Search

This study aimed to investigate the therapeutic potential of human umbilical cord mesenchymal stem cells derived exosomes (hUCMSC-Exo) in acute liver failure (ALF) in mice as well as its underlying mechanism. We found that a single tail vein administration of hucMSC-Exo effectively enhanced the survival rate, inhibited apoptosis in hepatocytes, and improved liver function in APAP-induced mouse model of ALF. Furthermore, the deletion of glutathione (GSH) and superoxide dismutase (SOD), generation of malondialdehyde (MDA), and the over production of cytochrome P450 E1 (CYP2E1) and 4-hydroxynonenal (4-HNE) caused by APAP were also inhibited by hucMSC-Exo, indicating that hucMSC-Exo inhibited APAP-induced apoptosis of hepatocytes by reducing oxidative stress. Moreover, hucMSC-Exo significantly down-regulated the levels of inflammatory cytokines IL-6, IL-1β, and TNF-α in APAP-treated livers. Western blot showed that hucMSC-Exo significantly promoted the activation of ERK1/2 and IGF-1R/PI3K/AKT signaling pathways in APAP-injured LO2 cells, resulting in the inhibition of apoptosis of LO2 cells. Importantly, PI3K inhibitor LY294002 and ERK1/2 inhibitor PD98059 could reverse the function of hucMSC-Exo on APAP-injured LO2 cells in some extent. Our results suggest that hucMSC-Exo offer antioxidant hepatoprotection against APAP in vitro and in vivo by inhibitiing oxidative stress-induced apoptosis via upregulation of ERK1/2 and PI3K/AKT signaling pathways.

Human fatty acid synthase (FASN) is the sole cytosolic enzyme responsible for de novo lipid synthesis. FASN is essential for cancer cell survival and contributes to drug and radiation resistance by up-regulating DNA damage repair but not required for most non-lipogenic tissues. Thus, FASN is an attractive target for drug discovery. However, despite decades of effort in targeting FASN, no FASN inhibitors have been approved due to poor pharmacokinetics or toxicities. Here, we show that the FDA-approved proton pump inhibitors (PPIs) effectively inhibit FASN and suppress breast cancer cell survival. PPI inhibition of FASN leads to suppression of non-homologous end joining repair of DNA damages by reducing FASN-mediated PARP1 expression, resulting in apoptosis from oxidative DNA damages and sensitization of cellular resistance to doxorubicin and ionizing radiation. Mining electronic medical records of 6754 breast cancer patients showed that PPI usage significantly increased overall survival and reduced disease recurrence of these patients. Hence, PPIs may be repurposed as anticancer drugs for breast cancer treatments by targeting FASN to overcome drug and radiation resistance.

Magnetic Resonance Fingerprinting (MRF) is a novel technique that simultaneously estimates multiple tissue-related parameters, such as the longitudinal relaxation time T1, the transverse relaxation time T2, off resonance frequency B0 and proton density, from a scanned object in just tens of seconds. However, the MRF method suffers from aliasing artifacts because it significantly undersamples the k-space data. In this work, we propose a compressed sensing (CS) framework for simultaneously estimating multiple tissue-related parameters based on the MRF method. It is more robust to low sampling ratio and is therefore more efficient in estimating MR parameters for all voxels of an object. Furthermore, the MRF method requires identifying the nearest atoms of the query fingerprints from the MR-signal-evolution dictionary with the L2 distance. However, we observed that the L2 distance is not always a proper metric to measure the similarities between MR Fingerprints. Adaptively learning a distance metric from the undersampled training data can significantly improve the matching accuracy of the query fingerprints. Numerical results on extensive simulated cases show that our method substantially outperforms state-of-the-art methods in terms of accuracy of parameter estimation.

Objective. Peer support is a concept of substantial significance to health scientists and practitioners today due to its focus shifting from disease treatment to health promotion. Effective incorporation peer relationships in support-enhancing interventions could improve quality care and health outcomes. More and more cases of chronic obstructive pulmonary disease (COPD) have been diagnosed in nonsmokers. In this study, the effects of peer-support nursing intervention on the pulmonary function and quality of life of nonsmoking patients with COPD were investigated. Methods. A total of 100 COPD nonsmoking patients admitted to our hospital from October 2018 to October 2020 were selected as study subjects. All nonsmoking patients were in accordance with the guidelines of COPD diagnosis and treatment issued by the Respiratory Medicine Branch of Chinese Medical Association, and they were not in the habit of smoking. According to the different interventions, the nonsmoking patients were divided into the control group (n = 50) and the observation group (n = 50). Among them, nonsmoking patients in the control group received routine care, and nonsmoking patients in the observation group received routine care and peer-support nursing. The difference on the scores of social support, self-management efficacy, healthy lifestyle, and the distance of six-minute walking were to be compared between the two groups before and after the intervention. Results. There was no significant statistical difference on the general information between the two groups in terms of age, gender, and course of disease ( P > 0.05 ). Before intervention, the social support score involving subjective support, objective support, utilization of support, and total score revealed slight difference between the two groups ( P > 0.05 ). However, after the intervention, the subjective support, utilization of support, and total score remained statistically different between the two groups ( P < 0.05 ), and the objective support showed no significant difference between the two groups ( P > 0.05 ). Before intervention, there was no statistical difference in the self-management efficacy scores such as positive attitude, stress reduction, self-decision-making, and total score between the two groups ( P > 0.05 ). After the intervention, the two groups indicated statistical difference in the self-management efficacy scores ( P < 0.05 ). Before intervention, there was no significant difference between the two groups in the healthy lifestyle score in terms of health responsibility, self-realization, interpersonal support, and stress management ( P > 0.05 ), and the abovementioned outcome measures indicated significant difference between the two groups after intervention ( P < 0.05 ). There was no statistical difference in six-minute walking distance between the two groups before the intervention ( P > 0.05 ), but after the intervention, the observation group revealed a significantly longer distance of six-minute walking compared to the control group ( P < 0.05 ). Conclusion. These data suggest that peer-support nursing intervention can effectively improve pulmonary function and quality of life of nonsmoking patients with COPD.

Yanhua Liang,1,* Shanglong Kou,1,2,* Xiaohe Li,1 Zhiyi Ke,1 Rongrong Zou,1 Yanchao Pan,1,3 Jing Yuan1 1Diagnosis and Treatment of Infectious Diseases Research Laboratory, Shenzhen Third People’s Hospital, Shenzhen, People’s Republic of China; 2College of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou, People’s Republic of China; 3Institute of Chemical Biology, Shenzhen Bay Laboratory, Shenzhen, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yanchao Pan; Jing YuanDiagnosis and Treatment of Infectious Diseases Research Laboratory, Shenzhen Third People’s Hospital, 29 Bulan Road, Buji District, Shenzhen, 518112, People’s Republic of ChinaTel +86 0755-61222333Fax +86 0755-61238928Email panychao@126.com; sz_yuanjing@163.comIntroduction: The novel coronavirus (COVID-19) has become a global pandemic with sharp rises in the number of confirmed cases and rapid spread across the world. Here, we looked at the effects of geographic differences on clinical manifestations of SARS-CoV-2 infected patients.Methods: A total of 114 confirmed COVID-19 patients were included in this study. The epidemiological, demographic, clinical, as well as laboratory findings were extracted from the electronic medical records of these patients.Results: We report the observation that patients from overseas residents diagnosed with COVID-19 were mildly symptomatic with cough and presented with lower inflammatory response and attenuated virus clearance rate, as well as correspondingly prolonged days of hospital stay than local Chinese patients. Moreover, the receiver-operating characteristic (ROC) analysis, performed to provide a measure of the difference between two groups, showed that serum albumin had the highest area under the curve value (0.81, p < 0.001).Discussion: Our results suggested that blood albumin level acted as a predictive value in distinguishing clinical features between local and overseas Chinese. This work underscores the need to identify distinguishably prognostic factors of geographical dissimilarity in COVID-19 patients.Keywords: geographic differences, clinical manifestations, inflammatory responses, COVID-19 patients

Facing with COVID-19 epidemic such a catastrophic health emergency, the mental health status of medical staff deserves attention. We conducted a two-stage of psychological status monitoring after the end of the assistance and 14 days of isolation, further targeted the vulnerable groups in need of intervention. The study is a cross-sectional survey on 1156 Yunnan medical staff aid to Hubei. Used Cluster sampling method to collect data at 2 time points (at the end of returning from Wuhan and the 14th day of isolation), from March 18, 2020 to April 6, 2020. Female and nurse had higher rates of depressive symptoms than male and doctors and other occupations. The proportion of female with mild and above moderate anxiety levels (22.91%, 2.61%) was higher than male (17.35%, 1.03%) (p

Studies showed that the increase of myeloid‐derived suppressor cells (MDSCs) in tumour microenvironment is closely related to the resistant treatment and poor prognosis of metastatic breast cancer. However, the effect of tumour‐derived exosomes on MDSCs and its mechanism are not clear. Here, we reported that breast cancer cells (4T1)‐secreted exosomes (BCC‐Ex) were able to differentiate bone marrow cells into MDSCs and significantly inhibited the proliferation of T lymphocytes to provide an immunosuppressive microenvironment for cancer cells in vivo and in vitro. The number of MDSCs in bone marrow and spleen of 4T1 tumour‐bearing mice and BCC‐Ex infused mice was significantly higher than that of normal mice, whereas the number of T lymphocytes in spleen was significantly decreased. In addition, BCC‐Ex markedly promoted the differentiation of MDSCs from bone marrow cells or bone marrow cells derived macrophages, seen as the increased expressions of MDSCs‐related functional proteins Arginase‐1 (Arg‐1) and inducible nitric oxide synthase (iNOS). Furthermore, BCC‐Ex significantly down‐regulated the expressions of chemokine receptor CXCR4 and markedly up‐regulated the levels of inflammatory cytokines IL‐6 and IL‐10 in bone marrow cells and macrophages and remarkably inhibited the division and proliferation of T cells. Importantly, CXCR4 agonist, CXCL12, could reverse the function of BCC‐Ex, indicating that BCC‐Ex‐induced MDSCs might be dependent on the down‐regulation of CXCR4. Western blot showed that BCC‐Ex significantly promoted the phosphorylation of STAT3 in bone marrow cells, resulting in the inhibitions of the proliferation and apoptosis of bone marrow cells, and the aggravation of the differentiation of bone marrow cells into MDSCs.

Background This study was conducted to develop a Chinese version of the Baby Eating Behaviour Questionnaire (BEBQ) and to evaluate its reliability and validity. Methods The Chinese version of the BEBQ was developed by translation and back‐translation of the original BEBQ, followed by revision according to experts on the most appropriate item content. Mothers of 300 infants aged

New SARS-CoV-2 mutants have been continuously indentified with enhanced transmission ever since its outbreak in early 2020. As an RNA virus, SARS-CoV-2 has a high mutation rate due to the low fidelity of RNA polymerase. To study the single nucleotide polymorphisms (SNPs) dynamics of SARS-CoV-2, 158 SNPs with high confidence were identified by deep meta-transcriptomic sequencing, and the most common SNP type was C > T. Analyses of intra-host population diversity revealed that intra-host quasispecies’ composition varies with time during the early onset of symptoms, which implicates viral evolution during infection. Network analysis of co-occurring SNPs revealed the most abundant non-synonymous SNP 22,638 in the S glycoprotein RBD region and 28,144 in the ORF8 region. Furthermore, SARS-CoV-2 variations differ in an individual’s respiratory tissue (nose, throat, BALF, or sputum), suggesting independent compartmentalization of SARS-CoV-2 populations in patients. The positive selection analysis of the SARS-CoV-2 genome uncovered the positive selected amino acid G251V on ORF3a. Alternative allele frequency spectrum (AAFS) of all variants revealed that ORF8 could bear alternate alleles with high frequency. Overall, the results show the quasispecies’ profile of SARS-CoV-2 in the respiratory tract in the first two months after the outbreak.

Background To investigate the clinical efficacy of the MyoSure hysteroscopic tissue removal system in the treatment of endometrial and cervical polyps in women with an intact hymen. Methods Retrospective analysis was performed on the clinical data of 32 patients treated with the MyoSure hysteroscopic tissue removal system for endometrial and cervical polyps. Results All the patients successfully completed the procedure. No intraoperative complications, such as cervical trauma, uterine perforation or TURP syndrome, were reported. The surgical time ranged from 5 to 35 min, with an average time of 19.3 min, and the intraoperative blood loss ranged from 2 to 50 ml with an average blood loss of 10.8 ml. After surgery, all patients were shown to have intact hymens. No residual polyp tissues were observed under the microscope, and abnormal uterine bleeding was relieved. Conclusions The MyoSure hysteroscopic tissue removal system can be a safe and effective treatment for endometrial and cervical polyps in women with an intact hymen.

Highlights • The impact of a multimodal infection control strategy originally designed for containment of COVID-19 on the rates of other hospital-acquired-infections (HAIs) was evaluated over a 7-month period across the largest healthcare system in Singapore. • During the COVID-19 pandemic, methicillin-resistant Staphylococcus aureus acquisition rates declined significantly, together with central-line-associated-bloodstream infection rates; likely due to increased compliance with standard precautions. • Enhanced infection control measures resulted in the unintended positive consequences of containing health care-associated respiratory viral infections, with a significant and sustained decline for both enveloped and nonenveloped respiratory viruses. • The ongoing COVID-19 pandemic provided the impetus to demonstrate the potential benefit of heightened infection control measures in controlling HAIs and acquisition of multidrug-resistant-organisms., Background In the current COVID-19 pandemic, aggressive Infection Prevention and Control (IPC) measures have been adopted to prevent health care-associated transmission of COVID-19. We evaluated the impact of a multimodal IPC strategy originally designed for the containment of COVID-19 on the rates of other hospital-acquired-infections (HAIs). Methodology From February-August 2020, a multimodal IPC strategy was implemented across a large health care campus in Singapore, comprising improved segregation of patients with respiratory symptoms, universal masking and heightened adherence to Standard Precautions. The following rates of HAI were compared pre- and postpandemic: health care-associated respiratory-viral-infection (HA-RVI), methicillin-resistant Staphylococcus aureus, and CP-CRE acquisition rates, health care-facility-associated C difficile infections and device-associated HAIs. Results Enhanced IPC measures introduced to contain COVID-19 had the unintended positive consequence of containing HA-RVI. The cumulative incidence of HA-RVI decreased from 9.69 cases per 10,000 patient-days to 0.83 cases per 10,000 patient-days (incidence-rate-ratio = 0.08; 95% confidence interval [CI] = 0.05-0.13, P< .05). Hospital-wide MRSA acquisition rates declined significantly during the pandemic (incidence-rate-ratio = 0.54, 95% CI = 0.46-0.64, P< .05), together with central-line-associated-bloodstream infection rates (incidence-rate-ratio = 0.24, 95% CI = 0.07-0.57, P< .05); likely due to increased compliance with Standard Precautions. Despite the disruption caused by the pandemic, there was no increase in CP-CRE acquisition, and rates of other HAIs remained stable. Conclusions Multimodal IPC strategies can be implemented at scale to successfully mitigate health care-associated transmission of RVIs. Good adherence to personal-protective-equipment and hand hygiene kept other HAI rates stable even during an ongoing pandemic where respiratory infections were prioritized for interventions.

Background/Aims Diabetic nephropathy (DN) is one of the main causes of end-stage kidney disease worldwide. Emerging studies have suggested that its pathogenesis is distinct from nondiabetic renal diseases in many aspects. However, it still lacks a comprehensive understanding of the unique molecular mechanism of DN. Methods A total of 255 Affymetrix U133 microarray datasets (Affymetrix, Santa Calra, CA, USA) of human glomerular and tubulointerstitial tissues were collected. The 22 215 Affymetrix identifiers shared by the Human Genome U133 Plus 2.0 and U133A Array were extracted to facilitate dataset pooling. Next, a linear model was constructed and the empirical Bayes method was used to select the differentially expressed genes (DEGs) of each kidney disease. Based on these DEG sets, the unique DEGs of DN were identified and further analyzed using gene ontology and pathway enrichment analysis. Finally, the protein–protein interaction networks (PINs) were constructed and hub genes were selected to further refine the results. Results A total of 129 and 1251 unique DEGs were identified in the diabetic glomerulus (upregulated n = 83 and downregulated n = 203) and the diabetic tubulointerstitium (upregulated n = 399 and downregulated n = 874), respectively. Enrichment analysis revealed that the DEGs in the diabetic glomerulus were significantly associated with the extracellular matrix, cell growth, regulation of blood coagulation, cholesterol homeostasis, intrinsic apoptotic signaling pathway and renal filtration cell differentiation. In the diabetic tubulointerstitium, the significantly enriched biological processes and pathways included metabolism, the advanced glycation end products–receptor for advanced glycation end products signaling pathway in diabetic complications, the epidermal growth factor receptor (EGFR) signaling pathway, the FoxO signaling pathway, autophagy and ferroptosis. By constructing PINs, several nodes, such as AGR2, CSNK2A1, EGFR and HSPD1, were identified as hub genes, which might play key roles in regulating the development of DN. Conclusions Our study not only reveals the unique molecular mechanism of DN but also provides a valuable resource for biomarker and therapeutic target discovery. Some of our findings are promising and should be explored in future work.

Haemophilus parasuis is commonly found in the upper respiratory tract of the pigs. Some isolates of H. parasuis can lead to both pneumonia and Glässer's disease of pigs with severe clinical symptoms. The virulence-associated genes for the various degrees of virulence observed in H. parasuis remains poorly understood. In the present study, we identified the differentially expressed genes between YK1603 (non-virulent strain) and XM1602 (moderately virulent strain) or CY1201 (highly virulent strain) of H. parasuis using Illumina sequencing technique. In comparison to YK1603, a total of 195 genes were significantly changed in CY1201, of which 71 genes were up-regulated and 124 genes were down-regulated, whereas 705 genes were significantly changed in XM1602, of which 415 genes were up-regulated and 290 genes were down-regulated. The enriched analysis of Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways on the differentially expressed genes showed that both enriched main GO terms and KEGG pathways appear to be different between the two kinds of comparision: CY1201 versus YK1603, and XM1602 versus YK1603. Based on real-time PCR technique, on the whole, it was confirmed that the expression of ten genes: lpxL, tbpB, kdtA, waaQ, oapA, napA, ptsH, mmsA, lpxM, and lpxB were agreement with the findings in Illumina sequencing analysis. These identified genes might participate in the regulation of a wide range of biological process involved in virulence of H. parasuis, such as phosphotransferase system and ABC transporters. Our results from this study provide a new way to gain insight into the virulent mechanisms of H. parasuis.

Background Arterial and venous thrombosis are reported to be common in critically ill COVID-19 patients. Method and results This is a national multicenter retrospective observational study involving all consecutive adult COVID-19 patients who required intensive care units (ICU) admission between 23 January 2020 and 30 April 2020 in Singapore. One hundred eleven patients were included and the venous and arterial thrombotic rates in ICU were 1.8% (n = 2) and 9.9% (n = 11), respectively. Major bleeding rate was 14.8% (n = 16). Conclusions Critically ill COVID-19 patients in Singapore have lower venous thromboembolism but higher arterial thrombosis rates and bleeding manifestations than other reported cohorts.

Mesenchymal stem cells-derived exosomes (MSC-exos) have attracted great interest as a cell-free therapy for acute kidney injury (AKI). However, the in vivo biodistribution of MSC-exos in ischemic AKI has not been established. The potential of MSC-exos in promoting tubular repair and the underlying mechanisms remain largely unknown. Methods: Transmission electron microscopy, nanoparticle tracking analysis, and western blotting were used to characterize the properties of human umbilical cord mesenchymal stem cells (hucMSCs) derived exosomes. The biodistribution of MSC-exos in murine ischemia/reperfusion (I/R) induced AKI was imaged by the IVIS spectrum imaging system. The therapeutic efficacy of MSC-exos was investigated in renal I/R injury. The cell cycle arrest, proliferation and apoptosis of tubular epithelial cells (TECs) were evaluated in vivo and in HK-2 cells. The exosomal miRNAs of MSC-exos were profiled by high-throughput miRNA sequencing. One of the most enriched miRNA in MSC-exos was knockdown by transfecting miRNA inhibitor to hucMSCs. Then we investigated whether this candidate miRNA was involved in MSC-exos-mediated tubular repair. Results: Ex vivo imaging showed that MSC-exos was efficiently homing to the ischemic kidney and predominantly accumulated in proximal tubules by virtue of the VLA-4 and LFA-1 on MSC-exos surface. MSC-exos alleviated murine ischemic AKI and decreased the renal tubules injury in a dose-dependent manner. Furthermore, MSC-exos significantly attenuated the cell cycle arrest and apoptosis of TECs both in vivo and in vitro. Mechanistically, miR-125b-5p, which was highly enriched in MSC-exos, repressed the protein expression of p53 in TECs, leading to not only the up-regulation of CDK1 and Cyclin B1 to rescue G2/M arrest, but also the modulation of Bcl-2 and Bax to inhibit TEC apoptosis. Finally, inhibiting miR-125b-5p could mitigate the protective effects of MSC-exos in I/R mice. Conclusion: MSC-exos exhibit preferential tropism to injured kidney and localize to proximal tubules in ischemic AKI. We demonstrate that MSC-exos ameliorate ischemic AKI and promote tubular repair by targeting the cell cycle arrest and apoptosis of TECs through miR-125b-5p/p53 pathway. This study provides a novel insight into the role of MSC-exos in renal tubule repair and highlights the potential of MSC-exos as a promising therapeutic strategy for AKI.

The microscopic visualization of large-scale three-dimensional (3D) samples by optical microscopy requires overcoming challenges in imaging quality and speed and in big data acquisition and management. We report a line-illumination modulation (LiMo) technique for imaging thick tissues with high throughput and low background. Combining LiMo with thin tissue sectioning, we further develop a high-definition fluorescent micro-optical sectioning tomography (HD-fMOST) method that features an average signal-to-noise ratio of 110, leading to substantial improvement in neuronal morphology reconstruction. We achieve a >30-fold lossless data compression at a voxel resolution of 0.32 × 0.32 × 1.00 μm3, enabling online data storage to a USB drive or in the cloud, and high-precision (95% accuracy) brain-wide 3D cell counting in real time. These results highlight the potential of HD-fMOST to facilitate large-scale acquisition and analysis of whole-brain high-resolution datasets. HD-fMOST is a microscopy technique for imaging large samples at high throughput and with high definition, which is achieved with a line-illumination modulation approach. The technology is illustrated by imaging fluorescently labeled neurons in whole mouse brains.

Aldosterone exerts an enormous function on proximal tubular cells (PTC) senescence, which is a common pathomechanism contributing to renal dysfunction. Numerous studies have shown that oxidative stress is deeply involved in the pathophysiologic processes of chronic kidney diseases. The study aims to investigate whether autophagy could regulate the process of senescence through oxidative stress in PTC both in vivo and ex vivo. Our results suggested that aldosterone treatment increased the senescence and oxidative stress as evidenced by increased percent of SA-β-Gal positive cells, reactive oxygen species level, expression of NADPH oxidase 4 (NOX4) rather than NOX2, and the up-regulation of p21 in cultured PTC. Furthermore, the alternation of the expression of p62 and LC3-II/LC3-I demonstrated that aldosterone treatment remarkably influenced autophagic flux. NOX4 siRNA treatment or autophagy induction with rapamycin reduced the oxidative stress and senescence in aldosterone-induced PTC. On the contrary, inhibition of autophagy with chloroquine worsened these changes. Similar results were further confirmed in vivo. Our results suggested that autophagy may become a realistic therapeutic strategy against aldosterone-induced PTC injury via improving oxidative stress.

Background Primary hyperoxaluria(PH)is a rare autosomal recessive genetic disease that contains three subtypes (PH1, PH2 and PH3). Approximately 80% of PH patients has been reported as subtype PH1, this subtype of PH has been related to a higher risk of renal failure at any age. Several genetic studies indicate that the variants in gene AGXT are responsible for the occurrence of PH1. However, the population heterogeneity of the variants in AGXT makes the genetic diagnosis of PH1 more challenging as it is hard to locate each specific variant. It is valuable to have a complete spectrum of AGXT variants from different population for early diagnosis and clinical treatments of PH1. Case presentation In this study, We performed high-throughput sequencing and genetic analysis of a 6-year-old male PH1 patient from a Chinese family. Two variants (c.346G > A: p.Gly116Arg; c.864G > A: p.Trp288X) of the gene AGXT were identified. We found a nonsense variant (c.864G > A: p.Trp288X) that comes from the proband’s mother and has never been reported previously. The other missense variant (c.346G > A: p.Gly116Arg) was inherited from his father and has been found previously in a domain of aminotransferase, which plays an important role in the function of AGT protein. Furthermore, we searched 110 pathogenic variants of AGXT that have been reported worldwide in healthy local Chinese population, none of these pathogenic variants was detected in the local genomes. Conclusions Our research provides an important diagnosis basis for PH1 on the genetic level by updating the genotype of PH1 and also develops a better understanding of the variants in AGXT by broadening the variation database of AGXT according to the Chinese reference genome.

Background Childhood overweight and obesity have become significant public health challenges worldwide. The present study aimed to investigate whether caregivers’ feeding behaviour and children's eating behaviour were associated with the weight status of preschool children in China. Methods A cross‐sectional questionnaire was administered to 912 caregivers of preschool children from April to July 2016. Caregivers’ feeding behaviours were assessed by the Chinese Preschooler's Caregiver Feeding Behaviour Scale. Children's eating behaviours were evaluated using the Chinese Preschooler's Eating Behaviour Questionnaire. After controlling for demographic characteristics, multiple linear regression and logistic regression analyses were performed to evaluate the relationship between caregivers’ feeding behaviour, children's eating behaviour and children's body mass index (BMI). Results The results showed that weight concerns on the part of caregivers (β = 0.53) and food responsiveness on the part of children (β = 0.93) were positively correlated with children's BMI, whereas caregivers’ responsibility for feeding (β = −0.68) and children's external eating (β = −0.53) were negatively correlated with BMI. Among caregiver feeding behaviours, weight concerns [odds ratio (OR) =4.54, p, This study aimed to explore whether caregivers' feeding behavior and children's eating behavior were associated with the weight status of preschool children in China. A cross‐sectional questionnaire was administered to 912 caregivers of preschool children in China. Caregivers' feeding behaviors and children's eating behaviors were assessed respectively by the Chinese Preschooler's Caregiver Feeding Behavior Scale (CPCFBS) and the Chinese Preschooler's Eating Behavior Questionnaire (CPEBQ). The results showed that among Chinese preschool children, caregivers' feeding behavior and children's eating behavior are related to their weight status and behavioral interventions can prevent weight problems of preschool children.

Mutations in IFN and MHC signaling genes endow immunotherapy resistance. Patients with colorectal cancer infrequently exhibit IFN and MHC signaling gene mutations and are generally resistant to immunotherapy. In exploring the integrity of IFN and MHC signaling in colorectal cancer, we found that optineurin was a shared node between the two pathways and predicted colorectal cancer patient outcome. Loss of optineurin occurs in early-stage human colorectal cancer. Immunologically, optineurin deficiency was shown to attenuate IFNGR1 and MHC-I expression, impair T-cell immunity, and diminish immunotherapy efficacy in murine cancer models and patients with cancer. Mechanistically, we observed that IFNGR1 was S-palmitoylated on Cys122, and AP3D1 bound with and sorted palmitoylated IFNGR1 to lysosome for degradation. Unexpectedly, optineurin interacted with AP3D1 to prevent palmitoylated IFNGR1 lysosomal sorting and degradation, thereby maintaining IFNγ and MHC-I signaling integrity. Furthermore, pharmacologically targeting IFNGR1 palmitoylation stabilized IFNGR1, augmented tumor immunity, and sensitized checkpoint therapy. Thus, loss of optineurin drives immune evasion and intrinsic immunotherapy resistance in colorectal cancer. Significance: Loss of optineurin impairs the integrity of both IFNγ and MHC-I signaling pathways via palmitoylation-dependent IFNGR1 lysosomal sorting and degradation, thereby driving immune evasion and intrinsic immunotherapy resistance in colorectal cancer. Our work suggests that pharmacologically targeting IFNGR1 palmitoylation can stabilize IFNGR1, enhance T-cell immunity, and sensitize checkpoint therapy in colorectal cancer. See related commentary by Salvagno and Cubillos-Ruiz, p. 1623. This article is highlighted in the In This Issue feature, p. 1601

NSD2 is the primary oncogenic driver in t(4;14) multiple myeloma. Using SILAC-based mass spectrometry, we demonstrate a novel role of NSD2 in chromatin remodeling through its interaction with the SWI/SNF ATPase subunit SMARCA2. SMARCA2 was primarily expressed in t(4;14) myeloma cells, and its interaction with NSD2 was noncanonical and independent of the SWI/SNF complex. RNA sequencing identified PTP4A3 as a downstream target of NSD2 and mapped NSD2–SMARCA2 complex on PTP4A3 promoter. This led to a focal increase in the permissive H3K36me2 mark and transcriptional activation of PTP4A3. High levels of PTP4A3 maintained MYC expression and correlated with a 54-gene MYC signature in t(4;14) multiple myeloma. Importantly, this mechanism was druggable by targeting the bromodomain of SMARCA2 using the specific BET inhibitor PFI-3, leading to the displacement of NSD2 from PTP4A3 promoter and inhibiting t(4;14) myeloma cell viability. In vivo, treatment with PFI-3 reduced the growth of t(4;14) xenograft tumors. Together, our study reveals an interplay between histone-modifying enzymes and chromatin remodelers in the regulation of myeloma-specific genes that can be clinically intervened. Significance: This study uncovers a novel, SWI/SNF–independent interaction between SMARCA2 and NSD2 that facilitates chromatin remodeling and transcriptional regulation of oncogenes in t(4;14) multiple myeloma, revealing a therapeutic vulnerability targetable by BET inhibition.

Background Several pharmacological agents, such as chloroquine/hydroxychloroquine, have been promoted for COVID-19 treatment or pre-exposure prophylaxis. However, no comprehensive evaluation of the safety of these possible agents is available, and is urgently needed. Objective The purpose of this study was to investigate the risks of cardiac adverse events associated with the possible pharmacotherapies for COVID-19, including certain antimalarial, antiviral, and antibiotic drugs. Patients and Methods We conduced retrospective pharmacovigilance analyses of the US Food and Drug Administration Adverse Event Reporting System database. The reporting odds ratio (ROR), a data mining algorithm commonly used in pharmacovigilance assessment, was generated to quantify the detection signal of adverse events. Results Among individuals without coronavirus infection from 2015 Q1 to 2020 Q1, increased risks for cardiac disorders were found for antiviral agents such as chloroquine/hydroxychloroquine (ROR: 1.68; 95% confidence interval [CI] 1.66–1.70), lopinavir/ritonavir (ROR: 1.52; 95% CI 1.39–1.66), and antibiotics such as azithromycin (ROR: 1.37; 95% CI 1.30–1.44) and ceftriaxone (ROR: 1.92; 95% CI 1.80–2.05). Increased serious cardiac adverse events, including myocardial infarction, arrhythmia, and cardiac arrest, were also reported for these drugs. Further analyses of individuals with coronavirus infections revealed that 40% of individuals receiving chloroquine/hydroxychloroquine reported serious cardiac adverse events. Two cases resulted in QT prolongations and one case resulted in cardiac arrest. Chloroquine/hydroxychloroquine and azithromycin contributed to all the QT prolongation and cardiac arrest cases. Conclusions The current pharmacotherapies for COVID-19 are associated with increased risks of cardiac adverse events. Variations in the cardiac safety profiles of these pharmacotherapies were also observed. Clinicians should closely monitor patients with COVID-19, especially those at high risk, using chloroquine/hydroxychloroquine and azithromycin.

Immune response plays a vital role in the pathogenesis of neuropathic pain. Immune response-targeted therapy becomes an effective strategy for treating neuropathic pain. Licochalcone A (Lic-A) possesses anti-inflammatory and neuroprotective effects. However, the potential of Lic-A to attenuate neuropathic pain has not been well explored. To investigate the protective effect and evaluate the underlying mechanism of Lic-A against neuropathic pain in a rat model. Chronic constriction injury (CCI) surgery was employed in rats to establish neuropathic pain model. Rats were intraperitoneally administrated with Lic-A (1.25, 2.50 and 5.00 mg/kg) twice daily. Mechanical withdrawal threshold and thermal withdrawal latency were used to evaluate neuropathic pain. After administration, the lumbar spinal cord enlargement of rats was collected for ELISA, Western blot and immunofluorescence analysis. Mechanical withdrawal threshold and thermal withdrawal latency results showed that Lic-A significantly attenuated CCI-evoked neuropathic pain in dose-dependent manner. Lic-A administration also effectively blocked microglia activation. Moreover, Lic-A suppressed p38 phosphorylation and the release of inflammatory factors such as tumor necrosis factor-α, interleukin-1 and interleukin-6. Our findings provide evidence that Lic-A may have the potential to attenuate CCI-evoked neuropathic pain in rats by inhibiting microglia activation and inflammatory response.

Technologies used in the processing of whole blood and blood component products, including pathogen reduction, are continuously being adopted into blood transfusion workflows to improve process efficiencies. However, the economic implications of these technologies are not well understood. With the advent of these new technologies and regulatory guidance on bacterial risk-control strategies, an updated systematic literature review on this topic was warranted. The objective of this systematic literature review was to summarize the current literature on the economic analyses of pathogen-reduction technologies (PRTs). A systematic literature review was conducted using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines to identify newly published articles in PubMed, MEDLINE Complete, and EconLit from 1 January 2000 to 17 July 2019 related to economic evaluations of PRTs. Only full-text studies in humans published in English were included in the review. Both budget-impact and cost-effectiveness studies were included; common outcomes included cost, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs). The initial searches identified 433 original abstracts, of which 16 articles were included in the final data extraction and reporting. Seven articles presented cost-effectiveness analyses and nine assessed budget impact. The introduction of PRT increased overall costs, and ICER values ranged widely across cost-effectiveness studies, from below $US150,000/QALY to upwards of $US20,000,000/QALY. This wide range of results was due to a multitude of factors, including comparator selection, target patient population, and scenario analyses included. Overall, the results of economic evaluations of bacterial risk-control strategies, regardless of mechanism, were highly dependent on the current screening protocols in place. The optimization of blood transfusion safety may not result in decisions made at the willingness-to-pay thresholds commonly seen in pharmaceutical evaluations. Given the critical public health role of blood products, and the potential safety benefits introduced by advancements, it is important to continue building this body of evidence with more transparency and data source heterogeneity. This updated literature review provides global context when making local decisions for the coverage of new and emerging bacterial risk-control strategies.

Mycoplasma pneumoniae is one of the leading causes of community-acquired pneumonia in children and adolescents. Because of the wide application of macrolides in clinical treatment, macrolide-resistant M. pneumoniae strains have become increasingly common worldwide. However, the molecular mechanisms underlying drug resistance in M. pneumoniae are poorly understood. In the present work, we analyzed the whole proteomes of macrolide-sensitive and macrolide-resistant strains of M. pneumoniae using a tandem mass tag-labeling quantitative proteomic technique, Data are available via ProteomeXchange with identifier PXD022220. In total, 165 differentially expressed proteins were identified, of which 80 were upregulated and 85 were downregulated in the drug-resistant strain compared with the sensitive strain. Functional analysis revealed that these proteins were predominantly involved in protein and peptide biosynthesis processes, the ribosome, and transmembrane transporter activity, which implicates them in the mechanism(s) of resistance of M. pneumoniae to macrolides. Our results provide new insights into drug resistance in M. pneumoniae and identify potential targets for further studies on resistance mechanisms in this bacterium.

Background Myocardial infarction (MI), a common type of coronary heart disease, is the major cause of morbidity and mortality around the world. Chemokine-mediated inflammatory cell infiltration and local inflammatory damage response are recent research hotspots. Hence, we attempted to examine the role of C-X-C motif chemokine 16 (CXCL16) as a potential candidate in MI. Methods Human cardiomyocytes were treated with hypoxia/reoxygenation (H/R) to establish an in vitro cell model. GEO database provided the clinical data of MI patients and GSEA verified the relationship of chemokine and MI. CCK-8 and flow cytometry analyses were used to measure cell viability and apoptosis. Bioinformatics analysis and luciferase reporter assay were conducted to determine the correlation between CXCL16 and miR-545. qRT-PCR and western blot assays were performed to investigate the expression level of the indicated genes. The activity of lactate dehydrogenase (LDH) and the levels of TNF-α, IL-6, IL-1β, and IL-10 were explored using ELISA assay. Results CXCL16 was increased in MI. CXCL16 knockdown can reverse the inhibitory effect of H/R treatment on cell viability, while overexpression of CXCL16 showed the opposite trend. MiR-545 directly targeted CXCL16 and negatively regulated CXCL16 levels. MiR-545 promoted cell proliferation and inhibited apoptosis in the MI cell model, which attenuated the CXCL16-induced injury on cardiomyocytes. Conclusion These findings demonstrated that CXCL16 aggravated MI damage through being directly targeted by miR-545 and mediating inflammatory responses, thereby providing potential therapeutic targets for MI therapy.

Purpose To prospectively investigate the impact of image reconstruction on MRI radiomics features. Methods An anthropomorphic phantom was scanned at 1.5 T using a standardized sequence for MR-guided radiotherapy under SENSE and compressed-SENSE reconstruction settings. A total of 93 first-order and texture radiomics features in 10 volumes of interest were assessed based on (1) accuracy measured by the percentage deviation from the reference, (2) robustness on reconstruction in all volumes of interest measured by the intraclass correlation coefficient, and (3) repeatability measured by the coefficient of variance over the repetitive acquisitions. Finally, reliable and unreliable radiomics features were comprehensively determined based on their accuracy, robustness, and repeatability. Results Better accuracy and robustness of the radiomics features were achieved under SENSE than compressed-SENSE reconstruction. The feature accuracy under SENSE reconstruction was more affected by acceleration factor than direction, whereas under compressed-SENSE reconstruction, accuracy was substantially impacted by the increasing denoising levels. Feature repeatability was dependent more on feature types than on reconstruction. A total of 45 reliable features and 13 unreliable features were finally determined for SENSE, compared with 22 reliable and 26 unreliable features for compressed SENSE. First-order and gray-level co-occurrence matrix features were generally more reliable than other features. Conclusion Radiomics features could be substantially affected by MRI reconstruction, so precautions need to be taken regarding their reliability for clinical use. This study helps the guidance of the preselection of reliable radiomics features and the preclusion of unreliable features in MR-guided radiotherapy.

The ever-evolving mesoscopic scale optical imaging systems facilitate the new discoveries in the neuroscience research. They excel at providing a complete view of the long projections of a single neuron across the whole brain. Although the preparation protocols and the optical imaging systems are rapidly evolving, there are still some noise and artifacts interfering downstream data processing and analysis due to the defects in the imaging system or during the sample preparation. A specific denoising procedure is usually developed for one optical imaging system as a post-processing measure. However, the development of the optical imaging systems usually follows in an incremental manner. It would be better to adapt the denoising model to the new optical imaging system than training a denoising model from scratch. In this paper, the proposed learning schema and practice learn a new denoising model for a new optical imaging system based on the existing denoise models and bootstrap a denoising model without the ground-truth denoising labels. We achieve this through a CycleGAN based model and the fact that the optical imaging systems usually produce images both from the signal area and the fixture area. The experiments show that our proposed procedure can provide a comparable denoising performance against other state-of-the-art denoising methods for several optical neuroimaging datasets.

Peripheral nerve injuries occur as the result of sudden trauma and lead to reduced quality of life. The peripheral nervous system has an inherent capability to regenerate axons. However, peripheral nerve regeneration following injury is generally slow and incomplete that results in poor functional outcomes such as muscle atrophy. Although conventional surgical procedures for peripheral nerve injuries present many benefits, there are still several limitations including scarring, difficult accessibility to donor nerve, neuroma formation and a need to sacrifice the autologous nerve. For many years, other therapeutic approaches for peripheral nerve injuries have been explored, the most notable being the replacement of Schwann cells, the glial cells responsible for clearing out debris from the site of injury. Introducing cultured Schwann cells to the injured sites showed great benefits in promoting axonal regeneration and functional recovery. However, there are limited sources of Schwann cells for extraction and difficulties in culturing Schwann cells in vitro. Therefore, novel therapeutic avenues that offer maximum benefits for the treatment of peripheral nerve injuries should be investigated. This review focused on strategies using mesenchymal stem cells to promote peripheral nerve regeneration including exosomes of mesenchymal stem cells, nerve engineering using the nerve guidance conduits containing mesenchymal stem cells, and genetically engineered mesenchymal stem cells. We present the current progress of mesenchymal stem cell treatment of peripheral nerve injuries.

Background Peritoneal dialysis (PD) patients experience accelerated arterial aging, which is characterized by elastin degradation. Elastin-derived peptides (EDPs) are direct products of elastin fragmentation. This study tried to explore the association between serum EDPs and abdominal aortic calcification (AAC) in PD patients. Methods Serum levels of EDPs were analyzed in 126 eligible PD patients and 30 controls. PD patients were grouped according to the annularity of AAC evaluated by an abdominal computed tomography (CT) scan. Serum EDPs were analyzed in relation to the presence of AAC or severe AAC in PD patients by logistic regression analysis. Results Serum EDPs in PD patients were significantly higher than age-matched controls. In 126 PD patients, higher EDPs was associated with greater risk of present AAC (OR = 1.056, 95%CI 1.010–1.103) and severe AAC (OR = 1.062, 95%CI 1.004–1.123). A combination of EDPs substantially improved the accuracy of diagnostic performance for AAC and severe AAC. Conclusions EDPs can predict the presence and extent of AAC in PD patients, indicating its possible role to recognize PD patients at risk for AAC and severe AAC.

Background Hyperhomocysteinemia (HHcy) plays an important role in the progression of many kidney diseases; however, the relationship between HHcy and ischemia-reperfusion injury (IRI)-induced acute kidney injury (IRI-induced AKI) is far from clear. In this study, we try to investigate the effect and possible mechanisms of HHcy on IRI-induced AKI. Methods Twenty C57/BL6 mice were reared with a regular diet or high methionine diet for 2 weeks (to generate HHcy mice); after that, mice were subgrouped to receive sham operation or ischemia-reperfusion surgery. Twenty four hour after reperfusion, serum creatinine, blood urea nitrogen, and Malondialdehyde (MDA) were measured. H&E staining for tubular injury, western blot for γH2AX, JNK, p-JNK, and cleaved caspase 3, and TUNEL assay for tubular cell apoptosis were also performed. Results Our results showed that HHcy did not influence the renal function and histological structure, as well as the levels of MDA, γH2AX, JNK, p-JNK, and tubular cell apoptosis in control mice. However, in IRI-induced AKI mice, HHcy caused severer renal dysfunction and tubular injury, higher levels of oxidative stress, DNA damage, JNK pathway activation, and tubular cell apoptosis. Conclusion Our results demonstrated that HHcy could exacerbate IRI-induced AKI, which may be achieved through promoting oxidative stress, DNA damage, JNK pathway activation, and consequent apoptosis.

Purpose: Targeting RAF for antitumor therapy in RAS-mutant tumors holds promise. Herein, we describe in detail novel properties of the type II RAF inhibitor, LXH254. Experimental Design: LXH254 was profiled in biochemical, in vitro, and in vivo assays, including examining the activities of the drug in a large panel of cancer-derived cell lines and a comprehensive set of in vivo models. In addition, activity of LXH254 was assessed in cells where different sets of RAF paralogs were ablated, or that expressed kinase-impaired and dimer-deficient variants of ARAF. Results: We describe an unexpected paralog selectivity of LXH254, which is able to potently inhibit BRAF and CRAF, but has less activity against ARAF. LXH254 was active in models harboring BRAF alterations, including atypical BRAF alterations coexpressed with mutant K/NRAS, and NRAS mutants, but had only modest activity in KRAS mutants. In RAS-mutant lines, loss of ARAF, but not BRAF or CRAF, sensitized cells to LXH254. ARAF-mediated resistance to LXH254 required both kinase function and dimerization. Higher concentrations of LXH254 were required to inhibit signaling in RAS-mutant cells expressing only ARAF relative to BRAF or CRAF. Moreover, specifically in cells expressing only ARAF, LXH254 caused paradoxical activation of MAPK signaling in a manner similar to dabrafenib. Finally, in vivo, LXH254 drove complete regressions of isogenic variants of RAS-mutant cells lacking ARAF expression, while parental lines were only modestly sensitive. Conclusions: LXH254 is a novel RAF inhibitor, which is able to inhibit dimerized BRAF and CRAF, as well as monomeric BRAF, while largely sparing ARAF.

Cancer cell expression of PD-L1 leads to T cells exhaustion by transducing co-inhibitory signal, and further understanding the regulation of PD-L1 in cancer cells may provide additional therapeutic strategies. Here by drug repurposing screen, we identified amlodipine as a potent inhibitor of PD-L1 expression in cancer cells. Further survey of calcium-associated pathways revealed calpain-dependent stabilization of the PD-L1 protein. Intracellular calcium delivered an operational signal to calpain-dependent Beclin-1 cleavage, blocking autophagic degradation of PD-L1 accumulated on recycling endosome (RE). Blocking calcium flux by amlodipine depleted PD-L1 expression and increased CD8+ T-cell infiltration in tumor tissues but not in myocardium, causing dose-dependent tumor suppression in vivo. Rescuing PD-L1 expression eliminated the effects of amlodipine, suggesting the PD-L1-dependent effect of amlodipine. These results reveal a calcium-dependent mechanism controlling PD-L1 degradation, and highlight calcium flux blockade as a potential strategy for combinatorial immunotherapy.

ObjectiveMicrobiota disorder promotes chronic inflammation and carcinogenesis. High glycolysis is associated with poor prognosis in patients with colorectal cancer (CRC). However, the potential correlation between the gut microbiota and glucose metabolism is unknown in CRC.Design18F-FDG (18F-fluorodeoxyglucose) PET (positron emission tomography)/CT image scanning data and microbiota PCR analysis were performed to measure the correlation between metabolic alterations and microbiota disorder in 33 patients with CRC. Multiple colorectal cancer models, metabolic analysis and Seahorse assay were established to assess the role of long non-coding RNA (lncRNA) enolase1-intronic transcript 1 (ENO1-IT1) in Fusobacterium (F.) nucleatum-induced glucose metabolism and colorectal carcinogenesis. RNA immunoprecipitation and chromatin immunoprecipitation sequencing were conducted to identify potential targets of lncRNA ENO1-IT1.ResultsWe have found F. nucleatum abundance correlated with high glucose metabolism in patients with CRC. Furthermore, F. nucleatum supported carcinogenesis via increasing CRC cell glucose metabolism. Mechanistically, F. nucleatum activated lncRNA ENO1-IT1 transcription via upregulating the binding efficiency of transcription factor SP1 to the promoter region of lncRNA ENO1-IT1. Elevated ENO1-IT behaved as a guider modular for KAT7 histone acetyltransferase, specifying the histone modification pattern on its target genes, including ENO1, and consequently altering CRC biological function.ConclusionF. nucleatum and glucose metabolism are mechanistically, biologically and clinically connected to CRC. Targeting ENO1 pathway may be meaningful in treating patients with CRC with elevated F. nucleatum.

This is a cross-sectional study that compares the sales of “healthy” and “unhealthy” vending machines following the introduction of healthier vending machines on a university campus. Method: Health...

Background There is an urgent need to better understand the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), for that the coronavirus disease 2019 (COVID-19) continues to cause considerable morbidity and mortality worldwide. This paper was to differentiate COVID-19 from other respiratory infectious diseases such as avian-origin influenza A (H7N9) and influenza A (H1N1) virus infections. Methods We included patients who had been hospitalized with laboratory-confirmed infection by SARS-CoV-2 (n = 83), H7N9 (n = 36), H1N1 (n = 44) viruses. Clinical presentation, chest CT features, and progression of patients were compared. We used the Logistic regression model to explore the possible risk factors. Results Both COVID-19 and H7N9 patients had a longer duration of hospitalization than H1N1 patients (P P = 0.01). H7N9 patients had similar patterns of lymphopenia, neutrophilia, elevated alanine aminotransferase, C-reactive protein, lactate dehydrogenase, and those seen in H1N1 patients, which were all significantly different from patients with COVID-19 (P P P = 0.78). For severe cases, the meantime from illness onset to severity was 8.0 days for COVID-19 vs 5.2 days for H7N9 (P P = 0.02). Multivariate analysis showed that chronic heart disease was a possible risk factor (OR > 1) for COVID-19, compared with H1N1 and H7N9. Conclusions The proportion of severe cases were higher for H7N9 and SARS-CoV-2 infections, compared with H1N1. The meantime from illness onset to severity was shorter for H7N9. Chronic heart disease was a possible risk factor for COVID-19.The comparison may provide the rationale for strategies of isolation and treatment of infected patients in the future.

Most colorectal cancer (CRC) are characterized by allele loss of the genes located on the short arm of chromosome 17 (17p13.1), including the tumor suppressor p53 gene. Although important, p53 is not the only driver of chromosome 17p loss. In this study, we explored the biological and prognostic significance of genes around p53 on 17p13.1 in CRC. The Cancer Genome Atlas (TCGA) were used to identify differentially expressed genes located between 1000 kb upstream and downstream of p53 gene. The function of CLDN7 was evaluated by both in vitro and in vivo experiments. Quantitative real-time PCR, western blot, and promoter luciferase activity, immunohistochemistry were used to explore the molecular drivers responsible for the development and progression of CRC. The results showed that CLDN7, located between 1000 kb upstream and downstream of p53 gene, were remarkably differentially expressed in tumor and normal tissues. CLDN7 expression also positively associated with p53 level in different stages of the adenoma-carcinoma sequence. Both in vitro and in vivo assays showed that CLDN7 inhibited cell proliferation in p53 wild type CRC cells, but had no effects on p53 mutant CRC cells. Mechanistically, p53 could bind to CLDN7 promoter region and regulate its expression. Clinically, high CLDN7 expression was negatively correlated with tumor size, invasion depth, lymphatic metastasis and AJCC III/IV stage, but was positively associated with favorable prognosis of CRC patients. Collectively, our work uncovers the tumor suppressive function for CLDN7 in a p53-dependent manner, which may mediate colorectal tumorigenesis induced by p53 deletion or mutation.

Purpose Glioblastoma (GBM) is the most lethal primary cancer in adult central nervous system, and new strategies are desperately needed. The secretory pathway kinase or kinase-like proteins (SPKKPs) have been shown to mediate multiple physiological functions by phosphorylating extracellular proteins and proteoglycans. However, their roles in cancers, especially GBM, remain poorly defined. Methods The least absolute shrinkage and selection operator (LASSO) regression was employed for establishing the SPKKPs signature for IDH wild type (wt) GBM prognosis. Integrative analyses with multiple datasets were employed to identify the core member of this gene family in glioma. The receiver operator characteristic (ROC) curves and immunohistochemistry were further used for evaluating its association with progressive malignancy in glioma and GBM patients' survival, respectively. Gene set enrichment analysis (GSEA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to interpret its functions in GBM, which were further verified in vitro. Results A SPKKPs classifier was constructed with 3 genes of this family. This signature could effectively distinguish IDH wt GBM survival. Family with sequence similarity 20 C (FAM20C) was further identified as the core member of this family in glioma. Elevated FAM20C expression was not only closely correlated with glioma malignancy progression and the mesenchymal subtype of GBM but also indicated unfavorable survival of GBM patients. FAM20C was also found to be associated with the disrupted immune response in GBM microenvironment and was required for the migration of glioma and immune cells. Conclusion These data indicate that the potential of FAM20C serving as a predictive molecule and a therapeutic target for GBM.

Purpose: Novel coronavirus disease has become such an escalating epidemic that the exponential growth of infected patients has overloaded the health-care systems in many countries. Determination of early assessments for patients with a risk of clinical deterioration would benefit the management of COVID-19 outbreaks. Patients and Methods: A total of 214 confirmed COVID-19 patients were enrolled from January 11th to February 11th 2020. Medical records including laboratory parameters, clinical outcomes and other characteristics of the admitted patients were analyzed retrospectively. Results: The critical patients experienced a significantly prolonged onset-admission interval and presented with lymphopenia (r=-0.547, p=0.015) and lower albumin level (p

Acute ischemic stroke is one of the leading causes of death in developed countries and the most common cause of disability in adults worldwide. Despite advances in the understanding of stroke pathophysiology, therapeutic options remain limited. In this study, we explored the interaction of Shrm4 and the metabotropic gamma-aminobutyric acid (GABA) receptors (GABAB ) in ischemic stroke. A transient middle cerebral artery occlusion (MCAO) model was induced by filament insertion in Shrm4+/+ and wild-type C57BL/6J mice, followed by reperfusion for up to 7 days. Baclofen was administered was used to activate GABAB in vivo during reperfusion. Neurological deficits, motor and memory functions, and infarct volume were determined in the various mouse groups. Furthermore, we also developed an oxygen-glucose deprivation (OGD) cell model in primary neurons to test Shrm4/GABAB interactions in vitro. Shrm4 was observed to decrease infarct volume and neuronal cell loss in penumbra, and rescue neurological deficits in MCAO mice. Notably, Shrm4 also increased pole climbing speed, reduced foot faults, and increased escape latency in the Morris water maze test, while reducing neuron autophagy through an interaction with GABAB receptors. GABAB activation using baclofen further reduced OGD-induced neuron damage in culture and stroke outcomes of MCAO, relative to Shrm4 alone. Taken together, Shrm4-mediated GABAB activation confers neuroprotection by reducing neuronal autophagy in acute ischemic stroke.

Background Product toxicity is one of the bottlenecks for microbial production of biofuels, and transporter-mediated biofuel secretion offers a promising strategy to solve this problem. As a robust microbial host for industrial-scale production of biofuels, Saccharomyces cerevisiae contains a powerful transport system to export a wide range of toxic compounds to sustain survival. The aim of this study is to improve the secretion and production of the hydrophobic product (β-carotene) by harnessing endogenous ABC transporters combined with physiological engineering in S. cerevisiae. Results Substrate inducibility is a prominent characteristic of most endogenous transporters. Through comparative proteomic analysis and transcriptional confirmation, we identified five potential ABC transporters (Pdr5p, Pdr10p, Snq2p, Yor1p, and Yol075cp) for β-carotene efflux. The accumulation of β-carotene also affects cell physiology in various aspects, including energy metabolism, mitochondrial translation, lipid metabolism, ergosterol biosynthetic process, and cell wall synthesis. Here, we adopted an inducible GAL promoter to overexpress candidate transporters and enhanced the secretion and intracellular production of β-carotene, in which Snq2p showed the best performance (a 4.04-fold and a 1.33-fold increase compared with its parental strain YBX-01, respectively). To further promote efflux capacity, two strategies of increasing ATP supply and improving membrane fluidity were following adopted. A 5.80-fold increase of β-carotene secretion and a 1.71-fold increase of the intracellular β-carotene production were consequently achieved in the engineered strain YBX-20 compared with the parental strain YBX-01. Conclusions Overall, our results showcase that engineering endogenous plasma membrane ABC transporters is a promising approach for hydrophobic product efflux in S. cerevisiae. We also highlight the importance of improving cell physiology to enhance the efficiency of ABC transporters, especially energy status and cell membrane properties.

Objective To explore pharmacogenetic relationships of NRG1 genotypes with neurocognitive performance and clinical symptoms after 12 week treatment of risperidone in Chinese Han first-episode schizophrenia. Methods A cohort of 221 patients with schizophrenia were recruited for this research. Finally 177 untreated first-episode patients were clinically evaluated with the Positive and Negative Syndrome Scale (PANSS), Raven's Standard Progressive Matrices (RSPM), Digit Vigilance Test (DVT), Digit Span (DS), underwent genotyping for five polymorphisms of NRG1, and completed a 12-week prospective study of risperidone monotherapy. Results 1. After risperidone treatment of 12 weeks, the total scores, positive score, negative score and general score of PANSS decreased significantly; the scores of RSPM, DVT and DS increased significantly. 2. No significant association with PANSS scores at baseline or change in scores after 12 weeks'treatment was found with any of the five SNPs. There was also neither significant association of DVT, DS or RSPM at baseline with any of the five SNPs. 3. After risperidone treatment of 12 weeks, rs3924999 and rs35753505 showed significant association with change in DVT and in RSPM in which there were significant differences among different genotype groups. Conclusion This study suggested pharmacogenetic relationships between NRG1 variants and changes in cognition response with exposure to 12 weeks of treatment with risperidone. Two variants, rs3924999 and rs35753505, in the NRG1 gene were associated with the changes in attention and reasoning ability after risperidone treatment of 12 weeks.

During this coronavirus disease 2019 (COVID-19) pandemic, physicians have the important task of risk stratifying patients who present with acute respiratory illnesses. Clinical presentation of COVID-19, however, can be difficult to distinguish from other respiratory viral infections. Thus, identifying clinical features that are strongly associated with COVID-19 in comparison to other respiratory viruses can aid risk stratification and testing prioritization especially in situations where resources for virological testing and resources for isolation facilities are limited. In our retrospective cohort study comparing the clinical presentation of COVID-19 and other respiratory viral infections, we found that anosmia and dysgeusia were symptoms independently associated with COVID-19 and can be important differentiating symptoms in patients presenting with acute respiratory illness. On the other hand, laboratory abnormalities and radiological findings were not statistically different between the two groups. In comparing outcomes, patients with COVID-19 were more likely to need high dependency or intensive care unit care and had a longer median length of stay. With our findings, we emphasize that epidemiological risk factors and clinical symptoms are more useful than laboratory and radiological abnormalities in differentiating COVID-19 from other respiratory viral infections.

Understanding the precise intracellular localization of lead (Pb) is a key in deciphering processes in Pb-induced toxicology. However, it is a great challenge to trace Pbin vitro, especially in cultured cells. We aimed to find an innovative and efficient approach to investigate distribution of Pb in cells and to validate it through determining the subcellular Pb content. We identified its ultra-structural distribution with autometallography under electron microscopy in a choroidal epithelial Z310 cell line. Electron microscopy in combination with energy-dispersive X-ray spectroscope (EDS) was employed to provide further evidence of Pb location. In addition, Pb content was determined in the cytosol, membrane/organelle, nucleus and cytoskeleton fractions with atomic absorption spectroscopy. Pb was found predominantly inside the nuclear membranes and some was distributed in the cytoplasm under low-concentration exposure. Nuclear existence of Pb was verified by EDS under electron microscopy. Once standardized for protein content, Pb percentage in the nucleus fraction reached the highest level (76%). Our results indicate that Pb is accumulated mainly in the nucleus of choroid plexus. This method is sensitive and precise in providing optimal means to study the ultra-structural localization of Pb forin vitromodels. In addition, it offers the possibility of localization of other metals in cultured cells. Some procedures may also be adopted to detect target proteins via immunoreactions.

Nerve demyelination or axonal lesions are characteristic of experimental autoimmune neuritis (EAN). Previous studies have demonstrated that microRNA-338 can regulate the differentiation and maturation of oligodendrocytes and Schwann cells and promote injured peripheral nerves in rats. In this study, we used microRNA-338 coded lentivirus vector (miR-338-LV) in a Lewis rat EAN model, in with the conjunction P0 peptide 180–199 which was injected into the footpads of animals to induce immunization. The clinical scores of miR-338-LV and intravenous immunoglobulin (IVIg) (positive drug) groups were significantly superior to those of untreated group at disease peak and disease plateau (p

Background. Acinetobacter baumannii (A. baumannii) has become one of the most important opportunistic pathogens inducing nosocomial pneumonia and increasing mortality in critically ill patients recently. The interaction between A. baumannii infection and immune response can influence the prognosis of A. baumannii related pneumonia. The target of the present study was to investigate the role of immunodeficiency in A. baumannii induced pneumonia. Methods. Male BALB/c mice were randomly divided into the normal immunity control (NIC) group, normal immunity infection (NIA) group, immune compromised control (CIC) group, and immune compromised infection (CIA) group (n = 15 for each group). Intraperitoneal injection of cyclophosphamide and intranasal instillation of A. baumannii solution were used to induce compromised immunity and murine pneumonia, respectively. The mice were sacrificed at 6 and 24 h later and the specimens were collected for further tests. Seven-day mortality of mice was also assessed. Results. After A. baumannii stimulation, the recruitment of neutrophils in mice with normal immunity increased sharply (P = 0.030 at 6 h), while there was no significant raise of neutrophil counts in mice with compromised immune condition (P = 0.092 at 6 h, P = 0.772 at 24 h). The Th cell polarization presented with pulmonary interleukin (IL)-4 and interferon (IFN)-γ level in response to the A. baumannii in CIA group were significantly depressed in comparison with in NIA group (IFN-γ: P = 0.003 at 6 h; P = 0.001 at 24 h; IL-4: P

Objectives. By performing an overview of systematic reviews and meta-analyses of the efficacy and safety of oral Chinese patent medicine combined with conventional therapy in the treatment of heart failure, to evaluate the reliability and applicability of the conclusions of the current studies and provide evidence for clinical decision-making. Methods. Systematic reviews and meta-analyses of oral Chinese patent medicine combined with conventional therapy treating heart failure were searched based on standardized search strategy in six electronic databases including PubMed, Embase, Cochrane Library (No. 2 of 2020), China National Knowledge Infrastructure (CNKI), Wanfang Database (Wanfang), and Chinese Scientific Journal Database (VIP) from inception to February 2020. The literature was independently screened and extracted by two researchers. The methodological quality of the included literature was evaluated using the AMSTAR-2 (A Measurement Tool to Assess Systematic Review 2). If necessary, we would summarize the original research data and further perform data synthesis using RevMan software (version 5.3), and the evidence quality of the included literature was graded using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. Results. A total of 38 systematic reviews and meta-analyses were included, involving 11 kinds of oral Chinese patent medicines, including Qili Qiangxin Capsules (11/38), Qishen Yiqi Dropping Pills (9/38), Shexiang Baoxin Pills (4/38), Wenxin Keli (2/38), Tongxinluo Capsules (2/38), Compound Danshen Dripping Pills (2/38), Zhenyuan Capsules (3/38), Buyi Qiangxin Tablets (2/38), Yangxinshi Tablets (1/38), Xuezhikang (1/38), and Yixinshu Capsules (1/38). The methodological quality of all literature was rated as critically low. The grading of the quality of evidence was 43 moderate, 101 low, and 40 very low. The main reason for the degradation of evidence quality was the risk of bias. In the evaluation of efficacy, there was no statistically significant difference between the two groups in terms of mortality, which is a piece of low-quality evidence. Qili Qiangxin Capsules or Qishen Yiqi Dripping Pills combined with conventional therapy can significantly reduce the hospitalization rate of patients with chronic heart failure, and the quality of the evidence is moderate. The overall efficacy of oral Chinese patent medicine combined with conventional therapy in improving the clinical symptoms, quality of life, exercise endurance, laboratory tests, physical examination, and other indicators of patients with heart failure is confirmed. In the evaluation of safety, there was no significant difference between the two groups. Conclusions. Oral Chinese patent medicine combined with conventional therapy has good clinical efficacy and safety in the treatment of heart failure. However, due to its low level of methodological quality and evidence quality, the current evidence-based conclusions need to be further verified.

Cardiac fibrosis is a typical pathological change in various cardiovascular diseases. Although it has been recognized as a crucial risk factor responsible for heart failure, there is still a lack of effective treatment. Recent evidence shows that microRNAs (miRNAs) play an important role in the development of cardiac fibrosis and represent novel therapeutic targets. In this study we tried to identify the cardiac fibrosis-associated miRNA and elucidate its regulatory mechanisms in mice. Cardiac fibrosis was induced by infusion of angiotensin II (Ang II, 2 mg·kg(−1)·d(−1)) for 2 weeks via osmotic pumps. We showed that Ang II infusion induced cardiac disfunction and fibrosis accompanied by markedly increased expression level of miR-99b-3p in heart tissues. Upregulation of miR-99b-3p and fibrotic responses were also observed in cultured rat cardiac fibroblasts (CFs) treated with Ang II (100 nM) in vitro. Transfection with miR-99b-3p mimic resulted in the overproduction of fibronectin, collagen I, vimentin and α-SMA, and facilitated the proliferation and migration of CFs. On the contrary, transfection with specific miR-99b-3p inhibitor attenuated Ang II-induced fibrotic responses. Similarly, intravenous injection of specific miR-99b-3p antagomir could prevent Ang II-infused mice from cardiac dysfunction and fibrosis. We identified glycogen synthase kinase-3 beta (GSK-3β) as a direct target of miR-99b-3p. In CFs, miR-99b-3p mimic significantly reduced the expression of GSK-3β, leading to activation of its downstream profibrotic effector Smad3, whereas miR-99b-3p inhibitor caused anti-fibrotic effects. GSK-3β knockdown ameliorated the anti-fibrotic role of miR-99b-3p inhibitor. These results suggest that miR-99b-3p contributes to Ang II-induced cardiac fibrosis at least partially through GSK-3β. The modulation of miR-99b-3p may provide a new approach for tackling fibrosis-related cardiomyopathy.

Hepatocellular carcinoma (HCC) is the third leading cause of the cancer-related death in the world. Human amniotic mesenchymal stem cells (hAMSCs) have been characterized with a pluripotency, low immunogenicity and no tumorigenicity. Especially, the immunosuppressive and anti-inflammatory effects of hAMSCs make them suitable for treating HCC. Here, we reported that hAMSCs administrated by intravenous injection significantly inhibited HCC through suppressing cell proliferation and inducing cell apoptosis in tumour-bearing mice with Hepg2 cells. Cell tracking experiments with GFP-labelled hAMSCs showed that the stem cells possessed the ability of migrating to the tumorigenic sites for suppressing tumour growth. Importantly, both hAMSCs and the conditional media (hAMSC-CM) have the similar antitumour effects in vitro, suggesting that hAMSCs-derived cytokines might be involved in their antitumour effects. Antibody array assay showed that hAMSCs highly expressed dickkopf-3 (DKK-3), dickkopf-1 (DKK-1) and insulin-like growth factor-binding protein 3 (IGFBP-3). Furthermore, the antitumour effects of hAMSCs were further confirmed by applications of the antibodies or the specific siRNAs of DKK-3, DKK-1 and IGFBP-3 in vitro. Mechanically, hAMSCs-derived DKK-3, DKK-1 and IGFBP-3 markedly inhibited cell proliferation and promoted apoptosis of Hepg2 cells through suppressing the Wnt/β-catenin signalling pathway and IGF-1R-mediated PI3K/AKT signalling pathway, respectively. Taken together, our study demonstrated that hAMSCs possess significant antitumour effects in vivo and in vitro and might provide a novel strategy for HCC treatment clinically.

The extreme complexity of mammalian brains requires a comprehensive deconstruction of neuroanatomical structures. Scientists normally use a brain stereotactic atlas to determine the locations of neurons and neuronal circuits. However, different brain images are normally not naturally aligned even when they are imaged with the same setup, let alone under the differing resolutions and dataset sizes used in mesoscopic imaging. As a result, it is difficult to achieve high-throughput automatic registration without manual intervention. Here, we propose a deep learning-based registration method called DeepMapi to predict a deformation field used to register mesoscopic optical images to an atlas. We use a self-feedback strategy to address the problem of imbalanced training sets (sampling at a fixed step size in nonuniform brains of structures and deformations) and use a dual-hierarchical network to capture the large and small deformations. By comparing DeepMapi with other registration methods, we demonstrate its superiority over a set of ground truth images, including both optical and MRI images. DeepMapi achieves fully automatic registration of mesoscopic micro-optical images, even macroscopic MRI datasets, in minutes, with an accuracy comparable to those of manual annotations by anatomists. Electronic supplementary material The online version of this article (10.1007/s12021-020-09483-7) contains supplementary material, which is available to authorized users.