COP9 signalosome (CSN) is an evolutionarily conserved regulatory component of the ubiquitin/proteasome system that plays crucial roles in plant growth and stress tolerance; however, the mechanism of COP9-mediated resistance to root-knot nematodes (RKNs, e.g. Meloidogyne incognita) is not fully understood in plants. In the present study, we found that RKN infection in the roots rapidly increases the transcript levels of CSN subunits 4 and 5 (CSN4 and CSN5) and their protein accumulation in tomato (Solanum lycopersicum) plants. Suppression of CSN4 or CSN5 expression resulted in significantly increased number of egg masses and aggravated RKN-induced lipid peroxidation of cellular membrane but inhibited RKN-induced accumulation of CSN4 or CSN5 protein in tomato roots. Importantly, the RKN-induced accumulation of jasmonic acid (JA) and JA-isoleucine (JA-Ile), as well as the transcript levels of JA-related biosynthetic and signaling genes were compromised by CSN4 or CSN5 gene silencing. Moreover, protein-protein interaction assays demonstrated that CSN4 and CSN5B interact with the jasmonate ZIM domain 2 (JAZ2), which is the signaling component of the JA pathway. Silencing of CSN4 or CSN5 also compromises RKN-induced JAZ2 expression. Together, our findings indicate that CSN4 and CSN5 play critical roles in JA-dependent basal defense against RKN.

Iron (Fe) and phosphorus (P) are two essential mineral nutrients whose acquisition by plants presents important environmental and economic implications. Both elements are abundant in most soils but scarcely available to plants. To prevent Fe or P deficiency dicot plants initiate morphological and physiological responses in their roots aimed to specifically acquire these elements. The existence of common signals in Fe and P deficiency pathways suggests the signaling factors must act in conjunction with distinct nutrient-specific signals in order to confer tolerance to each deficiency. Previous works have shown the existence of cross talk between responses to Fe and P deficiency, but details of the associated signaling pathways remain unclear. Herein, the impact of foliar application of either P or Fe on P and Fe responses was studied in P- or Fe-deficient plants of Arabidopsis thaliana, including mutants exhibiting altered Fe or P homeostasis. Ferric reductase and acid phosphatase activities in roots were determined as well as the expression of genes related to P and Fe acquisition. The results obtained showed that Fe deficiency induces the expression of P acquisition genes and phosphatase activity, whereas P deficiency induces the expression of Fe acquisition genes and ferric reductase activity, although only transitorily. Importantly, these responses were reversed upon foliar application of either Fe or P on nutrient-starved plants. Taken together, the results reveal interactions between P- and Fe-related phloem signals originating in the shoots that likely interact with hormones in the roots to initiate adaptive mechanisms to tolerate deficiency of each nutrient.

Biological data analysis is the key to new discoveries in disease biology and drug discovery. The rapid proliferation of high-throughput 'omics' data has necessitated a need for tools and platforms that allow the researchers to combine and analyse different types of biological data and obtain biologically relevant knowledge. We had previously developed TargetMine, an integrative data analysis platform for target prioritisation and broad-based biological knowledge discovery. Here, we describe the newly modelled biological data types and the enhanced visual and analytical features of TargetMine. These enhancements have included: an enhanced coverage of gene-gene relations, small molecule metabolite to pathway mappings, an improved literature survey feature, and in silico prediction of gene functional associations such as protein-protein interactions and global gene co-expression. We have also described two usage examples on trans-omics data analysis and extraction of gene-disease associations using MeSH term descriptors. These examples have demonstrated how the newer enhancements in TargetMine have contributed to a more expansive coverage of the biological data space and can help interpret genotype-phenotype relations. TargetMine with its auxiliary toolkit is available at https://targetmine.mizuguchilab.org. The TargetMine source code is available at https://github.com/chenyian-nibio/targetmine-gradle.

No abstract available

Cancer subtypes can improve our understanding of cancer, and suggest more precise treatment for patients. Multi-omics molecular data can characterize cancers at different levels. Up to now, many computational methods that integrate multi-omics data for cancer subtyping have been proposed. However, there are no consistent criteria to evaluate the integration methods due to the lack of gold standards (e.g., the number of subtypes in a specific cancer). Since comprehensive evaluation and comparison between different methods serves as a useful tool or guideline for users to select an optimal method for their own purpose, we develop a scalable platform, CEPICS, for comprehensively evaluating and comparing multi-omics data integration methods in cancer subtyping. Given a user-specified maximum number of subtypes, k-max, CEPICS provides (1) cancer subtyping results using up to five built-in state-of-the-art integration methods under the number of subtypes from two to k-max, (2) a report including the evaluation of each user-selected method and comparisons across them using clustering performance metrics and clinical survival analysis, and (3) an overall analysis of subtyping results by different methods representing a robust cancer subtype prediction for samples. Furthermore, users can upload subtyping results of their own methods to compare with the built-in methods. CEPICS is implemented as an R package and is freely available at https://github.com/GaoLabXDU/CEPICS.

Many infants worldwide are not breastfeeding according to WHO recommendations and this impacts on the health of women and children. Increasing breastfeeding is identified as a priority area supported by current policy targets. However, interventions are complex and multi-component and it is unclear which elements of interventions are most effective to increase breastfeeding in which settings. Breastfeeding counselling is often part of complex interventions but evidence is lacking on the specific effect of counselling interventions on breastfeeding practices. The aim of this systematic review is to examine evidence on effectiveness of breastfeeding counselling to inform global guidelines.

Background: Prunusarmeniaca is a member of the Rosacea family. The most important ingredient of this family is amygdalin that is believed to have anti-tumor and analgesic properties. The aim of this study was to evaluate the anti-proliferative effects of Armeniacae semen extract on the acute leukemia, NALM-6, and KG-1 cell lines, and investigate the effect of the extract on apoptosis of these cell lines and caspase-3 gene expression. Materials and Methods: We prepared aqueous, ethyl acetate, and hydro alcoholic extracts of the Armeniacae semen. The NALM-6 and KG-1 cell lines and mononuclear cells (PBMCs) of healthy controls were treated with different doses of the extracts for 48 hours, and then cell viability was investigated with the MTT test. High-Performance Liquid Chromatography was done for amygdalin identification. The percentage of apoptotic cells was determined using the Annexin V-FITC/PI flow cytometric kit, and caspase-3 gene expression was evaluated. Results: MTT test revealed that the strongest Inhibition Concentration (IC50) in KG-1 and NALM-6 cell lines was related to the ethyl acetate extract. This extract did not have toxic effects on PBMCs. Flow cytometric analysis showed that the ethyl acetate extract at its IC50 concentration led to almost 50% apoptosis in both cell lines after 48 hours. In the molecular examination, after treatment, a significant increase was seen in caspase-3 gene expression in NALM6 and KG1 cells compared to the control (P<0.001 and P <0.05, respectively). Conclusion: Our data confirmed that the ethyl acetate extract of Prunusarmeniaca could reduce the proliferation of KG-1 and NALM-6 cell lines probably by activating the apoptotic pathway.

Background: Lumbar puncture (LP) is a hematology procedure that can require repeated attempts leading to traumatic LP (TLP), which has been related to the central nervous system (CNS) relapse. LP success can depend on the size and anatomy of the patient and the skill of the hematologist. The main objective was to determine the influence of body mass index (BMI) on LP outcomes. Materials and Methods: Adults with lymphoid malignancies requiring LP were included prospectively over one year; hematology residents performed most procedures. A 22-gauge Quincke needle was employed. Comparison between non-traumatic vs. traumatic LPs according to BMI, CNS relapse, and residents' year was performed. Results: Fifty-four patients with a mean age of 31.5±15.57 years were included. Diagnosis was Acute Lymphoblastic Leukemia-B (74%), Acute Lymphoblastic Leukemia-T (13%) and Non-Hodgkin Lymphoma (13%). 227 LPs were performed, 121 (53.3%) successful, 98 (43.2%) traumatic, 11 (11.2%) TLPs were macroscopically detectable and 87 (88%) microscopic; 8 (3.5%) were dry-taps. Median time between punctures was 11 days (1-202). Median BMI was 25 (22.8-39.6). Main indication for LP was prophylactic (74.5%); 39.2% were performed by first-year, 35.2% by second-year, 19.6% by third-year hematology residents. No difference (p = 0.145) for a TLP was found among residents. A BMI ≥30 (p = 0.040), non-palpable intervertebral space (p = 0.001) and more than one attempt (p = 0.001) were significant for TLP. TLP was not associated with CNS relapse (p = 0.962). Conclusion: Obesity predicted a TLP. A traumatic puncture did not increase the risk of CNS relapse at one-year follow-up.

Renal cell carcinoma (RCC) is one of the most common malignant tumors affecting the urogenital system, accounting for 90% of renal malignancies. Traditional chemotherapy options are often the front-line choice of regimen in the treatment of patients with RCC, but responses may be modest or limited due to resistance of the tumor to anticarcinogen. Downregulated expression of organic cation transporter OCT2 is a possible mechanism underlying oxaliplatin resistance in RCC treatment. In this study, we observed that miR-489-3p and miR-630 suppress OCT2 expression by directly binding to the OCT2 3'-UTR. Meanwhile, via 786-O-OCT2-miRNAs stable expression cell models, we found that miRNAs could repress the classic substrate 1-methyl-4-phenylpyridinium (MPP+), fluorogenic substrate N,N-dimethyl-4-(2-pyridin-4-ylethenyl) aniline (ASP+), and oxaliplatin uptake by OCT2 both in vitro and in xenografts. In 33 clinical samples, miR-489-3p and miR-630 were significantly upregulated in RCC, negatively correlating with the OCT2 expression level compared to that in adjacent normal tissues, using tissue microarray analysis and qPCR validation. The increased binding of c-Myc to the promoter of pri-miR-630, responsible for the upregulation of miR-630 in RCC, was further evidenced by chromatin immunoprecipitation and dual-luciferase reporter assay. Overall, this study indicated that miR-489-3p and miR-630 function as oncotherapy-obstructing microRNAs by directly targeting OCT2 in RCC.

Chemotherapy is among the limited choices approved for the treatment of hepatocellular carcinoma (HCC) at intermediate and advanced stages. Preferential and prolonged drug exposure in diseased sites is required to maximize the therapeutic index of the drug. Here, we report an injectable supramolecular peptide hydrogel as an intraperitoneal depot for localized and sustained release of triptolide for the treatment of orthotopic HCC. We chose peptide amphiphile C16-GNNQQNYKD-OH-based nanofibers as gelators and carriers for triptolide. Sustained triptolide release from the hydrogel was achieved over 14 days in vitro, with higher accumulation in and cytotoxicity against human HCC Bel-7402 in comparison with L-02 fetal hepatocytes. After intraperitoneal injection, the hydrogel showed prolonged retention over 13 days and preferential accumulation in the liver, realizing HCC growth inhibition by 99.7 ± 0.1% and animal median survival extension from 19 to 43 days, without causing noticeable pathological changes in the major organs. These results demonstrate that injectable peptide hydrogel can be a potential carrier for localized chemotherapy of HCC.

The renewed interest in dimeric salicylates as broad-spectrum anti-inflammatory and anti-diabetic agents provided a rationale to investigate the dimerization of the substituted salicylate Δ 9-tetrahydrocannabinolic acid (THCA-A, 3a) as a strategy to solve its instability to decarboxylation and to generate analogues and/or pro-drugs of this native pre-cannabinoid. Activation of the carboxylic group with the DCC-HOBt-DMAP protocol afforded a high yield of the OBt ester 4, that was next converted into the highly crystalline di-depsidic dimer 5 upon treatment with DMAP. The mono-depsidic dimer 6 was also formed when the reaction was carried out with partially decarboxylated THCA-A samples. The structure of the depsidic dimers was established by spectroscopic methods and by aminolysis of 5 into the pre-cannabinoid amide 7. Both dimers showed excellent shelf stability and did not generate significant amounts of Δ 9-THC upon heating. However, only the didepsidic dimer 5 activated PPAR-γ, the major target of pre-cannabinoids, but strong binding to serum proteins abolished this activity, also shielding it from the action of esterases.

Dissociation, which is defined as the failure to associate consciousness, memory, identity, emotion, perception, body representation, motor control, and behavior into an integrated whole, has long been assumed to be generated by trauma. If dissociation is a product of trauma exposure, then dissociation would be a major mental health outcome observed in studies of disaster survivors. Although some studies have examined dissociation in disasters, no systematic literature reviews have been conducted to date on the topic.

Background: Multi-parametric MRI provides non-invasive methods for response assessment of soft-tissue sarcoma (STS) from non-surgical treatments. However, evaluation of MRI parameters over the whole tumor volume may not reveal the full extent of post-treatment changes as STS tumors are often highly heterogeneous, including cellular tumor, fat, necrosis, and cystic tissue compartments. In this pilot study, we investigate the use of machine-learning approaches to automatically delineate tissue compartments in STS, and use this approach to monitor post-radiotherapy changes. Methods: Eighteen patients with retroperitoneal sarcoma were imaged using multi-parametric MRI; 8/18 received a follow-up imaging study 2-4 weeks after pre-operative radiotherapy. Eight commonly-used supervised machine-learning techniques were optimized for classifying pixels into one of five tissue sub-types using an exhaustive cross-validation approach and expert-defined regions of interest as a gold standard. Final pixel classification was smoothed using a Markov Random Field (MRF) prior distribution on the final machine-learning models. Findings: 5/8 machine-learning techniques demonstrated high median cross-validation accuracies (82.2%, range 80.5-82.5%) with no significant difference between these five methods. One technique was selected (Naïve-Bayes) due to its relatively short training and class-prediction times (median 0.73 and 0.69 ms, respectively on a 3.5 GHz personal machine). When combined with the MRF-prior, this approach was successfully applied in all eight post-radiotherapy imaging studies and provided visualization and quantification of changes to independent STS sub-regions following radiotherapy for heterogeneous response assessment. Interpretation: Supervised machine-learning approaches to tissue classification in multi-parametric MRI of soft-tissue sarcomas provide quantitative evaluation of heterogeneous tissue changes following radiotherapy.

Introduction: Assessment of lymph node metastasis (LNM) is crucial for treatment decision and prognosis prediction for endometrial cancer (EC). However, the sensitivity of the routinely used magnetic resonance imaging (MRI) is low in assessing normal-sized LNM (diameter, 0-0.8 cm). We aimed to develop a predictive model based on magnetic resonance (MR) images and clinical parameters to predict LNM in normal-sized lymph nodes (LNs). Materials and Methods: A total of 200 retrospective patients were enrolled and divided into a training cohort (n = 140) and a test cohort (n = 60). All patients underwent preoperative MRI and had pathological result of LNM status. In total, 4,179 radiomic features were extracted. Four models including a clinical model, a radiomic model, and two combined models were built. Area under the receiver operating characteristic (ROC) curves (AUC) and calibration curves were used to assess these models. Subgroup analysis was performed according to LN size. All patients underwent surgical staging and had pathological results. Results: All of the four models showed predictive ability in LNM. One of the combined models, ModelCR1, consisting of radiomic features, LN size, and cancer antigen 125, showed the best discrimination ability on the training cohort [AUC, 0.892; 95% confidence interval [CI], 0.834-0.951] and test cohort (AUC, 0.883; 95% CI, 0.786-0.980). The subgroup analysis showed that this model also indicated good predictive ability in normal-sized LNs (0.3-0.8 cm group, accuracy = 0.846; <0.3 cm group, accuracy = 0.849). Furthermore, compared with the routinely preoperative MR report, the sensitivity and accuracy of this model had a great improvement. Conclusions: A predictive model was proposed based on MR radiomic features and clinical parameters for LNM in EC. The model had a good discrimination ability, especially for normal-sized LNs.

Background: Duodenal stump leakage (DSL) is a serious surgical complication after radical gastrectomy with Roux-en-Y or BillrothII reconstruction. This study was designed to evaluate the effectiveness of laparoscopic single purse-string suture for reinforcement of duodenal stump. Methods: A total of 183 patients harboring gastric adenocarcinoma following laparoscopic radical gastrectomy with Roux-en-Y or BillrothIIreconstruction and single purse-string suture for reinforcement of duodenal stump were retrospectively enrolled from Zhongshan Hospital of Fudan University (Shanghai, China) between January 2014 and December 2016. Operative variables and short-term complications were documented and analyzed. Clavien-Dindo classification system was used to identify surgical complications. Results: Among 183 patients, 108 (59.02%) patients received distal gastrectomy and 75 (40.98%) received total gastrectomy. 88 (48.09%) patients underwent Roux-en-Y reconstruction and 95 (51.91%) patients underwent Billroth-II reconstruction. The mean time of laparoscopic single purse-string suture was 5.01 ± 1.33 min (range from 3.6 to 10.2 min). Postoperative early complication occurred in 26 cases of the patients. There were 4 cases of system-related complications (2.19%), including 3 cases of pulmonary infection (1.64%) and 1 cases of cardiovascular event (0.55%); and 22 cases of surgery-related complications (12.02%), including 6 cases of intra-abdominal infection (3.28%), 4 cases of pancreatic leakage (2.19%), 4 cases of wound complications (2.19%), 3 cases of gastroparesis (1.64%), 2 cases of intra-abdominal bleeding (1.09%), 2 cases of ileus (1.09%), 1 cases of lymphatic leakage (0.55%), and no duodenal stump leakage. Conclusion: Reinforcement on duodenal stump using laparoscopic single purse-string suture during laparoscopic radical gastrectomy is simple and effective and could avoid the incidence of duodenal stump leakage to some extent.

Amino acid repeats play an important role in the structure and function of proteins. Analysis of long repeats in protein sequences enables one to understand their abundance, structure and function in the protein universe. In the present study, amino acid repeats of length >50 (long repeats) were identified in a non-redundant set of UniProt sequences using the RADAR program. The underlying structures and functions of these long repeats were carried out using the Gene3D for structural domains, Pfam for functional domains and enzyme and non-enzyme functional classification for catalytic and binding of the proteins. From a structural perspective, these long repeats seem to predominantly occur in certain architectures such as sandwich, bundle, barrel, and roll and within these architectures abundant in the superfolds. The lengths of the repeats within each fold are not uniform exhibiting different structures for different functions. We also observed that long repeats are in the domain regions of the family and are involved in the function of the proteins. After grouping based on enzyme and non-enzyme classes, we observed the abundant occurrence of long repeats in specific catalytic and binding of the proteins. In this study, we have analyzed the occurrence of long repeats in the protein sequence universe apart from well-characterized short tandem repeats in sequences and their structures and functions of the proteins at the domain level. The present study suggests that long repeats may play an important role in the structure and function of domains of the proteins.

While stem cell/biomaterial studies provide solid evidences that biomaterial intrinsic cues deeply affect cell fate, current strategies tend to neglect their effects on mesenchymal stem cells (MSCs) secretory activities and resulting cell-crosstalks. The present study aims to investigate the impact of bone-mimetic material (B-MM), with intrinsic osteoinductive property, on MSCs mediator secretions; and to explore underlying effects on cells involved in bone regeneration. Human MSCs were cultured, on B-MM, made from inorganic calcium phosphate supplemented with chitosan and hyaluronic acid biopolymers. Collected MSCs culture media were assessed for mediators release quantification and used further to stimulate endothelial cells (ECs) and alveolar bone derived osteoblasts (OBs). Without osteogenic supplements, MSCs committed into bone lineage forming thus 3D bone-like nodules after 21 days. Despite a weak percentage of cell commitment, our data elucidate new aspects of osteoinductive material effect on MSCs functions through the regulation of the secretion of mediators involved in bone regeneration and subsequently the MSCs/ECs indirect crosstalk with osteogenesis-boosting effect. Using MSCs culture media, we demonstrate a large potential of osteoinductive materials and MSCs in bone regenerative medicine. Such strategies could help to address some insights in cell-free therapies using MSCs derived media.

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease that causes breathlessness and cough that worsen over time, limiting daily activities and negatively impacting quality of life. Although treatments are now available that slow the rate of lung function decline, trials of these treatments have failed to show improvement in symptoms or quality of life. There is an immediate unmet need for evidenced-based interventions that improve patients' symptom burden and make a difference to everyday living. This study aims to assess the feasibility of conducting a definitive randomised controlled trial of a holistic, complex breathlessness intervention in people with IPF.

Occupational exposure to vapours, gases, dusts or fumes (VGDF) increases the prevalence of asthma-COPD overlap (ACO) in adult-onset asthma. VGDF exposure is independently associated with ACO and an additive effect with smoking is proposed. http://bit.ly/2LiMiXW.

Aldehyde dehydrogenase 2 (ALDH2) deficiency causes "Asian flush syndrome," presenting as alcohol-induced facial flushing, tachycardia, nausea, and headaches. One of the most common hereditary enzyme deficiencies, it affects 35%-40% of East Asians and 8% of the world population. ALDH2 is the key enzyme in ethanol metabolism; with ethanol challenge, the common ALDH2*2 (E487K) mutation results in accumulation of toxic acetaldehyde. ALDH2*2 heterozygotes have increased risk for upper digestive tract cancers, compounded by smoking and drinking alcohol. We hypothesized that a one-time administration of an adeno-associated virus (AAV) gene transfer vector expressing the human ALDH2 coding sequence (AAVrh.10hALDH2) would correct the deficiency state. AAVrh.10hALDH2 was administered intravenously to Aldh2 knockout (Aldh2 -/-) and Aldh2 E487K knockin homozygous (Aldh2 E487K+/+) mice. Following acute ethanol ingestion, untreated ALDH2-deficient mice had elevated acetaldehyde levels and performed poorly in behavioral tests. In contrast, treated Aldh2 -/- and Aldh2 E487K+/+ mice had lower serum acetaldehyde levels and improved behavior. Thus, in vivo AAV-mediated ALDH2 therapy may reverse the deficiency state in ALDH2*2 individuals, eliminating the Asian flush syndrome and reducing the risk for associated disorders.