Single Molecule DNA Analysis Based on Atomic-Controllable Nanopores in Covalent Organic Frameworks.

We explored the application of two-dimensional covalent organic frameworks (2D COFs) in single molecule DNA analysis. Two ultrathin COF nanosheets were exfoliated with pore sizes of 1.1 nm (COF-1.1) and 1.3 nm (COF-1.3) and covered closely on a quartz nanopipette with an orifice of 20 ± 5 nm. COF nanopores exhibited high size selectivity for fluorescent dyes and DNA molecules. The transport of long (calf thymus DNA) and short (DNA-80) DNA molecules through the COF nanopores was studied. Because of the strong interaction between DNA bases and the organic backbones of COFs, the DNA-80 was transported through the COF-1.1 nanopore at a speed of 270 µs/base, which is the slowest speed ever observed compared with 2D inorganic nanomaterials. This study shows that the COF nanosheet can work individually as a nanopore monomer with controllable pore size like its biological counterparts.

Study on Ammonia Content and Distribution in the Microenvironment Based on Covalent Organic Framework Nanochannels.

A crack-free micrometer-sized compact structure of 1,3,5-tris(4-aminophenyl)benzene-terephthaldehyde-covalent organic frameworks (TAPB-PDA-COFs) was constructed in situ at the tip of a theta micropipette (TMP). The COF-covered theta micropipette (CTP) then created a stable liquid-gas interface inside COF nanochannels, which was utilized to electrochemically analyze the content and distribution of ammonia gas in the microenvironments. The TMP-based electrochemical ammonia sensor (TEAS) shows a high sensing response, with current increasing linearly from 0 to 50,000 ppm ammonia, owing to the absorption of ammonia gas in the solvent meniscus that connects both barrels of the TEAS. The TEAS also exhibits a short response and recovery time of 5 ± 2 s and 6 ± 2 s, respectively. This response of the ammonia sensor is remarkably stable and repeatable, with a relative standard deviation of 6% for 500 ppm ammonia gas dispensing with humidity control. Due to its fast, reproducible, and stable response to ammonia gas, the TEAS was also utilized as a scanning electrochemical microscopy (SECM) probe for imaging the distribution of ammonia gas in a microspace. This study unlocks new possibilities for using a TMP in designing microscale probes for gas sensing and imaging.

Loss of NPPA-AS1 promotes heart regeneration by stabilizing SFPQ-NONO heteromer-induced DNA repair.

The role of long non-coding RNA (lncRNA) in endogenous cardiac regeneration remains largely elusive. The mammalian cardiomyocyte is capable of regeneration for a brief period after birth. This fact allows the exploration of the roles of critical lncRNAs in the regulation of cardiac regeneration. Through a cardiac regeneration model by apical resection (AR) of the left ventricle in neonatal mice, we identified an lncRNA named natriuretic peptide A antisense RNA 1 (NPPA-AS1), which negatively regulated cardiomyocyte proliferation. In neonates, NPPA-AS1 deletion did not affect heart development, but was sufficient to prolong the postnatal window of regeneration after AR. In adult mice, NPPA-AS1 deletion improved cardiac function and reduced infarct size after myocardial infarction (MI), associated with a significant improvement in cardiomyocyte proliferation. Further analysis showed that NPPA-AS1 interacted with DNA repair-related molecule splicing factor, proline- and glutamine-rich (SFPQ). A heteromer of SFPQ and non-POU domain-containing octamer-binding protein (NONO) was required for double-strand DNA break repair, but NPPA-AS1 was competitively bound with SFPQ due to the overlapped binding sites of SFPQ and NONO. NPPA-AS1 deletion promoted the binding of SFPQ-NONO heteromer, decreased DNA damage, and activated cardiomyocyte cell cycle re-entry. Together, loss of NPPA-AS1 promoted cardiomyocyte proliferation by stabilizing SFPQ-NONO heteromer-induced DNA repair and exerted a therapeutic effect against MI in adult mice. Consequently, NPPA-AS1 may be a novel target for stimulating cardiac regeneration to treat MI.

Global Prevalence of Myotonic Dystrophy: An Updated Systematic Review and Meta-Analysis.

INTRODUCTION: Myotonic dystrophy (DM), the most common muscular dystrophy in adults, is a group of autosomal inherited neuromuscular disorders characterized by progressive muscle weakness, myotonia, and cardiac conduction abnormalities. Due to the different gene mutations, DM has been subclassified into DM type 1 (DM1) and type 2 (DM2). However, the prevalence studies on DM and its subtypes are insufficient. METHODS: The PubMed (1966-2022), MEDLINE (1950-2022), Web of Science (1864-2022), and Cochrane Library (2022) databases were searched for original research articles published in English. The quality of the included studies was assessed by a checklist adapted from Strengthening the Reporting of Observational studies in Epidemiology. To derive the pooled epidemiological prevalence estimates, a meta-analysis was performed using the random-effects model. Heterogeneity was assessed using the Cochrane Q statistic and the I2 statistic. RESULTS: A total of 17 studies were included in the systematic review and meta-analysis. Of the 17 studies evaluated, 14 studies were considered medium quality, 2 studies were considered high quality, and 1 study was considered low quality. The global prevalence of DM varied widely from 0.37 to 36.29 cases per 100,000. The pooled estimate of the prevalence of DM was 9.99 cases (95% CI: 5.62-15.53) per 100,000. The pooled estimate of the prevalence of DM1 was 9.27 cases (95% CI: 4.73-15.21) per 100,000, ranging from 0.37 to 36.29 cases per 100,000. The pooled estimate of the prevalence of DM2 was 2.29 cases (95% CI: 0.17-6.53) per 100,000, ranging from 0.00 to 24.00 cases per 100,000. CONCLUSION: Our study provided accurate estimates of the prevalence of DM. The high heterogeneity and the lack of high-quality studies highlight the need to conduct higher quality studies on orphan diseases.

Complete genome sequencing and evolutionary analysis of hepatitis C virus subtype 6a, including strains from Guangdong Province, China.

We performed an evolutionary analysis using whole genome sequence isolates of hepatitis C virus (HCV) 6a from Guangdong Province and reference sequences from various countries. Less than 5% of the HCV genome was found to be under positive selection. The E1 and E2 proteins had the highest proportion of positively selected sites both within and outside of CD8 T cell epitopes in all of the strains. Regions corresponding to CD8 T cell epitopes were under negative selection except in the isolates from Guangdong. Furthermore, we found evidence of three introductions of the virus into Guangdong from Vietnam and other Southeast Asian countries. Thus, this study provides information about the transmission of HCV 6a by comparison of full-length sequences, indicating the impact of selective constraints in Guangdong and across China.

The role of G protein-coupled receptor kinase 4 in cardiomyocyte injury after myocardial infarction.

AIMS: G protein-coupled receptor kinase 4 (GRK4) has been reported to play an important role in hypertension, but little is known about its role in cardiomyocytes and myocardial infarction (MI). The goal of present study is to explore the role of GRK4 in the pathogenesis and progression of MI. METHODS AND RESULTS: We studied the expression and distribution pattern of GRK4 in mouse heart after MI. GRK4 A486V transgenic mice, inducible cardiomyocyte-specific GRK4 knockout mice, were generated and subjected to MI with their control mice. Cardiac infarction, cardiac function, cardiomyocyte apoptosis, autophagic activity, and HDAC4 phosphorylation were assessed. The mRNA and protein levels of GRK4 in the heart were increased after MI. Transgenic mice with the overexpression of human GRK4 wild type (WT) or human GRK4 A486V variant had increased cardiac infarction, exaggerated cardiac dysfunction and remodelling. In contrast, the MI-induced cardiac dysfunction and remodelling were ameliorated in cardiomyocyte-specific GRK4 knockout mice. GRK4 overexpression in cardiomyocytes aggravated apoptosis, repressed autophagy, and decreased beclin-1 expression, which were partially rescued by the autophagy agonist rapamycin. MI also induced the nuclear translocation of GRK4, which inhibited autophagy by increasing HDAC4 phosphorylation and decreasing its binding to the beclin-1 promoter. HDAC4 S632A mutation partially restored the GRK4-induced inhibition of autophagy. MI caused greater impairment of cardiac function in patients carrying the GRK4 A486V variant than in WT carriers. CONCLUSION: GRK4 increases cardiomyocyte injury during MI by inhibiting autophagy and promoting cardiomyocyte apoptosis. These effects are mediated by the phosphorylation of HDAC4 and a decrease in beclin-1 expression.

Low prevalence of antibodies against SARS-CoV-2 among voluntary blood donors in Guangzhou, China.

Since the first case of COVID-19 reported in late December of 2019 in Wuhan, China, the SARS-CoV-2 virus has caused approximately 20 million infections and 732 thousand deaths around the world by 11 August 2020. Although the pathogen generally infects the respiratory system, whether it is present in the bloodstream and whether it poses a threat to the blood supply during the period of the outbreak is of serious public concern. In this study, we used enzyme-linked immunosorbent assay (ELISA) to screen total antibodies against SARS-CoV-2 in 2199 blood donors, who had donated blood at the Guangzhou Blood Center during the epidemic. The Ig-reactive samples were further characterized for IgA, IgG, and IgM subtypes by ELISA and viral nucleic acid by real-time polymerase chain reaction. Among the 2199 plasma samples, seven were reactive under total antibodies' screening. Further testing revealed that none of them had detectable viral nucleic acid or IgM antibody, but two samples contained IgA and IgG. The IgG antibody titers of both positive samples were 1:16 and 1:4, respectively. Our results indicated a low prevalence of past SARS-CoV-2 infection in our blood donors, as none of the tests were positive for viral nucleic acid and only 2 out of 2199 (0.09%) of samples were positive for IgG and IgA. There would be a limited necessity for the implementation of such testing in blood screening in a COVID-19 low-risk area.

Mass Transfer Modulation and Gas Mapping Based on Covalent Organic Frameworks-Covered Theta Micropipette.

Covalent organic frameworks (COFs) consist nanochannels that are fundamentally important for their application. Up to now, the effect of gas phase on COF nanochannels are hard to explore. Here, TAPB-PDA-COFs (triphenylbenzene-terephthaldehyde-COFs) was synthesized in situ at the tip of a theta micropipette. The COF-covered theta micropipette (CTP) create a stable gas-liquid interface inside the COF nanochannels, through which the humidity-modulated ion mass transfer in the COF nanochannels can be recorded by recording the current across the two channels of the theta micropipette. Results show that the humid air changes the mobility of the ions inside the COF nanochannels, which leads to the change of ionic current. Humid air showed different effects on the ion transfer depending on the solvent polarity index and vapor pressure. Current decreases linearly with the increase of relative humidity (RH) from 11% to 98%. The CTP was also mounted on the scanning electrochemical microscopy as a probe electrode for mapping micrometer-scale humidity distribution.

Novel hepatitis B virus surface antigen mutations associated with occult genotype B hepatitis B virus infection affect HBsAg detection.

The causative factors of occult hepatitis B infection are complicated and not yet been fully elucidated. Mutations in hepatitis B virus (HBV) S gene are one of the factors may contributing to occult infection. In this study, 89 blood donors with genotype B occult HBV infection were investigated. Fifty-seven hepatitis B surface antigen (HBsAg)-positive/HBV DNA-positive blood donors served as control group for comparison. Occult HBV-related mutations with a high incidence (P < .05) in the S gene were identified. To further verify these occult infection-related mutations, a conservative full-gene expression vector of HBV B genotype (pHBV1.3B) was constructed. Then, the mutant plasmids on the basis of pHBV1.3B were constructed and transfected into HepG2 cells. Extracellular as well as intracellular HBsAg was analysed by electrochemical luminescence and cellular immunohistochemistry. Ten occult infection-related mutations (E2G, Q101R, K122R, M133T, D144E, G145R, V168A, S174N, L175S and I226S) were significantly more frequent in the occult infection group (P < .05). Five of the ten mutations (E2G, D144E, G145R, V168A and S174N) strongly decreased extracellular HBsAg level (P < .05) in the transfection system. Notably, the E2G mutation had the most significant impact on the ratio of extracellular HBsAg (3.8% vs pHBV1.3B) and intracellular HBsAg (239.3% vs pHBV1.3B) (P < .05), and the fluorescence density of E2G mutant HBsAg was significantly higher than that of pHBV1.3B (P < .0001). Hence, ten mutations were associated with genotype B occult HBV infection; E2G and V168A were novel mutations which we confirmed significantly affect HBsAg detection. E2G might cause HBsAg secretion impairment that results in intracellular accumulation and a decrease in HBsAg secretion.

pH-Dependent Slipping and Exfoliation of Layered Covalent Organic Framework.

Layered/two-dimensional covalent organic frameworks (2D COF) are crystalline porous materials composed of light elements linked by strong covalent bonds. Interlayer force is one of the main factors directing the formation of a stacked layer structure, which plays a vital role in the stability, crystallinity, and porosity of layered COFs. The as-developed new way to modulate the interlayer force of imine-linked 2D TAPB-PDA-COF (TAPB = 1,3,5-tris(4-aminophenyl)benzene, PDA = terephthaldehyde) by only adjusting the pH of the solution. At alkaline and neutral pH, the pore size of the COF decreases from 34 Šdue to the turbostratic effect. Under highly acidic conditions (pH 1), TAPB-PDA-COF shows a faster and stronger turbostratic effect, thus causing the 2D structure to exfoliate. This yields bulk quantities of an exfoliated few/single-layer 2D COF, which was well dispersed and displayed a clear Tyndall effect (TE). Furthermore, nanopipette-based electrochemical testing also confirms the slipping of layers with increase towards acidic pH. A model of pH-dependent layer slipping of TAPB-PDA-COF was proposed. This controllable pH-dependent change in the layer structure may open a new door for potential applications in controlled gas adsorption/desorption and drug loading/releasing.

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Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease affecting the upper and lower motor neurons. It is characterized by progressive muscle weakness, atrophy and ultimate death due to dysphagia and dyspnea. There are many causes of ALS, among which the genetic factors show great relevance. Imbalance of protein homeostasis in neurons, prion-like proliferation and propagation of abnormal proteins, mitochondrial dysfunction, glutamate mediated excitotoxicity, and intraneuronal substance transport disorders are recognized as the pathogenesis.The study on gene mutation related to pathogenesis will bridge the molecular and cellular research of ALS, which can deepen the understanding of the occurrence and development of ALS and the role of gene mutation in ALS, and provide new ideas and enlightenment for the treatment of ALS.

HCV genotype 6 prevalence, spontaneous clearance and diversity among elderly members of the Li ethnic minority in Baisha County, China.

The epidemiology of hepatitis C virus varies widely across geographical regions and ethnic groups. Our previous study showed that 6 strains isolated from Baisha County, Hainan Island, China, were all new genotype 6 (gt6) subtypes which differed significantly from subtypes of other regions. In the current study, we conducted a comprehensive epidemiological survey of HCV in the Li ethnic group, native to Baisha County. Anti-HCV antibodies were detected by 2 independent ELISAs in all participants, and positive results confirmed by the recombinant immunoblot assay (RIBA) and HCV RNA viral loads were measured. Univariate chi-square test and multivariable logistic regression analyses were used to determine the risk factors for HCV infection and spontaneous clearance rates. Indeterminate RIBA results were excluded or included in analyses; consequently, findings were expressed as a range. Direct sequencing of partial regions within NS5B and E1 was employed for genotyping. Among 1682 participants, 117 to 153 were anti-HCV positive (7.0%-9.1%), with 42.7%-52.6% confirmed to have cleared infection. Anti-HCV positivity was associated with older age (≥60 years) (OR = 0.02, 95% CI 0.01-0.05, P < 0.01) and surgery (OR = 2.75, 95% CI 1.36-5.57, P < 0.01), with no significant difference found between the HCV infection group and the HCV spontaneous clearance group. The gt6 subtype distribution characteristics of Baisha County were unique, complex and diverse. The sequences did not cluster with known gt6 subtypes but formed 4 Baisha community-specific groups. HCV infection in members of the Li minority ethnic group is characterized by high prevalence rates in the elderly, high spontaneous clearance rates and broad gt6 diversity.

Association of HLA-DQB1*03:01 and DRB1*11:01 with spontaneous clearance of hepatitis C virus in Chinese Li ethnicity, an ethnic group genetically distinct from Chinese Han ethnicity and infected with unique HCV subtype.

Specific human leukocyte antigen (HLA) class I and class II alleles have been associated with spontaneous clearance or persistent infection of hepatitis C virus (HCV), which seemed to be restricted by the host's ethnicity and viral genotype. Recently we reported a high prevalence and spontaneous clearance rate of HCV in a cohort of Chinese Li ethnicity who were infected with new variants of HCV genotype 6. In this study, we found that the distribution of HLA class I and class II alleles in HCV infected individuals of Chinese Li ethnicity (n = 143) was distinct from that of Chinese Han ethnicity which was reported in our previous study. HLA-DRB1*11:01 and DQB1*03:01 were more prevalent in Chinese Li subjects who cleared HCV spontaneously than those who were chronically infected (P = .036 and P = .024, respectively), which were consistent with our previous report regarding the Chinese Han population. Multivariate logistic regression analysis showed that DQB1*03:01 (odds ratio = 3.899, P = .017), but not DRB1*11:01, associated with HCV spontaneous clearance, independent of age, sex, and IFNL3 genotype. Because DQB1*03:01 and DRB1*11:01 were tightly linked because of linkage disequilibrium, our results clearly supported the associations of these two alleles with HCV spontaneous clearance in Chinese Li as well as Han ethnicity.

Characterization of monocytic and granulocytic subsets of myeloid-derived suppressor cells in blood donors with occult hepatitis B virus infection.

Myeloid-derived suppressor cells (MDSCs) accumulate from many diseases. MDSCs are rarely explored in occult hepatitis B virus infection (OBI). The frequency of monocytic MDSCs (M-MDSCs) and granulocytic MDSCs (G-MDSCs) in OBI carriers was analyzed for correlation with clinical parameters, which was no different between OBI and healthy individuals, whereas the frequency of M-MDSCs but G-MDSCs in OBI was significantly lower than that observed in chronic hepatitis B carriers (0.4% vs 0.7%, P = 0.0004). The frequency of MDSCs was not correlated with clinical parameters and viral load of OBI, suggesting that the absence of HBsAg in OBI carriers might not induce the accumulation of MDSCs.

Hepatitis C virus 3b strains in injection drug users in Guangdong Province, China, may have originated in Yunnan Province.

The distribution of hepatitis C virus (HCV) genotypes/subtypes varies among different populations. Here, we investigated HCV infection and its genotype distribution in injection drug users (IDUs) in Guangdong Province of China. A total of 318 IDUs from two prisons were recruited. The genotypes/subtypes of HCV in IDUs were determined by phylogenetic analysis using E1 and/or NS5B gene sequences. Our previous data on blood donors (BDs) with no history of drug use were used as control population data for comparison. Our results showed that the prevalence of HCV 3b (20.9% vs. 3.6%, P = 3.4E-9) and 6a (57.0% vs. 39.8%, P = 1.2E-5) was higher in IDUs than in BDs. In contrast, the prevalence of HCV 1b (43.4% vs. 5.6%, P = 9.8E-23) in BDs was higher than in IDUs. Phylogeographic analysis indicated that HCV 3b migrated from Yunnan to Guangdong Province and became endemic, with further transmission to other regions of China. The trend of HCV 3b dissemination in China in IDUs requires further attention, and a strategy for prevention and therapy is needed.

Irisin exerts a therapeutic effect against myocardial infarction via promoting angiogenesis.

Irisin, a myokine, is cleaved from the extracellular portion of fibronectin domain-containing 5 protein in skeletal muscle and myocardium and secreted into circulation as a hormone during exercise. Irisin has been found to exert protective effects against lung and heart injuries. However, whether irisin influences myocardial infarction (MI) remains unclear. In this study we investigated the therapeutic effects of irisin in an acute MI model and its underlying mechanisms. Adult C57BL/6 mice were subjected to ligation of the left anterior descending coronary artery and treated with irisin for 2 weeks after MI. Cardiac function was assessed using echocardiography. We found that irisin administration significantly alleviated MI-induced cardiac dysfunction and ventricular dilation at 4 weeks post-MI. Irisin significantly reduced infarct size and fibrosis in post-MI hearts. Irisin administration significantly increased angiogenesis in the infarct border zone and decreased cardiomyocyte apoptosis, but did not influence cardiomyocyte proliferation. In human umbilical vein endothelial cells (HUVEC), irisin significantly increased the phosphorylation of ERK, and promoted the migration of HUVEC detected in wound-healing and transwell chamber migration assay. The effects of irisin were blocked by the ERK inhibitor U0126. In conclusion, irisin improves cardiac function and reduces infarct size in post-MI mouse heart. The therapeutic effect is associated with its pro-angiogenic function through activating ERK signaling pathway.

Dedifferentiation, Proliferation, and Redifferentiation of Adult Mammalian Cardiomyocytes After Ischemic Injury.

BACKGROUND: Adult mammalian hearts have a limited ability to generate new cardiomyocytes. Proliferation of existing adult cardiomyocytes (ACMs) is a potential source of new cardiomyocytes. Understanding the fundamental biology of ACM proliferation could be of great clinical significance for treating myocardial infarction (MI). We aim to understand the process and regulation of ACM proliferation and its role in new cardiomyocyte formation of post-MI mouse hearts. METHODS: ß-Actin-green fluorescent protein transgenic mice and fate-mapping Myh6-MerCreMer-tdTomato/lacZ mice were used to trace the fate of ACMs. In a coculture system with neonatal rat ventricular myocytes, ACM proliferation was documented with clear evidence of cytokinesis observed with time-lapse imaging. Cardiomyocyte proliferation in the adult mouse post-MI heart was detected by cell cycle markers and 5-ethynyl-2-deoxyuridine incorporation analysis. Echocardiography was used to measure cardiac function, and histology was performed to determine infarction size. RESULTS: In vitro, mononucleated and bi/multinucleated ACMs were able to proliferate at a similar rate (7.0%) in the coculture. Dedifferentiation proceeded ACM proliferation, which was followed by redifferentiation. Redifferentiation was essential to endow the daughter cells with cardiomyocyte contractile function. Intercellular propagation of Ca2+ from contracting neonatal rat ventricular myocytes into ACM daughter cells was required to activate the Ca2+-dependent calcineurin-nuclear factor of activated T-cell signaling pathway to induce ACM redifferentiation. The properties of neonatal rat ventricular myocyte Ca2+ transients influenced the rate of ACM redifferentiation. Hypoxia impaired the function of gap junctions by dephosphorylating its component protein connexin 43, the major mediator of intercellular Ca2+ propagation between cardiomyocytes, thereby impairing ACM redifferentiation. In vivo, ACM proliferation was found primarily in the MI border zone. An ischemia-resistant connexin 43 mutant enhanced the redifferentiation of ACM-derived new cardiomyocytes after MI and improved cardiac function. CONCLUSIONS: Mature ACMs can reenter the cell cycle and form new cardiomyocytes through a 3-step process: dedifferentiation, proliferation, and redifferentiation. Intercellular Ca2+ signal from neighboring functioning cardiomyocytes through gap junctions induces the redifferentiation process. This novel mechanism contributes to new cardiomyocyte formation in post-MI hearts in mammals.

Association of killer cell immunoglobulin-like receptors with spontaneous clearance of hepatitis C virus in the Chinese population.

BACKGROUND: Natural killer (NK) cells are critical components in innate immune response to viral infection. Killer cell immunoglobulin-like receptors (KIRs) are involved in regulating the balance of activation or inhibitory function of NK cells. However, the association of KIRs with the spontaneous clearance of hepatitis C virus (HCV) remains unclear in the Chinese population. STUDY DESIGN AND METHODS: A total of 407 HCV-seropositive voluntary blood donors were recruited, including 203 with spontaneous viral clearance and 204 with chronic infection. The presence of KIR genes was detected individually by polymerase chain reaction with sequence-specific primers. Data of HLA and interleukin-28B (IL28B) genotypes were extracted from our previous study. RESULTS: Our results showed that KIR2DL2, 2DS2, 2DL2/2DL3, and 2DL5A-/2DL5B+ were more frequent in subjects with HCV clearance than those with chronic infection (odds ratio [OR], 1.640, p = 0.034; OR, 1.664, p = 0.032; OR, 1.636, p = 0.040; and OR, 2.601, p = 0.012, respectively). Multivariate logistic regression analysis showed that KIR2DL5A-/2DL5B+ associated with HCV clearance (OR, 2.448, p = 0.027), independent of sex, IL28B, and other KIRs. In contrast, KIR2DL3/2DL3 (OR, 0.610, p = 0.034) as well as 2DL3/2DL3+HLA-C1 or C1C1 (OR, 0.580, p = 0.017; and OR, 0.639, p = 0.025, respectively) was found associated with chronic HCV infection. The presence of the homozygous KIR2DL3 with or without its HLA ligand increased the OR of developing chronic HCV infection in the context of IL28B. CONCLUSIONS: In this study we identified KIR2DL5A-/2DL5B+ associated with HCV spontaneous clearance, while KIR2DL3/2DL3, 2DL3/2DL3+HLA-C1, or C1C1 associated with chronic infection. Our study highlighted the fact that the roles of KIR and KIR-HLA contributed to the control of HCV infection by innate immune responses.

[Mutations of G38R and D40G cause amyotrophic lateral sclerosis by reducing Annexin A11 protein stability].

OBJECTIVE: To explore the role of the mutations G38R and D40G of Annexin A11 (ANXA11) in the onset of amyotrophic lateral sclerosis (ALS).
 Methods: The plasmids expressing ANXA11 wild type protein, ANXA11 G38R protein and ANXA11 D40G protein were constructed, respectively. The recombinant plasmids were then transfected into HEK293 cells respectively followed by cycloheximide (CHX) treatment for 0, 2, 4 and 8 h. The protein expressions of ANXA11 wild type, ANXA11 G38R and ANXA11 D40G mutations were determined by Western blot. Gray analysis by Image J was performed to compare the half-life of each protein. The NSC-34 cell lines constantly expressing ANXA11 wild type protein, ANXA11 G38R protein and ANXA11 D40G protein were established. The cells were treated with NP-40 lysis buffer to examine the protein solubility by Western blot.
 Results: Both ANXA11 G38R protein and ANXA11 D40G protein showed a shorter half-life than ANXA11 wild type protein (P<0.05), while there was no difference between ANXA11 G38R protein and ANXA11 D40G protein (P>0.05). There was no visible insoluble substance in the NP-40 lysates for ANXA11 wild type protein, ANXA11 G38R protein and ANXA11 D40G protein.
 Conclusion: G38R and D40G mutations reduce the stability of ANXA11 protein. G38R and D40G mutations do not alter ANXA11 solubility.

Mesenchymal stem cells-derived extracellular vesicles, via miR-210, improve infarcted cardiac function by promotion of angiogenesis.

Mesenchymal stem cells (MSCs) exert therapeutic effect on treating acute myocardial infarction. Recent evidence showed that paracrine function rather than direct differentiation predominately contributes to the beneficial effects of MSCs, but how the paracrine factors function are not fully elucidated. In the present study, we tested if extracellular vesicles (EVs) secreted by MSC promotes angiogenesis in infracted heart via microRNAs. Immunostaining of CD31 and matrigel plug assay were performed to detect angiogenesis in a mouse myocardial infarction (MI) model. The cardiac function and structure was examined with echocardiographic analysis. Capillary-like tube formation, migration and proliferation of human umbilical vein endothelial cells (HUVECs) were determined. As a result, MSC-EVs significantly improved angiogenesis and cardiac function in post-MI heart. MSC-EVs increased the proliferation, migration and tube formation capacity of HUVECs. MicroRNA (miR)-210 was found to be enriched in MSC-EVs. The EVs collected from MSCs with miR-210 silence largely lost the pro-angiogenic effect both in-vitro and in-vivo. The miR-210 target gene Efna3, which plays a role in angiogenesis, was down-regulated by MSC-EVs treatment in HUVECs. In conclusion, MSC-EVs are sufficient to improve angiogenesis and exert therapeutic effect on MI, its pro- angiogenesis effect might be associated with a miR-210-Efna3 dependent mechanism. This article is part of a Special Issue entitled: Genetic and epigenetic control of heart failure - edited by Jun Ren & Megan Yingmei Zhang.