Advances in 4-Nitrophenol Detection and Reduction Methods and Mechanisms: An Updated Review.

This review emphasizes the progress in identifying and eliminating para-nitrophenol (4-NP), a toxic organic compound. It covers various strategical methods and materials, including organic and inorganic nanomaterials, for detecting and reducing 4-NP. Detection techniques such as electrochemical methods. Optical fiber-based surface plasmon resonance and photoluminescence, as well as the mechanisms of Förster Resonance Energy Transfer (FRET) and Inner Filter Effect (IFE) in fluorescence detection, are presented. Removal techniques for this contaminant include homogeneous catalysis, electrocatalysis, photocatalysis, and thermocatalysis, and their reaction mechanisms are also discussed. Further, the theoretical perspectives of 4-NP detection and reduction, parameters influencing the activities, and future perspectives are also reviewed in detail.

Quantitative assessment of morphological changes in lipid droplets and lipid-mito interactions with aging in brown adipose.

The physical characteristics of brown adipose tissue (BAT) are defined by the presence of multilocular lipid droplets (LDs) within the brown adipocytes and a high abundance of iron-containing mitochondria, which give it its characteristic color. Normal mitochondrial function is, in part, regulated by organelle-to-organelle contacts. For example, the contact sites that mediate mitochondria-LD interactions are thought to have various physiological roles, such as the synthesis and metabolism of lipids. Aging is associated with mitochondrial dysfunction, and previous studies show that there are changes in mitochondrial structure and the proteins that modulate organelle contact sites. However, how mitochondria-LD interactions change with aging has yet to be fully clarified. Therefore, we sought to define age-related changes in LD morphology and mitochondria-lipid interactions in BAT. We examined the three-dimensional morphology of mitochondria and LDs in young (3-month) and aged (2-year) murine BAT using serial block face-scanning electron microscopy and the Amira program for segmentation, analysis, and quantification. Our analyses showed reductions in LD volume, area, and perimeter in aged samples in comparison to young samples. Additionally, we observed changes in LD appearance and type in aged samples compared to young samples. Notably, we found differences in mitochondrial interactions with LDs, which could implicate that these contacts may be important for energetics in aging. Upon further investigation, we also found changes in mitochondrial and cristae structure for the mitochondria interacting with LDs. Overall, these data define the nature of LD morphology and organelle-organelle contacts during aging and provide insight into LD contact site changes that interconnect biogerontology with mitochondrial function, metabolism, and bioactivity in aged BAT.

Are Patient-Reported Outcome Measures for Anterior Cruciate Ligament Injuries Validated for Spanish Language and Culture?

Background: Patient-reported outcome measures (PROMs) have been adopted as a way to measure patient self-rated physical function and health status for patients with anterior cruciate ligament (ACL) injuries. Although multiple PROMs exist and have been translated into various languages, the cross-cultural adaptation and validity of these PROMs for Spanish-speaking patients is unknown. Purpose: To evaluate the adaptation quality and psychometric properties of Spanish-language adaptations of PROMs for patients with ACL injuries. Study Design: Scoping review; Level of evidence, 3. Methods: Under PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, we reviewed published studies related to adaptation quality and psychometric properties of Spanish PROMs in patients with ACL injuries. The methodological quality of the included studies was assessed using the Guidelines for the Process of Cross-Cultural Adaptation of Self-Reported Measures, the Quality Criteria for Psychometric Properties of Health Status Questionnaires, and the Consensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist. The level of evidence for each PROM was determined based on the number of studies, methodological quality, consistency of results, and sample size. Results: The initial search strategy identified 5687 articles. After removal of duplicates, 1882 titles were screened, and 114 articles were assessed for eligibility. Six articles were selected for final review, comprising 4 PROMs: the Lysholm knee score, the Anterior Cruciate Ligament-Return to Sport After Injury (ACL-RSI), the Lower Extremity Functional Scale, and the Lower Limb Functional Index. Three studies followed all 6 processes for cross-cultural adaptation. None of the studies demonstrated all 14 domains required for cross-cultural validity (eg, description of translator expertise). The ACL-RSI achieved the highest level of evidence, with 3 of 9 domains demonstrating moderate evidence. Conclusion: This review identified 4 instruments that have been translated for Spanish-speaking patients with ACL injuries, none of which demonstrated appropriate adaptation or robust psychometric properties. The study highlights the need for improvement in PROMs for Spanish-speaking patients and the potential for mismeasurement and inappropriate application of PROM results in patients with ACL injuries.

Adoption of Reverse Total Shoulder Arthroplasty for Surgical Treatment of Proximal Humerus Fractures Differs by Patient Race.

BACKGROUND: Reverse total shoulder arthroplasty (rTSA) has gained popularity for the operative treatment of proximal humerus fractures (PHF). The purpose of this study was to compare racial differences in surgical management of PHF between open reduction and internal fixation (ORIF), hemiarthroplasty, and rTSA. Our hypothesis was that there would be no difference in fixation by race. METHODS: The National Surgical Quality Improvement Program (NSQIP) database was queried for ORIF, rTSA, and hemiarthroplasty between 2006 and 2020 for patients with a PHF. Race, ethnicity, age, sex, body mass index (BMI), and American Society of Anesthesiologists (ASA) class were recorded. Chi squared tests were performed to assess relationships between patient factors and operative intervention. Factors significant at the 0.10 level in univariable analyses were included in a multivariable multinomial model to predict operative intervention. RESULTS: 7,499 patients underwent surgical treatment for a PHF, including 526 (7%) undergoing hemiarthroplasty, 5,011 (67%) undergoing ORIF, and 1,962 (26%) undergoing rTSA. 27% of white patients with PHF underwent rTSA compared to 21% of Black patients, 16% of Asian patients, and 14% of Native American and Alaskan Native patients (p<0.001). In the multivariable analysis, utilization of rTSA increased over time (OR 1.2 per year since 2006, p < 0.001) and hemiarthroplasty decreased over time (OR 0.86 per year since 2006, p < 0.001). Non-white patients had significantly lower odds of undergoing rTSA versus ORIF (OR 0.75, 95% CI 0.58-0.97), as did male patients (OR 0.77, 95% CI 0.66-0.88). Patients over 65 (OR 3.86, 95% CI 3.39-4.38), patients with higher ASA classifications (ASA2: OR 3.24, 95% CI 1.86-5.66, ASA3: OR 4.77, 95% CI 2.74-8.32, ASA4: OR 5.25, 95% CI 2.89-9.54), and patients who were overweight (OR 1.33, 95% CI 1.14-1.55) or obese (OR 1.52, 95% CI 1.32-1.75) had higher odds of undergoing rTSA versus ORIF. DISCUSSION: As utilization of rTSA increases, understanding disparities in surgical treatment of PHF is crucial to improving outcomes and equitable access to emerging orthopedic technologies. While patient factors such as age, BMI, and comorbidities are known to directly impact outcomes and thus may be predictive of the type of surgical intervention, patient race should not dictate treatment.

Relationship Between Metabolic Dysfunction-Associated Steatotic Liver Disease and Lipoprotein (a) and Other Biomarkers.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) primarily affects the adult population and is closely related to obesity. The most severe form of MASLD, metabolic dysfunction-associated steatohepatitis (MASH), can progress to liver fibrosis. While lipoprotein(a) (Lp(a)) is known to be associated with cardiovascular disease, its relationship with MASLD remains unclear. This study aims to determine the prevalence of MASLD in ambulatory patients and to explore the association between Lp(a) levels and advanced liver damage. METHODS: This retrospective cross-sectional study included 130 patients older than 18 years seen in a healthcare center in Medellin, Colombia, between April 2023 and May 2024. Sociodemographic, clinical, and specific biomarker data were collected. Patients with cirrhosis, previous liver disease, frequent alcohol consumption, cancer, and other severe conditions were excluded. Continuous variables were analyzed using Student's t-tests or Mann-Whitney tests according to their distribution, and categorical variables were analyzed using contingency tables and chi-square tests. RESULTS: Of the 130 patients, 57.9% (n=73) had MASLD, with a higher prevalence in patients with obesity (80%, n=32). Lp(a) levels were abnormally high in 43.1% (n=31) of patients; however, a weak but significant inverse correlation was found between Lp(a) levels and the Fibrosis-4 (FIB-4) score, which is used to assess the severity of liver fibrosis. Patients with MASLD had significantly lower high-density lipoprotein (HDL) and vitamin D levels, and higher levels of gamma-glutamyl transferase (GGT). CONCLUSIONS: This study highlights the significant prevalence of MASLD in outpatients and its relationship with various biomarkers, including Lp(a), HDL, vitamin D, and GGT. Although the findings suggest a possible utility of Lp(a) as a biomarker in MASLD, longitudinal studies are needed to confirm these associations and clarify their role in liver disease progression. The study's limitations include its cross-sectional nature and potential selection bias, indicating the need for further research to validate these results.

MICOS Complex Loss Governs Age-Associated Murine Mitochondrial Architecture and Metabolism in the Liver, While Sam50 Dictates Diet Changes.

The liver, the largest internal organ and a metabolic hub, undergoes significant declines due to aging, affecting mitochondrial function and increasing the risk of systemic liver diseases. How the mitochondrial three-dimensional (3D) structure changes in the liver across aging, and the biological mechanisms regulating such changes confers remain unclear. In this study, we employed Serial Block Face-Scanning Electron Microscopy (SBF-SEM) to achieve high-resolution 3D reconstructions of murine liver mitochondria to observe diverse phenotypes and structural alterations that occur with age, marked by a reduction in size and complexity. We also show concomitant metabolomic and lipidomic changes in aged samples. Aged human samples reflected altered disease risk. To find potential regulators of this change, we examined the Mitochondrial Contact Site and Cristae Organizing System (MICOS) complex, which plays a crucial role in maintaining mitochondrial architecture. We observe that the MICOS complex is lost during aging, but not Sam50. Sam50 is a component of the sorting and assembly machinery (SAM) complex that acts in tandem with the MICOS complex to modulate cristae morphology. In murine models subjected to a high-fat diet, there is a marked depletion of the mitochondrial protein SAM50. This reduction in Sam50 expression may heighten the susceptibility to liver disease, as our human biobank studies corroborate that Sam50 plays a genetically regulated role in the predisposition to multiple liver diseases. We further show that changes in mitochondrial calcium dysregulation and oxidative stress accompany the disruption of the MICOS complex. Together, we establish that a decrease in mitochondrial complexity and dysregulated metabolism occur with murine liver aging. While these changes are partially be regulated by age-related loss of the MICOS complex, the confluence of a murine high-fat diet can also cause loss of Sam50, which contributes to liver diseases. In summary, our study reveals potential regulators that affect age-related changes in mitochondrial structure and metabolism, which can be targeted in future therapeutic techniques.

Quantitative Assessment of Morphological Changes in Lipid Droplets and Lipid-Mito Interactions with Aging in Brown Adipose.

The physical characteristics of brown adipose tissue (BAT) are defined by the presence of multilocular lipid droplets (LD) within the brown adipocytes and a high abundance of iron-containing mitochondria, which give it its characteristic color. Normal mitochondrial function is, in part, regulated by organelle-to-organelle contacts. Particularly, the contact sites that mediate mitochondria-LD interactions are thought to have various physiological roles, such as the synthesis and metabolism of lipids. Aging is associated with mitochondrial dysfunction, and previous studies show that there are changes in mitochondrial structure and proteins that modulate organelle contact sites. However, how mitochondria-LD interactions change with aging has yet to be fully clarified. Therefore, we sought to define age-related changes in LD morphology and mitochondria-lipid interactions in BAT. We examined the three-dimensional morphology of mitochondria and LDs in young (3-month) and aged (2-year) murine BAT using serial block face-scanning electron microscopy and the Amira program for segmentation, analysis, and quantification. Analysis showed reductions in LD volume, area, and perimeter in aged samples compared to young samples. Additionally, we observed changes in LD appearance and type in aged samples compared to young samples. Notably, we found differences in mitochondrial interactions with LDs, which could implicate that these contacts may be important for energetics in aging. Upon further investigation, we also found changes in mitochondrial and cristae structure for mitochondria interacting with LD lipids. Overall, these data define the nature of LD morphology and organelle-organelle contacts during aging and provide insight into LD contact site changes that interconnect biogerontology and mitochondrial functionality, metabolism, and bioactivity in aged BAT.

Putative mechanism of a multivitamin treatment against insulin resistance.

Insulin resistance is caused by the abnormal secretion of proinflammatory cytokines in adipose tissue, which is induced by an increase in lipid accumulation in adipocytes, hepatocytes, and myocytes. The inflammatory pathway involves multiple targets such as nuclear factor kappa B, inhibitor of nuclear factor κ-B kinase, and mitogen-activated protein kinase. Vitamins are micronutrients with anti-inflammatory activities that have unclear mechanisms. The present study aimed to describe the putative mechanisms of vitamins involved in the inflammatory pathway of insulin resistance. The strategy to achieve this goal was to integrate data mining and analysis, target prediction, and molecular docking simulation calculations to support our hypotheses. Our results suggest that the multitarget activity of vitamins A, B1, B2, B3, B5, B6, B7, B12, C, D3, and E inhibits nuclear factor kappa B and mitogen-activated protein kinase, in addition to vitamins A and B12 against inhibitor of nuclear factor κ-B kinase. The findings of this study highlight the pharmacological potential of using an anti-inflammatory and multitarget treatment based on vitamins and open new perspectives to evaluate the inhibitory activity of vitamins against nuclear factor kappa B, mitogen-activated protein kinase, and inhibitor of nuclear factor κ-B kinase in an insulin-resistant context.

The MICOS Complex Regulates Mitochondrial Structure and Oxidative Stress During Age-Dependent Structural Deficits in the Kidney.

The kidney filters nutrient waste and bodily fluids from the bloodstream, in addition to secondary functions of metabolism and hormone secretion, requiring an astonishing amount of energy to maintain its functions. In kidney cells, mitochondria produce adenosine triphosphate (ATP) and help maintain kidney function. Due to aging, the efficiency of kidney functions begins to decrease. Dysfunction in mitochondria and cristae, the inner folds of mitochondria, is a hallmark of aging. Therefore, age-related kidney function decline could be due to changes in mitochondrial ultrastructure, increased reactive oxygen species (ROS), and subsequent alterations in metabolism and lipid composition. We sought to understand if there is altered mitochondrial ultrastructure, as marked by 3D morphological changes, across time in tubular kidney cells. Serial block facing-scanning electron microscope (SBF-SEM) and manual segmentation using the Amira software were used to visualize murine kidney samples during the aging process at 3 months (young) and 2 years (old). We found that 2-year mitochondria are more fragmented, compared to the 3-month, with many uniquely shaped mitochondria observed across aging, concomitant with shifts in ROS, metabolomics, and lipid homeostasis. Furthermore, we show that the mitochondrial contact site and cristae organizing system (MICOS) complex is impaired in the kidney due to aging. Disruption of the MICOS complex shows altered mitochondrial calcium uptake and calcium retention capacity, as well as generation of oxidative stress. We found significant, detrimental structural changes to aged kidney tubule mitochondria suggesting a potential mechanism underlying why kidney diseases occur more readily with age. We hypothesize that disruption in the MICOS complex further exacerbates mitochondrial dysfunction, creating a vicious cycle of mitochondrial degradation and oxidative stress, thus impacting kidney health.

Association of Spanish as a Primary Language With Retear Rates After Pediatric ACL Reconstruction.

Background: Anterior cruciate ligament (ACL) injuries are one of the most common knee injuries in pediatric patients in the United States. The patient's primary spoken language may affect outcomes after ACL reconstruction (ACLR). Purpose/Hypothesis: The purpose of this study was to identify differences in ACLR outcomes between patients whose primary, preferred spoken language was either English or Spanish. It was hypothesized that there would be a difference in retear rates between patients preferring English versus Spanish. Study Design: Cohort study; Level of evidence, 3. Methods: A retrospective cohort study was performed on pediatric and adolescent patients who underwent ACLR at a single institution. Patients were divided into 2 cohorts based on their preferred spoken language: English or Spanish. All patients underwent either hamstring tendon or bone-patellar tendon-bone autograft ACLR performed by the same surgeon with the same postoperative rehabilitation protocols. Linear regression, chi-square tests, and multivariate logistic regression were used to determine if outcomes, graft tear, revision surgery, and contralateral injury differed between groups. Results: A total of 68 patients were identified: 33 patients whose preferred language was English and 35 patients whose preferred language was Spanish. The overall mean age of the patients was 16.4 ± 1.4 years (range, 13.2-20.5 years), and the mean follow-up time was 3.26 ± 1.98 years (range, 0.53-8.13 years). Patients who preferred Spanish were more likely than those who preferred English to experience graft tears requiring revision surgery after ACLR (P = .02; odds ratio [OR] = 5.81; adjusted OR = 1.94), at a tear rate of 14.3%. Conclusion: Patients who preferred to speak Spanish experienced higher graft tear rates when compared with patients who preferred speaking English, even after adjusting for sex, sport played, graft type, type of insurance, and time to surgery.

Ablation of Sam50 is associated with fragmentation and alterations in metabolism in murine and human myotubes.

The sorting and assembly machinery (SAM) Complex is responsible for assembling ß-barrel proteins in the mitochondrial membrane. Comprising three subunits, Sam35, Sam37, and Sam50, the SAM complex connects the inner and outer mitochondrial membranes by interacting with the mitochondrial contact site and cristae organizing system complex. Sam50, in particular, stabilizes the mitochondrial intermembrane space bridging (MIB) complex, which is crucial for protein transport, respiratory chain complex assembly, and regulation of cristae integrity. While the role of Sam50 in mitochondrial structure and metabolism in skeletal muscle remains unclear, this study aims to investigate its impact. Serial block-face-scanning electron microscopy and computer-assisted 3D renderings were employed to compare mitochondrial structure and networking in Sam50-deficient myotubes from mice and humans with wild-type (WT) myotubes. Furthermore, autophagosome 3D structure was assessed in human myotubes. Mitochondrial metabolic phenotypes were assessed using Gas Chromatography-Mass Spectrometry-based metabolomics to explore differential changes in WT and Sam50-deficient myotubes. The results revealed increased mitochondrial fragmentation and autophagosome formation in Sam50-deficient myotubes compared to controls. Metabolomic analysis indicated elevated metabolism of propanoate and several amino acids, including ß-Alanine, phenylalanine, and tyrosine, along with increased amino acid and fatty acid metabolism in Sam50-deficient myotubes. Furthermore, impairment of oxidative capacity was observed upon Sam50 ablation in both murine and human myotubes, as measured with the XF24 Seahorse Analyzer. Collectively, these findings support the critical role of Sam50 in establishing and maintaining mitochondrial integrity, cristae structure, and mitochondrial metabolism. By elucidating the impact of Sam50-deficiency, this study enhances our understanding of mitochondrial function in skeletal muscle.

A review of undergraduate research programs aimed at underrepresented students.

It is well-understood that the science, technology, engineering, and mathematics (STEM) fields have unique challenges that discourage recruiting and retaining underrepresented minorities. Research programs aimed at undergraduates have arisen as a critical mechanism for fostering innovation and addressing the challenges faced by underrepresented minorities. Here, we review various undergraduate research programs designed to provide exposure to undergraduates, with a focus on underrepresented minorities in STEM disciplines. We provide insight into selected programs' objectives, key features, potential limitations, and outcomes. We also offer recommendations for future improvements of each research program, particularly in the context of mentorship. These programs range from broad-reaching initiatives (e.g., Leadership Alliance) to more specific programs targeting underrepresented students. By offering a nuanced understanding of each program's structure, we seek to provide a brief overview of the landscape of diversity-focused STEM initiatives and a guide on how to run a research program effectively.

Methods to Utilize Pulse Wave Velocity to Measure Alterations in Cerebral and Cardiovascular Parameters.

Alzheimer's Disease (AD) is a global health issue, affecting over 6 million in the United States, with that number expected to increase as the aging population grows. As a neurodegenerative disorder that affects memory and cognitive functions, it is well established that AD is associated with cardiovascular risk factors beyond only cerebral decline. However, the study of cerebrovascular techniques for AD is still evolving. Here, we provide reproducible methods to measure impedance-based pulse wave velocity (PWV), a marker of arterial stiffness, in the systemic vascular (aortic PWV) and in the cerebral vascular (cerebral PWV) systems. Using aortic impedance and this relatively novel technique of cerebral impedance to comprehensively describe the systemic vascular and the cerebral vascular systems, we examined the sex-dependent differences in 5x transgenic mice (5XFAD) with AD under normal and high-fat diet, and in wild-type mice under a normal diet. Additionally, we validated our method for measuring cerebrovascular impedance in a model of induced stress in 5XFAD. Together, our results show that sex and diet differences in wildtype and 5XFAD mice account for very minimal differences in cerebral impedance. Interestingly, 5XFAD, and not wildtype, male mice on a chow diet show higher cerebral impedance, suggesting pathological differences. Opposingly, when we subjected 5XFAD mice to stress, we found that females showed elevated cerebral impedance. Using this validated method of measuring impedance-based aortic and cerebral PWV, future research may explore the effects of modifying factors including age, chronic diet, and acute stress, which may mediate cardiovascular risk in AD.

Toward structure-multiple activity relationships (SMARts) using computational approaches: A polypharmacological perspective.

In the current era of biological big data, which are rapidly populating the biological chemical space, in silico polypharmacology drug design approaches help to decode structure-multiple activity relationships (SMARts). Current computational methods can predict or categorize multiple properties simultaneously, which aids the generation, identification, curation, prioritization, optimization, and repurposing of molecules. Computational methods have generated opportunities and challenges in medicinal chemistry, pharmacology, food chemistry, toxicology, bioinformatics, and chemoinformatics. It is anticipated that computer-guided SMARts could contribute to the full automatization of drug design and drug repurposing campaigns, facilitating the prediction of new biological targets, side and off-target effects, and drug-drug interactions.

Posterior Reversible Encephalopathy Syndrome With Hemorrhagic Transformation in the Postoperative Period of a Kidney Transplant.

Patients with end-stage renal disease (ESRD) who undergo kidney transplantation are at an increased risk of developing surgical and/or medical complications. Posterior reversible encephalopathy syndrome (PRES) is a rare complication that occurs in 0.34% of kidney transplant patients. It is characterized by a combination of neurological manifestations, risk factors, and characteristic radiological findings in neuroimaging studies. The development of PRES has been associated with various medical conditions and factors, including hypertension, the use of cytotoxic and immunosuppressive drugs, acute or chronic kidney disease, pre-eclampsia/eclampsia, autoimmune diseases, and solid organ and bone marrow transplantation. This report presents the case of a 19-year-old woman diagnosed with ESRD on hemodialysis due to lupus nephritis who experienced an episode of PRES with intraparenchymal hemorrhage during the postoperative period of kidney transplantation. The case emphasizes the importance of closely monitoring these patients during this period to enable early diagnosis and timely treatment of complications, ensuring a favorable prognosis.

Running a successful STEMM summer program: A week-by-week guide.

While some established undergraduate summer programs are effective across many institutions, these programs may only be available to some principal investigators or may not fully address the diverse needs of incoming undergraduates. This article outlines a 10-week science, technology, engineering, mathematics, and medicine (STEMM) education program designed to prepare undergraduate students for graduate school through a unique model incorporating mentoring dyads and triads, cultural exchanges, and diverse activities while emphasizing critical thinking, research skills, and cultural sensitivity. Specifically, we offer a straightforward and adaptable guide that we have used for mentoring undergraduate students in a laboratory focused on mitochondria and microscopy, but which may be customized for other disciplines. Key components include self-guided projects, journal clubs, various weekly activities such as mindfulness training and laboratory techniques, and a focus on individual and cultural expression. Beyond this unique format, this 10-week program also seeks to offer an intensive research program that emulates graduate-level experiences, offering an immersive environment for personal and professional development, which has led to numerous achievements for past students, including publications and award-winning posters.

ATF4-dependent increase in mitochondrial-endoplasmic reticulum tethering following OPA1 deletion in skeletal muscle.

Mitochondria and endoplasmic reticulum (ER) contact sites (MERCs) are protein- and lipid-enriched hubs that mediate interorganellar communication by contributing to the dynamic transfer of Ca2+, lipid, and other metabolites between these organelles. Defective MERCs are associated with cellular oxidative stress, neurodegenerative disease, and cardiac and skeletal muscle pathology via mechanisms that are poorly understood. We previously demonstrated that skeletal muscle-specific knockdown (KD) of the mitochondrial fusion mediator optic atrophy 1 (OPA1) induced ER stress and correlated with an induction of Mitofusin-2, a known MERC protein. In the present study, we tested the hypothesis that Opa1 downregulation in skeletal muscle cells alters MERC formation by evaluating multiple myocyte systems, including from mice and Drosophila, and in primary myotubes. Our results revealed that OPA1 deficiency induced tighter and more frequent MERCs in concert with a greater abundance of MERC proteins involved in calcium exchange. Additionally, loss of OPA1 increased the expression of activating transcription factor 4 (ATF4), an integrated stress response (ISR) pathway effector. Reducing Atf4 expression prevented the OPA1-loss-induced tightening of MERC structures. OPA1 reduction was associated with decreased mitochondrial and sarcoplasmic reticulum, a specialized form of ER, calcium, which was reversed following ATF4 repression. These data suggest that mitochondrial stress, induced by OPA1 deficiency, regulates skeletal muscle MERC formation in an ATF4-dependent manner.

The pursuit of accurate predictive models of the bioactivity of small molecules.

Property prediction is a key interest in chemistry. For several decades there has been a continued and incremental development of mathematical models to predict properties. As more data is generated and accumulated, there seems to be more areas of opportunity to develop models with increased accuracy. The same is true if one considers the large developments in machine and deep learning models. However, along with the same areas of opportunity and development, issues and challenges remain and, with more data, new challenges emerge such as the quality and quantity and reliability of the data, and model reproducibility. Herein, we discuss the status of the accuracy of predictive models and present the authors' perspective of the direction of the field, emphasizing on good practices. We focus on predictive models of bioactive properties of small molecules relevant for drug discovery, agrochemical, food chemistry, natural product research, and related fields.

Interactions Between the Ubiquitin-Proteasome System, Nrf2, and the Cannabinoidome as Protective Strategies to Combat Neurodegeneration: Review on Experimental Evidence.

Neurodegenerative disorders are chronic brain diseases that affect humans worldwide. Although many different factors are thought to be involved in the pathogenesis of these disorders, alterations in several key elements such as the ubiquitin-proteasome system (UPS), the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, and the endocannabinoid system (ECS or endocannabinoidome) have been implicated in their etiology. Impairment of these elements has been linked to the origin and progression of neurodegenerative disorders, while their potentiation is thought to promote neuronal survival and overall neuroprotection, as proved with several experimental models. These key neuroprotective pathways can interact and indirectly activate each other. In this review, we summarize the neuroprotective potential of the UPS, ECS, and Nrf2 signaling, both separately and combined, pinpointing their role as a potential therapeutic approach against several hallmarks of neurodegeneration.