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Alzheimer's disease (AD) is the most common neurodegenerative disorder seen in age-dependent dementia. There is currently no effective treatment for AD, which may be attributed in part to lack of a clear underlying mechanism. Studies within the last few decades provide growing evidence for a central role of amyloid β (Aβ) and tau, as well as glial contributions to various molecular and cellular pathways in AD pathogenesis. Herein, we review recent progress with respect to Aβ- and tau-associated mechanisms, and discuss glial dysfunction in AD with emphasis on neuronal and glial receptors that mediate Aβ-induced toxicity. We also discuss other critical factors that may affect AD pathogenesis, including genetics, aging, variables related to environment, lifestyle habits, and describe the potential role of apolipoprotein E (APOE), viral and bacterial infection, sleep, and microbiota. Although we have gained much towards understanding various aspects underlying this devastating neurodegenerative disorder, greater commitment towards research in molecular mechanism, diagnostics and treatment will be needed in future AD research. [ABSTRACT FROM AUTHOR]

A novel combined measurements techniques has been designed in this work, enabling the acquisition of laser-induced breakdown spectroscopy (LIBS) and Raman spectral signals at the same point on a sample. The application of this combined technique to the analysis of multi-layered mock-up blocks painted with orpiment and realgar pigments has yielded significant insights. By correlating variations in the emission line intensity of characteristic elements within the LIBS spectra with depth-specific Raman spectra, the number of laser pulses that penetrated the pigment layers has been accurately determined, thereby establishing a method to measure layer thickness. Finally, the technique wasto analysis the actual mural fragment from Mogao Cave 196, determining the types of pigment and the thickness of the pigment layers. [ABSTRACT FROM AUTHOR]

The wavelengths and transition rates of W40+-W42+ ions within the range of 40–140 Å, have been calculated using the Flexible Atomic Code of the Dirac-Fock-Slater method with a central potential. We investigated the charge state distribution of W38+-W45+ ions at different temperatures by constructing an appropriate rate equation and demonstrate the importance of the dielectronic recombination process. Additionally, we simulated the emission spectra of W40+-W42+ ions in a Tokamak plasma environment using collisional-radiative modeling. Our findings demonstrate strong agreement with experimental results and other related theoretical investigations. Finally, we propose certain pairs of transition lines as diagnostic tools for plasma temperature and density, leveraging the correlation between line intensity ratio and electron temperature and density. [ABSTRACT FROM AUTHOR]

Phospholipase A2s (PLA2) is a major component of snake venom with diverse pathologic toxicities and, therefore, a potential target for antivenom therapy. Varespladib was initially designed as an inhibitor of mammal PLA2s, and was recently repurposed to a broad-spectrum inhibitor of PLA2 in snake venom. To evaluate the protective abilities of varespladib to hemorrhage, myonecrosis, and systemic toxicities that are inflicted by different crude snake venoms, subcutaneous ecchymosis, muscle damage, and biochemical variation in serum enzymes derived from the envenomed mice were determined, respectively. Varespladib treatment showed a significant inhibitory effect to snake venom PLA2, which was estimated by IC50 in vitro and ED50 in vivo. In animal models, the severely hemorrhagic toxicity of D. acutus and A. halys venom was almost fully inhibited after administration of varespladib. Moreover, signs of edema in gastrocnemius muscle were remarkably attenuated by administration of varespladib, with a reduced loss of myonecrosis and desmin. Serum levels of creatine kinase, lactate dehydrogenase isoenzyme 1, aspartate transaminase, and alanine transaminase were down-regulated after treatment with varespladib, which indicated the protection to viscera injury. In conclusion, varespladib may be a potential first-line drug candidate in snakebite envenomation first aid or clinical therapy. [ABSTRACT FROM AUTHOR]

Exploration of the Inhibitory Potential of Varespladib for Snakebite Envenomation. Reference 1 Wang Y., Zhang J., Zhang D., Xiao H., Xiong S., Huang C. Exploration of the Inhibitory Potential of Varespladib for Snakebite Envenomation. The authors would like to correct an error in the original publication [[1]]. [Extracted from the article]

Background: Late blight disease (LBD) caused by the pathogen Phytophthora infestans (PI), is the most devastating disease limiting potato (Solanum tuberosum) production globally. Currently, this disease pathogen is re-emerging and appearing in new areas at a very high intensity. A better understanding of the natural defense mechanisms against PI in different potato cultivars especially at the protein level is still lacking. Therefore, to elucidate potato proteome response to PI, we investigated changes in the proteome and leaf morphology of three potato cultivars, namely; Favorita (FA), Mira (MA), and E-malingshu N0.14 (E14) infected with PI by using the iTRAQ-based quantitative proteomics analysis. Results: A total of 3306 proteins were found in the three potato genotypes, and 2044 proteins were quantified. Cluster analysis revealed MA and E14 clustered together separately from FA. The protein profile and related functions revealed that the cultivars shared a typical hypersensitive response to PI, including induction of elicitors, oxidative burst, and suppression of photosynthesis in the potato leaves. Meanwhile, MA and E14 deployed additional specific response mechanism different from FA, involving high induction of protease inhibitors, serine/threonine kinases, terpenoid, hormone signaling, and transport, which contributed to MA tolerance of LBD. Furthermore, inductions of pathogenesis-related proteins, LRR receptor-like kinases, mitogen-activated protein kinase, WRKY transcription factors, jasmonic acid, and phenolic compounds mediate E14 resistance against LBD. These proteins were confirmed at the transcription level by a quantitative polymerase chain reaction and at the translation level by western-blot. Conclusions: We found several proteins that were differentially abundant among the cultivars, that includes common and cultivar specific proteins which highlighted similarities and significant differences between FA, MA, and E14 in terms of their defense response to PI. Here the specific accumulation of mitogen-activated protein kinase, Serine/threonine kinases, WRKY transcription played a positive role in E14 immunity against PI. The candidate proteins identified reported in this study will form the basis of future studies and may improve our understanding of the molecular mechanisms of late blight disease resistance in potato. [ABSTRACT FROM AUTHOR]

Snake venom is a complex cocktail of toxins which induces a series of clinical and pathophysiological manifestations in victims, including severe local tissue damage and systemic alterations. Deinagkistrodon acutus (D. acutus) ranks among the “big four” life-threatening venomous species in China, whose venom possesses strong myotoxicity and hematotoxicity that often lead to permanent disability or muscle atrophy. Varespladib, an inhibitor of mammalian phospholipase A2 (PLA2), has been recently reproposed as an effective antidote against snakebite envenomation. The present study aimed at evaluating the protective role of varespladib on muscle regeneration in envenomed mice. Mice were grouped and subjected to inoculation with D. acutus venom or a mixture of venom and varespladib or control vehicle in the gastrocnemius muscle. Local injuries including hemorrhage, myonecrosis, ulceration, and systemic damages including general dysfunction, visceral failure, and inflammatory responses were observed at 1, 3, 7, 14, and 21 days. The results indicated that most of the muscle myonecrosis and hemorrhage were alleviated by varespladib. Besides, the pretreated mice recovered rapidly with lesser atrophy and muscle fibrosis. In conclusion, the findings of the present study suggested that varespladib is an effective antidote that could neutralize D. acutus venom and allow for earlier and improved rehabilitation outcome. [ABSTRACT FROM AUTHOR]

Mechanistic target of rapamycin (MTOR) plays a critical role in the regulation of cell growth and in the response to energy state changes. Drugs inhibiting MTOR are increasingly used in antineoplastic therapies. Myocardial MTOR activity changes during hypertrophy and heart failure (HF). However, whether MTOR exerts a positive or a negative effect on myocardial function remains to be fully elucidated. Here, we show that ablation of Mtor in the adult mouse myocardium results in a fatal, dilated cardiomyopathy that is characterized by apoptosis, autophagy, altered mitochondrial structure, and accumulation of eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1). 4E-BP1 is an MTOR-containing multiprotein complex-1 (MTORC1) substrate that inhibits translation initiation. When subjected to pressure overload, Mtor-ablated mice demonstrated an impaired hypertrophic response and accelerated HF progression. When the gene encoding 4E-BP1 was ablated together with Mtor, marked improvements were observed in apoptosis, heart function, and survival. Our results demonstrate a role for the MTORC1 signaling network in the myocardial response to stress. In particular, they highlight the role of 4E-BP1 in regulating cardiomyocyte viability and in HF. Because the effects of reduced MTOR activity were mediated through increased 4E-BP1 inhibitory activity, blunting this mechanism may represent a novel therapeutic strategy for improving cardiac function in clinical HF. [ABSTRACT FROM AUTHOR]

In order to get a better understanding of protein association during Solanum tuberosum (cv. Sarpo Mira)–Phytophthora infestans incompatible interaction, we investigated the proteome dynamics of cv. Sarpo Mira, after foliar application of zoospore suspension from P. infestans isolate, at three key time-points: zero hours post inoculation (hpi) (Control), 48 hpi (EI), and 120 hpi (LI); divided into early and late disease stages by the tandem mass tagging (TMT) method. A total of 1229 differentially-expressed proteins (DEPs) were identified in cv. Sarpo Mira in a pairwise comparison of the two disease stages, including commonly shared DEPs, specific DEPs in early and late disease stages, respectively. Over 80% of the changes in protein abundance were up-regulated in the early stages of infection, whereas more DEPs (61%) were down-regulated in the later disease stage. Expression patterns, functional category, and enrichment tests highlighted significant coordination and enrichment of cell wall-associated defense response proteins during the early stage of infection. The late stage was characterized by a cellular protein modification process, membrane protein complex formation, and cell death induction. These results, together with phenotypic observations, provide further insight into the molecular mechanism of P. infestans resistance in potatos. [ABSTRACT FROM AUTHOR]