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Abstract Background Type 2 diabetes (T2D) is a frequent comorbidity encountered in patients with severe aortic stenosis (AS), leading to an adverse left ventricular (LV) remodeling and dysfunction. Metabolic alterations have been suggested as contributors of the deleterious effect of T2D on LV remodeling and function in patients with severe AS, but so far, the underlying mechanisms remain unclear. Mitochondria play a central role in the regulation of cardiac energy metabolism. Objectives We aimed to explore the mitochondrial alterations associated with the deleterious effect of T2D on LV remodeling and function in patients with AS, preserved ejection fraction, and no additional heart disease. Methods We combined an in-depth clinical, biological and echocardiography phenotype of patients with severe AS, with (n = 34) or without (n = 50) T2D, referred for a valve replacement, with transcriptomic and histological analyses of an intra-operative myocardial LV biopsy. Results T2D patients had similar AS severity but displayed worse cardiac remodeling, systolic and diastolic function than non-diabetics. RNAseq analysis identified 1029 significantly differentially expressed genes. Functional enrichment analysis revealed several T2D-specific upregulated pathways despite comorbidity adjustment, gathering regulation of inflammation, extracellular matrix organization, endothelial function/angiogenesis, and adaptation to cardiac hypertrophy. Downregulated gene sets independently associated with T2D were related to mitochondrial respiratory chain organization/function and mitochondrial organization. Generation of causal networks suggested a reduced Ca2+ signaling up to the mitochondria, with the measured gene remodeling of the mitochondrial Ca2+ uniporter in favor of enhanced uptake. Histological analyses supported a greater cardiomyocyte hypertrophy and a decreased proximity between the mitochondrial VDAC porin and the reticular IP3-receptor in T2D. Conclusions Our data support a crucial role for mitochondrial Ca2+ signaling in T2D-induced cardiac dysfunction in severe AS patients, from a structural reticulum-mitochondria Ca2+ uncoupling to a mitochondrial gene remodeling. Thus, our findings open a new therapeutic avenue to be tested in animal models and further human cardiac biopsies in order to propose new treatments for T2D patients suffering from AS. Trial registration URL: https://www.clinicaltrials.gov ; Unique Identifier: NCT01862237. Graphical abstract

Citrinin (CTN) is a mycotoxin commonly found in contaminated foods and feed, posing health risks to both humans and animals. However, the mechanism by which CTN damages the intestine remains unclear. In this study, a model of intestinal injury was induced by administering 1.25 mg/kg and 5 mg/kg of CTN via gavage for 28 consecutive days in 6-week-old Kunming mice, aiming to explore the potential mechanisms underlying intestinal injury. The results demonstrate that CTN can cause structural damage to the mouse jejunum. Additionally, CTN reduces the protein expression of Claudin-1, Occludin, ZO-1, and MUC2, thereby disrupting the physical and chemical barriers of the intestine. Furthermore, exposure to CTN alters the structure of the intestinal microbiota in mice, thus compromising the intestinal microbial barrier. Meanwhile, the results showed that CTN exposure could induce excessive apoptosis in intestinal cells by altering the expression of proteins such as CHOP and GRP78 in the endoplasmic reticulum and Bax and Cyt c in mitochondria. The mitochondria and endoplasmic reticulum are connected through the mitochondria-associated endoplasmic reticulum membrane (MAM), which regulates the membrane. We found that the expression of bridging proteins Fis1 and BAP31 on the membrane was increased after CTN treatment, which would exacerbate the endoplasmic reticulum dysfunction, and could activate proteins such as Caspase-8 and Bid, thus further inducing apoptosis via the mitochondrial pathway. Taken together, these results suggest that CTN exposure can cause intestinal damage by disrupting the intestinal barrier and inducing excessive apoptosis in intestinal cells.

Abstract Background p66Shc, as a redox enzyme, regulates reactive oxygen species (ROS) production in mitochondria and autophagy. However, the mechanisms by which p66Shc affects autophagosome formation are not fully understood. Methods p66Shc expression and its location in the trophoblast cells were detected in vivo and in vitro. Small hairpin RNAs or CRISPR/Cas9, RNA sequencing, and confocal laser scanning microscope were used to clarify p66Shc’s role in regulating autophagic flux and STING activation. In addition, p66Shc affects mitochondrial-associated endoplasmic reticulum membranes (MAMs) formation were observed by transmission electron microscopy (TEM). Mitochondrial function was evaluated by detected cytoplastic mitochondrial DNA (mtDNA) and mitochondrial membrane potential (MMP). Results High glucose induces the expression and mitochondrial translocation of p66Shc, which promotes MAMs formation and stimulates PINK1-PRKN-mediated mitophagy. Moreover, mitochondrial localized p66Shc reduces MMP and triggers cytosolic mtDNA release, thus activates cGAS/STING signaling and ultimately leads to enhanced autophagy and cellular senescence. Specially, we found p66Shc is required for the interaction between STING and LC3II, as well as between STING and ATG5, thereby regulates cGAS/STING-mediated autophagy. We also identified hundreds of genes associated several biological processes including aging are co-regulated by p66Shc and ATG5, deletion either of which results in diminished cellular senescence. Conclusion p66Shc is not only implicated in the initiation of autophagy by promoting MAMs formation, but also helps stabilizing active autophagic flux by activating cGAS/STING pathway in trophoblast.

ABSTRACTPeptide mapping with mass spectrometry (MS) is an important tool for protein characterization in the biopharmaceutical industry. Historically, peptide mapping monitors post-translational modifications (PTMs) of protein products and process intermediates during development. Multi-attribute monitoring (MAM) methods have been used previously in commercial release and stability testing panels to ensure control of selected critical quality attributes (CQAs). Our goal is to use MAM methods as part of an overall analytical testing strategy specifically focused on CQAs, while removing or replacing historical separation methods that do not effectively distinguish CQAs from non-CQAs due to co-elution. For example, in this study, we developed a strategy to replace a profile-based ion-exchange chromatography (IEC) method using a MAM method in combination with traditional purity methods to ensure control of charge variant CQAs for a commercial antibody (mAb) drug product (DP). To support this change in commercial testing strategy, the charge variant CQAs were identified and characterized during development by high-resolution LC-MS and LC-MS/MS. The charge variant CQAs included PTMs, high molecular weight species, and low molecular weight species. Thus, removal of the IEC method from the DP specification was achieved using a validated LC-MS MAM method on a QDa system to directly measure the charge variant PTM CQAs in combination with size exclusion chromatography (SE-HPLC) and capillary electrophoresis (CE-SDS) to measure the non-PTM charge variant CQAs. Bridging data between the MAM, IEC, and SE-HPLC methods were included in the commercial marketing application to justify removing IEC from the DP specification. We have also used this MAM method as a test for identity to reduce the number of QC assays. This strategy has received approvals from several health authorities.

D-Aspartic Acid (D-Asp) affects spermatogenesis by enhancing the biosynthesis of the sex steroid hormones acting either through the hypothalamus-pituitary–testis axis or directly on Leydig cells. Recently, in vitro studies have also demonstrated the direct effects of D-Asp on the proliferation and/or activity of germ cells. However, although D-Asp is present in Sertoli cells (SC), the specific role of the amino acid in these cells remains unknown. This study investigated the effects of D-Asp on the proliferation and activity of TM4 SC, focusing on the mitochondrial compartment and its association with the endoplasmic reticulum (ER). We found that D-Asp enhanced the proliferation and activity of TM4 cells as evidenced by the activation of ERK/Akt/PCNA pathway and the increase in the protein levels of the androgen receptor. Furthermore, D-Asp reduced both the oxidative stress and apoptotic process. An increase in mitochondrial functionality and dynamics, as well as a reduction in ER stress, were also found in D-Asp-treated TM4 cells. It is known that mitochondria are closely associated with ER to form the Mitochondrial-Associated Endoplasmic Reticulum Membranes (MAM), the site of calcium ions and lipid transfer from ER to the mitochondria, and vice versa. The data demonstrated that D-Asp induced stabilization of MAM in TM4 cells. In conclusion, this study is the first to demonstrate a direct effect of D-Asp on SC activity and to clarify the cellular/molecular mechanism underlying these effects, suggesting that D-Asp could stimulate spermatogenesis by improving the efficiency of SC.

Abstract Acute malnutrition affects not only the growth and development but also the body composition of children. However, its specific effects have not yet been characterized. This study aims to compare the body composition of 5–7‐year‐old children with moderate acute malnutrition (MAM) to that of their well‐nourished (WN) peers and identify associated factors. A school‐based comparative cross‐sectional study was conducted from June to July 2022 in Jimma town, southwest Ethiopia. The study participants were selected from eight kindergartens and eight primary schools using a simple random sampling technique based on the proportional allocation of the sample to the size of the population in the respective school. Descriptive statistics and multivariable linear regression analyses were used to assess the mean differences and associations between variables and isolate independent predictors of body composition, respectively. The statistical significance was determined using ß‐coefficients with 95% confidence intervals and a p value of ≤ 0.05. Data were captured from 388 (194 MAM and 194 WN) children with a response rate of 97.9%. The mean fat‐free mass of WN children was significantly higher compared with those with MAM (p

In order to meet the requirements of informationized and intelligent air warfare characterized by system confrontation, countries all over the world keep pushing forward the new concept of air-to-air missile. The US Air Force’s Next Generation Air Dominance(NGAD) project sets up Air Dominance Air-to-Air Weapon program to explore and integrate new missile concepts for its next generation stealth fighter aircraft, examples include the AIM-260 Joint Advanced Tactical Missile(JATM) and Modular Advanced Mission(MAM). At the same time, the US Air Force has vigorously promoted missile digital engineering, for example Pathfinder projects such as Weapon ONE have been launched, utilizing digital twin technology to quickly enhance weapon combat capabilities and improve research and acquisition processes.France and Britain are developing much of the next generation missile technologies under Materials and Components for Missiles, Innovation and Technology Partnership(MCM ITP)and Complex Weapon Innovation and Technology Partnership(CW ITP) projects. Russia, Israel, India and Japan are also developing their own new generation of air-to-air missile. The emergence of a large number of new technologies promotes the rapid development of air-to-air missile. The anti-stealth, anti-jamming performance and the level of miniaturization, networking, multi-purpose, digitalization and intelligence for the new air-to-air missile to adapt to the complex combat environment. In the future, air-to-air missile will be given new missions with new attitudes and play a greater role in the air combat system.

Abstract Tumors often overexpress glucose‐regulated proteins, and agents that interfere with the production or activity of these proteins may represent novel cancer treatments. The chlorpromazine derivative JX57 exhibits promising effects against endometrial cancer with minimal extrapyramidal side effects; however, its mechanisms of action are currently unknown. Here, glucose‐regulated protein 75 kD (GRP75) is identified as a direct target of JX57 using activity‐based protein profiling and loss‐of‐function experiments. The findings show that GRP75 is necessary for the biological activity of JX57, as JX57 exhibits moderate anticancer properties in GRP75‐deficient cancer cells, both in vitro and in vivo. High GRP75 expression is correlated with poor differentiation and poor survival in patients with endometrial cancer, whereas the knockdown of GRP75 can significantly suppress tumor growth. Mechanistically, the direct binding of JX57 to GRP75 impairs the structure of the mitochondria‐associated endoplasmic reticulum membrane and disrupts the endoplasmic reticulum–mitochondrial calcium homeostasis, resulting in a mitochondrial energy crisis and AMP‐activated protein kinase activation. Taken together, these findings highlight GRP75 as a potential prognostic biomarker and direct therapeutic target in endometrial cancer and suggest that the chlorpromazine derivative JX57 can potentially be a new therapeutic option for endometrial cancer.

This paper gives a full description of development of foreign air-to-air missiles in 2022. It pre-sents the latest advancement of AIM-9X, AIM-120, Modular Advanced Missile, ASRAAM, IRIS-T, FCAAM, Meteor, innovative missile technologies, R-37M, Astra BVRAAM, Turkish new air-to-air missiles. In the end, the paper summarizes the new development features of air-to-air missiles.

A subsurface investigation was conducted to assess the suitability of a site for potential tunnel construction, focusing on the determination of shear wave velocities (Vs) in subsurface materials. This study employed three distinct methods to analyze Vs in weathered soft rock: drilling mechanism, multichannel analysis of surface waves (MASW), and microtremor array measurement (MAM). Through the utilization of MASW and MAM, empirical relationships were established, enabling the determination of Vs based solely on soil type and depth, offering a practical alternative to the limitations of SPT N-Value, particularly when exceeding 50 blows. The comparison of Vs values obtained from these methods revealed a close alignment between empirical techniques and MASW/MAM, which proved to be cost-effective and an efficient alternative to drilling for comprehensive underground structure assessments. The reliability of MASW was further underscored through its comparison with existing empirical methods. Moreover, the empirical approach demonstrated its efficacy in predicting velocities in weathered soft rock within the Central Himalayan region of Nepal, thus enhancing the feasibility study of underground structures. Lastly, this study proposed a Vs-Depth correlation specifically tailored for highly weathered meta-sandstone bedrock resulting in clay and sandy soils.

Skeletal muscle atrophy and the inhibition of muscle regeneration are known to occur as a natural consequence of aging, yet the underlying mechanisms that lead to these processes in atrophic myofibers remain largely unclear. Our research has revealed that the maintenance of proper mitochondrial-associated endoplasmic reticulum membranes (MAM) is vital for preventing skeletal muscle atrophy in microgravity environments. We discovered that the deletion of the mitochondrial fusion protein Mitofusin2 (MFN2), which serves as a tether for MAM, in human induced pluripotent stem (iPS) cells or the reduction of MAM in differentiated myotubes caused by microgravity interfered with myogenic differentiation process and an increased susceptibility to muscle atrophy, as well as the activation of the Notch signaling pathway. The atrophic phenotype of differentiated myotubes in microgravity and the regenerative capacity of Mfn2-deficient muscle stem cells in dystrophic mice were both ameliorated by treatment with the gamma-secretase inhibitor DAPT. Our findings demonstrate how the orchestration of mitochondrial morphology in differentiated myotubes and regenerating muscle stem cells plays a crucial role in regulating Notch signaling through the interaction of MAM.

Introduction Breast cancer is the most common cancer in women in India and accounts for 14% of all cancers in women. Rise in mortality is due to lack of awareness and proper screening. Mammography and presently available serum biomarkers have low sensitivity and specificity. In our quest to identify a better biomarker, we studied mammaglobin (MAM) in patients with breast cancer and benign breast tumors.

Habitat disturbance leads to biodiversity decline and modifications in the landscape structure and composition, affecting both dispersal movements and ecological processes at different temporal and spatial scales. The Ecuadorian Tropical Andes harbour suitable habitats for the distribution of a wide variety of species; however, there is a lack of studies focused on mammal diversity and its association with the habitat attributes in the central-eastern slopes. Here, we reported the diversity of terrestrial mammals recorded between 2019 and 2021 in a camera-trap monitoring study in the Candelaria and Machay reserves in the upper basin of the Pastaza River, Ecuador. We performed site-occupancy probability analysis to assess the influence of spatial variables in the species’ occurrence and also, based on natural marks, we reported preliminary findings in Andean bear individual identification. We detected 22 species of terrestrial mammals. Alpha diversity was similar between reserves with slightly higher species richness in Machay. Evenness indices showed unequal species distribution, with the Andean bear and domestic dogs exhibiting greater dominance. In addition, species composition was dissimilar between reserves, where the species turnover mostly explained the beta diversity. We observed that Andean bear and puma detections increased according to the natural vegetation cover. Conversely, domestic dogs were frequently detected in cells with an increasing proportion of pastures and crops. Additionally, we identified 26 Andean bears and six individuals recaptured during our study. Our results caution about the disturbance derived from human activities since we recorded unprecedented detections of domestic dogs in wild habitats. Nonetheless, it highlights the importance of private conservation areas (e.g. Candelaria, Machay and others) for supporting the occurrence and dispersal of terrestrial mammal species between larger areas in the upper basin of the Pastaza River.

Anticancer agents are playing an increasing role in the treatment of gastric cancer (GC); however, novel anticancer agents have not been fully developed. Therefore, it is important to investigate compounds that improve sensitivity to the existing anticancer drugs. We have reported that pterostilbene (PTE), a plant stilbene, enhances the antitumor effect of low doses of sunitinib in gastric cancer cells accumulating mitochondrial iron (II) (mtFe) at low doses. In this study, we investigated the relationship between the mtFe deposition and the synergistic effect of PTE and different anticancer drugs. For this study, we used 5-fluorouracil (5FU), cisplatin (CPPD), and lapatinib (LAP), which are frequently used in the treatment of GC, and doxorubicin (DOX), which is known to deposit mtFe. A combination of low-dose PTE and these drugs suppressed the expression of PDZ domain-containing 8 (PDZD8) and increased mtFe accumulation and mitochondrial H2O2. Consequently, reactive oxygen species-associated hypoxia inducible factor-1α activation induced endoplasmic reticulum stress and led to apoptosis, but not ferroptosis. In contrast, 5FU and CDDP did not show the same changes as those observed with PTE and DOX or LAP, and there was no synergistic effect with PTE. These results indicate that the combination of PTE with iron-accumulating anticancer drugs exhibits a strong synergistic effect. These findings would help in developing novel therapeutic strategies for GC. However, further clinical investigations are required.

Objetivo: analizar las memorias de los integrantes del pueblo mam de Soconusco en relación con el proceso de mexicanización en Cacahoatán, Tuxtla Chico, Huehuetán, Unión Juárez y Tapachula Chiapas. Metodología: cualitativa con un muestreo no probabilístico, sustentada en los estudios de la memoria y centrada en entrevistas a personas que se perciben a sí mismas como portadoras de esa cultura, para lo cual se recurre a herramientas del método biográfico. Limitaciones: los resultados corresponden solo a la información extraída de las entrevistas, por lo cual se requieren estudios históricos profundos que pongan el énfasis en otras variables coetáneas. Valor: el trabajo representa una aportación a la historiografía regional mediante el análisis de las memorias del pueblo mam. Conclusiones: dichas memorias dan cuenta de las interacciones entre el Estado y el pueblo mam como resultado del proceso de mexicanización en Soconusco.

Stress-induced release of glucocorticoid is an important amyloidogenic factor that upregulates amyloid precursor protein (APP) and β secretase 1 (BACE1) levels. Glucocorticoid also contributes to the pathogenesis of Alzheimer’s disease (AD) by increasing ER-mitochondria connectivity, in which amyloid β (Aβ) processing occurs rigorously because of its lipid raft-rich characteristics. However, the mechanism by which glucocorticoid enhances γ-secretase activity in the mitochondrial-associated membrane of ER (MAM) and subsequent accumulation of mitochondrial Aβ is unclear. In this study, we determined how glucocorticoid enhances Aβ production in MAM using SH-SY5Y cells and ICR mice. First, we observed that cortisol-induced Aβ accumulation in mitochondria preceded its extracellular apposition by enhancing γ-secretase activity, which was the result of increased presenilin 1 (PSEN1) localization in MAM. Screening data revealed that cortisol selectively downregulated the ER retrieval protein Rer1, which triggered its maturation and subsequent entry into the endocytic secretory pathway of PSEN1. Accordingly, overexpression of RER1 reversed the deleterious effects of mitochondrial Aβ on mitochondrial respiratory function and neuronal cell viability. Notably, we found that cortisol guided the glucocorticoid receptor (GR) to bind directly to the RER1 promoter, thus trans-repressing its expression. Inhibiting GR function reduced Aβ accumulation at mitochondria and improved the outcome of a spatial memory task in mice exposed to corticosterone. Taken together, glucocorticoid enhances PSEN1-mediated Aβ generation at MAM by downregulating Rer1, which is a potential target at early stages of AD pathogenesis.

This work is part of a research project aimed at developing a bio-based binder, composed mainly of polylactic acid (PLA), to produce Ti6Al4V feedstock suitable for use in MAM (Metal Additive Manufacturing) via mFFF (metal Fused Filament Fabrication), in order to manufacture a titanium alloy specimen. While in Bragaglia et al. the mechanical characteristics of this sample were analyzed, the aim used of this study is to compare the mentioned mFFF process with one of the most used MAM processes in aerospace applications, known as Selective Laser Sintering (SLS), based on the Life Cycle Assessment (LCA) method. Despite the excellent properties of the products manufactured via SLS, this 3D printing technology involves high upfront capital costs while mFFF is a cheaper process. Moreover, the mFFF process has the advantage of potentially being exported for production in microgravity or weightless environments for in-space use. Nevertheless, most scientific literature shows comparisons of the Fused Filament Fabrication (FFF) printing stage with other AM technologies, and there are no comparative LCA “Candle to Gate” studies with mFFF processes to manufacture the same metal sample. Therefore, both MAM processes are analyzed with the LCA “Candle to Gate” method, from the extraction of raw materials to the production of the finished titanium alloy sample. The main results demonstrate a higher impact (+50%) process for mFFF and higher electrical energy consumption (7.31 kWh) compared to SLS (0.32 kWh). After power consumption, the use of titanium becomes the main contributor of Global Warming Potential (GWP) and Abiotic Depletion Potential (ADP) for both processes. Finally, an alternative scenario is evaluated in which the electrical energy is exclusively generated through photovoltaics. In this case, the results show how the mFFF process develops a more sustainable outcome than SLS.

Understanding the spatial and temporal distribution of precipitation is important in agriculture, water management resources, and flood disaster management. The present study analyzed the changes in rainfall concentration over East Africa (EA). Three matrices—the precipitation concentration index (PCI), the precipitation concentration degree (PCD), and the precipitation concentration period (PCP)—were used to examine the changes in rainfall during 1981–2021. The changes in spatial variance annually and during two seasons, namely, “long rains” (March to May [MAM]) and “short rain” (October to December [OND]), were estimated using an empirical orthogonal function (EOF). The study employed the robust statistical metrics of the Theil–Sen estimator to detect the magnitude of change and modified Mann–Kendall (MMK) to examine possible changes in rainfall concentration. The localized variation of the power series within the series for PCI, PCD, and PCP variability was performed using the continuous wavelet transform. The findings showed that the concentration of rainfall patterns of EA occurred in four months of the total months in a year over most parts, with the western sides experiencing uniform rainfall events throughout the year. The EOF analysis revealed a homogeneous negative pattern during the MAM season over the whole region for PCD, PCI, and PCP for the first mode, which signified reduced rainfall events. Moreover, the MMK analysis showed evidence of declining trends in the PCD annually and during the MAM season, while the opposite tendency was noted for the OND season where an upward trend in the PCD was observed. Interestingly, areas adjacent to Lake Victoria in Uganda and Lake Tanganyika in Tanzania showed increasing trends in the PCD for annual and seasonal time scales. The analysis to characterize the rainfall cycle and possible return period, considering the indices of PCD, PCI, and PCP, showed higher variability during the year 2000, while much variability was presented in the PCP for the annual period. During the MAM and OND seasons, a 1-year band as a dominant period of variability was observed in all the indices. Overall, the findings of the present study are crucial in detecting the observed changes in rainfall concentration for avoiding the loss of life and property, as well as for coping with potential changes in water resources.

The Pernambuco Endemism Center is a key region for the maintenance of biodiversity of the Brazilian Atlantic Forest. Inventories of the medium-sized terrestrial mammals in this region are scarce, and several information gaps still remain. We conducted a camera trap survey at the Tapacurá Ecological Station, São Lourenço da Mata, Pernambuco. We obtained new records of at least four females and three male individuals of Ocelot, Leopardus pardalis (Linnaeus, 1758). The records provide important data about occurrence and distribution of a threatened population of this mesocarnivore in northeastern Brazil.

Underground space utilization is becoming increasingly essential for modern metropolitan cities such as Singapore. Mapping a soil/rock interface using traditional borehole investigation methods is expensive and difficult, owing to the numerous physical constraints within a built-up city. Boreholes are often far apart, resulting in many unforeseen ground conditions during subsequent excavation. Geophysical methods are sometimes employed as possible alternatives for fast, economical, and efficient bedrock surveys. The goal of this study is to investigate the practical details of applying microtremor array measurement (MAM) as a non-invasive surface wave survey for mapping soil/rock interfaces in Singapore. Critical configurations in field data acquisition are examined, and practical recommendations for array construction are provided. In addition, 30 in situ MAM tests are carried out for two major geological formations in Singapore. From the results, a standard shear wave velocity (Vs) of 500 m/s is found to be suitable for interpreting the soil/rock interface, for the Bukit Timah Granite and Jurong formations. However, the method does not predict well when soft Kallang formation deposits are present. Other limitations are also discussed in the later parts of this paper. Conclusions and practical recommendations are discussed, providing constructive guidance to the industry. The proposed Vs-based method and associated guidelines and limitations can be used to create a digital geological database and are especially useful for rock profiling in an urban environment.

Abstract Mitochondria‐associated endoplasmic reticulum membranes (MAM) are specialized subcellular compartments that are shaped by endoplasmic reticulum (ER) subdomains placed side by side to the outer membrane of mitochondria (OMM) being connected by tethering proteins in mammalian cells. Studies showed that MAM has multiple physiological functions. These include regulation of lipid synthesis and transport, Ca2+ transport and signaling, mitochondrial dynamics, apoptosis, autophagy, and formation and activation of an inflammasome. However, alterations of MAM integrity lead to deleterious effects due to an increased generation of mitochondrial reactive oxygen species (ROS) via increased Ca2+ transfer from the ER to mitochondria. This, in turn, causes mitochondrial damage and release of mitochondrial components into the cytosol as damage‐associated molecular patterns which rapidly activate MAM‐resident Nod‐like receptor protein‐3 (NLRP3) inflammasome components. This complex induces the release of pro‐inflammatory cytokines that initiate low‐grade chronic inflammation that subsequently causes the development of metabolic diseases. But, the mechanisms of how MAM is involved in the pathogenesis of these diseases are not exhaustively reviewed. Therefore, this review was aimed to highlight the contribution of MAM to a variety of cellular functions and consider its significance pertaining to the pathogenesis of inflammation‐mediated metabolic diseases.

The guatemalan mental health approach is a forgotten issue in the public health agenda, with a total budget of less than 0.68% of the total of what is spent on health, besides an ineffective healthcare system and overlapping privatization. Further on, there is an absent and weak program and policy in place, not suitable to assure the Human Rights of people living with disability. We present a panoramic view of the mental Health situation in the country through the analysis of three cases of children at Yalú, Guatemala, a poor comunity at Sibinal, San Marcos in the border of Unión Juárez, Chiapas, México, which, in the face of the State’s exclusion and a health system that denies them the exercise of their rights, have created their own strategies. This paper is a part of the partial results from an etnography developed between 2014 and 2019

Zhe Zhang,1,2 Di Cui,1,2 Tan Zhang,1,2 Yi Sun,1,2 Shuzhe Ding1,2 1Key Laboratory of Adolescent Health Assessment and Exercise Intervention of Ministry of Education, East China Normal University, Shanghai 200241, People’s Republic of China; 2College of Physical Education and Health, East China Normal University, Shanghai 200241, People’s Republic of ChinaCorrespondence: Shuzhe DingKey Laboratory of Adolescent Health Assessment and Exercise Intervention of Ministry of Education, East China Normal University, Shanghai 200241, People’s Republic of ChinaTel +86 13601798505Email szding@tyxx.ecnu.edu.cnPurpose: Mitochondrial dysfunction and endoplasmic reticulum stress (ERS) are associated with metabolic diseases such as obesity and Type 2 diabetes mellitus (T2DM). Mitochondria and ER are connected via mitochondria-associated membranes (MAM) that are involved in glucose homeostasis and insulin resistance. We postulated that exercise might positively benefit T2DM-induced ER and mitochondrial dysfunction that might be associated with MAM.Materials and Methods: Mice were fed a high-fat diet and injected with streptozotocin (STZ) to create T2DM models. Glucose tolerance, mitochondrial quality, MAM quality, and ERS were investigated in diabetic mice after six weeks of swimming.Results: Type 2 DM induced decreased MAM quantity, impaired mitochondrial quality, and deteriorated ERS in skeletal muscle that led to endoplasmic reticulum-associated degradation (ERAD). Swimming alleviated strong ERS caused by T2DM. Importantly, MAM quantity was positively associated with mitochondrial function and tended to negatively correlate with the ERS branch, ATF6. Moreover, both ATF6 branches of ERS and ERAD were positively associated with the pIRE1α branch of ERS.Conclusion: Type 2 DM induced glucose intolerance, powerful ERS, and mitochondrial dysfunction associated with decreased amounts of MAM. Swimming improved glucose intolerance and selectively mitigated the ERS in skeletal muscle. Therefore, MAM quality and ATF6 might be novel and important targets for T2DM treatment. Endoplasmic reticulum stress might be an effective target of swimming to improve diabetes.Keywords: T2DM, skeletal muscle, mitochondrial quality, ERS, MAM

Abstract Background Reprogramming human induced pluripotent stem cells (iPSCs) from somatic cells and generating three-dimensional brain organoids from these iPSCs provide access to live human neuronal tissue with disease-specific genetic backgrounds. Methods Cerebral organoids were generated from iPSCs of eight bipolar disorder (BPI) patients and eight healthy control individuals. RNA-seq experiments were undertaken using RNA isolated from the cerebral organoids. Functional activity in the cerebral organoids was studied using microelectrode arrays. Results RNA-seq data comparing gene expression profiles in the cerebral organoids showed downregulation of pathways involved in cell adhesion, neurodevelopment, and synaptic biology in bipolar disorder along with upregulation of genes involved in immune signaling. The central hub in the network analysis was neurocan (NCAN), which is located in a locus with evidence for genome-wide significant association in BPI. Gene ontology analyses suggested deficits related to endoplasmic reticulum biology in BPI, which was supported by cellular characterization of ER–mitochondria interactions. Functional studies with microelectrode arrays revealed specific deficits in response to stimulation and depolarization in BPI cerebral organoids. Conclusions Our studies in cerebral organoids from bipolar disorder showed dysregulation in genes involved in cell adhesion, immune signaling, and endoplasmic reticulum biology; implicated a central role for the GWAS hit NCAN in the biology of BPI; and showed evidence of deficits in neurotransmission.

The study assesses the covariability of Sea Surface Temperature (SST) and March to May (MAM) rainfall variability on East Africa (EA) from 1981 to 2018. Singular Value Decomposition (SVD) analysis reveals the significant influence of SST anomalies on MAM rainfall, with covariability of 91%, 88.61%, and 82.9% for Indian, Atlantic, and the Pacific Ocean, respectively. The Indian Ocean explains the variability of rainfall to the large extent followed by the Atlantic Ocean and the Pacific Ocean. The rainfall patterns over the EA correspond to SST variability over the western, central, and Eastern Indian Ocean. Likewise, the variability of SST anomalies was observed over the central, south, and North of the Atlantic Ocean while the Pacific Ocean captured the El Nino Modoki (ENSO) like pattern in the SVD1 (SVD2). The heterogeneous correlation of Indian SST anomalies and rainfall over EA of the first (second) principal component (PC) shows a positive correlation over much of the domain (central region). The SST anomalies over the Pacific Ocean show higher correlation values with the rainfall over much of the study domain except over the southwestern highland and southern region of Tanzania. Over the Atlantic Ocean, the correlation result shows the patterns of positive (negative) values over the northern (southern) part for PC1, while PC2 depicts negative correlation values over much of the Ocean. SST anomalies over the Indian (Atlantic) Ocean are highly correlated with MAM rainfall when SST leads by 1(7) month(s). The Pacific Ocean shows a weak (strong) correlation across all (zero) lead seasons.

Mitochondrial autophagy (or mitophagy) regulates the mitochondrial network and function to contribute to multiple cellular processes. The protective effect of homeostatic mitophagy in cardiovascular diseases (CVDs) has attracted increasing attention. FUN14 domain containing 1 (FUNDC1), an identified mitophagy receptor, plays an essential role in CVDs. Different expression levels of FUNDC1 and its phosphorylated state at different sites alleviate or exacerbate hypoxia and ischemia/reperfusion injury, cardiac hypertrophy, or metabolic damage through promotion or inhibition of mitophagy. In addition, FUNDC1 can be enriched at contact sites between mitochondria and the endoplasmic reticulum (ER), determining the formation of mitochondria-associated membranes (MAMs) that regulate cellular calcium (Ca2+) homeostasis and mitochondrial dynamics to prevent heart dysfunction. Moreover, FUNDC1 has also been involved in inflammatory cardiac diseases such as septic cardiomyopathy. In this review, we collect and summarize the evidence on the roles of FUNDC1 exclusively in various CVDs, describing its interactions with different cellular organelles, its involvement in multiple cellular processes, and its associated signaling pathways. FUNDC1 may become a promising therapeutic target for the prevention and management of various CVDs.

Regulation of cell life and death by members of the BCL-2 family of proteins occurs at the mitochondria. Large portions of the mitochondria’s outer membrane are found in tight approximation with the endoplasmic reticulum (ER), known as mitochondria-associated membranes (MAMs) or mitochondria-ER contact sites (MERCs). We recently reported that BOK is present within MAMs where it regulates Ca2+ transfer from the ER to the mitochondria, appropriate MAM components and MERC structure, and apoptosis.

HMG-CoA reductase (HMGCR) is the rate-limiting enzyme in cholesterol biosynthesis and the target for cholesterol-lowering therapy. Acetaldehyde dehydrogenase 2 (ALDH2) is primarily responsible for detoxifying ethanol-derived acetaldehyde and endogenous lipid aldehydes derived from lipid peroxidation. Epidemiological and Genome Wide Association Studies (GWAS) have linked an inactive ALDH2 rs671 variant, responsible for alcohol flush in nearly 8% world population and 40% of Asians, with cholesterol levels and higher risk of cardiovascular disease (CVD) but the underlying mechanism remains elusive. Here we find that the cholesterol levels in the serum and liver of ALDH2 knockout (AKO) and ALDH2 rs671 knock-in (AKI) mice are significantly increased, consistent with the increase of intermediates in the cholesterol biosynthetic pathways. Mechanistically, mitochondrial ALDH2 translocates to the endoplasmic reticulum to promote the formation of GP78/Insig1/HMGCR complex to increase HMGCR degradation through ubiquitination. Conversely, ALDH2 mutant or ALDH2 deficiency in AKI or AKO mice stabilizes HMGCR, resulting in enhanced cholesterol synthesis, which can be reversed by Lovastatin. Moreover, ALDH2-regulated cholesterol synthesis is linked to the formation of mitochondria-associated endoplasmic reticulum membranes (MAMs). Together, our study has identified that ALDH2 is a novel regulator of cholesterol synthesis, which may play an important role in CVD.

Abstract Background Program decision-making to prevent and treat acute malnutrition in an emergency can be hampered by a lack of accessible and relevant overviews of directly available robust research evidence. There is often evidence from related settings such as from low-income countries, but this is dispersed across many databases, may be inaccessible and requires assessment of its relevance to the humanitarian setting. We describe a process whereby a multi-disciplinary, international group of specialists worked together to build relevant and effective collections of available systematic reviews on acute malnutrition, published and disseminated as online collections, to improve access to the evidence and concise, synthesised, relevant up to date evidence for programming. By describing this process, we hope to inspire other professional groups to take part in similar multi-stakeholder, multi-disciplinary projects. Objectives This project was designed to make the evidence from relevant systematic reviews about malnutrition as accessible as possible to support evidence-based decision-making and to guide future research on the prevention and treatment of acute malnutrition in humanitarian emergencies. Methods Between March 2017 and March 2018, a large group (21 volunteers and stakeholders) with different backgrounds collaborated to review and curate collections of systematic reviews of interventions for the prevention and treatment of moderate and severe acute malnutrition relevant to humanitarian emergencies. The methodology loosely followed general guidance for overviews of systematic reviews with a pre-defined question (formulated using the PICOS format) and search strategies applied to multiple databases. Pairs of collaborators first screened the search yields to identify potentially eligible reviews, where after other pairs screened the list of potentially eligible reviews for relevance and thus included in the final collections. Results Search strategies were run in 12 databases, in the week of 15 September 2017, yielding a total of 4646 records after de-duplication. At this point, Cochrane reviews (n = 463) and non-Cochrane reviews (n = 4183) were separated and handled by different teams to compile three linked collections, namely the Evidence Aid Collection, consisting of relevant non-Cochrane reviews, and two Cochrane Special Collections, consisting of relevant Cochrane reviews, one for prevention and the other for treatment of acute malnutrition. The collections were published on the Evidence Aid website on 12 March 2018 and Cochrane website in August 2018. Discussion Through this collaboration, we have successfully generated three collections of systematic reviews to guide prevention and management of acute malnutrition in humanitarian emergencies: an Evidence Aid collection of non-Cochrane reviews, and two Cochrane Special Collections of Cochrane reviews. These collections provide accessible synthesised evidence that can be used to inform decision-making on strategies and policies in the humanitarian emergency and disaster risk reduction sectors and to guide future research by identifying gaps in robust evidence and areas that are under-researched. These collections did not set out to assess methodological quality, appraise in detail what the reviews found or summarise the evidence, but rather to curate the identified relevant systematic reviews into online resources for others to use. This unique collaboration of different individuals, organisations and stakeholders, and the collation of robust evidence can be repeated for other subjects, and Evidence Aid is eager to support new collections around other topics relevant to humanitarian emergencies.

This study used Empirical Orthogonal Function (EOF), student t test, composite and correlation analysis techniques to investigate the inter-annual variability of March to May rainy season over Tanzania and its association atmospheric circulation anomalies. The EOF results showed that the rainfall over Tanzania during MAM season does not vary too much with the first dominant mode (EOF1) showing the variance of 22.4% of the total rainfall and that much of the rainfall being concentrated over the coast, northeastern and southern regions. It was found that during wet years, the study area was dominated by convergence at lower level which is associated with enough moisture advected by south easterlies from Indian Ocean due to the relaxation of Mascarene high (MH) over the region and westerlies from Congo basin. The rising motion at lower level was enhanced with the presence of ascending limb of Walker circulation cell over the western Indian Ocean (WIO) and the coast region. Central Pacific and east coast of Atlantic Oceans are relatively warm during wet years. Furthermore, significantly negative correlation observed between southeast Indian Ocean (SEIO) region and MAM rainfall over Tanzania at the 95% confidence level portrays that much of the regions receive high sufficient amount of rainfall when the western Indian Ocean (WIO) is relatively warmer than the SEIO. The results show that Nino 3.4 and Tropical North Atlantic (TNA) indices are strongly positively correlated with MAM rainfall over the east coast region. This study will help to improve seasonal forecasts over Tanzania.

Mitochondria-associated ER membranes (MAMs) represent a crucial intracellular signaling hub, that regulates various cellular events including Ca2+ homeostasis, lipid metabolism, mitochondrial function, and cellular survival and death. All of these MAM-mediated cellular events contribute to carcinogenesis. Indeed, altered functions of MAMs in several types of cancers have been documented, in particular for breast cancer. Over the past years, altered expression of many MAM-resident proteins have been reported in breast cancer. These MAM-resident proteins play an important role in regulation of breast cancer initiation and progression. In the current review, we discuss our current knowledge about the functions of MAMs, and address the underlying mechanisms through which MAM-resident proteins regulate breast cancer. A fuller understanding of the pathways through which MAMs regulate breast cancer, and identification of breast cancer-specific MAM-resident proteins may help to develop novel therapeutic strategies for breast cancer.

Mitochondria–endoplasmic reticulum (ER) contact sites (MERCS) have been emerging as a multifaceted subcellular region of the cell which affects several physiological and pathological mechanisms. A thus far underexplored aspect of MERCS is their contribution to exocytosis. Here, we set out to understand the role of these contacts in exocytosis and find potential mechanisms linking these structures to vesicle release in human neuroblastoma SH-SY5Y cells. We show that increased mitochondria to ER juxtaposition through Mitofusin 2 (Mfn2) knock-down resulted in a substantial upregulation of the number of MERCS, confirming the role of Mfn2 as a negative regulator of these structures. Furthermore, we report that both vesicle numbers and vesicle protein levels were decreased, while a considerable upregulation in exocytotic events upon cellular depolarization was detected. Interestingly, in Mfn2 knock-down cells, the inhibition of the inositol 1,4,5-trisphosphate receptor (IP3R) and the mitochondrial calcium (Ca2+) uniporter (MCU) restored vesicle protein content and attenuated exocytosis. We thus suggest that MERCS could be targeted to prevent increased exocytosis in conditions in which ER to mitochondria proximity is upregulated.

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor (TF) that regulates a variety of biological processes, including a key role in mediating mitochondrial metabolism. It has been shown that STAT3 performs this function by translocating in minute amounts into mitochondria and interacting with mitochondrial proteins and genome. However, whether STAT3 localizes in mitochondria is still up for debate. To decipher the role of mitochondrial STAT3 requires a detailed understanding of its cellular localization. Using Percoll density gradient centrifugation, we surprisingly found that STAT3 is not located in the mitochondrial fraction, but instead, in the mitochondria-associated endoplasmic reticulum membrane (MAM) fraction. This was confirmed by sub-diffraction image analysis of labeled mitochondria in embryonic astrocytes. Also, we find that other TFs that have been previously found to localize in mitochondria are also found instead in the MAM fraction. Our results suggest that STAT3 and other transcriptional factors are, contrary to prior studies, consolidated specifically at MAMs, and further efforts to understand mitochondrial STAT3 function must take into consideration this localization, as the associated functional consequences offer a different interpretation to the questions of STAT3 trafficking and signaling in the mitochondria.

Abstract Idiopathic normal pressure hydrocephalus (iNPH) is a neuropathology with unknown cause characterised by gait impairment, cognitive decline and ventriculomegaly. These patients often present comorbidity with Alzheimer’s disease (AD), including AD pathological hallmarks such as amyloid plaques mainly consisting of amyloid β-peptide and neurofibrillary tangles consisting of hyperphosphorylated tau protein. Even though some of the molecular mechanisms behind AD are well described, little is known about iNPH. Several studies have reported that mitochondria-endoplasmic reticulum contact sites (MERCS) regulate amyloid β-peptide metabolism and conversely that amyloid β-peptide can influence the number of MERCS. MERCS have also been shown to be dysregulated in several neurological pathologies including AD. In this study we have used transmission electron microscopy and show, for the first time, several mitochondria contact sites including MERCS in human brain biopsies. These unique human brain samples were obtained during neurosurgery from 14 patients that suffer from iNPH. Three of these 14 patients presented comorbidities with other dementias: one patient with AD, one with AD and vascular dementia and one patient with Lewy body dementia. Furthermore, we report that the numbers of MERCS are increased in biopsies obtained from patients diagnosed with dementia. Moreover, the presence of both amyloid plaques and neurofibrillary tangles correlates with decreased contact length between endoplasmic reticulum and mitochondria, while amyloid plaques alone do not seem to affect endoplasmic reticulum-mitochondria apposition. Interestingly, we report a significant positive correlation between the number of MERCS and ventricular cerebrospinal fluid amyloid β-peptide levels, as well as with increasing age of iNPH patients.

We use the comparative method of language acquisition research in this article to investigate children’s expression of directional clitics in two Eastern Mayan languages – K’iche’ and Mam (Pye and Pfeiler, 2014; Pye, 2017). The comparative method in historical linguistics reconstructs the grammatical antecedents of modern languages and traces the evolution of each linguistic feature (Paul, 1889; Campbell, 1998). This history informs research on language acquisition by demonstrating how phonological and morphological features interact in the evolution of new uses for common inherited traits. Children acquiring modern languages must learn the arbitrary constraints imposed on their language by its history.

Presenilin 2 (PS2), one of the three proteins in which mutations are linked to familial Alzheimer’s disease (FAD), exerts different functions within the cell independently of being part of the γ-secretase complex, thus unrelated to toxic amyloid peptide formation. In particular, its enrichment in endoplasmic reticulum (ER) membrane domains close to mitochondria (i.e., mitochondria-associated membranes, MAM) enables PS2 to modulate multiple processes taking place on these signaling hubs, such as Ca2+ handling and lipid synthesis. Importantly, upregulated MAM function appears to be critical in AD pathogenesis. We previously showed that FAD-PS2 mutants reinforce ER–mitochondria tethering, by interfering with the activity of mitofusin 2, favoring their Ca2+ crosstalk. Here, we deepened the molecular mechanism underlying PS2 activity on ER–mitochondria tethering, identifying its protein loop as an essential domain to mediate the reinforced ER–mitochondria connection in FAD-PS2 models. Moreover, we introduced a novel tool, the PS2 loop domain targeted to the outer mitochondrial membrane, Mit-PS2-LOOP, that is able to counteract the activity of FAD-PS2 on organelle tethering, which possibly helps in recovering the FAD-PS2-associated cellular alterations linked to an increased organelle coupling.

Mitochondria associated membranes (MAM), which are the contact sites between endoplasmic reticulum (ER) and mitochondria, have emerged as an important hub for signaling molecules to integrate the cellular and organelle homeostasis, thus facilitating the adaptation of energy metabolism to nutrient status. This review explores the dynamic structural and functional features of the MAM and summarizes the various abnormalities leading to the impaired insulin sensitivity and metabolic diseases.

Abstract Background Maternal obesity alters oocytes and subsequent fetal metabolism. An increasing number of studies have shown that the endoplasmic reticulums (ER) or mitochondria have important effects on oocyte quality, but there has been no study of the effect of mitochondria-associated ER membranes (MAMs) on oocyte quality. The present study was designed to assess whether the level of MAM and MAM-related proteins were different in oocytes from obese and control mice. Results First, oocytes from mice with high-fat-diet (HFD)-induced obesity had higher levels (either greater numbers or a higher proportion for the same numbers) of MAM than oocytes from control mice. The abundance of MAM-related proteins in oocytes from obese mice was significantly greater at both the messenger RNA and protein levels, including inositol 1,4,5-trisphosphate receptor, type 1 (IP3R1), inositol 1,4,5-trisphosphate receptor, type 2 (IP3R2) and phosphofurin acidic cluster sorting protein 2 (PACS-2). Further, there was an increase in mitochondrial Ca2+ ([Ca2+]m) which was associated with increased apoptosis and compromised cytoplasmic maturation in oocytes from obese mice. Down-regulation of MAM-related protein IP3R1 in oocytes from obese mice decreased [Ca2+]m and apoptosis and improved cytoplasmic maturation but did not reduce the overall MAM level. However, down-regulating MAM-related protein PACS-2 in oocytes from obese mice did reduce the level of MAM and [Ca2+]m, which decreased the rate of apoptosis and improved cytoplasmic maturation of oocytes from obese mice. Conclusions It is possible that enriched MAM could increase [Ca2+]m, and this increase has been found to be associated with increased apoptosis and compromised cytoplasmic maturation in oocytes from obese mice. This finding suggests a novel therapeutic target for obesity-induced oocyte defects.

Organic polymers can be made porous via continuous or discontinuous expansion processes in scCO2. The resulting foams properties are controlled by the interplay of three groups of parameters: (i) Chemical, (ii) physico-chemical, and (iii) technological/process that are explained in this paper. The advantages and drawbacks of continuous (extrusion, injection foaming) or discontinuous (batch foaming) foaming processes in scCO2, will be discussed in this article; especially for micro or nano cellular polymers. Indeed, a challenge is to reduce both specific mass (e.g., ρ < 100 kg·m−3) and cell size (e.g., average pore diameter ϕaveragepores < 100 nm). Then a particular system where small “objects” (coreshells CS, block copolymer MAM) are perfectly dispersed at a micrometric to nanometric scale in poly(methyl methacrylate) (PMMA) will be presented. Such “additives”, considered as foaming aids, are aimed at “regulating” the foaming and lowering the pore size and/or density of PMMA based foams. Differences between these additives will be shown. Finally, in a PMMA/20 wt% MAM blend, via a quasi one-step batch foaming, a “porous to nonporous” transition is observed in thick samples. A lower limit of pore size (around 50 nm) seems to arise.

The pathogenesis of Parkinson’s disease (PD), the second most common neurodegenerative disorder, is complex and involves the impairment of crucial intracellular physiological processes. Importantly, in addition to abnormal α-synuclein aggregation, the dysfunction of various mitochondria-dependent processes has been prominently implicated in PD pathogenesis. Besides the long-known loss of the organelles’ bioenergetics function resulting in diminished ATP synthesis, more recent studies in the field have increasingly focused on compromised mitochondrial quality control as well as impaired biochemical processes specifically localized to ER−mitochondria interfaces (such as lipid biosynthesis and calcium homeostasis). In this review, we will discuss how dysregulated mitochondrial crosstalk with other organelles contributes to PD pathogenesis.

Las organizaciones contemporáneas se han visto abocadas a la gestión creciente de activos digitales de naturaleza audiovisual y multimedia, muchos de ellos de interés patrimonial. El presente artículo realiza la revisión y análisis de cinco gestores de activos multimedia de plena significación en la actualidad. Tras sistematizar las características generales y módulos que deben satisfacer este tipo de sistemas, hemos procedido a la evaluación de los sistemas de gestión documental seleccionados, alcanzando como resultado la discusión de las ventajas que nos proporciona cada uno de ellos, sus características distintivas, así como la evaluación de su adecuación profesional.

Sigma-1 receptor ligands have been long expected to serve as drugs for treatment of human diseases such as neurodegenerative disorders, depression, idiopathic pain, drug abuse, and cancer. Recent research exploring the molecular function of the sigma-1 receptor started unveiling underlying mechanisms of the therapeutic activity of those ligands. Via the molecular chaperone activity, the sigma-1 receptor regulates protein folding/degradation, ER/oxidative stress, and cell survival. The chaperone activity is activated or inhibited by synthetic sigma-1 receptor ligands in an agonist-antagonist manner. Sigma-1 receptors are localized at the endoplasmic reticulum (ER) membranes that are physically associated with the mitochondria (MAM: mitochondria-associated ER membrane). In specific types of neurons (e.g., those at the spinal cord), sigma-1 receptors are also clustered at ER membranes that juxtapose postsynaptic plasma membranes. Recent studies indicate that sigma-1 receptors, partly in sake of its unique subcellular localization, regulate the mitochondria function that involves bioenergetics and free radical generation. The sigma-1 receptor may thus provide an intracellular drug target that enables controlling ER stress and free radical generation under pathological conditions.

The human cytomegalovirus (HCMV) viral mitochondria-localized inhibitor of apoptosis (vMIA) protein, traffics to mitochondria-associated membranes (MAM), where the endoplasmic reticulum (ER) contacts the outer mitochondrial membrane (OMM). vMIA association with the MAM has not been visualized by imaging. Here, we have visualized this by using a combination of confocal and superresolution imaging. Deconvolution of confocal microscopy images shows vMIA localizes away from mitochondrial matrix at the Mitochondria-ER interface. By gated stimulated emission depletion (GSTED) imaging, we show that along this interface vMIA is distributed in clusters. Through multicolor, multifocal structured illumination microscopy (MSIM), we find vMIA clusters localize away from MitoTracker Red, indicating its OMM localization. GSTED and MSIM imaging show vMIA exists in clusters of ~100–150 nm, which is consistent with the cluster size determined by Photoactivated Localization Microscopy (PALM). With these diverse superresolution approaches, we have imaged the clustered distribution of vMIA at the OMM adjacent to the ER. Our findings directly compare the relative advantages of each of these superresolution imaging modalities for imaging components of the MAM and sub-mitochondrial compartments. These studies establish the ability of superresolution imaging to provide valuable insight into viral protein location, particularly in the sub-mitochondrial compartments, and into their clustered organization.

Mitochondria-associated membranes (MAM) are a well-recognized contact link between the mitochondria and endoplasmic reticulum that affects mitochondrial biology and vascular smooth muscle cells (VSMCs) proliferation via the regulation of mitochondrial Ca2+(Ca2+m) influx. Nogo-B receptor (NgBR) plays a vital role in proliferation, epithelial-mesenchymal transition, and chemoresistance of some tumors. Recent studies have revealed that downregulation of NgBR, which stimulates the proliferation of VSMCs, but the underlying mechanism remains unclear. Here, we investigated the role of NgBR in MAM and VSMC proliferation. We analyzed the expression of NgBR in pulmonary arteries using a rat model of hypoxic pulmonary hypertension (HPH), in which rats were subjected to normoxic recovery after hypoxia. VSMCs exposed to hypoxia and renormoxia were used to assess the alterations in NgBR expression in vitro. The effect of NgBR downregulation and overexpression on VSMC proliferation was explored. The results revealed that NgBR expression was negatively related with VSMCs proliferation. Then, MAM formation and the phosphorylation of inositol 1,4,5-trisphosphate receptor type 3 (IP3R3) was detected. We found that knockdown of NgBR resulted in MAM disruption and augmented the phosphorylation of IP3R3 through pAkt, accompanied by mitochondrial dysfunction including decreased Ca2+m, respiration and mitochondrial superoxide, increased mitochondrial membrane potential and HIF-1α nuclear localization, which were determined by confocal microscopy and Seahorse XF-96 analyzer. By contrast, NgBR overexpression attenuated IP3R3 phosphorylation and HIF-1α nuclear localization under hypoxia. These results reveal that dysregulation of NgBR promotes VSMC proliferation via MAM disruption and increased IP3R3 phosphorylation, which contribute to the decrease of Ca2+m and mitochondrial impairment.

The Aceh and Seulimeum Faults flank the Krueng Aceh Basin in Indonesia, and the shear-wave velocity (Vs) structure of the basin is not extensively available. Understanding the Vs structure is very important in order to figure out how the basin structures seemingly appear, and this can eventually be used to generate a microzonation map for other forthcoming studies. To provide this, Vs was measured over an area approximately covering Banda Aceh City and its surroundings, by setting two lines consisting of eight points projected in the NW–SE and SW–NE orientations. This research aims to facilitate the approximation of the Vs structure characteristics of the Krueng Aceh Basin using the microtremor array method (MAM). Triangular configurations were set by deploying four seismometers following an M-station geometry for three different array sizes (i.e., 3, 10, and 30 m in distance). The data were then processed by utilizing the spatial autocorrelation (SPAC) technique. The result shows that the Vs structure generally dips down from SE to NW, and it gradually declines from SW to NE. The combination of these Vs structures tends to be oblique toward the SW–NE direction. This form may be affected by the Aceh Segment Fault which is more active than the Seulimeum Segment Fault. The average maximum penetration depth and Vs are 603 m and 947.5 m/s in the SE–NW orientation, and 650 m and 958 m/s in the SW–NE direction. Generally, the thickness of the strata is greater in the upstream area compared to the downstream area. Their composition consists of alluvium (A) at the uppermost layer and diluvium (D) at the underlying layers. Then, all of the identified strata are aged from the Pleistocene to Tertiary Pleistocene (Tp). These characteristics of the strata could potentially cause surface damages as a result of site effect responses when an earthquake is occurring.

The turbine tip geometry can significantly alter the performance of the turbine stage; its design represents a challenge for a variety of reasons. Multiple disciplines are involved in its design and their requirements limit the creativity of the designer. Multi-Disciplinary Design Optimisation (MDO) offers the capability to improve the performance whilst satisfying all the design constraints. This paper presents a novel design of a turbine tip achieved via MDO techniques. A fully parametrised Computer-Aided Design (CAD) model of the turbine rotor is used to create the squealer geometry and to control the location of the cooling and dust holes. A Conjugate Heat Transfer Computational Fluid Dynamics (CFD) analysis is performed for evaluating the aerothermal performance of the component and the temperature the turbine operates at. A Finite Element (FE) analysis is then performed to find the stress level that the turbine has to withstand. A bi-objective optimisation reduces simultaneously the aerodynamic loss and the stress level. The Multipoint Approximation Method (MAM) recently enhanced for multi-objective problems is chosen to solve this optimisation problem. The paper presents its logic in detail. The novel geometry offers a significant improvement in the aerodynamic performance whilst reducing the maximum stress. The flow associated with the new geometry is analysed in detail to understand the source of the improvement.

Mitochondrial dysfunction and endoplasmic reticulum (ER) stress have been suggested to play a key role in insulin resistance development. Reactive oxygen species (ROS) production and lipid accumulation due to mitochondrial dysfunction seemed to be important mechanisms leading to cellular insulin resistance. Moreover, mitochondria are functionally and structurally linked to ER, which undergoes stress in conditions of chronic overnutrition, activating the unfolded protein response, which in turn activates the principal inflammatory pathways that impair insulin action. Among the nutrients, dietary fats are believed to play key roles in insulin resistance onset. However, not all dietary fats exert the same effects on cellular energy metabolism. Dietary omega 3 polyunsaturated fatty acids (PUFA) have been suggested to counteract insulin resistance development by modulating mitochondrial bioenergetics and ER stress. In the current review, we summarized current knowledge on the role played by mitochondrial and ER stress in inflammation and insulin resistance onset, focusing on the modulation role of omega 3 PUFA on these stress pathways. Understanding the mechanisms by which omega 3 PUFA modulates cellular metabolism and insulin resistance in peripheral tissues may provide additional details on the potential impact of omega 3 PUFA on metabolic function and the management of insulin resistance in humans.

Se analizan los flujos informativos y documentales de una redacción completamente digital como es el caso de laSexta Noticias, en la que ha desaparecido por completo el uso de cintas en la realización del Informativo. Los MAM (Media Asset Management) han cambiado los flujos de trabajo en televisión, así como las herramientas con las que trabaja a diario el documentalista, figura cada vez más próxima a la del periodista; ambos, trabajan con las mismas aplicaciones y las tareas de unos y otros llegan a fusionarse en distintos momentos del proceso.

Membrane-bound organelles such as mitochondria, peroxisomes or the endoplasmic reticulum (ER) create distinct environments to promote specific cellular tasks such as ATP production, lipid breakdown or protein export. During recent years, it has become evident that organelles are integrated into cellular networks regulating metabolism, intracellular signalling, cellular maintenance, cell fate decision and pathogen defence. In order to facilitate such signalling events, specialized membrane regions between apposing organelles bear distinct sets of proteins to enable tethering and exchange of metabolites and signalling molecules. Such membrane associations between the mitochondria and a specialized site of the ER, the mitochondria associated-membrane (MAM), as well as between the ER and the plasma membrane (PAM) have been partially characterized at the molecular level. However, historical and recent observations imply that other organelles like peroxisomes, lysosomes and lipid droplets might also be involved in the formation of such apposing membrane contact sites. Alternatively, reports on so-called mitochondria derived-vesicles (MDV) suggest alternative mechanisms of organelle interaction. Moreover, maintenance of cellular homeostasis requires the precise removal of aged organelles by autophagy – a process which involves the detection of ubiquitinated organelle proteins by the autophagosome membrane, representing another site of membrane associated-signalling. This review will summarize the available data on the existence and composition of organelle contact sites and the molecular specializations each site uses in order to provide a timely overview on the potential functions of organelle interaction.

Autophagy is a tightly regulated catabolic pathway that terminates in the lysosomal compartment after the formation of a cytoplasmic vacuole that engulfs macromolecules and organelles. Notably, autophagy is associated with several human pathophysiological conditions, playing either a cytoprotective or cytopathic role. Many studies have investigated the role of autophagy in cancer. However, whether autophagy suppresses tumorigenesis or provides cancer cells with a rescue mechanism under unfavorable conditions remains unclear. Mitochondria-associated membranes (MAMs) are juxtaposed between the endoplasmic reticulum and mitochondria and have been identified as a critical hub in the regulation of apoptosis and tumor growth. One key function of MAMs is to provide asylum to a number of proteins with tumor suppressor and oncogenic properties. Accordingly, mechanistic studies during tumor progression suggest a strong involvement of these proteins at various steps of the autophagic process. This paper discusses the present state of our knowledge about the intimate molecular networks between MAMs and autophagy in cancer cells and addresses how these networks might be manipulated to improve anticancer therapeutics.