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A series of novel methylated (–)-epigallocatechin-3-gallate-4β-triazolopodophyllotoxin derivatives is synthesized by utilizing the click reaction. Evaluation of their cytotoxicity against a panel of five human cancer cell lines (HL-60, SMMC-7721, A-549, MCF-7, and SW480) using the MTT assay shows that most of these compounds exhibit weak cytotoxicity. It is observed that compound 12 shows the highest activity against A-549 cells with an IC50 value of 10.27 ± 0.90 μM. Molecular docking results suggested that this compound 12 has a higher binding affinity for epidermal growth factor receptor than for tubulin. Our findings support the utility of compound 12 as a novel compound for the further development of anticancer agents.

Background Anterior cervical discectomy and fusion (ACDF) can induce lordosis and improve cervical sagittal vertical axis (SVA), but multilevel ACDF may inadvertently increase cervical SVA because of insufficient lordosis induction. Methods Patients who underwent 1-, 2-, or ≥3-level ACDF in the subaxial spine with minimum 2-year follow up were retrospectively studied. C2-C7 Cobb angle (lordosis), cervical SVA, and T1 slope were measured preoperatively, immediately postoperatively, and at last follow-up. Results Inclusion criteria were met by 127 patients. There were no differences in baseline demographics among 1-, 2-, and ≥3-level ACDF groups. Mean follow-up was 43.7 months (range, 24–142 months). Increase of cervical SVA immediately postoperatively was 1.94 mm, −1.44 mm, and 7.25 mm for 1-, 2-, and ≥3-level ACDF (P = 0.041) and at last follow-up was 2.97 mm, 0.70 mm, and 9.32 mm for 1-, 2-, and ≥3-level ACDF (P = 0.026). At last follow-up, 2-level ACDF patients had the greatest decrease in T1 slope (−0.43°) compared with increase of 2.71° for 1-level and 2.84° for ≥3-level patients (P = 0.028). In all 3 groups, segmental (ACDF levels) lordosis, cervical SVA, and T1 slope did not decrease from immediate postoperative to last follow-up. Only 2-level ACDF maintained C2-7 lordosis (2.16°) compared with loss of lordosis in 1-level (−0.84°) and ≥3-level (−2.00°) ACDF (P = 0.008) at last follow-up. Linear regression analysis showed that T1 slope had no relationship with correction of cervical SVA (P = 0.5310) but had a significant correlation with Cobb angle loss of C2-C7 lordosis (P = 0.0016). Conclusions Compared with 1- and 2-level ACDF, ≥3-level ACDF resulted in significant increase of cervical SVA and loss of overall lordosis. Compared with 1- and ≥3-level ACDF, 2-level ACDF had the greatest ability to maintain lordosis. T1 slope had a significant correlation with loss of C2-C7 lordosis after ACDF.

It is widely believed that information spread on social media is a percolation process, with parallels to phase transitions in theoretical physics. However, evidence for this hypothesis is limited, as phase transitions have not been directly observed in any social media. Here, through analysis of 100 million Weibo and 40 million Twitter users, we identify percolation-like spread, and find that it happens more readily than current theoretical models would predict. The lower percolation threshold can be explained by the existence of positive feedback in the coevolution between network structure and user activity level, such that more active users gain more followers. Moreover, this coevolution induces an extreme imbalance in users' influence. Our findings indicate that the ability of information to spread across social networks is higher than expected, with implications for many information spread problems., Comment: 15 pages, 3 figures

Rice is the most important food crop species of the developing world, and there are increasing concerns about food security to increase rice yields significantly. A 2-year field experiment was conducted in Chongqing, China, to evaluate differences in the characteristics of yield-related biomass accumulation and transport for extraheavy-panicle-type rice (ET), heavy-panicle-type rice (HT), and medium-panicle-type rice (MT) by measuring the biomass yield increase of different organs and total increase per stem of these rice types at all growth stages after booting. On the basis of the characteristics of yield-related biomass accumulation and transport, ET showed significantly higher biomass yield and harvest index than HT and MT did. There were significant positive correlations between biomass yield, harvest index and panicle weight of the analyzed rice cultivars. The higher biomass yield of ET was attributed to leaf area duration (LAD) and specific leaf weight duration (SLWD), which were significantly higher than those of HT and MT, and to leaf drooping angle duration (LDAD), which was significantly lower than that of HT and MT after the milking stage (MS). LDAD was more effective than LAD or SLWD for characterizing biomass yield. The relatively high harvest index of ET was due to the output amount (OA), output rate (OR) and transformation rate (TR) of photosynthate in the stems after the MS, and these values were significantly higher than those for HT and MT. TR was more effective than OA or OR of the stems for characterizing the harvest index. Thus, we believe that the LDAD of functional leaves and TR of photosynthate in the stems after the MS can be considered key indices for breeding ET cultivars in the future.

To investigate the potential benefits of acarbose therapy on cardiovascular events (CVD) in Type 2 diabetes (T2DM) in an urban community over 10-year follow-up. The study population of Beijing Community Diabetes Study (BCDS) were type 2 diabetes (T2DM) living in 21 communities in Beijing. All patients received comprehensive intervention in accordance with the Chinese guidelines for the prevention and treatment of diabetes. Professors in endocrinology from top tier hospitals regularly visited the communities for consultations, which was a feature of this study. A total of 1797 T2DM in BCDS study had complete screening data, including blood glucose, blood pressure, lipid profiles and acarbose continuous therapy. After 10-year follow-up, the risks of CVD outcomes were assessed according to whether patients had received acarbose therapy or not. All patients were followed-up to assess the long-term effects of the multifactorial interventions. At baseline, compared with the acarbose therapy free in T2DM, there was no significant difference in achieving the joint target control in patients with acarbose therapy. From the beginning of 8th year follow-up, the joint target control rate in patients with acarbose therapy was significantly higher than that of acarbose therapy free. During the 10-year follow-up, a total of 446 endpoint events occurred, including all-cause death, cardiovascular events, cerebrovascular events. The incidences of myocardial infarction (from the 4th year of follow-up) and all-cause death (from the 2nd year of follow-up) in patients who received acarbose therapy were significantly lower than that of acarbose therapy free respectively. In Cox multivariate analyses, there were significant differences in incidences of myocardial infarction and all-cause death between afore two groups during the 10-year follow-up, and the adjusted HRs were 0.50 and 0.52, respectively. After multifactorial interventions, T2DM with acarbose therapy revealed significant reductions of myocardial infarction and all-cause death. The long-term effects of with acarbose therapy on improving joint target control might be one of the main reasons of myocardial infarction and all-cause death reduction.Trial Registration: ChiCTR-TRC-13003978, ChiCTR-OOC-15006090.

The ADP-ribosylhydrolase ARH3 plays a key role in DNA damage repair, digesting poly(ADP-ribose) and removing ADP-ribose from serine residues of the substrates. Specific inhibitors that selectively target ARH3 would be a useful tool to examine DNA damage repair, as well as a possible strategy for tumor suppression. However, efforts to date have not identified any suitable compounds. Here, we used in silico and biochemistry screening to search for ARH3 inhibitors. We discovered a small molecule compound named ARH3 inhibitor 26 (AI26) as, to our knowledge, the first ARH3 inhibitor. AI26 binds to the catalytic pocket of ARH3 and inhibits the enzymatic activity of ARH3 with an estimated IC(50) of ∼2.41 μm in vitro. Moreover, hydrolysis of DNA damage–induced ADP-ribosylation was clearly inhibited when cells were pretreated with AI26, leading to defects in DNA damage repair. In addition, tumor cells with DNA damage repair defects were hypersensitive to AI26 treatment, as well as combinations of AI26 and other DNA-damaging agents such as camptothecin and doxorubicin. Collectively, these results reveal not only a chemical probe to study ARH3-mediated DNA damage repair but also a chemotherapeutic strategy for tumor suppression.

Stroke has become the most disabling and the second most fatal disease in the world. It has been a top priority to reveal the pathophysiology of stroke at cellular and molecular levels. A large number of long non-coding RNAs (lncRNAs) are identified to be abnormally expressed after stroke. Here, we summarize 35 lncRNAs associated with stroke, and clarify their functions on the prognosis through signal transduction and predictive values as biomarkers. Changes in the expression of these lncRNAs mediate a wide range of pathological processes in stroke, including apoptosis, inflammation, angiogenesis, and autophagy. Based on the exploration of the functions and mechanisms of lncRNAs in stroke, more timely, accurate predictions and more effective, safer treatments for stroke could be developed.

The number of coronavirus disease 2019 (COVID-19) cases has exceeded 10 million. However, little is known about the epidemiology and clinical characteristics of COVID-19 infants. We collected medical information of 46 confirmed patients (, Most of the 46 infants with coronavirus disease 2019 in this study experienced moderate disease, and the most common clinical symptoms were fever and cough. Cardiac injury and liver dysfunction were prominent complications in infant patients, but none had lymphocytosis.

Objective Following brain injury, the neurogenic niche provides a permissive cue for iatrogenesis rather than neurogenesis; reactive astrocytes play essential roles in orchestrating this process, markedly forming a glial scar around the area of damaged brain tissue. The objective of this study was to alter the neurogenic niche at the injured cortex and study its impact on neurogenesis. Methods We constructed a stromal cell-derived factor 1 (SDF-1) gradient matrix to attract reactive astrocytes to the glial scar core. Results SDF-1 reacted with the astrocytes in the injured site. By changing the neurogenic niche of the injured part of the brain after traumatic brain injury (TBI), SDF-1 downregulated thrombospondin 4 (Thbs4) promoting neuronal cell regeneration and playing a beneficial role in nerve function recovery after brain injury. Discussion The matrix we created in this study could attract and interact with reactive glial cells and, thus, we called it a glial pump. Using the glial pump, we identified a new mechanism of brain injury repair and neuronal regeneration after TBI, which relied on Thbs4 downregulation after the altered neurogenic niche promoted neuronal regeneration and functional recovery.

Ruxolitinib add-on in corticosteroid-refractory graft-vs-host disease after allogeneic stem cell transplantation: Results from a retrospective study on 38 Chinese patients

Introduction To date, research is lacking on the development of a cardiovascular disease (CVD) risk assessment tool for people with diabetes mellitus, in general, and for Chinese patients with diabetes in particular. We have explored CVD risk assessment tools for Chinese patients with diabetes. Here, we report our investigation of cardiovascular risk assessment using the improved Framingham Risk Score (I-FRS) in patients with type 2 diabetes mellitus (T2DM) in Beijing communities. Methods A total of 3232 patients with T2DM attending Beijing community health centers were enrolled in this study. FRS were used to predict CVD risk in all patients at baseline using the following risk scores for glycated hemoglobin (HbA1c) categories: 0 = HbA1c ≤ 7.0%; 1 = 7.0% 9.0%. The I-FRS was use to stratify all patients into low (I-FRS 20%) FRS strata. All treatments administered in the Beijing Communities Diabetes Study were in accordance with national guidelines for T2DM in China, and patients regularly attended clinical consultations with professors in endocrinology, who were experts in their respective speciality, from top tier hospitals. After 10 years, patients were followed-up to assess the long-term effects of the multifactorial interventions. Statistical analysis was performed using SAS® software (SAS Institute, Inc., Cary, NC, USA). Results The receiver operating characteristic curve of the I-FRS showed significant prediction accuracy for the actual incidence of CVD events. At baseline, subjects in the high FRS stratum for diabetes were more prone to be elderly and to have a longer duration of T2DM, higher systolic blood pressure, and higher lipid profiles. Subjects in the medium and high FRS strata had a higher incidence of CVD events than those in the no-complications group (DM group with no blood pressure issues) (P 20% was 12.5-fold higher than that of patients with I-FRS score

Simultaneous profiling of protein phosphorylation and glycosylation is very important to elucidate the bio-functions of these proteins. However, simultaneous enrichment of glyco- and phosphopeptides is the bottleneck in proteomics because of the low abundance of these species and ion suppression from non-modified peptides in mass spectrometry (MS). In this study, Fe3+ immobilized hydrophilic interaction chromatography (HILIC) materials (termed polySD-SiO2, recently reported in our lab) and polySD-SiO2 in the HILIC mode were employed for the simultaneous enrichment and subsequent separation of glyco- and phosphopeptides. The Fe3+ immobilized polySD-SiO2 could selectively enrich glycopeptides and phosphopeptides and the co-enriched peptides were further fractionated with polySD-SiO2 in the HILIC mode. With the established method, glyco- and phosphopeptides were well enriched and divided into two fractions even from tryptic digests of a-casein, fetuin and BSA at a molar ratio of 1 : 2 : 400. Application of the established method to HeLa cell lysate resulted in a total of 1903 phosphopeptides and 141 glycosylation sites. These results demonstrate that the established method could selectively and simultaneously enrich and fractionate glyco- and phosphopeptides from complex peptide mixtures.

Background Most colorectal cancer (CRC) patients are diagnosed at an advanced or metastatic stage with poor prognosis. Ubiquitin-specific protease 6 N-terminal-like protein (USP6NL) with high expression in CRC tissues regulates CRC cell proliferation via Wnt/β-catenin pathway. We hypothesized that USP6NL impacts CRC growth and inhibition of USP6NL may be a novel treatment strategy to improve CRC therapy. Methods USP6NL level in human CRC tissues and its association with tumor growth and metastasis were examined. Its roles and potential mechanisms in regulating tumor growth were studied by genetic and pharmacological manipulation of CRC cells in vitro and in vivo. Results Herein, we found that USP6NL was up-regulated in tumorous tissues of CRC patients. Our data suggested that knockdown of USP6NL in human CRC cell lines (HCT116 and LOVO cells) inhibited cell proliferation, induced G0/G1 cell cycle arrest, and prevented the tumorigenicity of HCT116 cells in nude mice, and which was associated with the prevention of Wnt/β-catenin pathway. On the contrary, USP6NL overexpression in human CRC cells (SW480) showed the opposite result. Our data suggested that the promoted cell proliferation, G1/S cell cycle progression, and the enhanced expression of β-catenin Cyclin D1 and C-myc while reduced P27 induced by the overexpression of USP6NL were significantly reversed by additional treatment of XAV939, indicating that activating Wnt/β-catenin pathway was the mechanism, by which USP6NL exerted carcinogenesis in CRC in vitro. Besides, our data suggested that knockdown of USP6NL increased the ubiquitination of β-catenin, indicating that USP6NL may serve as a deubiquitinase that regulated β-catenin accumulation in this process. Furthermore, 10058-F4 down-regulated USP6NL, inhibited CRC cell proliferation and induced cell cycle arrest. The result demonstrated a possible feedback loop between USP6NL, β-catenin and C-myc in regulating CRC cell growth. Conclusion USP6NL was an oncogene in CRC, and it may be a potential target for the treatment of CRC.

Background: Many inflammation-based markers have been reported their prognostic significance. Current study was designed to explore the prognostic value of albumin/globulin ratio (AGR), along with other inflammation-based markers, including neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR) and lymphocyte/monocyte ratio (LMR) in laryngeal squamous cell carcinoma (LSCC) patients. Method: This study was a retrospective analysis of the data related to 232 newly diagnosed LSCC patients. The potential prognostic factors were evaluated by univariate and multivariate survival analysis. The correlation between AGR and other prognostic factors were analyzed, and the area under the curve (AUC) were compared. Results: AGR, NLR, PLR and LMR were found to be associated with several aggressive clinicopathological features and poor prognosis. In multivariate analysis, AGR, NLR, PLR, LMR were independent prognostic markers of the shorter OS. However, NLR, PLR, and LMR showed no significance with the shorter DFS. AGR remained an independent prognostic marker for the shorter DFS. Furthermore, AGR was a superior prognosis factor than NLR, PLR, LMR in LSCC patients. Conclusion: AGR might be a promising marker to better predicting prognosis of LSCC patients. Future studies are warranted to validate our finding.

Uncoupling proteins (UCPs) belong to the family of mitochondrial transporter proteins and mediate regulated proton leak across the inner mitochondrial membrane. The UCPs play an important role in energy homeostasis and reactive oxygen species (ROS) release, and have been established as candidate genes for obesity, diabetes and hypertension. This study examined the possible association between the single nucleotide polymorphisms (SNPs) of UCP1–3 genes and essential hypertension (EH) in a northeastern Han Chinese population. A total of 2207 Chinese Han subjects were enrolled, including 1045 normotensives and 1162 hypertensives. Genotyping of UCP1 rs1800592, UCP1 rs12502572, UCP2 rs659366, UCP2 rs660339, and UCP3 rs3781907 was detected using Sequenom MassArray System. SHEsis was used to analyze linkage disequilibrium and haplotype. No evident association was observed between the genotype distributions and allele frequencies of individual SNPs and EH. Haplotype analysis showed the haplotype GAATA (rs1800592-rs12502572-rs659366-rs660339-rs3781907) was significantly associated with lower EH risk (p = 0.001, χ2 = 10.861, OR = 0.634, 95% CI = 0.483–0.833), and AGATG was associated with increased EH risk (p = 0.012, χ2 = 6.287, OR = 1.265, 95% CI = 1.052–1.521). These findings suggest haplotypes of UCP1–3 genes are linked to EH risk in a northeastern Han Chinese population. Further investigation with larger sample size in multiethnic population is needed to confirm our results.

Objective. The purpose of the study was to form a questionnaire of expert consensus about phlegm turbidity syndrome of coronary heart disease (CHD) using literature method and Delphi method, which could provide the objective evidences for the clinical diagnosis and treatment for CHD. Method. The CBM, CNKI, VIP, and PubMed were searched. The articles about phlegm turbidity syndrome for CHD with the definite related four diagnostic data were included. Based on the results of the literature method, two rounds of Delphi method were conducted. The TCM experts about CHD were enrolled. Concentration and coordination index of the experts were used to select the items. Results. Literature method: A total of 118 articles were included. Greasy fur, slippery pulse, chest fullness or chest pain, anorexia, nausea and vomiting, vertigo, excessive phlegm, abdominal fullness, head heaviness, obesity, stringy pulse, physical heaviness, soft pulse, somnolence, fatigue, and pale tongue (16 items) had the relatively high proportion, and they were eligible for Delphi process. Delphi method: A total of 93 experts (22 for the first round, 71 for the second round) were included. The reliability of the items was 0.885 for all the experts. The 16 items were not significantly different between the two rounds (P>0.05). According to the results of mean, frequency, sum of ranks and coefficient of variation, the item of nausea and vomiting, somnolence, pale tongue, and soft pulse were deleted. Conclusions. The questionnaire of phlegm turbidity syndrome of CHD was established, with good reliability. The sensitivity and specificity of the questionnaire are still necessary to further validate for clinical or scientific use.

Obesity increases the risk of developing cardiovascular disease and other metabolic diseases. We intended to compare three different anthropometric indicators of obesity, in predicting the incidence of cardiovascular events in Chinese type 2 diabetes. Beijing Community Diabetes Study was a prospective multi-center study conducted in Beijing community health centers. Type 2 diabetes patients from fourteen community health centers were enrolled at baseline. The primary endpoint was cardiovascular events. The upper quartile of neck circumference (NC) was set as greater NC. A total of 3299 diabetes patients were enrolled. In which, 941 (28.52%) had cardiovascular disease at baseline. Logistic analysis showed that central obesity (waist circumference (WC) above 90 cm in men and 85 cm in women) and greater NC were all related to baseline cardiovascular disease (adjusted OR = 1.49, and 1.55). After 10-year follow-up, 340 (10.31%) had cardiovascular events. Compared with patients without cardiovascular events, those having cardiovascular events had higher BMI, larger WC and NC. Cox regression analysis showed that greater WC and NC were all associated with the occurrence of cardiovascular events (adjusted HR = 1.41, and 1.38). A higher NC and WC might increase the risk of cardiovascular events by about 40% in type 2 diabetes patients in Beijing communities.

Colorectal cancer (CRC) is one of the most common malignant tumours in the world. Recent reports have revealed natural products displayed inhibition on colon cancer potential by suppressing transforming growth factor-β/Smads induced epidermal-mesenchymal transition (EMT). In this article, 12 kinds of natural berberine analogues were screened for their effects on the inhibition of the colon cancer cells, the results showed that demethyleneberberine (DM-BBR) exhibited an interesting and potential effect on inducing the apoptosis of HCT-116 cells with drug concentrations of 6, 12 and 18 μM. Particularly, DM-BBR reversed the EMT process by inhibiting the expression of p-Smad2 and p-Smad3 in the transforming growth factor-β/Smads signal pathway, up-regulated pro-apoptotic protein cleaved caspase-9, and blocked cell cycle at the S phase and increasing the expression of cyclin proteins P27 and P21. Taken together, these findings suggested that DM-BBR could promote apoptosis and suppress TGF-β/Smads induced EMT in the colon cancer cells HCT-116.

We report a case of coronavirus disease 2019 (COVID-19) after haploidentical transplantation with acute graft-versus-host disease (aGVHD). COVID-19 and aGVHD were improved under treatment with arbidol, remdesivir, methylprednisolone, and ruxolitinib. However, eventually, the patient died of septic shock and multiple organ failure. It was concluded that the disease condition of this COVID-19 patient after transplantation was serious, complex, and variable, with poor prognosis.

Radioactive iodine (RAI, 131I) therapy is the main treatment for thyroid carcinoma (TC). Long noncoding RNA (lncRNA)/microRNA (miR) competing endogenous RNA (ceRNA) networks have aroused great interest for their roles in gene expression. The present study aimed to investigate the effect of lncRNA SNHG7 on the growth and 131I resistance of TC. Differentially expressed lncRNAs in TC and paracancerous tissues were analyzed. The binding of miR‑9‑5p with small nucleolar RNA host gene 7 (SNHG7) and dipeptidyl‑peptidase 4 (DPP4) was identified. Gain‑ and loss‑of‑function analyses of SNHG7 and miR‑9‑5p were performed to determine their effects on the growth and 131I resistance of TC cells. The activity of the PI3K/Akt pathway was evaluated. Consequently, upregulated SNHG7 was revealed in TC tissues and correlated with 131I resistance. Silencing of SNHG7 or overexpressing miR‑9‑5p inhibited the growth and 131I resistance of TC cells. SNHG7 acted as a ceRNA of miR‑9‑5p to enhance DPP4 expression. Overexpressed SNHG7 increased DPP4 expression and activated the PI3K/Akt signaling pathway by sponging miR‑9‑5p. The in vitro results were reproduced in vivo. In summary, the present study provided evidence that the SNHG7/miR‑9‑5p/DPP4 ceRNA network could promote the growth and 131I resistance of TC cells via PI3K/Akt activation. The present study may offer novel options for TC treatment.

Triple negative breast cancer (TNBC) is characterized by lack of expression of the estrogen and progesterone receptors and HER2, which are common therapeutic targets. CDK4/6 inhibitor Palbociclib has been approved as an anti-cancer agent for breast cancer. However, identifying biomarkers that predict the response to Palbociclib has always been a challenge for molecular targeted therapy. In this study, we identify microRNA as a hallmark in TNBC patients and explore if miR-3613-3p might serve as a tumor suppressor biomarker for triple negative breast cancer patients and if overexpression of miR-3613-3p could enhance the sensitivity of TNBC cells to Palbociclib. We show that the expression of miR3613-3p was down-regulated in TNBC tumors and cells, and the overexpression of miR-3613-3p in patients’ tumor tissues was clinically and pathologically correlated with favorable prognosis, such as smaller tumor size and the lower Ki-67.In vitro, overexpression of miR-3613-3p inhibited cell proliferation, induced G1 cell-cycle arrest, and enhanced the sensitivity of TNBC cells to Palbociclib treatment.In vivostudy revealed that overexpression of miR-3613-3p inhibited TNBC tumorigenesis and exerted a significant inhibitory effect of Palbociclib on MDA-MB-231 cells. Mechanically, SMAD2 and EZH2 were found to be two direct targets of miR-3613-3p and mediate the proliferation of TNBC cells and the sensitivity of the cells to Palbociclib through inducing cellular senescence. Our findings suggested that miR-3613-3p acts as a cancer-suppressor miRNA in TNBC. Moreover, our study showed that miR-3613-3p might be used as a predictive biomarker for the response of TNBC to Palbociclib.

Highlights • Two subtypes with distinct default mode network profiles exist in major depression. • Subtypes of major depression are robust in validation datasets across brain atlases. • Hyper- & hypo-connectivity DMN subgroups have comparable clinical symptom variables. • Future studies should examine whether two subtypes have differing treatment response., Background Major depressive disorder (MDD) is heterogeneous disorder associated with aberrant functional connectivity within the default mode network (DMN). This study focused on data-driven identification and validation of potential DMN-pattern-based MDD subtypes to parse heterogeneity of the disorder. Methods The sample comprised 1397 participants including 690 patients with MDD and 707 healthy controls (HC) registered from multiple sites based on the REST-meta-MDD Project in China. Baseline resting-state functional magnetic resonance imaging (rs-fMRI) data was recorded for each participant. Discriminative features were selected from DMN between patients and HC. Patient subgroups were defined by K-means and principle component analysis in the multi-site datasets and validated in an independent single-site dataset. Statistical significance of resultant clustering were confirmed. Demographic and clinical variables were compared between identified patient subgroups. Results Two MDD subgroups with differing functional connectivity profiles of DMN were identified in the multi-site datasets, and relatively stable in different validation samples. The predominant dysfunctional connectivity profiles were detected among superior frontal cortex, ventral medial prefrontal cortex, posterior cingulate cortex and precuneus, whereas one subgroup exhibited increases of connectivity (hyperDMN MDD) and another subgroup showed decreases of connectivity (hypoDMN MDD). The hyperDMN subgroup in the discovery dataset had age-related severity of depressive symptoms. Patient subgroups had comparable demographic and clinical symptom variables. Conclusions Findings suggest the existence of two neural subtypes of MDD associated with different dysfunctional DMN connectivity patterns, which may provide useful evidence for parsing heterogeneity of depression and be valuable to inform the search for personalized treatment strategies.

Since December 2019, a novel coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly engulfed the world. Cancer patients infected with COVID-19 are considered to carry higher severity of the disease and higher mortality rate than common COVID-19 patients in previous studies. However, due to the poor clinical information on COVID-19 patients with cancer, the evidences that supported this conclusion are insufficient. At present, rather limited reports have analyzed the clinical data of breast cancer patients infected with COVID-19. Therefore, in this retrospective study, we described the clinical characteristics and the outcomes of 35 COVID-19 patients with breast cancer and compared 55 COVID-19 patients without cancer and 81 COVID-19 patients with other types of cancer as controls. Our data showed that there were no differences in disease severity and outcomes between the COVID-19 patients with breast cancer and the common COVID-19 patients, which was in contrast to previous studies. In addition, compared with other types of cancer patients, asymptomatic infections and mild cases among breast cancer patients made up a substantially larger proportion. Our results indicated that the clinical characteristics of breast cancer patients were milder than those of other types of cancer patients, but there were no significant differences in outcomes between the two groups.

The underlying molecular mechanisms that the hypoxic microenvironment could aggravate neuronal injury are still not clear. In this study, we hypothesized that the exosomes, exosomal miRNAs, and the mTOR signaling pathway might be involved in hypoxic peritumoral neuronal injury in glioma. Multimodal radiological images, HE, and HIF-1α staining of high-grade glioma (HGG) samples revealed that the peritumoral hypoxic area overlapped with the cytotoxic edema region and directly contacted with normal neurons. In either direct or indirect coculture system, hypoxia could promote normal mouse hippocampal neuronal cell (HT22) injury, and the growth of HT22 cells was suppressed by C6 glioma cells under hypoxic condition. For administrating hypoxia-induced glioma-derived exosomes (HIGDE) that could aggravate oxygen-glucose deprivation (OGD)/reperfusion neuronal injury, we identified that exosomes may be the communication medium between glioma cells and peritumoral neurons, and we furtherly found that exosomal miR-199a-3p mediated the OGD/reperfusion neuronal injury process by suppressing the mTOR signaling pathway. Moreover, the upregulation of miRNA-199a-3p in exosomes from glioma cells was induced by hypoxia-related HIF-1α activation. To sum up, hypoxia-induced glioma-derived exosomal miRNA-199a-3p can be upregulated by the activation of HIF-1α and is able to increase the ischemic injury of peritumoral neurons by inhibiting the mTOR pathway.

BackgroundThe prognostic value of Neutrophil-to-Lymphocyte Ratio (NLR) for the outcome of acute cervical traumatic spinal cord injury (tSCI) patients has rarely been studied by now throughout the world.MethodsWe performed a single-center retrospective cohort study to evaluate the prognostic value of NLR from peripheral whole blood count in patients with acute cervical tSCI. Patients within 6 h of acute cervical tSCI treated between Dec 2008 and May 2018 in Huashan Hospital of Fudan University were enrolled. Outcomes of patients with tSCI were assessed using American spinal injury association Impairment Scale (AIS). 6-month outcomes were dichotomized into poor outcome group (AIS A to C) and good outcome group (AIS D and E). Uni- and multivariate analyses were performed to assess the independent predictors of 6-month outcome. Two prediction models based on admission characteristics were built to evaluate the prognostic value of NLR. The discriminative ability of predictive models was evaluated using the area under the curve (AUC).ResultsA total of 377 patients were identified from our single center in China PR. Multivariate analysis showed that age, AIS grade at admission, NLR (p p = 0.003) were independent predictors of the 6-months outcome for acute cervical tSCI patients. The model combing NLR and standard variables (AUC = 0.944; 95% CI, 0.923–0.964) showed a more favorable prognostic value than that without NLR (AUC = 0.841; 95% CI, 0.798–0.885) in terms of 6-month outcome.ConclusionsNLR is firstly identified as an independent predictor of the 6-month outcome in acute cervical tSCI patients worldwide. The prognostic value of NLR is favorable, and a high NLR is associated with poor outcome in patients with acute cervical tSCI.

Neuropathic pain (NP) is a common complication that negatively affects the lives of patients with spinal cord injury (SCI). The disruption in the balance of excitatory and inhibitory neurons in the spinal cord dorsal horn contributes to the development of SCI and induces NP. The calcium-binding protein (CaBP) calbindin-D 28K (CaBP-28K) is highly expressed in excitatory interneurons, and the CaBP parvalbumin (PV) is present in inhibitory neurons in the dorsal horn. To better define the changes in the CaBPs contributing to the development of SCI-induced NP, we examined the changes in CaBP-28K and PV staining density in the lumbar (L4-6) lamina I and II, and their relationship with NP after mild spinal cord contusion injury in mice. We additionally examined the effects of alternate thermal stimulation (ATS). Compared with sham mice, injured animals developed mechanical allodynia in response to light mechanical stimuli and exhibited mechanical hyporesponsiveness to noxious mechanical stimuli. The decreased response latency to heat stimuli and increased response latency to cold stimuli at 7 days post injury suggested that the injured mice developed heat hyperalgesia and cold hypoalgesia, respectively. Temperature preference tests showed significant warm allodynia after injury. Animals that underwent ATS (15-18 and 35-40°C; +5 minutes/stimulation/day; 5 days/week) displayed significant amelioration of heat hyperalgesia, cold hypoalgesia, and warm allodynia after 2 weeks of ATS. In contrast, mechanical sensitivity was not influenced by ATS. Analysis of the CaBP-28K positive signal in L4-6 lamina I and II indicated an increase in staining density after SCI, which was associated with an increase in the number of CaBP-28K-stained L4-6 dorsal root ganglion (DRG) neurons. ATS decreased the CaBP-28K staining density in L4-6 spinal cord and DRG in injured animals, and was significantly and strongly correlated with ATS alleviation of pain behavior. The expression of PV showed no changes in lamina I and II after ATS in SCI animals. Thus, ATS partially decreases the pain behavior after SCI by modulating the changes in CaBP-associated excitatory-inhibitory neurons.

The influenza pandemic causes a large number of hospitalizations and even deaths. There is an urgent need for an efficient and effective method for detecting the outbreak of influenza so that timely, appropriate interventions can be made to prevent or at least prepare for catastrophic epidemics. In this study, we proposed a computational method, the shortest-path-based dynamical network marker (SP-DNM), to detect the pre-outbreak state of influenza epidemics by monitoring the dynamical change of the shortest path in a city network. Specifically, by mapping the real-time information to a properly constructed city network, our method detects the early-warning signal prior to the influenza outbreak in both Tokyo and Hokkaido for consecutive 9 years, which demonstrate the effectiveness and robustness of the proposed method.

Aim PAX6 is a transcription factor involved in embryonic development of many organs, including the eyes and the pancreas. Mutations of PAX6 gene is the main cause of a rare disease, congenital aniridia (CA). This case-control study aims to investigate the effects of PAX6 mutations on glucose metabolism and insulin secretion in families with CA. Methods Twenty-one families with CA were screened by Sanger sequencing. Patients with PAX6 mutations and CA (cases) and age-matched healthy family members (controls) were enrolled. Oral glucose tolerance test (OGTT) were performed to detect diabetes or impaired glucose tolerance (IGT). Insulin and proinsulin secretion were evaluated. Results Among 21 CA families, heterozygous PAX6 mutations were detected in five families. Among cases (n=10) from the five families, two were diagnosed with newly identified diabetes and another two were diagnosed with IGT. Among controls (n=12), two had IGT. The level of HbA1c were 36 ± 4 mmol/mol (5.57 ± 0.46 %) and 32 ± 5 mmol/L (5.21 ± 0.54 %) in the cases and the controls, respectively (P = 0.049). More importantly, levels of proinsulin in the cases were significantly higher than that of the controls, despite similar levels of total insulin. The areas under the curve (AUCs) of proinsulin in the cases (6425 ± 4390) were significantly higher than that of the controls (3709 ± 1769) (P = 0.032). Conclusion PAX6 may participate in the production of proinsulin to insulin and heterozygous PAX6 mutations may be associated with glucose metabolism in CA patients.

The aim of this study was to investigate the effect of enhanced recovery after surgery (ERAS) on perioperative outcomes, with an emphasis on patient-reported outcomes (PROs) and functional recovery. We compared the clinical outcomes in a cohort of 275 patients undergoing liver resection before and after the implementation of ERAS. The PROs were preoperatively and postoperatively compared until 14 days after surgery using the MD Anderson Symptom Inventory. The patients in the ERAS group experienced fewer symptoms and a shorter functional recovery time than the patients in the non-ERAS group. The group × time interactions were different between the groups for pain (F = 4.70, P = .001) and walking (F = 2.75, P = .03). On the 3rd, 4th, and 5th days after surgery, the ERAS group experienced less pain and more walking than the non-ERAS group. The ERAS group experienced less fatigue (0.407 [95% confidence interval, CI: −0.795, −0.020], P = .035), less sleep interference (0.615 [95% CI: −1.215, −0.014], P = .045), a lower rate of reduced appetite (0.281 [95% CI: −0.442, −0.120], P = .001), and less abdominal distension (0.262 [95% CI: −0.504, −0.020], P = .034) than the non-ERAS group. Those in the ERAS group had a significantly shorter median time from surgery to mild fatigue (5.41 vs 6.87 days, P = .003), mild pain (4.45 vs 6.09 days, P = .001), mild interference when walking (3.85 vs 5.54 days, P < .001), and mild interference when sleeping (5.49 vs 7.43 days, P < .001). ERAS patients were more likely than non-ERAS patients to achieve a functional recovery (5.70 vs 6.79 days, P < .001) status in a shorter time period. The ERAS pathway, operation time, and the minimally invasive approach were independent predictors of functional recovery time. In hepatocellular carcinoma liver resection patients, the primary mechanism of ERAS is to reduce the postoperative interference burden and promote rapid functional recovery.

Axin1 is a negative regulator of β-catenin signaling and its role in osteoblast precursor cells remains undefined. In the present studies, we determined changes in postnatal bone growth by deletion of Axin1 in osteoblast precursor cells and analyzed bone growth in newborn and postnatal Axin1Osx mice and found that hypertrophic cartilage area was largely expanded in Axin1Osx KO mice. A larger number of chondrocytes and unabsorbed cartilage matrix were found in the bone marrow cavity of Axin1Osx KO mice. Osteoclast formation in metaphyseal and subchondral bone areas was significantly decreased, demonstrated by decreased TRAP-positive cell numbers, associated with reduction of MMP9- and cathepsin K-positive cell numbers in Axin1Osx KO mice. OPG expression and the ratio of Opg to Rankl were significantly increased in osteoblasts of Axin1Osx KO mice. Osteoclast formation in primary bone marrow derived microphage (BMM) cells was significantly decreased when BMM cells were cultured with conditioned media (CM) collected from osteoblasts derived from Axin1Osx mice compared with BMM cells cultured with CM derived from WT mice. Thus, the loss of Axin1 in osteoblast precursor cells caused increased OPG and the decrease in osteoclast formation, leading to delayed bone growth in postnatal Axin1Osx KO mice.

Background: Major depressive disorder (MDD) is known to be characterized by altered brain functional connectivity (FC) patterns. However, whether and how the features of dynamic FC would change in patients with MDD are unclear. In this study, we aimed to characterize dynamic FC in MDD using a large multi-site sample and a novel dynamic network-based approach. Methods: Resting-state functional magnetic resonance imaging (fMRI) data were acquired from a total of 460 MDD patients and 473 healthy controls, as a part of the REST-meta-MDD consortium. Resting-state dynamic functional brain networks were constructed for each subject by a sliding-window approach. Multiple spatio-temporal features of dynamic brain networks, including temporal variability, temporal clustering and temporal efficiency, were then compared between patients and healthy subjects at both global and local levels. Results: The group of MDD patients showed significantly higher temporal variability, lower temporal correlation coefficient (indicating decreased temporal clustering) and shorter characteristic temporal path length (indicating increased temporal efficiency) compared with healthy controls (corrected p < 3.14×10−3). Corresponding local changes in MDD were mainly found in the default-mode, sensorimotor and subcortical areas. Measures of temporal variability and characteristic temporal path length were significantly correlated with depression severity in patients (corrected p < 0.05). Moreover, the observed between-group differences were robustly present in both first-episode, drug-naïve (FEDN) and non-FEDN patients. Conclusions: Our findings suggest that excessive temporal variations of brain FC, reflecting abnormal communications between large-scale bran networks over time, may underlie the neuropathology of MDD.

BACKGROUND Long non-coding RNAs (lncRNAs) were recently identified as crucial regulators of papillary thyroid cancer (PTC). However, the clinical role and regulatory functions of lncRNA cancer susceptibility candidate 2 (CASC2) in PTC remain unknown. METHODS LncRNA CASC2 expression was examined in plasma samples from 68 PTC patients and 39 patients with nodular goiter (NG). Cell proliferation, migration and invasion abilities were evaluated using CCK8 assay and transwell migration and invasion assay. QRT-PCR and western blot analysis were performed to detect the expression of epithelial-to-mesenchymal (EMT) markers ZEB1, E-cadherin and vimentin in PTC cells. RESULTS We demonstrated that lncRNA CASC2 expression was significantly downregulated in tumor tissues and plasma samples in patients with PTC compared with those in nodular goiters (P< 0.05). Decreased plasma lncRNA CASC2 expression associated with lymph node metastasis (LNM) of PTC patients and was identified as an independent risk for patients with LNM (P< 0.05). Furthermore, functional assays demonstrated that overexpression of lncRNA CASC2 inhibited cell proliferation, migration and invasion of PTC. Moreover, we demonstrated that overexpression of lncRNA CASC2 suppressed cell epithelial-mesenchymal transition (EMT) process of PTC by increasing the E-cadherin expression, but downregulating ZEB1 and N-cadherin expression. CONCLUSIONS Thus, these results indicated that lncRNA CASC2 was a predictor for LNM of PTC patients and may serve as a potential target of PTC treatment.

Objective To investigate the BRCA status in Chinese patients with ovarian cancer (OC). Though there were two large prevalence studies in Chinese OC patients, this was the first time to observe it in healthy controls. Methods We performed BRCA mutation screening using next-generation sequencing to determine the prevalence of BRCA germline deleterious mutations in an unselected cohort of Chinese OC patients (n = 1331) versus healthy controls (n = 1763) and describe the types and spectrum of BRCA deleterious variants. Results Among the 1331 patients with OC, 227 (17.1%) carried deleterious variants in BRCA1 and 70 (5.3%) carried deleterious variants in BRCA2. Of 1763 control subjects, 6 (0.3%) and 2 (0.1%) had deleterious variants in BRCA1 and BRCA2. No patient carried mutations in both BRCA1 and BRCA2 simultaneously. Sixty-three novel mutations were identified, and three Chinese specific hot-spot mutations were notified as BRCA1 c.5470_5477delATTGGGCA, BRCA1 c.981_982delAT, and BRCA1 c.3770_3771delAG. Interestingly, all these high-frequency recurrent mutations were distributed on exon 10, which may also be the Chinese OC BRCA mutations' distinct characteristics. In addition, in our study, the estimated odds ratio (OR) of OC associated with BRCA1 positive variants were approximately 34.6 (95% CI, 12.5–95.7) in age group under 40 and 42.4 (95% CI, 5.9–305.2) in group older than 50 in the Chinese population, respectively. Conclusions We recommend BRCA testing to all Chinese OC patients and those general Chinese who have family members with hereditary breast and ovarian related cancer (HBOC)-related cancers. Variants carriers would not only benefit from early prevention of OC but also for the medical management.

Objective Spinal cord intramedullary cavernous malformation (SICM) is kind of rare vascular disease, and the therapeutic strategy is still under debate. The purpose of this article is to analyze outcome of SICM surgical resection and to find the possible factors indicating a better outcome. Methods A retrospective analysis of 83 patients with SICM in a single center from 2005 to 2017 was performed. Neurologic status was assessed using the McCormick Scale. Clinical information was collected and analyzed using multivariate logistic regression analysis. Results Eighty patients with SICM were included, 48% of whom were male (n = 40). The mean age was 39.0 years; 7% of patients (n = 6) had a family history and 4% of patients (n = 3) had multiple lesions; and 41% (n = 34) were found with definite hemorrhage. Before surgery, neurologic status of the patients was 43.4%, 31.3%, 13.3%, and 12.0% in grades I (n = 36), II (n = 26), III (n = 11), and IV (n = 10), respectively. Sixty-three patients received long-term follow-up, of whom 19 improved, 39 remained in stable condition, and 5 deteriorated. Patients with duration of symptoms less than 3 months showed a higher improved outcome rate than those with duration longer than 3 months. Conclusions The finding suggests that if total resection of SICM is achievable, surgical therapy could be considered to avoid risks of severe complications followed by lesion bleeding. Early microsurgical resection (usually within 3 months) for patients with SICM can lead to better clinical outcomes.

Over the last two decades, it has become increasingly apparent that Wnt signaling plays a critical role in development and adult tissue homeostasis in multiple organs and in the pathogenesis of many diseases. In particular, a crucial role for Wnt signaling in bone development and bone tissue homeostasis has been well recognized. Numerous genome-wide association studies (GWASs) confirmed the importance of Wnt signaling in controlling bone mass. Moreover, ample evidence suggests that Wnt signaling is essential for kidney, intestine, and adipose tissue development and homeostasis. Recent emerging evidence demonstrates that Wnt signaling may play a fundamental role in the aging process of those organs. New discoveries show that bone is not only the major reservoir for calcium and phosphate storage, but also the largest organ with multiple functions, including mineral and energy metabolism. The interactions among bone, kidney, intestine, and adipose tissue are controlled and regulated by several endocrine signals, including FGF23, klotho, sclerostin (SOST), osteocalcin, vitamin D, and leptin. Since the aging process is characterized by structural and functional decline in almost all tissues and organs, understanding the Wnt signaling–related interactions among bone, kidney, intestine, and adipose tissue in aging may shed light on the pathogenesis of age-related diseases.

Temperature distributions inside a living cell reflect the thermodynamics and functions of cellular components. We used a newly-developed method of mitochondrial thermometry based on Rhodamine B methyl ester, which equilibrates as a thermosensitive mixture of nonfluorescent and fluorescent resonance forms. Prostaglandin E2 (PGE2) is released from hepatic non-parenchymal Kupffer cells and acts as an inflammatory factor to impact various functions of hepatocytes. The activity of PGE2 on energy mechanism of hepatocytes has not been fully elucidated and in particular, which PGE2 receptor mediates the functions has been elusive. We identified EP4 as the major receptor of PGE2 via our mitochondrion-thermometry approach and then substantiated this receptor’s role in hepatic metabolism. We discovered that PGE2 is able to decrease intracellular temperature of hepatocytes, via increasing some lipogenic genes’ expressions, hampering lipolysis and mitochondrial β-oxidation, reducing intracellular ATP level and elevating cAMP level through EP4 receptor. The redox status of hepatocytes represented by FAD vs FAD + NADH ratio is influenced by PGE2 in an EP4 receptor-dependent manner. Collectively, these data demonstrate that PGE2 regulates metabolism of hepatocytes mainly through EP4 receptor.

Xue-Lian Zhang,1 Ming-Xia Yuan,1 Gang Wan,2 Guang-Ran Yang,1 Dong-Mei Li,3 Han-Jing Fu,1 Liang-Xiang Zhu,1 Rong-Rong Xie,1 Jian-Dong Zhang,4 Yu-Jie Lv,5 Yu-Ling Li,6 Xue-Ping Du,7 Zi-Ming Wang,8 Xue-Li Cui,9 De-Yuan Liu,10 Ying Gao,11 Shu-Yan Cheng,12 Qian Wang,13 Yu Ji,14 Guang-Wei Li,15,16 Shen-Yuan Yuan1 1Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Medical Records and Statistics Department, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China; 3Clinical and Translational Science Institute, School of Medicine and Dentistry, University of Rochester, Rochester, NY, USA; 4Department of General Practice, Jinsong Community Health Service Center, Beijing, People’s Republic of China; 5Department of General Practice, Cuigezhuang Community Health Service Center, Beijing, People’s Republic of China; 6Department of General Practice, Xinjiekou Community Health Service Center, Beijing, People’s Republic of China; 7Department of General Practice, Yuetan Community Health Service Center of Fuxing Hospital, Capital Medical University, Beijing, People’s Republic of China; 8Department of General Practice, Jiangtai Community Health Service Center, Beijing, People’s Republic of China; 9Department of General Practice, Sanlitun Community Health Service Center, Beijing, People’s Republic of China; 10Department of General Practice, Zuojiazhuang Community Health Service Center, Beijing, People’s Republic of China; 11Department of General Practice, The First People’s Hospital of Chongwen District, Beijing, People’s Republic of China; 12Department of General Practice, Balizhuang Community Health Service Center, Beijing, People’s Republic of China; 13Department of General Practice, Majiapu Community Health Service Center, Beijing, People’s Republic of China; 14Department of Endocrinology, Beijing Aerospace General Hospital, Beijing, People’s Republic of China; 15Department of Endocrinology, China-Japan Friendship Hospital, Beijing, People’s Republic of China; 16Center of Endocrinology and Cardiovascular Disease, Department of Endocrinology, National Center of Cardiology and Fuwai Hospital, Beijing, People’s Republic of China Objective: It is well known that diabetic kidney disease is a risk factor for cardiovascular diseases (CVD) in patients with type 2 diabetes mellitus (T2DM). In this study, the effects of urine albumin excretion rate (AER) and estimated glomerular filtration rate (eGFR) on CVD outcomes were analyzed in a population of T2DM. Methods: The study was carried out using recorded information of a cohort study. A total of 1,914 patients with T2DM with no prevalent CVD were enrolled in an 8 years prospective study and received multifactorial intervention. The risk of CVD outcomes was assessed according to chronic kidney disease staging, which was categorized using AER (mg/d) and eGFR (mL/min/1.73 m2). The effects of AER and eGFR on risk of CVD onset were also analyzed. Results: During the follow-up period (median 6.8 years), 71 CVD events occurred. At baseline, those with AER ≥300 mg/d and coexisting eGFR 60–89 mL/min/ 1.73 m2 or

53BP1 performs essential functions in DNA double-strand break (DSB) repair and it was recently reported that Tudor interacting repair regulator (TIRR) negatively regulates 53BP1 during DSB repair. Here, we present the crystal structure of the 53BP1 tandem Tudor domain (TTD) in complex with TIRR. Our results show that three loops from TIRR interact with 53BP1 TTD and mask the methylated lysine-binding pocket in TTD. Thus, TIRR competes with histone H4K20 methylation for 53BP1 binding. We map key interaction residues in 53BP1 TTD and TIRR, whose mutation abolishes complex formation. Moreover, TIRR suppresses the relocation of 53BP1 to DNA lesions and 53BP1-dependent DNA damage repair. Finally, despite the high-sequence homology between TIRR and NUDT16, NUDT16 does not directly interact with 53BP1 due to the absence of key residues required for binding. Taken together, our study provides insights into the molecular mechanism underlying TIRR-mediated suppression of 53BP1-dependent DNA damage repair.

N-Acetylgalactosaminyltransferase-14 (GALNT14) is a member of acetylgalactosaminyltransferases family. We have shown that GALNT14 could promote breast cancer cell invasion. However, the underlying molecular mechanism is unclear. Here, using yeast two hybrid, we find that EGF-containing fibulin-like extracellular matrix protein 2 (EFEMP2) interacts with GALNT14. Both in vitro and in vivo binding assays show that EFEMP2 is associated with GALNT14. Moreover, we find that GALNT14 mediates glycosylation of EFEMP2. EFEMP2 significantly increased the invasion ability of breast cancer cells including MCF-7 and MBA-MD-231 cells, and this phenomenon is suppressed by knockdown expression of GALNT14. In addition, the GALNT14-dependent O-glycosylation of EFEMP-2 regulates the stability of EFEMP-2 protein in breast cancer cells. Taken together, our results demonstrate a novel molecular mechanism underlying breast cancer invasion.

Alpha-lipoic Acid(ALA), an endogenous short-chain fatty acid, has been found inducing a protective effect against ischemia and reperfusion(I/R) injury. Recently, mTOR signaling pathway has been proved to involve in the mechanism of I/R injury. In our previous study, we determined that ALA could protect cerebral endothelial cells against I/R injury via mTOR signaling pathway. However, whether ALA can protect against brain I/R injury in vivo and its mechanisms is uncertain. In this study, we try to explore if the ALA treatment can protect against brain I/R injury and confirm the relationship between ALA and mTOR signaling pathway. ALA was administrated to the animals after dMCAo and reperfusion model established with or without rapamycin pre-treatment. The results showed the infarct size was obviously reduced after ALA treatment in acute stage, neurological functions were also improved distinctly. The mTOR signaling pathway was remarkably blocked after brain I/R injury while it could be activated through ALA treatment. However, rapamycin, can abolish the protective effects induced by ALA treatment in both acute and long-term phase. In conclusion, we demonstrate the protective effects induced by ALA treatment against the brain I/R injury in rats and mTOR signaling pathway is required for the protective effects of ALA against brain I/R injury. The results might contribute to the potential clinical application of ALA and provide a potential therapeutic target on ischemic stroke.

Cancer vaccines mostly aim to induce cytotoxic T lymphocytes (CTLs) against tumors. An appropriate adjuvant is of fundamental importance for inducing cellular immune response. Since the antigen in particulate form is substantially more immunogenic than soluble form antigen, it is beneficial to interact with antigen-presenting cells membrane to induce robust CD8+ T cell activation following vaccination. Based on previous research, we designed an adjuvant formulation by combining Astragalus saponins, cholesterol, and liposome to incorporate antigen into a particulate delivery system, so as to enhance cellular immune response. Meanwhile, angiogenesis contributes to tumor growth and metastasis, and basic fibroblast growth factor (bFGF) is involved in tumor angiogenesis. Therefore, using lipo-saponins adjuvant formulation and a human recombinant bFGF antigen protein, we tried to induce bFGF-specific CTL response to inhibit tumor angiogenesis to achieve antitumor activity. After five immunizations, the lipo-saponins/bFGF complex elicited robust antibody response and markedly higher amount of interferon-γ in BALB/c mice, resulting in superior antitumor activities. Decreased microvessel density in CD31 immunohistochemistry and the lysis of vascular endothelial cells by the T lymphocytes from the immunized mice indicated that the immunity inhibited the angiogenesis of tumors and further led to the inhibition of tumors. Our data suggest that the approach to construct adjuvant formulation between liposome and Astragalus saponins appeared highly desirable, and that Astragalus saponins may be utilized as a valuable additive for enhancing the effectiveness of vaccines and stimulating an appropriate immune response that can benefit tumor therapy.

Lectin inspired polymers were prepared through modification of silica microspheres with Ser-Asp (SD). This functional polymer showed distinct adsorption and retention towards different disaccharides and demonstrated high-efficiency enrichment of glycopeptides.

Lung cancer is one of the most commonly occurring cancer mortality worldwide. The epidermal growth factor receptor (EGFR) plays an important role in cellular functions and has become the new promising target. Natural products and their derivatives with various structures, unique biological activities, and specific selectivity have served as lead compounds for EGFR. D-glucose and EGCG were used as starting materials. A series of glucoside derivatives of EGCG (7–12) were synthesized and evaluated for their in vitro anticancer activity against five human cancer cell lines, including HL-60, SMMC-7721, A-549, MCF-7, and SW480. In addition, we investigated the structure-activity relationship and physicochemical property–activity relationship of EGCG derivatives. Compounds 11 and 12 showed better growth inhibition than others in four cancer cell lines (HL-60, SMMC-7721, A-549, and MCF), with IC50 values in the range of 22.90–37.87 μM. Compounds 11 and 12 decreased phosphorylation of EGFR and downstream signaling protein, which also have more hydrophobic interactions than EGCG by docking study. The most active compounds 11 and 12, both having perbutyrylated glucose residue, we found that perbutyrylation of the glucose residue leads to increased cytotoxic activity and suggested that their potential as anticancer agents for further development.

Postaxial limb hypoplasia (PALH) is a group of nonhereditary diseases with congenital lower limb deficiency affecting the fibular ray, including fibular hemimelia, proximal femoral focal deficiency, and tarsal coalition. The etiology and the developmental biology of the anomaly are still not fully understood. Here, we review the previous classification systems, present the clinical features, and discuss the developmental biology of PALH.

Mitochondrion is the main intracellular site for thermogenesis and attractive energy expenditure targeting for obesity therapy. Here, we develop a method of mitochondrial thermometry based on Rhodamine B methyl ester, which equilibrates as a thermosensitive mixture of nonfluorescent and fluorescent resonance forms. Using this approach, we are able to demonstrate that the efficacy of norepinephrine-induced thermogenesis is low, and measure the maximum transient rate of temperature increase in brown adipocytes. Electronic Supplementary Material The online version of this article (doi:10.1007/s41048-017-0039-6) contains supplementary material, which is available to authorized users.

Background Pituitary stalk thickening (PST) used as an imaging diagnosis plays a major role in diagnosis and treatment of the hypothalamus and pituitary disease at an early stage. Up until now, several lines of systematic investigations have been conducted among adolescents, and the results indicated that PST is possibly one of the principal early manifestations of sellar region tumor. To characterize the major clinical features of PST and to identify the most effective treatments we conducted this study. Methods This was a retrospective review of patients with PST evaluated at Huashan Hospital over an eight-year period between 2007 and 2014. One hundred fifty nine patients who were diagnosed PST were included. The data including demographics, clinical presentations, imaging examinations, laboratory results and surgery were thoroughly reviewed and carefully analyzed. According to their clinical presentations and examinations, relevant treatments were adopted and different prognosis were observed. Results Of the 159 patients, 57 were males and 102 were females (median age was 29 and 43.4% were under the age of 21 years). And of the patients in the age group between 30 and 35 years, 84% were females. “Polydipsia and polyuria” was the most common clinical manifestation observed in 90 cases (>50%). 49.5% of the patients were diagnosed to have at least one anterior pituitary dysfunction. The sellar region MRI (SR-MRI) data showed that patients who had different clinical presentations or pituitary function showed different SR-MRI appearance. Over 60% patients who performed follow-up MRI showed shrunken PST. Fourteen cases who received radiotherapy appeared to be improved as shown by MRI. Conclusions PST is most commonly seen in the teenagers and the women of reproductive age. Distinct etiology may be identified based on the clinical manifestations, age and SR-MRI, which would help to make the final decision for treatments. Radiotherapy and immuno-suppressed therapy are effective in alleviating clinical symptoms and shrinking the stalk thickening.

Spinal cord ischemia–reperfusion (I/R) injury is a severe clinical condition, while the mechanism is still not clarified and the therapeutic approach is limited. Ischemia post-conditioning (PC) has been found to have the protective effects against I/R injury in brain. Recently p53 has been reported to take part in the regulation and protection of I/R injury. We hypothesize that PC has the protective effects in primary cultured spinal cord neurons against ischemia–reperfusion injury, and MDM2-p53 signaling pathway may involve in its protective mechanism. In this study, we used an OGD (oxygen and glucose deprivation)-reperfusion model in primary cultured spinal cord neurons to simulate the I/R injury of spinal cord in vitro, and PC was conducted by 3 cycles of 15 min restoration of glucose and oxygen with 15 min OGD, followed by 6 h fully restoration as reperfusion. Lentiviral vectors were used to knock down MDM2 or over-express p53 genes in primary cultured spinal cord neurons. The results showed that 3 cycles of 15 min PC generated the most significant protective effects in primary cultured spinal cord neurons against OGD-reperfusion injury. The levels of MDM2 were decreased while p53, Bax, and cleaved Caspase 3 were increased under OGD-reperfusion condition. PC could significantly reverse the down-regulation of MDM2 and up-regulation of p53, Bax, and cleaved Caspase 3 by OGD-reperfusion injury. Moreover, MDM2 knockdown or p53 over-expression could induce the cleaved Caspase 3 expression and blocked the protective effects of PC in primary cultured spinal cord neurons against OGD-reperfusion injury. In conclusion, our work demonstrated that MDM2-p53 pathway plays a pivotal role in the protective effect of PC against OGD-reperfusion injury and PC may be a feasible therapy strategy in the treatment for spinal cord I/R injury.

AV1 is the next-generation open video coding format, and it can achieve significant coding efficiency with novel coding tools. It supports Lagrangian rate distortion optimization (RDO) method to optimize the coding performance. However, the distortion and the Lagrangian multiplier used in RDO ignore the characteristics of human visual system (HVS), which leads to insufficiency for perceptual video coding. To solve this problem, a perceptual RDO scheme based on the Just Noticeable Distortion (JND) threshold of HVS is proposed. The JND for each pixel is first measured according to three perceptual features: luminance adaptation, masking effects and structure sensitivity. Based on the observation that the regions with smaller distortion visibility thresholds are more sensitive to HVS, a JND-based Lagrangian multiplier is derived to adaptively adjust the rate-distortion (RD) performance for each coding block. Experiments demonstrate that the proposed method can achieve an average SSIM-based −3.93% BD-Rate saving compared with the original AV1 encoder, which effectively improve the coding performance.

Hyperglycemia, a key characteristic and risk factor for diabetes mellitus (DM), causes neuronal senescence. Hydrogen sulfide (H2S) is a novel neuroprotectant. The present work was to investigate the potential effect of H2S on hyperglycemia-induced neuronal senescence and the underlying mechanisms. We found that NaHS, a donor of H2S, inhibited high glucose (HG)-induced cellular senescence in HT22 cells (an immortalized mouse hippocampal cell line), as evidenced by a decrease in the number of senescence associated-β-galactosidase (SA-β-gal) positive cells, increase in the growth of cells, and down-regulations of senescence mark proteins, p16INK4a and p21CIP1. NaHS improved the autophagic flux, which is judged by a decrease in the amount of intracellular autophagosome as well as up-regulations of LC3II/I and P62 in HG-exposed HT22 cells. Furthermore, blocked autophagic flux by chloroquine (CQ) significantly abolished NaHS-exerted improvement in the autophagic flux and suppression in the cellular senescence of GH-exposed HT22 cells, which indicated that H2S antagonizes HG-induced neuronal senescence by promoting autophagic flux. We also found that NaHS up-regulated the expression of silent mating type information regulation 2 homolog 1 (SIRT1), an important anti-aging protein, in HG-exposed HT22 cells. Furthermore, inhibition of SIRT1 by sirtinol reversed the protection of H2S against HG-induced autophagic flux blockade and cellular senescence in HT22 cells. These data indicated that H2S protects HT22 cells against HG-induced neuronal senescence by improving autophagic flux via up-regulation of SIRT1, suggesting H2S as a potential treatment strategy for hyperglycemia-induced neuronal senescence and neurotoxicity.

The definition of consciousness remains a difficult issue that requires urgent understanding and resolution. Currently, consciousness research is an intensely focused area of neuroscience. However, to establish a greater understanding of the concept of consciousness, more detailed, intrinsic neurobiological research is needed. Additionally, an accurate assessment of the level of consciousness may strengthen our awareness of this concept and provide new ideas for patients undergoing clinical treatment of consciousness disorders. In addition, research efforts that help elucidate the concept of consciousness have important scientific and clinical significance. This review presents the latest progress in consciousness research and proposes our assumptions with regard to the network of consciousness.