Chronic Morphine Alters the Presynaptic Protein Profile: Identification of Novel Molecular Targets Using Proteomics and Network Analysis

Opiates produce significant and persistent changes in synaptic transmission; knowledge of the proteins involved in these changes may help to understand the molecular mechanisms underlying opiate dependence. Using an integrated quantitative proteomics and systems biology approach, we explored changes in the presynaptic protein profile following a paradigm of chronic morphine administration that leads to the development of dependence. For this, we isolated presynaptic fractions from the striata of rats treated with saline or escalating doses of morphine, and analyzed the proteins in these fractions using differential isotopic labeling. We identified 30 proteins that were significantly altered by morphine and integrated them into a protein-protein interaction (PPI) network representing potential morphine-regulated protein complexes. Graph theory-based analysis of this network revealed clusters of densely connected and functionally related morphine-regulated clusters of proteins. One of the clusters contained molecular chaperones thought to be involved in regulation of neurotransmission. Within this cluster, cysteine-string protein (CSP) and the heat shock protein Hsc70 were downregulated by morphine. Interestingly, Hsp90, a heat shock protein that normally interacts with CSP and Hsc70, was upregulated by morphine. Moreover, treatment with the selective Hsp90 inhibitor, geldanamycin, decreased the somatic signs of naloxone-precipitated morphine withdrawal, suggesting that Hsp90 upregulation at the presynapse plays a role in the expression of morphine dependence. Thus, integration of proteomics, network analysis, and behavioral studies has provided a greater understanding of morphine-induced alterations in synaptic composition, and identified a potential novel therapeutic target for opiate dependence

An exploration of dropout with RNNs for natural language inference.

Dropout is a crucial regularization technique for the Recurrent Neural Network (RNN) models of Natural Language Inference (NLI). However, dropout has not been evaluated for the effectiveness at different layers and dropout rates in NLI models. In this paper, we propose a novel RNN model for NLI and empirically evaluate the effect of applying dropout at different layers in the model. We also investigate the impact of varying dropout rates at these layers. Our empirical evaluation on a large (Stanford Natural Language Inference (SNLI)) and a small (SciTail) dataset suggest that dropout at each feed-forward connection severely affects the model accuracy at increasing dropout rates. We also show that regularizing the embedding layer is efficient for SNLI whereas regularizing the recurrent layer improves the accuracy for SciTail. Our model achieved an accuracy 86.14% on the SNLI dataset and 77.05% on SciTail

Evaluation of haptoglobin phenotypes in acute myocardial infarction (AMI) and their association with some risk factors

Acute myocardial infarction (AMI) is one of the most common cardiovascular complications with a complex pathogenesis where inflammatory markers are involved in disease etiology. The aim of this study was to investigate haptoglobin phenotypes and their association with some risk factors in patients with a history of AMI. 120 patients who were referred to the emergency department of Amir Al Momenin hospital of Zahedan city, Zahedan-Iran were recruited in a cross-sectional case control study. 120 normal individuals were also chosen as controls for this study. Serum was isolated from routine bloods taken for diagnostic tests and used to determine haptoglobin phenotype distribution by electrophoresis. Phenotype differences as percent of phenotype frequency in patient and control groups were analysed using the χ2 test and SPSS software. A high frequency of serum Hp2-2 haptoglobin phenotype in patients and healthy control were found (62.5% and 58.3% respectively). A meaningful statistical correlation between high frequency of Hp2-2 haptoglobin phenotype and AMI was not found (p value = 0.484). Whereas high frequency of Hp1-1 and HP2-2 phenotypes was associated with hyperlipidemia and hypertension respectively (p value = 0.01 and 0.04). Our results showed that there was a high frequency of Hp2-2 haptoglobin phenotype in patients as well as healthy controls in the population studies. High frequencies of Hp1-1and Hp2-2 phenotypes were associated with AMI in patients with hyperlipidemia and hypertension respectively. Thus these phenotypes in AMI patients may modulate the inflammatory response in combination with hyperlipidemia and hypertension

Ten Simple Rules for Organizing a Virtual Conference—Anywhere

Etienne P. de Villiers and Sheila C. Ommeh are ILRI author

Designing with biosignals: Challenges, opportunities, and future directions for integrating physiological signals in human-computer interaction

Biosensing technologies are a rapidly increasing presence in our daily lives. These sensor-based technologies measure physiological processes including heart rate, breathing, skin conductance, brain activity and more. Researchers are exploring biosensing from perspectives including: engineering, human-computer interaction, medicine, mental health, consumer products, and interactive art. These technologies can enhance our interactions allowing connection to our bodies and others around us across diverse application areas. However, designing with biosignals in Human-Computer Interaction presents new challenges pertaining to User Experience, Input/Output, interpretation of signals, representation, and ethics. There is an urgent need to build a scholarly community that includes the diverse perspectives of researchers, designers, industry practitioners and policymakers. The goal of this workshop is to leverage the knowledge of this community aiming to map out the research landscape of emerging challenges and opportunities, and to build a research agenda for future directions

CpG-island methylation of the ER promoter in colorectal cancer: analysis of micrometastases in lymph nodes from UICC stage I and II patients

Patients with UICC stage II colorectal cancer (CRC) have a risk of approximately 20% to develop disease recurrence after tumour resection. The presence and significance of micrometastases for locoregional recurrence in these patients lacking histopathological lymph node involvement on routine stained HE sections is undefined. Oestrogen receptor (ER) promoter methylation has earlier been identified in CRC. Therefore, we evaluated the methylation status of the ER promoter in lymph nodes from 49 patients with CRC UICC stage I and II as a molecular marker of micrometastases and predictor of local recurrence. DNA from 574 paraffin-embedded lymph nodes was isolated and treated with bisulphite. For the detection of methylated ER promoter sequences, quantitative real-time methylation-specific PCR was used. Of the 49 patients tested, 15 (31%) had ER methylation-positive lymph nodes. Thirteen of those (86%) remained disease free and two (14%) developed local recurrence. In the resected lymph nodes of 34 of the 49 patients (69%), no ER promoter methylation could be detected and none of these patients experienced a local relapse. The methylation status of the ER promoter in lymph nodes of UICC stage I and II CRC patients may be a useful marker for the identification of patients at a high risk for local recurrence

Large-scale Phenotyping of Patients With Long Covid Post-hospitalization Reveals Mechanistic Subtypes of Disease

One in ten severe acute respiratory syndrome coronavirus 2 infections result in prolonged symptoms termed long coronavirus disease (COVID), yet disease phenotypes and mechanisms are poorly understood1. Here we profiled 368 plasma proteins in 657 participants ≥3 months following hospitalization. Of these, 426 had at least one long COVID symptom and 233 had fully recovered. Elevated markers of myeloid inflammation and complement activation were associated with long COVID. IL-1R2, MATN2 and COLEC12 were associated with cardiorespiratory symptoms, fatigue and anxiety/depression; MATN2, CSF3 and C1QA were elevated in gastrointestinal symptoms and C1QA was elevated in cognitive impairment. Additional markers of alterations in nerve tissue repair (SPON-1 and NFASC) were elevated in those with cognitive impairment and SCG3, suggestive of brain–gut axis disturbance, was elevated in gastrointestinal symptoms. Severe acute respiratory syndrome coronavirus 2-specific immunoglobulin G (IgG) was persistently elevated in some individuals with long COVID, but virus was not detected in sputum. Analysis of inflammatory markers in nasal fluids showed no association with symptoms. Our study aimed to understand inflammatory processes that underlie long COVID and was not designed for biomarker discovery. Our findings suggest that specific inflammatory pathways related to tissue damage are implicated in subtypes of long COVID, which might be targeted in future therapeutic trials

Detection of microRNA Expression in Human Peripheral Blood Microvesicles

MicroRNAs (miRNA) are small non-coding RNAs that regulate translation of mRNA and protein. Loss or enhanced expression of miRNAs is associated with several diseases, including cancer. However, the identification of circulating miRNA in healthy donors is not well characterized. Microvesicles, also known as exosomes or microparticles, circulate in the peripheral blood and can stimulate cellular signaling. In this study, we hypothesized that under normal healthy conditions, microvesicles contain miRNAs, contributing to biological homeostasis.Microvesicles were isolated from the plasma of normal healthy individuals. RNA was isolated from both the microvesicles and matched mononuclear cells and profiled for 420 known mature miRNAs by real-time PCR. Hierarchical clustering of the data sets indicated significant differences in miRNA expression between peripheral blood mononuclear cells (PBMC) and plasma microvesicles. We observed 71 miRNAs co-expressed between microvesicles and PBMC. Notably, we found 33 and 4 significantly differentially expressed miRNAs in the plasma microvesicles and mononuclear cells, respectively. Prediction of the gene targets and associated biological pathways regulated by the detected miRNAs was performed. The majority of the miRNAs expressed in the microvesicles from the blood were predicted to regulate cellular differentiation of blood cells and metabolic pathways. Interestingly, a select few miRNAs were also predicted to be important modulators of immune function.This study is the first to identify and define miRNA expression in circulating plasma microvesicles of normal subjects. The data generated from this study provides a basis for future studies to determine the predictive role of peripheral blood miRNA signatures in human disease and will enable the definition of the biological processes regulated by these miRNA

Rab27a co-ordinates actin-dependent transport by controlling organelle-associated motors and track assembly proteins

Abstract: Cell biologists generally consider that microtubules and actin play complementary roles in long- and short-distance transport in animal cells. On the contrary, using melanosomes of melanocytes as a model, we recently discovered that the motor protein myosin-Va works with dynamic actin tracks to drive long-range organelle dispersion in opposition to microtubules. This suggests that in animals, as in yeast and plants, myosin/actin can drive long-range transport. Here, we show that the SPIRE-type actin nucleators (predominantly SPIRE1) are Rab27a effectors that co-operate with formin-1 to generate actin tracks required for myosin-Va-dependent transport in melanocytes. Thus, in addition to melanophilin/myosin-Va, Rab27a can recruit SPIREs to melanosomes, thereby integrating motor and track assembly activity at the organelle membrane. Based on this, we suggest a model in which organelles and force generators (motors and track assemblers) are linked, forming an organelle-based, cell-wide network that allows their collective activity to rapidly disperse the population of organelles long-distance throughout the cytoplasm