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Pathways to control the spreading of α-synuclein (α-syn) and associated neuropathology in Parkinson’s disease (PD), multiple system atrophy (MSA) and dementia with Lewy bodies (DLB) are unclear. Here, we show that preformed α-syn fibrils (PFF) increase the association between TLR2 and MyD88, resulting in microglial activation. The TLR2-interaction domain of MyD88 (wtTIDM) peptide-mediated selective inhibition of TLR2 reduces PFF-induced microglial inflammation in vitro. In PFF-seeded A53T mice, the nasal administration of the wtTIDM peptide, NEMO-binding domain (wtNBD) peptide, or genetic deletion of TLR2 reduces glial inflammation, decreases α-syn spreading, and protects dopaminergic neurons by inhibiting NF-κB. In summary, α-syn spreading depends on the TLR2/MyD88/NF-κB pathway and it can be reduced by nasal delivery of wtTIDM and wtNBD peptides. The mechanisms underlying the spreading of α-synuclein in various α-synucleinopathies are unclear. Here, the authors show that targeting the TLR2/MyD88/NF-κB pathway can reduce α-synuclein spreading, reduce neuroinflammation, and protect dopaminergic neurons in vitro and in mouse models

Glial activation and inflammation coincide with neurofibrillary tangles (NFT) formation in neurons. However, the mechanism behind tau fibril and glia interaction is poorly understood. Here, we found that tau preformed fibrils (PFF) caused induction of inflammation in microglia by specifically activating the TLR2-MyD88, but not TLR4-MyD88, pathway. Accordingly, TLR2 interacting domain of MyD88 (wtTIDM) peptide inhibited tau PFF-induced activation of TLR2-MyD88-NF-κB pathway resulting in reduced inflammation. Nasal administration of wtTIDM in P301S tau-expressing PS19 mice was found to inhibit gliosis and inflammatory markers, along with reduction of pathogenic tau in the hippocampus, resulting in improved cognitive behavior in PS19 mice. The inhibitory effect of wtTIDM on tau pathology was absent in PS19 mice lacking TLR2, reinforcing the essential involvement of TLR2 in wtTIDM- mediated effects in vivo. While understanding the mechanism further, we found that tau promoter harboured a potential NF-κB binding site and that proinflammatory molecules increased the transcription of tau in neurons via NF-κB. These results suggest that tau-induced neuroinflammation and neuropathology require TLR2 and that neuroinflammation directly upregulates tau in neurons via NF-κB, highlighting a direct connection between inflammation and tauopathy.

Aggregation of the microtubule-associated protein tau (MAPT) is the hallmark pathology in a spectrum of neurodegenerative disorders collectively called tauopathies. Physiologically, tau is an inherent neuronal protein that plays an important role in the assembly of microtubules and axonal transport. However, disease-associated mutations of this protein reduce its binding to the microtubule components and promote self-aggregation, leading to formation of tangles in neurons. Tau is also expressed in oligodendrocytes, where it has significant developmental roles in oligodendrocyte maturation and myelin synthesis. Oligodendrocyte-specific tau pathology, in the form of fibrils and coiled coils, is evident in major tauopathies including progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick’s disease (PiD). Multiple animal models of tauopathy expressing mutant forms of MAPT recapitulate oligodendroglial tau inclusions with potential to cause degeneration/malfunction of oligodendrocytes and affecting the neuronal myelin sheath. Till now, mechanistic studies heavily concentrated on elucidating neuronal tau pathology. Therefore, more investigations are warranted to comprehensively address tau-induced pathologies in oligodendrocytes. The present review provides the current knowledge available in the literature about the intricate relations between tau and oligodendrocytes in health and diseases.

Wireless data communications in form of Short Message Service (SMS) and Wireless Access Protocols (WAP) browsers have gained global popularity, yet, not much has been done to extend the usage of these devices in electronic learning (e-learning) and information sharing. This project explores the extension of e learning into wireless/ handheld (W/H) computing devices with the help of a mobile learning (m-learning) framework. This framework provides the requirements to develop m-learning application that can be used to share academic and administrative information among people within the university campus. A prototype application has been developed to demonstrate the important functionality of the proposed system in simulated environment. This system is supposed to work both in bulk SMS and interactive SMS delivery mode. Here we have combined both Short Message Service (SMS) and Wireless Access Protocols (WAP) browsers. SMS is used for Short and in time information delivery and WAP is used for detailed information delivery like course content, training material, interactive evolution tests etc. The push model is used for sending personalized multicasting messages to a group of mobile users with a common profile thereby improving the effectiveness and usefulness of the cntent delivered. Again pull mechanism can be applied for sending information as SMS when requested by end user in interactive SMS delivery mode. The main strength of the system is that, the actual SMS delivery application can be hosted on a mobile device, which can operate even when the device is on move.

Drug drug Interactions (DDI) present considerable challenges in healthcare, often resulting in adverse effects or decreased therapeutic efficacy. This article proposes a novel deep sequential learning architecture called DDINet to predict and classify DDIs between pairs of drugs based on different mechanisms viz., Excretion, Absorption, Metabolism, and Excretion rate (higher serum level) etc. Chemical features such as Hall Smart, Amino Acid count and Carbon types are extracted from each drug (pairs) to apply as an input to the proposed model. Proposed DDINet incorporates attention mechanism and deep sequential learning architectures, such as Long Short-Term Memory and gated recurrent unit. It utilizes the Rcpi toolkit to extract biochemical features of drugs from their chemical composition in Simplified Molecular-Input Line-Entry System format. Experiments are conducted on publicly available DDI datasets from DrugBank and Kaggle. The model’s efficacy in predicting and classifying DDIs is evaluated using various performance measures. The experimental results show that DDINet outperformed eight counterpart techniques achieving overall accuracy which is also statistically confirmed by Confidence Interval tests and paired t-tests. This architecture may act as an effective computational technique for drug drug interaction with respect to mechanism which may act as a complementary tool to reduce costly wet lab experiments for DDI prediction and classification.

Summary Background: Post-COVID-19 cases are being reported with features of hyperinflammatory state causing multiple system dysfunctions in previously healthy children. Objectives: To describe clinical characteristics, laboratory, and radiological profile of children affected with COVID-19-related multisystem inflammatory syndrome postsecond wave in India and compare them with respect to adverse outcome. Materials and Methods: This prospective, observational study was conducted in the department of pediatrics of a tertiary care center in Eastern India over a period of 3 months. Demographic data, clinical details, biochemical parameters, and treatment with clinical outcome were recorded. Children who survived the clinical course were compared with those died during hospital stay. Results: Thirty-five children with a median age of 4.8 (3.9) years were included who were admitted between June 16 and September 15, 2021. Only 17.14% had reverse transcription-polymerase chain reaction positivity previously with 77.14% had positive COVID-19 serology. Most common features were fever (100%), edema (68.6%), gastrointestinal (71.4%), mucocuteneous (65.7%), cardiovascular (57.1%), and neurological symptoms (45.7%). Twenty (57.1%) children had shock at presentation. Decreased ejection fraction (<55%) was the most common echocardiographic feature (37.14%) followed by coronary dilatation (20%). Majority (77.14%) of the patients required intensive care with inotrope requirement in 62.86% cases. Forty percent patients were intubated with mean duration of 9.94 (±10.5) days. All patients received methylprednisolone and 76% were given intravenous immunoglobulin. Tocilizumab was used in three patients. Nine patients died (25.7%) with overall median pediatric intensive care unit stay of 13 (14) days. Conclusion: Of the parameters described, we have found shock, heart failure, neurological involvement at presentation, infancy, and laboratory parameters such as C-reactive protein, CPK, D-Dimer, and lactate dehydrogenase were the predictors of mortality.

The parasitic protozoan Leishmania donovani is the causative organism for visceral leishmaniasis (VL) which persists in the host macrophages by deactivating its signaling machinery resulting in a critical shift from proinflammatory (Th1) to an anti-inflammatory (Th2) response. The severity of this disease is mainly determined by the production of IL-12 and IL-10 which could be reversed by use of effective immunoprophylactics. In this study we have evaluated the potential of Arabinosylated Lipoarabinomannan (Ara-LAM), a cell wall glycolipid isolated from non pathogenic Mycobacterium smegmatis, in regulating the host effector response via effective regulation of mitogen-activated protein kinases (MAPK) signaling cascades in Leishmania donovani infected macrophages isolated from BALB/C mice. Ara-LAM, a Toll-like receptor 2 (TLR2) specific ligand, was found to activate p38 MAPK signaling along with subsequent abrogation of extracellular signal-regulated kinase (ERKs) signaling. The use of pharmacological inhibitors of p38MAPK and ERK signaling showed the importance of these signaling pathways in the regulation of IL-10 and IL-12 in Ara-LAM pretreated parasitized macrophages. Molecular characterization of this regulation of IL-10 and IL-12 was revealed by chromatin immunoprecipitation assay (CHIP) which showed that in Ara-LAM pretreated parasitized murine macrophages there was a significant induction of IL-12 by selective phosphorylation and acetylation of histone H3 residues at its promoter region. While, IL-10 production was attenuated by Ara-LAM pretreatment via abrogation of histone H3 phosphorylation and acetylation at its promoter region. This Ara-LAM mediated antagonistic regulations in the induction of IL-10 and IL-12 genes were further correlated to changes in the transcriptional regulators Signal transducer and activator of transcription 3 (STAT3) and Suppressor of cytokine signaling 3 (SOCS3). These results demonstrate the crucial role played by Ara-LAM in regulating the MAPK signaling pathway along with subsequent changes in host effector response during VL which might provide crucial clues in understanding the Ara-LAM mediated protection during Leishmania induced pathogenesis.

Bevacizumab and trastuzumab are two antibody based antiangiogenic drugs that are in clinical practice for the treatment of different cancers. Presently applications of these drugs are based on the empirical choice of clinical experts that follow towards population based clinical trials and, hence, their molecular efficacies in terms of quantitative estimates are not being explored. Moreover, different clinical trials with these drugs showed different toxicity symptoms in patients. Here, using molecular docking study, we made an attempt to reveal the molecular rationale regarding their efficacy and off-target toxicity. Though our study reinforces their antiangiogenic potentiality and, among the two, trastuzumab has much higher efficacy; however, this study also reveals that compared to bevacizumab, trastuzumab has higher toxicity effect, specially on the cardiovascular system. This study also reveals the molecular rationale of ocular dysfunction by antiangiogenic drugs. The molecular rationale of toxicity as revealed in this study may help in the judicious choice as well as therapeutic scheduling of these drugs in different cancers.

We have calculated the energy spectra for almost all the filling fractions in the Jain series low energy fundamental mode as well as higher energy modes using composite fermion theory. The nature of the low energy mode and higher energy mode is nearly identical to the roton mode. We have observed that, these series of filling fractions \\(\\nu=\\frac{n}{2pn+1}\\) possess \\(n\\) number of roton minima in their higher energy mode.

We have focussed to study the even-denominator fractional quantum Hall (EDFQH) states observed in monolayer graphene. In this letter, we have studied polarization mainly for the two EDFQH states at filling fractions \\(\\nu = 1/2, 1/4\\), which are observed in an experimental study [Nat. Phys. 14, 930 (2018)] a few years ago. We have applied Chern Simon's gauge field theory to explain the possible variational wave functions for different polarized states and calculated their ground state energies using the Coulomb potential. We have chosen the lowest energy states using suitable combinations of flux attached with the electrons for different polarized states of those EDFQH states.