Adaptive evolution of antioxidase-related genes in hypoxia-tolerant mammals.

To cope with the damage from oxidative stress caused by hypoxia, mammals have evolved a series of physiological and biochemical traits, including antioxidant ability. Although numerous research studies about the mechanisms of hypoxia evolution have been reported, the molecular mechanisms of antioxidase-related genes in mammals living in different environments are yet to be completely understood. In this study, we constructed a dataset comprising 7 antioxidase-related genes (CAT, SOD1, SOD2, SOD3, GPX1, GPX2, and GPX3) from 43 mammalian species to implement evolutionary analysis. The results showed that six genes (CAT, SOD1, SOD2, SOD3, GPX1, and GPX3) have undergone divergent evolution based on the free-ratio (M1) model. Furthermore, multi-ratio model analyses uncovered the divergent evolution between hypoxic and non-hypoxic lineages, as well as various hypoxic lineages. In addition, the branch-site model identified 9 positively selected branches in 6 genes (CAT, SOD1, SOD2, SOD3, GPX2, and GPX3) that contained 35 positively selected sites, among which 31 positively selected sites were identified in hypoxia-tolerant branches, accounting for 89% of the total number of positively selected sites. Interestingly, 65 parallel/convergent sites were identified in the 7 genes. In summary, antioxidase-related genes are subjected to different selective pressures among hypoxia-tolerant species living in different habitats. This study provides a valuable insight into the molecular evolution of antioxidase-related genes in hypoxia evolution in mammals.

Results of a Pilot External Quality Assessment Scheme for Genetic Testing of Newborns with Spinal Muscular Atrophy.

BACKGROUND: This study aims to evaluate the ability of laboratories to perform spinal muscular atrophy (SMA) genetic testing in newborns based on dried blood spot (DBS) samples, and to provide reference data and advance preparation for establishing the pilot external quality assessment (EQA) scheme for SMA genetic testing of newborns in China. METHODS: The pilot EQA scheme contents and evaluation principles of this project were designed by National Center for Clinical Laboratories (NCCL), National Health Commission. Two surveys were carried out in 2022, and 5 batches of blood spots were submitted to the participating laboratory each time. All participating laboratories conducted testing upon receiving samples, and test results were submitted to NCCL within the specified date. RESULTS: The return rates were 75.0% (21/28) and 95.2% (20/21) in the first and second surveys, respectively. The total return rate of the two examinations was 83.7% (41/49). Nineteen laboratories (19/21, 90.5%) had a full score passing on the first survey, while in the second survey twenty laboratories (20/20, 100%) scored full. CONCLUSIONS: This pilot EQA survey provides a preliminary understanding of the capability of SMA genetic testing for newborns across laboratories in China. A few laboratories had technical or operational problems in testing. It is, therefore, of importance to strengthen laboratory management and to improve testing capacity for the establishment of a national EQA scheme for newborn SMA genetic testing.

A Post-Marketing Surveillance Study of Nusinersen for Spinal Muscular Atrophy in Routine Medical Practice in China: Interim Results.

INTRODUCTION: Spinal muscular atrophy (SMA) is a rare, autosomal recessive, neuromuscular disease that leads to progressive muscular weakness and atrophy. Nusinersen, an antisense oligonucleotide, was approved for SMA in China in February 2019. We report interim results from a post-marketing surveillance phase 4 study, PANDA (NCT04419233), that collects data on the safety, efficacy, and pharmacokinetics of nusinersen in children with SMA in routine clinical practice in China. METHODS: Participants enrolled in PANDA will be observed for 2 years following nusinersen treatment initiation. The primary endpoint is the incidence of adverse events (AEs)/serious AEs (SAEs) during the treatment period. Efficacy assessments include World Health Organization (WHO) Motor Milestones assessment, the Hammersmith Infant Neurological Examination (HINE), and ventilation support. Plasma and cerebrospinal fluid (CSF) concentrations of nusinersen are measured at each dose visit. RESULTS: Fifty participants were enrolled as of the January 4, 2023, data cutoff: 10 with infantile-onset (≤ 6 months) and 40 with later-onset (> 6 months) SMA. All 50 participants have received at least one dose of nusinersen; 6 have completed the study. AEs were experienced by 45 (90%) participants and were mostly mild/moderate; no AEs led to nusinersen discontinuation or study withdrawal. Eleven participants experienced SAEs, most commonly pneumonia (n = 9); none were considered related to study treatment. Stability or gain of WHO motor milestone was observed and mean HINE-2 scores improved in both subgroups throughout the study. No serious respiratory events occurred, and no permanent ventilation support was initiated during the study. Pre-dose nusinersen CSF concentrations increased steadily through the loading-dose period, with no accumulation in plasma after multiple doses. CONCLUSION: Nusinersen was generally well tolerated with an acceptable overall safety profile, consistent with the known safety of nusinersen. Efficacy, safety, and nusinersen exposure are consistent with prior observations. These results support continuing PANDA and evaluation of nusinersen in Chinese participants with SMA. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04419233.

Influence of Interlayer Cation Ordering on Na Transport in P2-Type Na0.67-xLiy Ni0.33-zMn0.67+zO2 for Sodium-Ion Batteries.

P2-type Na2/3Ni1/3Mn2/3O2 (PNNMO) has been extensively studied because of its desirable electrochemical properties as a positive electrode for sodium-ion batteries. PNNMO exhibits intralayer transition-metal ordering of Ni and Mn and intralayer Na+/vacancy ordering. The Na+/vacancy ordering is often considered a major impediment to fast Na+ transport and can be affected by transition-metal ordering. We show by neutron/X-ray diffraction and density functional theory (DFT) calculations that Li doping (Na2/3Li0.05Ni1/3Mn2/3O2, LFN5) promotes ABC-type interplanar Ni/Mn ordering without disrupting the Na+/vacancy ordering and creates low-energy Li-Mn-coordinated diffusion pathways. A structure model is developed to quantitatively identify both the intralayer cation mixing and interlayer cationic stacking fault densities. Quasielastic neutron scattering reveals that the Na+ diffusivity in LFN5 is enhanced by an order of magnitude over PNNMO, increasing its capacity at a high current. Na2/3Ni1/4Mn3/4O2 (NM13) lacks Na+/vacancy ordering but has diffusivity comparable to that of LFN5. However, NM13 has the smallest capacity at a high current. The high site energy of Mn-Mn-coordinated Na compared to that of Ni-Mn and higher density of Mn-Mn-coordinated Na+ sites in NM13 disrupts the connectivity of low-energy Ni-Mn-coordinated diffusion pathways. These results suggest that the interlayer ordering can be tuned through the control of composition, which has an equal or greater impact on Na+ diffusion than the Na+/vacancy ordering.

Decreased HMGCS1 inhibits proliferation and inflammatory response of keratinocytes and ameliorates imiquimod-induced psoriasis via the STAT3/IL-23 axis.

Psoriasis is an immuno-inflammatory disease characterized by excessive keratinocyte proliferation, requiring extensive lipids. 3-hydroxy-3-methylglutaryl-coenzyme A synthase 1 (HMGCS1) is an essential enzyme in the mevalonate pathway, involved in cholesterol synthesis and the inflammatory response. However, the role of HMGCS1 in psoriasis has remained elusive. This study aims to elucidate the mechanism by which HMGCS1 controls psoriasiform inflammation. We discovered an increased abundance of HMGCS1 in psoriatic lesions when analyzing two Gene Expression Omnibus (GEO) datasets and confirmed this in psoriatic animal models and psoriatic patients by immunohistochemistry. In a TNF-α stimulated psoriatic HaCaT cell line, HMGCS1 was found to be overexpressed. Knockdown of HMGCS1 using siRNA suppressed the migration and proliferation of HaCaT cells. Mechanistically, HMGCS1 downregulation also reduced the expression of IL-23 and the STAT3 phosphorylation level. In imiquimod-induced psoriatic mice, intradermal injection of HMGCS1 siRNA significantly decreased the expression of HMGCS1 in the epidermis, which in turn led to an improvement in the Psoriasis Area and Severity Index score, epidermal thickening, and pathological Baker score. Additionally, expression levels of inflammatory cytokines IL-23, IL1-ß, chemokine CXCL1, and innate immune mediator S100A7-9 were downregulated in the epidermis. In conclusion, HMGCS1 downregulation improved psoriasis in vitro and in vivo through the STAT3/IL-23 axis.

Enterococcus durans 98D alters gut microbial composition and function to improve DSS-induced colitis in mice.

Enterococcus durans, is a potential functional strain with the capacity to regulate intestinal health and ameliorate colonic inflammation. However, the strain requires further investigation regarding its safety profile and potential mechanisms of colitis improvement. In this study, the safety of E. durans 98D (Ed) as a potential probiotic was studied using in vitro methods. Additionally, a dextran sulfate sodium (DSS)-induced murine colitis model was employed to investigate its impact on the intestinal microbiota and colitis. In vitro antimicrobial assays revealed Ed sensitivity to common antibiotics and its inhibitory effect on the growth of Escherichia coli O157, Streptococcus pneumoniae CCUG 37328, and Staphylococcus aureus ATCC 25923. To elucidate the functional properties of Ed, 24 weight-matched 6-week-old female C57BL/6J mice were randomly divided into three groups (n = 8): NC group, Con group (DSS), and Ed group (DSS + Ed). Ed administration demonstrated a protective effect on colitis mice, as evidenced by improvements in body weight, colonic length, reduced disease activity index, histological scores, diminished splenomegaly, and decreased goblet cell loss. Furthermore, Ed downregulated the expression of the pro-inflammatory cytokine genes (IL-6, IL-1ß, and TNF-α) and upregulated the expression of the anti-inflammatory cytokine gene IL-10. The 16S rRNA gene sequencing revealed significant alterations in microbial α-diversity, with principal coordinate analysis indicating distinct differences in microbial composition among the three groups. At the phylum level, the relative abundance of Actinomycetota significantly increased in the Ed-treated group. At the genus level, Ed treatment markedly elevated the relative abundance of Paraprevotella, Rikenellaceae_RC9, and Odoribacter in DSS-induced colitis mice. In conclusion, Ed exhibits potential as a safe and effective therapeutic agent for DSS-induced colitis by reshaping the colonic microbiota.

Macaque Brainnetome Atlas: A multifaceted brain map with parcellation, connection, and histology.

The rhesus macaque (Macaca mulatta) is a crucial experimental animal that shares many genetic, brain organizational, and behavioral characteristics with humans. A macaque brain atlas is fundamental to biomedical and evolutionary research. However, even though connectivity is vital for understanding brain functions, a connectivity-based whole-brain atlas of the macaque has not previously been made. In this study, we created a new whole-brain map, the Macaque Brainnetome Atlas (MacBNA), based on the anatomical connectivity profiles provided by high angular and spatial resolution ex vivo diffusion MRI data. The new atlas consists of 248 cortical and 56 subcortical regions as well as their structural and functional connections. The parcellation and the diffusion-based tractography were evaluated with invasive neuronal-tracing and Nissl-stained images. As a demonstrative application, the structural connectivity divergence between macaque and human brains was mapped using the Brainnetome atlases of those two species to uncover the genetic underpinnings of the evolutionary changes in brain structure. The resulting resource includes: (1) the thoroughly delineated Macaque Brainnetome Atlas (MacBNA), (2) regional connectivity profiles, (3) the postmortem high-resolution macaque diffusion and T2-weighted MRI dataset (Brainnetome-8), and (4) multi-contrast MRI, neuronal-tracing, and histological images collected from a single macaque. MacBNA can serve as a common reference frame for mapping multifaceted features across modalities and spatial scales and for integrative investigation and characterization of brain organization and function. Therefore, it will enrich the collaborative resource platform for nonhuman primates and facilitate translational and comparative neuroscience research.

Inhibition of vascular calcification by Compound Danshen Dripping Pill through multiple mechanisms.

BACKGROUND: Vascular calcification refers to the abnormal accumulation of calcium in the walls of blood vessels and is a risk factor often overlooked in cardiovascular disease. However, there is currently no specific drug for treating vascular calcification. Compound Danshen Dripping Pill (CDDP) is widely used to treat cardiovascular diseases, but its effect on vascular calcification has not been reported. PURPOSE: We investigated the effects of CDDP on vascular calcification in ApoE-/- mice and in vitro and elucidated its mechanism of action. STUDY DESIGN: Firstly, we found that CDDP has the potential to improve calcification based on network pharmacology analysis. Then, we performed the following experiments: in vivo, ApoE-/- mice were fed a high-fat diet randomly supplemented with CDDP for 16 weeks. Atherosclerosis and vascular calcification were determined. In vitro, human aortic smooth muscle cells (HASMCs), human umbilical vein endothelial cells (HUVECs), and human aortic endothelial cells (HAECs) were used to determine the mechanisms for CDDP-inhibited vascular calcification. RESULTS: In this study, we observed that CDDP reduced intimal calcification in atherosclerotic lesions of ApoE-deficient mice fed a high-fat diet, as well as the calcification in cultured SMCs and ECs. Mechanistically, CDDP inhibited the Wnt/ß-catenin pathway by up-regulating the expression of DKK1 and LRP6, which are upstream inhibitors of Wnt, leading to a reduction in the expression of osteoblastic transition markers (ALP, OPN, BMP2, and RUNX2). Furthermore, CDDP enhanced the secretion of DKK1, which plays a role in mediating EC-SMC crosstalk in calcification. Additionally, VC contributes to vascular aging by inhibiting Sirt1 and increasing senescence parameters (SA-ß-gal, p21, and p16). However, CDDP reversed these changes by activating Sirt1. CDDP also reduced the levels of pro-inflammatory cytokines and the senescence-associated secretory phenotype in vivo and in vitro. CONCLUSIONS: Our study suggests that CDDP reduces vascular calcification by regulating the DKK1/LRP6/ß-catenin signaling pathway in ECs/SMCs and interactions with the crosstalk of ECs and SMCs. It also reduces the senescence of ECs/SMCs, contributing to the Sirt1 activation, indicating CDDP's novel role in ameliorating vascular calcification.

A LATS2 and ALKBH5 positive feedback loop supports their oncogenic roles.

N(6)-methyladenosine (m6A) critically regulates RNA dynamics in various biological processes. The m6A demethylase ALKBH5 promotes tumorigenesis of glioblastoma, while the intricate web that orchestrates its regulation remains enigmatic. Here, we discover that cell density affects ALKBH5 subcellular localization and m6A dynamics. Mechanistically, ALKBH5 is phosphorylated by the large tumor suppressor kinase 2 (LATS2), preventing its nuclear export and enhancing protein stability. Furthermore, phosphorylated ALKBH5 reciprocally erases m6A from LATS2 mRNA, thereby stabilizing this transcript. Unexpectedly, LATS2 depletion suppresses glioblastoma stem cell self-renewal independent of yes-associated protein activation. Additionally, deficiency in either LATS2 or ALKBH5 phosphorylation impedes tumor progression in mouse xenograft models. Moreover, high levels of LATS2 expression and ALKBH5 phosphorylation are associated with tumor malignancy in patients with gliomas. Collectively, our study unveils an oncogenic positive feedback loop between LATS2 and ALKBH5, revealing a non-canonical branch of the Hippo pathway for RNA processing and suggesting potential anti-cancer interventions.

Research hotspots and trend of wrist arthroscopy: A bibliometrics analysis from 2013 to 2023.

BACKGROUND: Wrist arthroscopy technology is a surgical technology invented in recent years and widely used in clinical treatment of various wrist diseases. This study uses the methods of bibliometrics and visual analysis to understand the global research status, research hotspots, and future development trends of wrist arthroscopy. METHODS: The relevant literature of global publications on wrist arthroscopy from 2013 to 2023 was extracted from the Web of Science Core Collection database, and the annual output, cooperation, hot spots, research status, and development trend of this field were analyzed by using the bibliometric software (VOSviewers, CiteSpace, and the R package "Bibliometrix"). RESULTS: A total of 635 articles were included, from 2013 to 2023, the number of publications related to wrist arthroscopy showed an overall upward trend, the USA, France, and China are the top 3 countries in terms of the number of publications, whereas Mayo Clinic is the institution with the highest number of publications, Ho PC holds a core position in this field, keyword analysis indicates that the research hotspots are the applications of wrist arthroscopy in triangular fibrocartilage complex injuries, scaphoid nonunion, and avascular necrosis of the lunate. CONCLUSION SUBSECTIONS: Wrist arthroscopy has shown tremendous potential in treating various wrist diseases. However, there are still some challenges in its research domain. With continuous deep research, strengthened international collaboration, and ongoing technological advancements, wrist arthroscopy has the potential to become the standard treatment in hand surgery, offering more efficient and safer treatment options for patients worldwide.

Added Value of Frequency of Imaging Markers for Prediction of Outcome After Intracerebral Hemorrhage: A Secondary Analysis of Existing Data.

BACKGROUND: Frequency of imaging markers (FIM) has been identified as an independent predictor of hematoma expansion in patients with intracerebral hemorrhage (ICH), but its impact on clinical outcome of ICH is yet to be determined. The aim of the present study was to investigate this association. METHODS: This study was a secondary analysis of our prior research. The data for this study were derived from six retrospective cohorts of ICH from January 2018 to August 2022. All consecutive study participants were examined within 6 h of stroke onset on neuroimaging. FIM was defined as the ratio of the number of imaging markers on noncontrast head tomography (i.e., hypodensities, blend sign, and island sign) to onset-to-neuroimaging time. The primary poor outcome was defined as a modified Rankin Scale score of 3-6 at 3 months. RESULTS: A total of 1253 patients with ICH were included for final analysis. Among those with available follow-up results, 713 (56.90%) exhibited a poor neurologic outcome at 3 months. In a univariate analysis, FIM was associated with poor prognosis (odds ratio 4.36; 95% confidence interval 3.31-5.74; p < 0.001). After adjustment for age, Glasgow Coma Scale score, systolic blood pressure, hematoma volume, and intraventricular hemorrhage, FIM was still an independent predictor of worse prognosis (odds ratio 3.26; 95% confidence interval 2.37-4.48; p < 0.001). Based on receiver operating characteristic curve analysis, a cutoff value of 0.28 for FIM was associated with 0.69 sensitivity, 0.66 specificity, 0.73 positive predictive value, 0.62 negative predictive value, and 0.71 area under the curve for the diagnosis of poor outcome. CONCLUSIONS: The metric of FIM is associated with 3-month poor outcome after ICH. The novel indicator that helps identify patients who are likely within the 6-h time window at risk for worse outcome would be a valuable addition to the clinical management of ICH.

Biosafe cerium oxide nanozymes protect human pluripotent stem cells and cardiomyocytes from oxidative stress.

BACKGROUND: Cardiovascular diseases (CVDs) have the highest mortality worldwide. Human pluripotent stem cells (hPSCs) and their cardiomyocyte derivatives (hPSC-CMs) offer a valuable resource for disease modeling, pharmacological screening, and regenerative therapy. While most CVDs are linked to significant over-production of reactive oxygen species (ROS), the effects of current antioxidants targeting excessive ROS are limited. Nanotechnology is a powerful tool to develop antioxidants with improved selectivity, solubility, and bioavailability to prevent or treat various diseases related to oxidative stress. Cerium oxide nanozymes (CeONZs) can effectively scavenge excessive ROS by mimicking the activity of endogenous antioxidant enzymes. This study aimed to assess the nanotoxicity of CeONZs and their potential antioxidant benefits in stressed human embryonic stem cells (hESCs) and their derived cardiomyocytes (hESC-CMs). RESULTS: CeONZs demonstrated reliable nanosafety and biocompatibility in hESCs and hESC-CMs within a broad range of concentrations. CeONZs exhibited protective effects on the cell viability of hESCs and hESC-CMs by alleviating excessive ROS-induced oxidative stress. Moreover, CeONZs protected hESC-CMs from doxorubicin (DOX)-induced cardiotoxicity and partially ameliorated the insults from DOX in neonatal rat cardiomyocytes (NRCMs). Furthermore, during hESCs culture, CeONZs were found to reduce ROS, decrease apoptosis, and enhance cell survival without affecting their self-renewal and differentiation potential. CONCLUSIONS: CeONZs displayed good safety and biocompatibility, as well as enhanced the cell viability of hESCs and hESC-CMs by shielding them from oxidative damage. These promising results suggest that CeONZs may be crucial, as a safe nanoantioxidant, to potentially improve the therapeutic efficacy of CVDs and be incorporated into regenerative medicine.

Clinical features and genetic spectrum of a multicenter Chinese cohort with myotonic dystrophy type 1.

BACKGROUND: As the most common subtype of adult muscular dystrophy worldwide, large cohort reports on myotonic dystrophy type I (DM1) in China are still lacking. This study aims to analyze the genetic and clinical characteristics of Chinese Han DM1 patients. METHODS: Based on the multicenter collaborating effort of the Pan-Yangtze River Delta Alliance for Neuromuscular Disorders, patients with suspected clinical diagnoses of DM1 were genetically confirmed from January 2020 to April 2023. Peak CTG repeats in the DMPK gene were analyzed using triplet repeat-primed PCR (TP-PCR) and flanking PCR. Time-to-event analysis of onset age in females and males was performed. Additionally, detailed clinical features and longitudinal changes from the disease onset in 64 DM1 patients were retrospectively collected and analyzed. The Epworth Sleepiness Scale and Fatigue Severity Scale were used to quantify the severity of daytime sleepiness and fatigue. RESULTS: Among the 211 genetically confirmed DM1 patients, the mean age at diagnosis was 40.9 ± 12.2 (range: 12-74) with a male-to-female ratio of 124:87. The average size of CTG repeats was 511.3 (range: 92-1945). Among the DM1 patients with comprehensive clinical data (n = 64, mean age 41.0 ± 12.0), the age at onset was significantly earlier in males than in females (4.8 years earlier, p = 0.026). Muscle weakness (92.2%), myotonia (85.9%), and fatigue (73.4%) were the most prevalent clinical features. The predominant involved muscles at onset are hands (weakness or myotonia) (52.6%) and legs (walking disability) (42.1%). Of them, 70.3% of patients had daytime sleepiness, 14.1% had cataract surgery, 7.8% used wheelchairs, 4.7% required ventilatory support, and 1.6% required gastric tubes. Regarding the comorbidities, 4.7% of patients had tumors, 17.2% had diabetes, 23.4% had dyspnea, 28.1% had intermittent insomnia, 43.8% experienced dysphagia, and 25% exhibited cognitive impairment. Chinese patients exhibited smaller size of CTG repeats (468 ± 139) than those reported in Italy (613 ± 623), the US (629 ± 386), and Japan (625 [302, 1047]), and milder phenotypes with less multisystem involvement. CONCLUSION: The Chinese Han DM1 patients presented milder phenotypes compared to their Caucasian and Japanese counterparts. A male predominance and an early age of onset were identified in male Chinese Han DM1 patients.

Emerging lead-free all inorganic perovskite single crystals K7Bi3X16 (X = Cl, Br) toward photodetector application.

Lead-free inorganic perovskites have attracted intensive attention in the field of photodetectors owing to their high stability, non-toxicity, and remarkable photoelectric characteristics. Herein, we designed and developed a series of thus-far unreported lead-free all inorganic perovskite single crystals, K7Bi3X16 (X = Cl, Br). In particular, we resorted to cooling crystallization and intercalated K+ to inorganic Bi-Br and Bi-Cl frameworks as inorganic A-site cations, obtaining zero-dimensional (0D) K7Bi3X16 (X = Cl, Br) perovskite single crystals, which display suitable bandgaps, excellent electron mobility and low trap-state density, as analysed by experimental characterization and density functional theory (DFT) calculations. Accordingly, the vertical structure K7Bi3Br16 photodetector can achieve a fast ON/OFF switch under the irradiation of 395 nm light. When the light intensity is 5 mW cm-2 and the voltage is 3 V, the responsivity is calculated to be 0.052 mA W-1. The above characteristics make K7Bi3Br16 a promising material for fabricating ultraviolet photodetectors.

Glycolysis-non-canonical glutamine dual-metabolism regulation nanodrug enhanced the phototherapy effect for pancreatic ductal adenocarcinoma treatment.

Clinical pancreatic ductal adenocarcinoma (PDAC) treatment is severely limited by lack of effective KRAS suppression strategies. To address this dilemma, a reactive oxygen species (ROS)-responsive and PDAC-targeted nanodrug named Z/B-PLS was constructed to confront KRAS through dual-blockade of its downstream PI3K/AKT/mTOR and RAF/MEK/ERK for enhanced PDAC treatment. Specifically, photosensitizer zinc phthalocyanine (ZnPc) and PI3K/mTOR inhibitor BEZ235 (BEZ) were co-loaded into PLS which was constructed by click chemistry conjugating MEK inhibitor selumetinib (SEL) to low molecular weight heparin with ROS-responsive oxalate bond. The BEZ and SEL blocked PI3K/AKT/mTOR and RAF/MEK/ERK respectively to remodel glycolysis and non-canonical glutamine metabolism. ZnPc mediated photodynamic therapy (PDT) could enhance drug release through ROS generation, further facilitating KRAS downstream dual-blockade to create treatment-promoting drug delivery-therapeutic positive feedback. Benefiting from this broad metabolic modulation cascade, the metabolic symbiosis between normoxic and hypoxic tumor cells was also cut off simultaneously and effective tumor vascular normalization effects could be achieved. As a result, PDT was dramatically promoted through glycolysis-non-canonical glutamine dual-metabolism regulation, achieving complete elimination of tumors in vivo. Above all, this study achieved effective multidimensional metabolic modulation based on integrated smart nanodrug delivery, helping overcome the therapeutic challenges posed by KRAS mutations of PDAC.

A multi-scale attention residual-based U-Net network for stroke electrical impedance tomography.

Electrical impedance tomography (EIT), a non-invasive, radiation-free, and convenient imaging technique, has been widely used in the diagnosis of stroke. However, due to soft-field nonlinearity and the ill-posed inverse problem, EIT images always suffer from low spatial resolution. Therefore, a multi-scale convolutional attention residual-based U-Net (MARU-Net) network is proposed for stroke reconstruction. Based on the U-Net network, a residual module and a multi-scale convolutional attention module are added to the concatenation layer. The multi-scale module extracts feature information of different sizes, the attention module strengthens the useful information, and the residual module improves the performance of the network. Based on the above advantages, the network is used in the EIT system for stroke imaging. Compared with convolutional neural networks and one-dimensional convolutional neural networks, the MARU-Net network has fewer artifacts, and the reconstructed image is clear. At the same time, the reduction of noisy artifacts in the MARU-Net network is verified. The results show that the image correlation coefficient of the reconstructed image with noise is greater than 0.87. Finally, the practicability of the network is verified by a model physics experiment.

Treatment of childhood intraneural perineurioma: A case report and literature review.

Background: Intraneural perineurioma is a rare, benign slow-growing lesion that usually involves a single main trunk nerve during childhood and young adulthood. The treatment of intraneural perineurioma is still a subject of controversy, especially in fast-growing children. To date, there was no systemic analysis of intraneural perineurioma in children. Method: A case of Intraneural perineurioma affecting the left sciatic nerve with 2 years of follow-up was presented. A systematic review was performed on literature published before June 2023, focusing on intraneural perineurioma diagnosed at no older than 18 years old. Result: A 9-year-old boy presented with progressive left foot-drop and abnormal gait for 2 years. The electromyography and magnetic resonance neurography study confirmed neuropathy involving the left sciatic nerves and its branches. Pathological investigation of the left sural nerve confirmed the diagnosis of intraneural perineurioma. The boy received physical therapy, and the disease was stable during the 2 years of follow-up. Fifty-seven childhood cases were identified in literature. Five patients with oral intraneural perineurioma underwent excision of the mass with good outcomes. In the other 52 patients with peripheral nerve involvement, 25 of them received surgical treatment, with different outcomes according to different operations. Out of 33 cases with precise lesion sizes, the length of the lesion in patients without nerve resection was significantly longer than that in patients with nerve resection (12.86 ± 7.44 cm vs 4.57 ± 4.5 cm. p < 0.05). Conclusions: Intraneural perineuriomas are rare benign tumors with slow progression. The options for surgery should be cautiously considered in childhood patients with long segmental peripheral nerve involvement.

Gut-immunity-joint axis: a new therapeutic target for gouty arthritis.

Gouty arthritis (GA) is an inflammatory disease characterized by pain. The primary goal of current treatment strategies during GA flares remains the reduction of inflammation and pain. Research suggests that the gut microbiota and microbial metabolites contribute to the modulation of the inflammatory mechanism associated with GA, particularly through their effect on macrophage polarization. The increasing understanding of the gut-joint axis emphasizes the importance of this interaction. The primary objective of this review is to summarize existing research on the gut-immune-joint axis in GA, aiming to enhance understanding of the intricate processes and pathogenic pathways associated with pain and inflammation in GA, as documented in the published literature. The refined comprehension of the gut-joint axis may potentially contribute to the future development of analgesic drugs targeting gut microbes for GA.

Detection of the DNA methylation of seven genes contribute to the early diagnosis of lung cancer.

BACKGROUND: Low-dose Computed Tomography (CT) is used for the detection of pulmonary nodules, but the ambiguous risk evaluation causes overdiagnosis. Here, we explored the significance of the DNA methylation of 7 genes including TAC1, CDO1, HOXA9, ZFP42, SOX17, RASSF1A and SHOX2 in the blood cfDNA samples in distinguishing lung cancer from benign nodules and healthy individuals. METHOD: A total of 149 lung cancer patients [72 mass and 77 ground-glass nodules (GGNs)], 5 benign and 48 healthy individuals were tested and analyzed in this study. The lasso-logistic regression model was built for distinguishing cancer and control/healthy individuals or IA lung cancer and non-IA lung cancer cases. RESULTS: The positive rates of methylation of 7 genes were higher in the cancer group as compared with the healthy group. We constructed a model using age, sex and the ΔCt value of 7 gene methylation to distinguish lung cancer from benign and healthy individuals. The sensitivity, specificity and AUC (area under the curve) were 86.7%, 81.4% and 0.891, respectively. Also, we assessed the significance of 7 gene methylation together with patients' age and sex in distinguishing of GGNs type from the mass type. The sensitivity, specificity and AUC were 77.1%, 65.8% and 0.753, respectively. Furthermore, the methylation positive rates of CDO1 and SHOX2 were different between I-IV stages of lung cancer. Specifically, the positive rate of CDO1 methylation was higher in the non-IA group as compared with the IA group. CONCLUSION: Collectively, this study reveals that the methylation of 7 genes has a big significance in the diagnosis of lung cancer with high sensitivity and specificity. Also, the 7 genes present with certain significance in distinguishing the GGN type lung cancer, as well as different stages.