In addition to the stepwise manner of lymph-node metastasis from the primary tumour, the skip lymph-node metastasis (SLNM) was identified as a low-incidence metastasis of gastric cancer (GC). So far, both the mechanism and outcome of SLNM have not been elucidated completely. The purpose of this study was to analyse the clinical significance and the potential mechanism of SLNM in GC patients who had lymph-node metastasis.

High aortic stiffness may reduce myocardial perfusion pressure and contribute to development of myocardial ischaemia. Whether high aortic stiffness is associated with myocardial ischaemia in patients with stable angina and non-obstructive coronary artery disease (CAD) is less explored.

The optimal timing of renal replacement therapy (RRT) initiation in critically ill patients with acute kidney injury (AKI) remains controversial.

Heat-shock protein of 90 kDa (Hsp90) is a key molecular chaperone involved in folding the synthesized protein and controlling protein quality. Conformational dynamics coupled to ATPase activity in N-terminal domain is essential for Hsp90's function. However, the relevant process is still largely unknown in plant Hsp90s, especially those required for plant embryogenesis which is inextricably tied up with human survival. Here, AtHsp90.6, a member of Hsp90 family in Arabidopsis, was firstly identified as a protein essential for embryogenesis. Thus we modelled AtHsp90.6 in its functionally closed 'lid-down' and open 'lid-up' states, exploring the nucleotide binding mechanism in these two states. Free energy landscape and electrostatic potential analysis revealed the switching mechanism between these two states. Collectively, this study quantitatively analysed the conformational changes of AtHsp90.6 bound to ATP or ADP. This result may help us understand the mechanism of action of AtHsp90.6 in future.

Preoperative axillary nerve palsy is a contraindication to reverse total shoulder arthroplasty (rTSA) due to the theoretical risk of higher dislocation rates and poor functional outcomes. Treatment of fracture-dislocations of the proximal humerus with rTSA is particularly challenging, as these injuries commonly present with concomitant neurologic and soft tissue injury. The aim of the current study was to determine the efficacy of rTSA for this fracture pattern in geriatric patients presenting with occult or profound neurologic injury.

Microbes have been recognized as important symbionts to regulate host life. The animal gut harbors abundance and diverse bacteria. Numerous internal and external factors influence intestinal bacterial communities, including diet, seasonal fluctuations and habitat sites. However, the factors that influence the gut bacterial communities of wild bird is poorly characterized.

Trichosporon asahii is the major pathogen causing invasive trichosporonosis. Conventional methods of its detection are time-consuming or costly and often require complex DNA extraction and purification steps, which hinders rapid clinical diagnosis. In this study, we evaluated colony PCR, which directly uses colonies or trace clinical samples as the template for amplification, for rapid detection of T. asahii infection. Four methods, namely, direct colony, freeze-thaw, glass beads, and enzymolysis, were compared to select the best DNA extraction strategy. We subsequently designed and screened species-specific primers targeting the intergenic spacer 1 (IGS1) of the ribosomal DNA of T. asahii and used them to detect mock infection clinical samples. The species-specific colony PCR based on glass beads proved advantageous, with short procedure time (154.8 ± 0.6 min), good sensitivity (detection limit, 102 CFU/mL), and specificity for T. asahii, indicating that this method can be used for the rapid and simple identification of clinical samples of T. asahii infection.

Receptor tyrosine kinase (RTK) is activated by its natural ligand, mediating multiple essential biological processes. Copper (II) ions are bioactive ions and are crucial in the regulation of cell signaling pathway. However, the crosstalk between copper (II) ions and RTK-mediated cellular signaling remains unclear. Herein, we reported the effect of copper (II) ions on the ligand-independent RTK cellular signaling pathway. Our results indicate that both EGFR and MET signaling were activated by copper (II) in the absence of the corresponding ligands, EGF and HGF, respectively. Consequently, copper (II) ions initiate two RTK-mediated downstream signal transductions, including AKT and ERK. Moreover, copper (II) significantly increased proliferation and cellular migration. Our study proposes a novel role of copper in RTK-mediated signaling for growth factor-independent cancer cell proliferation and migration, implying that targeting both the copper (II) and growth factor in tumor microenvironments may be necessary for cancer treatment.

Brain tumor surgery requires careful balance between maximizing tumor excision and preserving eloquent cortex. In some cases, the surgeon may opt to perform an awake craniotomy including intraoperative mapping of brain function by direct cortical stimulation (DCS) to assist in surgical decision-making. Preoperatively, functional magnetic resonance imaging (fMRI) facilitates planning by identification of eloquent brain areas, helping to guide DCS and other aspects of the surgical plan. However, brain deformation (shift) limits the usefulness of preoperative fMRI during surgery. To address this, an integrated visualization method for fMRI and DCS results is developed that is intuitive for the surgeon.

Large-scale human genetics studies are now employing whole genome sequencing with the goal of conducting comprehensive trait mapping analyses of all forms of genome variation. However, methods for structural variation (SV) analysis have lagged far behind those for smaller scale variants, and there is an urgent need to develop more efficient tools that scale to the size of human populations. Here, we present a fast and highly scalable software toolkit (svtools) and cloud-based pipeline for assembling high quality SV maps-including deletions, duplications, mobile element insertions, inversions and other rearrangements-in many thousands of human genomes. We show that this pipeline achieves similar variant detection performance to established per-sample methods (e.g. LUMPY), while providing fast and affordable joint analysis at the scale of ≥100 000 genomes. These tools will help enable the next generation of human genetics studies.

Despite acknowledged benefits of residents in nursing homes spending time outdoors, little is known about factors related to their use of outdoor space. This systematic review summarizes reported barriers and enablers to nursing home residents' use of outdoor spaces.

In PEGASUS-TIMI 54, ticagrelor significantly reduced the risk of the composite of major adverse cardiovascular (CV) events by 15-16% in stable patients with a prior myocardial infarction (MI) 1-3 years earlier. We report the efficacy and safety in the subpopulation recommended for treatment in the European (EU) label, i.e. treatment with 60 mg b.i.d. initiated up to 2 years from the MI, or within 1 year after stopping previous adenosine diphosphate receptor inhibitor treatment.

Congenital hyperinsulinism (CHI) is a clinically, genetically, and morphologically heterogeneous disorder. 18F DOPA-PET CT scanning greatly improves its clinical outcome. Here, we presented the first Chinese 18F DOPA-PET CT scanning-based CHI cohort highlighting the variable ethic clinical phenotypes and genotypes. Fifty CHI patients were recruited. Median age at presentation was 2 days. Median fasting time was 2 h. Mean insulin level was 25.6 μIU/ml. Fifty-two percent of patients were diazoxide-unresponsive with significantly shorter fasting tolerance time and higher serum insulin level compared with the responsive patients. Seventy-four percent of patients experienced at least one adverse drug reaction. Tremendously increased focal lesions (32%) were detected and 75% of them were cured through surgery. Thirty-one nucleotide sequence changes were identified in 48% patients. Four novel variants (Q608X, Q1347X, Q289X, F1489S) in ABCC8 gene and 2 novel variants (G132A, V138E) in KCNJ11 gene were detected. Of the variants, 87.1% harbored in ABCC and KCNJ11 genes. T1042Qfs*75 in ABCC8 gene was the most common mutation.Conclusion: Highly increased portion of focal lesion was presented in Chinese CHI patients compared with that of the previous reports. Intolerance to diazoxide was much more evident in Chinese or East Asian than other populations. Certain hotspot mutations harbored in Chinese CHI patients. What is Known: • 18F DOPA-PET CT scanning can provide informative guidance for surgical procedure when medical therapy is not well responded in CHI patients. What is New: • Intolerance to diazoxide is much more evident in Chinese and East Asian CHI patients compared with the other ethnic populations. • Novel mutations were detected in ABCC8 and KCNJ11 gene. Hotspot mutations such as T1042Qfs*75, I1511K, E501K, G111R in ABCC8 gene, and R34H in KCNJ11 gene are predominantly responsible for Chinese CHI patients.

The cost of rural health continues to be high in the United States despite an overall improvement in national health insurance enrolment. Stakeholder's perception of adverse selection remains a paramount culprit in the challenges of rural insurance markets. Risk attitude has been revealed as an alternative for measuring this phenomenon, given the 2014 prohibition law on pre-existing conditions and a subsequent repeal in 2018 accompanied by extensive debate among congress. We examine the existence of adverse selection in rural insurance markets by comparing the effects of pre-existing or chronic health conditions and risk attitudes in a Principal-Agent model.

The application of convolutional neural networks (ConvNets) to harness high-content screening images or 2D compound representations is gaining increasing attention in drug discovery. However, existing applications often require large data sets for training, or sophisticated pretraining schemes. Here, we show using 33 IC50 data sets from ChEMBL 23 that the in vitro activity of compounds on cancer cell lines and protein targets can be accurately predicted on a continuous scale from their Kekulé structure representations alone by extending existing architectures (AlexNet, DenseNet-201, ResNet152 and VGG-19), which were pretrained on unrelated image data sets. We show that the predictive power of the generated models, which just require standard 2D compound representations as input, is comparable to that of Random Forest (RF) models and fully-connected Deep Neural Networks trained on circular (Morgan) fingerprints. Notably, including additional fully-connected layers further increases the predictive power of the ConvNets by up to 10%. Analysis of the predictions generated by RF models and ConvNets shows that by simply averaging the output of the RF models and ConvNets we obtain significantly lower errors in prediction for multiple data sets, although the effect size is small, than those obtained with either model alone, indicating that the features extracted by the convolutional layers of the ConvNets provide complementary predictive signal to Morgan fingerprints. Lastly, we show that multi-task ConvNets trained on compound images permit to model COX isoform selectivity on a continuous scale with errors in prediction comparable to the uncertainty of the data. Overall, in this work we present a set of ConvNet architectures for the prediction of compound activity from their Kekulé structure representations with state-of-the-art performance, that require no generation of compound descriptors or use of sophisticated image processing techniques. The code needed to reproduce the results presented in this study and all the data sets are provided at https://github.com/isidroc/kekulescope .

DJ-1 is a protein with a wide range of functions importantly related to redox regulation in the cell. In humans, dysfunction of the PARK7 gene is associated with neurodegeneration and Parkinson's disease. Our objective was to establish a novel DJ-1 knockout zebrafish line and to identify early brain proteome changes, which could be linked to later pathology. The CRISPR-Cas9 method was used to target exon 1 of the park7-/- gene to produce a transgenic DJ-1-deficient zebrafish model of Parkinson's disease. Label-free mass spectrometry was employed to identify altered protein expression in the DJ-1 null brain of early adult animals. The park7-/- line appears to develop normally at young adult and larval stages. With aging however, DJ-1 null fish exhibit lower tyrosine hydroxylase levels, respiratory failure in skeletal muscle, and lower body mass which is especially prevalent among male fish. By proteomic analysis of early adult brains, we determined that less than 5% of the 4091 identified proteins were influenced by the lack of DJ-1. The dysregulated proteins were mainly proteins known to be involved in mitochondrial metabolism, mitophagy, stress response, redox regulation, and inflammation. This dysregulation in protein networks of our novel DJ-1-deficient zebrafish model occurs in the early adult stage preceding a Parkinson's disease-related phenotype and the reduction of tyrosine hydroxylase level. The identified protein changes provide new mechanistic background for DJ-1 function. The experimental power of zebrafish makes this model a highly valuable tool to understand and modulate cellular signaling leading to neurodegeneration.

To determine clinical predictors of lithium response in bipolar disorder.

Ralstonia solanacearum is the causal agent of bacterial wilt in solanaceous crops. This pathogen injects approximately 70 effector proteins into plant cells via the Hrp type III secretion system in an early stage of infection. To identify an as-yet-unidentified avirulence factor possessed by the Japanese tobacco-avirulent strain RS1000, we transiently expressed RS1000 effectors in Nicotiana benthamiana leaves and monitored their ability to induce effector-triggered immunity (ETI). The expression of RipB strongly induced the production of reactive oxygen species and the expressions of defence-related genes in N. benthamiana. The ripB mutant of RS1002, a nalixidic acid-resistant derivative of RS1000, caused wilting symptoms in N. benthamiana. A pathogenicity test using R. solanacearum mutants revealed that the two already known avirulence factors RipP1 and RipAA contribute in part to the avirulence of RS1002 in N. benthamiana. The Japanese tobacco-virulent strain BK1002 contains mutations in ripB and expresses a C-terminal-truncated RipB that lost the ability to induce ETI in N. benthamiana, indicating a fine-tuning of the pathogen effector repertoire to evade plant recognition. RipB shares homology with Xanthomonas XopQ, which is recognized by the resistance protein Roq1. The RipB-induced resistance against R. solanacearum was abolished in Roq1-silenced plants. These findings indicate that RipB acts as a major avirulence factor in N. benthamiana and that Roq1 is involved in the recognition of RipB.

Patients with cancer, especially breast, prostate, and lung cancer, commonly experience bone metastases that are difficult to manage and are associated with bone cancer pain. Amitriptyline is often used to treat chronic pain, such as neuropathic pain. In this study, the effects of amitriptyline on the mechanical withdrawal threshold and its underlying mechanisms were evaluated in rat models of bone cancer pain. Walker 256 rat mammary gland carcinoma cells were injected into the bone marrow cavity of the right tibia of rats to provoke bone cancer pain. Then, amitriptyline was intraperitoneally administered twice daily from fifth day after the operation. Rats with bone cancer showed an apparent decline in the mechanical withdrawal threshold at day 11 after Walker 256 cells inoculation. The levels of the glutamate-aspartate transporter in the spinal cord dorsal horn decreased remarkably, and the concentration of the excitatory amino acid glutamate in the cerebrospinal fluid increased substantially. Amitriptyline injection could prevent the decline of mechanical withdrawal threshold in bone cancer pain rats. In addition, glutamate-aspartate transporter was upregulated on the glial cell surface, and glutamate levels were reduced in the cerebrospinal fluid. However, amitriptyline injection could not prevent the bone cancer pain-induced reduction in glutamate-aspartate transporter in the glial cell cytosol, it further downregulated cytosolic glutamate-aspartate transporter. Amitriptyline had no significant effect on GLAST messenger RNA expression, and bone cancer pain-invoked protein kinase A/protein kinase C upregulation was prevented. Taken together, these results suggest that the intraperitoneal injection of amitriptyline can prevent the decrease of mechanical withdrawal threshold in bone cancer pain rats, the underlying mechanisms may be associated with the inhibition of protein kinase A/protein kinase C expression, thus promoting glutamate-aspartate transporter trafficking onto the glial cell surface and reducing excitatory amino acid concentrations in the cerebrospinal fluid.

This study investigated interleukin (IL)-33 expression in chronic apical periodontitis (CAP) lesions and possible relationships with receptor activator of nuclear factor κ-Β ligand (RANKL) and osteoprotegerin (OPG).