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Background Atrial fibrillation (AF) is the most common cardiac arrhythmia in patients with chronic kidney disease (CKD) and acute coronary syndrome (ACS). This study aimed to explore the frequency and impact of AF on clinical outcomes in CKD patients with ACS. Methods CKD inpatients with ACS between November 2014 and December 2018 were included based on the improving care for cardiovascular disease in China-ACS (CCC-ACS) project. Included patients were divided into an AF group and a non-AF group according to the discharge diagnosis. Multivariable logistic regression was used to adjust for potential confounders. Results A total of 16,533 CKD patients with ACS were included. A total of 1418 (8.6%) patients had clinically recognized AF during hospitalization, 654 of whom had an eGFR of 45 to 2, and 764 had an estimated glomerular filtration rate (eGFR) 2. Compared with the non-AF group, the AF group had a higher risk of in-hospital mortality [OR 1.250; 95% CI (1.001–1.560), P = 0.049] and major adverse cardiovascular events (MACEs) [OR 1.361; 95% CI (1.197–1.547), P 2, patients with eGFR 2 had a 1.512-fold increased risk of mortality and a 1.435-fold increased risk of MACEs. Conclusions AF was a risk factor affecting the short-term prognosis of ACS patients in the CKD population. Furthermore, the lower the eGFR, the higher the risk of in-hospital mortality and MACEs in CKD patients with ACS. Trial registry: Clinicaltrial.gov, NCT02306616. Registered 29 November 2014, https://clinicaltrials.gov/ct2/show/NCT02306616?term=NCT02306616&draw=2&rank=1

The quorum-sensing (QS) system between the phages and their hosts is important for the phage lysis-lysogeny decision. In Vibrio cholerae, the QS system consists of a LuxR-type receptor VqmA (VqmAVc) and an autoinducer molecule 3,5-dimethylpyrazin-2-ol (DPO). A VqmA homolog encoded by vibriophage VP882 (VqmAPhage) can intervene the host QS system via binding to both the host-produced DPO and its cognate promoter (Pqtip) to induce the phage lysogeny-to-lysis transition, whereas VqmAVc cannot influence the VqmAPhage-induced pathway, suggesting an asymmetry regulation. In this study, we report the crystal structure of VqmAPhage-DPO complex at 2.65 A and reveal that the mechanism of DPO recognition is conserved in VqmA homologs. Besides, we identify a non-classical palindrome sequence in Pqtip, which can be effectively recognized by VqmAPhage but not VqmAVc. The sequence contains an interval longer than that in the vqmR promoter recognized by VqmAVc. In addition, the two DBD regions in the VqmAPhage dimer exhibit more relaxed architecture than that of the reported VqmAVc, which is likely to be in the conformation that may easily bind to target promoter containing a longer interval. In summary, our findings provide a structural and biochemical basis for the DBD-dependent DNA recognition in different promoter regions in the phage lysogeny-to-lysis decision communication system, and provide clues for developing phage therapies against Vibrio cholerae infection.

BACKGROUND AND PURPOSE Restless legs syndrome (RLS) has been suggested as a prodromal symptom of Parkinson disease (PD). Olfactory or taste dysfunction can also occur preceding PD diagnosis. However, whether RLS is associated with chemosensory dysfunction remains unknown. We thus aim to investigate the association between RLS and perceived olfactory and taste dysfunction. METHODS We performed a cross-sectional analysis including 90,337 Chinese adults free of neurodegenerative diseases in the Kailuan study in 2016. Presence of RLS was defined using revised RLS diagnostic criteria or the Cambridge-Hopkins questionnaire for RLS. Perceived olfactory and taste dysfunction was collected via a questionnaire. The association between RLS and perceived olfactory and taste dysfunction was assessed using logistic regression model, adjusting for potential cofounders such as age, sex, and medical history. RESULTS RLS was associated with high odds of having perceived olfactory and/or taste dysfunction (adjusted odds ratio = 5.92, 95% confidence interval = 3.11-11.3). The significant association persisted when using the Cambridge-Hopkins questionnaire (adjusted odds ratio = 5.55, 95% confidence interval = 2.37-13.0) or when excluding participants with major chronic diseases. CONCLUSIONS RLS was associated with increased odds of perceived olfactory and taste dysfunction.

Objective This study aimed to systematically evaluate the association between triceps skinfold (TSF) thickness (which indicates subcutaneous fat) mid-arm muscle circumference (MAMC; which reflects muscle mass), mid-upper arm circumference (MUAC), and all-cause mortality. Methods A total of 17,717 adults from the China Health and Nutrition Survey (1993-2015) were included. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause mortality. The joint effect of TSF thickness and MAMC was examined, and planned subgroup analyses were performed. Results The highest quartiles of TSF thickness, MAMC, and MUAC were significantly associated with low all-cause mortality, independent of BMI (TSF thickness: HR = 0.704 [95% CI: 0.575-0.862]; MAMC: HR = 0.729 [95% CI: 0.607-0.876]; MUAC: HR = 0.713 [95% CI: 0.583-0.872]). A 1-SD increase showed comparable risk reductions for TSF thickness and MAMC (14.6% and 14.0%), with 16.1% risk reductions in MUAC. There were positive additive interactions between TSF thickness and MAMC. The inverse association existed in young, middle-aged, and elderly participants (P-heterogeneity > 0.05). Conclusions Mid-arm muscle and subcutaneous fat were inversely associated with all-cause mortality, independent of BMI, beyond the elderly population. Mid-arm muscle and subcutaneous fat made comparable contributions to and had positive joint effects on all-cause mortality.

Nerve root metastases are extremely rare with only a handful of cases ever reported. Metastasis to sites other than the primary site is common in malignant tumors whereas spinal ganglion metastasis is extremely rare and has been only reported in individual cases. The lumbar spine tends to be more common areas of presentation whereas breast cancer metastasis has been rarely reported. We herein reported two cases of breast carcinoma metastasis to multiple spinal nerve roots. The metastasis sites were S1 nerve root in Case 1 and left L5 and bilateral cervical nerve roots in Case 2. On magnetic resonance imaging (MRI), the nerve roots in the intervertebral foramen zones appeared thickened and contrast-enhanced MRI exhibited intense enhancement. Pathological examination showed that these primary lesions were breast cancer in both cases, and there were intracranial multiple metastases in both cases, including preoperative metastasis to multiple nerve roots (lumbar and cervical) and postoperative recurrence. The clinical course was characterized by worsening radicular symptoms—especially intractable pain. The radiologic appearance might mimic a neurogenic tumor, which is performed intervertebral foraminal area lesion, and the corresponding ganglion/nerve root became thickened and was enhanced significantly. Surgical intervention with tumor debulking followed by radiotherapy provides local tumor control and palliation from pain, but it is palliative. Therefore, for patients with radiological manifestations of radiculopathy, the possibility of metastatic tumors should be considered.

Genetic variation plays a fundamental role in pathogen's adaptation to environmental stresses. Pathogens with low genetic variation tend to survive and proliferate more poorly due to their lack of genotypic/phenotypic polymorphisms in responding to fluctuating environments. Evolutionary theory hypothesizes that the adaptive disadvantage of genes with low genomic variation can be compensated for structural diversity of proteins through post‐translation modification (PTM) but this theory is rarely tested experimentally and its implication to sustainable disease management is hardly discussed. In this study, we analyzed nucleotide characteristics of eukaryotic translation elongation factor‐1α (eEF‐lα) gene from 165 Phytophthora infestans isolates and the physical and chemical properties of its derived proteins. We found a low sequence variation of eEF‐lα protein, possibly attributable to purifying selection and a lack of intra‐genic recombination rather than reduced mutation. In the only two isoforms detected by the study, the major one accounted for >95% of the pathogen collection and displayed a significantly higher fitness than the minor one. High lysine representation enhances the opportunity of the eEF‐1α protein to be methylated and the absence of disulfide bonds is consistent with the structural prediction showing that many disordered regions are existed in the protein. Methylation, structural disordering, and possibly other PTMs ensure the ability of the protein to modify its functions during biological, cellular and biochemical processes, and compensate for its adaptive disadvantage caused by sequence conservation. Our results indicate that PTMs may function synergistically with nucleotide codes to regulate the adaptive landscape of eEF‐1α, possibly as well as other housekeeping genes, in P. infestans. Compensatory evolution between pre‐ and post‐translational phase in eEF‐1α could enable pathogens quickly adapting to disease management strategies while efficiently maintaining critical roles of the protein playing in biological, cellular, and biochemical activities. Implications of these results to sustainable plant disease management are discussed.

BACKGROUND Germinoma is a type of germ cell tumor that most frequently arises in the midline axis of the brain. Impaired vision is a clinical manifestation of germinnoma. Although rare, intracranial germinoma seeding to the perioptic arachnoid space is one cause of visual acuity decrease. CASE SUMMARY An 11yearold girl who presented with polyuria and polydipsia and subsequently developed diminution of vision. Imaging showed bilateral heterogeneous enhancement of the optic nerve sheaths and atrophy of the optic nerve, and transsphenoidal biopsy revealed a germinoma. The patient experienced poor visual recovery following chemotherapy and radiotherapy. Germinomas are rare and they are mostly identified in children and adolescents. The manifestations include diabetes insipidus, pituitary dysfunction, visual complaints, etc. The mechanisms that lead to visual loss include intracranial hypertension, compression of optic chiasma, and tumor invasion. A literature review was performed to summarize the cases with a tumor infiltrating the optic nerve. Most of the reported patients were adolescents and presented with anterior pituitary hormone deficiency. Enhancement of optic nerve sheaths and optic disc pallor could be identified in most of the cases. The purpose of this report is to provide awareness that in cases where a germinoma is associated with visual loss, though rare, perioptic meningeal seeding should be taken into consideration. CONCLUSION The case report suggests that children with diabetes insipidus need a complete differential diagnosis.

Aeromonas veronii can cause a variety of diseases such as sepsis in humans and animals. However, there has been no effective way to eradicate A. veronii. In this study, the intracellular antibacterial activities of the C-terminal aminated marine peptide N6 (N6NH2) and its D-enantiomer (DN6NH2) against A. veronii were investigated in macrophages and in mice, respectively. The result showed that DN6NH2 with the minimum inhibitory concentration (MIC) of 1.62 μM is more resistant to cathepsin B than N6NH2 (3.23 μM). The penetration percentages of the cells treated with 4–200 μg/mL fluorescein isothiocyanate (FITC)-DN6NH2 were 52.5–99.6%, higher than those of FITC-N6NH2 (27.0–99.1%). Both N6NH2 and DN6NH2 entered macrophages by macropinocytosis and an energy-dependent manner. DN6NH2 reduced intracellular A. veronii by 34.57%, superior to N6NH2 (19.52%). After treatment with 100 μg/mL DN6NH2, the levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-1β were reduced by 53.45%, 58.54%, and 44.62%, respectively, lower than those of N6NH2 (15.65%, 12.88%, and 14.10%, respectively); DN6NH2 increased the IL-10 level (42.94%), higher than N6NH2 (7.67%). In the mice peritonitis model, 5 μmol/kg DN6NH2 reduced intracellular A. veronii colonization by 73.22%, which was superior to N6NH2 (32.45%) or ciprofloxacin (45.67%). This suggests that DN6NH2 may be used as the candidate for treating intracellular multidrug-resistant (MDR) A. veronii. • DN6NH 2 improved intracellular antibacterial activity against MDR A. veronii. • DN6NH 2 entered macrophages by micropinocytosis and enhanced the internalization rates. • DN6NH 2 effectively protected the mice from infection with A. veronii.

Objectives Our aim was to generalize the available evidence and evaluate the effectiveness of acupuncture for urinary incontinence in middle-aged and elderly women. Methods Six databases including VIP, CNKI, Wan Fang, Web of Science, PubMed and The Cochrane Library were systematically searched to retrieve similar studies updated to December 2019 to gather RCTs regarding the effectiveness of acupuncture for middle-aged and elderly women with urinary incontinence. Two researchers independently performed the whole process of retrieving the studies, extracting the data and assessing the risk of bias of the included studies. The current meta-analysis was performed using RevMan 5.3 software. Results A total of eight studies with 607 patients were included in the evaluation. The current meta-analysis showed that Compared with rehabilitation exercise or medication, acupuncture intervention significantly improved the clinical effectiveness (OR = 5.52, 95 % CI, 3.13–9.73), reduced the urine leakage in pad test (SMD = −2.67, 95 % CI, −4.05 to −1.29) and decrease the ICIQ-SF score (MD = −3.46, 95 % CI, −3.69 to −3.22). The results indicated that acupuncture intervention can help the patients alleviate the symptoms effectively. Conclusion Based on this study, acupuncture intervention of stress urinary incontinence in middle-aged and elderly women can improve the clinical effectiveness, reduce the urine leakage in pad test and ICIQ-SF score. More high-quality studies with large sample size are required for further verification.

Piglets, especially weaning piglets, show a lower level of immunity and higher morbidity and mortality, owing to their rapid growth, physiological immaturity, and gradual reduction of maternal antibodies, which seriously affects their growth and thus, value. It is important that piglets adapt to nutrient digestion and absorption and develop sound intestinal function and colonization with gut microbiota as soon as possible during their early life stage. Lactoferrin is a natural glycoprotein polypeptide that is part of the transferrin family. It is widely found in mucosal secretions such as saliva and tears, and most highly in milk and colostrum. As a multifunctional bioactive protein and a recommended food additive, lactoferrin is a potential alternative therapy to antibiotics and health promoting additive for piglet nutrition and development. It is expected that lactoferrin, as a natural food additive, could play an important role in maintaining pig health and development. This review examines the following known beneficial effects of lactoferrin: improves the digestion and capacity for absorption in the intestinal tract; promotes the absorption of iron and reduces the incidence of iron deficiency anemia; regulates intestinal function and helps to balance the microbial biota; and enhances the resistance to disease of the piglets via modulating and enhancing the immune system.

Inflammatory cytokines produced by muscularis macrophages largely contribute to the pathological signs of postoperative ileus (POI). Electroacupuncture (EA) can suppress inflammation, mainly or partly via activation of vagal efferent. The goal of this study was to investigate the mechanisms by which EA stimulation at an hindlimb region ameliorates inflammation in POI. Methods: Intestinal motility and inflammation were examined after 24 h after intestinal manipulation (IM)-induced POI in mice. Local immune response in the intestinal muscularis, expression of macrophages, α7 nicotinic acetylcholine receptor (α7nAChR), Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) were determined by flow cytometry, Western Blot, qPCR and immunofluorescence. The effects of α7nAChR antagonists (methyllycaconitine and α-bungarotoxin) and JAK2/STAT3 inhibitors (AG490 and WP1066) were also administered in a subset of mice prior to EA. In the parasympathetic pathways, intestinal motility and inflammation were determined after cervical vagotomy and sub-diaphragmatic vagotomy. The expression of gamma absorptiometry aminobutyric acid (GABAA) receptor in dorsal motor nucleus of vagal (DMV) cholinergic neurons was assessed by immunofluorescence and the response to DMV microinjection of bicuculine (antagonist of GABAA receptor) or muscimol (agonist of GABAA receptor) were assessed. Results: EA suppressed intestinal inflammation and promoted gastrointestinal motility. Mechanistically, EA activated the α7nAChR-mediated JAK2/STAT3 signaling pathway in macrophages which reduced the production of inflammatory cytokines. Furthermore, we also demonstrated that hindlimb region stimulation drove vagal efferent output by inhibiting the expression of GABAA receptor in DMV to ameliorate inflammation. Conclusions: The present study revealed that EA of hindlimb regions inhibited the expression of GABAA receptor in DMV neurons, whose excited vagal nerve, in turn suppressed IM-induced inflammation via activation of α7nAChR-mediated JAK2/STAT3 signaling pathway.

Background The incidence and the risk factors of in-hospitalized acute kidney injury (AKI) in patients hospitalized for atrial fibrillation (AF) were unclear. Methods The Improving Care for Cardiovascular Disease in China-AF (CCC-AF) project is an ongoing registry and quality improvement project, with 240 hospitals recruited across China. We selected 4527 patients hospitalized for AF registered in the CCC-AF from January 2015 to January 2019. Patients were divided into the AKI and non-AKI groups according to the changes in serum creatinine levels during hospitalization. Results Among the 4527 patients, the incidence of AKI was 8.0% (361/4527). Multivariate logistic analysis results indicated that the incidence of in-hospital AKI in patients with AF on admission was 2.6 times higher than that in patients with sinus rhythm (OR 2.60, 95% CI 1.77–3.81). Age (per 10-year increase, OR 1.22, 95% CI 1.07–1.38), atrial flutter/atrial tachycardia on admission (OR 2.16, 95% CI 1.12–4.15), diuretics therapy before admission (OR 1.48, 95% CI 1.07–2.04) and baseline hemoglobin (per 20 g/L decrease, OR 1.21, 95% CI 1.10–1.32) were independent risk factors for in-hospital AKI. β blockers therapy given before admission (OR 0.67, 95% CI 0.51–0.87) and non-warfarin therapy during hospitalization (OR 0.71, 95% CI 0.53–0.96) were associated with a decreased risk of in-hospital AKI. After adjustment for confounders, in-hospital AKI was associated with a 34% increase in risk of major adverse cardiovascular (OR 1.34, 95% CI 1.02–1.90, p = 0.023). Conclusions Clinicians should pay attention to the monitoring and prevention of in-hospital AKI to improve the prognosis of patients with AF.

Bats and pangolins are considered to be potential hosts of the new coronavirus SARS-CoV-2, based on its genome similarity to coronaviruses of these species (Bat-CoV-RaTG13 and Pangolin-CoV). The receptor-binding domain (RBD), a functional component of the spike protein, is responsible for binding of SARS-CoV-2 by human ACE2 receptors and is also key to cross-species viral transmission. We performed molecular dynamics (MD) simulations using structures of hACE2 in complex with the RBD of SARS-CoV-2, SARS-CoV, Pangolin-CoV and Bat-CoV-RaTG13, respectively. By analyzing the hydrogen-bonding network at the RBD-hACE2 interface and estimating the binding free energies between RBD and hACE2, we found Pangolin-CoV bound hACE2 in a similar state as did SARS-CoV-2, and both of them bound hACE2 more strongly than did Bat-CoV-RaTG13 or SARS-CoV. We further identified two major adaptation mutations of SARS-CoV-2-RBD, which may have significant roles in regulating the recognition and binding between RBD and hACE2. Our results add to existing evidence that Pangolins have the potential to act as an intermediate host for SARS-CoV-2, and provide guidance for future design of antiviral drugs and vaccines.

This work aimed to assess the role of TLR8 in cerebral I/R injury and its in-depth pathogenesis. Bioinformatics analysis indicated that TLR8 was up-regulated in patients with ischemic stroke than that in healthy control, and miR-18a-5p was the upstream regulatory of TLR8. Then, the rat pheochromocytoma PC12 cells were exposed in oxygen-glucose-deprivation/reoxygenation (OGD/R) conditions to construct a model in vitro. The functional experiments indicated that OGD/R can decline the viability and elevate the apoptosis of PC12 cells, while up-regulation of miR-18a-5p can alleviate OGD/R-induced cell injury. Notably, overexpression of TLR8 reverses the miR-18a-5p-mediated protection on OGD/R-induced cells injury. Finally, we found that up-regulation of miR-18a-5p obviously declined the protein levels of TLR4 and TLR7 as well as the phosphorylation of NF-κB, while overexpression of TLR8 canceled the decrease caused by miR-18a-5p up-regulation. In summing, our results illustrated that miR-18a-5p/TLR8 axis can mitigate OGD/R-induced cells injury through TLRs and NF-κB pathway. Overexpression of TLR8 reverses the miR-18a-5p-mediated protection on OGD/R-induced cells injury.

The ongoing COVID-19 pandemic is causing huge impact on health, life, and global economy, which is characterized by rapid spreading of SARS-CoV-2, high number of confirmed cases and a fatality/case rate worldwide reported by WHO. The most effective intervention measure will be to develop safe and effective vaccines to protect the population from the disease and limit the spread of the virus. An inactivated, whole virus vaccine candidate of SARS-CoV-2 has been developed by Wuhan Institute of Biological Products and Wuhan Institute of Virology. The low toxicity, immunogenicity, and immune persistence were investigated in preclinical studies using seven different species of animals. The results showed that the vaccine candidate was well tolerated and stimulated high levels of specific IgG and neutralizing antibodies. Low or no toxicity in three species of animals was also demonstrated in preclinical study of the vaccine candidate. Biochemical analysis of structural proteins and purity analysis were performed. The inactivated, whole virion vaccine was characterized with safe double-inactivation, no use of DNases and high purity. Dosages, boosting times, adjuvants, and immunization schedules were shown to be important for stimulating a strong humoral immune response in animals tested. Preliminary observation in ongoing phase I and II clinical trials of the vaccine candidate in Wuzhi County, Henan Province, showed that the vaccine is well tolerant. The results were characterized by very low proportion and low degree of side effects, high levels of neutralizing antibodies, and seroconversion. These results consistent with the results obtained from preclinical data on the safety.

The transcription factor MYC is deregulated in almost all human cancers, especially in aggressive lymphomas, through chromosomal translocation, amplification, and transcription hyperactivation. Here, we report that high expression of tribbles homologue 3 (TRIB3) positively correlates with elevated MYC expression in lymphoma specimens; TRIB3 deletion attenuates the initiation and progression of MYC-driven lymphoma by reducing MYC expression. Mechanistically, TRIB3 interacts with MYC to suppress E3 ubiquitin ligase UBE3B-mediated MYC ubiquitination and degradation, which enhances MYC transcriptional activity, causing high proliferation and self-renewal of lymphoma cells. Use of a peptide to disturb the TRIB3-MYC interaction together with doxorubicin reduces the tumor burden in MycEμ mice and patient-derived xenografts. The pathophysiological relevance of UBE3B, TRIB3 and MYC is further demonstrated in human lymphoma. Our study highlights a key mechanism for controlling MYC expression and a potential therapeutic option for treating lymphomas with high TRIB3-MYC expression., c-MYC is often deregulated in human cancers including lymphomas. Here, the authors show that a member of the pseudokinase family, tribbles homologue 3 (TRIB3), interacts with c-MYC to suppress c-MYC ubiquitination and degradation, leading to increased proliferation and self-renewal of lymphoma cells.

Tanshinone IIA (tan IIA), a key component of Salvia miltiorrhiza Bunge (Danshen), has been proven to play a significant role in suppressing inflammation. However, the molecular mechanisms underlying the anti-inflammatory properties of tan IIA against lipopolysaccharide (LPS)-induced neuroinflammation and neurotoxicity in human U87 astrocytoma cells have not been well justified. Therefore, in this study, U87 cells were pretreated with tan IIA (1, 5 and 10 μM) for 30 min, followed by stimulation with LPS for 24 h. Immunofluorescence, reverse transcription-polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), and western blotting were performed to investigate the effects of tan IIA on neuroinflammatory responses. The findings demonstrated that tan IIA prevented LPS-induced cell viability decrease, inhibited U87 cells activation, and suppressed the expression of glial fibrillary acidic protein (GFAP). Furthermore, tan IIA significantly reduced the mRNA expression of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) in LPS-stimulated U87 cells. Meanwhile, the increased protein levels of IL-1β, TNF-α, and IL-6 in cell culture supernatants were also markedly inhibited by tan IIA. Moreover, tan IIA significantly alleviated the phosphorylation of IκBα, nuclear factor-kappa B (NF-κB), p38, and JNK induced by LPS. Additionally, tan IIA suppressed the upstream signaling adaptor molecules toll-like receptor 4 (TLR4), myeloid differentiation primary response protein 88 (MyD88), and tumor necrosis factor receptor-associated factor 6 (TRAF6). Blockade of NF-κB, p38, and JNK obviously attenuated IL-1β, TNF-α, and IL-6 in U87 cells. In conclusion, the present results suggested that tan IIA can attenuate LPS-induced neurotoxicity and neuroinflammation partly by inhibiting TLR4/NF-κB/MAPKs signaling pathways in U87 cells.

Purpose High-sensitivity C-reactive protein (hs-CRP) has been shown as an important predictor of cardiovascular risk, and sleep duration is an important factor influencing health outcomes. However, the association between hs-CRP and sleep duration among Chinese adults remained unknown and controversial. We aimed to explore the associations between sleep duration and hs-CRP levels among Chinese adults, and the differences in sex and geographical regions. Methods This cross-sectional study was based on nationally representative Chinese samples from the 2009 China Health and Nutrition Survey, which employed multistage, random cluster designs. Habitual sleep duration was self-reported with short and long sleep duration defined as ≤6h and ≥9h per day, respectively. Participants were divided into 4 groups based on the categories of self-reported sleep duration (≤6h, 7h, 8h, ≥9h per day), excluding hs-CRP levels ≥10 mg/L. Subset samples were stratified by sex and geographical regions. Results A total of 8170 Chinese adults with a mean age of 50.0±14.9 years and 4369 (53.5%) men were included. Participants sleeping eight hours had the lowest hs-CRP levels. Long sleep duration (≥9h) was significantly associated with elevated hs-CRP levels after adjusting for multiple covariates in full samples (β=0.0356; 95% CI: 0.0050-0.0663; P=0.0228), but the associations of short sleep duration (≤ 6h) were limited to the unadjusted model. Long sleep duration was associated with elevated hs-CRP levels in women (β= 0.0512; 95% CI: 0.0097-0.0927; P=0.0155) and in the northern region of China (β=0.0699; 95% CI: 0.0210-0.1187; P=0.0051), but not in men or the southern region. Conclusion Long but not short sleep duration was positively associated with elevated hs-CRP levels, independent from traditional risk factors among Chinese adults, and sex and geographical differences were observed. Our findings imply that modifications of long sleep duration might be added to behavioral therapy to reduce cardiovascular risk in Chinese adults.

Toxoplasma gondii is an obligate intracellular protozoan parasite, which can infect almost all warm-blooded animals, including humans, leading to toxoplasmosis. Currently, the effective treatment for human toxoplasmosis is the combination of sulphadiazine and pyrimethamine. However, both drugs have serious side-effects and toxicity in the host. Therefore, there is an urgent need for the discovery of new anti-T. gondii drugs with high potency and less or no side-effects. Our findings suggest that lumefantrine exerts activity against T. gondii by inhibiting its proliferation in Vero cells in vitro without being toxic to Vero cells (P ≤ 0.01). Lumefantrine prolonged mice infected with T. gondii from death for 3 days at the concentration of 50 μg L−1 than negative control (phosphate-buffered saline treated only), and reduced the parasite burden in mouse tissues in vivo (P ≤ 0.01; P ≤ 0.05). In addition, a significant increase in interferon gamma (IFN-γ) production was observed in high-dose lumefantrine-treated mice (P ≤ 0.01), whereas interleukin 10 (IL-10) and IL-4 levels increased in low-dose lumefantrine-treated mice (P ≤ 0.01). The results demonstrated that lumefantrine may be a promising agent to treat toxoplasmosis, and more experiments on the protective mechanism of lumefantrine should be undertaken in further studies.

Objective To summarize the research progress of music therapy in hospice care and to provide reference for further research. Methods A wide range of literatures on music therapy and hospice care at home and abroad were searched and read, and the literature was integrated, judged, analyzed, and summarized. Results The related research on music therapy in hospice care mainly focused on western developed countries such as Europe and the United States. China is still in the stage of theoretical exploration, lacking qualitative research based on case investigation and empirical research based on data statistics. Conclusions Music therapy supports the management of symptoms in hospice care, which can meet the diverse needs of patients and their family members including physical, psychological, social, and spiritual.

Introduction Simultaneous administration of acetylsalicylic acid (ASA) and clopidogrel has demonstrated efficacy in the treatment of acute coronary syndrome. Clopidogrel + ASA in a fixed-dose combination (FDC) provides a pharmaceutical option to enhance adherence to the coadministration of dual antiplatelet therapy (DAPT). Herein, we evaluate the bioequivalence of enteric ASA and clopidogrel in an FDC compared with simultaneous administration of the individual formulations. Methods This study is a randomized, single-center, open-label, three-sequence, three-period, two-treatment, crossover study conducted in healthy Chinese male and female subjects under fed conditions. Subjects were randomized to receive, in each period, a single dose of (1) a combination tablet containing 75-mg clopidogrel and 100-mg enteric ASA (test formulation) or (2) coadministration of one 75-mg clopidogrel tablet and one 100-mg enteric-coated ASA tablet (reference formulations) under fed conditions. Plasma samples were analyzed for ASA, salicylic acid, clopidogrel, and the clopidogrel metabolite SR26334. For ASA, the reference-scaled average bioequivalence (RSABE) analysis was conducted for Cmax of ASA because within-subject standard deviation (SDW) was ≥ 0.294 for log-transformed Cmax. Results The point estimate (test/reference geometric mean ratio) was between 0.80 and 1.25, and the upper one-sided 95% confidence interval (CI) for the scaled average bioequivalence metric was ≤ 0 (-0.08). AUC of ASA as SDW was

Nitrospira is the most diverse genus of nitrite-oxidizing bacteria, and its members are widely spread in various natural and engineered ecosystems. In this study, the phylogenetic diversity of Nitrospira and monthly changes of its abundance from Zhanjiang Bay were investigated. Phylogenetic analysis showed that among 58 OTUs with high abundance, 74% were not affiliated with any previously described Nitrospira species, revealing a previously unrecognized diversity of coastal Nitrospira. The abundances of both Nitrospira and Nitrospina exhibited a significantly monthly change. During most of the months, abundance of Nitrospina was greater than that of Nitrospira. In particle-attached communities, either abundance of Nitrospina or Nitrospira was highly correlated with that of ammonia-oxidizing archaea (AOA), whereas abundance of ammonia-oxidizing bacteria was only highly correlated with that of Nitrospina. In free-living communities, either abundance of Nitrospina or Nitrospira was correlated only with that of AOA. These results suggest that both Nitrospira and Nitrospina can be involved in nitrite oxidation by coupling with AOA, but Nitrospina may play a greater role than Nitrospira in this tropical bay.

Viruses remain a major challenge in the fierce fight against diseases. There have been many pandemics caused by various viruses throughout the world over the years. Recently, the global outbreak of COVID-19 has had a catastrophic impact on human health and the world economy. Antiviral drug treatment has become another essential means to overcome pandemics in addition to vaccine development. How to quickly find effective drugs that can control the development of a pandemic is a hot issue that still needs to be resolved in medical research today. To accelerate the development of drugs, it is necessary to target the key target proteins in the development of the pandemic, screen active molecules, and develop reliable methods for the identification and characterization of target proteins based on the active ingredients of drugs. This article discusses key target proteins and their biological mechanisms in the progression of COVID-19 and other major epidemics. We propose a model based on these foundations, which includes identifying potential core targets, screening potential active molecules of core targets, and verifying active molecules. This article summarizes the related innovative technologies and methods. We hope to provide a reference for the screening of drugs related to pandemics and the development of new drugs.

Background: In this study, we aimed to investigate the dynamic changes of lipid profile under double filtration plasmapheresis (DFPP) in severe hypertriglyceridemia-induced acute pancreatitis (sHTGP) patients and ascertain whether these changes were associated with the prognosis of the disease.Methods: This retrospective study was conducted at a tertiary critical care center in China. We included sHTGP patients who were admitted within 72h after AP onset. All the sHTGP patients received DFPP within 24h after admission. Lipid profile changes was measured in 47 patients with sHTGP on admission, consecutive 4 days after DFPP and at discharge. According to the TG levels in the first day after DFPP, we divided patients into two group: non-target (TG>5.6mmol/L) and target group (TG ≤5.6mmol/L). Propensity score matching was used to investigate association between TG-lowering effect and the prognosis. Linear regression analysis on four models was used to determine the relationship between other lipid parameters and the outcome.Results: Except for low density lipoprotein, all the parameters of lipid profile at disease onset showed significant difference from their normal levels. The median serum triglyceride (TG) level of the sHTGP patients was 42.9 mmol/L on admission. In the first day after DFPP, serum TG, cholesterol (TC) and very low density lipoprotein decreased significantly, and the high-density lipoprotein (HDL) as well as apoprotein A1 increased meanwhile. TG continued to fall for the following three days and the other indicators held steady. After propensity score matching, the hospitalization duration was significantly lower in the target group (14.5 [13.0, 16.0] vs 8.0 [6.0, 15.3], P=0.035). Linear regression analysis revealed that the levels of HDL were negatively associated with the duration of hospitalization in three adjusted models.Conclusion: There was distinct fluctuation of the lipid profile upon the burst of sHTGP and the parameters changed significantly in the first day after DFPP. Among these parameters, HDL may serve as a biomarker for disease prognosis in patients with sHTGP. Moreover, reaching the TG-lowering target of 5.6mmol/L may shorten hospitalization duration.

As an important noninvasive tumor treatment method, phototherapy has drawn extensive research interest. However, the requirements of separate excitation wavelengths, high degree of electron-hole recombination, and low reactive oxygen species (ROS) production capability are still the major barriers. This work reports the construction of a novel nanoplatform: design and synthesis of an aza-BODIPY (AB) probe-decorated mesoporous black titanium dioxide (TiO2) (MT) nanoparticles (NPs) for enhanced photodynamic therapy and photothermal therapy under single-wavelength near-infrared (NIR) laser irradiation for the first time. AB probe-decorated MT NPs (abbreviated as MTAB) were synthesized through the Al reduction of mesoporous anatase TiO2 NPs and subsequent adsorption of the AB probe. The mesoporous structure of MT ensured AB loading capacity and avoided the complicated modification and synthesis processes. Heterogeneous MTAB, which possessed staggered energy levels, were assessed for their capability for effective separation of photogenerated electrons and holes for the first time. Upon NIR laser light irradiation, MTAB exhibited sufficient ROS generation, resulting in distinct tumor cell killing and tumor tissue elimination. This unique heterogeneous nanoplatform with staggered energy levels provides a new strategy to enhance ROS generation and improve the therapeutic efficacy.

AIM To study the involvement and interrelationship of epithelial cell adhesion molecule (EpCAM) and epithelial-mesenchymal transition (EMT) in endometriosis. METHODS Samples from 114 patients undergoing endometrial biopsy or operation for endometriosis and 23 premenopausal women undergoing endometrial biopsy for non-endometriotic benign disease. Immunohistochemistry was used to detect expression level of EpCAM, E-cadherin and N-cadherin in endometrium from patients with (n = 24) and without endometriosis (n = 23), and in lesions from bowel (n = 46), peritoneal (n = 20) and ovarian (n = 24) endometriosis. RESULTS There was no significant difference in the expression level of EpCAM, E-cadherin and N-cadherin, respectively, between endometrium from women with and without endometriosis (P > 0.05). There was also no significant difference in the expression level of EpCAM, E-cadherin and N-cadherin, respectively, among lesions from the bowel, peritoneal and ovarian endometriosis (P > 0.05). We found that the immunoreactivity of endometriotic epithelial cells to EpCAM and N-cadherin was significantly higher than that of eutopic endometrium, but decreased to E-cadherin (P

Objective To examine the results of raloxifene for prevention of periprosthetic bone loss around the femoral stem in patients undergoing total hip arthroplasty (THA). Methods Between January 2015 and May 2017, 240 female patients between 55 and 80 years underwent primary THA and were randomly allocated to receive 60 mg raloxifene hydrochloride per day (treatment group, TG, n = 120) or placebo (control group, CG, n = 120) orally at bedtime using computer‐generated randomization sequence generation. Baseline data, the Western Ontario McMaster Universities Osteoarthritis Index (WOMAC), women's quality of life (QoL) score, bone mineral density (BMD) around the prosthesis, and adverse events were compared between the two groups. The measuring range of BMD around the prosthesis was divided into seven regions of interest (ROI). The sample size was calculated to detect a mean difference in BMD of 0.15 g/cm2 with a standard deviation (SD) of 0.3. The error was set at 0.05 and the power level at 90% with additional compensation for a possible dropout rate of 20%. Results A total of 240 participants in the study up to 24 months after THA. There were no significant differences in the mean BMD of all the zones between groups before surgery (all P > 0.05). However, there were significant differences in the BMD of Gruen zones 4 and 7 between groups at 6 months postoperatively (both P 0.05), but did show decreased odds of breast cancer in comparison with those using a placebo (P = 0.0437). Conclusion Raloxifene can help inhibit bone loss around the prosthesis and improve the QoL of postmenopausal women after THA with no increased adverse events, and can even decrease the odds of breast cancer.

Intrinsic disorder is a common structural characteristic of proteins and a central player in the biochemical processes of species. However, the role of intrinsic disorder in the evolution of plant-pathogen interactions is rarely investigated. Here, we explored the role of intrinsic disorder in the development of the pathogenicity in the RXLR AVR2 effector of Phytophthora infestans. We found AVR2 exhibited high nucleotide diversity generated by point mutation, early-termination, altered start codon, deletion/insertion, and intragenic recombination and is predicted to be an intrinsically disordered protein. AVR2 amino acid sequences conferring a virulent phenotype had a higher disorder tendency in both the N- and C-terminal regions compared with sequences conferring an avirulent phenotype. In addition, we also found virulent AVR2 mutants gained one or two short linear interaction motifs, the critical components of disordered proteins required for protein-protein interactions. Furthermore, virulent AVR2 mutants were predicted to be unstable and have a short protein half-life. Taken together, these results support the notion that intrinsic disorder is important for the effector function of pathogens and demonstrate that SLiM-mediated protein-protein interaction in the C-terminal effector domain might contribute greatly to the evasion of resistance-protein detection in P. infestans.

To screen the key Chinese Herbal Medicines (KCHMs) against breast cancer by data mining, and analyze the potential mechanism of KCHMs using network pharmacology method. Clinical prescriptions consisted of CHMs for treating breast cancer were screened, and then Traditional Chinese Medicine Inheritance Support System (TCMISS) was applied to obtain the KCHMs. Subsequently, active ingredients and corresponding target genes of KCHMs were searched by Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) database, and target genes of breast cancer were collected using OMIM and MalaCards. After that, the overlapping target genes of KCHMs and breast cancer were screened, and the protein-protein interaction (PPI) network was built. In addition, a network of “KCHMs-active ingredients-breast cancer-targets” was constructed by Cytoscape 3.7.1. Finally, Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analysis were performed with Database for Annotation, Visualization and Integrated Discovery (DAVID) database to reveal the action mechanism of KCHMs. A total of 7 KCHMs were identified, whose active ingredients include quercetin, luteolin, nobiletin, kaempferol, isorhamnetin, naringenin, and be-ta-sitosterol, etc. Based on protein-protein interaction analysis, core targets were ESR1, MYC, CCND1, EGFR, CASP3, ERBB2, etc. Several KEGG pathways (e.g, PI3K-Akt, p53, ErbB, and HIF-1 signaling pathways) were found. Based on the combination of the data mining method and network pharmacology approach, the therapeutic effect of KCHMs on breast cancer may be realized by acting on target genes and signaling pathways related to the formation and progression of breast cancer.

Drugs that induce thrombosis in the tumour vasculature have not resulted in long-term tumour eradication owing to tumour regrowth from tissue in the surviving rim of the tumour, where tumour cells can derive nutrients from adjacent non-tumoral blood vessels and tissues. Here, we report the performance of a combination of tumour-infarction therapy and chemotherapy, delivered via chitosan-based nanoparticles decorated with a tumour-homing peptide targeting fibrin-fibronectin complexes overexpressed on tumour-vessel walls and in tumour stroma, and encapsulating the coagulation-inducing protease thrombin and the chemotherapeutic doxorubicin. Systemic administration of the nanoparticles into mice and rabbits bearing subcutaneous or orthotopic tumours resulted in higher tumour growth suppression and decreased tumour recurrence than nanoparticles delivering only thrombin or doxorubicin, with histological and haematological analyses indicating an absence of detectable toxicity. The co-administration of a cytotoxic payload and a protease to elicit vascular infarction in tumours with biodegradable tumour-targeted nanoparticles represents a promising strategy for improving the therapeutic index of coagulation-based tumour therapy.

Staphylococcus aureus is a common pathogen that can cause clinical and subclinical endometritis in humans and animals. In this study, a designed CSαβ peptide ID13 from DLP4 exhibited high stable antibacterial activity in simulated gastric fluid (90.79%), serum (99.54%), and different pH buffers (> 99%) against S. aureus CVCC 546 and lower cytotoxicity (89.62% viability) than its parent peptide DLP4 (74.14% viability) toward mouse endometrial epithelial cells (MEECs). ID13 caused a depolarization of bacterial membrane and downregulation of the expression of genes involved in membrane potential maintenance and biofilm formation. The in vitro efficacy analysis of ID13 showed a synergistic effect with vancomycin, ampicillin, rifampin, and ciprofloxacin; intracellular antimicrobial activity against S. aureus CVCC 546 in MEECs; and the ability to inhibit lipoteichoic acid-induced pro-inflammatory cytokines from RAW 264.7. In the S. aureus-induced endometritis of mice, similar to vancomycin, ID13 remarkably alleviated pathological conditions, inhibited the production of cytokines (TNF-α, IL-1ß, IL-6, and IL-10), and suppressed the TLR2-NF-κB signal pathway. Collectively, these results suggest that ID13 could be a potential candidate peptide for therapeutic application in S. aureus-induced endometritis.Key Points•Higher antibacterial activity and lower hemolysis of ID13 than DLP4.•ID13 could downregulate the genes of bacterial survival and infection.•ID13 could alleviate the S. aureus-induced endometritis of mice.•ID13 could regulate the cytokines and suppress the TLR2-NF-κB signal pathway. Electronic supplementary material The online version of this article (10.1007/s00253-020-10685-x) contains supplementary material, which is available to authorized users.

The study aimed to assess whether caesarean section and nonbreastfeeding can prevent mother-to-child transmission (MTCT) in HBsAg- and HBeAg-positive mothers via a cohort study and a meta-analysis. (1) Pregnant women who were positive for HBsAg and HBeAg and did not receive antiviral treatment during pregnancy were recruited from the First Hospital of Jilin University, Maternal and Child Health Care Center of Jiangsu and Henan from August 2009 to June 2015. Infants received active and passive immunity. (2) In addition, a systematic literature search was performed in the PubMed, Embase, Cochrane, China National Knowledge Infrastructure and Wanfang Chinese databases. The retrieval strategy was [("HBV" or "hepatitis b" or "hepatitis b virus") and ("mother-to-infant transmission" or "vertical transmission")]. Studies were screened, and data were extracted. The fixed-effect model was used to analyse the studies. A total of 852 mothers and 857 newborns were enrolled. At the age of 7 months, 41 infants (4.78%) were positive for HBsAg. Multivariate analysis showed that mothers with higher HBV DNA levels (>108 IU/mL; RR = 3.03, 95% CI: 1.41-6.52) were associated with an increased risk of infection. Although there was no statistical significance, caesarean section (RR = 0.61) and nonbreastfeeding (RR = 0.88) showed a tendency to reduce the risk of infection. (2) A total of 5726 studies were identified. Together with our study, 13 were included in the analysis of delivery mode, and 12 were included in the analysis of feeding mode. The risk of infection in the caesarean section group was lower than that in the vaginal delivery group (RR = 0.58, 95% CI: 0.46-0.74). In the analysis of feeding mode, the risk in the nonbreastfeeding group was significantly lower (RR = 0.74, 95% CI: 0.56-0.98). In conclusion, caesarean section and nonbreastfeeding reduced the risk of MTCT in infants of HBsAg- and HBeAg-positive mothers who did not receive antiviral therapy during pregnancy.

Glycyrrhetinic acid (GA), a hydrolysate of glycyrrhizic acid from licorice root extract, has been used to treat liver fibrotic diseases. However, the molecular mechanism involved in the antifibrotic effects of GA remains unclear. The involvement of miR-663a and its roles in TGF-β-1-induced hepatic stellate cell (HSC) activation remains unclear. In this study, we investigated the roles of miR-663a in the activation of HSCs and the antifibrosis mechanism of GA. MiR-663a expression was downregulated in TGF-β-treated HSCs. The overexpression of miR-663a inhibited HSC proliferation. TGF-β-1was confirmed as a direct target gene of miR-663a. MiR-663a alleviated HSC activation, concomitant with decreased expression of α-smooth muscle actin (α-SMA), human α2 (I) collagen (COL1A2), TGF-β1, TGF-βRI, Smad4, p-Smad2, and p-Smad3. GA upregulated miR-663a expression and inhibited the TGF-β/Smad pathway in HSCs. Further studies showed that miR-663a inhibitor treatment reversed GA-mediated downregulation of TGF-β1, TGF-βRI, Smad4, p-Smad2, p-Smad3, α-SMA, and CoL1A2 in TGF-β1-treated HSCs. These results show that miR-663a suppresses HSC proliferation and activation and the TGF-β/Smad signaling pathway, highlighting that miR-663a can be utilized as a therapeutic target for hepatic fibrosis. GA inhibits, at least in part, HSC proliferation and activation via targeting the miR-663a/TGF-β/Smad signaling pathway.

BACKGROUND Many patients with major depressive disorder (MDD) have been found to have psychotic symptoms. However, few studies have reported the prevalence of comorbid psychotic symptoms in first-episode drug naive (FEDN) MDD patients. This study was to investigate the prevalence of psychotic symptoms and related risk factors in a large sample size of FEDN MDD patients in a Chinese population. METHODS A total of 573 patients with diagnosis of MDD at their first episode were recruited with their demographic and clinical data. Positive scale of the Positive and Negative Syndrome Scale was utilized for psychotic symptoms, Hamilton Anxiety Rating Scale (HAMA) for anxiety symptoms, and Hamilton Depression Rating Scale (HAMD) for depressive symptoms. RESULTS The prevalence of psychotic symptoms in these MDD patients was 9.8%. MDD patients with psychotic symptoms had significantly higher HAMD and HAMA total scores than those without psychotic symptoms (both p

Introduction Dual antiplatelet therapy, aspirin and a P2Y12 inhibitor, is recommended to prevent thrombotic complications of acute coronary syndrome. Clopidogrel plus acetylsalicylic acid combination is the most commonly used dual antiplatelet therapy recommended by international guidelines and in Chinese clinical practice. Poor adherence to dual antiplatelet therapy or premature interruption of dual antiplatelet therapy is an important contributor to cardiovascular mortality and lethal cardiovascular events. Clopidogrel + acetylsalicylic acid fixed-dose combination enhances adherence to dual antiplatelet therapy. Herein, we aimed to evaluate bioequivalence of acetylsalicylic acid and clopidogrel in fixed-dose combination compared with simultaneous administration of their individual formulations in healthy Chinese subjects under fasting conditions. Methods This was a randomized, single-center, open-label, three-sequence, three-period, two-treatment, crossover study with a washout period of 10 days conducted in healthy Chinese volunteers. Subjects were randomized to receive Co-Plavix® (test formulation- fixed-dose combination of 100 mg acetylsalicylic acid and 75 mg clopidogrel) once and reference formulations (coadministration of individual formulations of 100 mg acetylsalicylic acid and 75 mg clopidogrel) twice during the study period. Pharmacokinetic parameters were analyzed for acetylsalicylic acid, its metabolite salicylic acid, clopidogrel, and its metabolite SR26334. As acetylsalicylic acid shows high intrasubject variability, the reference-scaled average bioequivalence (RSABE) approach was implemented for acetylsalicylic acid analysis, while bioequivalence of clopidogrel was assessed using the average bioequivalence method. Point ratios and confidence intervals (CIs) for AUC, AUClast, and Cmax for acetylsalicylic acid and clopidogrel were calculated. Results In total, 171 healthy subjects were enrolled in this study. Subjects were randomized and 170 subjects were treated with test or reference formulation; 164 subjects completed the study. Regarding acetylsalicylic acid exposure, as reference within-subject standard deviation (SDW) was at least 0.294 for acetylsalicylic acid Cmax, AUClast, and AUC, the RSABE analysis method was used to assess bioequivalence for all three parameters. The point estimates were within the 0.80–1.25 range (1.19, 1.09, and 1.04, respectively), and upper one-sided 95% CIs of scaled average bioequivalence metric were at most 0 (− 0.30, − 0.14, and − 0.10, respectively). Thus, bioequivalence was demonstrated with acetylsalicylic acid. Bioequivalence was also achieved with clopidogrel as the 90% CIs for geometric mean ratios of clopidogrel Cmax, AUClast, and AUC were within the bioequivalence range (0.80–1.25). Conclusion Application of the reference-scaled average bioequivalence approach to evaluate bioequivalence of acetylsalicylic acid in Chinese male and female healthy volunteers under fasting conditions demonstrated bioequivalence of test and reference formulations. Trial Registration CTR20181695. Electronic supplementary material The online version of this article (10.1007/s12325-020-01369-z) contains supplementary material, which is available to authorized users.

Lung adenocarcinoma (LUAD) is one of several malignant tumours with the highest incidence rates. Currently, there is an urgent need for effective diagnostic and therapeutic targets for LUAD in clinical practice. Numerous studies have shown that there may be differences in the development pattern of LUAD between male and female patients, leading to the need for differential treatment. At the same time, previous studies have shown that competitive endogenous (ce)RNA plays an important role in the development of LUAD, but there is no relevant research on whether there is a gender difference in the ceRNA network of LUAD. In this study, we constructed gender-independent, male-specific, and female-specific ceRNA networks using RNA sequencing results from TCGA database. Subsequently, through analysis of the core genes of the ceRNA network, we determined that the male and female ceRNA networks indeed display different features. In addition, we also found that the osteoclast-associated receptor (OSCAR) gene was a potential diagnostic target for detecting LUAD in females, and that increased expression of this gene promoted the proliferation and migration of A549 and H1975 LUAD cell lines; more specifically, A549 and H1975 are male and female LUAD cell lines, respectively. This suggests that the OSCAR gene has the potential to serve as target molecule for the diagnosis and treatment of female-specific LUADs.

This study was aimed to develop and conduct an Omaha system-based continuing nursing program for chronic kidney disease (CKD) patients undergoing peritoneal dialysis (PD) and to explore its effect on patients’ nutritional status. A randomized controlled trial was performed in a teaching hospital in China between June 2017 and July 2018. A total of 203 eligible patients were included and then randomly assigned to the study group (n = 101) or the control group (n = 102). In the study group, health education, treatments and procedures, case management, and surveillance based on the Omaha system were used. In the control group, only common outpatient nursing intervention was given to the patients. Changes in subjective global assessment (SGA), anthropometric measurements including body mass index (BMI), triceps skin-fold thickness (TSF), mid-arm muscle circumference (MAMC), and handgrip strength (HGS), and biochemical parameters (hemoglobin, albumin, pre-albumin, total cholesterol, and creatinine) were evaluated before the intervention and 6 months after the intervention and differences in measurements were analyzed. After intervention, the proportion of well-nourished patients in the study group was significantly improved from 6.19 to 29.90% ($$\chi$$2 = 18.441, P

Infection remains the most significant complication of ventriculoperitoneal shunt (VPS) surgery. The objective of this study was to investigate intracranial infections complicating VPS surgery in adults with hydrocephalus. Patients who underwent VPS surgery for hydrocephalus between 2000 and 2016 were included. Clinical data and follow-up evaluations were examined and analysed retrospectively. A total of 502 patients with hydrocephalus who underwent VPS surgery were included. They were followed up for at least 2 years. Twelve patients with incomplete data were excluded. Four hundred and ninety patients were included in the final analysis. Twenty-five cases of intracranial infection occurred, accounting for 5.1% of patients with VPS surgery. The mean age of the patients was 57.1 ± 10.1 years (range, 39-72 years). The incidence of intracranial infection in patients over 60 years of age was higher than that in patients under 60 years of age (P = .007). Age (P = .007), diabetes (P = .026), skin infection (P = .028), bed-ridden (P = .007), and modified operation (P = .011) were highly correlated with the incidence of intracranial infection. The findings of this retrospective study show that age, diabetes, skin infection, bed-ridden, and modified operation of hydrocephalus significantly and independently correlated with the incidence of infection. Prospective studies are needed to assess the relationship between the incidence of infection and risk factors in patients with hydrocephalus after VPS.

Many obligate intracellular apicomplexan parasites have adapted a distinct invasion mechanism involving a close interaction between the parasite ligands and the sialic acid (SA) receptor. We found that sialic acid binding protein-1 (SABP1), localized on the outer membrane of the zoonotic parasite Toxoplasma gondii, readily binds to sialic acid on the host cell surface. The binding was sensitive to neuraminidase treatment. Cells preincubated with recombinant SABP1 protein resisted parasite invasion in vitro. The parasite lost its invasion capacity and animal infectivity after the SABP1 gene was deleted, whereas complementation of the SABP1 gene restored the virulence of the knockout strain. These data establish the critical role of SABP1 in the invasion process of T. gondii. The previously uncharacterized protein, SABP1, facilitated T. gondii attachment and invasion via sialic acid receptors., A Toxoplasma gondii surface protein TgSABP1 was identified as a ligand of sialic acid receptor. Recombinant SABP1 and SABP1-specific antibodies blocked T. gondii invasion into host cells. Parasites with TgSABP1 gene deletion lost their invasion capability.

Background Ondansetron, a widely prescribed antiemetic, has been implicated in drug-induced long QT syndrome. Recent patch clamp experiments have shown that ondansetron inhibits the apamin-sensitive small conductance calcium-activated potassium current (IKAS). Objective The purpose of this study was to determine whether ondansetron causes action potential duration (APD) prolongation by IKAS inhibition. Methods Optical mapping was performed in rabbit hearts with pacing-induced heart failure (HF) and in normal hearts before and after ondansetron (100 nM) infusion. APD at 80% repolarization (APD80) and arrhythmia inducibility were determined. Additional studies with ondansetron were performed in normal hearts perfused with hypokalemic Tyrode's (2.4 mM) solution before or after apamin administration. Results The corrected QT interval in HF was 326 ms (95% confidence interval [CI] 306–347 ms) at baseline and 364 ms (95% CI 351–378 ms) after ondansetron infusion (P Conclusion Ondansetron is a specific IKAS blocker at therapeutic concentrations. Ondansetron may prolong the QT interval in HF by inhibiting small conductance calcium-activated potassium channels, which increases the vulnerability to ventricular arrhythmias.

Background: Atorvastatin belongs to the group of statins and is the leading drug for hypercholesterolemia treatment. Although, its anticancer effects are highly appreciated, its properties are still unclear. The aim of this study was to explore the underlying anticancer mechanisms induced by atorvastatin and enlarge the potential target in non-small cell lung cancer. Methods: arget genes of atorvastatin were collected by the DrugBank database. Prediction of interaction between primary targets and secondary targets was performed, and protein-protein interaction network was constructed though the STRING. Then, KEGG pathway enrichment analysis was performed with WebGestalt and ClueGO, including the pathways in non-small cell lung cancer. Furthermore, a genomic alteration analysis of the selected seed genes of atorvastatin benefit and non-small cell lung cancer pathway was conducted by cBioPortal. Finally, a survival analysis with the selected seed genes in lung cancer (lung adenocarcinoma, lung squamous cell carcinoma) was conducted using Kaplan-Meier (KM) plotter. Results: To identify seed genes, 65 potential candidate genes were screened as targets for atorvastatin using STRING with DrugBank database, while the KEGG pathway was enriched to get the overlap match of pathways in non-small cell lung cancer. Then 4 seed genes, Epidermal Growth Factor Receptor (EGFR), erb-b2 receptor tyrosine kinase 2 (ERBB2), AKT serine/threonine kinase 1 (AKT1) and tumor protein p53 (TP53), were selected and their genomic alternation were evaluated by cBioPortal. Survival analysis found that TP53 and EGFR showed a significant correlation (log rank P = 3e-07 and 0.023) with lung adenocarcinoma and lung squamous cell carcinoma, according to the KM analysis. Conclusion: Gene-phenotype connectivity for atorvastatin in non-small cell lung cancer was identified using functional/activity network analysis method, and our findings demonstrated that TP53 and EGFR could be the potential targets in cancer patients with atorvastatin therapy.

Sirtuins are a family of highly conserved NAD-dependent deacetylase that are involved in multiple biological processes in both prokaryotes and eukaryotes. Many sirtuin-activating compounds (STACs) have been reported for SIRT1, which is the best-characterized sirtuin. However, the molecular mechanism of SIRT1 activation by STACs remains controversial. Here, we developed a multiscale simulation model to explore this mechanism. By quantifying the free energy landscape for the closed conformation of a SIRT1-FdL peptide-resveratrol complex, we found a positive correlation between the barrier height of the active free energy basin and the experimentally determined fluctuations in the rate of SIRT1 deacetylation by resveratrol. In addition, by monitoring dynamics, we found that the open conformation of a SIRT1-p53-STAC-1 complex had a faster rate of conformational change than the closed structure. We also determined the structural properties of each thermodynamic or dynamic state and found that two potential activating factors, the stability of FdL peptide (the p53 peptide substrate including an AMC fluorophore group) binding and the stability of the SIRT1 conformation, were weakly correlated under certain conditions. These results address the controversial question of whether the AMC fluorophore group and native hydrophobic residues have similar roles in the SIRT1 activation process. Finally, we captured the global landscape of the transition, including less stable and more stable states, and proposed a global physical landscape for the mechanism of SIRT1 activation by STACs.

Dynamic changes of RNA and antibodies in SARS-CoV-2 infected patients remain largely unknown, and influence factors for antibody production have not been fully clarified. In this study, consecutive throat swabs specimens (n = 1875) from 187 patients were collected to analyse the dynamic changes of RNA. Moreover, 162 serial serum samples from 31 patients were tested for seroconversion of IgM and IgG. Meanwhile, IgM and IgG were also detected in 409 COVID-19 patients and 389 controls. Additionally, the logistic regression analysis was executed to identify the possible influence factors for antibody production. The median positive conversion time for RNA was day 7 (IQR, 3–11), and the positive rate was highest in day 1–5 (74.59 %) and then gradually decreased. The median time of seroconversion for IgM and IgG were both day 12 (IQR, 10–15). The sensitivity and specificity for IgM (or IgG) was 87.04% and 96.92%, respectively. Multivariate logistic regression indicated that reduced lymphocytes and short positive conversion time for SARS-CoV-2 RNA were independent factors for negative results of IgM and IgG. In conclusion, RNA and antibodies should be combined for COVID-19 diagnosis, and delayed seroconversion was influenced by the decreased lymphocytes and short positive conversion time for RNA.

Although dyslipidemia commonly occurs in patients with acute promyelocytic leukemia (APL) in response to anti-APL therapy, the underlying mechanism and the lipid statuses of patients with newly diagnosed APL remain to be addressed. Methods: We conducted a retrospective study to investigate the lipid profiles of APL patients. PML-RARα transgenic mice and APL cells-transplanted mice were used to assess the effects of APL cells on the blood/liver lipid levels. Subsequently, gene set enrichment analysis, western blot and dual luciferase reporter assay were performed to examine the role and mechanism of PML-RARα and TRIB3 in lipid metabolism regulation in APL patients at pretreatment and after induction therapy. Results: APL patients exhibited a higher prevalence of dyslipidemia before anti-APL therapy based on a retrospective study. Furthermore, APL cells caused secretion of triglycerides, cholesterol, and PCSK9 from hepatocytes and degradation of low-density lipoprotein receptors in hepatocytes, which elevated the lipid levels in APL cell-transplanted mice and Pml-Rarα transgenic mice. Mechanistically, pseudokinase TRIB3 interacted with PML-RARα to inhibit PPARγ activity by interfering with the interaction of PPARγ and RXR and promoting PPARγ degradation. Thus, reduced PPARγ activity in APL cells decreased leptin but increased resistin expression, causing lipid metabolism disorder in hepatocytes and subsequent dyslipidemia in mice. Although arsenic/ATRA therapy degraded PML-RARα and restored PPARγ expression, it exacerbated dyslipidemia in APL patients. The elevated TRIB3 expression in response to arsenic/ATRA therapy suppressed PPARγ activity by disrupting the PPARγ/RXR dimer, which resulted in dyslipidemia in APL patients undergoing therapy. Indeed, the PPAR activator not only enhanced the anti-APL effects of arsenic/ATRA by suppressing TRIB3 expression but also reduced therapy-induced dyslipidemia in APL patients. Conclusion: Our work reveals the critical role of the PML-RARα/PPARγ/TRIB3 axis in the development of dyslipidemia in APL patients, potentially conferring a rationale for combining ATRA/arsenic with the PPAR activator for APL treatment.

The proposed induction heating method was applied in the pasteurization of grapefruit juice. In this processing, an alternating magnetic field acted as the stimulus instead of conventional electrodes to create an induced electric field (IEF) for heat treatment of the continuous-flow juice sample, which excluded the possibility of electrochemical reaction and electrode corrosion that might occur in conventional electric field treatments. As a typical food pathogen, Escherichia coli O157:H7 was selected as a representative to investigate its inactivation by the heating process under different voltages and frequencies, initial temperatures, and flow rates (or retention time). The grapefruit juice was successfully heated up by IEF and the temperature curve was achieved when the juice exposed to IEF. The heating rate and terminal temperature increased with the increasing induced voltage, decreasing frequency and at higher initial temperature. A highest terminal temperature of 93.7 °C for grapefruit juice with an initial temperature of 20 °C was achieved under induced voltage of 2700 V, frequency of 300 Hz and residence time of 400 s. At the same time, E. coli O157:H7 in the grapefruit juice was thoroughly inactivated. There was a trend that the pathogen survival rate was reduced at higher induced voltage, lower frequency and higher initial temperature during the heating treatment. No significant changes in pH and °Brix was observed after this innovative induction heating, but the color of grapefruit juice was brightened. The proposed induction heating can be regarded as a sister technology of ohmic heating, and it provide a reference for the application of this heating method in liquid food pasteurization.

Temperature plays a multidimensional role in host–pathogen interactions. As an important element of climate change, elevated world temperature resulting from global warming presents new challenges to sustainable disease management. Knowledge of pathogen adaptation to global warming is needed to predict future disease epidemiology and formulate mitigating strategies. In this study, 21 Phytophthora infestans isolates originating from seven thermal environments were acclimated for 200 days under stepwise increase or decrease of experimental temperatures and evolutionary responses of the isolates to the thermal changes were evaluated. We found temperature acclimation significantly increased the fitness and genetic adaptation of P. infestans isolates at both low and high temperatures. Low‐temperature acclimation enforced the countergradient adaptation of the pathogen to its past selection and enhanced the positive association between the pathogen's intrinsic growth rate and aggressiveness. At high temperatures, we found that pathogen growth collapsed near the maximum temperature for growth, suggesting a thermal niche boundary may exist in the evolutionary adaptation of P. infestans. These results indicate that pathogens can quickly adapt to temperature shifts in global warming. If this is associated with environmental conditions favoring pathogen spread, it will threaten future food security and human health and require the establishment of mitigating actions.

The existence of breast cancer stem cells (BCSCs) is a major reason underlying cancer metastasis and recurrence after chemotherapy and radiotherapy. Targeting BCSCs may ameliorate breast cancer relapse and therapy resistance. Here we report that expression of the pseudokinase Tribble 3 (TRIB3) positively associates with breast cancer stemness and progression. Elevated TRIB3 expression supports BCSCs by interacting with AKT to interfere with the FOXO1-AKT interaction and suppress FOXO1 phosphorylation, ubiquitination, and degradation by E3 ligases SKP2 and NEDD4L. The accumulated FOXO1 promotes transcriptional expression of SOX2, a transcriptional factor for cancer stemness, which in turn, activates FOXO1 transcription and forms a positive regulatory loop. Disturbing the TRIB3-AKT interaction suppresses BCSCs by accelerating FOXO1 degradation and reducing SOX2 expression in mouse models of breast cancer. Our study provides insights into breast cancer development and confers a potential therapeutic strategy against TRIB3-overexpressed breast cancer., Cancer stem cells contribute to breast cancer metastasis and recurrence. Here the authors show that TRIB3 enhances breast cancer stemness through interaction with AKT to promote FOXO1 stability, which then increases SOX2 activity.

Objective To investigate the potential role of protease-activated receptor 2 (PAR2) in the prognosis of hepatocellular carcinoma (HCC). Methods A total of 202 HCC patients who underwent liver resections were included. Tissue microarray was established with specimens of both HCC and paired adjacent liver tissues. PAR2 expression was detected by immunohistochemistry (IHC) assays.. A semi-quantification method was used to define the expression level of PAR2. The correlations between PAR2 expression and clinical features of patients with HCC was explored. The association of different PAR2 expressions with both overall survival and disease-free survival was analyzed. Results Results showed that the expression of PAR2 in HCC tissues was higher than that in paired para-cancerous liver tissues (4.12 ± 3.55 vs. 2.71 ± 2.56, P P = 0.015). Kaplan-Meier survival analysis indicated that HCC patients with high PAR2 expression had decreased overall survival (P = 0.033) and disease-free survival (P = 0.043) compared to patients with lower PAR2 expression. Multivariate analysis indicated that PAR2 expression (P = 0.032) was a significant independent prognostic factor for both overall survival and disease-free survival (P = 0.032; P = 0.032, respectively). Conclusion Our data revealed that PAR2 expression was increased in HCC. High PAR2 expression was correlated with both decreased overall survival and disease-free survival in patients with HCC. High PAR2 expression indicated a poor prognosis.

Toxoplasma gondii is a unicellular protozoan parasite of the phylum Apicomplexa. The parasite repeatedly goes through a cycle of invasion, division and induction of host cell rupture, which is an obligatory process for proliferation inside warm-blooded animals. It is known that the biology of the parasite is controlled by a variety of mechanisms ranging from genomic to epigenetic to transcriptional regulation. In this study, we investigated the global protein posttranslational lysine crotonylation and 2-hydroxyisobutyrylation of two T. gondii strains, RH and ME49, which represent distinct phenotypes for proliferation and pathogenicity in the host. Proteins with differential expression and modification patterns associated with parasite phenotypes were identified. Many proteins in T. gondii were crotonylated and 2-hydroxyisobutyrylated, and they were localized in diverse subcellular compartments involved in a wide variety of cellular functions such as motility, host invasion, metabolism and epigenetic gene regulation. These findings suggest that lysine crotonylation and 2-hydroxyisobutyrylation are ubiquitous throughout the T. gondii proteome, regulating critical functions of the modified proteins. These data provide a basis for identifying important proteins associated with parasite development and pathogenicity.

Background The shape of the glucose response curve during an oral glucose tolerance test (OGTT) can predict β-cell function and insulin resistance. However, there have been few studies conducted on Chinese people. Thus, we aimed to verify the usefulness of the glucose response curve in a large Chinese population. Methods A total of 9059 OGTT (3-h tests) were categorized into either a monophasic or a multiphasic group based on the shape of the glucose response. Homeostasis model assessments of fasting insulin resistance, the Matsuda Index, the insulinogenic index, and the disposition index were assessed by plasma glucose and serum insulin concentration obtained at fasting or during an OGTT. Results The shape of the OGTT glucose response curve was monophasic in 87.3% and multiphasic in 12.7% of participants. Individuals in the multiphasic group were younger compared to those in the monophasic group (38.6 ± 13.6 vs. 35.4 ± 13.5, P P P P P Conclusion The monophasic OGTT glucose response curve could reflect impaired β-cell function in a large Chinese population.