A bio-orthogonal linear ubiquitin probe identifies STAT3 as a direct substrate of OTULIN in glioblastoma.

While linear ubiquitin plays critical roles in multiple cell signaling pathways, few substrates have been identified. Global profiling of linear ubiquitin substrates represents a significant challenge because of the low endogenous level of linear ubiquitination and the background interference arising from highly abundant ubiquitin linkages (e.g. K48- and K63-) and from the non-specific attachment of interfering proteins to the linear polyubiquitin chain. We developed a bio-orthogonal linear ubiquitin probe by site-specific encoding of a norbornene amino acid on ubiquitin (NAEK-Ub). This probe facilitates covalent labeling of linear ubiquitin substrates in live cells and enables selective enrichment and identification of linear ubiquitin-modified proteins. Given the fact that the frequent overexpression of the linear linkage-specific deubiquitinase OTULIN correlates with poor prognosis in glioblastoma, we demonstrated the feasibility of the NAEK-Ub strategy by identifying and validating substrates of linear ubiquitination in patient-derived glioblastoma stem-like cells (GSCs). We identified STAT3 as a bona fide substrate of linear ubiquitin, and showed that linear ubiquitination negatively regulates STAT3 activity by recruitment of the phosphatase TC-PTP to STAT3. Furthermore, we demonstrated that preferential expression of OTULIN in GSCs restricts linear ubiquitination on STAT3 and drives persistent STAT3 signaling, and thereby maintains the stemness and self-renewal of GSCs.

Apple Polyphenol Extract Suppresses Clostridioides difficile Infection in a Mouse Model.

Fruits such as apples are a dietary source of polyphenols and have health benefits. We studied the benefits of apple polyphenols in reducing intestinal infections. We explored the potential roles of apple polyphenols in combating Clostridioides difficile-induced intestinal infections by modulating the intestinal microbiota and metabolism in our study. Mice fed with apple polyphenols exhibited higher survival rates and improved diarrhea symptoms in a C. difficile infection mouse model given once-daily apple polyphenol extract (200 or 400 mg/kg bw) or phosphate-buffered saline. Feeding polyphenols enhanced anti-inflammatory effects and colon barrier integrity. In addition, apple polyphenols mitigated intestinal microbiota disorders in C. difficile infection, modulating the intestinal microbiota and increasing the abundance of beneficial microbiota. Apple polyphenols also improved fecal metabolic alterations in C. difficile-infected mice and modulated the expression of pathways related to intestinal inflammation. Our results suggest that apple polyphenol extract is a potential prebiotic agent that affects the intestinal microbiota and metabolism, thereby positively influencing intestinal infections.

Integrated metabolomics, network pharmacology and biological verification to reveal the mechanisms of Nauclea officinalis treatment of LPS-induced acute lung injury.

BACKGROUND: Acute lung injury (ALI) is a severe inflammatory disease, underscoring the urgent need for novel treatments. Nauclea officinalis Pierre ex Pitard (Danmu in Chinese, DM) is effective in treating inflammatory respiratory diseases. However, there is still no evidence of its protective effect against ALI. METHODS: Metabolomics was applied to identify the potential biomarkers and pathways in ALI treated with DM. Further, network pharmacology was introduced to predict the key targets of DM against ALI. Then, the potential pathways and key targets were further verified by immunohistochemistry and western blot assays. RESULTS: DM significantly improved lung histopathological characteristics and inflammatory response in LPS-induced ALI. Metabolomics analysis showed that 16 and 19 differential metabolites were identified in plasma and lung tissue, respectively, and most of these metabolites tended to recover after DM treatment. Network pharmacology analysis revealed that the PI3K/Akt pathway may be the main signaling pathway of DM against ALI. The integrated analysis of metabolomics and network pharmacology identified 10 key genes. These genes are closely related to inflammatory response and cell apoptosis of lipopolysaccharide (LPS)-induced ALI in mice. Furthermore, immunohistochemistry and western blot verified that DM could regulate inflammatory response and cell apoptosis by affecting the PI3K/Akt pathway, and expression changes in Bax and Bcl-2 were also triggered. CONCLUSION: This study first integrated metabolomics, network pharmacology and biological verification to investigate the potential mechanism of DM in treating ALI, which is related to the regulation of inflammatory response and cell apoptosis. And the integrated analysis can provide new strategies and ideas for the study of traditional Chinese medicines in the treatment of ALI.

Identification and functional characterization of the xyloglucan endotransglucosylase/hydrolase 32 (AhXTH32) in peanut during aluminum-induced programmed cell death.

The toxicity of aluminum (Al) in acidic soil is a prevalent problem and causes reduced crop yields. In the plant response to Al toxicity, programmed cell death (PCD) appears to be an important mechanism. The plant cell wall of crop roots is the predominant site targeted by Al. Here, studies of the capacities of different cell wall constituents (pectin, hemicellulose 1 {HC1} and HC2) to adsorb Al indicated that HC1 has the greater ability to bind Al. The activity of xyloglucan endotransglucosylase (XET) was significantly inhibited by Al in the Al-tolerant peanut cultivar '99-1507' compared to that in 'ZH 2' (Al-sensitive). Results from qPCR analysis suggested that the suppression of XET activity by Al was transcriptionally regulated and that xyloglucan endotransglucosylase/hydrolase 32 (AhXTH32) was the major contributor to these changes. The overexpression of AhXTH32 in Arabidopsis strongly inhibited root growth with a loss of viability in root cells and the occurrence of typical hallmarks of PCD, while largely opposite effects were observed after xth32 suppression. AhXTH32 contributed to the modulation XET and xyloglucan endohydrolase (XEH) activity in vivo. Taken together, our results demonstrate that Al-tolerant peanut cultivar root tips cell walls bind Al predominantly in the HC1 fraction, which results in the inhibition of AhXTH32, with consequences to root growth, Al sensitivity, the occurrence of PCD and the XET/XEH activity ratio.

Robot-Assisted Needle Insertion for CT-Guided Puncture: Experimental Study with a Phantom and Animals.

PURPOSE: This study aimed to evaluate the accuracy and safety of robotic CT-guided needle insertion in phantom and animal experiments. MATERIALS AND METHODS: A robotic system was developed for CT-guided needle insertion. For the phantom experiment, a specially made phantom containing multiple spherical was used. 15 robotic and manual insertions were conducted, and the accuracy, time, number of needle insertions, and radiation dose were compared between the robotic and manual insertion using Student's t-test. For the animal experiment, 20 robotic needle insertions were attempted toward simulated pulmonary nodules in the swine lung. The accuracy and safety of robotic CT-guided needle insertions were evaluated. RESULTS: In the phantom experiment, the mean accuracies of manual and robotic insertion were 1.8 ± 0.3 mm and 1.9 ± 0.2 mm. The accuracy of robotic needle insertion had no significant difference with manual needle insertion, but the number of needle insertions and radiation dose of the robotic needle placement significantly decreased compared to manual needle placement. In the animal experiment, the mean accuracy of the robotic needle insertion was 3.8 ± 1.3 mm. The time for the whole needle insertion was 14.4 ± 4.8 min. The whole robotic needle insertions were safe and only one mild pneumothorax occurred. CONCLUSION: CT-guided robotic needle insertion showed accuracy comparable to manual needle insertion, but the number of needle insertions, confirmatory scans, and radiation exposure had been reduced significantly. In future, we will further apply the robotic system to clinical experiments.

Patterns of HIV or AIDS Mortality Among Older People From 1990 to 2019 in China: Age-Period-Cohort Analysis.

BACKGROUND: With the increasing effectiveness of antiretroviral therapy and shifting demographics, the problem of older people with HIV or AIDS is increasingly grim in China, and neglecting infection among them may cause more serious social problems, exacerbate the difficulty of controlling HIV or AIDS transmission, and increase the risk of death. OBJECTIVE: We investigated the variations in the trends of Chinese mortality by age, period, and cohort, from 1990 to 2019, to reveal the relationship between age, period, cohort, and HIV burden, as well as providing guidance for resource allocation to prevent HIV-related deaths in vulnerable target populations. METHODS: We extracted the HIV or AIDS mortality data from the Global Burden of Disease. The joinpoint regression model was applied to detect changes in HIV or AIDS trends. The age-period-cohort model was used to explore the age, period, and cohort effects. RESULTS: The trends in age-standardized mortality rates in HIV or AIDS were increased in both genders, from 0.50 to 4.54/105 individuals for males, and from 0.19 to 1.43/105 individuals for females. Joinpoint regression model showed the average annual percentage change of age-standardized mortality rates was 7.0 for male and 6.4 for female individuals, showing an increasing trend. The age effect of male HIV or AIDS mortality showed a net increase of 0.59 (-0.21 to 0.38) from the ages 50-79 years. There is a gradual upward trend in the change in risk of death from HIV or AIDS for the period effect among the older population, lowest at ages 50-54 years (-0.80 for male and -0.78 for female individuals) and highest at ages 75-79 years (0.86 for male and 0.69 for female individuals). The variation of cohort effects was complex, but both genders had a nearly consistent tendency; people born in 1920-1929 had the lowest cohort effect, and those born in 1950-1954 had the highest values. CONCLUSIONS: Our study showed a marked rise in HIV mortality for both genders in China from 1990 to 2019. Aging is an important issue in current HIV prevention and control. There is an urgent need to promote HIV testing and health education. Our findings will help predict future HIV or AIDS mortality changes and identify age-specific priority populations for intervention.

Role of insulin in pancreatic microcirculatory oxygen profile and bioenergetics.

BACKGROUND: The pancreatic islet microcirculation adapts its metabolism to cope with limited oxygen availability and nutrient delivery. In diabetes, the balance between oxygen delivery and consumption is impaired. Insulin has been proven to exert complex actions promoting the maintenance of homeostasis of the pancreas under glucotoxicity. AIM: To test the hypothesis that insulin administration can improve the integrated pancreatic microcirculatory oxygen profile and bioenergetics. METHODS: The pancreatic microcirculatory partial oxygen pressure (PO2), relative hemoglobin (rHb) and hemoglobin oxygen saturation (SO2) were evaluated in nondiabetic, type 1 diabetes mellitus (T1DM), and insulin-treated mice. A three-dimensional framework was generated to visualize the microcirculatory oxygen profile. Ultrastructural changes in the microvasculature were examined using transmission electron microscopy. An Extracellular Flux Analyzer was used to detect the real-time changes in bioenergetics by measuring the oxygen consumption rate and extracellular acidification rate in islet microvascular endothelial cells (IMECs). RESULTS: Significantly lower PO2, rHb, and SO2 values were observed in T1DM mice than in nondiabetic controls. Insulin administration ameliorated the streptozotocin-induced decreases in these microcirculatory oxygen parameters and improved the mitochondrial ultrastructural abnormalities in IMECs. Bioenergetic profiling revealed that the IMECs did not have spare respiratory capacity. Insulin-treated IMECs exhibited significantly greater basal respiration than glucotoxicity-exposed IMECs (P < 0.05). An energy map revealed increased energetic metabolism in insulin-treated IMECs, with significantly increased ATP production, non-mitochondrial respiration, and oxidative metabolism (all P < 0.05). Significant negative correlations were revealed between microcirculatory SO2 and bioenergetic parameters. CONCLUSION: Glucotoxicity deteriorates the integrated pancreatic microcirculatory oxygen profile and bioenergetics, but this deterioration can be reversed by insulin administration.

Glioblastoma stem cell-specific histamine secretion drives pro-angiogenic tumor microenvironment remodeling.

The communication between glioblastoma stem cells (GSCs) and the surrounding microenvironment is a prominent feature accounting for the aggressive biology of glioblastoma multiforme (GBM). However, the mechanisms by which GSCs proactively drive interactions with microenvironment is not well understood. In this study, we interrogated metabolites that are preferentially secreted from GSCs and found that GSCs produce and secrete histamine to shape a pro-angiogenic tumor microenvironment. This histamine-producing ability is attributed to H3K4me3 modification-activated histidine decarboxylase (HDC) transcription via MYC. Notably, HDC is highly expressed in GBM, which is associated with poor survival of these patients. GSC-secreted histamine activates endothelial cells by triggering a histamine H1 receptor (H₁R)-Ca²⁺-NF-κB axis, thereby promoting angiogenesis and GBM progression. Importantly, pharmacological blockage of H₁R using antihistamines impedes the growth of GBM xenografts in mice. Our findings establish that GSC-specific metabolite secretion remodels the tumor microenvironment and highlight histamine targeting as a potential strategy for GBM therapy.

Gastric cancer incidence trends in China and Japan from 1990 to 2019: Disentangling age-period-cohort patterns.

BACKGROUND: Recent data have shown divergent trends in gastric cancer (GC) incidence between China and Japan; however, the cause for has not been explored. METHODS: We retrieved GC incidence data from 1990 to 2019 from the Global Burden of Disease study, stratified by sex for both countries. We analyzed annual average percentage change (AAPC) via a joinpoint regression model and estimated the effects of age, period, and cohort via the age-period-cohort model. RESULTS: The age-standardized incidence rate trends for GC decreased in both countries and both sexes, but the reduction was more pronounced in Japan because the AAPC for Japanese males (AAPC = -2.65%; 95% CI, -2.98 to -2.32) was eight times greater than that of Chinese males (AAPC = -0.30%; 95% CI, -0.5 to -0.09). The age and cohort effects on the trend are similar in both countries: the risk of GC incidence increased with age among the Chinese and the Japanese but was lower among younger birth cohorts. The two countries showed contrasting trends over the study period; although the risk of GC rapidly decreased for Japanese males and females, it increased by twofold among Chinese males. CONCLUSIONS: The period effect is the main reason for the divergent trends in age-standardized incidence rate for GC in China and Japan. By comparing national cancer control programs in both countries, we concluded that countries with a high prevalence of GC, such as China, can learn from Japan's experience in controlling GC by actively conducting national population screening, which is expected to facilitate both prevention and treatment of GC. LAY SUMMARY: More than one-half of all new gastric cancer (GC) worldwide occur in China and Japan, but the reasons for the different incidence trends have not been thoroughly analyzed. Analysis using the age-period-cohort model confirmed that the cohort effect was the main reason for the decline in age-standardized incidence rate (ASIR) for GC and that the period effect may be the main reason for the divergent trends in gastric cancer ASIR in China and Japan.

Braille literacy as a human right: A challenge to the "inefficiency" argument against braille instruction.

The United Nations Convention on the Rights of Persons with Disabilities (CRPD) affirms a right to education for disabled persons and aims to ensure braille instruction for blind individuals. However, there is evidence that braille instruction is often circumvented or abandoned early in CRPD nations because it is perceived as an inefficient learning medium for blind students. This perception persists despite insufficient empirical evidence and a lack of understanding of the efficiency of reading versus listening for learning in sighted individuals. We therefore investigated the efficiency of learning written versus spoken words in blind and sighted samples. Participants (23 blind, 20 sighted) studied the written definitions of 70 rare English words in successive rounds, presented in conjunction with written or spoken wordforms. Blind participants learned with equal efficiency across modalities, whereas sighted participants learned spoken words more efficiently. The findings indicate the inefficiency argument against teaching braille is groundless, both because braille word learning is not less efficient than auditory word learning for blind individuals, and because reading is valued in the education of sighted individuals despite its apparent inefficiency in that population.

The Distribution of HIV and AIDS Cases in Luzhou, China, From 2011 to 2020: Bayesian Spatiotemporal Analysis.

BACKGROUND: The vastly increasing number of reported HIV and AIDS cases in Luzhou, China, in recent years, coupled with the city's unique geographical location at the intersection of 4 provinces, makes it particularly important to conduct a spatiotemporal analysis of HIV and AIDS cases. OBJECTIVE: The aim of this study is to understand the spatiotemporal distribution of HIV and the factors influencing this distribution in Luzhou, China, from 2011 to 2020. METHODS: Data on the incidence of HIV and AIDS in Luzhou from 2011 to 2020 were obtained from the AIDS Information Management System of the Luzhou Center for Disease Control and Prevention. ArcGIS was used to visualize the spatiotemporal distribution of HIV and AIDS cases. The Bayesian spatiotemporal model was used to investigate factors affecting the spatiotemporal distribution of HIV and AIDS, including the gross domestic product (GDP) per capita, urbanization rate, number of hospital beds, population density, and road mileage. RESULTS: The reported incidence of HIV and AIDS rose from 8.50 cases per 100,000 population in 2011 to 49.25 cases per 100,000 population in 2020-an increase of 578.87%. In the first 5 years, hotspots were concentrated in Jiangyang district, Longmatan district, and Luxian county. After 2016, Luzhou's high HIV incidence areas gradually shifted eastward, with Hejiang county having the highest average prevalence rate (41.68 cases per 100,000 population) from 2011 to 2020, being 2.28 times higher than that in Gulin county (18.30 cases per 100,000), where cold spots were concentrated. The risk for the incidence of HIV and AIDS was associated with the urbanization rate, population density, and GDP per capita. For every 1% increase in the urbanization rate, the relative risk (RR) increases by 1.3%, while an increase of 100 people per square kilometer would increase the RR by 8.7%; for every 1000 Yuan (US $148.12) increase in GDP per capita, the RR decreases by 1.5%. CONCLUSIONS: In Luzhou, current HIV and AIDS prevention and control efforts must be focused on the location of each district or county government; we suggest the region balance urban development and HIV and AIDS prevention. Moreover, more attention should be paid to economically disadvantaged areas.

N-acetyl Cysteine inhibits cell proliferation and differentiation of LPS-induced MC3T3-E1 cells via regulating inflammatory cytokines.

BACKGROUND: Peri-implantitis is one of the most common complications in oral implantation and could lead to the loss of the function of bone tissues around implants. METHODS: This study used lipopolysaccharide (LPS) as a stimulant for MC3T3-E1 cells and N-acetyl cysteine (NAC) as an inhibitor to inhibit the effect of LPS to investigate the effect of NAC on the expression of bone formation related factors and inflammatory related factors of osteoblasts under the action of LPS. RESULTS: In this study, we found that the cell proliferation and cell differentiation were significantly promoted when NAC concentrations were between 0 ~ 0.5 mM, but was inhibited when the concentration exceeded 0.5 mM. LPS had a slightly promoting effect on the cell proliferation before 20 µg /mL but inhibited the cell proliferation after 20 µg/mL. LPS reduced protein and gene expressions of Runx2, ALP and BGP and increased protein and gene expressions of NF-κB and TNF-α. NAC reversibly regulated the LPS's regulation on the expression of MC3T3-E1 cell cytokine gene and protein. CONCLUSION: The optimal NAC concentration for treating MC3T3-E1 cells is 0.5 mM and the optimal LPS concentration for stimulating MC3T3-E1 cells is 20 µg/mL. NAC plays an active role in regulating the differentiation of MC3T3-E1 cells, and can inhibit LPS to regulate the differentiation of MC3T3-E1 cells. NAC promotes the expression of osteogenic factor of MC3T3-E1cells and inhibits the expression of inflammatory cytokines.

Sodium Pentobarbital Suppresses Breast Cancer Cell Growth Partly via Normalizing Microcirculatory Hemodynamics and Oxygenation in Tumors.

Breast cancer remains the leading cause of cancer-related death among women worldwide. Sodium pentobarbital was found to play an inhibitory role in glioma growth in rats. In this study, we aimed to evaluate the effects of sodium pentobarbital on breast cancer growth both in vitro and in vivo, and its impacts on the microcirculatory changes on both skin and tumor surface in mice bearing subcutaneous xenograft. Cell counting assay was used to assess the antiproliferative effect of sodium pentobarbital on MDA-MB-231 breast cancer cells. Subcutaneous xenograft model was established to study the role of sodium pentobarbital on in vivo tumor growth. Speed-resolved blood perfusion, hemoglobin oxygen saturation (SO2, %), total hemoglobin tissue concentration (ctTHb, µM), and red blood cell (RBC) tissue fraction (%) were examined simultaneously by using enhanced perfusion and oxygen saturation system to investigate the effects of sodium pentobarbital on microcirculatory hemodynamics and oxygenation. Sodium pentobarbital suppressed breast tumor growth both in vitro and in vivo. Cutaneous blood flux in nutritive capillaries with low-speed flow was significantly increased in tumor-bearing mice, and high-dose sodium pentobarbital treatment cause a reduction in this low-speed blood flux, whereas sodium pentobarbital therapy caused an elevated blood flux in larger microvessels with mid and high speed in a dose-dependent manner. Different doses of sodium pentobarbital exerted different actions on SO2, ctTHb, and RBC tissue fraction. Collectively, the inhibitory effect of sodium pentobarbital on breast tumor growth was at least partly associated with its ability to normalize microcirculatory hemodynamics and oxygenation in tumors. SIGNIFICANCE STATEMENT: This study is the first to demonstrate the inhibiting effect of sodium pentobarbital on breast cancer growth both in vitro and in vivo, and such an inhibition was at least partly associated with its ability to normalize microcirculatory hemodynamics and oxygenation in tumors.

Chemerin Regulates the Proliferation and Migration of Pulmonary Arterial Smooth Muscle Cells via the ERK1/2 Signaling Pathway.

Pulmonary arterial hypertension (PAH) is an incurable disease with high mortality. Chemerin has been found to be associated with pulmonary hypertension (PH). However, the specific role of chemerin in mediating PH development remains unclear. This study aimed to elucidate the regulatory effects and the underlying mechanism of chemerin on PH and to investigate the expression levels of chemerin protein in plasma in PAH patients. In vivo, two animal models of PH were established in rats by monocrotaline (MCT) injection and hypoxia. We found that the expression levels of chemerin and its receptor, chemokine-like receptor 1 (CMKLR1), were significantly upregulated in the lungs of PH rats. Primary cultured pulmonary arterial smooth muscle cells [(PASMCs) (isolated from pulmonary arteries of normal healthy rats)] were exposed to hypoxia or treated with recombinant human chemerin, we found that CMKLR1 expression was upregulated in PASMCs in response to hypoxia or chemerin stimulation, whereas the exogenous chemerin significantly promoted the migration and proliferation of PASMCs. Notably, the regulatory effects of chemerin on PASMCs were blunted by PD98059 (a selective ERK1/2 inhibitor). Using enzyme linked immunosorbent assay (ELISA), we found that the protein level of chemerin was also markedly increased in plasma from idiopathic pulmonary arterial hypertension (IPAH) patients compared to that from healthy controls. Moreover, the diagnostic value of chemerin expression in IPAH patients was determined through receiver operating characteristic (ROC) curve analysis and the result revealed that area under ROC curve (AUC) for plasma chemerin was 0.949. Taken together, these results suggest that chemerin exacerbates PH progression by promoting the proliferation and migration of PASMCs via the ERK1/2 signaling pathway, and chemerin is associated with pulmonary hypertension.

Targeting impaired autophagy as a therapeutic strategy for Koolen-de Vries syndrome.

Koolen-de Vries syndrome (KdVS) is a genomic disorder characterized by intellectual disability, heart failure, hypotonia and congenital malformations, which is caused by haploinsufficiency of KANSL1. Because the pathogenesis of the disease is unknown, there is still no effective treatment. Here, we discuss our recent work identifying KANSL1 as an essential gene for macroautophagy/autophagy. We find that KANSL1 modulates autophagosome-lysosome fusion for cargo degradation by transcriptionally regulating Stx17 expression. Kansl1 heterozygous mice exhibit impaired neuronal and cardiac functions, resulting from the obstruction of autophagic clearance of damaged mitochondria and accumulation of reactive oxygen species in these tissues. Furthermore, we discovered an FDA-approved drug, 13-cis retinoic acid, is capable of alleviating these mitophagic defects and neurobehavioral abnormalities in Kansl1 heterozygous mice by promoting autophagosome-lysosome fusion via directly binding to STX17 and SNAP29. Our study provides the proof of concept to set up a link between KANSL1, autophagic defects and KdVS, and also proposes a therapeutic strategy for treatment of KdVS.

Oncolytic Zika virus promotes intratumoral T cell infiltration and improves immunotherapy efficacy in glioblastoma.

Glioblastoma (GBM) is the deadliest primary brain tumor and is generally resistant to immunotherapy because of severe dysfunction of T cells. Novel treatment options are critically needed to overcome the immunotherapy resistance of GBM. Here we demonstrate that Zika virus (ZIKV) treatment improves the efficacy of anti-PD ligand 1 (PD-L1) immunotherapy in GBM. We found that ZIKV induces a strong pro-inflammatory response and increases CD4+ and CD8+ T cell intratumoral infiltration and activation in GBM mouse models. ZIKV treatment of mice bearing GBM tumors inhibits tumor growth and prolongs survival. These therapeutic effects of ZIKV on GBM tumors are negated in mice depleted of T cells. Moreover, ZIKV dramatically promotes activation of the type I interferon signaling pathway in GBM cells. ZIKV treatment potently sensitizes GBM to PD-L1 blockade and provides significant and durable survival benefits. Our findings reveal that ZIKV overcomes the resistance of GBM to immune checkpoint blockade, which may lead to therapeutic applications of ZIKV in individuals with GBM receiving immunotherapy.

Comparison of visual acuity between phacoemulsification and extracapsular cataract extraction: a systematic review and meta-analysis.

BACKGROUND: Surgical treatment is the primary intervention for cataracts. Extracapsular cataract extraction (ECCE) is a routine surgery for cataracts, phacoemulsification (PE) is another procedure with a small incision and injury area. This study investigated the comparison of the effects of these two procedures on the patient's visual acuity. METHODS: Embase, PubMed, Cochrane Library, and SpringerLink databases were searched from January 2000 to August 2021 to obtain randomized controlled trial (RCT) studies of PE and ECCE procedures for cataract in English. After the initial screening, Revman 5.4 software was used for the meta-analysis. RESULTS: This meta-analysis included a total of eight articles with 1,015 affected eyes. The results showed that the rate of good final visual acuity in the PE group was higher than that in the ECCE group [odds ratio (OR) =2.94, 95% confidence interval (CI): 2.17-3.99, P<0.00001], the incidence of vitreous Loss during PE surgery was lower than that in ECCE surgery (OR =0.16, 95% CI: 0.04-0.64, P=0.01), as was the incidence of capsular tear (OR =0.29, 95% CI: 0.10-0.85, P=0.02), the incidence of capsule opacification after surgery (OR =0.20, 95% CI: 0.08-0.53, P=0.001), and the incidence of cystoid macular edema after surgery (OR =0.16, 95% CI: 0.04-0.74, P=0.02). DISCUSSION: Compared with ECCE, PE demonstrates an improvement in postoperative visual acuity and has fewer complications for cataract patients.

Objective quantification of the severity of postural tremor based on kinematic parameters: A multi-sensory fusion study.

BACKGROUND: Current clinical assessments of essential tremor (ET) are primarily based on expert consultation combined with reviewing patient complaints, physician expertise, and diagnostic experience. Thus, traditional evaluation methods often lead to biased diagnostic results. There is a clinical demand for a method that can objectively quantify the severity of the patient's disease. METHODS: This study aims to develop an artificial intelligence-aided diagnosis method based on multi-sensory fusion wearables. The experiment relies on a rigorous clinical trial paradigm to collect multi-modal fusion of signals from 98 ET patients. At the same time, three clinicians scored independently, and the consensus score obtained was used as the ground truth for the machine learning models. RESULTS: Sixty kinematic parameters were extracted from the signals recorded by the nine-axis inertial measurement unit (IMU). The results showed that most of the features obtained by IMU could effectively characterize the severity of the tremors. The accuracy of the optimal model for three tasks classifying five severity levels was 97.71%, 97.54%, and 97.72%, respectively. CONCLUSIONS: This paper reports the first attempt to combine multiple feature selection and machine learning algorithms for fine-grained automatic quantification of postural tremor in ET patients. The promising results showed the potential of the proposed approach to quantify the severity of ET objectively.

Kansl1 haploinsufficiency impairs autophagosome-lysosome fusion and links autophagic dysfunction with Koolen-de Vries syndrome in mice.

Koolen-de Vries syndrome (KdVS) is a rare disorder caused by haploinsufficiency of KAT8 regulatory NSL complex subunit 1 (KANSL1), which is characterized by intellectual disability, heart failure, hypotonia, and congenital malformations. To date, no effective treatment has been found for KdVS, largely due to its unknown pathogenesis. Using siRNA screening, we identified KANSL1 as an essential gene for autophagy. Mechanistic study shows that KANSL1 modulates autophagosome-lysosome fusion for cargo degradation via transcriptional regulation of autophagosomal gene, STX17. Kansl1+/- mice exhibit impairment in the autophagic clearance of damaged mitochondria and accumulation of reactive oxygen species, thereby resulting in defective neuronal and cardiac functions. Moreover, we discovered that the FDA-approved drug 13-cis retinoic acid can reverse these mitophagic defects and neurobehavioral abnormalities in Kansl1+/- mice by promoting autophagosome-lysosome fusion. Hence, these findings demonstrate a critical role for KANSL1 in autophagy and indicate a potentially viable therapeutic strategy for KdVS.