived effector cells, but sustained in HIF-1αlow memory precursor effector cells (MPECs) with the help of autocrine IL-2. AhR then licenses CD8+ MPECs in a quiescent state for memory formation. These findings partially resolve the long-standing issue of how Teff cells are regulated to differentiate into memory cells.

Amide Proton Transfer-Weighted MRI, Associations with Clinical Severity and Prognosis in Ischemic Strokes.

BACKGROUND: The National Institutes of Health Stroke Scale (NIHSS) and the modified Rankin scale (mRS) scores have important shortcomings. Amide proton transfer-weighted (APTw) imaging might offer more valuable information in ischemic strokes assessment. PURPOSE: To utilize APTw, apparent diffusion coefficient (ADC), and computed tomography perfusion (CTP) for the assessment of clinical symptom severity and 90-day prognosis in patients diagnosed with ischemic stroke. STUDY TYPE: Prospective. SUBJECTS: 61 patients (mean age 63.2 ± 9.7 years; 46 males, 15 females) with ischemic strokes were included in the study. FIELD STRENGTH/SEQUENCE: 3T/turbo spin echo (TSE) T1 -weighted imaging, T2 -weighted imaging, T2 -fluid attenuated inversion recovery (T2 -FLAIR), diffusion-weighted imaging (DWI), and single-shot TSE APTw imaging. ASSESSMENT: APTw, ADC, and CTP were used to compare patient subgroups and construct a prognostic nomogram model. STATISTICAL TESTS: Kolmogorov-Smirnov test, t-test, Mann-Whitney U test, chi-square test, Pearson correlation analysis, multivariate logistic regression analysis, decision curve analysis (DCA), receiver operating characteristic curves (ROCs). The significance threshold was set at P < 0.05. RESULTS: Correlation analysis revealed that APTw and NIHSS exhibit the highest correlation (r = -0.634, 95% confidence interval [CI] -0.418 to -0.782), surpassing that of ADC and lesion size. Multivariable analysis revealed APTw (odds ratio [OR] 0.905, 95% CI 0.845-0.970), ADC (OR 0.745, 95% CI 0.609-0.911), and infarct core-cerebral blood volume (IC-CBV) (OR 0.547, 95% CI 0.310-0.964) as potential risk factors associated with a poor prognosis. The nomogram model demonstrated the highest predictive efficacy, with an area under the curve (AUC) of 0.960 (95% CI 0.911-0.988), exceeding that of APTw, ADC, and IC-CBV individually. DATA CONCLUSION: The APTw technique holds potential value in categorizing and managing patients with ischemic stroke, offering guidance for the implementation of clinical treatment strategies. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 2.

Correlation of GABA+ levels in the medial prefrontal cortex and circulating follicular helper T cells in neuromyelitis optica spectrum disorder patients with cognitive impairment.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) associated with cognitive impairment (CI) is acknowledged. However, the underlying pathogenesis and involvement of the immune system remain unclear. OBJECTIVES: This study aimed to investigate the alterations in immune cells, cytokines, and GABA+ levels in NMOSD patients with cognitive deficits. METHODS: Thirty-eight NMOSD patients and 38 healthy controls (HCs) were included. NMOSD patients were stratified as NMOSD-CI and NMOSD-CP groups. The difference in cognitive functions, Tfh and cytokines, and GABA+ levels were assessed, and their correlations were calculated. RESULTS: NMOSD-CI patients showed worse performance on all cognitive tests, and the percentage of circulating follicular helper T cells (cTfh) was significantly elevated. The frequency of cTfh was positively and negatively correlated with Stroop-A and AVLT long-delayed scores, respectively. IL-21 was remarkably higher in NMOSD-CI and NMOSD-CP. The level of GABA+ in medial prefrontal cortex (mPFC) was significantly decreased in NMOSD-CI and was proved positively and negatively correlated with Symbol Digit Modalities Test and the frequency of circulating Tfh cells, respectively. CONCLUSION: In NMOSD-CI patients, all cognitive domains were impacted, , while GABA+ levels in mPFC were decreased. GABA+ levels in NMOSD-CI were negatively correlated with the frequency of cTfh, suggesting the underlying coupling mechanism between immune responses and neurotransmitter metabolism in CI in NMOSD patients.

A biodegradable semiconducting polymer phototherapeutic agent for safe cancer phototherapy.

Combined photodynamic therapy (PDT) and photothermal therapy (PTT) not only effectively reduce the hypoxic resistance to PDT, but also overcome the heat shock effect to PTT. However, the residual phototherapeutic agents still produce reactive oxygen species (ROS) to damage normal tissue under sunlight after treatment, which induces undesirable side effects to limit their biomedical application. Herein, a facile strategy is proposed to construct a biodegradable semiconducting polymer p-DTT, which is constructed by thieno[3,2-b]thiophene modified diketopyrrolopyrrole and (E)-1,2-bis(5-(trimethylstannyl)thiophen-2-yl)ethene moieties, to avoid the post-treatment side effects of phototherapy. Additionally, p-DTT exhibits strong photoacoustic (PA) for imaging, as well as good ROS production capacity and high photothermal conversion efficiency for synergistic PDT and PTT, which has been confirmed by both in vitro and in vivo results. After phototherapy, p-DTT could be gradually oxidized and degraded by endogenous ClO-, and subsequently lose ROS production and photothermal conversion capacities, which can guarantee the post-treatment safety, and address above key limitation of traditional phototherapy.

A multi-subsystem collaborative Bi-LSTM-based adaptive soft sensor for global prediction of ammonia-nitrogen concentration in wastewater treatment processes.

Ammonia-nitrogen concentration is a key water quality indicator, which reflects changes in pollutant components during wastewater treatment processes. The timely and accurate detection results contribute to optimizing control and operational management of wastewater treatment plants (WWTPs), but current detection methods only focus on the effluent location. This paper proposes a multi-subsystem collaborative Bi-LSTM-based adaptive soft sensor to achieve the global prediction of ammonia-nitrogen concentration. Firstly, the wastewater treatment process is divided into several independent subsystems depending on the reaction mechanism, and the variable selection is performed using mutual information. Subsequently, the bidirectional long short-term memory network (Bi-LSTM) is employed to construct a model for predicting ammonia-nitrogen concentration within each subsystem, and the outputs between neighboring subsystems are incorporated as a set of new variables added into the training dataset to strengthen their connection. Finally, to address performance degradation caused by environmental factors, a probability density function (PDF)-based dynamic moving window method is proposed to enhance the robustness. The effectiveness and superiority of the proposed soft sensor are validated in the Benchmark Simulation Model no. 1 (BSM1). The experimental results demonstrate that the proposed soft sensor can accurately predict the global ammonia-nitrogen concentration in the face of different weather conditions including sunny, rainy, and stormy days. This study contributes to the stable operation of WWTPs with higher treatment efficiency and lower economic costs.

Neurometabolic and Brain Functional Alterations Associated with Cognitive Impairment in Patients with Myasthenia Gravis: A Combined 1H-MRS and fMRI Study.

Whether patients with myasthenia gravis (MG) exhibit cognitive impairment is controversial. Also the underlying mechanisms are unknown. We aimed to investigate alterations in cognitive function, neurometabolite levels, and brain function in patients with MG and to explore the associations between abnormal regional brain functional activity, neurometabolite concentrations in the MPFC and left thalamus, and cognitive activity in patients with MG. Neuropsychological tests, proton magnetic resonance spectroscopy, and resting-state functional magnetic resonance imaging were performed on 41 patients with MG and 45 race-, sex-, age-, and education-matched healthy controls (HCs). The results suggest that MG is accompanied by cognitive decline, as indicated by global cognitive function, visual-spatial function, language, memory, abnormalities in regional brain functional activity, and neurometabolite alterations (including GABA, NAA, and Cho) in the medial prefrontal cortex (MPFC) and left thalamus. Cognitive impairment in patients with MG may be related to abnormal regional brain functional activity and changes in neurometabolites, and regional brain functional activity may be modulated by specific neurometabolites.

Video-assisted thoracoscopic surgery for non-cystic fibrosis bronchiectasis in children.

BACKGROUND: Pediatric bronchiectasis is a common respiratory disease in children. The use of video-assisted thoracoscopic surgery (VATS) for its treatment remains controversial. OBJECTIVES: The objective of our study was to compare and analyze the clinical efficacy of thoracoscopic surgery and thoracotomy in the treatment of pediatric bronchiectasis and summarize the surgical treatment experience of VATS in children with bronchiectasis. DESIGN: Retrospective single-center cohort study. METHODS: A retrospective analysis was conducted on the clinical data of 46 pediatric patients who underwent surgery with bronchiectasis at the Children's Hospital of Chongqing Medical University from May 2015 to May 2023. The patients were divided into two groups: the VATS group (25 cases) and the thoracotomy group (21 cases). Comparative analysis was performed on various parameters including basic clinical data, surgical methods, operation time, intraoperative blood loss, transfusion status, postoperative pain, postoperative mechanical ventilation time, chest tube drainage time, length of hospital stay, incidence of complications, and follow-up information. RESULTS: There were no statistically significant differences between the two groups of patients in terms of age, weight, gender, etiology, duration of symptoms, site of onset, and comorbidities (p > 0.05). The operation time in the VATS group was longer than that in the thoracotomy group (p < 0.001). However, the VATS group had better outcomes in terms of intraoperative blood loss, transfusion status, postoperative pain, postoperative mechanical ventilation time, chest tube drainage time, and length of hospital stay (p < 0.05). The incidence of postoperative complications in the VATS group was lower than that in the thoracotomy group, although the difference was not statistically significant (p = 0.152). Follow-up data showed no statistically significant difference in the surgical treatment outcomes between the two groups (p = 0.493). CONCLUSION: The incidence of complications and mortality in surgical treatment of bronchiectasis is acceptable. Compared with thoracotomy surgery, VATS has advantages such as smaller trauma, less pain, faster recovery, and fewer complications. For suitable pediatric patients with bronchiectasis, VATS is a safe and effective surgical method.

The value of preoperative diagnosis of colorectal adenocarcinoma pathological T staging based on dual-layer spectral-detector computed tomography extracellular volume fraction: a preliminary study.

PURPOSE: To investigate the value of preoperative diagnosis of colorectal adenocarcinoma (CRAC) pathological T staging based on dual-layer spectral-detector computed tomography (DLCT) extracellular volume fraction (ECV) of CRAC lesions. METHODS: We prospectively collected clinical and DLCT imaging data from 165 patients with CRAC who attended two hospitals from June 2022 to April 2023. The enrolled patients were divided into a training group (n = 110, from Hospital 1) and an external validation group (n = 55, from Hospital 2). Measuring and calculating DLCT parameters of lesions, including CT values of 40 and 100 keV virtual mono-energetic images (VMI), iodine concentration (IC) and effective atomic number (Eff-Z) in the arterial phases (AP) and venous phases (VP), and ECV in the delayed phase (DP). The differences in clinical characteristics and DLCT parameters were compared between different pT subgroups. The correlation between DLCT parameters and pT stages were evaluated by Spearman correlation analysis. A multifactorial binary logistic stepwise forward regression analysis was performed to obtain independent influences associated with pT stage. Receiver operating characteristic curves (ROCs) were used to assess diagnostic efficacy and were expressed as area under the curve (AUC). RESULTS: Each DLCT parameter was higher in pT3 stage tumors than in pT1-2 stage tumors (all P < 0.05). The highest correlation was found between ECV and pT stage (r = 0.637). ECV were independent influences associated with pT stage. ECV had excellent diagnostic efficacy for CRAC pT staging in both the training and external validation groups (AUC = 0.919 and 0.892). CONCLUSION: ECV based on DLCT measurement can be used for preoperative noninvasive diagnosis of CRAC pT staging with excellent diagnostic efficacy. It can provide a new imaging marker for the preoperative evaluation of CRAC and help clinicians formulate individualized treatment earlier. However, it needs to be confirmed with a larger sample size.

Multi-DNA-Modified Double-Network Hydrogel with Customized Microstructure: A Novel System for Living Circulating Tumor Cells Capture and Real-Time Detection.

The precise and effective isolation of living circulating tumor cells (CTCs) from peripheral blood, followed by their real-time monitoring, is crucial for diagnosing cancer patients. In this study, a cell-imprinted double-network (DN) hydrogel modified with circular multi-DNA (CMD), coined the CMD-imprinted hydrogel with fixed cells as templates (CMD-CIDH), was developed. The hydrogel featured a customized surface for proficient capture of viable CTCs and in situ real-time fluorescent detection without subsequent release. The customized surface, constructed using polyacrylamide/chitosan DN hydrogel as the matrix on the cell template, had a dense network structure, thereby ensuring excellent stability and a low degradation rate. Optimal capture efficiencies, recorded at 93 ± 3% for MCF-7 cells and 90 ± 2% for Hela cells, were achieved by grafting the CMD and adjusting the nodule size on the customized surface. The capture efficiency remained significantly high at 67 ± 11% in simulated breast cancer patient experiments even at a minimal concentration of 5 cells mL-1. Furthermore, CMD grafted onto the surface produced a potent fluorescence signature, enabling in situ real-time fluorescent detection of the target cell's growth state even in complex environments. The customized surface is highly efficient for screening CTCs in peripheral blood and has promising potential for setting up the CTCs culture.

Nav1.7 as a chondrocyte regulator and therapeutic target for osteoarthritis.

Osteoarthritis (OA) is the most common joint disease. Currently there are no effective methods that simultaneously prevent joint degeneration and reduce pain1. Although limited evidence suggests the existence of voltage-gated sodium channels (VGSCs) in chondrocytes2, their expression and function in chondrocytes and in OA remain essentially unknown. Here we identify Nav1.7 as an OA-associated VGSC and demonstrate that human OA chondrocytes express functional Nav1.7 channels, with a density of 0.1 to 0.15 channels per µm2 and 350 to 525 channels per cell. Serial genetic ablation of Nav1.7 in multiple mouse models demonstrates that Nav1.7 expressed in dorsal root ganglia neurons is involved in pain, whereas Nav1.7 in chondrocytes regulates OA progression. Pharmacological blockade of Nav1.7 with selective or clinically used pan-Nav channel blockers significantly ameliorates the progression of structural joint damage, and reduces OA pain behaviour. Mechanistically, Nav1.7 blockers regulate intracellular Ca2+ signalling and the chondrocyte secretome, which in turn affects chondrocyte biology and OA progression. Identification of Nav1.7 as a novel chondrocyte-expressed, OA-associated channel uncovers a dual target for the development of disease-modifying and non-opioid pain relief treatment for OA.

Lithium carbonate revitalizes tumor-reactive CD8+ T cells by shunting lactic acid into mitochondria.

The steady flow of lactic acid (LA) from tumor cells to the extracellular space via the monocarboxylate transporter symport system suppresses antitumor T cell immunity. However, LA is a natural energy metabolite that can be oxidized in the mitochondria and could potentially stimulate T cells. Here we show that the lactate-lowering mood stabilizer lithium carbonate (LC) can inhibit LA-mediated CD8+ T cell immunosuppression. Cytoplasmic LA increased the pumping of protons into lysosomes. LC interfered with vacuolar ATPase to block lysosomal acidification and rescue lysosomal diacylglycerol-PKCθ signaling to facilitate monocarboxylate transporter 1 localization to mitochondrial membranes, thus transporting LA into the mitochondria as an energy source for CD8+ T cells. These findings indicate that targeting LA metabolism using LC could support cancer immunotherapy.

Relationship between C-reactive protein and antipsychotics levels in schizophrenic patients infected with COVID-19.

In the context of the COVID-19, inflammation emerges as a prominent characteristic. C-reactive protein (CRP) serves as a commonly employed marker for the evaluation of inflammation. This study aimed to examine the correlation between CRP levels and antipsychotic drug concentrations in patients diagnosed with SCZ during the COVID-19 pandemic. A total of 186 SCZ patients were included in this study, which utilized electronic medical records. The collected data encompassed SCZ diagnoses based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria, respiratory symptoms, and treatments. Laboratory assessments involved the measurement of CRP levels and monitoring of blood drug concentrations. The most prevalent symptoms observed in the patient cohort were fever (59.14%), cough (52.15%), fatigue (45.7%), sore throat (46.24%), runny nose (28.49%), and stuffy nose (25.27%). The levels of CRP during the infection period were significantly higher compared to both the prophase and anaphase of infection (all p < 0.001). The serum levels of clozapine, olanzapine, aripiprazole, quetiapine, and risperidone were elevated during the infection period (all p < 0.001). During the anaphase of infection, patients exhibited higher serum levels of clozapine, olanzapine, and risperidone (all p < 0.001) compared to the infection period, but there was no significant change in serum levels of aripiprazole and quetiapine. Multiple regression analysis revealed a statistically significant positive correlation (P < 0.0001) between CRP and clozapine concentration. In light of the COVID-19 pandemic, it is crucial to adjust the dosage based on drug serum concentration to prevent intoxication or adverse drug reactions.

The role of receptors in the cross-species spread of coronaviruses infecting humans and pigs.

The pandemic caused by SARS-CoV-2, which has proven capable of infecting over 30 animal species, highlights the critical need for understanding the mechanisms of cross-species transmission and the emergence of novel coronavirus strains. The recent discovery of CCoV-HuPn-2018, a recombinant alphacoronavirus from canines and felines that can infect humans, along with evidence of SARS-CoV-2 infection in pig cells, underscores the potential for coronaviruses to overcome species barriers. This review investigates the origins and cross-species transmission of both human and porcine coronaviruses, with a specific emphasis on the instrumental role receptors play in this process.