Molecular determinants and heterogeneity underlying host response to EV-A71 infection at single-cell resolution.

The pathogenic human enterovirus EV-A71 has raised serious public health concerns. A hallmark of EV-A71 infection is the distortion of host transcriptomes in favour of viral replication. While high-throughput approaches have been exploited to dissect these gene dysregulations, they do not fully capture molecular perturbations at the single-cell level and in a physiologically relevant context. In this study, we applied a single-cell RNA sequencing approach on infected differentiated enterocyte cells (C2BBe1), which model the gastrointestinal epithelium targeted initially by EV-A71. Our single-cell analysis of EV-A71-infected culture provided several lines of illuminating observations: 1) This systems approach demonstrated extensive cell-to-cell variation in a single culture upon viral infection and delineated transcriptomic differences between the EV-A71-infected and bystander cells. 2) By analysing expression profiles of known EV-A71 receptors and entry facilitation factors, we found that ANXA2 was closely correlated in expression with the viral RNA in the infected population, supporting its role in EV-A71 entry in the enteric cells. 3) We further catalogued dysregulated lncRNAs elicited by EV-A71 infection and demonstrated the functional implication of lncRNA CYTOR in promoting EV-A71 replication. Viewed together, our single-cell transcriptomic analysis illustrated at the single-cell resolution the heterogeneity of host susceptibility to EV-A71 and revealed the involvement of lncRNAs in host antiviral response.

A novel antisense RNA ASPACT confers multi-level suppression of PACT and associated signalling.

The innate immune system is the frontline host protection against pathogens. Effective antiviral immunity is elicited upon recognition of viral RNAs by the host pattern recognition receptors. One of the major viral RNA sensors is retinoic acid inducible gene-1, which triggers the production of interferons (IFNs). In turn, this protective response requires another viral sensor and immunity factor interferon-inducible protein kinase RNA activator (PACT/PRKRA). Here, we report the identification and characterization of a novel antisense PACT gene that expresses a non-coding RNA in a convergent and interferon-inducible manner. Publicly available gene structure and expression data revealed that this gene, that we termed ASPACT, overlaps with the 3' -end of the PACT locus and is highly expressed during viral infection. Our results confirm the IFN-ß-inducibility of ASPACT, which is dependent on STAT-1/2. We further discovered that downregulation of ASPACT impacts both the expression and localization of the PACT transcript. At the transcription level, ChIP and ChIRP assays demonstrated that the ASPACT non-coding RNA occupies distinct chromatin regions of PACT gene and is important for promoter recruitment of the epigenetic silencer HDAC1. In parallel, ASPACT was also found to mediate nuclear retention of the PACT mRNA via direct RNA-RNA interaction, as revealed by RNA antisense purification assay. In summary, our results support the model that the non-coding RNA ASPACT acts as a negative regulator of PACT at multiple levels, and reveal a novel regulator of the viral counteractive response.

Isoform Evolution in Primates through Independent Combination of Alternative RNA Processing Events.

Recent RNA-seq technology revealed thousands of splicing events that are under rapid evolution in primates, whereas the reliability of these events, as well as their combination on the isoform level, have not been adequately addressed due to its limited sequencing length. Here, we performed comparative transcriptome analyses in human and rhesus macaque cerebellum using single molecule long-read sequencing (Iso-seq) and matched RNA-seq. Besides 359 million RNA-seq reads, 4,165,527 Iso-seq reads were generated with a mean length of 14,875 bp, covering 11,466 human genes, and 10,159 macaque genes. With Iso-seq data, we substantially expanded the repertoire of alternative RNA processing events in primates, and found that intron retention and alternative polyadenylation are surprisingly more prevalent in primates than previously estimated. We then investigated the combinatorial mode of these alternative events at the whole-transcript level, and found that the combination of these events is largely independent along the transcript, leading to thousands of novel isoforms missed by current annotations. Notably, these novel isoforms are selectively constrained in general, and 1,119 isoforms have even higher expression than the previously annotated major isoforms in human, indicating that the complexity of the human transcriptome is still significantly underestimated. Comparative transcriptome analysis further revealed 502 genes encoding selectively constrained, lineage-specific isoforms in human but not in rhesus macaque, linking them to some lineage-specific functions. Overall, we propose that the independent combination of alternative RNA processing events has contributed to complex isoform evolution in primates, which provides a new foundation for the study of phenotypic difference among primates.

Association between platelet function and recurrent ischemic vascular events after TIA and minor stroke
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Platelet activation and aggregation play an important role in the pathological and physiological processes of recurrent ischemic vascular events in stroke patients. The purpose of this study is to determine the association between platelet function measured in the acute period and recurrent ischemic vascular events in patients with transient ischemic attack (TIA) or minor stroke. A total of 417 patients who were within the 24-hour period of clopidogrel-aspirin therapy after onset of a minor stroke or high-risk transient ischemic attack according to the Clopidogrel in High-risk patients with Acute Nondisabling Cerebrovascular Events (CHANCE) trial were included in this study. The platelet aggregation ratio was detected using a method of continuous platelet counting; patients underwent CYP2C19 genotyping, and the baseline data were recorded. The patients underwent a 6-month follow-up period during which the recurrent ischemic vascular events were observed. Logistic regression analysis was performed to obtain the risk factors for recurrent ischemic vascular events. The number of patients with recurrent ischemic events who had an arachidonic acid-induced maximum platelet aggregation ratio (MAR-AA) (aspirin 100 mg) (31.85 ± 12.86 vs. 26.71 ± 12.44, p = 0.007) and adenosine diphosphate-induced maximum platelet aggregation ratio (MAR-ADP) after the administration of 75 mg clopidogrel for 12 ± 2 days (65.82 ± 10.72 vs. 53.10 ± 12.98, p < 0.001) was significantly higher compared with the no ischemic vascular event group. Multivariate logistic regression analyses showed that being a carrier of the CYP2C19 loss-of-function (LOF) allele (OR = 2.308, 95% CI: 1.087 ~ 4.901, p = 0.029) as well as the MAR-AA (aspirin 100 mg) (OR = 1.028, 95% CI: 1.006  ~  1.052, p = 0.014) and MAR-ADP after the administration of 75 mg clopidogrel (OR = 1.067, 95% CI: 1.037 ~ 1.095, p < 0.001) were risk factors for ischemic vascular events. The MAR-ADP after the administration of 75 mg clopidogrel was significantly higher in patients who were carriers of the CYP2C19 (LOF) allele compared with non-carriers (57.53 ± 13.32 vs. 50.86 ± 12.55, p < 0.001), and no significant differences between the CYP2C19 LOF allele carriers and non-carriers in the MAR-ADP were detected after the administration of 300 mg clopidogrel (37.18 ± 11.36 vs. 35.86 ± 12.49, p = 0.264). Being a carrier of the CYP2C19 LOF allele has a significant influence on clopidogrel response. Platelet function is closely related to recurrent ischemic vascular events in acute minor stroke or TIA patients.
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Epigenetic silencing of myogenic gene program by Myb-binding protein 1a suppresses myogenesis.

Skeletal myogenesis involves highly coordinated steps that integrate developmental cues at the chromatin of muscle progenitors. Here, we identify Myb-binding protein 1a (Mybbp1a) as a novel negative regulator of muscle-specific gene expression and myoblast differentiation. The mode of action of Mybbp1a was linked to promoter regulation as illustrated by its interaction with MyoD at the genomic regions of silent muscle-specific genes as well as its negative effect on MyoD-mediated transcriptional activity. We propose that Mybbp1a exerts its repressive role by inducing a less permissible chromatin structure following recruitment of negative epigenetic modifiers such as HDAC1/2 and Suv39h1. At the onset of differentiation, Mybbp1a undergoes a promoter disengagement that may be due to the differentiation-responsive, miR-546-mediated downregulation of Mybbp1a expression. Moreover, such alteration gave rise to promoter enrichment of activators and histone acetylation, an epigenetic status amenable to gene activation. Together, these findings unveil a hitherto unrecognized transcriptional co-repressor role of Mybbp1a in proliferating muscle progenitor cells, and highlight an epigenetic mechanism by which Mybbp1a and miR-546 interplay to control myoblast differentiation transition.

Chromatin binding protein HMGN1 promotes HBV cccDNA transcription and replication by regulating the phosphorylation of histone 3.

BACKGROUND AND AIMS: Direct elimination of cccDNA remains a formidable obstacle due to the persistent and stable presence of cccDNA in hepatocyte nuclei. The silencing of cccDNA transcription enduringly is one of alternative strategies in the treatment of hepatitis B. Protein binding to cccDNA plays an important role in its transcriptional regulation; thus, the identification of key factors involved in this process is of great importance. APPROACHES AND RESULTS: In the present study, high mobility group nucleosome binding domain 1 (HMGN1) was screened out based on our biotin-avidin enrichment system. First, chromatin immunoprecipitation and fluorescent in situ hybridization assays confirmed the binding of HMGN1 with cccDNA in the nucleus. Second, functional experiments in HBV-infected cells showed that the promoting effect of HMGN1 on HBV transcription and replication depended on the functional region of the nucleosomal binding domain, while transfection of the HMGN1 mutant showed no influence on HBV compared with the vector. Third, further mechanistic exploration revealed that the silencing of HMGN1 increased the level of phosphorylase CLK2 and promoted H3 phosphorylation causing the reduced accessibility of cccDNA. Moreover, silenced HMGN1 was mimicked in HBV (r) cccDNA mouse model of HBV infection in vivo. The results showed that silencing HMGN1 inhibited HBV replication in vivo. CONCLUSIONS: In summary, our study identified that a host protein can bind to cccDNA and promote its transcription, providing a candidate strategy for anti-HBV targeting to interfere with the transcriptional activity of cccDNA microchromosomes.

Cognitive enhancement and neuroprotection by catechin-rich oil palm leaf extract supplement.

BACKGROUND: Catechin-rich oil palm (Elaeis guineensis) leaf extract (OPLE) has good cardiovascular and phytoestrogenic properties. The OPLE (0.5 g day(-1) ) was supplemented to young, healthy, adult human volunteers, and their cognitive learning abilities were compared to placebo-controlled groups (N = 15). Their short-term memories, spatial visualisations, processing speeds, and language skills, were assessed over 2 months by cognitive tests computer programs. RESULTS: Relative to the controls, volunteers taking OPLE had improved (P < 0.05) short-term memory, after 1 month of intervention which became highly significant (P < 0.005) after 2 months. The spatial visualisation ability and processing speed improved (P < 0.05) after 2 months consumption. The dietary OPLE showed neuroprotection in nitric oxide-deficient rats. The mechanisms involved systemic and cellular modulations that eventually enhance neuron survival. The longer the duration of OPLE consumption, the more significant was the enhancement, as shown for short-term memory. CONCLUSION: This is the first report on the cognitive-enhancing effects of dietary OPLE in humans. The computer-assisted cognitive tests were simple, low in cost, errors and man hours, and hence are better than conventional cognitive test methods. In rats, the equivalent OPLE dose showed brain antioxidant enzymes modulating properties and neuroprotection under nitric oxide deficiency, with possibly neurogenesis in normal rats. This supported the effects in humans.

Ciliatoside A, isolated from Peristrophe japonica, inhibits HBsAg expression and cccDNA transcription by inducing autophagy.

Hepatitis B surface antigen (HBsAg) loss and seroconversion are considered as an end point of a functional cure. Therefore, it is crucial to find new agents which could efficiently decrease HBsAg. Traditional herbal plants have been considered as an important source of new hepatitis B drugs development for their extensive use in antimicrobial and anti-inflammation. In this study, Peristrophe japonica, which could remarkably reduce HBsAg in the supernatant of HepG2.2.15 cells, was screened out for further extraction. Here, an active ethyl acetate fraction of Peristrophe japonica containing 34 sub-fractions was extracted. Subsequently, the monomeric compound Ciliatoside A was isolated and identified as a potential antiviral reagent with low cytotoxicity from Fraction 30. Ciliatoside A exhibited strong inhibition on intracellular and circulating HBsAg and HBV RNAs in HBV-infected cells and an HBV recombinant-cccDNA mouse model. The mechanistic study revealed that Ciliatoside A exhibited a potent anti-HBV effect through inducing autophagy-lysosomal pathway to autophagic degradation of HBc by activating AMPK-ULK1 axis and inhibiting mTOR activation. In summary, we have identified a novel antiviral compound Ciliatoside A isolated from Peristrophe japonica. This study may provide important direction and new ideas for the discovery of hepatitis B cure drugs.

Echocardiography and strain analysis in Malaysian elite athletes versus young healthy adults.

Background: Athletes have changes that can mimic pathological cardiomyopathy. Methods: Echocardiographic study of 50 male, female athletes (MA, FA) and non-athletes (MNA, FNA) age 18 to 30 years. These athletes participate in sports with predominantly endurance component. All participants exhibit no known medical illnesses or symptoms. Results: MA have thicker wall (IVSd) than MNA. No MA have IVSd > 1.2 cm and no FA have IVSd > 1.0 cm. Left ventricle internal dimension (LVIDd), left ventricle end diastolic volume index (LVEDVi) is bigger in athletes. None have LVIDd > 5.8 cm. Right ventricle fractional area change (FAC) is lower in athletes. (MA vs MNA, p = 0.013, FA vs FNA, p = 0.025). Athletes have higher septal and lateral e' (Septal e'; MA 13.57 ± 2.66 cm/s vs MNA 11.46 ± 2.93 cm/s, p < 0.001, Lateral e'; MA 17.17 ± 3.07 cm/s vs MNA 14.82 ± 3.14 cm/s, p < 0.001), (Septal e'; FA 13.46 ± 2.32 cm/s vs FNA 12.16 ± 2.05 cm/s, p = 0.04, Lateral e'; FA 16.92 ± 2.97 cm/s vs FNA 15.44 ± 2.29 cm/s, p = 0.006).No difference in Global longitudinal (GLS), Right ventricle free wall (RVFWS) and Global circumferential strain (GCS). Left atrial reservoir (LArS) and left atrial booster strain (LAbS) is smaller in athletes. (LArS, MA 44.12 ± 9.55% vs MNA 52.95 ± 11.17%, p < 0.001 LArS, FA 48.07 ± 10.06% vs FNA 53.64 ± 8.99%, p = 0.004), (LAbS, MA 11.59 ± 5.13% vs MNA 17.35 ± 5.27%, p < 0.001 LAbS FA 11.77 ± 4.65% vs FNA 15.30 ± 4.19%, p < 0.001). Conclusion: Malaysian athletes have thicker wall and bigger left ventricle than controls. No athletes have IVSd > 1.2 cm and/or LVIDd > 5.8 cm. There is no difference in GLS, RVFWS and GCS but athletes have smaller LArS and LAbS.

Comprehensive functional genomic analyses link APC somatic mutation and mRNA-miRNA networks to the clinical outcome of stage-III colorectal cancer patients.

BACKGROUND: Colorectal cancer (CRC) is a major health concern globally, but exhibits regional and/or environmental distinctions in terms of outcome especially for patients with stage III CRC. METHODS: From 2014 to 2016, matched pairs of tumor and adjacent normal tissue samples from 60 patients with stage I-IV CRC from Chang Gung Memorial Hospital in Taiwan were analyzed using next-generation sequencing. The DNA, mRNA, and miRNA sequences of paired tumor tissues were profiled. An observational study with survival analysis was done. Online datasets of The Cancer Genome Atlas (TCGA) and The International Cancer Genome Consortium (ICGC) were also integrated and compared. RESULTS: The gene that exhibited the highest mutation rate was adenomatous polyposis coli (APC) (75.0%), followed by TP53 (70.0%), KRAS (56.6%), and TTN (48.3%). APC was also the most frequently mutated gene in TCGA and ICGC datasets. Surprisingly, for non-metastatic cases (stages I-III), CRC patients with mutated APC had better outcome in terms of overall survival (p = 0.041) and recurrence free survival (p = 0.0048). Particularly for stage III CRC, the overall survival rate was 94.4% and 67.7%, respectively (p = 0.018), and the recurrence free survival rate was 94.4% and 16.7%, respectively (p = 0.00044). Further clinical and gene expression analyses revealed that the APC wt specimens to a greater extent exhibit poor differentiation state as well as EGFR upregulation, providing molecular basis for the poor prognosis of these patients. Finally, based on integrated transcriptome analysis, we constructed the mRNA-miRNA networks underlying disease recurrence of the stage III CRC and uncovered potential therapeutic targets for this clinical condition. CONCLUSION: For stage III CRC, patients with mutated APC had better overall and recurrence free survival.

Significantly enhanced coupling effect and gap plasmon resonance in a MIM-cavity based sensing structure.

Herein, we design a high sensitivity with a multi-mode plasmonic sensor based on the square ring-shaped resonators containing silver nanorods together with a metal-insulator-metal bus waveguide. The finite element method can analyze the structure's transmittance properties and electromagnetic field distributions in detail. Results show that the coupling effect between the bus waveguide and the side-coupled resonator can enhance by generating gap plasmon resonance among the silver nanorods, increasing the cavity plasmon mode in the resonator. The suggested structure obtained a relatively high sensitivity and acceptable figure of merit and quality factor of about 2473 nm/RIU (refractive index unit), 34.18 1/RIU, and 56.35, respectively. Thus, the plasmonic sensor is ideal for lab-on-chip in gas and biochemical analysis and can significantly enhance the sensitivity by 177% compared to the regular one. Furthermore, the designed structure can apply in nanophotonic devices, and the range of the detected refractive index is suitable for gases and fluids (e.g., gas, isopropanol, optical oil, and glucose solution).

A Prospective Multicenter Study of the Chinese Scoring System for Hepatitis B Liver Failure.

Objective: To evaluate the clinical utility of a Chinese scoring system for hepatitis B liver failure in a prospective and multicenter study. Methods: Clinical data for 1,143 patients with hepatitis B liver failure who had been followed up for a minimum of 6 months were collected from seven liver disease centers across China. The disease severity and prognosis for the patients were predicted using the Chinese scoring system and compared to those predicted with the model for end-stage liver disease (MELD) score, MELD-Na score, and Child-Turcotte-Pugh (CTP) score. Results: The Chinese scoring system was more effective at predicting the outcomes of survival and mortality than the MELD score. In the peak disease stage, the area under the receiver operating characteristic curve for the Chinese scoring system was 0.954, significantly higher than that (0.896) for the MELD scoring system (P < 0.001). The positive prediction at 30, 90, and 180 days with the Chinese scoring system was 0.764 (95% CI: 0.714-0.808), 0.731 (95% CI: 0.694-0.769), and 0.724 (95% CI: 0.679-0.765), also significantly higher than that with the MELD, MELD-Na, and CTP scores (P < 0.001). In addition, the Chinese scoring system was superior to the MELD, MELD-Na, and CTP scores (P < 0.001) at predicting the prognosis of patients with hepatitis B liver failure at both 30 and 180 days. Conclusion: The Chinese scoring system demonstrated superior performance to the three established scoring systems in assessing the severity and outcomes of hepatitis B liver failure in this cohort.

Defects in CISD-1, a mitochondrial iron-sulfur protein, lower glucose level and ATP production in Caenorhabditis elegans.

BACKGROUND: CDGSH iron sulfur domain-containing protein 1 (CISD-1) belongs to the CISD protein family that is evolutionary conserved across different species. In mammals, CISD-1 protein has been implicated in diseases such as cancers and diabetes. As a tractable model organism to study disease-associated proteins, we employed Caenorhabditis elegans in this study with an aim to establish a model for interrogating the functional relevance of CISD-1 in human metabolic conditions. METHODS: We first bioinformatically identified the human Cisd-1 homologue in worms. We then employed N2 wild-type and cisd-1(tm4993) mutant to investigate the consequences of CISD-1 loss-of-function on: 1) the expression pattern of CISD-1, 2) mitochondrial morphology pattern, 3) mitochondrial function and bioenergetics, and 4) the effects of anti-diabetes drugs. RESULTS: We first identified C. elegans W02B12.15 gene as the human Cisd-1 homologous gene, and pinpointed the localization of CISD-1 to the outer membrane of mitochondria. As compared with the N2 wild-type worm, cisd-1(tm4993) mutant exhibited a higher proportion of hyperfused form of mitochondria. This structural abnormality was associated with the generation of higher levels of ROS and mitochondrial superoxide but lower ATP. These physiological changes in mutants did not result in discernable effects on animal motility and lifespan. Moreover, the amount of glucose in N2 wild-type worms treated with troglitazone and pioglitazone, derivatives of TZD, was reduced to a comparable level as in the mutant animals. CONCLUSIONS: By focusing on the Cisd-1 gene, our study established a C. elegans genetic system suitable for modeling human diabetes-related diseases.

Repetitive control approach towards automatic tuning of Smith predictor controllers.

This paper proposes a new method for automatic tuning of the Smith predictor controller based on a Repetitive Control (RC) approach. The method requires the input of a periodic reference signal which can be derived from a relay feedback experiment. A modified repetitive control scheme repetitively changes the control signal to achieve tracking error convergence. Once a satisfactory performance is achieved through the learning control, the parameters of the Smith predictor controller can be computed from the signals using a nonlinear least squares algorithm. The same relay feedback experiment can provide an initial parameter vector for an efficient implementation of the parameter estimation. Simulations and experimental results will be furnished to illustrate the effectiveness of the proposed tuning method.

Mechanism of amino acid metabolism in nonalcoholic fatty liver disease / 临床肝胆病杂志

Nonalcoholic fatty liver disease （NAFLD） is one of the most prevalent chronic liver diseases in the world， affecting about one quarter of the global population， and it is estimated that NAFLD will become the main indication for liver transplantation by 2030. NAFLD can lead to significant abnormalities in the levels of a variety of amino acids including branched-chain amino acids， thereby promoting the development and progression of NAFLD. These results suggest that in addition to glucose and lipid metabolism， amino acid metabolism also plays an important role in the progression of NAFLD. In order to systematically understand the role and mechanism of amino acid metabolism in NAFLD， this article reviews the research advances in amino acid metabolism in NAFLD. This article aims to explore the role and mechanism of amino acid metabolism in the progression of NAFLD， so as to provide ideas and a theoretical basis for clinical prevention and treatment.

Severe prostate enlargement with severe lower urinary tract symptoms in poorly controlled acromegaly successfully treated with 5α-reductase inhibitors: A 15-year longitudinal case report.

Acromegaly is a rare disease associated with an increased risk of prostate enlargement. Severe prostate enlargement with severe lower urinary tract symptoms (LUTS) in an acromegalic patient is even more uncommon. Herein we report on a 55-year-old man who was diagnosed with acromegaly and prostate enlargement at 40 years of age. Transsphenoidal surgery, postoperative radiotherapy, and octreotide medical therapy failed to control the acromegaly, and growth hormone (GH) and insulin-like growth factor 1 (IGF-1) levels remained elevated. When the patient was 53 years of age, severe LUTS and prostate enlargement (prostate volume = 128 mL) were noted. However, LUTS improved and prostate volume decreased markedly after 5α-reductase inhibitors were used, despite the poorly controlled acromegaly (elevated GH and IGF-1 levels). This is the first long-term observation of LUTS and prostate enlargement in a poorly controlled acromegalic patient. Although the GH-IGF-1 axis was a factor contributing to prostate enlargement, the present case suggests that androgens may still play an essential role in prostate enlargement and symptoms in active acromegalic patients >50 years of age. Indeed, we should be aware that suppressing the GH-IGF-1 axis is not the only treatment choice for prostate enlargement in acromegalic patients, and even in poorly controlled acromegalic patients in whom suppression of the GH-IGF-1 axis is difficult. Symptomatic prostate enlargement in cases of active acromegaly can be treated with 5α-reductase inhibitors, as in general benign prostate hyperplasia populations.

Unusual Case of a Volleyball Athlete Presenting with Posterior Shoulder Pain and Infraspinatus Muscle Wasting.

INTRODUCTION: Entrapment of the suprascapular nerve is an uncommon but important differential in patients who present with posterior shoulder pain. Frequently misdiagnosed as rotator cuff or cervical disc disease, this increasingly recognized entity can result from traction-related or compression-related etiology. Two sites of compression include the suprascapular and spinoglenoid notches with the latter less commonly encountered. CASE REPORT: In our study, we describe a case of arthroscopic decompression of suprascapular nerve entrapment at the spinoglenoid notch due to hypertrophied spinoglenoid ligament using an improvised arthroscopic technique. CONCLUSION: Spinoglenoid notch compression of the suprascapular nerve is an important cause of posterior shoulder pain with infraspinatus wasting. A clear understanding of the nerve anatomy and the common site of compression allow for accurate diagnosis. The modified arthroscopic technique described is easily reproducible and provides good visualization of the anatomy, allowing adequate and safe decompression of the suprascapular nerve.

Dual pH-Responsive Shell-Cleavable Polycarbonate Micellar Nanoparticles for in Vivo Anticancer Drug Delivery.

To exploit tumor and intracellular microenvironments, pH-responsive diblock copolymers of poly(ethylene glycol) and catechol-functionalized polycarbonate with acid-labile acetal bond as the linker are synthesized to prepare micellar nanoparticles that shed the shell at acidic tumor tissues and inside cancer cells, hence accelerating drug release at the target. The pH-dependent cleavage of the shell is demonstrated at pH 5.0 and 6.5 using 1H NMR. Bortezomib (BTZ, an anticancer drug containing a phenylboronic acid group) is conjugated to the polymers through formation of pH-responsive boronate ester bond between boronic acid and catechol in the polymers. Dual pH-responsive bortezomib-polymer conjugates (BTZ-PC) self-assemble into micellar nanoparticles of small size (<110 nm) with narrow size distribution and high drug loading capacity. Acidic pH accelerates BTZ release from BTZ-PC micelles and enhances intracelluar uptake of the micelles, hence increasing in vitro cytotoxicity against human breast cancer cells. More importantly, the BTZ-PC micelles achieve a stronger antitumor effect in a human breast cancer BT-474 xenograft mouse model than free BTZ and mitigate in vivo hepatotoxicity of BTZ. These dual pH-responsive shell-cleavable nanoparticles are a potentially promising carrier for BTZ delivery.

The predictive value of serum human leukocyte differentiation antigen 36 levels in cardiovascular risk in patients with rheumatoid arthritis / 中华风湿病学杂志

Objective:To explore the expression and predictive value of serum CD36 level in cardio-vascular risk in patients with rheumatoid arthritis (RA) and to provide a new theoretical basis for clinical iden-tification and prediction of patients at moderate and high cardiovascular risk in RA patients.Methods:Eighty-four RA patients hospitalized to the Department of Rheumatology and Immunology of the second hospital of Lanzhou University in Gansu Province were selected as the study subjects, and 34 healthy people were selected as the controls. All RA patients were divided into low cardiovascular risk groups and medium and high cardiovascular risk groups according to prediction for ASCVD risk in China (China-PAR) cardiovascular risk assessment. At the same time, they were tested for serological indicators at admission. Statistical Product and Service Solutions (SPSS)) 26.0 software was used for the statistical data analysis. T-test and nonparametric test were used for comparison of the measurement data. The Chi-square test and Fisher's exact test were used for the comparison of classified data. Variables with P<0.05 in univariate analysis were included into the Logistic regression model. Results:Compared with the healthy control group, the number of patients with medium and high cardiovascular risk in RA[8 cases (23.5)% and 38 cases (45.2)%, χ2=4.80, P=0.029] was significantly higher and was negatively correlated with serum CD36 ( r=-0.27, P<0.05). Logistic regression analysis showed that age [ OR(95% CI)=1.654(1.157, 2.365), P=0.006] and diastolic blood pressure [ OR(95% CI)=1.225(1.040, 1.442) , P=0.015] were independent risk factors for medium and high cardiovascular risk in RA patients, and serum CD36 level [ OR(95% CI)=0.569(0.352, 0.922) , P=0.022] was the protective factor of medium and high cardiovascular risk in RA patients according to the results of Logistic regression analysis. The area under the receiver operating characteristic (ROC) area under the curve (AUC) was 0.691, the cut-off value was 4.27 pg/ml, and the sensitivity and specificity were 89.7% and 41.0% respectively. Conclusion:The serum CD36 level decreases with the increase of cardiovascular risk in RA patients. A higher serum CD36 level is a protective factor of cardiovascular risk in RA patients, and CD36 has a certain predictive value for cardiovascular risk in RA patients and is a potential predictor.

Mycena subpiligera sp. nov., a Symbiotic Species from China Associated with the Seed Germination of Gastrodia elata

Mycena subpiligera, a new taxon in sect. Fragilipedes that can strongly enhance the germination efficiency of Gastrodia elata seeds, was discovered in subtropical areas of China. As revealed by a morphological comparison with related Mycena species as well as maximum likelihood (ML) and Bayesian phylogenetic analyses based on sequences of the internal transcribed spacer (ITS) and the large subunit (LSU) regions of nuclear ribosomal RNA, the new taxon can be distinguished from phenotypically similar and phylogenetically related species. Optimal cultural conditions for M. subpiligera basidiomata are reported, and the germination rate of the new species is compared with that of M. citrinomarginata.