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Recently, functional homotopy (FH) architecture, defined as robust functional connectivity (FC) between homotopic regions, has been frequently reported to be altered in MDD patients (MDDs) but with divergent locations.In this study, we obtained resting-state functional magnetic resonance imaging (R-fMRI) data from 1004 MDDs (mean age, 33.88 years; age range, 18-60 years) and 898 matched healthy controls (HCs) from an aggregated dataset from 20 centers in China. We focused on interhemispheric function integration in MDDs and its correlation with clinical characteristics using voxel-mirrored homotopic connectivity (VMHC) devised to inquire about FH patterns.As compared with HCs, MDDs showed decreased VMHC in visual, motor, somatosensory, limbic, angular gyrus, and cerebellum, particularly in posterior cingulate gyrus/precuneus (PCC/PCu) (false discovery rate [FDR] q 0.002, z = -7.07). Further analysis observed that the reduction in SMG and insula was more prominent with age, of which SMG reflected such age-related change in males instead of females. Besides, the reduction in MTG was found to be a male-special abnormal pattern in MDDs. VMHC alterations were markedly related to episode type and illness severity. The higher Hamilton Depression Rating Scale score, the more apparent VMHC reduction in the primary visual cortex. First-episode MDDs revealed stronger VMHC reduction in PCu relative to recurrent MDDs.We confirmed a significant VMHC reduction in MDDs in broad areas, especially in PCC/PCu. This reduction was affected by gender, age, episode type, and illness severity. These findings suggest that the depressive brain tends to disconnect information exchange across hemispheres.

The ability to discriminate species and recognize individuals is crucial for reproductive success and/or survival in most animals. However, the temporal order and neural localization of these decision-making processes has remained unclear. In this study, event-related potentials (ERPs) were measured in the telencephalon, diencephalon, and mesencephalon of the music frog Nidirana daunchina. These ERPs were elicited by calls from 1 group of heterospecifics (recorded from a sympatric anuran species) and 2 groups of conspecifics that differed in their fundamental frequencies. In terms of the polarity and position within the ERP waveform, auditory ERPs generally consist of 4 main components that link to selective attention (N1), stimulus evaluation (P2), identification (N2), and classification (P3). These occur around 100, 200, 250, and 300 ms after stimulus onset, respectively. Our results show that the N1 amplitudes differed significantly between the heterospecific and conspecific calls, but not between the 2 groups of conspecific calls that differed in fundamental frequency. On the other hand, the N2 amplitudes were significantly different between the 2 groups of conspecific calls, suggesting that the music frogs discriminated the species first, followed by individual identification, since N1 and N2 relate to selective attention and stimuli identification, respectively. Moreover, the P2 amplitudes evoked in females were significantly greater than those in males, indicating the existence of sexual dimorphism in auditory discrimination. In addition, both the N1 amplitudes in the left diencephalon and the P2 amplitudes in the left telencephalon were greater than in other brain areas, suggesting left hemispheric dominance in auditory perception. Taken together, our results support the hypothesis that species discrimination and identification of individual characteristics are accomplished sequentially, and that auditory perception exhibits differences between sexes and in spatial dominance.

Carbon quantum dots (CQDs) are extensively applied for bioimaging due to their unique photoluminescence properties, while less attention has been paid to their inherent bio-functions as targeted drug delivery vehicles. To address this limitation, a novel CQDs-based drug delivery system (Arg-Ag@Cu) was constructed using l -arginine as precursor with duplex metal co-doping (Ag&Cu) for further DOX-loading/releasing and synergistic tumor theranostics. Specifically, the functional residues retention ability of CQDs guaranteed the reactive nitrogen species (RNS) replenishment, Ag-doping enhanced the photoluminescence intensity, and Cu2+-functionalizing could act as the anchor for further interparticle self-assembly, resulting in intelligent adjustable CQDs size for increasing the drug-loading capacity. After reaching targeted sites, CQDs could act as NO/ONOO− donors for gas-involving therapy, and Cu2+ could not only generate ROS through chemodynamic therapy (CDT), but also modulate the band structure of as-prepared CQDs for laser-induced photodynamic therapy (PDT) to further replenishing ROS. Simultaneously, with Cu2+ depletion, the structure of Arg-Ag@Cu was disrupted, which guaranteed in situ DOX-releasing. As such, these orchestrated procedures fully exerted the intrinsic bio-functions of CQDs then act as adjuvants in drug delivery systems, thus representing synergistic effects in suppressing tumor progression and migration with minimal side effects, and provides a paradigm of potent CQDs-based nanotheranostics.

Aberrant topological organization of whole-brain networks has been inconsistently reported in studies of patients with major depressive disorder (MDD), reflecting limited sample sizes. To address this issue, we utilized a big data sample of MDD patients from the REST-meta-MDD Project, including 821 MDD patients and 765 normal controls (NCs) from 16 sites. Using the Dosenbach 160 node atlas, we examined whole-brain functional networks and extracted topological features (e.g., global and local efficiency, nodal efficiency, and degree) using graph theory-based methods. Linear mixed-effect models were used for group comparisons to control for site variability; robustness of results was confirmed (e.g., multiple topological parameters, different node definitions, and several head motion control strategies were applied). We found decreased global and local efficiency in patients with MDD compared to NCs. At the nodal level, patients with MDD were characterized by decreased nodal degrees in the somatomotor network (SMN), dorsal attention network (DAN) and visual network (VN) and decreased nodal efficiency in the default mode network (DMN), SMN, DAN, and VN. These topological differences were mostly driven by recurrent MDD patients, rather than first-episode drug naive (FEDN) patients with MDD. In this highly powered multisite study, we observed disrupted topological architecture of functional brain networks in MDD, suggesting both locally and globally decreased efficiency in brain networks.

The homeostasis of bone metabolism depends on the coupling and precise regulation of various types of cells in bone tissue. However, the communication and interaction between bone tissue cells at the single-cell level remains poorly understood. Thus, we performed single-cell RNA sequencing (scRNA-seq) on the primary human femoral head tissue cells (FHTCs). Nine cell types were identified in 26,574 primary human FHTCs, including granulocytes, T cells, monocytes, B cells, red blood cells, osteoblastic lineage cells, endothelial cells, endothelial progenitor cells (EPCs) and plasmacytoid dendritic cells. We identified serine protease 23 (PRSS23) and matrix remodeling associated protein 8 (MXRA8) as novel bone metabolism-related genes. Additionally, we found that several subtypes of monocytes, T cells and B cells were related to bone metabolism. Cell-cell communication analysis showed that collagen, chemokine, transforming growth factor and their ligands have significant roles in the crosstalks between FHTCs. In particular, EPCs communicated with osteoblastic lineage cells closely via the "COL2A1-ITGB1" interaction pair. Collectively, this study provided an initial characterization of the cellular composition of the human FHTCs and the complex crosstalks between them at the single-cell level. It is a unique starting resource for in-depth insights into bone metabolism.

Background : Functional specialization is a feature of human brain for understanding the pathophysiology of major depressive disorder (MDD). The degree of human specialization refers to within and cross hemispheric interactions. However, most previous studies only focused on interhemispheric connectivity in MDD, and the results varied across studies. Hence, brain functional connectivity asymmetry in MDD should be further studied. Methods : Resting-state fMRI data of 753 patients with MDD and 451 healthy controls were provided by REST-meta-MDD Project. Twenty-five project contributors preprocessed their data locally with the Data Processing Assistant State fMRI software and shared final indices. The parameter of asymmetry (PAS), a novel voxel-based whole-brain quantitative measure that reflects inter- and intrahemispheric asymmetry, was reported. We also examined the effects of age, sex and clinical variables (including symptom severity, illness duration and three depressive phenotypes). Results : Compared with healthy controls, patients with MDD showed increased PAS scores (decreased hemispheric specialization) in most of the areas of default mode network, control network, attention network and some regions in the cerebellum and visual cortex. Demographic characteristics and clinical variables have significant effects on these abnormalities. Limitations : Although a large sample size could improve statistical power, future independent efforts are needed to confirm our results. Conclusions : Our results highlight the idea that many brain networks contribute to broad clinical pathophysiology of MDD, and indicate that a lateralized, efficient and economical brain information processing system is disrupted in MDD. These findings may help comprehensively clarify the pathophysiology of MDD in a new hemispheric specialization perspective.

AIM: To investigate and evaluate healing patterns around flaps made with different side-cut angulations after femtosecond laser in situ keratomileusis (FS-LASIK). METHODS: Thirty-four patients (68 eyes) received a 90° side-cut (n=34) or a 120° side-cut flaps (n=34) made with a femtosecond laser. One day, 1wk, 1 and 3mo postoperatively, side-cut scar was evaluated under slit-lamp photography according to a new grading system (Grade 0=transparent scar, 1=faint healing opacity, and 2=evident healing opacity). In vivo corneal confocal microscopy and anterior segment optical coherence tomography (AS-OCT) were used to observe wound-healing patterns around flap margin in the two groups. Sirius Scheimpflug Analyzer was also used to analyze higher order aberrations 3mo after surgery. RESULTS: There were no significant differences in flap wound-healing patterns at each follow up between the two groups (P>0.05). Three months after surgery, the flap edge scar classified as Grade 0 had excellent apposition and rapid nerve regeneration. At 3 mm and 5 mm pupil diameters, there were significant differences in trefoil aberrations between the two groups (P0.05). CONCLUSION: Flap edge scars classified as Grade 0 have excellent apposition and rapid nerve regeneration, and 120° side-cut angle flaps induce less trefoil aberrations after FS-LASIK.

Pleiotrophin (PTN) is a potent mitogenic cytokine whose activities are controlled by its interactions with glycosaminoglycan (GAG). We examined the specificity of PTN for several types of GAG oligosaccharides. Our data indicate that the interaction of PTN with GAGs is dependent on the sulfation density of GAGs. Surprisingly, an acidic peptide also had similar interactions with PTN as GAGs. This shows that the interaction of PTN with anionic polymers is flexible and adaptable and that the charge density is the main determinant of the interaction. In addition, we show that PTN can compensate for the loss of its termini in interactions with heparin oligosaccharides, allowing it to maintain its affinity for GAGs in the absence of the termini. Taken together, these data provide valuable insight into the interactions of PTN with its proteoglycan receptors.

As Information and Communication Technology (ICT) infrastructure has rapidly become commonplace in most countries worldwide, the development of ICT-related competence is now considered to be a key goal in Taiwan’s curriculum. Nowadays, society expects undergraduates to develop essential computer abilities before entering the workplace. In addition to possessing computing skills, students are also required to have problem-solving ability and teamwork competency. To equip students to meet these expectations, the researchers integrated two teaching approaches, using content-based knowledge awareness (CoKA) and team learning (TL) to enhance students’ programming skills in an online computing course, and to reduce students’ anxiety and regulate cognitive load in the cloud classroom involved in this study. In this research, the authors conducted a quasi-experiment to examine the influences of CoKA and TL. Therefore, the design for the experiment was a 2 (CoKA vs. non-CoKA) × 2 (TL vs. non-TL) factorial pretest/posttest design. There were 184 participants, who were neither information nor computer majors, from four classes, enrolled in a required course titled ‘Programming Design’. The first class (G1) simultaneously received the online CoKA and TL intervention, the second class (G2) received only the online CoKA intervention, and the third class (G3) received only the online TL intervention; these served as the experimental groups, while the last class (G4), which received a traditional teaching approach, served as the control group. According to the results, students who received online TL had significant increase in their computing skills, and significant decrease in their level of anxiety and cognitive load. However, the expected effects of CoKA on developing students’ skills in designing mobile applications, reducing anxiety level and regulating cognitive load were not found. The design of integrating CoKA and TL in an online course could be a reference for educators when conducting online, flipped, or blended courses, particularly for those focusing on developing skills in computer programming.

Background Hepatocellular carcinoma (HCC) caused by hepatitis C virus (HCV) infection has become less and less due to the use of direct-acting antiviral agents (DAAs). Although it may be common to assume that eradication of the virus should improve the survival of HCC patients, large-scale randomized clinical data to support the correlation between viral load and prognosis are still lacking in China. The aim of the study was to evaluate the efficacy of antiviral therapy for HCC patients with active HCV infection. Patients and methods We retrospectively enrolled 80 HCC patients with active HCV infection. Active HCV infection was defined as positive for HCV antibody with detectable HCV RNA by polymerase chain reaction. Results Forty-four patients (55.0%) received interferon combined with ribavirin treatment and 23 patients achieved sustained virological response (SVR). The 1-year survival rate in patients who achieved SVR was the highest, followed by those with non-SVR after antiviral treatment, and those without antiviral therapy (1-year survival rate were 91.3%, 88.4%, and 73.1%, respectively, P = 0.012). In the univariate analysis, alcohol intake and alpha-fetoprotein >20 ng/mL were associated with lower overall survival (OS) (P = 0.025 and P = 0.044, respectively), while SVR after antiviral treatment was associated with longer OS (P = 0.016). In the multivariate analysis, only SVR after antiviral treatment was significantly associated with OS (P = 0.014). Conclusion Our results ensured that the elimination of HCV substantially improved OS in HCC patients with active HCV infection, and the prognosis of those patients without antiviral therapy was poor.

Despite the widespread use of antiplatelets and anticoagulants, women with antiphospholipid syndrome (APS) may face pregnancy complications associated with placental dysplasia. Neutrophil extracellular traps (NETs) are involved in the pathogenesis of many autoimmune diseases, including vascular APS; however, their role in obstetric APS is unclear. Herein, we investigated the role of NETs by quantifying cell‐free DNA and NET marker levels. Live‐cell imaging was used to visualize NET formation, and MAPK signalling pathway proteins were analysed. Cell migration, invasion and tube formation assays were performed to observe the effects of NETs on trophoblasts and human umbilical vein endothelial cells (HUVECs). The concentrations of cell‐free DNA and NETs in sera of pregnant patients with APS were elevated compared with that of healthy controls (HCs) matched to gestational week. APS neutrophils were predisposed to spontaneous NET release and IgG purified from the patients (APS‐IgG) induced neutrophils from HCs to release NETs. Additionally, APS‐IgG NET induction was abolished with inhibitors of reactive oxygen species, AKT, p38 MAPK and ERK1/2. Moreover, NETs were detrimental to trophoblasts and HUVECs. In summary, APS‐IgG‐induced NET formation deserves further investigation as a potential novel therapeutic target in obstetrical APS.

Lipid overload results in lipid redistribution among metabolic organs such as liver, adipose, and muscle; therefore, the interplay between liver and other organs is important to maintain lipid homeostasis. Here, we show that liver responds to lipid overload first and sends hepatocyte-derived extracellular vesicles (EVs) targeting adipocytes to regulate adipogenesis and lipogenesis. Geranylgeranyl diphosphate synthase (Ggpps) expression in liver is enhanced by lipid overload and regulates EV secretion through Rab27A geranylgeranylation. Consistently, liver-specific Ggpps deficient mice have reduced fat adipose deposition. The levels of several EV-derived miRNAs in the plasma of non-alcoholic fatty liver disease (NAFLD) patients are positively correlated with body mass index (BMI), and these miRNAs enhance adipocyte lipid accumulation. Thus, we highlight an inter-organ mechanism whereby the liver senses different metabolic states and sends corresponding signals to remodel adipose tissue to adapt to metabolic changes in response to lipid overload., Extracellular vesicles (EVs) containing miRNAs or proteins can coordinate metabolic responses between tissues. Here the authors demonstrate that during lipid overload, the liver secretes miRNA-containing EVs through a Ggpps-Rab27 dependent mechanism, which controls adipose tissue lipid storage capacity.

Background Diffuse large B-cell lymphoma (DLBCL) is a common subtype of non-Hodgkin’s lymphoma (NHL). We assessed serum biomarkers to identify patients with DLBCL and healthy controls, as well as prognosis-related paired pre- and post-R-CHOP therapy effect of patients with DLBCL. Methods Serum samples from 329 DLBCL patients and 100 healthy controls were collected in this study, as well as 72 samples from additional DLBCL patients with paired pre- and post-R-CHOP therapy (n=36). All serum samples were pretreated and detected by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Serum biomarkers were discriminated between DLBCL patients and healthy controls, as well as between DLBCL patients with prognosis-related paired pre- and post-R-CHOP therapy, and identified by Veristrat Identification Platform 1.0, Bioyong Explore 1.0 and mMass software. Results Two peaks, m/z values of 15,140.74 and 15,885.43, were significantly different from all peaks among the DLBCL patients and healthy controls (P

Yi-Qun Che,1,2 Yue Zhang,1 Han-Bing Li,1 Di Shen,1 Wei Cui1 1Department of Clinical Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People’s Republic of China; 2Center for Clinical Laboratory, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, People’s Republic of ChinaCorrespondence: Wei CuiDepartment of Clinical Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, People’s Republic of ChinaTel/Fax +86-10-87788448Email wendycuiwei@sina.cnPurpose: With the advancement of minimally invasive surgery and catheters for hepatocellular carcinoma (HCC), it is becoming more and more inconvenient to get tissues or the tissues gained are insufficient for testing. Screening of blood-derived markers is of great significance for prognosis assessment.Patients and Methods: Data-independent acquisition (DIA) and parallel reaction monitoring (PRM) were implemented to identify valuable prognostic HCC biomarkers in 48 patients with different prognosis. The potential candidate biomarkers were examined in 205 HCC patients using enzyme-linked immunosorbent assay (ELISA) and then validated in The Cancer Genome Atlas (TCGA) HCC cohort.Results: DIA screened 86 significantly differentially regulated proteins between patients with poor prognosis and those with good prognosis. Eight proteins from the DIA proteomic analyses were quantified by PRM, and six of them (KLKB1, IGFBP3, SHBG, SAA1, C7, and CD44) presented consistent expression trends between DIA and PRM. Then, the results of ELISA indicated that KLKB1 was abnormally expressed in HCC patients, and the serum level of KLKB1 also exhibited significant changes before and after treatment (P = 0.016). Patients with higher KLKB1 serum levels had significantly superior overall survival (P = 0.035) and progression-free survival (P = 0.027) than those with lower KLKB1 expression. In the TCGA-HCC cohort, Cox regression analysis suggested that KLKB1 was an independent prognostic factor for overall survival (P = 0.032) of HCC patients.Conclusion: Aberrant expression of KLKB1 was strongly associated with the prognosis of HCC patients. KLKB1 may be used to evaluate the prognosis and guide the treatment for HCC.Keywords: KLKB1, hepatocellular carcinoma, prognostic, data-independent acquisition, parallel reaction monitoring

To simplify the preparation process of a glucose-responsive microneedle patch, a cross-linking-density changeable microneedle patch was designed. The microneedle patch was made up of a hydrogel formed by phenylboronic acid-grafted polyallylamine and poly(vinyl alcohol) (PVA). The gel was cross-linked by boronate ester bonds between phenylboronic acid groups and PVA. It still had fluidity and could be filled into a mold to prepare microneedle patches. Moreover, insulin could be directly loaded into the microneedle patch by mixing with the gel. The boronate ester bond would be broken in the presence of glucose, resulting in a decrease in the cross-linking density. Therefore, the gel could achieve a greater swelling degree and insulin could be released faster. In addition, PVA chains were crystallized by repeatedly freezing and thawing to improve the mechanical strength of the microneedle patch. In terms of glucose-dependent insulin release, the gel showed good glucose-responsive insulin-release ability. Through additional ion cross-linking, the microneedle patch could also control the insulin release according to glucose concentration. In the hypoglycemic experiment of diabetic rats, the microneedle patch effectively pierced the skin and slowly released insulin.

Li-Yan Qiao,1,* Han-Bing Li,2,* Yue Zhang,2 Di Shen,2 Peng Liu,3 Yi-Qun Che2 1Department of Stomatology, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, People’s Republic of China; 2Department of Clinical Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People’s Republic of China; 3Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yi-Qun CheDepartment of Clinical Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People’s Republic of ChinaTel/Fax + 86-10-87788746Email cyq@cicams.ac.cnPeng LiuDepartment of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People’s Republic of ChinaTel/Fax + 86-10-87788507Email 13910216310@163.comPurpose: Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin’s lymphoma and of which the prognosis of activated B-cell-like (ABC) subtype is poor. Although R-CHOP significantly improves the survival of patients with DLBCL, 20% to 40% of patients were resistant to R-CHOP therapy. Thus, screening for candidate therapeutic targets for R-CHOP resistant patients is urgent. The previous researches have shown that CD24 is related to the development, invasion, and metastasis of cancer. Our project aims to clarify the relationship between CD24 and ABC-DLBCL.Patients and Methods: The expression of CD24 mRNA in 118 ABC-DLBCL cases treated with R-CHOP was detected by RNAscope, and the relationship between CD24 expression and R-CHOP treatment response was analyzed. The correlation between CD24 expression and treatment efficiency was further analyzed by data downloaded from the Gene Expression Omnibus (GEO) database. The association between CD24 expression and immune response was conducted using Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT) methodology and Gene Ontology (GO) biological process (BP) analysis.Results: The positive expression rate of CD24 mRNA in ABC-DLBCL patients was 38.1% (45/118). Complete Response (CR) rate was significantly higher in patients with CD24 high expression than those with CD24 low expression (P=0.039; 44.4% vs 26.0%). CR rate was significantly different between CD24 high and low expression groups in the analysis of GEO datasets (P=0.003; 83.2% vs 58.0%). The CD24 high expression patients had significantly lower proportions of T cells and nonspecific immune cells in the CIBERSORT analysis. In addition, T−helper 2 cell differentiation and monocyte chemotaxis were repressed in CD24 high expression group in the GO BP analysis.Conclusion: CD24 was correlated with better R-CHOP treatment response and tumor immunosuppression in ABC-DLBCL. CD24 may be a promising signal in treatment and prognosis evaluation in ABC-DLBCL patients.Keywords: ABC-DLBCL, CD24, RNA in situ hybridization, treatment response, tumor immunosuppression

Background Increasing evidence suggests that human gut microbiome plays an important role in variation of skeletal muscle mass (SMM). However, specific causal mechanistic relationship of human gut microbiome with SMM remains largely unresolved. Understanding the causal mechanistic relationship may provide a basis for novel interventions for loss of SMM. This study investigated whether human gut microbiome has a causal effect on SMM among Chinese community‐dwelling healthy menopausal women. Methods Estimated SMM was derived from whole‐body dual‐energy X‐ray absorptiometry. We performed integrated analyses on whole‐genome sequencing, shotgun metagenomic sequencing, and serum short‐chain fatty acids (SCFAs), as well as available host SMM measurements among community‐dwelling healthy menopausal women (N = 482). We combined the results with summary statistics from genome‐wide association analyses for human gut microbiome (N = 952) and SMM traits (N = 28 330). As a prerequisite for causality, we used a computational protocol that was proposed to measure correlations among gut metagenome, metabolome, and the host trait to investigate the relationship between human gut microbiome and SMM. Causal inference methods were applied to assess the potential causal effects of gut microbial features on SMM, through one‐sample and two‐sample Mendelian randomization (MR) analyses, respectively. Results In metagenomic association analyses, the increased capacity for gut microbial synthesis of the SCFA butyrate was significantly associated with serum butyrate levels [Spearman correlation coefficient (SCC) = 0.13, P = 0.02] and skeletal muscle index (SCC = 0.084, P = 0.002). Of interest was the finding that two main butyrate‐producing bacterial species were both positively associated with the increased capacity for gut microbial synthesis of butyrate [ Faecalibacterium prausnitzii (SCC = 0.25, P = 6.6 × 10−7) and Butyricimonas virosa (SCC = 0.15, P = 0.001)] and for skeletal muscle index [ F. prausnitzii (SCC = 0.16, P = 6.2 × 10−4) and B. virosa (SCC = 0.17, P = 2.4 × 10−4)]. One‐sample MR results showed a causal effect between gut microbial synthesis of the SCFA butyrate and appendicular lean mass (β = 0.04, 95% confidence interval 0.029 to 0.051, P = 0.003). Two‐sample MR results further confirmed the causal effect between gut microbial synthesis of the SCFA butyrate and appendicular lean mass (β = 0.06, 95% confidence interval 0 to 0.13, P = 0.06). Conclusions Our results may help the future development of novel intervention approaches for preventing or alleviating loss of SMM.

Ascorbate is an antioxidant in plants. Its content is an important index to evaluate the nutritional quality of celery. In higher plant, ascorbate accumulation is effected by CO2 concentration. To study the effects of elevated CO2 (1000 µmol mol−1) on ascorbate accumulation in celery, ascorbate contents and the transcript levels of genes related to ascorbate metabolism in the leaves (leaf blade and petiole) were detected. The results of current study showed that the ascorbate and total ascorbate levels increased during all the treated stages in celery petioles, and they were 1.09–3.91 fold of the control. In leaf blades, the ascorbate contents exhibited a lower level (96.12% and 90.46% of the control) in treatments at 2 and 4 days, and then increased to 1.04 and 1.27 fold of the control in treatments at 6 and 8 days, respectively. Elevated CO2 altered the expression profiles of ascorbate-related genes and the activities of corresponding enzymes. Expression levels of the genes, AgPGI2, AgGMP, AgPMI, AgGalDH, AgGalLDH, GalUR, AgDHAR1, AgAPX1, and AgAO, in the leaf blades corresponded well to the change in ascorbate contents. At 6 days of treatment, the relative expression levels of AgPGI2, AgPMI, AgGGP1, AgGGP2, AgGalUR, AgMDHAR, AgDHAR1, and AgAPX1 in leaf blades increased, and were 4.41, 2.39, 4.65, 3.64, 3.11, 4.53, 4.59, and 3.86 times higher than that of the control. Increased ascorbate accumulation in celery leaves under elevated CO2 treatments might be also related to the change in SOD, POD, and CAT activities, as well as GSH content. These results will enhance our understanding on the effects of elevated CO2 on ascorbate accumulation and potential molecular mechanism regulating ascorbate metabolism in celery.

In order to study the biomechanical properties of the puffer skin, the puffer dorsal and abdominal skin was cut horizontally and lengthways. The mechanical parameters of quasi static axial ...

Purpose Despite selection based on human epidermal growth factor receptor 2 (HER2) overexpression, not all HER2-positive patients benefit from trastuzumab therapy. Recent reports indicate that trastuzumab treatment failure may be associated with immune system dysfunction. We examined the prognostic relevance of the absolute lymphocyte count (ALC) in patients with HER2-positive metastatic breast cancer (MBC) who received trastuzumab combined with chemotherapy. Methods Baseline ALC and neutrophil-to-lymphocyte ratio (NLR) data from trastuzumab-treated patients with MBC were studied retrospectively, and associations between baseline ALC and clinical characteristics evaluated. Kaplan-Meier analysis and the Cox regression hazard model were applied to assess effects on outcomes. Results Of a total of 68 patients, 19.1% (13/68) had baseline ALCs ≤ 1 G/L. Baseline lymphopenia was correlated with increased lactate dehydrogenase (LDH) and higher NLR. In univariate analysis, higher alkaline phosphatase (ALP) was associated with inferior overall survival (OS) (P = 0.001); higher LDH was associated with inferior progression-free survival (PFS) (P = 0.045) and OS (P = 0.010). We did not observe any differences in objective response rate or disease control rate between patients with lymphopenia and those with normal ALC. Importantly, patients with baseline lymphopenia had inferior PFS (0.60 years vs 1.17 years, P = 0.000009) and OS (1.88 years vs 3.80 years, P = 0.0003). In multivariable analysis, significance of ALCs was retained for lymphopenia (PFS: P = 0.0005; OS: P = 0.016). Conclusion Our data indicate that baseline ALC value of ≤1 G/L is a predictor of poor outcomes, but not of response, in patients with MBC treated with trastuzumab.

Since its discovery in Escherichia coli, the emergence and rapid spread of the plasmid-mediated colistin resistance gene mcr-1 have become a public health concern. Livestock manure is a potentially important reservoir of mcr-1 because colistin has been widely used in livestock production. Efforts made to accurately quantify the prevalence of mcr-1 in livestock manure and the dynamic changes therein during thermophilic composting have been few and far between. In this study, mcr-1 in 51 collected samples from four kinds of livestock manures was detected and quantified. In total, 16 manure samples were found to be mcr-1 positive, with a detection frequency of 31% in 51 samples. The numbers of mcr-1 gene copies in 12 positive manure samples with a high prevalence of mcr-1 were 107–109 copies/g dry weight. During composting, >90% of mcr-1 in the manure was eliminated in 15 days at high temperature (44–65 °C), and mcr-1 was completely undetectable after 22 days. The reduction of mcr-1 following manure composting may be ascribed to the decreased number of potential mcr-1–harboring bacteria, Enterobacteriaceae and Pseudomonas. The results indicated that thermophilic composting effectively eliminated mcr-1 and inhibited its spread from livestock manure to the environment. Keywords: Mcr-1, QPCR, Thermophilic composting, Enterobacteriaceae, Pseudomonas

Significance Functional connectivity within the default mode network in patients with major depressive disorder has been frequently reported to be abnormal but with contradicting directions in previous studies with small sample sizes. In creating the REST-meta-MDD consortium containing neuroimaging data of 1,300 depressed patients and 1,128 normal controls from 25 research groups in China, we found decreased default mode network functional connectivity in depressed patients, driven by patients with recurrent depression, and associated with current medication treatment but not with disease duration. These findings suggest that default mode network functional connectivity remains a prime target for understanding the pathophysiology of depression, with particular relevance to revealing mechanisms of effective treatments., Major depressive disorder (MDD) is common and disabling, but its neuropathophysiology remains unclear. Most studies of functional brain networks in MDD have had limited statistical power and data analysis approaches have varied widely. The REST-meta-MDD Project of resting-state fMRI (R-fMRI) addresses these issues. Twenty-five research groups in China established the REST-meta-MDD Consortium by contributing R-fMRI data from 1,300 patients with MDD and 1,128 normal controls (NCs). Data were preprocessed locally with a standardized protocol before aggregated group analyses. We focused on functional connectivity (FC) within the default mode network (DMN), frequently reported to be increased in MDD. Instead, we found decreased DMN FC when we compared 848 patients with MDD to 794 NCs from 17 sites after data exclusion. We found FC reduction only in recurrent MDD, not in first-episode drug-naïve MDD. Decreased DMN FC was associated with medication usage but not with MDD duration. DMN FC was also positively related to symptom severity but only in recurrent MDD. Exploratory analyses also revealed alterations in FC of visual, sensory-motor, and dorsal attention networks in MDD. We confirmed the key role of DMN in MDD but found reduced rather than increased FC within the DMN. Future studies should test whether decreased DMN FC mediates response to treatment. All R-fMRI indices of data contributed by the REST-meta-MDD consortium are being shared publicly via the R-fMRI Maps Project.

Platelet-derived microparticles (PMPs) are a type of microparticle budding from platelets undergoing activation or apoptosis in many autoimmune diseases, including antiphospholipid antibody syndrome (APS). PMPs may also contribute to recurrent miscarriage, although the exact mechanism is unclear. The aim of this study was to determine the potential biological mechanism by which abnormal PMP activation may affect recurrent miscarriage. PMPs were counted by fluorescence-activated cell sorting (FACS) and compared between the healthy control (HC) and recurrent miscarriage/APS groups. Different effects of PMPs isolated by FACS from patients with recurrent miscarriage/APS and HCs were explored. Capillary electrophoresis immunoquantification, RT-qPCR, Luminex xMAP and immunofluorescence staining were performed to investigate all these different effects of PMPs. We found that the difference in the counts of PMP was not significant. However the expression of the inflammatory cytokine tumour necrosis factor-α (TNF-α) and the adhesion molecules intracellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were increased by PMPs derived from the recurrent miscarriage/APS group. PMPs isolated from patients with recurrent miscarriage/APS also more potently stimulated monocyte recruitment, inhibited angiogenesis and promoted human umbilical vein endothelial cell (HUVEC) apoptosis, in comparison to PMPs from HCs matched for gestational week. Moreover, PMPs could be ternalized by HTR-8/SVneo cells and could increase apoptosis of these cells and decrease trophoblastic invasion and migration. To supplement our work, the limited sample size needs to be increased, and further in-vivo work is necessary. Findings from this study indicate that abnormal activation of PMPs contributes to recurrent miscarriage/APS progression and provides potential therapeutic targets.

Background: Bone marrow metastasis occurs in lung adenocarcinoma patients with a poor prognosis due to the late course and lack of definitive treatments, although reports on this are limited. This study analyzed the clinical manifestation, laboratory examination, treatment, and prognosis of patients with lung adenocarcinoma with bone marrow metastasis. Methods: All patients were confirmed to have bone marrow infiltration by bone marrow aspiration. The clinical data of 12 patients with lung adenocarcinoma with bone marrow metastasis were analyzed retrospectively. The prognostic factors were analyzed by Kaplan-Meier statistics. Results: The common biomarker abnormalities in 12 patients were elevated carcinoembryonic antigen in 12 cases (100%), elevated lactate dehydrogenase in 9 cases (75%), increased alkaline phosphatase and anemia in 8 cases each (66.7%), and thrombocytopenia in 4 cases (33.3%). After diagnosis of bone marrow metastasis, 5 patients were treated with platinum-based chemotherapy, 3 patients received chemotherapy and targeted drug tyrosine kinase inhibitor (TKI) therapy, 2 patients received simple TKI therapy, and 2 patients received only best supportive care (BSC) therapy. The median duration of survival after the diagnosis of bone marrow involvement was 422 days. The survival time of patients receiving TKI therapy after bone marrow metastasis was significantly better than that of patients receiving only BSC and chemotherapy (χ2=4.636, P=0.031). Conclusions: The survival period of patients with lung adenocarcinoma with bone marrow metastasis is short, and targeted drug TKI treatment can prolong the survival time for patients with EGFR mutation–carrying lung adenocarcinoma with bone marrow metastasis.

Background Tension bands structures are widely used to treat transverse patellar fractures. However, many implants-related complications have been reported. The purpose of this study is to evaluate effects and compare complications of three methods used to treat transverse patellar fractures, including titanium cable tension bands, compression screws with titanium cable cerclage, and X-shaped plating technique. Methods From January 2010 to March 2016, 120 cases of transverse patellar fracture received open reduction and internal fixation with one of three methods: titanium cable tension band (group A), compression screws with titanium cable cerclage (group B), and X-shaped plating technique (group C). Of these, 108 cases were followed for >2 years. Clinical and radiographic data were retrospectively collected and statistically compared. Results Final analysis included 108 patients (n = 38 in group A, 36 in B, and 34 in C). Reduction was satisfactory in all patients after surgery. No significant differences were noted in age, gender, time from injury to surgery, postoperative articular step-off, Lysholm score, and range of motion at 24 months among all groups. At final follow-up, 12 (31.6%) symptomatic implant complications were encountered in group A, along with 6 (16.7%) and 2 (5.9%) in groups B and C, respectively (p Conclusion All three methods could achieve the goal of rigid fixation and early functional rehabilitation. However, the X-plate technique had the lowest risk of symptomatic implant complications and could thus be a safe and effective alternative for internal fixation of transverse patellar fractures.

Background Accurate and robust pathological image analysis for colorectal cancer (CRC) diagnosis is time-consuming and knowledge-intensive, but is essential for CRC patients’ treatment. The current heavy workload of pathologists in clinics/hospitals may easily lead to unconscious misdiagnosis of CRC based on daily image analyses. Methods Based on a state-of-the-art transfer-learned deep convolutional neural network in artificial intelligence (AI), we proposed a novel patch aggregation strategy for clinic CRC diagnosis using weakly labeled pathological whole-slide image (WSI) patches. This approach was trained and validated using an unprecedented and enormously large number of 170,099 patches, > 14,680 WSIs, from > 9631 subjects that covered diverse and representative clinical cases from multi-independent-sources across China, the USA, and Germany. Results Our innovative AI tool consistently and nearly perfectly agreed with (average Kappa statistic 0.896) and even often better than most of the experienced expert pathologists when tested in diagnosing CRC WSIs from multicenters. The average area under the receiver operating characteristics curve (AUC) of AI was greater than that of the pathologists (0.988 vs 0.970) and achieved the best performance among the application of other AI methods to CRC diagnosis. Our AI-generated heatmap highlights the image regions of cancer tissue/cells. Conclusions This first-ever generalizable AI system can handle large amounts of WSIs consistently and robustly without potential bias due to fatigue commonly experienced by clinical pathologists. It will drastically alleviate the heavy clinical burden of daily pathology diagnosis and improve the treatment for CRC patients. This tool is generalizable to other cancer diagnosis based on image recognition.

Anxious major depressive disorder is a common subtype of major depressive disorder; however, its unique neural mechanism is not well-understood currently. Using multimodal MRI data, this study examined common and specific alterations of amygdala subregions between patients with and without anxiety. No alterations were observed in the gray matter volume or intra-region functional integration in either patient group. Compared with the controls, both patient groups showed decreased functional connectivity between the left superficial amygdala and the left putamen, and between the right superficial amygdala and the bilateral anterior cingulate cortex and medial orbitofrontal cortex, while only patients with anxiety exhibited decreased activity in the bilateral laterobasal and superficial amygdala. Moreover, the decreased activity correlated negatively with the Hamilton depression scale scores in the patients with anxiety. These findings provided insights into the pathophysiologic processes of anxious major depressive disorder and may help to develop new and effective treatment programs.

Semaphorin 3B (SEMA-3B), which belongs to the semaphorin family, has an important role in cell apoptosis and inhibition of angiogenesis. A previous study by our group revealed that SEMA-3B was downregulated in tumor tissues of patients with hepatocellular carcinoma (HCC) and exerts anti-motility and anti-invasion effects on tumor cells. However, the serum levels of SEMA-3B and their clinical significance have remained elusive; therefore, the aim of the present study was to monitor its expression in HCC and investigate its clinical significance. ELISA was used to determine the serum levels of SEMA-3B in 132 patients with HCC and 57 healthy individuals. The association between SEMA-3B and clinicopathological parameters was investigated. Serum SEMA-3B was indicated to be significantly decreased in patients with HCC as compared with that in the controls (P

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.

Yi-Qun Che,1 Yue Zhang,1 Kai-Ping Ou,2 Di Wang,3 Di Shen,1 Hui-Ying Liu,4 Yang Luo5 1Department of Clinical Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, People’s Republic of China; 2Department of Medical Oncology, Beijing Chaoyang District Sanhuan Cancer Hospital, Beijing 100122, People’s Republic of China; 3State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, People’s Republic of China; 4Department of Clinical Laboratory, Jinzhou Central Hospital, Jinzhou 121000, Liaoning Province, People’s Republic of China; 5Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, People’s Republic of ChinaCorrespondence: Yang LuoDepartment of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. No.17 Panjiayuan Nanli, Chaoyang District, Beijing 100021, People’s Republic of ChinaTel/Fax + 86-10-87788820Email luoyang@cicams.ac.cnBackground: To evaluate whether the depth of response (DepRe) and early tumor shrinkage (ETS) are predictive factors of clinical outcomes in HER2-positive metastatic breast cancer (mBC) patients treated with trastuzumab.Methods: We performed a retrospective study of 100 HER2-positive mBC patients who received trastuzumab combined with chemotherapy as first-line treatment. ETS and DepRe were calculated. We employed Youden’s index to determine the optimal cutoff value of ETS and DepRe for predicting progression-free survival (PFS) and overall survival (OS). We used Kaplan–Meier analysis, Log-rank tests, and Cox proportional hazards regression models to evaluate the impacts of ETS and DepRe on clinical outcomes.Results: The optimal cutoff values were 30% for ETS and 40% for DepRe; ETS and DepRe were observed in 51.0% (51/100) and in 56.0% (56/100) of patients, respectively. Both ETS≥ 30% and DepRe≥ 40% were significant tumor-size metrics for predicting PFS (ETS: median 1.43 vs 0.69 years, hazard ratio [HR] = 0.384; 95% confidence interval [CI]: 0.245 to 0.601; P=0.000030; DepRe: median 1.43 vs 0.59 years, HR = 0.390; 95% CI: 0.250 to 0.609; P=0.0000034), but only DepRe≥ 40% was a significant predictor for OS (median 4.02 vs 3.07 years, HR = 0.484; 95% CI: 0.255 to 0.919; P = 0.027). Multivariate analyses also identified DepRe as an independent prognostic factor for PFS (HR = 0.52; 95% CI: 0.29 to 0.93; P = 0.028) and OS (HR=0.37; 95% CI:0.15 to 0.90; P = 0.029).Conclusion: ETS≥ 30% and DepRe≥ 40% were significant predictors of better clinical outcomes in mBC patients treated with first-line trastuzumab-based chemotherapy. Further validation in prospective trials with larger patient populations is needed.Keywords: depth of response, early tumor shrinkage, metastatic breast cancer, trastuzumab, survival

Background: Unstable distal clavicle fracture is common, and there is no consensus regarding the gold standard treatment. The purpose of this study was to report a new surgical technique for the treatment of unstable distal clavicle fracture with modified coracoclavicular (CC) stabilization using a ligament augmentation and reconstruction system (LARS) artificial ligament, and to evaluate the clinical and radiographic outcomes.Patients and methods: We retrospectively reviewed 18 patients with acute unstable distal clavicle fractures (type Ⅱb) treated between January 2009 and June 2018 with modified CC stabilization using LARS artificial ligament. Indexes for evaluation included fracture healing, quality of reduction, and presence of complications (e.g., infections, nerve injuries, iatrogenic clavicle or coracoid fracture, the fixation loop failure, or loss of reduction). Shoulder function was evaluated using the Constant-Murley score.Results: Patients were assessed at a mean time of 31.8 months follow-up. All 18 patients experienced radiographic union. Follow-up radiographs showed anatomical reduction in 15 patients and slight loss of reduction in 3 patients. There were 2 cases of calcification of the CC ligament, 1 case of degenerative change around the acromioclavicular (AC) joint, and 1 case of clavicular osteolysis around screws noted during the follow-up. At the final follow-up, Constant scores were 91.2 ± 6.9.Conclusions: Treating unstable distal clavicle fractures (type Ⅱb) with modified CC stabilization using LARS artificial ligament resulted in a high union rate, satisfactory fracture reduction, a low complication rate, and excellent shoulder function. We consider this simple surgical technique that naturally restores stability to the distal clavicle fracture is an efficient method for treating the fracture.

FAM172A, as a newly discovered gene, is little known in cancer development, especially in pancreatic cancer (PC). We investigated the potential role and molecular mechanism of FAM172A in epithelial to mesenchymal transition (EMT) in both human clinical samples and PC cells. FAM172A was downregulated in human PC tissues compared with that in non-cancerous pancreas cells by immunohistochemistry and qRT-PCR. FAM172A expression was negatively associated with tumor size (P=0.015), T stage (P=0.006), lymph node metastasis (P=0.028) and the worst prognosis of PC patients (P=0.004). Meanwhile, a positive relationship between FAM172A and E-cadherin (E-cad) (r=0.381, P=0.002) was observed in clinical samples, which contributed to the better prognosis of PC patients (P=0.014). FAM172A silencing induced EMT in both AsPC-1 and BxPC-3 cells, including inducing the increase of Vimentin, MMP9 and pERK and the decrease of E-cad and β-catenin expression, stimulating EMT-like cell morphology and enhancing cell invasion and migration in PC cells. However, MEK1 inhibitor PD98059 reversed FAM172A silencing-enhanced EMT in PC cells. We conclude that FAM172A inhibits EMT of PC cells via ERK-MAPK signaling., Summary: FAM172A inhibits EMT in pancreatic cancer via specifically regulating ERK-MAPK signaling.

Background: Mounting evidence suggested associations between gut microbiota (GM), serum metabolites and blood pressure (BP). To date, the impact of GM and serum metabolites on BP variation was not well elucidated, particularly in postmenopausal women. Epidemiologic studies showed a higher prevalence of hypertension in postmenopausal women than in premenopausal women. Therefore, significant gut bacterial species and serum metabolites associated with BP in early postmenopausal women may serve as biomarkers for early diagnosis, prevention, intervention and treatment of hypertension in postmenopausal older women. Methods: In the present study, we carried out analyses on metagenomic, serum untargeted and targeted metabolomics and whole genome sequencing from 402 early postmenopausal Chinese women to search for early omics-biomarkers and gain novel insights into the potential mechanisms of BP regulation in postmenopausal women. Findings: We totally identified four gut bacterial species were significantly associated with both systolic BP and diastolic BP. Systematic integrative multi-omics analysis indicated that increased Bacteroides fragilis could elevate BP via decreased caproic acid, and phenylacetylglutamine mediated the causal relationships of both Bacteroides fragilis and Clostridium sp.CAG.226 on diastolic BP variation in early postmenopausal Chinese women. Interpretation: The application of systematic integrative multi-omics analysis discovered a list of candidate omics-biomarkers for future BP related biological experiments, which would be considered as potential biomarkers for early diagnosis, prevention, intervention and treatment of hypertension in older postmenopausal women, and detected the causal effects among GM, metabolic activity and BP variation. Funding Statement: Hong-Wen Deng was partially supported by grants from the National Institutes of Health [U19AG05537301, R01AR069055, P20GM109036, R01MH104680, R01AG061917, U54MD007595]. Hong-Mei Xiao was partially supported by the National Key R&D Program of China (2017YFC1001100 and 2016YFC1201805). Declaration of Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest. Ethics Approval Statement: All the participants had signed informed consent form before they were recruited, and this study was approved by the Third Affiliated Hospital of Southern Medical University (Guangzhou City, China) institutional review board.

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.

Patients with obesity have a high prevalence of non-alcoholic fatty liver disease (NAFLD) and, in parallel, increased susceptibility to fibrosis/cirrhosis/hepatocellular carcinoma (HCC). Herein, we report that a high-fat diet (HFD) can augment glycolysis and then accelerate NAFLD-fibrosis progression by downregulating the expression of geranylgeranyl diphosphate synthase (GGPPS), which is a critical enzyme in the mevalonate pathway. Long-term HFD overloading decreases GGPPS expression in mice, which shifts the fuel preference from fatty acids towards glucose. Liver-specific Ggpps deficiency drives the Warburg effect by impairing mitochondrial function, and then induces hepatic inflammation, thus exacerbating fibrosis. Ggpps deficiency also enhances the hyperfarnesylation of liver kinase B1, and promotes metabolic reprogramming by regulating 5'-AMP-activated protein kinase activity. Clinical data further imply that GGPPS expression can predict the stage of NAFLD and recurrence of NAFLD-associated HCC. We conclude that the level of GGPPS is a susceptibility factor for NAFLD-fibrosis progression, and requires more stringent surveillance to ensure early prediction and precision of treatment of NAFLD-related HCC. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Backgroud To better identify patients with high mortality risk, we developed a systematic inflammation index (IPI) based on neutrophil to lymphocyte ratio (NLR) and albumin. Methods The performance of pretreatment IPI was evaluated in patients with surgically resected non-metastatic colorectal cancer. IPI was predefined and compared with Glasgow Prognostic Score (GPS)/modified GPS in terms of discrimination and calibration abilities. Results In multivariate analysis, patients with an IPI of 1 or 2 had 1.68(95%CI:1.15–2.44) or 3.56(95%CI:2.12–5.98)-fold increased cancer specific mortality risk(CSMR) respectively in comparison to patients with an IPI of 0. The prognostic significance was independent of tumor locations and nodal status. Compared with the GPS/mGPS, IPI had the higher c statistics and lower Akaike Information Criterion. IPI showed good calibration in predicting 1-year, 3-year and 5-year CSMR. Conclusions IPI is readily available, independently prognostic and may reflect the host inflammation, immune and nutritional status that could have impact on cancer progression.

Gestational diabetes mellitus (GDM) is a metabolic syndrome occurring in pregnant women and increases the risk of placental dysplasia. Neutrophil extracellular traps (NETs) may play a critical role in placental dysplasia. NETosis (neutrophil cell death by NET release) depends on NADPH/ROS pathway. In view of the adiponectin which is widely believed to be reduced in GDM patients suppresses NADPH oxidase and ROS generation of neutrophil. We speculate that increased NET release is associated with hypoadiponectinemia. Trophoblast apoptosis is significantly increased in GDM patients, but it is not clear whether NETs promotes cell apoptosis. This study aims to reveal the mechanism of Neutrophil Extracellular Traps generation and their role in trophoblast apoptosis in Gestational Diabetes Mellitus. We investigated the generation of NETs by cell-free DNA (cf-DNA) quantification, live-cell imaging, and reactive oxygen species (ROS) measurement. ERK1/2 and p38 MAPK signalling pathway proteins were detected by western blotting. The Cell Counting Kit-8 (CCK-8) assay, flow cytometry, and western blotting were performed to explore the effects of NETs on trophoblast apoptosis. We found that adiponectin inhibited NET release by suppressing ROS production, and p38 MAPK and ERK1/2 proteins were involved in the process. Further, NETs promoted trophoblast apoptosis by activating the ROS-dependent mitochondrial pathway, which is mediated by ERK1/2 signalling. The current study demonstrated that hypoadiponectinemia is the cause of NETs formation and NETs promoting trophoblast apoptosis.

Diabetes mellitus is an intractable chronic disease manifested as high blood glucose levels (BGLs) accompanied by a series of complications. Exogenous insulin supplement is essential for both type I and advanced type II diabetics to manage blood glucose in their daily life. Thus insulin delivery has become a hot research topic and a lot of effort has been witnessed on the development of insulin delivery methods. Being like artificial pancreases, smart glucose-responsive insulin delivery systems that are able to automatically release insulin on-demanded according to the real-time BGLs are considered to be ideal alternatives to damaged islets and have significant potential for diabetes treatment. Therefore, this review is aimed to summarize the recent advances in the smart glucose-responsive insulin delivery systems, including microscopic or macroscopic systems based on the glucose oxidase (GOx), phenylboronic acid (PBA) and concanavalin A (Con A). From the point of view of materials science and engineering, preparation, properties and glucose response mechanism of different systems are introduced. Their advantages, challenges and opportunities are also discussed.

While gastrointestinal (GI) symptoms are very common in patients with major depressive disorder (MDD), few studies have investigated the neural basis behind these symptoms. In this study, we sought to elucidate the neural basis of GI symptoms in MDD patients by analyzing the changes in regional gray matter volume (GMV) and gray matter density (GMD) in brain structure.Subjects were recruited from 13 clinical centers and categorized into three groups, each of which is based on the presence or absence of GI symptoms: the GI symptoms group (MDD patients with at least one GI symptom), the non-GI symptoms group (MDD patients without any GI symptoms), and the healthy control group (HCs). Structural magnetic resonance images (MRI) were collected of 335 patients in the GI symptoms group, 149 patients in the non-GI symptoms group, and 446 patients in the healthy control group. The 17-item Hamilton Depression Rating Scale (HAMD-17) was administered to all patients. Correlation analysis and logistic regression analysis were used to determine if there was a correlation between the altered brain regions and the clinical symptoms.There were significantly higher HAMD-17 scores in the GI symptoms group than that of the non-GI symptoms group (P 0.001). Both GMV and GMD were significant different among the three groups for the bilateral superior temporal gyrus, bilateral middle temporal gyrus, left lingual gyrus, bilateral caudate nucleus, right Fusiform gyrus and bilateral Thalamus (GRF correction, cluster-P 0.01, voxel-P 0.001). Compared to the HC group, the GI symptoms group demonstrated increased GMV and GMD in the bilateral superior temporal gyrus, and the non-GI symptoms group demonstrated an increased GMV and GMD in the right superior temporal gyrus, right fusiform gyrus and decreased GMV in the right Caudate nucleus (GRF correction, cluster-P 0.01, voxel-P 0.001). Compared to the non-GI symptoms group, the GI symptoms group demonstrated significantly increased GMV and GMD in the bilateral thalamus, as well as decreased GMV in the bilateral superior temporal gyrus and bilateral insula lobe (GRF correction, cluster-P 0.01, voxel-P 0.001). While these changed brain areas had significantly association with GI symptoms (P 0.001), they were not correlated with depressive symptoms (P 0.05). Risk factors for gastrointestinal symptoms in MDD patients (p 0.05) included age, increased GMD in the right thalamus, and decreased GMV in the bilateral superior temporal gyrus and left Insula lobe.MDD patients with GI symptoms have more severe depressive symptoms. MDD patients with GI symptoms exhibited larger GMV and GMD in the bilateral thalamus, and smaller GMV in the bilateral superior temporal gyrus and bilateral insula lobe that were correlated with GI symptoms, and some of them and age may contribute to the presence of GI symptoms in MDD patients.