The influence that neurons exert on astrocytic function is poorly understood. To investigate this, we first developed a system combining cortical neurons and astrocytes from closely related species, ...followed by RNA-seq and in silico species separation. This approach uncovers a wide programme of neuron-induced astrocytic gene expression, involving Notch signalling, which drives and maintains astrocytic maturity and neurotransmitter uptake function, is conserved in human development, and is disrupted by neurodegeneration. Separately, hundreds of astrocytic genes are acutely regulated by synaptic activity via mechanisms involving cAMP/PKA-dependent CREB activation. This includes the coordinated activity-dependent upregulation of major astrocytic components of the astrocyte-neuron lactate shuttle, leading to a CREB-dependent increase in astrocytic glucose metabolism and elevated lactate export. Moreover, the groups of astrocytic genes induced by neurons or neuronal activity both show age-dependent decline in humans. Thus, neurons and neuronal activity regulate the astrocytic transcriptome with the potential to shape astrocyte-neuron metabolic cooperation.
Alzheimer's disease (AD) alters astrocytes, but the effect of Aß and Tau pathology is poorly understood. TRAP-seq translatome analysis of astrocytes in APP/PS1 ß-amyloidopathy and MAPT
tauopathy mice ...revealed that only Aß influenced expression of AD risk genes, but both pathologies precociously induced age-dependent changes, and had distinct but overlapping signatures found in human post-mortem AD astrocytes. Both Aß and Tau pathology induced an astrocyte signature involving repression of bioenergetic and translation machinery, and induction of inflammation pathways plus protein degradation/proteostasis genes, the latter enriched in targets of inflammatory mediator Spi1 and stress-activated cytoprotective Nrf2. Astrocyte-specific Nrf2 expression induced a reactive phenotype which recapitulated elements of this proteostasis signature, reduced Aß deposition and phospho-tau accumulation in their respective models, and rescued brain-wide transcriptional deregulation, cellular pathology, neurodegeneration and behavioural/cognitive deficits. Thus, Aß and Tau induce overlapping astrocyte profiles associated with both deleterious and adaptive-protective signals, the latter of which can slow patho-progression.
The role of RORγ as a transcription factor for Th17 cell differentiation and thereby regulation of IL-17 levels is well known. Increased RORγ expression along with IL-17A levels was observed in ...animal models, immune cells and BAL fluid of COPD patients. Increased IL-17A levels in severe COPD patients are positively correlated with decreased lung functions and increased severity symptoms and emphysema, supporting an urgency to develop novel therapies modulating IL-17 or RORγ for COPD treatment. We identified a potent RORγ inhibitor, PCCR-1 using hit to lead identification followed by extensive lead optimization by structure-activity relationship. PCCR-1 resulted in RORγ inhibition with a high degree of specificity in a biochemical assay, with > 300-fold selectivity over other isoforms of ROR. Our data suggest promising potency for IL-17A inhibition in human and canine PBMCs and mouse splenocytes with no significant impact on Th1 and Th2 cytokines. In vivo, PCCR-1 exhibited significant efficacy in the acute CS model with dose-dependent inhibition of the PD biomarkers that correlated well with the drug concentration in lung and BAL fluid, demonstrating an acceptable safety profile. This inhibitor effectively inhibited IL-17A release in whole blood and BALf samples from COPD patients. Overall, we identified a selective inhibitor of RORγ to pursue further development of novel scaffolds for COPD treatment.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Alzheimer's disease (AD) is characterised by Aβ and tau pathology as well as synaptic degeneration, which correlates best with cognitive impairment. Previous work suggested that this pathological ...complexity may result from changes in mRNA translation. Here, we studied whether mRNA translation and its underlying signalling are altered in an early model of AD, and whether modelling this deficiency in mice causes pathological features with ageing. Using an unbiased screen, we show that exposure of primary neurons to nanomolar amounts of Aβ increases FMRP-regulated protein synthesis. This selective regulation of mRNA translation is dependent on a signalling cascade involving MAPK-interacting kinase 1 (Mnk1) and the eukaryotic initiation factor 4E (eIF4E), and ultimately results in reduction of CYFIP2, an FMRP-binding protein. Modelling this CYFIP2 reduction in mice, we find age-dependent Aβ accumulation in the thalamus, development of tau pathology in entorhinal cortex and hippocampus, as well as gliosis and synapse loss in the hippocampus, together with deficits in memory formation. Therefore, we conclude that early stages of AD involve increased translation of specific CYFIP2/FMRP-regulated transcripts. Since reducing endogenous CYFIP2 expression is sufficient to cause key features of AD with ageing in mice, we suggest that prolonged activation of this pathway is a primary step toward AD pathology, highlighting a novel direction for therapeutic targeting.
The nutrient supply to the oceanic surface water is largely regulated by the extrinsic and intrinsic ambient atmospheric aerosol properties, particularly chemistry. In this context, we measured the ...comprehensive chemical composition (inorganic ions and major elements) of atmospheric aerosols and studied their spatial distribution over the Arabian Sea during the southwest monsoon (SWM) period for 2 consecutive years (2017 and 2018). We found that the water-soluble ionic concentration (WSIC) is dominated by Na+ and Cl– ions followed by Ca2+ and SO4 2– with a minor contribution of Mg2+ and NO3 –. The relative contribution of ionic species to WSIC remained similar for both the monsoon seasons with higher WSIC during 2018 (69.3 ± 63 μg m–3) compared to 2017 (40.6 ± 33 μg m–3). Sea salt (estimated from Na+ and Cl– ions) and mineral dust (calculated from the Al concentration) are dominant constituents of aerosols, with negligible contribution from anthropogenic species found to be temporally and spatially consistent during both the campaigns. The mineral dust is characterized by a uniform Nd isotopic signature during both campaigns, indicating its source to the Arabian Peninsula during the study period. Source apportionment of mineral dust using the Nd isotope is supported by back-trajectory analyses as well as satellite retrieved (MODIS and CALIPSO) data. The Cl– deficit, which is mainly attributed to the interaction of sea salt with acidic species, is found to be relatively low (10–12%) compared to that during continental outflow over the Arabian Sea, indicating the insignificant contribution from anthropogenic emissions during the SWM months.
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Burn injuries are not uncommon, and a decade ago, more than one subject with major burn injury arrived in our emergency department each day. We here report of some basic epidemiological data of burn ...injury for a period of 11 years and propose an approach for prevention and care of burn. Authors obtained the records of the 5500 patients admitted in tertiary care unit of central India from March 2005 to March 2016. The preclinical, clinical, and stage of resolution variables are included in the customized proforma. Few additional data was available in the case sheets of year 2016 and analyzed separately. Data are analyzed using Statistical Package for the Social Sciences. The mean age was 28.6 years with standard deviation of 13.26. Male to female ratio was 1:1.36. Frequency from neighboring district (51.81%), Hindus (86.83%), accidental intent of burn (85.2%), flame type of injuries (76.45%), kerosene as agent of burn (69.4%), home as place of burn (90.92%) are other recognizable variables. Clinical and outcome variables are total body surface area (> 50%) in 57%, hospital stay (> 3 days) in 61.5%, mortality rate (46%), left against medical advice (LAMA) in 36.4%, and survival rate (15.4%). In a select group of 500 patients, some other useful variables like careless attitude in handling kerosene (84%), illiteracy (74.2%), low socioeconomic status (83.4%), married status (75.8%), and family size (> 3) in 74.8% were recorded. In India, burns are preventable by elimination of kerosene/distribution in closed containers. Community-based prevention program is a must. Author’s “SIREN” reaction plan is for first responders. Authors prepared a burn management guideline for primary healthcare level with an acronym “ALERT-DAY” protocol to decrease morbidity of burn. Upgradation of existing burn center is essential to curb the mortality and LAMA rates and improve the survival.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Conclusion: It can be concluded that the use of a rubber drain do not have any positive impact on reducing the postoperative sequel Keywords: Impacted molars, postoperative swelling, Trismus, ...postoperative pain Introduction Literature is replete with evidence suggesting that surgical removal of the unerupted wisdom tooth is the frequently performed clinical intervention in oral surgical practice.1 An attempt to remove a deep seated impacted wisdom tooth is associated with substantial surgical challenge even to an experienced operator. Numerous options have been put forth in the literature pertaining to the management of the extraction sockets subsequent to third molar surgery beginning from a simple primary closure of the surgical wound to the placement of several kinds of drains, gauze strips or dressings.8,9,10,11 Even though some previous studies in the past have suggested a beneficial effect following the placement of drains on the postoperative swelling, pain or trismus few previous studies have contradicted their use.9,12 Hence, this paper is aimed at assessing the role of rubber drain in the postoperative sequel following third molar surgery. Statistical Methods: The recorded data was compiled and entered in a spreadsheet (Microsoft Excel) and then exported to data editor of SPSS Version 20.0 version 18 and Chi-square test was employed to evaluate both the groups with regards pain, swelling, trismus and wound infections. Even though primary closure is considered the gold standard few advocate the surgical wound to heal by secondary intention with the aid of drains.13 Cerqueira et al. advocated that a drain reduces pain, swelling and trismus because it permits the drainage of the residual blood collected in the tissue spaces.14 Drains soaked in tetracycline hydrochloride are also used to minimize the postoperative discomfort. 10 A recent study employed 3D face scans to quantify the amount of swelling following wisdom tooth removal and advocated that the 3D scans can be considered as a reliable tool that works without having physical contact with the patient or exposing the patient to radiation.12 They concluded that this technique is better than other techniques by providing fast and reliable results without any negative side effects to the patients.12 Literature reveals numerous studies which evaluated the effect of rubber drains and compared them with conventional primary suturing on postoperative discomfort after extraction of impacted mandibular third molars.15,16 They advocated
Blessed with a salubrious climate, the city of Bengaluru over the past few decades has constantly witnessed thermal discomfort owing to several Urban Heat islands that have mushroomed within the ...city. The subsequent increase in builtup area, consequent loss of productive agricultural lands/green zones, encroachment of surface water bodies coupled with the ill-preparedness of decision makers to handle the demand for land have invariably crumbled the natural micro-climate of the city. In this present research, an attempt has been made to detect the distribution of Urban Heat Islands in Bengaluru City by conducting real-time survey at 100 observatories marked across the entire urban & rural locations; with thermohygrometers as per the W.M.O. guidelines. The study confirmed the violation of the Human Thermal Comfort Range in 9, 83, 98, 99, 98 and 80 observatories for the monitoring at 6 AM, 9 AM, 12 PM, 3 PM, 6 PM and 9 PM respectively.
In Alzheimer's disease synapse loss precedes neuronal loss and correlates best with impaired memory formation. However, the mechanisms underlying synaptic degeneration in Alzheimer's disease are not ...well known. Further, it is unclear why synapses in AD cerebellum are protected from degeneration. Our recent work on the cyclin-dependent kinase 5 activator p25 suggested that expression of the multifunctional presynaptic molecule cysteine string protein alpha (CSPalpha) may be affected in Alzheimer's disease.
Using western blots and immunohistochemistry, we found that CSPalpha expression is reduced in hippocampus and superior temporal gyrus in Alzheimer's disease. Reduced CSPalpha expression occurred before synaptophysin levels drop, suggesting that it contributes to the initial stages of synaptic degeneration. Surprisingly, we also found that CSPalpha expression is upregulated in cerebellum in Alzheimer's disease. This CSPalpha upregulation reached the same level as in young, healthy cerebellum. We tested the idea whether CSPalpha upregulation might be neuroprotective, using htau mice, a model of tauopathy that expresses the entire wild-type human tau gene in the absence of mouse tau. In htau mice CSPalpha expression was found to be elevated at times when neuronal loss did not occur.
Our findings provide evidence that the presynaptic vesicle protein CSPalpha is a key player in synaptic degeneration and protection in Alzheimer's disease. In the forebrain CSPalpha expression is reduced early in the disease and this may contribute to the initial stages of synaptic degeneration. In the cerebellum CSPalpha expression is upregulated to young, healthy levels and this may protect cerebellar synapses and neurons to survive. Accordingly, CSPalpha upregulation also occurs in a mouse model of tauopathy only at time when neuronal loss does not take place.
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Nature Communications 8: Article number: 15132 (2017); Published: 2 May 2017; Updated: 6 February 2018 Michel Goedert, who developed the Thy1-P301S transgenic mouse, was inadvertently omitted from ...the Acknowledgments section of this Article. The Acknowledgements should have included the following: ‘We thank Michel Goedert for providing the Thy1-P301S transgenic mouse that was used in this study.
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