BATF promotes extramedullary infiltration through TGF-ß1/Smad/MMPs axis in acute myeloid leukemia.

Acute myeloid leukemia (AML) is one of the most prevalent types of leukemia and is challenging to cure for most patients. Basic Leucine Zipper ATF-Like Transcription Factor (BATF) has been reported to participate in the development and progression of numerous tumors. However, its role in AML is largely unknown. In this study, the expression and prognostic value of BATF were examined in AML. Our results demonstrated that BATF expression was upregulated in AML patients, which was significantly correlated with poor clinical characteristics and survival. Afterward, functional experiments were performed after knocking down or overexpressing BATF by transfecting small interfering RNAs and overexpression plasmids into AML cells. Our findings revealed that BATF promoted the migratory and invasive abilities of AML cells in vitro and in vivo. Moreover, the target genes of BATF were searched from databases to explore the binding of BATF to the target gene using ChIP and luciferase assays. Notably, our observations validated that BATF is bound to the promoter region of TGF-ß1, which could transcriptionally enhance the expression of TGF-ß1 and activate the TGF-ß1/Smad/MMPs signaling pathway. In summary, our study established the aberrantly high expression of BATF and its pro-migratory function via the TGF-ß1-Smad2/3-MMP2/9 axis in AML, which provides novel insights into extramedullary infiltration of AML.

Inflammation in pathogenesis of chronic pain: Foe and friend.

Chronic pain is a refractory health disease worldwide causing an enormous economic burden on individuals and society. Accumulating evidence suggests that inflammation in the peripheral nervous system (PNS) and central nervous system (CNS) is the major factor in the pathogenesis of chronic pain. The inflammation in the early- and late phase may have distinctive effects on the initiation and resolution of pain, which can be viewed as friend or foe. On the one hand, painful injuries lead to the activation of glial cells and immune cells in the PNS, releasing pro-inflammatory mediators, which contribute to the sensitization of nociceptors, leading to chronic pain; neuroinflammation in the CNS drives central sensitization and promotes the development of chronic pain. On the other hand, macrophages and glial cells of PNS and CNS promote pain resolution via anti-inflammatory mediators and specialized pro-resolving mediators (SPMs). In this review, we provide an overview of the current understanding of inflammation in the deterioration and resolution of pain. Further, we summarize a number of novel strategies that can be used to prevent and treat chronic pain by controlling inflammation. This comprehensive view of the relationship between inflammation and chronic pain and its specific mechanism will provide novel targets for the treatment of chronic pain.

Changing patterns of the East Asian monsoon drive shifts in migration and abundance of a globally important rice pest.

Numerous insects including pests and beneficial species undertake windborne migrations over hundreds of kilometers. In East Asia, climate-induced changes in large-scale atmospheric circulation systems are affecting wind-fields and precipitation zones and these, in turn, are changing migration patterns. We examined the consequences in a serious rice pest, the brown planthopper (BPH, Nilaparvata lugens) in East China. BPH cannot overwinter in temperate East Asia, and infestations there are initiated by several waves of windborne spring or summer migrants originating from tropical areas in Indochina. The East Asian summer monsoon, characterized by abundant rainfall and southerly winds, is of critical importance for these northward movements. We analyzed a 42-year dataset of meteorological parameters and catches of BPH from a standardized network of 341 light-traps in South and East China. We show that south of the Yangtze River during summer, southwesterly winds have weakened and rainfall increased, while the summer precipitation has decreased further north on the Jianghuai Plain. Together, these changes have resulted in shorter migratory journeys for BPH leaving South China. As a result, pest outbreaks of BPH in the key rice-growing area of the Lower Yangtze River Valley (LYRV) have declined since 2001. We show that these changes to the East Asian summer monsoon weather parameters are driven by shifts in the position and intensity of the Western Pacific subtropical high (WPSH) system that have occurred during the last 20 years. As a result, the relationship between WPSH intensity and BPH immigration that was previously used to predict the size of the immigration to the LYRV has now broken down. Our results demonstrate that migration patterns of a serious rice pest have shifted in response to the climate-induced changes in precipitation and wind pattern, with significant consequences for the population management of migratory pests.

Importance of circulating adipocytokines in multiple myeloma: a systematic review and meta-analysis based on case-control studies.

BACKGROUND: Adipocytes and their products, adipocytokines, play important roles in the generation and development of multiple myeloma (MM). Studies have demonstrated some adipocytokines to be associated with MM, although those results are controversial. Therefore, we conducted a meta-analysis to verify the association of adipocytokines with MM. METHODS: We performed a systematic retrieval of literature published prior to 26 October 2021. Standardized mean difference (SMD) with a 95% confidence interval (CI) was calculated to evaluate pooled effects. Subgroup analysis and meta-regression analysis were conducted to detect sources of heterogeneity. Sensitivity analysis was performed to evaluate the stability of the study. Publication bias was assessed by funnel plots and Egger's linear regression test. RESULTS: Ten eligible studies with 1269 MM patients and 2158 controls were included. The pooled analyses indicated that circulating leptin levels of MM patients were significantly higher than control levels (SMD= 0.87, 95%CI: 0.33 to 1.41), while the circulating adiponectin levels in MM patients were significantly lower than controls with a pooled SMD of -0.49 (95%CI: -0.78 to -0.20). The difference of circulating resistin levels were not significant between MM patients and controls (SMD= -0.08, 95%CI: -0.55 to 0.39). Subgroup analysis and meta-regression analysis found that sample size, age, and sex were possible sources of heterogeneity. Sensitivity analysis demonstrated our pooled results to be stable. CONCLUSION: Decreased circulating adiponectin and increased leptin levels were associated with the occurrence and development of MM. Adiponectin and leptin may be potential biomarkers and therapeutic targets for MM.

Development of a novel nano-based detection card by electrospinning for rapid and sensitive analysis of pesticide residues.

BACKGROUND: Increasing food safety awareness of consumers promotes the development of rapid and sensitive detection techniques for pesticide residues. In this study, a new type of rapid detection card for organophosphorus and carbamate pesticide residues was developed by electrospinning. The card involved enzyme fiber mat (EFM) and substrate fiber mat (SFM) which were prepared by mixing poly(vinyl alcohol) with acetylcholinesterase (AChE) and indolyl acetate (IA), respectively. RESULTS: The mean diameter of fibers was 240 ± 53 nm for EFM and 387 ± 84 nm for SFM. Results of Fourier transform infrared and X-ray photoelectron spectroscopies confirmed that AChE and IA were successfully encapsulated into the fibers. The minimum concentrations of AChE and IA for effective detection were 1 and 3 mg mL-1 , respectively, and the optimal detection time was 15 min. The limits of detection for this card were 0.5 mg L-1 for omethoate, 1.5 mg L-1 for malathion, 0.1 mg L-1 for carbaryl and 0.02 mg L-1 for carbofuran. The detection card exhibited good storage stability and its activity could be maintained when stored at room temperature for at least 4 months. Additionally, the EFM can be reused three times. CONCLUSIONS: The detection card obtained here was superior to a commercial card in detecting pesticide residues in real food samples. Hence, this electrospun detection card has potential for simple, rapid and sensitive analysis of pesticide residues. © 2020 Society of Chemical Industry.

[Network pharmacology research and experimental validation of "Coptidis Rhizoma-Pinelliae Rhizoma" in treating gastric carcinoma].

To investigate the mechanism of Coptidis Rhizoma-Pinelliae Rhizoma in the treatment of gastric cancer based on syste-matic pharmacology and data mining. The chemical constituents of Coptidis Rhizoma and Pinelliae Rhizoma were obtained from Traditio-nal Chinese Medicine Systems Pharmacology Database(TCMSP) and Shanghai Institute of Organic Chemistry database of Chinese Academy of Sciences by data mining. Then the active ingredients were screened by ADME, and the targets of the active ingredients were predicted by chemometrics. Molecular docking and free energy analysis were used to verify and screen the targets, so as to obtain the therapeutic targets of Coptidis Rhizoma and Pinelliae Rhizoma for gastric cancer. The biological functions, diseases and related signal pathways corresponding to the targets were further analyzed, and then the multi-component, multi-target and multi-channel mechanism of Coptidis Rhizoma and Pinelliae Rhizoma for gastric cancer were elaborated. Finally, MTT, Scratch, Transwell and Western blot experiments were carried out to verify the inhibitory effect of Coptidis Rhizoma and Pinelliae Rhizoma on human gastric cancer cell line MKN-45. A total of 46 active ingredients of Coptidis Rhizoma and Pinelliae Rhizoma were screened, as well as 77 corresponding targets, 38 targets related to gastric cancer and its complications, top 8 related signaling pathways, and top 20 target molecular functions by GO analysis. Cell experiments also proved that Coptidis Rhizoma and Pinelliae Rhizoma could effectively inhibit the proliferation, invasion and migration ability of gastric cancer cells and inhibit TGF-ß1-induced Wnt/ß-catenin signaling pathway activation. Coptidis Rhizoma and Pinelliae Rhizoma drug pair has many active ingredients, which can regulate nervous and mental system, cell cycle, cell differentiation and metastasis, and enhance anti-inflammatory and immune functions, playing a synergistic anti-cancer role in gastric cancer and its complications and providing new ideas for the follow-up clinical treatment of gastric cancer.

[Characteristics of vocalization in children with autism spectrum disorder during the still-face paradigm].

OBJECTIVE: To study the characteristics of vocalization during the still-face paradigm (SFP) before the age of 2 years and their correlation with the severity of autism spectrum disorder (ASD) symptoms at diagnosis in children with ASD. METHODS: A total of 43 children aged 7-23 months, who were suspected of ASD, were enrolled as the suspected ASD group, and 37 typical development (TD) children, aged 7-23 months, were enrolled as the TD group. The frequency and durations of vocalization in the SFP were measured. The children in the suspected ASD group were followed up to the age of 2 years, and 34 children were diagnosed with ASD. Autism Diagnostic Observation Schedule (ADOS) was used to assess the severity of symptoms. The correlation of the characteristics of vocalization before the age of 2 years with the severity of ASD symptoms was analyzed. RESULTS: Compared with the TD group, the ASD group had significant reductions in the frequency and durations of meaningful vocalization and vocalization towards people and a significant increase in the duration of vocalization toward objects (P<0.05). The Spearman correlation analysis showed that in the ASD group, the frequency and durations of total vocalization, non-speech vocalization, babbling, vocalization towards people, and vocalization towards objects were negatively correlated with the score of communication in ADOS (P<0.05). The frequency and durations of total vocalization, babbling, and vocalization towards people and the duration of vocalization towards objects were negatively correlated with the score of reciprocal social interaction in ADOS (P<0.05). The frequency of total vocalization, the duration of babbling, and the frequency and duration of vocalization towards people were negatively correlated with the score of play in ADOS (P<0.05). The frequency of total vocalization and non-speech vocalization and the frequency and durations of vocalization towards people were negatively correlated with the score of stereotyped behaviors and restricted interests in ADOS (P<0.05). The multiple linear regression analysis showed that the frequency of total vocalization was a negative predictive factor for the score of communication in ADOS (P<0.001), and the duration of vocalization towards people was a negative predictive factor for the score of reciprocal social interaction in ADOS (P<0.05). CONCLUSIONS: SFP can better highlight the abnormal vocalization of ASD children before the age of 2 years, and such abnormalities can predict the severity of ASD symptoms early.

CNOT3 contributes to cisplatin resistance in lung cancer through inhibiting RIPK3 expression.

Chemotherapeutic resistance always results in poor clinical outcomes of cancer patients and its intricate mechanisms are large obstacles in overcoming drug resistance. CCR4-NOT transcription complex subunit 3 (CNOT3), a post-translational regulator, is suggested to be involved in cancer development and progression. However, its role in chemotherapeutic resistance is not well understood. In this study, after screening the CNOT3 mRNA in a cancer microarray database called Oncomine and examining the expression levels of CNOT3 mRNA in normal tissues and lung cancer tissues, we found that CNOT3 was up-regulated in lung cancer tissues. Besides, its high-expression was associated with poor prognosis of lung cancer patients. We also found higher expression level of CNOT3 and lower expression level of receptor-interacting protein kinase 3 (RIPK3) in cisplatin-resistant A549 (A549/DDP) cells, and knocking down CNOT3 expression could sensitize A549/DDP cells to cisplatin-induced apoptosis. We demonstrated that CNOT3 depletion up-regulated the expression level of RIPK3 and the enhanced apoptosis was mediated by the elevated RIPK3 to further trigger Caspase 8 activation. Taken together, our results reveal a role of CNOT3 in cisplatin resistance of lung cancer and provide a potential target for lung cancer therapy.

[Screening of nucleic acid aptamer of lung cancer cells based on cell exponential enrichment ligand system evolution and its application in tumor diagnosis and treatment].

Nucleic acid aptamer is an oligonucleotide sequence screened by the exponential enrichment ligand system evolution technology (SELEX). Previous studies have shown that nucleic acid aptamer has a good application prospect in tumor diagnosis and treatment. Therefore, we reviewed the selection and identification of nucleic acid aptamer of lung cancer cells in recent years, and discussed the effect of aptamer as targeting drugs and targeting vectors on the diagnosis of tumors, which provide a new idea for early diagnosis and treatment of tumor.

2,3,5,4'-Tetrahydroxystilbene-2-O-ß-D-glucoside protects murine hearts against ischemia/reperfusion injury by activating Notch1/Hes1 signaling and attenuating endoplasmic reticulum stress.

2,3,5,4'-Tetrahydroxystilbene-2-O-ß-D-glucoside (TSG) is a water-soluble active component extracted from Polygonum multiflorum Thunb. A number of studies demonstrate that TSG exerts cardioprotective effects. Since endoplasmic reticulum (ER) stress plays a key role in myocardial ischemia/reperfusion (MI/R)-induced cell apoptosis, we sought to determine whether modulation of the ER stress during MI/R injury was involved in the cardioprotective action of TSG. Male mice were treated with TSG (60 mg·kg-1·d-1, ig) for 2 weeks and then were subjected to MI/R surgery. Pre-administration of TSG significantly improved post-operative cardiac function, and suppressed MI/R-induced myocardial apoptosis, evidenced by the reduction in the myocardial apoptotic index, serum levels of LDH and CK after 6 h of reperfusion. TSG (0.1-1000 µmol/L) did not affect the viability of cultured H9c2 cardiomyoblasts in vitro, but pretreatment with TSG dose-dependently decreased simulated ischemia/reperfusion (SIR)-induced cell apoptosis. Furthermore, both in vivo and in vitro studies revealed that TSG treatment activated the Notch1/Hes1 signaling pathway and suppressed ER stress, as evidenced by increasing Notch1, Notch1 intracellular domain (NICD), Hes1, and Bcl-2 expression levels and by decreasing p-PERK/PERK ratio, p-eIF2α/eIF2α ratio, and ATF4, CHOP, Bax, and caspase-3 expression levels. Moreover, the protective effects conferred by TSG on SIR-treated H9c2 cardiomyoblasts were abolished by co-administration of DAPT (the Notch1 signaling inhibitor). In summary, TSG ameliorates MI/R injury in vivo and in vitro by activating the Notch1/Hes1 signaling pathway and attenuating ER stress-induced apoptosis.

Berberine protects rat heart from ischemia/reperfusion injury via activating JAK2/STAT3 signaling and attenuating endoplasmic reticulum stress.

AIM: Berberine (BBR), an isoquinoline-derived alkaloid isolated from Rhizoma coptidis, exerts cardioprotective effects. Because endoplasmic reticulum (ER) stress plays a pivotal role in myocardial ischemia/reperfusion (MI/R)-induced apoptosis, it was interesting to examine whether the protective effects of BBR resulted from modulating ER stress levels during MI/R injury, and to define the signaling mechanisms in this process. METHODS: Male rats were treated with BBR (200 mg · kg(-1) · d(-1), ig) for 2 weeks, and then subjected to MI/R surgery. Cardiac dimensions and function were assessed using echocardiography. Myocardial infarct size and apoptosis was examined. Total serum LDH levels and CK activities, superoxide production, MDA levels and the antioxidant SOD activities in heart tissue were determined. An in vitro study was performed on cultured rat embryonic myocardium-derived cells H9C2 exposed to simulated ischemia/reperfusion (SIR). The expression of apoptotic, ER stress-related and signaling proteins were assessed using Western blot analyses. RESULTS: Pretreatment with BBR significantly reduced MI/R-induced myocardial infarct size, improved cardiac function, and suppressed myocardial apoptosis and oxidative damage. Furthermore, pretreatment with BBR suppressed MI/R-induced ER stress, evidenced by down-regulating the phosphorylation levels of myocardial PERK and eIF2α and the expression of ATF4 and CHOP in heart tissues. Pretreatment with BBR also activated the JAK2/STAT3 signaling pathway in heart tissues, and co-treatment with AG490, a specific JAK2/STAT3 inhibitor, blocked not only the protective effects of BBR, but also the inhibition of BBR on MI/R-induced ER stress. In H9C2 cells, treatment with BBR (50 µmol/L) markedly reduced SIR-induced cell apoptosis, oxidative stress and ER stress, which were abolished by transfection with JAK2 siRNA. CONCLUSION: BBR ameliorates MI/R injury in rats by activating the AK2/STAT3 signaling pathway and attenuating ER stress-induced apoptosis.

Identification and functional analysis of a SLC33A1: c.339T>G (p.Ser113Arg) variant in the original SPG42 family.

Using whole-exome sequencing, we surveyed all the potential pathogenic variants in an SPG42 family and found five SNPs and four indels that are shared by two patients and lie in the mapped region. Two variants, SLC33A1 p.Ser113Arg and VEPH1 p.Gln433His, cosegregated with the disease. However, VEPH1 p.Gln433His was predicted to be tolerated, thus leaving SLC33A1 p.Ser113Arg as the most plausible causal variant in this family. We found that the phosphorylated SMAD1/5/8 (P-SMAD1/5/8) and BMP receptor type 1A (BMPR1A) were substantially upregulated in fibroblasts derived from an SPG42 individual. Slc33a1 knockdown zebrafish, which exhibited defects in morphology and axon outgrowth, also showed a significant elevation in the level of P-smad1/5/8. While the phenotypes in slc33a1 knockdown zebrafish could be rescued by human wild-type SLC33A1 mRNA, this rescuing effect was diminished by coinjected mutant mRNA encoding p.Ser113Arg, indicating that p.Ser113Arg variant acts in a dominant-negative manner. Importantly, pharmacological blockade of BMPR1 activity by dorsomorphin could efficiently rescue the phenotypic defects in slc33a1 knockdown zebrafish. These results indicate that SLC33A1 can negatively regulate BMP signaling.

Unactuated and Actuated States Simultaneously Constrained Optimal Trajectory Planning-Based Path-Following Control for Underactuated Robots.

For underactuated robots working in complex environments, an important objective is to drive all variables (particularly for unactuated end-effectors) to move along the specific path and restrict positions/velocities to avoid obstacles, rather than using only point-to-point control. Unfortunately, most path planning methods are only suitable to fully actuated systems or depend on linearized models. The main motivations of our work are to directly fulfill motion constraints and achieve path following for both actuated and unactuated states (e.g., payload swing of cranes) when lacking effective control inputs. To this end, this article presents a new time-optimal trajectory planning-based motion control method for general underactuated robots. By constructing auxiliary signals (in Cartesian space) to express all actuated/unactuated variables (in joint space), their position/velocity constraints are converted into some convex/nonconvex inequalities related to a to-be-optimized path parameter and its derivatives. Then, an optimization algorithm is constructed to solve the available path parameter and derive a group of time-optimal trajectories for actuated states. As we know, this is the first study to ensure path following and necessary full-state constraints for actuated/unactuated states. Then, a tradeoff among path-constrained motions, time optimization, and state constraints is achieved together. This article takes the rotary crane as an example and provides detailed analysis of calculating desired trajectories based on the proposed planning frame, whose effectiveness is also verified through hardware experiments.

Interfacial Protein Fibril Polymorphisms Regulate In Vivo Adipose Expansion for Control of Obesity.

Obesity is becoming a worldwide pandemic. Interfacial engineering of food lipid is expected to inhibit diet-induced obesity without damage to the eating enjoyment brought by high-fat diets. Unfortunately, this strategy has not been achieved yet. After screening different plant proteins, bromelain and papain were found to form wormlike and long-straight protein fibrils, respectively. The conversion of long-straight amyloid-like fibrils to wormlike fibrils was demonstrated in the fibrillation of bromelain. Using oil-in-water high internal phase emulsions (HIPEs) as a proof of concept, bromelain fibrils showed dramatically stronger interfacial stabilization capabilities than papain fibrils with high application potentials in the real-world formulation of high-fat food products such as mayonnaise. Compared with papain fibrils, oral administration of HIPEs stabilized by bromelain fibrils resulted in substantially higher fecal lipid contents and significantly decreased expression levels of the genes related to lipid absorption and transport in the intestine, including CD36, FATP-2, FATP-4, and APOA-4, without a difference in intervening gut microbiota. Consequently, dramatically less lipid absorption in the small intestine, markedly smaller chylomicron particles in the plasma, lower serum triglycerides, and controlled energy and lipid metabolism, as well as the inhibition of adipose expansion and overweight, were observed in the group with gavage of HIPEs stabilized by the bromelain fibrils rather than the papain fibrils. Furthermore, with the same calorie, substitution of all the fat in the standard high-fat feed of mice with the HIPEs emulsified by the bromelain fibrils showed a significantly stronger effect than the ones prepared by the papain fibrils on preventing high-fat-diet (HFD)-induced obesity including alleviation of adipose expansion and inflammation as well as fatty liver, also via inhibiting the absorption and transport of lipid in the intestine. The effect is ascribed to the suppressed lipolysis caused by a more compact and elastic interfacial layer formed by the wormlike fibrils than that of the long-straight fibrils, which are resistant to gastric environments and replacement by bile acids in digestion. Therefore, we provide an appealing and general strategy for controlling obesity by reducing the supply of free fatty acids (FAs) for absorption in the enteric lumen through protein fibril polymorphisms at the interface.

KIF22 promotes multiple myeloma progression by regulating the CDC25C/CDK1/cyclinB1 pathway.

PURPOSE: Multiple myeloma (MM) is an incurable hematological malignancy characterized by clonal proliferation of malignant plasma B cells in bone marrow, and its pathogenesis remains unknown. The aim of this study was to determine the role of kinesin family member 22 (KIF22) in MM and elucidate its molecular mechanism. METHODS: The expression of KIF22 was detected in MM patients based upon the public datasets and clinical samples. Then, in vitro assays were performed to investigate the biological function of KIF22 in MM cell lines, and subcutaneous xenograft models in nude mice were conducted in vivo. Chromatin immunoprecipitation (ChIP) and luciferase reporter assay were used to determine the mechanism of KIF22-mediated regulation. RESULTS: The results demonstrated that the expression of KIF22 in MM patients was associated with several clinical features, including gender (P = 0.016), LDH (P < 0.001), ß2-MG (P = 0.003), percentage of tumor cells (BM) (P = 0.002) and poor prognosis (P < 0.0001). Furthermore, changing the expression of KIF22 mainly influenced the cell proliferation in vitro and tumor growth in vivo, and caused G2/M phase cell cycle dysfunction. Mechanically, KIF22 directly transcriptionally regulated cell division cycle 25C (CDC25C) by binding its promoter and indirectly influenced CDC25C expression by regulating the ERK pathway. KIF22 also regulated CDC25C/CDK1/cyclinB1 pathway. CONCLUSION: KIF22 could promote cell proliferation and cell cycle progression by transcriptionally regulating CDC25C and its downstream CDC25C/CDK1/cyclinB1 pathway to facilitate MM progression, which might be a potential therapeutic target in MM.

Augmented microglial endoplasmic reticulum-mitochondria contacts mediate depression-like behavior in mice induced by chronic social defeat stress.

Extracellular ATP (eATP) signaling through the P2X7 receptor pathway is widely believed to trigger NLRP3 inflammasome assembly in microglia, potentially contributing to depression. However, the cellular stress responses of microglia to both eATP and stress itself remain largely unexplored. Mitochondria-associated membranes (MAMs) is a platform facilitating calcium transport between the endoplasmic reticulum (ER) and mitochondria, regulating ER stress responses and mitochondrial homeostasis. This study aims to investigate how MAMs influence microglial reaction and their involvement in the development of depression-like symptoms in response to chronic social defeat stress (CSDS). CSDS induced ER stress, MAMs' modifications, mitochondrial damage, and the formation of the IP3R3-GRP75-VDAC1 complex at the ER-mitochondria interface in hippocampal microglia, all concomitant with depression-like behaviors. Additionally, exposing microglia to eATP to mimic CSDS conditions resulted in analogous outcomes. Furthermore, knocking down GRP75 in BV2 cells impeded ER-mitochondria contact, calcium transfer, ER stress, mitochondrial damage, mitochondrial superoxide production, and NLRP3 inflammasome aggregation induced by eATP. In addition, reduced GRP75 expression in microglia of Cx3cr1CreER/+Hspa9f/+ mice lead to reduce depressive behaviors, decreased NLRP3 inflammasome aggregation, and fewer ER-mitochondria contacts in hippocampal microglia during CSDS. Here, we show the role of MAMs, particularly the formation of a tripartite complex involving IP3R3, GRP75, and VDAC1 within MAMs, in facilitating communication between the ER and mitochondria in microglia, thereby contributing to the development of depression-like phenotypes in male mice.

Transcatheter mitral valve replacement to treat severe calcified rheumatic native mitral stenosis: role of three-dimensional printing-a case report.

Background: Rheumatic heart disease is a major disease that seriously affects human health and survival worldwide. Rheumatic mitral stenosis often has relatively complex pathological changes, and its progression leads to various manifestations of mitral valve dysfunction and adverse clinical events. Case summary: We present a 60-year-old patient who developed chest tightness, shortness of breath, and bilateral lower limb oedema in 2018 (New York Heart Association functional class III). Systolic and diastolic murmurs could be heard in the mitral auscultation area. In December 2021, the patient was admitted to the hospital with stroke. Thereafter, transthoracic echocardiography and computed tomography were performed, and the progress of rheumatic mitral stenosis was recorded. Due to the patient's high surgical risk, a patient-specific three-dimensional printed model was used to observe anatomical structures and simulate main procedures, and the surgeons finally chose to perform transcatheter mitral valve replacement. The balloon-expandable bioprothesis was released from the right femoral artery to treat the rheumatic mitral stenosis. The patient remained asymptomatic at the 6-month follow-up. Discussion: For patients with rheumatic mitral stenosis with high surgical risk, it is feasible to conduct transcatheter mitral valve replacement under the guidance of three-dimensional printing.

Epidemiological Characteristics and Spatiotemporal Distribution Patterns of Human Norovirus Outbreaks in China, 2012-2018.

Objective: To clarify the epidemiological characteristics and spatial distribution patterns of human norovirus outbreaks in China, identify high-risk areas, and provide guidance for epidemic prevention and control. Methods: This study analyzed 964 human norovirus outbreaks involving 50,548 cases in 26 provinces reported from 2012 to 2018. Epidemiological analysis and spatiotemporal scanning analysis were conducted to analyze the distribution of norovirus outbreaks in China. Results: The outbreaks showed typical seasonality, with more outbreaks in winter and fewer in summer, and the total number of infected cases increased over time. Schools, especially middle schools and primary schools, are the most common settings of norovirus outbreaks, with the major transmission route being life contact. More outbreaks occurred in southeast coastal areas in China and showed significant spatial aggregation. The highly clustered areas of norovirus outbreaks have expanded northeast over time. Conclusion: By identifying the epidemiological characteristics and high-risk areas of norovirus outbreaks, this study provides important scientific support for the development of preventive and control measures for norovirus outbreaks, which is conducive to the administrative management of high-risk settings and reduction of disease burden in susceptible areas.

Targeting the up-regulated CNOT3 reverses therapeutic resistance and metastatic progression of EGFR-mutant non-small cell lung cancer.

Lung cancer is the leading cause of cancer-related mortality worldwide. CNOT3, a subunit of the CCR4-NOT complex, has recently been suggested to be overexpressed in lung cancer and involved in tumor malignancy. However, its precise role and the underlying mechanisms still need to be fully revealed. In the present study, we found in lung cancer cells the expression of CNOT3 could be regulated by EGFR signaling pathway and c-Jun, a transcription factor downstream of EGFR, transcriptionally regulated its expression. Interestingly, CNOT3 could inversely regulate the expression of c-Jun via modulating its translation. Thus, a feedback loop existed between c-Jun and CNOT3. CNOT3 reduction post EGFR blockade facilitated the drug-induced cell death, and simultaneously inhibited cell proliferation via impacting TSC1/mTOR axis. Whereas, further up-regulation of the CNOT3 expression was observed in gefitinib-resistant cells, which dampened gefitinib sensitivity. Mechanically, the elevation of CNOT3 was induced by the bypass activation of HER2/c-Jun signaling. Depleting CNOT3 in vitro and in vivo sensitized the drug-resistant cells to gefitinib treatment and inhibited metastatic progression. These results give novel insights into the role of CNOT3 in lung cancer malignancy and provide a theoretical basis for the development of therapeutic strategies to solve acquired resistance to EGFR-TKIs.

N6-methyladenosine reader YTHDF2 promotes multiple myeloma cell proliferation through EGR1/p21cip1/waf1/CDK2-Cyclin E1 axis-mediated cell cycle transition.

Multiple myeloma (MM) is the second most common hematological malignancy. N6-methyladenosine (m6A) is the most abundant RNA modification. YTH domain-containing family protein 2 (YTHDF2) recognizes m6A-cotaining RNAs and accelerates degradation to regulate cancer progression. However, the role of YTHDF2 in MM remains unclear. We investigated the expression levels and prognostic role of YTHDF2 in MM, and studied the effect of YTHDF2 on MM proliferation and cell cycle. The results showed that YTHDF2 was highly expressed in MM and was an independent prognostic factor for MM survival. Silencing YTHDF2 suppressed cell proliferation and caused the G1/S phase cell cycle arrest. RNA immunoprecipitation (RIP) and m6A-RIP (MeRIP) revealed that YTHDF2 accelerated EGR1 mRNA degradation in an m6A-dependent manner. Moreover, overexpression of YTHDF2 promoted MM growth via the m6A-dependent degradation of EGR1 both in vitro and in vivo. Furthermore, EGR1 suppressed cell proliferation and retarded cell cycle by activating p21cip1/waf1 transcription and inhibiting CDK2-cyclinE1. EGR1 knockdown could reverse the inhibited proliferation and cell cycle arrest upon YTHDF2 knockdown. In conclusion, the high expression of YTHDF2 promoted MM cell proliferation via EGR1/p21cip1/waf1/CDK2-cyclin E1 axis-mediated cell cycle transition, highlighting the potential of YTHDF2 as an effective prognostic biomarker and a promising therapeutic target for MM.