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To investigate the duration of humoral immune response in convalescent coronavirus disease 2019 (COVID-19) patients, we conduct a 12-month longitudinal study through collecting a total of 1,782 plasma samples from 869 convalescent plasma donors in Wuhan, China and test specific antibody responses. The results show that positive rate of IgG antibody against receptor-binding domain of spike protein (RBD-IgG) to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the COVID-19 convalescent plasma donors exceeded 70% for 12 months post diagnosis. The level of RBD-IgG decreases with time, with the titer stabilizing at 35.7% of the initial level by the 9th month. Moreover, male plasma donors produce more RBD-IgG than female, and age of the patients positively correlates with the RBD-IgG titer. A strong positive correlation between RBD-IgG and neutralizing antibody titers is also identified. These results facilitate our understanding of SARS-CoV-2-induced immune memory to promote vaccine and therapy development., COVID-19 pandemic is a global health risk, but our understanding on the induced durable immunity remains scarce. Here the authors assess antibody responses in 869 convalescent COVID-19 patients to find that specific antibody titers reduce with time, and the RBD-IgG positive rate exceed 70% at 12 month post diagnosis, with male and older patients showing stronger responses.

Cardiac hypertrophy is the result of increased myocardial cell size responding to an increased workload and developmental signals. These extrinsic and intrinsic stimuli as key drivers of cardiac hypertrophy have spurred efforts to target their associated signaling pathways. The extracellular signal-regulated kinases 1/2 (ERK1/2), as an essential member of mitogen-activated protein kinases (MAPKs), has been widely recognized for promoting cardiac growth. Several modified transgenic mouse models have been generated through either affecting the upstream kinase to change ERK1/2 activity, manipulating the direct role of ERK1/2 in the heart, or targeting phosphatases or MAPK scaffold proteins to alter total ERK1/2 activity in response to an increased workload. Using these models, both regulation of the upstream events and modulation of each isoform and indirect effector could provide important insights into how ERK1/2 modulates cardiomyocyte biology. Furthermore, a plethora of compounds, inhibitors, and regulators have emerged in consideration of ERK, or its MAPK kinases, are possible therapeutic targets against cardiac hypertrophic diseases. Herein, is a review of the available evidence regarding the exact role of ERK1/2 in regulating cardiac hypertrophy and a discussion of pharmacological strategy for treatment of cardiac hypertrophy.

Hepatitis C virus (HCV) natural history studies are limited by not knowing the time of infection, small numbers and non-representative populations. No studies are available from the direct-acting antiviral agents (DAA) era. We created the largest known cohort of persons with HCV with a known window of seroconversion in the DAA era. We compared the annual cumulative incident events and incidence rate/1000 person-years of follow-up for liver cirrhosis, hepatic decompensation, hepatocellular carcinoma (HCC) and mortality from the time of seroconversion among untreated and those treated and attaining a sustained virologic response (SVR). Among 12,881 persons in the final analyses, 10,417 had never been treated for HCV, 2464 (23.6%) were treated with a DAA regimen and 1836 (74.5%) attained SVR. After 9 years of follow-up, cirrhosis was diagnosed in 17.4% of untreated and 13.6% of the SVR group. Overall, 29.5% in the untreated versus 3.5% in the SVR group died. Incidence rates/1000 person-years of follow-up (95% CI) for untreated versus SVR group were 22.7 (21.6, 23.9) versus 19.5 (17.0, 21.9) for cirrhosis (p = 0.03), 0.1 (0.03, 0.2) versus 0.07 (-0.07, 0.2) for HCC (p = 0.74) and 35.4 (34.0, 36.8) versus 4.53 (3.4, 5.7) for mortality (p < 0.0001). After excluding those with alcohol-related diagnoses at baseline, the difference in cirrhosis was not statistically significant. Cirrhosis and mortality occur early and steadily increase over the first decade after acquiring HCV infection, while HCC is rarely observed. Those treated with a DAA regimen have sharply lower cirrhosis and mortality rates, particularly among those without alcohol abuse or dependence.

Nitrous oxide (N2O), also known as "laughing gas," is a colorless, nonirritating gas. Clinically, it is widely used as an inhaled anesthetic, analgesic, and anxiolytic. In recent years, recreational abuse of N2O has become increasingly common, especially among young adults and adolescents, but many of them lack awareness of the possible side effects associated with this drug. N2O abuse can damage multiple systems, especially the nervous system, but the exact mechanism of N2O toxicity remains controversial. At present, an increasing number of cases of nervous system damage caused by N2O abuse have been reported both at home and abroad. Discontinuation of N2O use and timely supplementation with vitamin B12 are essential for a good prognosis. Long-term abuse without timely treatment will eventually lead to irreversible neurological damage. In this article, we discuss the epidemiology of N2O abuse, neurotoxicity mechanisms, clinical manifestations, relevant auxiliary examinations, treatments, and prognosis to improve social awareness of N2O exposure risk, especially among users and clinicians.

Purpose: This work describes a stepwise surgical approach to draining choroidal detachments and 2 cases for which this approach was used. Methods: The first step involves insertion of an anterior chamber maintainer and a nonvalved 23- or 25-gauge trocar cannula at the highest peak of hemorrhagic choroidal detachment (as determined using B-scan ultrasonography), 6 to 8 mm from and angled 20° to 30° toward the limbus. The second step involves removal of the trocar to expose the sclerotomy. Alternatively, the second step can be insertion of a second trocar. The third step involves the creation of a small focal peritomy around the preexisting sclerotomy and enlargement of the preexisting sclerotomy into a radial sclerotomy. Progression between steps only occurs if prior steps did not provide adequate drainage. Results: Two cases of appositional hemorrhagic choroidal detachments in hypotonic eyes were successfully resolved by this stepwise approach. In case 1, a choroidal detachment developed after a corneal ulcer perforation. The hemorrhagic choroidal detachment in case 1 was resolved with steps 1 and 2, and an unnecessary scleral cutdown was avoided. In case 2, a choroidal detachment developed after a trabeculectomy. The detachment in case 2 required progression to step 3, extension of the trocar insertion site into a radial sclerotomy. Conclusions: This stepwise approach should be considered to reduce excessive manipulation of the globe and conjunctiva in hemorrhagic and serous choroidal detachments that warrant surgical intervention.

High-throughput sequencing of the Phoebe bournei transcriptome was performed, and novel SSR markers were identified. A total of 73,518 nonredundant unigenes were assembled and annotated by sequence similarity searching in diverse public databases. A total of 40,853 SSRs were identified from 73,518 unigenes. Twenty-three pairs of polymorphic EST-SSR markers were selected from 98 markers and used for genetic analyses in 75 individuals from three P. bournei populations. The 23 pairs of markers could detect abundant genetic information from the samples (PIC = 0.769), and cross-species amplification was successfully performed in other related species. Three populations had high level of genetic diversity (He = 0.658 in average), of which the population YS from Jiangxi province had the most abundant genetic diversity (He = 0.722). The results of genetic structure analyses showed that the population YS from Jiangxi province had obvious genetic differences from the other two populations, and the genetic information of the population SX from Fujian province was related to that of the population LC from Guangdong province and the population YS. The transcriptomic resources and EST-SSR markers are valuable tools not only for the ecological conservation of P. bournei but also for phylogenetic studies.

To investigate the mechanisms of electroacupuncture (EA) at Zusanli (ST 36), Liangmen (ST 21) and Sanyinjiao (SP 6) in intervening diabetic gastroparesis (DGP) based on calcium-activated chloride channel. Forty Sprague-Dawley rats were randomly divided into four groups, including a normal control group (group A), a model group (group B), an EA group (group C) and a metoclopramide group (group D), with 10 rats in each group. A single intraperitoneal injection of 2% streptozotocin (STZ) combined with 8-week high-glucose high-fat diet was used to establish a DGP rat model. After intervention, gastrointestinal propulsive rate was observed; the expression level of transmembrane protein 16A (TMEM16A) was examined by immunohistochemistry; the Ca2+ concentration in interstitial cells of Cajal (ICCs) was detected by immunofluorescence; and whole-cell patch-clamp technique was applied to detect the current intensity of calcium-activated chloride channel (ICaCC) in ICCs in gastric antrum. After modeling, the blood glucose levels in group B, group C and group D were significantly increased compared with group A (all P

Objective To review the literature on noninfectious endophthalmitis (NIE) following intravitreal triamcinolone acetonide (IVTA). Design A literature review and case report. Participants Individuals who developed NIE after IVTA injection. Methods A review of the literature was undertaken using Ovid MEDLINE and EMBASE databases, and articles available up to and including December 30, 2019, were included. A total of 518 articles were identified, of which 27 were selected. We also present an illustrative case report. Results The incidence rate of NIE lies between 0.1% and 7.3% in most studies. Although the etiology of NIE is still the subject of investigation, proposed mechanisms include excipients and rheologic stress caused by small crystals. The time to presentation of NIE is often 1–3 days after IVTA injection, with symptoms of moderate to marked reduction in visual acuity along with signs of anterior chamber inflammatory reaction, hypopyon, and vitritis. Resolution occurs in 1–3 weeks in the majority of patients, and almost all return to their pre-injection visual acuity. Differences in the presentations of NIE, infectious endophthalmitis, and pseudo-endophthalmitis are discussed. We also present an illustrative case report of an 80-year-old woman who developed NIE after an IVTA injection for cystoid macular edema. Conclusions It is important to distinguish NIE from other forms of endophthalmitis because they have different natural histories and require different interventions and follow-up. NIE is rarely accompanied by significant pain or conjunctival erythema. Visual acuity is inconsistently affected and is therefore not a good criterion for identifying the type of presenting endophthalmitis.

Osteoarthritis is the most prevalent arthritis typically characterized by degradation of cartilage. However, its pathogenesis is not fully understood. Currently, osteoarthritis is best considered a disease of the whole "joint organ". Infrapatellar fat pad (IFP), an adipose tissue near synovium, is now attaching importance to researchers for its inflammatory phenotype. In this narrative review, a large body of evidence has been gathered for the involvement of IFP in the development of knee osteoarthritis. Additionally, the underlying mechanisms of how IFP can be involved in this process have been proposed. However, further investigations are needed to better understand its precise role in this process and its underlying mechanism, and beyond that, to develop new strategies to slow down the degenerative process and explore an effective and timely diagnosis of the disease.

BACKGROUND mTOR gene is a key component of the PI3K/Akt/mTOR signaling pathway, and its dysregulation is associated with various diseases. Several studies have demonstrated that tea drinking is a protective factor against tuberculosis (TB). This study was designed to explore five single nucleotide polymorphisms (SNPs) of mTOR in the Han population of China to determine how their interactions with tea drinking affect susceptibility to TB. AIM To investigate if the polymorphisms of mTOR gene and the gene-tea interaction are associated with susceptibility to TB. METHODS In this case-control study, 503 patients with TB and 494 healthy controls were enrolled by a stratified sampling method. The cases were newly registered TB patients from the county-level centers for disease control and prevention, and the healthy controls were permanent residents from Xin’ansi Community, Changsha city. Demographic data and environmental exposure information including tea drinking were obtained from the study participants. We genotyped five potentially functional SNP sites (rs2295080, rs2024627, rs1057079, rs12137958, and rs7525957) of mTOR gene and assessed their associations with the risk of TB using logistic regression analysis, and marginal structural linear odds models were used to estimate the gene-environment interactions. RESULTS The frequencies of four SNPs (rs2295080, rs2024627, rs1057079, and rs7525957) were found to be associated with susceptibility to TB (P < 0.05). Genotypes GT (OR 1.334), GG (OR 2.224), and GT + GG (OR 1.403) at rs2295080; genotypes CT (OR 1.562) and CT + TT (OR 1.578) at rs2024627, genotypes CT (OR 1.597), CC (OR 2.858), and CT + CC (OR 1.682) at rs1057079; and genotypes CT (OR 1.559) and CT + CC (OR 1.568) at rs7525957 of mTOR gene were significantly more prevalent in TB patients than in healthy controls. The relative excess risk of interaction between the four SNPs (rs2295080, rs2024627, rs1057079, and rs7525957) of mTOR genes and tea drinking were found to be -1.5187 (95%CI: -1.9826, -1.0547, P < 0.05), -1.8270 (95%CI: -2.3587, -1.2952, P < 0.05), -2.3246 (95%CI: -2.9417, -1.7076, P < 0.05) and -0.4235 (95%CI: -0.7756, -0.0714, P < 0.05), respectively, which suggest negative interactions. CONCLUSION The polymorphisms of mTOR (rs2295080, rs2024627, rs1057079, and rs7525957) are associated with susceptibility to TB, and there is a negative interaction between each of the four SNPs and tea drinking.

Background It has reported that long non-coding RNAs (lncRNAs) exerted regulatory functions by targeting specific genes through a competing endogenous RNA (ceRNA) pathway. LncRNA OIP5-AS1 has been identified as a tumor-enhancer in several tumor types. Nonetheless, its molecular mechanism in HCC remains to be masked. Aim of the study This study was aimed at exploring whether and how OIP5-AS1 exert functions in HCC. Methods qRT-PCR and western blot were employed for detecting gene expression. CCK-8, colony formation and EdU assays were implemented to evaluate the proliferative ability of HCC cells. Caspase-3 activity and flow cytometry analyses were implemented to determine cell apoptosis and cell cycle distribution. RNA pull down, ChIP, RIP and luciferase reporter assays explored the interplays between molecules. Results YY1 was upregulated in HCC cells, and silenced YY1 restrained HCC cell proliferation in vitro and hampered tumor growth in vivo. Later, we discovered that miR-300 could regulate WNT pathway via targeting YY1. Furthermore, OIP5-AS1 was identified as the sponge of miR-300 and promoted cell growth in HCC. Importantly, YY1 transcriptionally activate OIP5-AS1 in turn. Rescue experiments indicated that miR-300 inhibition or YY1 overexpression abrogated the inhibitive effect of OIP5-AS1 silencing on the malignant growth of HCC cells. Conclusions OIP5-AS1/miR-300/YY1 feedback loop facilitates cell growth in HCC by activating WNT pathway.

An intraductal papillary mucinous neoplasm (IPMN) is a common pancreatic precursor lesion, and it often harbors mutations in KRAS, GNAS, and RNF43. To clarify the molecular profiles of IPMNs, we conducted mutation analysis of KRAS, GNAS, and RNF43 in 61 IPMN formalin-fixed, paraffin-embedded (FFPE) specimens. The mutation rates of codons 12, 13, and 61 in KRAS and codon 201 in GNAS were detected by Sanger sequencing. Next-generation sequencing was performed on RNF43, and the results were further verified by Sanger sequencing. We identified KRAS and GNAS mutations in 35 (57%) and 40 (66%) IPMN cases, respectively. GNAS mutations were significantly correlated with the morphologic subtype (P<0.001) and were more prevalent in the intestinal subtype (93%) than in the gastric (55%) and pancreatobiliary subtypes (44%) but were absent in the oncocytic subtype. RNF43 mutations were found in 5 cases (8%), all of which occurred in high-grade dysplasia and invasive lesions (2/5 and 3/5). All 5 cases harboring RNF43 mutations also exhibited GNAS mutations. RNF43 mutations were associated with a worse prognosis in invasive IPMN patients (P=0.002), while KRAS and GNAS mutations did not affect the prognosis of patients.

Treating HCV infection reduces overall mortality and reduces the risk of multiple extrahepatic complications. Whether the reduction in mortality is primarily due to a reduction in liver-related causes or extrahepatic complications is unknown.We identified HCV-positive individuals treated for HCV, and propensity score-matched them to HCV-positive/untreated and HCV-uninfected individuals in ERCHIVES between 2002-2016. We extracted cause of death data from the National Center for Health Statistics' National Death Index. Viral hepatitis-associated liver-related mortality rates among treated and untreated HCV-infected persons were calculated by treatment and attainment of sustained virologic response (SVR).Among 50,674 HCV-positive/treated (Group A), 31,749 HCV-positive/untreated (Group B) and 73,526 HCV-uninfected persons (Group C), 8.6% in Group A, 35.0% in Group B, and 14.3% in Group C died. Among those who died, viral hepatitis-associated liver-related mortality rates per 100 patient-years (95% CI) were: 0.28 (0.27-0.30) for Group A; 1.44 (1.38-1.49) for Group B; and 0.06 (0.05-0.06) for Group C; (p0.0001 for both comparisons). Among HCV-positive/treated persons, rates were 0.06 (0.05-0.06) for those with SVR vs. 0.78 (0.74-0.83) for those without SVR. In competing risks Cox proportional hazards analysis, treatment with all-oral DAA regimens (adjusted hazard ratio 0.11; 95% CI 0.09-0.14) and SVR (adjusted hazard ratio 0.10; 95% CI 0.08-0.11) were associated with reduced hazards of liver-related mortality.Treatment for HCV is associated with a significant reduction in viral hepatitis-associated liver-related mortality, which is particularly pronounced in those treated with DAA regimens and those who attain SVR. This may account for a significant proportion of the reduction in all-cause mortality reported in previous studies.Treating hepatitis C virus (HCV) infection is known to reduce overall mortality. However, whether the reduction in mortality is primarily due to a reduction in liver-related causes or extrahepatic complications was previously unknown. Herein, we show that while treating HCV with direct-acting antiviral regimens has numerous extrahepatic benefits, a significant benefit can be attributed specifically to the reduction in liver-related mortality.

Objectives To develop a new Chinese medicine (CM)-based drug and to evaluate its safety and effect for suppressing acute respiratory distress syndrome (ARDS) in COVID-19 patients. Methods A putative ARDS-suppressing drug Keguan-1 was first developed and then evaluated by a randomized, controlled two-arm trial. The two arms of the trial consist of a control therapy (alpha interferon inhalation, 50 µg twice daily; and lopinavir/ritonavir, 400 and 100 mg twice daily, respectively) and a testing therapy (control therapy plus Keguan-1 19.4 g twice daily) by random number table at 1:1 ratio with 24 cases each group. After 2-week treatment, adverse events, time to fever resolution, ARDS development, and lung injury on newly diagnosed COVID-19 patients were assessed. Results An analysis of the data from the first 30 participants showed that the control arm and the testing arm did not exhibit any significant differences in terms of adverse events. Based on this result, the study was expanded to include a total of 48 participants (24 cases each arm). The results show that compared with the control arm, the testing arm exhibited a significant improvement in time to fever resolution (P=0.035), and a significant reduction in the development of ARDS (P=0.048). Conclusions Keguan-1-based integrative therapy was safe and superior to the standard therapy in suppressing the development of ARDS in COVID-19 patients. (Trial registration No. NCT 04251871 at www.clinicaltrials.gov) Electronic Supplementary Material Supplementary material is available in the online version of this article at 10.1007/s11655-020-3426-7.

Small-cell lung cancer (SCLC) is a special type of lung cancer that belongs to highly aggressive neuroendocrine tumors. At present, radiotherapy and chemotherapy remain the mainstay of treatment for SCLC. Progress in targeted therapies for SCLC with driver mutations has been slow, and these therapies are still under investigation in preclinical or early-phase clinical trials, and research on antiangiogenic tyrosine kinase inhibitors (e.g., anlotinib) has achieved some success. Immunotherapy is becoming an important treatment strategy for SCLC after radiotherapy and chemotherapy. In this article we review the recent advances in immunotherapy for SCLC.

Few studies about nucleotide-oligomerization domain-like receptor subfamily C3 (NLRC3) in PASMCs have been conducted. This research aimed to investigate the role of NLRC3 on platelet-derived growth factor (PDGF)-induced proliferation of pulmonary artery smooth muscle cells (PASMCs) and its underlying mechanism. We found that the proliferation of PASMCs stimulated with PDGF decreased when phosphoinositide 3-kinase (PI3K) or mammalian target of rapamycin (mTOR) inhibitors pretreatment. Overexpression of NLRC3 inhibited the proliferation of PASMCs and the phosphorylation of PI3K and mTOR while knocking down NLRC3 reversed this effect. Targeted to PI3K or mTOR can also reverse the effect of NLRC3. Activation of PI3K increased the phosphorylation of mTOR while inhibition of PI3K reduced it. Our data suggest that PDGF can induce abnormal proliferation of PASMCs, and NLRC3 suppresses activation of the PI3K-mTOR signaling thus inhibits PASMCs proliferation. These findings unveiled the effect of NLRC3 as an inhibitor of the PI3K-mTOR pathway mediating protection against PASMCs proliferation.

Background Aging is the most important risk factor for prostate cancer (PCa), but how age contributes to PCa is poorly understood. Aging is characterized by low-grade systemic inflammation (i.e., inflammaging) that is often attributed to the progressive activation of immune cells over time, which may play an important role in prostate carcinogenesis. Th17 response is elevated in aging humans and mice, but it remains unknown whether it is increased in prostate tissue or contributes to prostate carcinogenesis during aging. In this study, we aimed to determine the role of age-related Th17 response in PCa cell growth, migration, and invasion. Methods C57BL/6J (B6) mouse was used as an aging animal model and the prostate histopathology during aging was analyzed. Splenic CD4+ T cells were isolated from young (16-20 weeks old) and aged (96-104 weeks old) mice, and cultured in the presence of plate-bound anti-CD3/anti-CD28, with or without Th17 differentiation conditions. The cells were collected and used for subsequent flow cytometry or quantitative reverse transcription polymerase chain reaction. The supernatant was collected and used to treat PCa cell lines. The treated PCa cells were analyzed for cell viability, migration, invasion, and nuclear factor kappa B (NF-κB) signaling. Results Aged mice had enlarged prostate glands and increased morphological alterations, with not only increased inflammatory cell infiltration but also increased Th17 cytokines in prostate tissue, compared to young mice. Naive CD4+ T cells from aged mice differentiated increased interleukin (IL)-17-expressing cells. CD4+ T cells from aged mice spleen had increased Th17 cells, Th17 cytokines and Th17/Treg ratio compared to young mice. Factors secreted from aged CD4+ T cells, especially from ex vivo differentiated Th17 cells, not only promoted PCa cell viability, migration, and invasion but also activated the NF-κB signaling in PCa cells compared to young mice. Conclusions These results indicate that age-related CD4+ T cells, especially Th17 cells-secreted factors have the potential to contribute to prostate carcinogenesis. Our work could prompt further research using autochthonous PCa mouse models at different ages to elucidate the functional role of Th17 response in prostate carcinogenesis during aging.

Background This study aims to estimate prognostic indicators of new onset atrial fibrillation (AF) in patients with acute coronary syndrome (ACS) through 3 to 5 years of follow‐up. Hypothesis For patients with ACS, some prognostic indicators can be used to predict new onset AF. Methods The Improving Care for Cardiovascular Disease in China‐ACS (CCC‐ACS) program was launched in 2014 by a collaborative initiative of the American Heart Association and Chinese Society of Cardiology. We enrolled 866 patients with ACS in a telephone follow‐up program. We inquired about each patient's general health and invited each patient to our hospital for further consultation. We also performed ambulatory electrocardiography and other relevant examinations. Results A total of 743 ACS patients were included in the study. After 3 to 5 years, 50 (0.67%) patients developed AF. In multivariable Cox models adjusting for AF risk factors in ACS patients, we found that NT‐proBNP [hazard ratio (HR) 2.625, 1.654‐4.166, P

Chilling has become a major meteorological disaster affecting the spring maize (Zea mays L.) production region in Northeast China. Our objective was to assess the effect of a novel plant growth regulator on relieving chilling stress among early- and late-maturing maize cultivars in three different regions in Northeast China. Field experiments were conducted in Haerbin country, Suihua country, and Yi-an county in 2011 and 2012. Two widely planted maize cultivars (early maturing—‘Fengdan 3’ and late maturing—‘Zhengdan 958’) in Northeast China were planted. A PKN (a combination of synthetic plant growth regulator, its principal components were polyaspartic acid, kinetin and α-naphthalene acetic acid) solution was applied to the maize surfaces at the six-expanded-leaf stage. The results demonstrated that spring maize yield was significantly influenced by region, cultivar and PKN; spring maize planted in the low-latitude region (Haerbin) had a higher yield than that in the high-latitude region (Suihua and Yi-an countries); the late-maturing cultivar had a higher yield than the early-maturing cultivar. In comparison to the control treatment, the PKN treatment increased the spring maize yield significantly. The variation in the grain yield across regions, cultivars and PKN treatments was mainly due to variation in the kernel weight. Compared to the control, the PKN treatment significantly increased kernel weight. Moreover, the PKN treatment increased the leaf area index, net assimilation rate, ear-leaf sucrose content, and sucrose synthase and sucrose phosphate synthase activities. In addition, the abovementioned indicators increased more for late-maturing cultivars than for early-maturing cultivars in the high-latitude region. In conclusion, PKN can be used to partly relieve chilling stress for spring maize, especially for late-maturing cultivars in high-latitude regions.

The available literature regarding Oguchi disease is limited, with around 50 cases described to date. Caused by mutations to either the SAG gene coding for arrestin (Hayashi et al. in Ophthalmic Res 46:175–180, 2011) or the GRK1 gene coding for rhodopsin kinase (Yamamoto et al. in Nat Genet 15:175–178. https://doi.org/10.1038/ng0297-175 , 1997), Oguchi disease is an autosomal recessive condition with a good visual prognosis. The clinical diagnosis of the condition is based on the presence of night blindness (nyctalopia), as well as fundoscopic observation of the Mizuo–Nakamura phenomenon. The Mizuo–Nakamura phenomenon refers to a fundus discolouration described as a golden-brown colour with a yellow-grey metallic sheen most prominent in the peripheral retina; after prolonged dark adaptation, the fundus appears normal. The prevalence of Oguchi disease is highest in Japan, particularly with SAG mutations (Nakazawa et al. in Retina 17:17–22, 1997), although patients from Europe, Pakistan and India have also been described. Formal diagnosis requires genetic testing. Wide-field fundus images were obtained in both dark-adapted and light-adapted retina. Optical coherence tomography and dark-adapted electroretinography responses were used to further characterize the clinical phenotype. Existing descriptions of Oguchi disease have been limited by available technology. The flashes required for 45°-montage photographs in a dark-adapted eye quickly cause light adaptation. Recent advances in technology enable the capture of larger retinal areas in a single image. Wide-field 133° images were obtained of the native and dark-adapted fundus in natural colour. To our knowledge, these represent the first reported single-wide-field images of Oguchi disease, showing the characteristic Mizuo–Nakamura phenomenon in true colour. Genetic testing revealed a novel homozygous mutation in GRK1. Here, we demonstrate how characterizing this condition with single-shot true-colour wide-field imaging has distinct advantages over scanning laser technology, which applies artificial colouration, or stitched true-colour images. Images captured with wide-field systems create a much better representation of the native and dark-adapted fundus than can be observed by the ophthalmologist using direct fundoscopy and are essential in the clinical characterization of new mutations.

OBJECTIVE To assess the diagnostic value of serum Candida mannan antigen (MN) and anti-mannan IgG and IgM antibodies for candidiasis. METHODS This study was a prospective cohort study. Clinical data and venous blood samples from 23 medical centres in Beijing, China were collected between 1 January 2017 and 31 December 2018. All collected specimens were tested within one week for serum Candida MN and IgG and IgM antibodies using an ELISA kit. RESULTS A total of 452 patients were enrolled, including 188 patients in the Candida exposure groups (56 patients with Candida bloodstream infection, 69 patients with Candida-positive tracheal aspirate cultures and 63 patients with Candida-positive urine cultures) and 264 patients in the control groups (212 healthy controls and 52 patients with bacteraemia). The receiver operating characteristic (ROC) curve of the 56 patients with Candida bloodstream infection and 212 healthy controls showed that serum MN and IgG had good diagnostic value. The area under the ROC curve (AUC) values were 0.812 (95% CI, 0.750-0.873) and 0.866 (95% CI, 0.808-0.924), respectively, wherein the MN specificity and sensitivity were 86.79% and 60.71%, and the IgG were 84.43% and 80.36%, respectively. The AUC of the combination of serum MN and IgG was 0.871(95% CI, 0.813-0.929), and the specificity and sensitivity were 93.87% and 57.14%. CONCLUSIONS The serum levels of Candida MN and its IgG antibody have diagnostic value for Candida bloodstream infection, and combination of MN and IgG can improve diagnostic specificity and may provide a new approach for diagnosis of candidaemia.

Background Accumulating evidence supports the involvement of microRNAs (miRNAs) in the progression of human cancers including glioma. Recently, miR-769-5p has been reported to play a tumor suppressive role in colorectal cancer and lung cancer, whereas it exerts an oncogenic role in melanoma. However, the role of miR-769-5p and its related mechanism are poorly elucidated. Methods The levels of miR-769-5p in glioma tissues and adjacent non-tumor tissues were detected by qRT-PCR. In addition, the effects of miR-769-5p on cell proliferation and apoptosis were evaluated by CCK-8, EdU, colony formation and flow cytometric assays, respectively. Meanwhile, the dual-luciferase reporter assay was used to investigate the interaction of miR-769-5p and lysine methyltransferase 2A (KMT2A) in glioma. Results We found that miR-769-5p expression was strongly upregulated in glioma tissues and cell lines. Glioma tissues with high World Health Organization (WHO) grades had obvious higher levels of miR-769-5p compared to samples with low WHO grades. Interestingly, glioma patients highly expressing miR-769-5p showed prominent poorer survivals. Knockdown of miR-769-5p significantly suppressed cell proliferation and resulted in apoptosis in glioma cells. Additionally, miR-769-5p silencing restrained in vivo growth of glioma cells in mice. Interestingly, KMT2A was identified to be a direct target of miR-769-5p in glioma cells. The expression of KMT2A mRNA was downregulated in glioma tissues and inversely correlated with miR-769-5p level. KMT2A overexpression inhibited cell proliferation and induced the apoptosis of A172 cells. Moreover, siRNA-mediated KMT2A silencing could partially abolish miR-769-5p knockdown-induced suppressive effects on A172 cells. Conclusion In summary, our findings suggest that targeting miR-769-5p/KMT2A axis may be a promising therapeutic target for glioma treatment.

The explosive growth of machine learning is largely due to the recent advancements in hardware and architecture. The engineering of network structures, taking advantage of the spatial or temporal translational isometry of patterns, naturally leads to bio-inspired, shared-weight structures such as convolutional neural networks, which have markedly reduced the number of free parameters. State-of-the-art microarchitectures commonly rely on weight-sharing techniques, but still suffer from the von Neumann bottleneck of transistor-based platforms. Here, we experimentally demonstrate the in situ training of a five-level convolutional neural network that self-adapts to non-idealities of the one-transistor one-memristor array to classify the MNIST dataset, achieving similar accuracy to the memristor-based multilayer perceptron with a reduction in trainable parameters of ~75% owing to the shared weights. In addition, the memristors encoded both spatial and temporal translational invariance simultaneously in a convolutional long short-term memory network—a memristor-based neural network with intrinsic 3D input processing—which was trained in situ to classify a synthetic MNIST sequence dataset using just 850 weights. These proof-of-principle demonstrations combine the architectural advantages of weight sharing and the area/energy efficiency boost of the memristors, paving the way to future edge artificial intelligence. Memristive devices can provide energy-efficient neural network implementations, but they must be tailored to suit different network architectures. Wang et al. develop a trainable weight-sharing mechanism for memristor-based CNNs and ConvLSTMs, achieving a 75% reduction in weights without compromising accuracy.

The objective of this work was to investigate the effect of boletus polysaccharide (BPS) on diabetic hepatopathy in streptozotocin (STZ)–induced type 2 diabetes mellitus (T2DM) rats for the first time. The rats were fed with high-fat diet (HFD) for 4 weeks and induced with STZ by a single intraperitoneal injection to develop T2DM model. The HFD was given continually for another 4 weeks after diabetes induction, following the drugs of BPS (400 mg/kg bw/day) infused to stomach of rats once a day. After the administration, blood was drawn from the posterior orbital venous plexus of the inner canthus and the rats were then sacrificed. The blood glucose and lipid, alanine transaminase (ALT) and aspartate transaminase (AST) were detected immediately. Besides, their livers were dissected for biochemical and histopathological assays. And the levels of malonaldehyde, glutathione and antioxidant enzymes in liver were detected. In addition, histopathological examinations of liver were performed to verify the liver injury. The expressions of NF-κB, TNF-α, SREBP1c, and CYP7A1 were test to trace out the mechanistic pathways. Compared with T2DM model group, the blood glucose, TC, TG, ALT, AST, and MDA and so on were significantly reduced, and CAT, SOD, GSH, GPx were significantly increased in the rats treated with BPS. The histopathological examination showed the liver injury in BPS treated rats was alleviated. The expressions of SREBP1c, NF-κB and TNF-α were significantly decreased, and the expressions of CYP7A1 was significantly increased. All these experimental findings demonstrate that BPS exhibited antidiabetic effects rats possibly through its inhibition of oxidative stress and inflammation, supporting that BPS has a promising therapeutic effect in the treatment of diabetic hepatopathy in rats.

Background Chronic obstructive pulmonary disease (COPD) is a disease of continuous progress and environmental factors may affect the progress. COPD patients' activity tolerance and quality of life are associated with air quality. COPD exacerbation from the perspective of geographical air quality has not been reported. Objectives To explore environmental effect of two different geographical places on COPD exacerbation and the effect of cigarette smoke extract and carbon particles on bronchial epithelial cell viability. Methods Total 139 COPD patients, who lived in Beijing during summer and temporarily migrated to Sanya city in winter, have been enrolled. Respiratory symptoms and lung function data were collected when they were living in Beijing or Sanya, respectively. Effect of cigarette smoke extract plus ultrafine carbon particles on airway epithelial cells were studied. Measurements and main results Air pollution as measured by air quality index (AQI) in Beijing summer (113.1±14.2) was significantly worse than that in Sanya winter (49.4±8.9, p

OBJECTIVE The use of the Pipeline embolization device (PED) for posterior circulation aneurysms is controversial. The aim of this study was to explore the safety and efficacy of PED for these aneurysms in a meta-analysis. Meta-regression was used to identify predictors for incomplete aneurysm occlusion and procedure-related complications. METHODS PubMed, Web of Science, and OVID databases were searched to identify all published references evaluating the treatment effect of PED for posterior circulation aneurysms. Only studies written in English that reported original data and included >10 cases were considered for inclusion. Patient demographics, aneurysm characteristics, angiographic outcomes, and clinical outcomes were extracted. A random-effects model was adopted to pool the obliteration rates and complication rates across selected studies. Finally, we conducted meta-regression analysis to identify predictors of angiographic outcomes. RESULTS 12 studies including 358 patients with 365 aneurysms were included. The pooled complete aneurysm obliteration rate was 82% (95% confidence interval 73%–90%), and pooled procedure-related complication rate was 18% (95% confidence interval 14%–22%). Increasing age predicted incomplete obliteration of aneurysms after PED treatment in these patients (P = 0.01). CONCLUSIONS PED is an alternative to treat intracranial aneurysms of the posterior circulation, achieving high complete occlusion rates, but it is less effective in elderly patients. The risk of procedure-related complications is not negligible. Further larger, long-term follow-up studies are needed before definitive conclusions can be drawn.

Objective To explore predictors of epilepsy presentation in unruptured brain arteriovenous malformations (bAVMs) with quantitative evaluation of location and radiomics features on T2-weighted imaging. Methods This retrospective study identified 117 patients with unruptured bAVMs. Cases were randomly split into training dataset (n = 90) and test dataset (n = 27). On the training dataset, we applied atlas-based analysis to identify epilepsy-susceptible brain regions of bAVMs, and then applied the radiomics technique to explore shape, intensity, and textural features that were correlated with epilepsy presentation. Informative radiomics predictors were selected by least absolute shrinkage and selection operator with 3-fold cross-validation. A linear classification score was then constructed, and we tested if we could precisely identify epilepsy-susceptible bAVMs with the location and radiomics predictors. Results Two brain regions and 4 radiomics features were screened out as predictors for epilepsy. The percent of damage of the right precentral gyrus and the right superior longitudinal fasciculus was associated with epilepsy presentation. The 4 radiomics features were Original_firstorder_Median, Wavelet-LHL_firstorder_InterquartileRange, Wavelet-HHL_firstorder_InterquartileRange, and Wavelet-HHH_glrlm_RunVariance. Epileptogenic bAVMs had larger variance of run lengths, larger median value, and interquartile range of voxel intensities. On the training dataset, these 6 predictors were able to classify epilepsy-susceptible bAVMs with accuracy at 0.822, and the area under the curve was 0.866 (95% confidence interval, 0.791–0.940). On the test dataset, sensitivity, specificity, and accuracy of classification reached 0.786, 0.769, and 0.778, respectively. Conclusions Epilepsy-susceptible bAVMs had distinct locations and radiomics features on T2-weighted imaging.

Flavonoids are the most abundant polyphenols in tea (Camellia sinensis L.) with diverse medicinal values and stress adaptive roles. Flavonoid biosynthesis is largely influenced by environmental factors, including high atmospheric CO2. Although accumulation of certain flavonoids in tea leaves can be triggered by high CO2, the underlying mechanisms remain far from being substantiated. Despite the involvement of salicylic acid (SA) and nitric oxide (NO) in plant responses to biotic and abiotic stressors under high CO2, their roles in high CO2-induced plant secondary metabolism remain largely unknown, particularly in tea plants. This study revealed that the exposure of tea plants to high CO2 levels (550 and 800 μmol mol−1) rapidly increased the concentrations of flavonoid, SA and NO. Exogenous SA and sodium nitroprusside (a NO donor) increased flavonoid concentration only at ambient CO2 (400 μmol mol−1) but not at elevated CO2. Furthermore, suppression of endogenous SA by its biosynthesis inhibitor paclobutrazol and scavenging of NO by cPTIO (4-carboxyphenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide) reduced flavonoid concentration and phenylalanine ammonia-lyase activity under elevated CO2. While the scavenging of NO showed no effect on endogenous SA levels, SA deficiency attenuated elevated CO2-induced NO accumulation, suggesting that SA acts upstream of NO in elevated CO2-induced flavonoid biosynthesis. Notably, NO levels in SA-suppressed plants were several times greater than that of cPTIO-treated plants, indicating that SA-independent NO production might have a contribution to total NO accumulation under elevated CO2. This study unraveled the functional hierarchy and relationships of SA and NO in elevated CO2-induced flavonoid biosynthesis in tea leaves.

Objective To explore the predictors of periprocedural complications and angiographic outcomes in large and giant intracranial posterior circulation aneurysms after endovascular treatment. Methods Data from 99 patients with 103 large (≥10 mm; n = 94) and giant (>25 mm; n = 9) posterior circulation aneurysms treated with endovascular therapy at a single center were retrospectively analyzed. The treatment procedures included endovascular trapping (n = 15), coiling (n = 6), stent only (n = 10), stent-assisted coiling (n = 48), and pipeline embolization device (PED; n = 24). The outcome endpoints were the number of periprocedural complications and number of complete occlusions without any complication. Results Multivariate analysis revealed that intradural vertebral aneurysms (P = 0.041) and aneurysms ≤25 mm (P = 0.042) were associated with low periprocedural complication rates after endovascular therapy. Aneurysms not involving side branches (P = 0.024) and intradural vertebral aneurysms (P = 0.032) were predictors of complete aneurysm obliteration. No statistically significant differences were found in aneurysmal complete obliteration (P = 0.119) or periprocedural complications (P = 0.248) between a PED and traditional stent and coiling. Additionally, aneurysms not involving side branches (P = 0.030), intradural vertebral artery aneurysms (P = 0.003), and aneurysms treated with a PED (P = 0.020) were more likely to achieve complete occlusion over time. Conclusions Aneurysm location, aneurysm size, and side branch involvement were predictors of periprocedural complications and angiographic outcomes of endovascular therapy for large and giant intracranial posterior circulation aneurysms. PED use provided no advantages compared with traditional stent and coiling in aneurysmal occlusion rates and periprocedural complications. Large case-control and long-term follow-up studies are needed to further explore the predictors of complications and angiographic outcomes and optimal treatment options for these aneurysms.

Hydrogen sulfide (H2S) nowadays is regarded as a novel gaseous signaling molecule in plants during environmental stress response. The spermidine (Spd), an important plant growth regulator, plays critical roles in regulating stress tolerance in plant species. Objectives of this study were to examine whether Spd could act as a H2S signaling activator to regulate stress-responsive transcription factors (TFs) and antioxidant defense and to further explore the possible crosstalk among Spd-induced hydrogen peroxide (H2O2), nitric oxide (NO), and H2S signaling in leaves of white clover. Results showed that dehydration or exogenous application of Spd could significantly increase L/D-cysteine desulfhydrate (L/DCD) activities and then cause a quick accumulation of H2S, followed by significant improvement of antioxidant enzyme (SOD, CAT, GPOX, APX, GR, DHAR, and MDHAR) activities and transcript levels of TFs (bZIP37, bZIP107, DREB2, DREB4, and WRKY108715) and genes encoding antioxidant enzymes. The inhibitors (AOA and NH2OH) of L/DCD activities could effectively attenuate dehydration- or Spd-induced these effects in leaves. Additionally, dehydration-induced increase in H2S accumulation, L/DCD and antioxidant enzyme activities, and genes expression were remarkably abolished by the application of Spd biosynthesis inhibitor (DCHA), whereas exogenous Spd significantly alleviate the inhibitory effect of DCHA on these parameters under dehydration condition. This indicated that H2S which was derived from L/DCD pathway might act as a downstream signaling of Spd, and Spd-activated H2S signaling was involved in dehydration-regulated TFs and antioxidant defense associated with dehydration tolerance. Further analyses found that Spd-induced H2O2 production could not be attenuated by scavengers of NO and H2S, but the scavenger of H2O2 effectively inhibited Spd-induced increases in NO and H2S. The Spd-induced H2S signaling was also substantially inhibited by the application of the NO scavenger. The result implied that Spd-induced H2O2 could be an upstream signal molecule of NO and H2S, and the Spd-induced H2S might act as the downstream signaling of NO in leaves. These obtained results provide the basic evidence to understand Spd-regulated signal transduction in white clover.

To analyze and compare safety and efficacy of different endovascular treatment modalities for unruptured intracranial large or giant aneurysms.We retrospectively reviewed 126 consecutive patients with 128 large (15-24 mm) or giant (≥25 mm) aneurysms that were treated with different endovascular procedures between January 2014 and February 2017. We compared clinical and angiographic outcomes and occurrence of technical events among 3 treatment modalities.Complete occlusion at last follow-up was achieved in 65.6%, 90.5%, and 72.0% of aneurysms in stent-assisted coiling, parent artery occlusion, and Pipeline embolization device (PED) groups (P = 0.119). Complete occlusion rate at 6-month follow-up (odds ratio = 1.81, P = 0.396) and at last angiographic follow-up (odds ratio = 3.64, P = 0.123), was not superior with parent artery occlusion compared with PED. Retreatment rate was significantly different among all groups (P0.001); the rate was highest in the stent-assisted coiling group (21.9%). Rates of hemorrhagic events and ischemic events were not significantly different among groups (P = 0.581). Mass effect exacerbation was more frequently seen in the stent-assisted coiling group (24.4% vs. 7.7% and 3.3%, P = 0.004). Major complication rate was higher in the parent artery occlusion group compared with the PED group, but the difference was not statistically significant (19.2% vs. 16.4%, odds ratio = 1.21, P = 0.763). Rate of technical events was significantly different in the 3 groups (P = 0.0437), and technical events occurred more often in the PED group (18.0%).For large and giant aneurysms located in the internal carotid artery, outcome for endovascular treatment remains poor, even with the introduction of PED.

Land-use changes could potentially exert a strong influence on soil quality and soil microbial communities. Moreover, microbial taxa are also important drivers of soil ecological functions. However, the linkage between soil quality and soil microbial communities is in need of deeper understanding. In this study, we examined the effects of soil quality on microbial community structure and functions after forest conversion to vegetable cropland and tea plantations. Soil quality index was significantly increased after natural forest conversion to vegetable cropland and tea plantations. Soil bacterial beta diversity significantly correlated to soil quality, but the sensitivity of individual microbial groups varied in response to changes in soil quality. Higher soil quality promoted bacterial diversity in vegetable cropland but decreased it in tea plantations, which implied soil quality was a structural factor in bacterial community composition but had contrasting effects for croplands versus plantations. Agricultural management played a negative role in maintaining microbial interactions, as identified by the network analysis, and furthermore the analysis revealed key functions of the microbial communities. After land-use change, the abundance (e.g., level, intensity) of microbial N-cycling function increased in tea plantations but decreased in vegetable cropland. The abundance of C-cycling function featured an opposite trend. Higher level of N-fixation in tea plantations but the higher abundance of N-oxidation in vegetable cropland was demonstrated. Higher abundance of ammonia-oxidizing bacteria and ammonia-oxidizing archaea as identified by qPCR in vegetable cropland corroborated the FAPROTAX function prediction. Therefore, the key taxa of soil microbial communities and microbial functions were largely dependent on changes in soil quality and determined responses to specific agricultural management.

Background and Purpose: This study aimed to analyze the association between hyperattenuated lesions (HALs) and postoperative intracranial hemorrhage (IH) and predict perioperative IH through quantitative analysis of HALs in acute ischemic stroke (AIS) with anterior large vessel occlusion (LVO) after endovascular therapy (ET).Materials and Methods: This retrospective, propensity-matched study enrolled AIS who received ET from a single-center registry study between August 2017 and May 2020. The enrolled patients were divided into two groups: IH and non-IH, by follow-up postoperative CT. The occurrences of HALs on immediate CT after ET were also recorded. The association between IH and HALs after propensity score matching (PSM) was determined by binary logistic regression models. The receiver operating characteristic (ROC) curve was used to determine the predictive value of the highest CT Hounsfield units (HU) value on immediate CT.Results: Initially, 1,418 patients who underwent digital subtraction angiography were reviewed and 114 AIS patients with immediate postoperative CT and follow-up CT after ET were enrolled. Forty-nine out of the 114 patients developed IH after therapy. After PSM analysis, patients with IH were more likely to have HALs on immediate CT (Odds Ratio, OR 11.9, P = 0.002, and 95% CI: 2.485–57.284). For 80 patients with HALs, ROC analysis of the highest CT value in the HALs territory showed that the cut-off value was 97 HU, the sensitivity was 70.21%, and the specificity was 81.82%.Conclusions: Patients with HALs after ET are more likely to have perioperative IH. The highest CT value in the HALs area might be used to predict IH.

Background: Increased serum neuron-specific enolase (NSE) level was found in a substantial proportion (30–69%) of patients with non-small-cell lung cancer (NSCLC), but little was known about the clinical properties of NSE in NSCLC. Objective: We aimed to assess the level of serum NSE to predict prognosis and treatment response in patients with advanced or metastatic non-neuroendocrine NSCLC. Methods: We retrospectively analyzed 363 patients with advanced and metastatic NSCLC between January 2011 and October 2016. The serum NSE level was measured before initiation of treatment. Results: Patients with high NSE level (≥26.1 ng/ml) showed significantly shorter progression-free survival (PFS) (5.69 vs 8.09 months; P=0.02) and significantly shorter overall survival (OS) than patients with low NSE level (11.41 vs 24.31 months; P=0.01). NSE level was an independent prognostic factor for short PFS (univariate analysis, hazard ratio [HR] = 2.40 (1.71–3.38), P Conclusion: The survival of NSCLC patients with high serum NSE level was shorter than that of NSCLC patients with low serum NSE levels. Serum NSE level was a predictor of treatment response and an independent prognostic factor.

Aconitine is attracting increasing attention for its unique potential pharmacological effects on the cardiovascular system. However, underlying molecular mechanisms, especially in the context of the positive inotropic effect induced by repeated-dosing of aconitine at low levels, are still not fully understood. The cardiotonic effect always requires abundant energy supplement, which is mainly related to mitochondrial function. And OPA1 has been documented to play a critical role in mitochondrial morphology and energy metabolism in cardiomyocytes. Hence, this study was designed to investigate the possible mechanism involved in the positive inotropic effect caused by repeated aconitine treatment and to further elucidate the potential role of OPA1 in this progress. Our results showed that repeated treatment with low-doses (0-10 μM) of aconitine for 7 days did not induce detectable cytotoxicity and enhanced myocardial contraction in NRVMs. Also, we first identified that 5 μM of aconitine could trigger an obvious perturbation of mitochondrial homeostasis in cardiomyocytes by accelerating mitochondrial fusion, biogenesis, and Parkin-mediated mitophagy, followed by the increase in mitochondrial function and the cellular ATP content, which was identified to be related to the upregulation of ATP synthase α-subunit (ATP5A1). Besides, co-treatment with Compound C, an inhibitor of AMPK, could reverse aconitine-increased the content of phosphor-AMPK, OPA1, and ATP5A1, and the following mitochondrial function. In conclusion, this study first demonstrated that repeated aconitine treatment could cause the remodeling of mitochondrial function via AMPK-OPA1-ATP5A1 pathway, and provide a possible explanation for the cardiotonic or rejuvenation effect induced by aconitine-containing herbs at recommended or lower doses.

Objective To assess the ablative margin of microwave ablation (MWA) for stage I non-small cell lung cancer (NSCLC) using a three-dimensional (3D) reconstruction technique. Materials and methods We retrospectively analyzed 36 patients with stage I NSCLC lesions undergoing MWA and analyzed the relationship between minimal ablative margin and the local tumor progression (LTP) interval, the distant metastasis interval and disease-free survival (DFS). The minimal ablative margin was measured using the fusion of 3D computed tomography reconstruction technique. Results Univariate and multivariate analyses indicated that tumor size (hazard ratio [HR] = 1.91, P P = 0.01) and minimal ablative margin (HR = 0.13, P P P P P P Conclusions The minimal ablative margin is an independent factor of NSCLC relapse after MWA, and the fusion of 3D reconstruction technique can feasibly assess the minimal ablative margin.

Objective To investigate the response of the infrapatellar fat pad (IFP) to running at different intensities and further explore the underlying mechanisms of these responses under different running-induced loadings. Methods Animals were randomly assigned into the sedentary (SED), low-intensity running (LIR), medium-intensity running (MIR), and high-intensity running (HIR) groups. The rats in the LIR, MIR, and HIR groups were subjected to an 8-week treadmill running protocol. In each group, the IFP was examined at the baseline and at the 8th week to perform histomorphology, immunohistochemistry, and mRNA expression analyses. Results Compared with LIR and MIR, HIR for 8 weeks led to a substantial increase in the surface cellularity (1.67 ± 1.15), fibrosis (1.29 ± 0.36), and vascularity (33.31 ± 8.43) of the IFP but did not increase IFP inflammation or M1 macrophage polarization. Low-to-medium-intensity running resulted in unchanged or decreased fibrosis, vascularity, and surface cellularity in the IFP compared to those of the SED group. Furthermore, serum leptin and visfatin levels were significantly lower in the LIR and MIR groups than in the SED group or the HIR group (P < 0.05). Conclusion The effect of running on IFP remodeling was intensity dependent. In contrast to LIR and MIR, HIR increased the fibrosis and vascularity of the IFP. HIR-induced IFP fibrosis was probably due to mechanical stress, rather than pathological proinflammatory M1/M2 polarization.

Biological staggered composites, like bone, nacre, and dentin, possess the superior capacity of energy dissipation than that of conventional materials. In these nanocomposites, different staggered microstructures are widely observed, for example, symmetric staggered structures with regular platelet layouts and asymmetric staggered structures with offset and stairwise platelet layouts. In addition, the thickness of platelets in these biological materials is at the nanoscale, and the distance between the adjacent ends of platelets is large enough in staggered structures, which indicates the interface effect and tension region (TR) cannot be ignored in staggered nanocomposites. In order to investigate the possible synergistic effect of the platelet layouts, interface effects, and tension region on the dynamic properties of the nanocomposites, a generalized tension-shear chain model (TSCM) with TR is proposed. According to the analytical solutions derived, the staggered nanocomposites with optimal structures can be designed to obtain superior energy dissipation capacity. Considering different loading frequencies in natural environment, the optimal dynamic properties of nacre can be achieved with a regular staggering platelet distribution, while the optimal dynamic properties of bone can be achieved when the number of periodic stairwise staggering platelets is appropriately smaller. These optimal platelet layouts in nacre and bone are consistent with the experimental results reported in many literatures. Therefore, the energy dissipation capacity of staggered nanocomposites can be highly improved, based on the profound understanding of the damping mechanism in biological nanocomposites.

Bacterial and viral infection is a common cause of pneumonia, respiratory failure, and even acute respiratory distress syndrome. Increasing evidence indicates that red blood cells (RBCs) may contribute to immune response and inflammation. However, the precise molecular mechanisms that link RBC and hemolysis to the development and progression of inflammatory pathologies are not entirely understood. In this study, we used bacterial endotoxin, lipopolysaccharide (LPS), to mimic an infectious hemolysis and found that RBCs dynamically regulated cell aggregation between immune cells and human lung microvascular endothelial cells (HLMVEC). When RBCs were treated with LPS, integrin α4β1 was increased and was accompanied by cytokines and chemokines release (TNF-α, IL-1β, IL-6, IL-8, IFN-γ, CXCL12, CCL5, CCL7 and CCL4). Upon α4β1 elevation, RBCs not only facilitated mature monocyte derived dendritic cell (mo-DCs) adhesion but also promoted HLMVEC aggregation. Furthermore, co-culture of the supernatant of LPS pre-treated RBCs with mo-DCs could promote naïve CD4 T cell proliferation. Notably, the filtered culture from LPS-lysed RBCs further promoted mo-DCs migration in a concentration dependent manner. From a therapeutic perspective, cyclic peptide inhibitor of integrin α4β1 combined with methylprednisolone (α4β1/Methrol) remarkably blocked RBCs aggregation to mo-DCs, HLMVEC, or mo-DCs and HLMVEC mixture. Moreover, α4β1/Methrol dramatically reduced mo-DCs migration up-regulated glucocorticoid-induced leucine zipper in mo-DCs, and ultimately reversed immune cell dysfunction induced by hemolysis. Taken together, these results indicate that integrin α4β1 on RBCs could mediate cell-cell interaction for adaptive immunity through influencing cell adhesion, migration, and T cell proliferation.

Korla pear (Pyrus sinkiangensis Yü) is a landrace selected from a hybrid pear species in the Xinjiang Autonomous Region in China. In recent years, pericarp roughening has been one of the major factors that adversely affects fruit quality. Compared with regular fruits, rough-skin fruits have a greater stone cell content. Stone cells compose sclerenchyma tissue that is formed by secondary thickening of parenchyma cell walls. In this work, we determined the main components of stone cells by isolating them from the pulp of rough-skin fruits at the ripening stage. Stone cell staining and apoptosis detection were then performed on fruit samples that were collected at three different developmental stages (20, 50 and 80 days after flowering (DAF)) representing the prime, late and stationary stages of stone cell differentiation, respectively. The same batches of samples were used for parallel transcriptomic and proteomic analysis to identify candidate genes and proteins that are related to SCW biogenesis in Korla pear fruits. The results showed that stone cells are mainly composed of cellulose (52%), hemicellulose (23%), lignin (20%) and a small amount of polysaccharides (3%). The periods of stone cell differentiation and cell apoptosis were synchronous and primarily occurred from 0 to 50 DAF. The stone cell components increased abundantly at 20 DAF but then decreased gradually. A total of 24,268 differentially expressed genes (DEGs) and 1011 differentially accumulated proteins (DAPs) were identified from the transcriptomic and proteomic data, respectively. We screened the DEGs and DAPs that were enriched in SCW-related pathways, including those associated with lignin biosynthesis (94 DEGs and 31 DAPs), cellulose and xylan biosynthesis (46 DEGs and 18 DAPs), S-adenosylmethionine (SAM) metabolic processes (10 DEGs and 3 DAPs), apoplastic ROS production (16 DEGs and 2 DAPs), and cell death (14 DEGs and 6 DAPs). Among the identified DEGs and DAPs, 63 significantly changed at both the transcript and protein levels during the experimental periods. In addition, the majority of these identified genes and proteins were expressed the most at the prime stage of stone cell differentiation, but their levels gradually decreased at the later stages.

Species of the order Crocodylia are mostly large, predatory and semi-aquatic reptiles. Crocodylia, the closest living relatives of birds, first appeared in the Late Cretaceous period. In the present study, the complete mitochondrial (mt) genomes of 19 Crocodylia species, including two species (Melanosuchus niger and Caiman yacare) that have not been previously sequenced for mitogenomes, were processed through Illumina sequencing to offer genetic resources and compare with the mitogenomes of Crocodylia species reported previously. In addition, a high-resolution phylogenetic tree of nearly all current recognized species of Crocodylia is constructed based on mitogenomic data. Phylogenetic analyses support monophyly of three families: Alligatoridae (four genera: Alligator, Caiman, Melanosuchus and Paleosuchus), Crocodylidae (three genera: Crocodylus, Mecistops and Osteolaemus) and Gavialidae (two genera: Gavialis and Tomistoma). The tree topology is generally similar to previous studies. Molecular dating suggests that the first split within Crocodylia date back to the Upper Cretaceous (approx. 86.75 Mya). The estimated time to the most recent common ancestor (TMRCA) of Alligatoridae is 53.33 Mya and that of Crocodylidae and Gavialidae is 50.13 Mya, which might be closely linked to climate changes during the Late Palaeocene and Early Eocene. Additionally, this study proves that the diversification rate within Crocodylia began to increase from the Late Eocene (about 36 Mya) and two diversification peak periods of Crocodylia (0–10 Mya and 10–20 Mya) are disclosed, which is roughly consistent with the estimated crocodylian species richness through time. Combining all these clues, we can suggest that climate fluctuation may have played a decisive role in the speciation of Crocodylia.

At present, twice-a-year pruning is usually adopted for the tea garden, in which only spring tea is picked. Effects of different times and heights of summer pruning on tea trees are unknown. Here the effects of summer pruning on ‘Jin Guan Yin’ oolong mature tea trees were studied. The results showed that pruning at 30 cm (summer pruning at 30 cm above the cut surface of spring pruning) on Jul 25 could benefit to the growth of lateral branches, whereas two pruning treatments in August reduced their growth vigor. Pruning at 30 cm could also provide a benefit by decreasing the ratio of total tea polyphenols to free amino acids (TP/AA), an important factor in tea quality. Pruning at 30 cm and two pruning in August all significantly enhanced the contents of ester catechins [‘(−)-epigallocatechin gallate (EGCG) + (−)-epicatechin gallate (ECG)’] as compared to conventional summer pruning. Pruning on Aug 15 (summer pruning at 20 cm on Aug 15) had the lowest (EGCG + ECG)%. In addition, enhanced AA content induced by pruning at 30 cm was significantly associated with enhanced transcription of glutamine synthetase (CsGS) or glutamine:2-oxoglutarate aminotransferase (CsGOGAT). In a word, the summer pruning at 30 cm on Jul 25 was best to benefit the growth of lateral branches and spring tea yield and quality, whereas pruning on Aug 15 had the worst comprehensive effects.

Prescription opioid use (POU) is often a precursor to opioid use disorder (OUD) and subsequent consequences. Persons with chronic hepatitis C virus infection (CHC) may be at a higher risk of POU due to a higher comorbidity burden and social vulnerability factors. We sought to determine the burden of POU and associated risk factors among persons with CHC in the context of social vulnerability. We identified CHC persons and propensity-score matched HCV− controls in the electronically retrieved Cohort of HCV-Infected Veterans and determined the frequency of acute, episodic long-term and chronic long-term POU and the prevalence of social vulnerability factors among persons with POU. We used logistic regression analysis to determine factors associated with POU. Among 160,856 CHC and 160,856 propensity-score matched HCV-controls, acute POU was recorded in 38.4% and 38.0% (P = 0.01) respectively. Episodic long-term POU was recorded in 3.9% in each group (P = 0.5), while chronic long-term POU was recorded in 28.4% and 19.2% (P

Background Impact of SARS‐CoV‐2 infection upon hospitalization, intensive care unit (ICU) admissions and mortality in persons with hepatitis C virus (HCV) infection is unknown. Methods We used the Electronically Retrieved Cohort of HCV infected Veterans (ERCHIVES) database to determine the impact of HCV infection upon the rates of acute care hospitalization, ICU admission and all‐cause mortality. We identified Veterans with chronic HCV infection and propensity score matched controls without HCV in ERCHIVES. We excluded those with HIV or hepatitis B virus coinfection. Results We identified 975 HCV+ and 975 propensity score matched HCV− persons with SARS‐CoV‐2 infection. Mean FIB‐4 score (±SD) was higher in those with HCV (1.9 ± 2.1 vs 1.2 ± 0.9; P 3.25, the rate‐ was 9.4 and 0.6 (P

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to an infection. It is a disease with a high incidence, mortality, and recurrence rate and frequently results in its survivors requiring readmission into hospitals. The readmission is mainly due to recurrent sepsis. Patients with recurrent sepsis are more susceptible to secondary infections partly due to immune dysfunction, leading to a higher mortality in the long term. However, there remains a gap in the understanding of immunological characteristics and underlying mechanisms of recurrent sepsis. In this study, we used mouse models of acute and recurrent sepsis to investigate their different immunological characteristics. And then we subjected the two mouse models to a secondary influenza A virus (H1N1) infection and characterized the different immune responses. Here, we demonstrated that CD4+ T cells present an exacerbated exhaustion phenotype in response to recurrent sepsis as illustrated by the decreased frequency of CD4+ T cells, reduced co-stimulatory CD28 and increased inhibitory PD-1 and Tim-3 expression on CD4+ T cells, increased frequency of regulatory T cells, and reduced MHC-II expression on antigen-presenting cells. Moreover, we showed that antiviral immune responses decrease in the recurrent sepsis mouse model subjected to a secondary infection as illustrated by the reduced pathogen clearance and inflammatory response. This may be a consequence of the exacerbated CD4+ T cell exhaustion. In summary, recurrent sepsis exacerbates CD4+ T cell exhaustion and decreases antiviral immune responses, contributing to significant morbidity, increased late mortality, and increased health care burden in recurrent sepsis patients.

Leaf angle is an important agronomic trait in cereals that helps determine plant yield by affecting planting density. However, the regulation mechanism of leaf angle remained elusive. Here, we show that OsbHLH98, a rice bHLH transcription factor, negatively regulates leaf angle. osbhlh98 mutant leaves formed a larger leaf angle, whereas transgenic plants overexpressing OsbHLH98 exhibited a slight reduction in leaf angle. We determined that the changes in leaf angle resulted from increased number and size of parenchyma cells on the adaxial side of the lamina joint in osbhlh98 mutants. Experiments using reporter constructs showed that OsbHLH98 is expressed on the adaxial side of lamina joints, consistent with its proposed function in regulating leaf angle. Furthermore, we established by chromatin immunoprecipitation and CUT&RUN that OsBUL1 is a direct downstream target of OsbHLH98. Transactivation assays and reverse transcription quantitative polymerase chain reaction (RT-qPCR) analysis indicated that OsbHLH98 represses OsBUL1 transcription. Our results demonstrate that OsbHLH98 negatively regulates leaf angle by counteracting brassinosteroid-induced cell elongation via the repression of OsBUL1 transcription. The characterization of OsbHLH98 and its role in determining leaf angle will lay the foundation to develop the ideal plant architecture for adaptation to high planting density.

The adaptation mechanism of a wild type (WT) and resistant type (Re) strain of the aerobic denitrifier Enterobacter cloacae strain HNR to short-term ZnO nanoparticle (NP) stresses was investigated. The results showed that Re maintained higher nitrite reductase (NIR) and nitrate reductase (NR) activities and showed lower increment of reactive oxygen species (ROS) than WT, under ZnO NP stresses. The affinity constant (KA) of WT to Zn2+ was 5.06 times that of Re, indicating that Re was more repulsive to Zn2+ released by ZnO NPs. Transcriptomic analysis revealed that the up-regulation of the nitrogen metabolism of Re helped maintain NIR and NR activities, that the enhancement of purine metabolism lowered the intracellular ROS increment, and that the up-regulation of cationic antimicrobial peptide resistance contributed to the lower KA of Re to Zn2+. These findings provided new insights into the adaptation mechanism of aerobic denitrifying bacteria to ZnO NPs.

Although it is well established that the Polycomb Group (PcG) complexes maintain gene repression through the incorporation of H2AK121ub and H3K27me3, little is known about the effect of these modifications on chromatin accessibility, which is fundamental to understand PcG function. Here, by integrating chromatin accessibility, histone marks and expression analyses in different Arabidopsis PcG mutants, we show that PcG function regulates chromatin accessibility. We find that H2AK121ub is associated with a less accessible but still permissive chromatin at transcriptional regulation hotspots. Accessibility is further reduced by EMF1 acting in collaboration with PRC2 activity. Consequently, H2AK121ub/H3K27me3 marks are linked to inaccessible although responsive chromatin. In contrast, only-H3K27me3-marked chromatin is less responsive, indicating that H2AK121ub-marked hotspots are required for transcriptional responses. Nevertheless, despite the loss of PcG activities leads to increased chromatin accessibility, this is not necessarily accompanied by transcriptional activation, indicating that accessible chromatin is not always predictive of gene expression., Polycomb Group complexes maintain gene repression through the incorporation of H2AK121ub and H3K27me3. Here, the authors show that H2AK121ub marks less accessible but transcriptionally permissive chromatin, while H3K27me3 enforces a repressed transcriptionally less-permissive state.

Green tea extract (GTE) is popular in weight loss, and epigallocatechin gallate (EGCG) is considered as the main active component. However, GTE is the primary cause of herbal and dietary supplement-induced liver injury in the United States. Whether there is a greater risk of liver injury when EGCG is consumed during dieting for weight loss has not been previously reported. This study found for the first time that EGCG could induce enhanced lipid metabolism pathways, suggesting that EGCG had the so-called “fat burning” effect, although EGCG did not cause liver injury at doses of 400 or 800 mg/kg in normal mice. Intriguingly, we found that EGCG caused dose-dependent hepatotoxicity on mice under dietary restriction, suggesting the potential combination effects of dietary restriction and EGCG. The combination effect between EGCG and dietary restriction led to overactivation of linoleic acid and arachidonic acid oxidation pathways, significantly increasing the accumulation of pro-inflammatory lipid metabolites and thus mediating liver injury. We also found that the disruption of Lands’ cycle and sphingomyelin-ceramides cycle and the high expression of taurine-conjugated bile acids were important metabolomic characteristics in EGCG-induced liver injury under dietary restriction. This original discovery suggests that people should not go on a diet while consuming EGCG for weight loss; otherwise the risk of liver injury will be significantly increased. This discovery provides new evidence for understanding the “drug-host” interaction hypothesis of drug hepatotoxicity and provides experimental reference for clinical safe use of green tea-related dietary supplements.

Sacha inchi (Plukenetia volubilis L.) is a shrub native to Amazon rainforests that’s of commercial interest as its seeds contain 35–60% edible oil (dry weight). This oil is one of the healthiest vegetable oils due to its high polyunsaturated fatty acid content and favourable ratio of omega-6 to omega-3 fatty acids. De novo transcriptome assembly and comparative analyses were performed on sacha inchi seeds from five stages of seed development in order to identifying genes associated with oil accumulation and fatty acid production. Of 30,189 unigenes that could be annotated in public databases, 20,446 were differentially expressed unigenes. A total of 14 KEGG pathways related to lipid metabolism were found, and 86 unigenes encoding enzymes involved in α-linolenic acid (ALA) biosynthesis were obtained including five unigenes encoding FATA (Unigene0008403), SAD (Unigene0012943), DHLAT (Unigene0014324), α-CT (Unigene0022151) and KAS II (Unigene0024371) that were significantly up-regulated in the final stage of seed development. A total of 66 unigenes encoding key enzymes involved in the synthesis of triacylglycerols (TAGs) were found, along with seven unigenes encoding PDCT (Unigene0000909), LPCAT (Unigene0007846), Oleosin3 (Unigene0010027), PDAT1 (Unigene0016056), GPDH (Unigene0022660), FAD2 (Unigene0037808) and FAD3 (Unigene0044238); these also proved to be up-regulated in the final stage of seed development.