Search

Short-term plasticity preserves a brief history of synaptic activity that is communicated to the postsynaptic neuron. This is primarily regulated by a calcium signal initiated by voltage dependent calcium channels in the presynaptic terminal. Imaging studies of CA3-CA1 synapses reveal the presence of another source of calcium, the endoplasmic reticulum (ER) in all presynaptic terminals. However, the precise role of the ER in modifying STP remains unexplored. We performed in-silico experiments in synaptic geometries based on reconstructions of the rat CA3-CA1 synapses to investigate the contribution of ER. Our model predicts that presynaptic ER is critical in generating the observed short-term plasticity profile of CA3-CA1 synapses and allows synapses with low release probability to operate more reliably. Blocking the ER lowers facilitation in a manner similar to what has been previously characterized in animal models of Alzheimer’s disease and underscores the important role played by presynaptic stores in normal function., Singh and colleagues report that the endoplasmic reticulum (ER) contributes to short-term plasticity (STP). Using modelling approaches they reveal that ER’s buffering capacities are crucial in this process.

Purpose To identify and characterize studies evaluating clinician compliance with infection-related guidelines, and to explore trends in guideline design and implementation strategies. Data sources PubMed database, April 2017. Followed the PRISMA Statement for systematic reviews. Study selection Scope was limited to studies reporting compliance with guidelines pertaining to the prevention, detection, and/or treatment of acute hospital-based infections. Initial search (1,499 titles) was reduced to 49 selected articles. Data extraction Extracted publication and guideline characteristics, outcome measures reported, and any results related to clinician compliance. Primary summary measures were frequencies and distributions of characteristics. Interventions that led to improved compliance results were analyzed to identify trends in guideline design and implementation. Results of data synthesis Of the 49 selected studies, 18 (37%), 13 (27%), and 10 (20%) focused on sepsis, pneumonia, and general infection, respectively. Six (12%), 17 (35%), and 26 (53%) studies assessed local, national, and international guidelines, respectively. Twenty studies (41%) reported 1-instance compliance results, 28 studies (57%) reported 2-instance compliance results (either before-and-after studies or control group studies), and 1 study (2%) described compliance qualitatively. Average absolute change in compliance for minimal, decision support, and multimodal interventions was 10%, 14%, and 25%, respectively. Twelve studies (24%) reported no patient outcome alongside compliance. Conclusions Multimodal interventions and quality improvement initiatives seem to produce the greatest improvement in compliance, but trends in other factors were inconsistent. Additional research is required to investigate these relationships and understand the implications behind various approaches to guideline design, communication, and implementation, in addition to effectiveness of protocol impact on relevant patient outcomes.

Entamoeba histolytica, a pathogenic parasite, is the causative organism of amoebiasis and uses human colon to complete its life cycle. It destroys intestinal tissue leading to invasive disease. Since it does not form cyst in culture medium, a reptilian parasite Entamoeba invadens serves as the model system to study encystation. Detailed investigation on the mechanism of cyst formation, information on ultra-structural changes and cyst wall formation during encystation are still lacking in E. invadens. Here, we used electron microscopy to study the ultrastructural changes during cyst formation and showed that the increase in heterochromatin patches and deformation of nuclear shape were early events in encystation. These changes peaked at ∼20 h post induction, and normal nuclear morphology was restored by 72 h. Two types of cellular structures were visible by 16 h. One was densely stained and consisted of the cytoplasmic mass with clearly visible nucleus. The other consisted of membranous shells with large vacuoles and scant cytoplasm. The former structure developed into the mature cyst while the latter structure was lost after 20 h, This study of ultra-structural changes during encystation in E. invadens opens up the possibilities for further investigation into the mechanisms involved in this novel process.

The healthcare sector has been stretched to its maximum capacity with the outbreak of coronavirus. With a worldwide impact it has highlighted the maximum capabilities and limitations in the existing healthcare facilities worldwide. Such an unprecedented load of healthcare requirements can be supported with Internet of Things (IoT) and cloud services. The limited number of healthcare staff and limited resources urge the use of emerging technologies to support healthcare provision. In such circumstance IoT and cloud computing offer sufficient potential that can be used for monitoring, diagnosis, support, and intelligent decisioning. A smart environment can be created with the collected data from patients, medical equipment, hospitals, ambulances, recovery centers, old-age houses, and nursing homes. The use of cloud services integrated with IoT allows the collection, analysis, and provisioning of support and solution at a rapid rate. This facilitates remote patient-monitoring and safeguards healthcare providers from coming in direct contact with the patient and highly infectious and contagious work environment. It also brings in great potentials for smart-health solutions with enhanced patient observation, monitoring, support, and prediction of vital needs essential in emergency situations.

International audience; With the spread of drug resistance, new antimicrobials are urgently needed. Here, we set out to tackle this problem by high-throughput exploration for novel antifungal synergies among combinations of approved, nonantifungal drugs; a novel strategy exploiting the potential of alternative targets, low chemicals usage and low development risk. We screened the fungal pathogen Candida albicans by combining a small panel of nonantifungal drugs (all in current use for other clinical applications) with 1280 compounds from an approved drug library. Screens at sublethal concentrations of the antibiotic paromomycin (PM), the antimalarial primaquine (PQ), or the anti-inflammatory drug ibuprofen (IF) revealed a total of 17 potential strong, synergistic interactions with the library compounds. Susceptibility testing with the most promising combinations corroborated marked synergies [fractional inhibitory concentration (FIC) indices ≤0.5] between PM + β-escin, PQ + celecoxib, and IF + pentamidine, reducing the MICs of PM, PQ, and IF in C. albicans by >64-, 16-, and 8-fold, respectively. Paromomycin + β-escin and PQ + celecoxib were effective also against C. albicans biofilms, azole-resistant clinical isolates, and other fungal pathogens. Actions were specific, as no synergistic effect was observed in mammalian cells. Mode of action was investigated for one of the combinations, revealing that PM + β-escin synergistically increase the error-rate of mRNA translation and suggesting a different molecular target to current antifungals. The study unveils the potential of the described combinatorial strategy in enabling acceleration of drug-repurposing discovery for combatting fungal pathogens.

Novel coronavirus disease 2019 (COVID-19) is the biggest threat to human being globally. The first case was identified in a patient with flu symptoms along with severe acute respiratory syndrome in Wuhan, China in December 2019 and now it has spread in more than 200 countries. COVID-19 is more lethal in the elderly and people with an underlying condition such as asthma, cancer, diabetes. Here we performed bioinformatic analysis to investigate the interaction of S2 subunit protein of SARS-nCoV-2 of novel coronavirus with tumor suppressor proteins p53 and BRCA-1/2. In this short communication we report the interaction between S2 subunit proteins with tumor suppressor proteins for the first time. This preliminary result will open up a new direction to investigate the effect of a novel coronavirus in cancer patients.

To assess whether quantitative T1 relaxometry can measure permeability, chronic inflammation and mural thickening of mouse bladder wall. Adult female C57BL6 mice unexposed to radiation (controls) or 40 wk postirradiation of 10 Gy were scanned at 9.4 T before and after instillation (0.1 mL) of aqueous, novel contrast mixture (NCM) containing 4 mM gadobutrol and 5 mM ferumoxytol. Rapid acquisition with refocused echo (RARE) sequence was used with variable repetition times (TR). Pixel-wise maps of T1 relaxation times for the segmented bladder wall layers were generated from voxel-wise, nonlinear least square data fitting of TR-dependent signal intensity acquired with TR array of 0.4–10 s followed by the histology of harvested bladder. Significant differences between precontrast and postcontrast T1 (ΔT1) were noted in urothelium and lamina propria of both groups but only in detrusor of irradiated group ( P < 0.001; 2-way ANOVA). Nearly twofold higher gadobutrol permeability (550 ± 73 vs. 294 ± 160 μM; P < 0.01) derived as per 1/ΔT1 = r1. [C] in urothelium of irradiated group. Inflammation and bladder wall thickening (0.75 ± 0. vs. 0.44 ± 0.08 mm; P < 0.001) predicted by MRI was subsequently confirmed by histology and altered expression of CD45 and zonula occludens-1 (ZO-1) relative to controls. NCM enhanced MRI relies on the retention of large molecular weight ferumoxytol in lumen for negative contrast, while permeation of the non-ionic, small molecular weight gadobutrol through ZO-1 generates positive contrast in bladder wall for virtual measurement of paracellular permeability and assessment of chronic inflammation in thin and distensible bladder wall, which is also defined by its variable shape and location within pelvis.

Skin offers protection against external insults, with the skin microbiota playing a crucial defensive role against pathogens that gain access when the skin barrier is breached. Linkages between skin microbes, biofilms and disease have not been well established although single-species biofilm formation by skin microbiota in vitro has been extensively studied. Consequently, the purpose of this work was to optimize and validate a simple polymicrobial biofilm keratinocyte model for investigating commensal, pathogen and keratinocyte interactions and for evaluating therapeutic agents or health promoting interventions. The model incorporates the commensals (Staphylococcus epidermidis and Micrococcus luteus) and pathogens (Staphylococcus aureus and Pseudomonas aeruginosa) which form robust polymicrobial biofilms on immortalized keratinocytes (HaCat cells). We observed that the commensals reduce the damage caused to the keratinocyte monolayer by either pathogen. When the commensals were combined with P. aeruginosa and S. aureus, much thinner biofilms were observed than those formed by the pathogens alone. When P. aeruginosa was inoculated with S. epidermidis in the presence or absence of M. luteus, the commensals formed a layer between the keratinocytes and pathogen. Although S. aureus completely inhibited the growth of M. luteus in dual-species biofilms, inclusion of S. epidermidis in triple or quadruple species biofilms, enabled M. luteus to retain viability. Using this polymicrobial biofilm keratinocyte model, we demonstrate that a quorum sensing (QS) deficient S. aureus agr mutant, in contrast to the parent, failed to damage the keratinocyte monolayer unless supplied with the exogenous cognate autoinducing peptide. In addition, we show that treatment of the polymicrobial keratinocyte model with nanoparticles containing an inhibitor of the PQS QS system reduced biofilm thickness and P. aeruginosa localization in mono- and polymicrobial biofilms., This work was supported by the Unilever, the EMPIR program co-financed by the Participating States and the European Union (grant ref. 15HLT01 MetVBadBugs) and Medical Research Council, United Kingdom (grant no. MR/N010477/1). AK was funded via a Wellcome Trust Doctoral Training Program (Antimicrobials and Antimicrobial Resistance) (grant no. 108876/B/15/Z). NS was funded by the Engineering and Physical Sciences Research Council (EPSRC) (grant nos. EP/N006615/1, EP/K005138/1, and EP/N03371X/1).

Mental calculation demanding tasks cause changes in the autonomic modulation of the cardiac function. Heart rate variability (HRV) is a parameter to understand the autonomic changes. To examine HRV in young individuals in the performance of two levels of arithmetic mental calculation tasks. We assessed 22 participants (18–25 years; both male and female) who performed two levels of mental arithmetic calculations, i.e., 15 easy and 15 calculative. Each task was for 10 s, for both easy and calculative and presented in random manner, through Superlab 4.5 (Cedrus Inc.) and electrocardiogram data were acquired by MP35 (Biopac Inc., Goleta, California, USA). Acqknowledge 4.1 and KUBIOS 2.1 software were used for HRV analysis. Decreased heart rate in calculative task as compared to easy task (p

The receptor for activated c-kinase (RACK1, Asc1 in yeast) is a eukaryotic ribosomal protein located in the head region of the 40S subunit near the mRNA exit channel. This WD-repeat β-propeller protein acts as a signaling molecule and is involved in metabolic regulation, cell cycle progression, and translational control. However, the exact details of the RACK1 recruitment and stable association with the 40S ribosomal subunit remain only partially known. X-ray analyses of the yeast, Saccharomyces cerevisiae, ribosome revealed that the RACK1 propeller blade (4-5) interacts with the eukaryote-specific C-terminal domain (CTD) of ribosomal protein S3 (uS3 family). To check the functional significance of this interaction, we generated mutant yeast strains harboring C-terminal deletions of uS3. We found that deletion of the 20 C-terminal residues (interacting with blade 4-5) from the uS3-CTD abrogates RACK1 binding to the ribosome. Strains with truncated uS3-CTD exhibited compromised cellular growth and protein synthesis similar to that of RACK1Δ strain, thus suggesting that the uS3-CTD is crucial not only for the recruitment and association of RACK1 with the ribosome, but also for its intracellular function. We suggest that eukaryote-specific RACK1-uS3 interaction has evolved to act as a link between the ribosome and the cellular signaling pathways.

Ubiquitination is the vital system for controlling protein degradation and regulation of basic cellular processes. Deubiquitinases (DUBs) are emerging as an important regulator of several pathways related to cancer and other diseases. Their ability to detach ubiquitin from the target substrate and regulation of signaling makes it potential target to treat cancer and other fatal diseases. In the current review, we are trying to summarize deubiquitination, and their role in cancer and potential small molecules DUBs inhibitors which can be used as drugs for cancer treatment.

OBJECTIVE: To evaluate whether approved gastroprokinetic agent, acotiamide exerts a direct excitatory effect in bladder to help explain the reported meaningful reduction of post-void residual urine volume (PVR) in detrusor underactivity (DU) patients after thrice daily oral intake of acotiamide 100 mg for 2 weeks. METHODS: Effect of acotiamide [1–16μM] was assessed on nerve-mediated contractions evoked by electrical field stimulation (EFS) for 5s with 5ms pulse trains of 10V in longitudinal, mucosa intact rat and human bladder strips to construct frequency response curve (1–32Hz) and repeat 10Hz stimulation at 60s interval. Effect of acotiamide 2μM on spontaneous and carbachol evoked contractions was also assessed. RESULTS: Acotiamide 2μM significantly enhanced the Atropine and Tetrodotoxin (TTX)-sensitive EFS evoked contractions of rat and human bladder at 8–32Hz (Two-way ANOVA followed Sidak’s multiple comparison; *p

Background We aimed to locate, appraise, and synthesize the available literature to assess the functional outcome of modular bicompartmental knee arthroplasty (BKA) compared to total knee arthroplasty (TKA) for medio-patellofemoral osteoarthritis. Methods After an extensive literature search based on electronic databases such as MEDLINE, EMBASE, CINAHL, and PubMed, and grey literature, 9 articles satisfied our selection criteria which included 1 randomized controlled trial, 1 prospective cohort, 3 retrospective cohort, and 4 case series. Narrative synthesis was performed due to clinical, methodological, and statistical heterogeneity among the included studies. Results There were 331 participants (341 knees) in this systematic review. BKA group included 229 patients (239 knees) and TKA group included 102 patients (102 knees). The quality of included studies ranged from moderate to very low as per GRADE (grading of recommendations, assessment, development, and evaluation working group) score with low to high risk of bias. Most of the studies showed comparable functional outcome in BKA compared to TKA such as Knee Society Score, Knee Osteoarthritis and Outcome Score, Short Form-36 score, and revision surgery in short-term to midterm follow-up. BKA patients achieved better range of movement and forgotten knee status than TKA patients. It resulted in longer operative time, but less intraoperative blood loss. Long-term series showed 95.1% survivorship of BKA at 5 years and 58% at 17 years. Conclusion Current evidence suggests that modular BKA provides comparable functional outcome to TKA at short-term to midterm follow-up, however, with poor long-term survivorship.

Aims and Objectives: The aim of this study was to analyze and compare the effects of tobacco on salivary pH between tobacco chewers, smokers and controls. Materials and Methods: A total of 60 subjects (males and females) aged 25-40 years, were divided equally into three groups: Tobacco smokers (Group A), chewers (Group B) and controls (Group C). Saliva of each subject was collected under resting condition. Salivary pH was determined using the specific salivary pH meter. Results: The mean (±standard deviation) pH for Group A was 6.75 (±0.11), Group B was 6.5 (±0.29) and Group C was 7.00 (±0.28) after comparison. The significant results showed lower salivary pH in Groups A and B as compared to controls. Salivary pH was lowest in Group B compared to Group A and Group C. Conclusion : This study indicates that a lower (acidic) salivary pH was observed in tobacco users as compared with control. These alterations in pH due to the long-term effect of tobacco use can render oral mucosa vulnerable to various oral and dental diseases.

The small ribosomal subunit protein uS9 (formerly called rpS16 in Saccharomyces cerevisiae), has a long protruding C-terminal tail (CTT) that extends towards the mRNA cleft of the ribosome. The last C-terminal residue of uS9 is an invariably conserved, positively charged Arg that is believed to enhance interaction of the negatively charged initiator tRNA with the ribosome when the tRNA is base-paired to the AUG codon in the P-site. In order to more fully characterize the role of the uS9 CTT in eukaryotic translation, we tested how truncations, extensions and substitutions within the CTT affect initiation and elongation processes in Saccharomyces cerevisiae. We found that uS9 C-terminal residues are critical for efficient recruitment of the eIF2•GTP•Met-tRNAiMet ternary complex to the ribosome and for its proper response to the presence of an AUG codon in the P-site during the scanning phase of initiation. These residues also regulate hydrolysis of the GTP in the eIF2•GTP•Met-tRNAiMet complex to GDP and Pi. In addition, our data show that uS9 CTT modulates elongation fidelity. Therefore, we propose that uS9 CTT is critical for proper control of the complex interplay of events surrounding accommodation of initiator and elongator tRNAs in the P- and A-sites of the ribosome.

MicroRNAs (miRNAs) are generated by endonuclease activity of Dicer, which also helps in loading of miRNAs to their target sequences. SH-SY5Y, a human neuroblastoma and a cellular model of neurodevelopment, consistently expresses genes related to neurodegenerative disorders at different biological levels (DNA, RNA, and proteins). Using SH-SY5Y cells, we have studied the role of Dicer and miRNAs in neuronal differentiation and explored involvement of P53, a master regulator of gene expression in differentiation-induced induction of miRNAs. Knocking down Dicer gene induced senescence in differentiating SH-SY5Y cells, which indicate the essential role of Dicer in brain development. Differentiation of SH-SY5Y cells by retinoic acid (RA) or RA + brain-derived neurotrophic factor (BDNF) induced dramatic changes in global miRNA expression. Fully differentiated SH-SY5Y cells (5-day RA followed by 3-day BDNF) significantly (p 0.05 and atleast3-fold change) upregulated and downregulated the expression of 77 and 17 miRNAs, respectively. Maximum increase was observed in the expression of miR-193-5p, miR-199a-5p, miR-192, miR-145, miR-28-5p, miR-29b, and miR-222 after RA exposure and miR-193-5p, miR-146a, miR-21, miR-199a-5p, miR-153, miR-29b, and miR-222 after RA + BDNF exposure in SH-SY5Y cells. Exploring the role of P53 in differentiating SH-SY5Y cells, we have observed that induction of miR-222, miR-192, and miR-145 is P53 dependent and expression of miR-193a-5p, miR-199a-5p, miR-146a, miR-21, miR-153, and miR-29b is P53 independent. In conclusion, decreased Dicer level enforces differentiating cells to senescence, and differentiating SH-SY5Y cells needs increased expression of P53 to cope up with changes in protein levels of mature neurons.

Background: Alopecia areata is a common auto-immune condition, characterized by circumscribed, patches of hair loss usually of the scalp. There are various treatment modalities available but no treatment is fully curative or preventive. Also, alopecia areata can have devastating effects on the patient’s quality of life and self-esteem. The aim of this study was to determine dermoscopy findings of alopecia areata that could be used as a clinical indicator of disease and also to evaluate the efficacy of intralesional injection Triamcinolone acetonide in the treatment of alopecia areata. Methods: Seventy patients with alopecia areata, aged between 11 and 56 years were injected with intralesional triamcinolone acetonide at a 4 weeks interval. Treatment response was evaluated using re-growth scale approach. Dermlite DL3 dermoscope was used to assess disease activity, response to treatment and side effects. Using Wilcoxon signed rank test, changes were assessed in the severity of the disease during follow-ups. Results: Baseline mean percentage area of scalp involved was 23.21±10.70. All the patients had black dots, 98.6% had yellow dots, 27.1% had broken hair, 74.3% had tapering hair and only 71.4% had vellus hair. At baseline, 15 (21.4%) patients had Alopecia Grading Score (AGS) 1, 29 (41.4%) had score 2 and 26 (37.1%) had a score of 3. Injection Triamcinolone acetonide (5 mg/ml) was injected at 1 cm intervals with 0.1 ml on each site and the procedure was repeated every 4 weeks for a maximum period of 24 weeks. From baseline level to the last follow up, proportion of patients with black dots reduced from 100% to 4.3%, yellow dots from 98.6% to 0%, broken hair from 17% to 0% and tapering hair from 74.3% to 0%. Vellus hair increased from 71.4% to 100%. Overall success rate in terms of achievement of re-growth Ssore 4 at last follow up was 60%. Conclusions: Dermoscopic characteristics, such as black dots, yellow dots, broken hair, tapering hair and clustered short vellus hair are primary indicators of alopecia areata.

A miniaturized assay was optimized to evaluate the enhanced apparent water solubility of pyrazolo[3,4-d]pyrimidine derivatives used extensively as anticancer drug scaffolds. The applied amount of drugs used in the reported strategy ranged from 5-10 ?g per formulation which were dispensed by an inkjet 2D printer directly into a 96-well plate. The selected polymer/drug formulations with high water solubility demonstrated improved cytotoxicity against a human lung adenocarcinoma cancer cell line (A549) compared to the free drugs. We attribute the enhanced efficacy to the improved apparent-solubility of the drug molecules achieved via this methodology. This novel miniaturized method showed promising results in terms of water solubility improvement of the highly hydrophobic pyrazolo[3,4-d]pyrimidine derivatives, requiring only a few ?g of each drug per tested polymeric formulation. In addition, the reported experimental evidence may facilitate identification of suitable polymers for combination with drug leading to investigations on biological properties or mechanisms of action in a single formulation.