No abstract

Cancer remains a global health problem and approximately 1.7 million new cancer cases are diagnosed every year worldwide. Although diverse molecules are currently being explored as targets for cancer therapy the tumor treatment and therapy is highly tricky. Secondary messengers are important for hormone-mediated signaling pathway. Cyclic AMP (cAMP), a secondary messenger responsible for various physiological processes regulates cell metabolism by activating Protein kinase A (PKA) and by targeting exchange protein directly activated by cAMP (EPAC). EPAC is present in two isoforms EPAC1 and EPAC2, which exhibit different tissue distribution and is involved in GDP/GTP exchange along with activating Rap1- and Rap2-mediated signaling pathways. EPAC is also known for its dual role in cancer as pro- and anti-proliferative in addition to metastasis. Results after perturbing EPAC activity suggests its involvement in cancer cell migration, proliferation, and cytoskeleton remodeling which makes it a potential therapeutic target for cancer treatments.

Background A novel electromechanical robotic-exoskeleton was designed in-house for the rehabilitation of wrist joint and Metacarpophalangeal (MCP) joint. Objective The objective was to compare the rehabilitation effectiveness (clinical-scales and neurophysiological-measures) of robotic-therapy training sessions with dose-matched conventional therapy in patients with stroke. Methods A pilot prospective parallel randomized controlled study at clinical settings was designed for patients with stroke within 2 years of chronicity. Patients were randomly assigned to receive an intervention of 20 sessions of 45 min each, five days a week for four weeks, in Robotic-therapy Group (RG) (n = 12) and conventional upper-limb rehabilitation in Control-Group (CG) (n = 11). We intended to evaluate the effects of a novel exoskeleton based therapy on the functional rehabilitation outcomes of upper-limb and cortical-excitability in patients with stroke as compared to the conventional-rehabilitation. Clinical-scales– Modified Ashworth Scale, Active Range of Motion, Barthel-Index, Brunnstrom-stage and Fugl-Meyer (FM) scale and neurophysiological measures of cortical-excitability (using Transcranial Magnetic Stimulation) –Motor Evoked Potential and Resting Motor threshold, were acquired pre- and post-therapy. Results No side effects were noticed in any of the patients. Both RG and CG showed significant (p < 0.05) improvement in all clinical motor-outcomes except Modified Ashworth Scale in CG. RG showed significantly (p < 0.05) higher improvement over CG in Modified Ashworth Scale, Active Range of Motion and Fugl-Meyer scale and FM Wrist-/Hand component. An increase in cortical-excitability in ipsilesional-hemisphere was found to be statistically significant (p < 0.05) in RG over CG, as indexed by a decrease in Resting Motor Threshold and increase in the amplitude of Motor Evoked Potential. No significant changes were shown by the contralesional-hemisphere. Interhemispheric RMT-asymmetry evidenced significant (p < 0.05) changes in RG over CG indicating increased cortical-excitability in ipsilesional-hemisphere along with interhemispheric changes. Conclusion Robotic-exoskeleton training showed improvement in motor outcomes and cortical-excitability in patients with stroke. Neurophysiological changes in RG could most likely be a consequence of plastic reorganization and use-dependent plasticity. Trial registry number: ISRCTN95291802

Conventional analysis of motor-evoked potential (MEP) is performed in time domain using amplitude and latency, which encapsulates information relevant to the cortical excitability of the brain. The study investigated the importance of time-frequency analysis by comparing MEPs in time-frequency domains (TFD) of healthy versus stroke survivors. Six healthy subjects and ten patients with stroke were enrolled. Single-pulse transcranial magnetic stimulation (TMS) at resting motor threshold (RMT) was given at extensor digitorum communis muscle cortical representation to obtain MEP. MEPs were obtained at resting motor threshold (100% RMT subjects and patients), supra-threshold range (100-170% RMT), and different voluntary contractions (100% RMT) to subjects. Fast Fourier transform and continuous wavelet transform (CWT) were used for analysis. Frequency spectrum showed 98% and 66% of signal power in 0-100 Hz for subjects and patients, respectively. Top 10, top 25, and top 50 percentile power of CWT were calculated for each MEP. Frequency spectrum of top 10 and top 25 percentile power of subjects were different (p < 0.05) and dispersed to 0-500 Hz for patients; both groups having a 40-Hz peak. Total power of MEP was found to be low (p < 0.05) in patients as compared to subjects and top 10, top 25, and top 50 percentile power showed decrease. Clinical scores-MAS and FM-were observed to be correlated to frequency and time-frequency features (p < 0.05). Frequency spectrum belonging top 10 percentile power of different level voluntary contractions showed statistical significance (p < 0.05). However, no significant differences were observed for MEPs at different supra-threshold intensities. Results suggest time-frequency analysis might provide objective ways to quantify TMS measures for stroke patients.

RIG1 and MDA5 have emerged as important intracellular innate pattern recognition receptors that recognize viral RNA and mediate cellular signals controlling Type I interferon (IFN-I) response. Buffalo RIG1 and MDA5 genes were investigated to understand the mechanism of receptor induced antiviral response. Sequence analysis revealed that RIG1 and MDA5 maintain a domain arrangement that is common in mammals. Critical binding site residues of the receptors are evolutionary conserved among mammals. Molecular dynamics simulations suggested that RIG1 and MDA5 follow a similar, if not identical, dsRNA binding pattern that has been previously reported in human. Moreover, binding free energy calculation revealed that MDA5 had a greater affinity towards dsRNA compared to RIG1. Constitutive expressions of RLR genes were ubiquitous in different tissues without being specific to immune organs. Poly I:C stimulation induced elevated expressions of IFN-β and IFN-stimulated genes (ISGs) through interferon regulatory factors (IRFs) mediated pathway in buffalo foetal fibroblast cells. The present study provides crucial insights into the structure and function of RIG1 and MDA5 receptors in buffalo.