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The pH of the endolysosomal system is tightly regulated by a balance of proton pump and leak mechanisms that are critical for storage, recycling, turnover, and signaling functions in the cell. Dysregulation of endolysosomal pH has been linked to aging, amyloidogenesis, synaptic dysfunction, and various neurodegenerative disorders, including Alzheimer's disease. Therefore, understanding the mechanisms that regulate luminal pH may be key to identifying new targets for managing these disorders. Meta-analysis of yeast microarray databases revealed that nutrient-limiting conditions inhibited the histone deacetylase (HDAC) Rpd3 and thereby up-regulated transcription of the endosomal Na+/H+ exchanger Nhx1, resulting in vacuolar alkalinization. Consistent with these findings, Rpd3 inhibition by the HDAC inhibitor and antifungal drug trichostatin A induced Nhx1 expression and vacuolar alkalinization. Bioinformatics analysis of Drosophila and mouse databases revealed that caloric control of the Nhx1 orthologs DmNHE3 and NHE6, respectively, is also mediated by HDACs. We show that NHE6 is a target of the transcription factor cAMP-response element- binding protein (CREB), a known regulator of cellular responses to low-nutrient conditions, providing a molecular mechanism for nutrient- and HDAC-dependent regulation of endosomal pH. Of note, pharmacological targeting of the CREB pathway to increase NHE6 expression helped regulate endosomal pH and correct defective clearance of amyloid Aβ in an apoE4 astrocyte model of Alzheimer's disease. These observations from yeast, fly, mouse, and cell culture models point to an evolutionarily conserved mechanism for HDAC-mediated regulation of endosomalNHEexpression. Our insights offer new therapeutic strategies for modulation of endolysosomal pH in fungal infection and human disease. [ABSTRACT FROM AUTHOR]

The present research aims to investigate the effect of oxide dispersion on the synthesis of High-Entropy (HE) alloy and its properties. For this FeNiCoCrAlMn High-Entropy (HE) alloy dispersed with 2 wt percentage alumina (Al 2 O 3 ) was synthesized by mechanical activated synthesis. The mechanical activation was carried out by milling the elemental powder mixture of aluminum, cobalt, chromium, iron, nickel and manganese in an equiatomic ratio up to 20 h 2 wt% of Al 2 O 3 was added during mechanical alloying to obtain oxide dispersed HE alloy. Upon pyrolysis at high temperature FCC emerged as major phase in both alloys (with and without oxide dispersion). The alumina dispersed HE alloy shows increase in size of AlNi and CrFeMn rich phase after sintering, relatively less thermal expansion coefficient and better oxidation resistance than HE alloy without oxide dispersion. Hardness was found to be doubled after adding 2% alumina. The obtained result indicate that oxide dispersed HE alloy can be useful material for high temperature coating application. [ABSTRACT FROM AUTHOR]

Early intervention may be key to safe and effective therapies in patients with Alzheimer disease. Endosomal dysfunction is an early step in neurodegeneration. Endosomes are a major site of production of Aβ peptide from the processing of amyloid precursor protein (APP) by clipping enzymes (β- and γ-secretases). The β-secretase enzyme BACE1 requires acidic lumen pH for optimum function, and acid pH promotes Aβ aggregation. The Na+/H+ exchanger NHE6 provides a leak pathway for protons, limiting luminal acidification by proton pumps. Like APP, NHE6 expression was induced upon differentiation of SH-SY5Y neuroblastoma cells and localized to an endosomal compartment. Therefore, we investigated whether NHE6 expression altered APP localization and processing in a stably transfected cell culture model of human APP expression. We show that coexpression with NHE6 or treatment with the Na+/H+ ionophore monensin shifted APP away from the trans-Golgi network into early and recycling endosomes in HEK293 cells. NHE6 alkalinized the endosomal lumen, similar to monensin, and significantly attenuated APP processing and Aβ secretion. In contrast, Aβ production was elevated upon NHE6 knockdown. Weshow thatNHE6transcript and protein levels are lowered in Alzheimer brains relative to control. These findings, taken together with emerging genetic evidence linking endosomal Na+/H+ exchangers with Alzheimer disease, suggest that proton leak pathways may regulate Aβ generation and contribute to disease etiology. [ABSTRACT FROM AUTHOR]

The plywood manufacturing process involves debarking of log, peeling and pressing of ribbons of wood after glueing with proper resin, trimming, sanding and finishing. Washings of glue mixer, resin kettle and a glue spreader generate solids and various hazardous chemicals like phenol, sodium hydroxide and formaldehyde. To protect the environment and human health, it is necessary to treat and reuse the wastewater of plywood manufacturing. There are several methods available for the treatment of plywood industries wastewater and use of lime is one of them. In the present study viability of lime treatment was performed to achieve zero liquid discharge in a Plywood Industry. An optimum lime dose of 1.5 g/L was applied to the wastewater of melamine urea formaldehyde and phenol formaldehyde resin units. After treatment, removal of 28.6% and 41.2% total dissolved solid and 36.8% and 37.5% total suspended solid were observed in melamine urea formaldehyde and phenol formaldehyde resin units wastewater. Phenol and chemical oxygen demand removals were more than 38% and 40% from the wastewater of both units. Lime treated wastewater was used to prepare melamine urea formaldehyde and phenol formaldehyde glue/resin by mixing chemicals. The prepared resins exhibit characteristics within prescribed limits of plywood manufacturing. The mechanical and physical properties of plywood specimen have also found satisfactory. Image 1 • HL1: Plywood industry wastewater was lime treated for resin manufacturing. • HL2: Lime dose of 1.5 g/L was found suitable to treat liquid wastewater. • HL3: Treated wastewater was suitable for preparing resin without affecting plywood quality. • HL4: Resin preparation from wastewater was effective in achieving Zero Liquid Discharge. • HL5: Properties of plywood specimens using this resin were greater than prescribed values. [ABSTRACT FROM AUTHOR]

Abstract: Electrocardiogram (ECG) is widely used as a diagnostic tool to identify atrial tachyarrhythmias such as atrial fibrillation. The ECG signal is a P-QRS-T wave representing the cardiac function. The minute variations in the durations and amplitude of these waves cannot be easily deciphered by the naked eye. Hence, there is a need for computer aided diagnosis (CAD) of cardiac healthcare. The current paper presents a methodology for ECG based pattern analysis of normal sinus rhythm and atrial fibrillation (AF) beats. The denoised and registered ECG beats were subjected to independent component analysis (ICA) for data reduction. The weights of ICA were used as features for classification using Naive Bayes and Gaussian mixture model (GMM) classifiers. The performance and the upper bound on probability of error in classification were analyzed using Chernoff and Bhattacharyya bounds. The Naive Bayes classifier provided an average sensitivity of 99.32%, specificity of 99.33% and accuracy of 99.33%, while the GMM provided an average sensitivity of 100%, specificity of 99% and accuracy of 99.42%. The probability of error during classification was less for GMM compared to Naive Bayes classifier (NBC) as GMM provided higher performance than the NBC. [Copyright &y& Elsevier]

• Facile and efficient approach for the synthesis of 4(5)-aryl-1 H -imidazoles. • Transition-metal-free, mild reaction conditions with operational simplicity. • Short reaction times with higher yields. A facile and efficient method was developed for the synthesis of N -unsubstituted imidazoles via the cycloaddition of N -sulfinyl imines and p -toluenesulfonylmethyl isocyanide (TosMIC). This methodology is operationally simple and useful for the preparation of various aromatic and heteroaromatic imidazoles in good to excellent yields. [ABSTRACT FROM AUTHOR]

Passive Systems are increasingly playing a prominent role in the advanced nuclear reactor systems and are being utilised in normal operations as well as safety systems of the reactors following an accident. The Passive Containment Cooling System (PCCS) is one of the several passive safety features in an Advanced Reactor (AHWR). In this paper, the APSRA methodology has been employed for reliability evaluation of the PCCS of AHWR. Performance assessment of the PCCS is initially performed during a postulated design basis LOCA using the best-estimate code RELAP5/Mod 3.2. The parameters affecting the system performance are then identified and considered for further analysis. Based on some pre-determined failure criterion, the failure surface for the system is predicted using the best-estimate code taking into account the deviations of the identified parameters from their nominal states as well as the model uncertainties inherent to the best estimate code. Root diagnosis is then carried out to determine the various failure causes, which occurs mainly due to malfunctioning of mechanical components. The failure probabilities of the various components are assessed through a classical PSA treatment using generic data. The reliability of the PCCS is then evaluated from the probability of availability of these components. [ABSTRACT FROM AUTHOR]

Abstract: In this paper, a methodology known as APSRA (Assessment of Passive System ReliAbility) is used for evaluation of reliability of passive isolation condenser system of the Indian Advanced Heavy Water Reactor (AHWR). As per the APSRA methodology, the passive system reliability evaluation is based on the failure probability of the system to perform the design basis function. The methodology first determines the operational characteristics of the system and the failure conditions based on a predetermined failure criterion. The parameters that could degrade the system performance are identified and considered for analysis. Different modes of failure and their cause are identified. The failure surface is predicted using a best estimate code considering deviations of the operating parameters from their nominal states, which affect the isolation condenser system performance. Once the failure surface of the system is predicted, the causes of failure are examined through root diagnosis, which occur mainly due to failure of mechanical components. Reliability of the system is evaluated through a classical PSA treatment based on the failure probability of the components using generic data. [Copyright &y& Elsevier]

Abstract: In this paper, a methodology known as APSRA (Assessment of Passive System ReliAbility) has been employed for evaluation of the reliability of passive systems. The methodology has been applied to the passive containment isolation system (PCIS) of the Indian advanced heavy water reactor (AHWR). In the APSRA methodology, the passive system reliability evaluation is based on the failure probability of the system to carryout the desired function. The methodology first determines the operational characteristics of the system and the failure conditions by assigning a predetermined failure criterion. The failure surface is predicted using a best estimate code considering deviations of the operating parameters from their nominal states, which affect the PCIS performance. APSRA proposes to compare the code predictions with the test data to generate the uncertainties on the failure parameter prediction, which is later considered in the code for accurate prediction of failure surface of the system. Once the failure surface of the system is predicted, the cause of failure is examined through root diagnosis, which occurs mainly due to failure of mechanical components. The failure probability of these components is evaluated through a classical PSA treatment using the generic data. The reliability of the PCIS is evaluated from the probability of availability of the components for the success of the passive containment isolation system. [Copyright &y& Elsevier]

Osteoclasts are multinuclear cells that resorb bone. Osteoclast differentiation is regulated by multiple transcription factors which may be acting in a single or multiple factor complex to regulate gene expression. Myocyte enhancer factor 2 (MEF2) is a family of transcription factors whose role during osteoclast differentiation has not been well characterized. Because MEF2A and MEF2D are the family members most highly expressed during osteoclast differentiation, we created conditional knockout mice models for MEF2A and/or MEF2D. In vitro cultures of A- and D-KO osteoclasts were smaller and less numerous than wild type cultures, while AD-KO osteoclasts were almost completely devoid of TRAP positive mononuclear cells. Female A-KO mice are osteopetrotic while male A- and D-KO mice of either sex had no significant in vivo skeletal phenotype, suggesting a sex-specific regulation of osteoclasts by MEF2A. Lastly, in vivo male AD-KO mice are osteopenic, indicating while MEF2 is required for M-CSF and RANKL-stimulated osteoclastogenesis in vitro , osteoclasts can form in the absence of MEF2 in vivo via a RANKL-alternative pathway. • MEF2A and D are the most abundant MEF2 family members in osteoclasts • Loss of MEF2A and D result in a complete loss of osteoclast differentiation in vitro • MEF2A null female mice have an osteopetrotic phenotype in vivo • MEF2A and D null mice are osteopenic in vivo [ABSTRACT FROM AUTHOR]