B-Cell-Specific Diversion of Glucose Carbon Utilization Reveals a Unique Vulnerability in B Cell Malignancies.

B cell activation during normal immune responses and oncogenic transformation impose increased metabolic demands on B cells and their ability to retain redox homeostasis. While the serine/threonine-protein phosphatase 2A (PP2A) was identified as a tumor suppressor in multiple types of cancer, our genetic studies revealed an essential role of PP2A in B cell tumors. Thereby, PP2A redirects glucose carbon utilization from glycolysis to the pentose phosphate pathway (PPP) to salvage oxidative stress. This unique vulnerability reflects constitutively low PPP activity in B cells and transcriptional repression of G6PD and other key PPP enzymes by the B cell transcription factors PAX5 and IKZF1. Reflecting B-cell-specific transcriptional PPP-repression, glucose carbon utilization in B cells is heavily skewed in favor of glycolysis resulting in lack of PPP-dependent antioxidant protection. These findings reveal a gatekeeper function of the PPP in a broad range of B cell malignancies that can be efficiently targeted by small molecule inhibition of PP2A and G6PD.

PARP5A and RNF146 phase separation restrains RIPK1-dependent necroptosis.

Phase separation is a vital mechanism that mediates the formation of biomolecular condensates and their functions. Necroptosis is a lytic form of programmed cell death mediated by RIPK1, RIPK3, and MLKL downstream of TNFR1 and has been implicated in mediating many human diseases. However, whether necroptosis is regulated by phase separation is not yet known. Here, we show that upon the induction of necroptosis and recruitment by the adaptor protein TAX1BP1, PARP5A and its binding partner RNF146 form liquid-like condensates by multivalent interactions to perform poly ADP-ribosylation (PARylation) and PARylation-dependent ubiquitination (PARdU) of activated RIPK1 in mouse embryonic fibroblasts. We show that PARdU predominantly occurs on the K376 residue of mouse RIPK1, which promotes proteasomal degradation of kinase-activated RIPK1 to restrain necroptosis. Our data demonstrate that PARdU on K376 of mouse RIPK1 provides an alternative cell death checkpoint mediated by phase separation-dependent control of necroptosis by PARP5A and RNF146.

Endothelial peroxiredoxin-4 is indispensable for blood-brain barrier integrity and long-term functional recovery after ischemic stroke.

The endothelial lining of cerebral microvessels is damaged relatively early after cerebral ischemia/reperfusion (I/R) injury and mediates blood-brain barrier (BBB) disruption, neurovascular injury, and long-term neurological deficits. I/R induces BBB leakage within 1 h due to subtle structural alterations in endothelial cells (ECs), including reorganization of the actin cytoskeleton and subcellular redistribution of junctional proteins. Herein, we show that the protein peroxiredoxin-4 (Prx4) is an endogenous protectant against endothelial dysfunction and BBB damage in a murine I/R model. We observed a transient upregulation of Prx4 in brain ECs 6 h after I/R in wild-type (WT) mice, whereas tamoxifen-induced, selective knockout of Prx4 from endothelial cells (eKO) mice dramatically raised vulnerability to I/R. Specifically, eKO mice displayed more BBB damage than WT mice within 1 to 24 h after I/R and worse long-term neurological deficits and focal brain atrophy by 35 d. Conversely, endothelium-targeted transgenic (eTG) mice overexpressing Prx4 were resistant to I/R-induced early BBB damage and had better long-term functional outcomes. As demonstrated in cultures of human brain endothelial cells and in animal models of I/R, Prx4 suppresses actin polymerization and stress fiber formation in brain ECs, at least in part by inhibiting phosphorylation/activation of myosin light chain. The latter cascade prevents redistribution of junctional proteins and BBB leakage under conditions of Prx4 repletion. Prx4 also tempers microvascular inflammation and infiltration of destructive neutrophils and proinflammatory macrophages into the brain parenchyma after I/R. Thus, the evidence supports an indispensable role for endothelial Prx4 in safeguarding the BBB and promoting functional recovery after I/R brain injury.

LMBR1L regulates the proliferation and migration of endothelial cells through Norrin/ß-catenin signaling.

Precise Norrin and ß-catenin (Norrin/ß-catenin; encoded by NDP and CTNNB1, respectively) signaling is critical for proper angiogenesis. Dysregulation of this signaling leads to various diseases, of which retinal exudative vitreoretinopathy is the most prevalent. Here, we used a global knockout mouse model to show that limb development membrane protein 1 like (LMBR1L), a transmembrane protein of unknown function in angiogenesis, is essential for retinal vascular development. In vitro experiments revealed that LMBR1L depletion results in aberrant activation of the Norrin/ß-catenin signaling pathway via decreased ubiquitylation of FZD4 and increased Norrin co-receptor LRP5 and p-GSK3ß-Ser9 expression levels, which cause accumulation of ß-catenin. Moreover, inhibition of LMBR1L in human retinal microvascular endothelial cells (HRECs) caused increased proliferation ability and defective cell migration, which might have occurred as a result of upregulated expression levels of the apical junction components. Treatment with p-GSK3ß-Ser9 inhibitor AR-A014418 restored the phenotypes in LMBR1L-null HRECs, which further demonstrated the important regulatory role of LMBR1L in the Norrin/ß-catenin signaling pathway. Taken together, our data reveal an essential role for LMBR1L in angiogenesis. This article has an associated First Person interview with the first author of the paper.

Investigation of folate-modified EGCG-loaded thermosensitive nanospheres inducing immunogenic cell death and damage-associated molecular patterns in hepatocellular carcinoma.

BACKGROUND: The systemic treatment of advanced hepatocellular carcinoma is currently facing a bottleneck. EGCG, the primary active compound in green tea, exhibits anti-tumor effects through various pathways. However, there is a lack of study on EGCG-induced immunogenic cell death (ICD) in hepatocellular carcinoma. METHODS: In a previous study, we successfully synthesized folate-modified thermosensitive nano-materials, encapsulated EGCG within nanoparticles using a hydration method, and established the EGCG nano-drug delivery system. The viability of HepG2 cells post-EGCG treatment was assessed via the MTT and EdU assays. Cell migration and invasion were evaluated through wound healing experiments, Transwell assays, and Annexin V-FITC/PI assay for apoptosis detection. Additionally, the expression levels of damage-associated molecular patterns (DAMPs) were determined using immunofluorescence, ATP measurement, RT-qPCR, and Western Blot. RESULTS: The drug sensitivity test revealed an IC50 value of 96.94 µg/mL for EGCG in HepG2 cells after 48 h. EGCG at a low concentration (50 µg/mL) significantly impeded the migration and invasion of HepG2 cells, showing a clear dose-dependent response. Moreover, medium to high EGCG concentrations induced cell apoptosis in a dose-dependent manner and upregulated DAMPs expression. Immunofluorescence analysis demonstrated a notable increase in CRT expression following low-concentration EGCG treatment. As EGCG concentration increased, cell viability decreased, leading to CRT exposure on the cell membrane. EGCG also notably elevated ATP levels. RT-qPCR and Western Blot analyses indicated elevated expression levels of HGMB1, HSP70, and HSP90 following EGCG intervention. CONCLUSION: EGCG not only hinders the proliferation, migration, and invasion of hepatocellular carcinoma cells and induces apoptosis, but also holds significant clinical promise in the treatment of malignant tumors by promoting ICD and DAMPs secretion.

Concentration-Gradient Structural LiFe0.5Mn0.5PO4/C Prepared via Co-precipitation Reaction for Advanced Lithium-Ion Batteries.

The intrinsically low electronic conductivity and slow ion diffusion kinetics limit further development of olivine LiFexMn1-xPO4 cathode materials. In this paper, with the aim of improving the performance of such materials and alleviating the Jahn-Taller effect of Mn3+ ion, a bimetallic oxalate precursor with gradient distribution of elemental concentration followed with an efficient process is applied to synthesize LiFe0.5Mn0.5PO4 nanocomposite. The results shown that with certain structural modulation of the precursor, the discharge capacity of synthesized LiFe0.5Mn0.5PO4 increased from 149 mAh g-1 to 156 mAh g-1 at 0.1 C, the cycling capacity was also remarkably improved. the Fe0.5Mn0.5C2O4 ⋅ 2H2O-1 precursor with gradient distribution of elemental concentration effectively restricts the reaction between electrode material and electrolyte, thereby alleviates the dissolution of Mn3+ ion, reduces the decay of capacity and improves the stability of the material.

Association of 8-hydroxy-2'-deoxyguanosine with motoric cognitive risk in elderly Chinese people: RUGAO longevity and aging cross-sectional study.

BACKGROUND: Motor cognitive risk syndrome (MCR) represents a critical pre-dementia and disability state characterized by a combination of objectively measured slow walking speed and subjective memory complaints (SMCs). This study aims to identify risk factors for MCR and investigate the relationship between plasma levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and MCR among Chinese community-dwelling elderly populations. METHODS: A total of 1312 participants were involved in this study based on the data of the Rugao Longevity and Aging Study (RuLAS). The MCR was characterized by SMCs and slow walking speed. The SCCs were defined as a positive answer to the question 'Do you feel you have more problems with memory than most?' in a 15-item Geriatric Depression Scale. Slow walking speed was determined by one standard deviation or more below the mean value of the patient's age and gender group. The plasma of 8-OHdG were measured by a technician in the biochemistry laboratory of the Rugao People's Hospital during the morning of the survey. RESULTS: The prevalence of MCR was found to be 7.9%. After adjusting for covariates, significant associations with MCR were observed in older age (OR 1.057; p = 0.018), history of cerebrovascular disease (OR 2.155; p = 0.010), and elevated 8-OHdG levels (OR 1.007; p = 0.003). CONCLUSIONS: This study indicated the elevated plasma 8-OHdG is significantly associated with increased MCR risk in the elderly, suggesting its potential as a biomarker for early detection and intervention in MCR. This finding underscores the importance of monitoring oxidative DNA damage markers in predicting cognitive and motor function declines, offering new avenues for research and preventive strategies in aging populations.

Violet light suppresses lens-induced myopia via neuropsin (OPN5) in mice.

Myopia has become a major public health concern, particularly across much of Asia. It has been shown in multiple studies that outdoor activity has a protective effect on myopia. Recent reports have shown that short-wavelength visible violet light is the component of sunlight that appears to play an important role in preventing myopia progression in mice, chicks, and humans. The mechanism underlying this effect has not been understood. Here, we show that violet light prevents lens defocus-induced myopia in mice. This violet light effect was dependent on both time of day and retinal expression of the violet light sensitive atypical opsin, neuropsin (OPN5). These findings identify Opn5-expressing retinal ganglion cells as crucial for emmetropization in mice and suggest a strategy for myopia prevention in humans.

Integration of Single-Cell and Bulk RNA-seq Data to Identify the Cancer-Associated Fibroblast Subtypes and Risk Model in Glioma.

Cancer-associated fibroblasts (CAFs) are an important component of the stroma. Studies showed that CAFs were pivotally in glioma progression which have long been considered a promising therapeutic target. Therefore, the identification of prognostic CAF markers might facilitate the development of novel diagnostic and therapeutic approaches. A total of 1333 glioma samples were obtained from the TCGA and CGGA datasets. The EPIC, MCP-counter, and xCell algorithms were used to evaluate the relative proportion of CAFs in glioma. CAF markers were identified by the single-cell RNA-seq datasets (GSE141383) from the Tumor Immune Single-Cell Hub database. Unsupervised consensus clustering was used to divide the glioma patients into different distinct subgroups. The least absolute shrinkage and selection operator regression model was utilized to establish a CAF-related signature (CRS). Finally, the prognostic CAF markers were further validated in clinical specimens by RT‒qPCR. Combined single-cell RNA-seq analysis and differential expression analysis of samples with high and low proportions of CAFs revealed 23 prognostic CAF markers. By using unsupervised consensus clustering, glioma patients were divided into two distinct subtypes. Subsequently, based on 18 differentially expressed prognostic CAF markers between the two CAF subtypes, we developed and validated a new CRS model (including PCOLCE, TIMP1, and CLIC1). The nomogram and calibration curves indicated that the CRS was an accurate prognostic marker for glioma. In addition, patients in the high-CRS score group had higher immune infiltration and tumor mutation burden levels. Moreover, the CRS score had the potential to predict the response to immune checkpoint blockade (ICB) therapy and chemotherapy. Finally, the expression profiles of three CAF markers were verified by RT‒qPCR. In general, our study classified glioma patients into distinct subgroups based on CAF markers, which will facilitate the development of individualized therapy. We also provided insights into the role of the CRS in predicting the response to ICB and chemotherapy in glioma patients.

Integrating Network Pharmacology and In Vitro Experiments for Assessing the Anti-Tumor Effects of Phyllanthus Urinaria L Anti-neoplastic Decoction in Hepatocellular Carcinoma.

Background: In China, traditional Chinese medicine (TCM) is an important part of the comprehensive treatment of hepatocellular carcinoma (HCC), and Chinese herb formulas with the effect of "yiqi jianpi jiedu huayu" (replenishing qi, strengthening spleen, and removing toxicity and blood stasis) are the common and efficient treatments for HCC. However, the mechanism of these formulas in treating HCC remain unclear. Objective: In this paper, our goal is to explore the potential mechanism of Phyllanthus urinaria L anti-neoplastic decoction (PAD), the representative formula of "yiqi jianpi jiedu huayu", in treating HCC. Design: The research team performed the network pharmacology and in vitro experiment (preparation of PAD aqueous extract, cell cultures and MTT assay, cell apoptosis assay, wound healing assay, transwell assays, western blot). Setting: The study took place in the Department of Hepatology, the Fourth Clinical Medical College of Guangzhou University of Chinese Medicine (Shenzhen Traditional Chinese Medicine Hospital), China. Outcome Measures: The active components and targets of PAD and HCC targets were screened by five Chinese herbs and two disease databases respectively. The network pharmacology was utilized to construct the relationship network between PAD and HCC, and the mechanism was predicted by pathway enrichment analysis. The experiment was performed to verify the intervention effect of PAD on HCC and phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathway. Results: The relationship network between PAD and HCC suggested that PAD mainly regulated the potential therapeutic targets of HCC by key active components such as quercetin, luteolin, calycosin, wogonin, and pinocembrin. Pathway analysis demonstrated PAD could play an anti-HCC effect via multiple pathways (e.g., PI3K/Akt). Results of the experiment showed that PAD could effectively inhibit the proliferation and migration of HCC cells, and promote HCC cells apoptosis in a concentration-dependent behavior. Additionally, PAD could decrease the protein expression of phosphorylated PI3K/Akt. Conclusion: PAD mainly exerts an anti-HCC effect through multiple active components represented by quercetin and multiple pathways represented by the PI3K/Akt pathway. This study provided an experimental basis for the clinical application of PAD.

A bulit-in self-calibration ratiometric self-powered photoelectrochemical sensor for high-precision and sensitive detection of microcystin-RR.

A novel high-precision aptasensor of microcystin-RR (MC-RR) is developed based on a ratiometric self-powered photoelectrochemical platform. In detail, the defective MoS2/Ti3C2 nanocomposite with good photoelectric activity was designed to serve as the photoanode of the sensor for enhancing the signal and improving the detection sensitivity. In order to effectively eliminate external interferences, the key point of this ratiometric device is the introduction of the spatial-resolved technique, which includes the detection section and the reference section, generating reference signals and response signals, respectively. Moreover, output power was used as the detection signal, instead of the traditional photocurrent or photovoltage. Further, potassium persulfate was introduced as electron acceptor, which was beneficial for improving the electron transport efficiency, hindering electron-hole recombination, and significantly promoting the performance of the sensor. Finally, aptamer was adopted as recognition element to capture MC-RR molecules. The prepared sensor had a linear range from 10-12 to 10-6 M, and the detection limit was 5.6 × 10-13 M (S/N = 3). It has good precision, selectivity, and sensitivity, which shows great prospects in the on-site accurate analysis of samples with high energy output in the self-powered sensing field.

Social frailty and the incidence of motoric cognitive risk syndrome in older adults.

INTRODUCTION: Various associations between social factors and motoric cognitive risk syndrome (MCR) have been reported. However, whether social frailty (integrated from multiple social factors) is associated with MCR is still unclear. METHODS: We included 4657 individuals without MCR at Round 1 of the NHATS as the discovery sample, and 3075 newly recruited individuals from Round 5 of the NHATS as the independent validation sample. Social frailty was assessed by five social items. MCR was defined as the presence of both subjective cognitive complaints and slow gait speed in individuals without dementia or mobility disability. RESULTS: Compared with normal individuals, those with social frailty had higher risk of incident MCR (hazard ratio [HR]: 1.57, 95% confidence interval [CI]: 1.34-1.84). Each additional unfavorable social item was associated with an increased risk of MCR (HR: 1.32, 95% CI: 1.22-1.43). DISCUSSION: Social frailty was associated with an increased risk of incident MCR in older adults. HIGHLIGHTS: Various associations between social factors and motoric cognitive risk syndrome (MCR) have been reported. Social frailty that integrated from multiple social factors was associated with an increased risk of incident MCR. Social frailty should be included in the early screening of individuals to identify those at higher risk of MCR.

Clinical Insights into Structure, Regulation, and Targeting of ABL Kinases in Human Leukemia.

Chronic myeloid leukemia is a multistep, multi-lineage myeloproliferative disease that originates from a translocation event between chromosome 9 and chromosome 22 within the hematopoietic stem cell compartment. The resultant fusion protein BCR::ABL1 is a constitutively active tyrosine kinase that can phosphorylate multiple downstream signaling molecules to promote cellular survival and inhibit apoptosis. Currently, tyrosine kinase inhibitors (TKIs), which impair ABL1 kinase activity by preventing ATP entry, are widely used as a successful therapeutic in CML treatment. However, disease relapses and the emergence of resistant clones have become a critical issue for CML therapeutics. Two main reasons behind the persisting obstacles to treatment are the acquired mutations in the ABL1 kinase domain and the presence of quiescent CML leukemia stem cells (LSCs) in the bone marrow, both of which can confer resistance to TKI therapy. In this article, we systemically review the structural and molecular properties of the critical domains of BCR::ABL1 and how understanding the essential role of BCR::ABL1 kinase activity has provided a solid foundation for the successful development of molecularly targeted therapy in CML. Comparison of responses and resistance to multiple BCR::ABL1 TKIs in clinical studies and current combination treatment strategies are also extensively discussed in this article.

Encephalopsin (OPN3) is required for normal refractive development and the GO/GROW response to induced myopia.

Purpose: Myopia, or nearsightedness, is the most common form of refractive error and is increasing in prevalence. While significant efforts have been made to identify genetic variants that predispose individuals to myopia, these variants are believed to account for only a small portion of the myopia prevalence, leading to a feedback theory of emmetropization, which depends on the active perception of environmental visual cues. Consequently, there has been renewed interest in studying myopia in the context of light perception, beginning with the opsin family of G-protein coupled receptors (GPCRs). Refractive phenotypes have been characterized in every opsin signaling pathway studied, leaving only Opsin 3 (OPN3), the most widely expressed and blue-light sensing noncanonical opsin, to be investigated for function in the eye and refraction. Methods: Opn3 expression was assessed in various ocular tissues using an Opn3eGFP reporter. Weekly refractive development in Opn3 retinal and germline mutants from 3 to 9 weeks of age was measured using an infrared photorefractor and spectral domain optical coherence tomography (SD-OCT). Susceptibility to lens-induced myopia was then assessed using skull-mounted goggles with a -30 diopter experimental and a 0 diopter control lens. Mouse eye biometry was similarly tracked from 3 to 6 weeks. A myopia gene expression signature was assessed 24 h after lens induction for germline mutants to further assess myopia-induced changes. Results: Opn3 was found to be expressed in a subset of retinal ganglion cells and a limited number of choroidal cells. Based on an assessment of Opn3 mutants, the OPN3 germline, but not retina conditional Opn3 knockout, exhibits a refractive myopia phenotype, which manifests in decreased lens thickness, shallower aqueous compartment depth, and shorter axial length, atypical of traditional axial myopias. Despite the short axial length, Opn3 null eyes demonstrate normal axial elongation in response to myopia induction and mild changes in choroidal thinning and myopic shift, suggesting that susceptibility to lens-induced myopia is largely unchanged. Additionally, the Opn3 null retinal gene expression signature in response to induced myopia after 24 h is distinct, with opposing Ctgf, Cx43, and Egr1 polarity compared to controls. Conclusions: The data suggest that an OPN3 expression domain outside the retina can control lens shape and thus the refractive performance of the eye. Prior to this study, the role of Opn3 in the eye had not been investigated. This work adds OPN3 to the list of opsin family GPCRs that are implicated in emmetropization and myopia. Further, the work to exclude retinal OPN3 as the contributing domain in this refractive phenotype is unique and suggests a distinct mechanism when compared to other opsins.

Targeting AXL kinase sensitizes leukemic stem and progenitor cells to venetoclax treatment in acute myeloid leukemia.

The abundance of genetic abnormalities and phenotypic heterogeneities in acute myeloid leukemia (AML) poses significant challenges to the development of improved treatments. Here, we demonstrated that a key growth arrest-specific gene 6/AXL axis is highly activated in cells from patients with AML, particularly in stem/progenitor cells. We developed a potent selective AXL inhibitor that has favorable pharmaceutical properties and efficacy against preclinical patient-derived xenotransplantation (PDX) models of AML. Importantly, inhibition of AXL sensitized AML stem/progenitor cells to venetoclax treatment, with strong synergistic effects in vitro and in PDX models. Mechanistically, single-cell RNA-sequencing and functional validation studies uncovered that AXL inhibition, alone or in combination with venetoclax, potentially targets intrinsic metabolic vulnerabilities of AML stem/progenitor cells and shows a distinct transcriptomic profile and inhibits mitochondrial oxidative phosphorylation. Inhibition of AXL or BCL-2 also differentially targets key signaling proteins to synergize in leukemic cell killing. These findings have a direct translational impact on the treatment of AML and other cancers with high AXL activity.

Suppressive effects of violet light transmission on myopia progression in a mouse model of lens-induced myopia.

The prevalence of myopia has been steadily increasing for several decades, and this condition can cause extensive medical and economic issues in society. Exposure to violet light (VL), a short wavelength (360-400 nm) of visible light from sunlight, has been suggested as an effective preventive and suppressive treatments for the development and progression of myopia. However, the clinical application of VL remains unclear. In this study, we aimed to investigate the preventive and suppressive effects of VL on myopia progression. Various transmittances of VL (40%, 70%, and 100%) were tested in C57BL/6J mice with lens-induced myopia (LIM). Changes in the refractive error, axial length, and choroid thickness during the 3-week LIM were measured. The myopic shift in refractive error and difference in axial length between the 0 and -30 diopter lens was lessened in a transmission-dependent manner. Choroidal thinning, which was observed in myopic conditions, was suppressed by VL exposure and affected by its transmission. The results suggest that myopia progression can be managed using VL transmittance. Therefore, these factors should be considered for the prevention and treatment of myopia.

Effectiveness of inspector mechanism for the emergency infection prevention and control in the SARS-CoV-2 epidemic period: a self-control real-word study.

BACKGROUND: To ensure emergency infection prevention and control (IPC) can be fully supervised and monitored in coronavirus disease (COVID-19) epidemic period, a three-level inspector mechanism called "Internal self-check, Departmental cross-check, and Verification of outstanding key and difficult issues" was established in southwest China. The present study aimed to explore the effectiveness of inspector mechanism for the emergency IPC. METHODS: A self-control real-world study was conducted during COVID-19 epidemic period from 2020 to 2022. An innovative designed mobile phone application was used to realize paperless information transmission and data management. Data were compared between inspection levels using SPSS 19.0 software. RESULTS: A total of 2,800,132 supervision records were collected, including 149,137 comprehensive epidemic IPC projects, 1,410,093 personal protective equipment (PPE) use, 1,223,595 wearing and removing process of PPE and 17,307 ultraviolet light-detectable fluorescent (UV/F) surface marker. During the study period, the inspectors and subjects explored many optimized IPC measures. The compliance rate of check items has exceeded 98%, and internal self-check has a statistically significant higher rate than departmental cross-check (99.95% versus 98.74%, χ2 = 26111.479, P < 0.001). Compare with the failure rate in internal self check, the failure rate of PPE usage and wearing/removing process was statistically higher in departmental cross-check (χ2 = 1957.987, P < 0.001, χ2 = 465.610, P < 0.001, respectively). The overall clearance rate of UV/F surface markers is 87.88%, but there is no statistically significant difference over the three years of the present study (F = 2.902, P = 0.071). CONCLUSIONS: Inspector mechanism for the emergency IPC completed an incredible inspection workload and offered creative assistance to combat the COVID-19 outbreak. These methods and accumulated experiences should be helpful for us to strengthen IPC for future epidemic.

Phenome-wide association study and precision medicine of cardiovascular diseases in the post-COVID-19 era.

SARS-CoV-2 infection causes injuries of not only the lungs but also the heart and endothelial cells in vasculature of multiple organs, and induces systemic inflammation and immune over-reactions, which makes COVID-19 a disease phenome that simultaneously affects multiple systems. Cardiovascular diseases (CVD) are intrinsic risk and causative factors for severe COVID-19 comorbidities and death. The wide-spread infection and reinfection of SARS-CoV-2 variants and the long-COVID may become a new common threat to human health and propose unprecedented impact on the risk factors, pathophysiology, and pharmacology of many diseases including CVD for a long time. COVID-19 has highlighted the urgent demand for precision medicine which needs new knowledge network to innovate disease taxonomy for more precise diagnosis, therapy, and prevention of disease. A deeper understanding of CVD in the setting of COVID-19 phenome requires a paradigm shift from the current phenotypic study that focuses on the virus or individual symptoms to phenomics of COVID-19 that addresses the inter-connectedness of clinical phenotypes, i.e., clinical phenome. Here, we summarize the CVD manifestations in the full clinical spectrum of COVID-19, and the phenome-wide association study of CVD interrelated to COVID-19. We discuss the underlying biology for CVD in the COVID-19 phenome and the concept of precision medicine with new phenomic taxonomy that addresses the overall pathophysiological responses of the body to the SARS-CoV-2 infection. We also briefly discuss the unique taxonomy of disease as Zheng-hou patterns in traditional Chinese medicine, and their potential implications in precision medicine of CVD in the post-COVID-19 era.

Contralateral effect in progression and recovery of lens-induced myopia in mice.

PURPOSE: Apart from genetic factors, recent animal studies on myopia have focused on localised mechanisms. In this study, we aimed to examine the contralateral effects of monocular experimental myopia and recovery, which cannot be explained by a mere local mechanism. METHODS: One eye of 3-week-old C57BL/6 male mice was fitted with a -30 dioptre (D) lens. The mice were distributed into two groups based on different conditions in the contralateral eye: either no lens (NLC) (n = 10) or a Plano lens on the contralateral eye (PLC) group (n = 6). Mice receiving no treatment on either eye were set as a control group (n = 6). Lenses were removed after 3 weeks of myopia induction. All mice were allowed to recover for 1 week in the same environment. Refractive status, axial length (AL) and choroidal thickness were measured before myopia induction, after 1 and 3 weeks of lens wear and after 1 week of recovery. RESULTS: One week after removing the lenses, complete recovery was observed in the eyes that wore the -30 D lenses. In both the PLC and NLC groups, the refractive status showed a myopic shift after lens removal. Additionally, the choroid was significantly thinned in these eyes. The -30 D wearing eye showed a significant increase in AL after 3 weeks of lens wear. While the AL of the -30 D wearing eye ceased to grow after the lens was removed, the AL in the PLC and NLC contralateral eyes increased, and the binocular ALs gradually converged. CONCLUSIONS: Recovery of lens-induced myopia was observed in mouse models. In the fellow eyes, the effects, including thinning of the choroid and changes in refractive status, were triggered by contralateral visual cues.

Mettl14-mediated m6A modification is essential for visual function and retinal photoreceptor survival.

BACKGROUND: As the most abundant epigenetic modification of eukaryotic mRNA, N6-methyladenosine (m6A) modification has been shown to play a role in mammalian nervous system development and function by regulating mRNA synthesis and degeneration. However, the role of m6A modification in retinal photoreceptors remains unknown. RESULTS: We generated the first retina-specific Mettl14-knockout mouse models using the Rho-Cre and HRGP-Cre lines and investigated the functions of Mettl14 in retinal rod and cone photoreceptors. Our data showed that loss of Mettl14 in rod cells causes a weakened scotopic photoresponse and rod degeneration. Further study revealed the ectopic accumulation of multiple outer segment (OS) proteins in the inner segment (IS). Deficiency of Mettl14 in cone cells led to the mislocalization of cone opsin proteins and the progressive death of cone cells. Moreover, Mettl14 depletion resulted in drastic decreases in METTL3/WTAP levels and reduced m6A methylation levels. Mechanistically, transcriptomic analyses in combination with MeRIP-seq illustrated that m6A depletion via inactivation of Mettl14 resulted in reduced expression levels of multiple phototransduction- and cilium-associated genes, which subsequently led to compromised ciliogenesis and impaired synthesis and transport of OS-residing proteins in rod cells. CONCLUSIONS: Our data demonstrate that Mettl14 plays an important role in regulating phototransduction and ciliogenesis events and is essential for photoreceptor function and survival, highlighting the importance of m6A modification in visual function.