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SUMMARY Although plants harbor a huge phytochemical diversity, only a fraction of plant metabolites is functionally characterized. In this work, we aimed to identify the genetic basis of metabolite functions during harsh environmental conditions in Arabidopsis thaliana. With machine learning algorithms we predicted stress‐specific metabolomes for 23 (a)biotic stress phenotypes of 300 natural Arabidopsis accessions. The prediction models identified several aliphatic glucosinolates (GLSs) and their breakdown products to be implicated in responses to heat stress in siliques and herbivory by Western flower thrips, Frankliniella occidentalis. Bivariate GWA mapping of the metabolome predictions and their respective (a)biotic stress phenotype revealed genetic associations with MAM, AOP, and GS‐OH, all three involved in aliphatic GSL biosynthesis. We, therefore, investigated thrips herbivory on AOP, MAM, and GS‐OH loss‐of‐function and/or overexpression lines. Arabidopsis accessions with a combination of MAM2 and AOP3, leading to 3‐hydroxypropyl dominance, suffered less from thrips feeding damage. The requirement of MAM2 for this effect could, however, not be confirmed with an introgression line of ecotypes Cvi and Ler, most likely due to other, unknown susceptibility factors in the Ler background. However, AOP2 and GS‐OH, adding alkenyl or hydroxy‐butenyl groups, respectively, did not have major effects on thrips feeding. Overall, this study illustrates the complex implications of aliphatic GSL diversity in plant responses to heat stress and a cell‐content‐feeding herbivore. [ABSTRACT FROM AUTHOR]

D-Aspartic Acid (D-Asp) affects spermatogenesis by enhancing the biosynthesis of the sex steroid hormones acting either through the hypothalamu-spituitary-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-Asptreated 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 FROM AUTHOR]

The metal additive manufacturing (MAM) process has most employed methods to build complex geometry and lightweight 3-dimensional (3-D) parts directly from a computerized solid model. Distortion of the printed part is a highly significant concern within the MAM process. This issue is because of the heating and cooling effect of printing process that could accumulate residual stress (RS) during part building up. The aim of the literature work is to present various methodologies for measuring RS in MAM components and to furnish a brief summary of recent developments in the domain. These details aid scholars in the discernment of suitable techniques, namely destructive, semi-destructive, or non-destructive, contingent on their particular applications and the accessibility of these methods. Moreover, it facilitates the explication of their formation mechanisms, effectiveness of process parameters, prediction, and control techniques. The effect of RS on the mechanical characteristics of printed parts is analyzed and presented. Additionally, common defects incorporated into RS are discussed. Moreover, this review article discusses about the future challenges and opportunities in the RS analysis of MAM parts.Highlights: ●Different technique of residual stress measurement in additive manufacturing process. ●Influence of process parameter on residual stress. Scanning speed, layer height, laser power, laser energy density etc. ●Impact of residual stress on mechanical properties. ●Common defect due to residual stress. Delamination, parts cracking, separation from support, grain boundary cracking etc. ●Impact of in-process and post-process techniques in residual stress modification. Shot peening, heat treatment, hot isotatic pressing, laser shock peening etc. [ABSTRACT FROM AUTHOR]

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

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. [ABSTRACT FROM AUTHOR]

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 < 0.001). The mean (SD) of fat mass of MAM children was 4.23 ± 0.72 kg, 4.36 ± 0.88 kg and 4.08 ± 0.89 kg for 5, 6 and 7‐year‐olds, respectively. For WN children, the mean (SD) of fat mass was 4.92 ± 0.88 kg for 5 years old, 5.64 ± 1.01 kg for 6 years old and 5.75 ± 1.26 kg for 7 years old (p < 0.001). On the multivariable linear regression analysis after controlling for background variables, WN children exhibited 1.51 times higher fat‐free mass compared with MAM children (β = 1.51, p = 0.003). A unit increase in age of the study participants was associated with a 1.37 increment in fat‐free mass (β = 1.37, p < 0.001). WN children had 1.07 times higher fat mass compared with children with MAM (β = 1.07, p < 0.001). A unit increase in the age of the child resulted in 0.15 times increment in fat mass (β = 0.15, p = 0.020), and being female was associated with a 0.37 increase in fat mass (β = 0.37, p < 0.001). The results showed that the mean fat mass and fat‐free mass were significantly lower among moderately acute malnourished children than in WN children showing the loss of both body compartments due to malnutrition. The body mass index for age, age of the child and sex of the child were significantly linked to both fat‐free mass and fat mass. Key messages: This study demonstrated that children aged 5–7 years suffering from moderate acute malnutrition (MAM) have lower mean body fat mass (FM) and fat‐free mass (FFM) as compared with well‐nourished (WN) children.The substantial difference observed between MAM and WN children in body FM and FFM calls for the integration of MAM treatment into the routine health services to prevent their sliding down to SAM and associated mortality. [ABSTRACT FROM AUTHOR]

Over the past two decades, we have witnessed a growing appreciation for the importance of membrane contact sites (CS) in facilitating direct communication between organelles. CS are tiny regions where the membranes of two organelles meet but do not fuse and allow the transfer of metabolites between organelles, playing crucial roles in the coordination of cellular metabolic activities. The significant advancements in imaging techniques and molecular and cell biology research have revealed that CS are more complex than what originally thought, and as they are extremely dynamic, they can remodel their shape, composition, and functions in accordance with metabolic and environmental changes and can occur between more than two organelles. Here, we describe how recent studies led to the identification of a three‐way mitochondria–ER–lipid droplet CS and discuss the emerging functions of these contacts in maintaining lipid storage, homeostasis, and balance. We also summarize the properties and functions of key protein components localized at the mitochondria–ER–lipid droplet interface, with a special focus on lipid transfer proteins. Understanding tripartite CS is essential for unraveling the complexities of inter‐organelle communication and cooperation within cells. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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.

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The "amyloid cascade" hypothesis of Alzheimer's disease (AD) pathogenesis invokes the accumulation in the brain of plaques (containing the amyloid-β protein precursor [AβPP] cleavage product amyloid-β [Aβ]) and tangles (containing hyperphosphorylated tau) as drivers of pathogenesis. However, the poor track record of clinical trials based on this hypothesis suggests that the accumulation of these peptides is not the only cause of AD. Here, an alternative hypothesis is proposed in which the AβPP cleavage product C99, not Aβ, is the main culprit, via its role as a regulator of cholesterol metabolism. C99, which is a cholesterol sensor, promotes the formation of mitochondria-associated endoplasmic reticulum (ER) membranes (MAM), a cholesterol-rich lipid raft-like subdomain of the ER that communicates, both physically and biochemically, with mitochondria. We propose that in early-onset AD (EOAD), MAM-localized C99 is elevated above normal levels, resulting in increased transport of cholesterol from the plasma membrane to membranes of intracellular organelles, such as ER/endosomes, thereby upregulating MAM function and driving pathology. By the same token, late-onset AD (LOAD) is triggered by any genetic variant that increases the accumulation of intracellular cholesterol that, in turn, boosts the levels of C99 and again upregulates MAM function. Thus, the functional cause of AD is upregulated MAM function that, in turn, causes the hallmark disease phenotypes, including the plaques and tangles. Accordingly, the MAM hypothesis invokes two key interrelated elements, C99 and cholesterol, that converge at the MAM to drive AD pathogenesis. From this perspective, AD is, at bottom, a lipid disorder. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

This article describes the journey I embarked on as a teacher-researcher to better understand the realities of two of my Maya English learners (ELs) in our learning environment. This yearlong (2018–2019) study took the form of a qualitative case study inquiry whose purpose was to explore how two Maya migrant youth from Guatemala experienced and negotiated language, culture, and identity in a suburban U.S. high school. Findings highlight the need for acknowledging the participants' Mayan culture, and including academic resources and support in their first languages (Mam and Q'eqchi'), instead of Spanish, to learn English. In addition, recorded conversations with the participants shed light on the complexities dwelling at the intersection of language, culture, and identity in formal education settings and beyond. [ABSTRACT FROM AUTHOR]

This article examines the way the Maya-Mam, an Indigenous people divided by the Guatemala–Mexico border, define territory in relation to and across state borders. As state borders geographically, socially, culturally, and politically divide the pueblo Mam, state maps bolster these divisions and state subjugation by promoting a nation-state framework that circumscribes the Mam within its borders. However, the Mam are problematizing state depictions of spatiality: they denaturalize state borders by articulating alternative ontologies of territory. This study shows that in their everyday lives, Mam councils, activists, and individuals aim to promote broader cross-border Mam unification to better defend territory from potential harm. They use a dual-prong approach for articulating territory: through the development of narratives that draw upon a more holistic understanding of territory's 'nature' and by making counter-maps that incorporate Mam understanding of territory. I argue that these Indigenous efforts weave together a resistance to and refusal of state frames. [ABSTRACT FROM AUTHOR]

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.

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. [ABSTRACT FROM AUTHOR]

Sigma-1 receptor (S1R) is a calcium-sensitive, ligand-operated receptor chaperone present on the endoplasmic reticulum (ER) membrane. S1R plays an important role in ER-mitochondrial inter-organelle calcium signaling and cell survival. S1R and its agonists confer resilience against various neurodegenerative diseases; however, the molecular mechanism of S1R is not yet fully understood. At resting state, S1R is either in a monomeric or oligomeric state but the ratio of these concentrations seems to change upon activation of S1R. S1R is activated by either cellular stress, such as ER-calcium depletion, or ligands. While the effect of ligands on S1R quaternary structure remains unclear, the effect of cellular stress has not been studied. In this study we utilize cellular and an in-vivo model to study changes in quaternary structure of S1R upon activation. We incubated cells with cellular stressors (H2O2 and thapsigargin) or exogenous ligands, then quantified monomeric and oligomeric forms. We observed that benzomorphan-based S1R agonists induce monomerization of S1R and decrease oligomerization, which was confirmed in the liver tissue of mice injected with (+)-Pentazocine. Antagonists block this effect but do not induce any changes when used alone. Oxidative stress (H2O2) increases the monomeric/oligomeric S1R ratio whereas ER calcium depletion (thapsigargin) has no effect. We also analyzed the oligomerization ability of various truncated S1R fragments and identified the fragments favorizing oligomerization. In this publication we demonstrate that quaternary structural changes differ according to the mechanism of S1R activation. Therefore, we offer a novel perspective on S1R activation as a nuanced phenomenon dependent on the type of stimulus. [ABSTRACT FROM AUTHOR]

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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. [ABSTRACT FROM AUTHOR]

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.

In 1950, Drs. Chevigny and Braverman authored a book about people's attitudes and prejudices toward the blind, noting that out of the thousands of schizophrenia patients they and others had treated, not one was blind. This led some to the intriguing hypothesis that congenital blindness may provide protection against schizophrenia. In this study, we directly examined whether congenital blindness protects against a schizophrenia-related phenotype in the methylazoxymethanol acetate (MAM) rodent model. Enucleation surgeries were performed on pups of MAM- or saline-treated rats on post-natal day 10. Once pups reached adulthood, male and female rats were evaluated for schizophrenia-like phenotypes using behavioral and electrophysiological measures. Consistent with previous work, MAM-treated rats display elevated dopamine neuron population activity, deficits in pre-pulse inhibition of startle, and hypersensitivity to psychomotor stimulants. Blindness did not protect against any of the MAM-induced phenotypes. Surprisingly, blindness in saline-treated rats caused changes in behavior and dopamine neuron activity. To examine the circadian rhythms of enucleated rats, we performed non-invasive measurements of corticosterone, a steroid hormone known to vary across the light/dark period, revealing blind rats display aberrant (non-cycling) corticosterone levels. Alterations in dopamine neuron activity and associated behaviors observed in blind rats are likely secondary to aberrant circadian regulation. This is the first preclinical study examining whether congenital blindness protects against a schizophrenia-like phenotype. While support of this hypothesis would have led to novel avenues of research and potential novel therapies, the results of current study suggest that blindness does not protect against schizophrenia. [ABSTRACT FROM AUTHOR]

Copyright of Aero Weaponry is the property of Aero Weaponry Editorial Office and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

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.

(1) Background: Synthetic cannabinoids (SCs) are emerging drugs of abuse sold as 'K2', 'K9' or 'Spice'. Evidence shows that using SCs products leads to greater health risks than cannabis. They have been associated with greater toxicity and higher addiction potential unrelated to the primary psychoactive component of marijuana, Δ9-tetrahydrocannabinol (Δ9-THC). Moreover, early cases of intoxication and death related to SCs highlight the inherent danger that may accompany the use of these substances. However, there is limited knowledge of the toxicology of Spice ingredients. This systematic review intends to analyze the toxicity of SCs compounds in Spice/K2 drugs. (2) Methods: Studies analyzing synthetic cannabinoid toxicity and dependence were included in the present review. We searched the PubMed database of the US National Library of Medicine, Google Scholar, CompTox Chemicals, and Web of Science up to May 2022. (3) Results: Sixty-four articles reporting the effects of synthetic cannabinoids in humans were included in our review. Ten original papers and fifty-four case studies were also included. Fourteen studies reported death associated with synthetic cannabinoid use, with AB-CHMINACA and MDMB-CHMICA being the main reported SCs. Tachycardia and seizures were the most common toxicity symptoms. The prevalence of neuropsychiatric symptoms was higher in third-generation SCs. (4) Conclusion: SCs may exhibit higher toxicity than THC and longer-lasting effects. Their use may be harmful, especially in people with epilepsy and schizophrenia, because of the increased risk of the precipitation of psychiatric and neurologic disorders. Compared to other drugs, SCs have a higher potential to trigger a convulsive crisis, a decline in consciousness, and hemodynamic changes. Therefore, it is crucial to clarify their potential harms and increase the availability of toxicology data in both clinical and research settings. [ABSTRACT FROM AUTHOR]

Declining cerebral blood flow leads to chronic cerebral hypoperfusion which can induce neurodegenerative disorders, such as vascular dementia. The reduced energy supply of the brain impairs mitochondrial functions that could trigger further damaging cellular processes. We carried out stepwise bilateral common carotid occlusions on rats and investigated long-term mitochondrial, mitochondria-associated membrane (MAM), and cerebrospinal fluid (CSF) proteome changes. Samples were studied by gel-based and mass spectrometry-based proteomic analyses. We found 19, 35, and 12 significantly altered proteins in the mitochondria, MAM, and CSF, respectively. Most of the changed proteins were involved in protein turnover and import in all three sample types. We confirmed decreased levels of proteins involved in protein folding and amino acid catabolism, such as P4hb and Hibadh in the mitochondria by western blot. We detected reduced levels of several components of protein synthesis and degradation in the CSF as well as in the subcellular fractions, implying that hypoperfusion-induced altered protein turnover of brain tissue can be detected in the CSF by proteomic analysis. [ABSTRACT FROM AUTHOR]

Persistent poly (ADP‐ribose) polymerase 1 (PARP‐1) activation has proven detrimental and can lead to PARP‐1‐dependent cell death. Mitochondria‐associated endoplasmic reticulum (ER) membranes (MAMs) serve as essential hubs for many biological pathways, such as autophagy and mitochondria fission and fusion. This study aimed to alleviate the effects of hydrogen peroxide (H2O2)‐induced persistent PARP‐1 activation and MAM dysregulation by the usage of a PARP‐1 inhibitor. Results showed that receptor‐interacting protein kinase (RIPK) 1 inhibitor (necrostatin‐1) and PARP‐1 inhibitor (olaparib) protected retinal precursor cells from H2O2‐induced death, while a pan‐caspase inhibitor (Z‐VAD‐FMK) failed to protect R28 cells. Olaparib also alleviated H2O2‐induced MAM dysregulation, as evidenced by decreased VDAC1/ITPR3 interactions and reduced mitochondrial membrane potential collapse. Additionally, olaparib also inhibited H2O2‐induced autophagy. Inhibiting autophagic flux increased MAM signaling under both normal and oxidative conditions. Furthermore, H2O2 treatment caused a reduction in the protein level of mitofusin‐2 (MFN2) in a dose‐ and time‐dependent manner. Mfn2 knockdown was found to further magnify MAM dysregulation and mitochondrial dysfunction under normal and oxidative conditions. Mfn2 overexpression surprisingly enhanced H2O2‐induced MAM signaling and failed to rescue H2O2‐induced mitochondrial dysfunction. These results indicate that MAMs probably serve as a membrane source for oxidative stress‐associated autophagy. MAM dysregulation also contributed to H2O2‐induced PARP‐1‐dependent cell death. However, more studies are required to decipher the link between the modulation of Mfn2 expression, changes in MAM integrity, and alterations in mitochondrial performances. [ABSTRACT FROM AUTHOR]

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. Aim To evaluate serum mammaglobin in breast cancer patients and compare it with benign breast tumor patients and healthy controls. To compare it with existing biomarkers serum carcinoembryonic antigen (CEA) and cancer antigen 15–3 (CA 15–3). Materials and methods: This is a cross-sectional, case–control study of 77 subjects, of which 27 were breast cancer patients, 20 benign breast tumor patients, and 30 healthy controls. Serum CEA and CA15–3 were estimated by electrochemiluminescence immunoassay (ECLIA) and mammaglobin (MAM) by enzyme-linked immunosorbent assay (ELISA). Results Mammaglobin and CEA levels were elevated in breast cancer patients, followed by benign breast tumors when compared with controls (P < 0.000001). Mammaglobin showed 81.5% sensitivity, 100% specificity, 100% positive predictive value (PPV), and 88.9% negative predictive value (NPV). CEA showed 88.9% sensitivity, 82.5% specificity, 77.4% PPV, and 91.7% NPV. The area under the curve was the highest for MAM (0.892), followed by CEA (0.889) and CA 15–3 (0.555). CA15–3 showed poor diagnostic efficacy. Combined receiver operating characteristic (ROC) curve of the biomarkers MAM and CEA had an AUC of 0.913. Conclusion Mammaglobin proved to be an efficacious biomarker in diagnosing breast cancer. [ABSTRACT FROM AUTHOR]

Diabetic cardiomyopathy (DCM) is one of the severe complications of diabetes with no known biomarkers for early detection. Mitochondria-associated endoplasmic reticulum membranes (MAM) are less studied subcellular targets but an emerging area for exploration in metabolic disorders including DCM. We herein studied the role of MAMs and downstream mitochondrial functions in DCM. We also explored the efficacy of ferulic acid (FeA) against DCM via modulation of MAM and its associated signaling pathway. The H9c2 cardiomyoblast cells were incubated with high concentration (33 mM) of d -glucose for 48 h to create a high glucose ambience in vitro. The expression of various critical proteins of MAM, mitochondrial function, oxidative phosphorylation (OxPhos) and the genesis of apoptosis were examined. The rats fed with high fat/high fructose/streptozotocin (single dose, i.p.) were used as a diabetic model and analyzed the insulin resistance and markers of cardiac hypertrophy and apoptosis. High glucose conditions caused the upregulation of MAM formation via PACS2, IP3R2, FUNDC1, and VDAC1 and decreased mitochondrial biogenesis, fusion and OxPhos. The upregulation of mitochondria-driven SMAC-HTRA2-ARTS-XIAP apoptosis and other cell death pathways indicate their critical roles in the genesis of DCM at the molecular level. The diabetic rats also showed cardiomyopathy with increased heart mass index, TNNI3K, troponin, etc. FeA effectively prevented the high glucose-induced MAM alterations and associated cellular anomalies both in vitro and in vivo. High glucose-induced MAM distortion and subsequent mitochondrial dysfunctions act as the stem of cardiomyopathy. MAM could be explored as a potential target to treat diabetic cardiomyopathy. Also, the FeA could be an attractive nutraceutical agent for diabetic cardiomyopathy. Schematic representation of the mechanism of diabetic cardiomyopathy by MAM and effect of ferulic acid. High glucose promotes MAM formation via PACS2/IP3R2/FUNDC1/VDAC1 which induces alteration in mitochondrial dynamics, OxPhos leads apoptosis via mitochondria-induced SMAC/HTRA2/ARTS/XIAP inhibition and AIF/ENDOG-Caspase independent pathways in rat cardiomyoblasts which paves the way to diabetic cardiomyopathy. [Display omitted] • Hyperglycaemia in H9c2 cells causes distortion of MAMs, contributing significantly to DCM. • MAM distortion causes apoptosis in H9c2 cells via mitochondrial pathways. • Diabetes induces fibrosis and hypertrophy in the heart. • Ferulic acid and metformin are effective against DCM. [ABSTRACT FROM AUTHOR]

A Double-layer banana leaves-based absorber is designed and can be treated as a potential alternative to conventional MAM. The dielectric relaxation parameters of the dry banana leaves in powder form and the composites of dry banana leaves and charcoal powder have are measured by OCP method using vector network analyzer in the frequency range of 1–16 GHz. Further, the return loss of two single-layers and a double-layer with a thickness of 4 and 8.02 mm, respectively, is investigated in the frequency range of 1–20 GHz. Results show that the electromagnetic properties along with absorption performance of the double layer absorber are appreciably ameliorated as compared to its single-layer counterparts. [ABSTRACT FROM AUTHOR]

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.

Background: In mouse liver hepatocytes, nearly half of the surface area of every mitochondrion is covered by wrappER, a wrapping-type of ER that is rich in fatty acids and synthesizes lipoproteins (VLDL) (Anastasia et al. in Cell Rep 34:108873, 2021; Hurtley in Science (80-) 372:142–143, 2021; Ilacqua et al. in J Cell Sci 135:1–11, 2021). A disruption of the ultrastructure of the wrappER-mitochondria contact results in altered fatty acid flux, leading to hepatic dyslipidemia (Anastasia et al. 2021). The molecular mechanism that regulates the extent of wrappER-mitochondria contacts is unknown. Methods: We evaluated the expression level of the mitochondrial protein Synj2bp in the liver of normal and obese (ob/ob) mice. In addition, we silenced its expression in the liver using an AAV8 vector. We coupled quantitative EM morphometric analysis to proteomics and lipid analyses on these livers. Results: The expression level of Synj2bp in the liver positively correlates with the extent of wrappER-mitochondria contacts. A 50% reduction in wrappER-mitochondria contacts causes hepatic dyslipidemia, characterized by a gross accumulation of lipid droplets in the liver, an increased hepatic secretion of VLDL and triglycerides, a curtailed ApoE expression, and an increased capacity of mitochondrial fatty acid respiration. Conclusion: Synj2bp regulates the extent of wrappER-mitochondria contacts in the liver, thus contributing to the control of hepatic lipid flux. [ABSTRACT FROM AUTHOR]

To observe whether downhill running can lead to DNA damage in skeletal muscle cells and changes in mitochondrial membrane permeability and to explore whether the DNA damage caused by downhill running can lead to changes in mitochondrial membrane permeability by regulating the components of the endoplasmic reticulum mitochondrial coupling structure (MAM). A total of 48 male adult Sprague–Dawley rats were randomly divided into a control group (C, n = 8) and a motor group (E, n = 40). Rats in Group E were further divided into 0 h (E0), 12 h (E12), 24 h (E24), 48 h (E48) and 72 h (E72) after prescribed exercise, with 8 rats in each group. At each time point, flounder muscle was collected under general anaesthesia. The DNA oxidative damage marker 8-hydroxydeoxyguanosine (8-OHdG) was detected by immunofluorescence. The expression levels of the DNA damage-related protein p53 in the nucleus and the EI24 protein and reep1 protein in whole cells were detected by Western blot. The colocalization coefficients of the endoplasmic reticulum protein EI24 and the mitochondrial protein Vdac2 were determined by immunofluorescence double staining, and the concentration of Ca2+ in skeletal muscle mitochondria was detected by a fluorescent probe. Finally, the opening of the mitochondrial membrane permeability transition pore (mPTP) was detected by immunofluorescence. Twelve hours after downhill running, the mitochondrial membrane permeability of the mPTP opened the most (P < 0.05), the content of 8-OHdG in skeletal muscle peaked (P < 0.05), and the levels of the regulatory protein p53, mitochondrial Ca2+, and the EI24 and reep1 proteins peaked (P < 0.01). Moreover, the colocalization coefficients of EI24 and Vdac2 and the Mandes coefficients of the two proteins increased first and then recovered 72 h after exercise (P < 0.05). (1) Downhill running can lead to DNA damage in skeletal muscle cells, overload of mitochondrial Ca2+ and large opening of membrane permeability transformation pores. (2) The DNA damage caused by downhill running may result in p53 promoting the transcriptional activation of reep1 and EI24, enhancing the interaction between EI24 and Vdac2, and then leading to an increase in Ca2+ in skeletal muscle mitochondria and the opening of membrane permeability transition pores. [ABSTRACT FROM AUTHOR]

The commentary amplifies Kidd and Garcia's call for increased attention to language diversity in research on language acquisition by noting several implications of language diversity for acquisition theory and practice. An examination of the languages discussed in six recent articles on acquisition theory echos Kidd and Garcia's observations on the inordinate role that better-studied languages play in acquisition research. Documenting the acquisition of 7,000 languages over the coming decade requires a new infrastructure for acquisition research. Sketches of child languages offer a community-based solution to processing bottlenecks and promote the use of indigenous languages. [ABSTRACT FROM AUTHOR]

Terbuthylazine (TBA) is a common triazine herbicide used in agricultural production, which causes toxic damage in multiple tissues. Hesperidin (HSP) is a flavonoid derivative that has anti-inflammatory, antioxidant and cytoprotective effects, but its role in reducing toxic damage caused by pesticides is still unclear. In this study, we aimed to investigate the toxic effect of TBA exposure on chicken hepatocytes and the therapeutic effect of HSP on the TBA-induced hepatotoxicity. Our results demonstrated that HSP could alleviate TBA exposure-induced endoplasmic reticulum (ER) stress. Interestingly, TBA significantly disrupted the integrity of mitochondria-associated endoplasmic reticulum membrane (MAM), while HSP treatment showed the opposite tendency. In addition, TBA could significantly trigger ferroptosis in liver, and HSP treatment reversed ferroptosis under TBA exposure. These results suggested that HSP could inhibit ER stress and alleviate ferroptosis under TBA exposure via maintaining MAM integrity, which provided a novel strategy to take precautions against TBA toxicity. [Display omitted] • TBA induce ferroptosis via maintenance of MAM integrity. • HSP is a novel strategy to take precautions against TBA toxicity. • ER stress and MAM integrity play crucial roles in TBA-induced liver injury. [ABSTRACT FROM AUTHOR]