Deletion of Sigmar1 leads to increased arterial stiffness and altered mitochondrial respiration resulting in vascular dysfunction.

Sigmar1 is a ubiquitously expressed, multifunctional protein known for its cardioprotective roles in cardiovascular diseases. While accumulating evidence indicate a critical role of Sigmar1 in cardiac biology, its physiological function in the vasculature remains unknown. In this study, we characterized the expression of Sigmar1 in the vascular wall and assessed its physiological function in the vascular system using global Sigmar1 knockout (Sigmar1-/-) mice. We determined the expression of Sigmar1 in the vascular tissue using immunostaining and biochemical experiments in both human and mouse blood vessels. Deletion of Sigmar1 globally in mice (Sigmar1-/-) led to blood vessel wall reorganizations characterized by nuclei disarray of vascular smooth muscle cells, altered organizations of elastic lamina, and higher collagen fibers deposition in and around the arteries compared to wildtype littermate controls (Wt). Vascular function was assessed in mice using non-invasive time-transit method of aortic stiffness measurement and flow-mediated dilation (FMD) of the left femoral artery. Sigmar1-/- mice showed a notable increase in arterial stiffness in the abdominal aorta and failed to increase the vessel diameter in response to reactive-hyperemia compared to Wt. This was consistent with reduced plasma and tissue nitric-oxide bioavailability (NOx) and decreased phosphorylation of endothelial nitric oxide synthase (eNOS) in the aorta of Sigmar1-/- mice. Ultrastructural analysis by transmission electron microscopy (TEM) of aorta sections showed accumulation of elongated shaped mitochondria in both vascular smooth muscle and endothelial cells of Sigmar1-/- mice. In accordance, decreased mitochondrial respirometry parameters were found in ex-vivo aortic rings from Sigmar1 deficient mice compared to Wt controls. These data indicate a potential role of Sigmar1 in maintaining vascular homeostasis.

Incidence of Facial Nerve Injury and Sialocele Formation Following Mandibular Condylar and Sub-condylar Fracture Fixation.

Purpose: To study the incidence of sialocele formation in the parotid gland and to study the incidence of facial nerve affliction following treatment of mandibular condylar and sub-condylar fractures. Materials and methods: The present study is a retrospective study conducted on a total of 82 patients with 107 sub-condylar and condylar fractures treated in this centre from August 2008 to August 2020. The surgical approaches used to treat the fractures were considered, and the occurrence of sialocele, salivary fistula and facial nerve paralysis was noted. The facial nerve function was analysed using House-Brackmann system of classification. Results: The incidence of sialocele formation was seen in 15.87% of cases, and the incidence was seen more commonly during a preauricular approach (52.94%) followed by retromandibular (41.17%) followed by anterior parotid transmassetric approach (11.76%). The incidence of facial nerve affliction was seen in 17.57% of cases with majority of them showing temporal branch involvement in 21.05% of cases. Conclusion: During the treatment of condylar and sub-condylar fractures, the facial nerve is at considerable risk of damage; however, understanding the anatomy of the nerve is of importance to avoid such complications. Sialocele formation is also an undesirable complication of such surgeries, a prompt diagnosis and early treatment is mandatory to overcome further unwanted sequel.

Knowledge, Preventive Practices and Effect of Different Information Sources on Level of Knowledge Related to Covid-19 among Residents of Sylhet, Bangladesh.

The increasing number of new cases and death related to Covid-19 poses a major challenge in Bangladesh. People obtain information on the Covid-19 from different sources of information. Appropriate information sources aids in proper implementation of health education program on the disease and its preventive practices. The study aimed to identify the sources of information and corresponding knowledge level related to Covid-19 among residents of Sylhet, Bangladesh. This cross sectional study was conducted in Sylhet division of Bangladesh from September 2020 to November 2020 involving the residents irrespective of sex, age ≥18 years old. A pre-structured questionnaire having twelve validated knowledge questions and five practice questions regarding Covid-19 was used to assess the knowledge and practice. Knowledge level was categorized as good (>6) and poor (≤6). Pearson Chi-square test and Logistic regression was employed to determine whether sources of information were related to respondents' knowledge on Covid-19. Television was popular source for obtaining information on Covid-19 among study participants (55.8%). Majority (86.3%) had 'Good' (>6) level of knowledge. Most of the participants (93.9%) were found to wear mask in outdoor. The association of information sources with knowledge level was statistically significant (p= 0.000). Participants seeking information from Television (AOR: 9.873, 95% CI 0.147-0.838) were more likely to have good level of knowledge than the other sources. The policymakers need to consider mostly utilized source: Television for dissemination of information and design awareness program to increase knowledge and preventive practices related to Covid-19 in Bangladesh.

Economic burden of dengue in urban Bangladesh: A societal perspective.

BACKGROUND: Dengue, a vector-borne disease, is a major public health problem in many tropical and subtropical countries including Bangladesh. The objective of this study is to estimate the societal cost of illness of dengue infections among the urban population in Dhaka, Bangladesh. METHODS: A cost-of-illness study was conducted using a prevalence-based approach from a societal perspective. Costs attributable to dengue were estimated from a bottom-up strategy using the guideline proposed by the World Health Organization for estimating the economic burden of infectious diseases. RESULTS: A total of 302 hospitalized confirmed dengue patients were enrolled in this study. The average cost to society for a person with a dengue episode was US$ 479.02. This amount was ranged between US$ 341.67 and US$ 567.12 for those patients who were treated at public and private hospitals, respectively. The households out-of-pocket cost contributed to a larger portion of the total costs of illness (66%) while the cost burden was significantly higher for the poorest households than the richest quintile. CONCLUSIONS: Dengue disease imposes a substantial financial burden on households and society. Therefore, decision-makers should consider the treatment cost of dengue infections, particularly among the poor in the population while balancing the benefits of introducing potentially effective dengue preventive programs in Bangladesh.

Non-Puerperal Chronic Inversion of Uterus Due to Big Fibroid Uterus in a Post-Menopausal Woman.

Uterine inversion occurs in puerperal and non-puerperal conditions; non-puerperal uterine inversion (NPUI) may run acute and chronic clinical course. Most on the NPUI are chronic variety while a few are acute variety. NPUI occurs if there is long standing big sub-mucosal fibroid and it is very rare to present in acute setting. Here we report a case of acutely presented NPUI. A 58-year-old widow of lower socioeconomic status presenting to the emergency center of Chittagong medical college Hospital with complaints of sudden protrusion of a big mass through introitus in an attempt of passing out hard stool during defecation on the day of admission with a history of per vaginal watery discharge for a long time and severe anemia. Anemia was corrected and a broad-spectrum antibiotic was given prior to operative management. Under general anesthesia vaginal myomectomy followed by vaginal hysterectomy was performed in the same sitting. Pathological examination revealed a fibroid uterus. Postoperatively patient recovered without any residual problem. Infection should be suspected and treated with appropriate broad-spectrum antibiotics before planning surgery. Vaginal route restoration of NPUI is very difficult but possible with careful attempt. During a vaginal hysterectomy, care to locate and salvage the bladder and distal urinary collecting system is warranted. So, a high index of suspicion is the key to limit morbidity and approach for proper management of such rare clinical condition.

A novel Doppler backscattering (DBS) system to simultaneously measure radio frequency plasma fluctuations and low frequency turbulence.

A novel quadrature Doppler Backscattering (DBS) system has been developed and optimized for the E-band (60-90 GHz) frequency range using either O-mode or X-mode polarization in DIII-D plasmas. In general, DBS measures the amplitude of density fluctuations and their velocity in the lab frame. The system can simultaneously monitor both low-frequency turbulence (f < 10 MHz) and radiofrequency plasma density fluctuations over a selectable frequency range (20-500 MHz). Detection of high-frequency fluctuations has been demonstrated for low harmonics of the ion cyclotron frequency (e.g., 2fci ∼ 23 MHz) and externally driven high-frequency helicon waves (f = 476 MHz) using an adjustable frequency down conversion system. Importantly, this extends the application of DBS to a high-frequency spectral domain while maintaining important turbulence and flow measurement capabilities. This unique system has low phase noise, good temporal resolution (sub-millisecond), and excellent wavenumber coverage (kθ ∼ 1-20 cm-1 and kr ≲ 30 cm-1). As a demonstration, localized internal DIII-D plasma measurements are presented from turbulence (f ≤ 5 MHz), Alfvenic waves (f ∼ 6.5 MHz), ion cyclotron waves (f ≥ 20 MHz), as well as fluctuations around 476 MHz driven by an external high-power 476 MHz helicon wave antenna. In the future, helicon measurements will be used to validate GENRAY and AORSA modeling tools for prediction of helicon wave propagation, absorption, and current drive location for the newly installed helicon current drive system on DIII-D.

Understanding the Impact of Obesity on Ageing in the Radiance of DNA Metabolism.

Ageing is a multi-factorial phenomenon which is considered as a major risk factor for the development of neurodegeneration, osteoporosis, cardiovascular disease, dementia, cancer, and other chronic diseases. Phenotypically, ageing is related with a combination of molecular, cellular, and physiological levels like genomic and epi-genomic alterations, loss of proteostasis, deregulation of cellular and subcellular function and mitochondrial dysfunction. Though, no single molecular mechanism accounts for the functional decline of different organ systems in older humans but accumulation of DNA damage or mutations is a dominant theory which contributes largely to the development of ageing and age-related diseases. However, mechanistic, and hierarchical order of these features of ageing has not been clarified yet. Scientific community now focus on the effect of obesity on accelerated ageing process. Obesity is a complex chronic disease that affects multiple organs and tissues. It can not only lead to various health conditions such as diabetes, cancer, and cardiovascular disease but also can decrease life expectancy which shows similar phenotype of ageing. Higher loads of DNA damage were also observed in the genome of obese people. Thus, inability of DNA damage repair may contribute to both ageing and obesity apart from cancer predisposition. The present review emphasizes on the involvement of molecular phenomenon of DNA metabolism in development of obesity and how it accelerates ageing in mammals.

Sigmar1 ablation leads to lung pathological changes associated with pulmonary fibrosis, inflammation, and altered surfactant proteins levels.

Sigma1 receptor protein (Sigmar1) is a small, multifunctional molecular chaperone protein ubiquitously expressed in almost all body tissues. This protein has previously shown its cardioprotective roles in rodent models of cardiac hypertrophy, heart failure, and ischemia-reperfusion injury. Extensive literature also suggested its protective functions in several central nervous system disorders. Sigmar1's molecular functions in the pulmonary system remained unknown. Therefore, we aimed to determine the expression of Sigmar1 in the lungs. We also examined whether Sigmar1 ablation results in histological, ultrastructural, and biochemical changes associated with lung pathology over aging in mice. In the current study, we first confirmed the presence of Sigmar1 protein in human and mouse lungs using immunohistochemistry and immunostaining. We used the Sigmar1 global knockout mouse (Sigmar1-/-) to determine the pathophysiological role of Sigmar1 in lungs over aging. The histological staining of lung sections showed altered alveolar structures, higher immune cells infiltration, and upregulation of inflammatory markers (such as pNFκB) in Sigmar1-/- mice compared to wildtype (Wt) littermate control mice (Wt). This indicates higher pulmonary inflammation resulting from Sigmar1 deficiency in mice, which was associated with increased pulmonary fibrosis. The protein levels of some fibrotic markers, fibronectin, and pSMAD2 Ser 245/250/255 and Ser 465/467, were also elevated in mice lungs in the absence of Sigmar1 compared to Wt. The ultrastructural analysis of lungs in Wt mice showed numerous multilamellar bodies of different sizes with densely packed lipid lamellae and mitochondria with a dark matrix and dense cristae. In contrast, the Sigmar1-/- mice lung tissues showed altered multilamellar body structures in alveolar epithelial type-II pneumocytes with partial loss of lipid lamellae structures in the lamellar bodies. This was further associated with higher protein levels of all four surfactant proteins, SFTP-A, SFTP-B, SFTP-C, and SFTP-D, in the Sigmar1-/- mice lungs. This is the first study showing Sigmar1's expression pattern in human and mouse lungs and its association with lung pathophysiology. Our findings suggest that Sigmar1 deficiency leads to increased pulmonary inflammation, higher pulmonary fibrosis, alterations of the multilamellar body stuructures, and elevated levels of lung surfactant proteins.

Deep, rapid, and durable prostate-specific antigen decline with apalutamide plus androgen deprivation therapy is associated with longer survival and improved clinical outcomes in TITAN patients with metastatic castration-sensitive prostate cancer.

BACKGROUND: The first interim analysis of the phase III, randomized, double-blind, placebo-controlled, multinational TITAN study demonstrated improved overall survival (OS) and radiographic progression-free survival (rPFS) with apalutamide added to ongoing androgen deprivation therapy (ADT) in patients with metastatic castration-sensitive prostate cancer. The final analysis confirmed improvement in OS and other long-term outcomes. We evaluated prostate-specific antigen (PSA) kinetics and the association between PSA decline and outcomes in patients with metastatic castration-sensitive prostate cancer from TITAN. PATIENTS AND METHODS: Patients received apalutamide (240 mg/day) or placebo plus ADT (1 : 1). This post hoc exploratory analysis evaluated PSA kinetics and decline in relation to rPFS (22.7 months' follow-up) and OS, time to PSA progression, and time to castration resistance (44.0 months' follow-up) in patients with or without confirmed PSA decline using a landmark analysis, the Kaplan-Meier method, and Cox proportional hazards model. RESULTS: One thousand and fifty-two patients (apalutamide, 525; placebo, 527) were enrolled. Best confirmed PSA declines (≥50% or ≥90% from baseline or to ≤0.2 ng/ml) were achieved at any time during the study in 90%, 73%, and 68% of apalutamide-treated versus 55%, 29%, and 32% of placebo-treated patients, respectively. By 3 months of apalutamide treatment, best deep PSA decline of ≥90% or to ≤0.2 ng/ml occurred in 59% and 51% of apalutamide- and in 13% and 18% of placebo-treated patients, respectively. Achievement of deep PSA decline at landmark 3 months of apalutamide treatment was associated with longer OS [hazard ratio (HR) 0.35; 95% confidence interval (CI) 0.25-0.48), rPFS (HR 0.44; 95% CI 0.30-0.65), time to PSA progression (HR 0.31; 95% CI 0.22-0.44), and time to castration resistance (HR 0.38; 95% CI 0.27-0.52) compared with no decline (P < 0.0001 for all). Similar results were observed at landmark 6 and 12 months of apalutamide treatment. CONCLUSIONS: Apalutamide plus ADT demonstrated a robust (rapid, deep, and durable) PSA decline that was associated with improved clinical outcomes, including long-term survival.

Language Barriers in Organismal Biology: What Can Journals Do Better?

In the field of organismal biology, as in much of academia, there is a strong incentive to publish in internationally recognized, highly regarded, English-language journals to promote career advancement. This expectation has created a linguistic hegemony in scientific publishing, whereby scholars for whom English is an additional language face additional barriers to achieving the same scientific recognition as scholars who speak English as a first language. Here, we surveyed the author guidelines of 230 journals in organismal biology with impact factors of 1.5 or greater for linguistically inclusive and equitable practices and policies. We looked for efforts that reflect first steps toward reducing barriers to publication for authors globally, including the presence of statements that encouraged submissions from authors of diverse nationalities and backgrounds, policies regarding manuscript rejection based on perceived inadequacies of the English language, the existence of bias-conscious reviewer practices, whether translation and editing resources or services are available, allowance for non-English abstracts, summaries, or translations, and whether journals offer license options that would permit authors (or other scholars) to translate their work and publish it elsewhere. We also directly contacted a subset of journals to verify whether the information on their author guidelines page accurately reflects their policies and the accommodations they would make. We reveal that journals and publishers have made little progress toward beginning to recognize or reduce language barriers. Counter to our predictions, journals associated with scientific societies did not appear to have more inclusive policies compared to non-society journals. Many policies lacked transparency and clarity, which can generate uncertainty, result in avoidable manuscript rejections, and necessitate additional time and effort from both prospective authors and journal editors. We highlight examples of equitable policies and summarize actions that journals can take to begin to alleviate barriers to scientific publishing.

ResumenEn el campo de la biología organísmica, al igual que en el mundo académico en general, existe un gran incentivo para publicar en revistas científicas de lengua inglesa que son reconocidas internacionalmente y que poseen gran prestigio con el fin de avanzar profesionalmente. Esta expectativa ha creado una hegemonía lingüística en la publicación científica en la que los académicos para quienes el inglés es una lengua adicional se enfrentan a barreras adicionales para lograr el mismo reconocimiento científico que los académicos que hablan inglés como primera lengua. En este estudio examinamos las instrucciones para autores de 230 revistas de biología organísmica con Factor de Impacto igual o superior a 1.5 en busca de prácticas y políticas lingüísticamente inclusivas y equitativas. Buscamos iniciativas que reflejen pasos iniciales hacia la reducción de barreras de publicación para autores a nivel mundial. Estas incluyen la presencia de anuncios que incentiven el envío de trabajos por autores de diversas nacionalidades, políticas relacionadas al rechazo de manuscritos debido a la percepción de insuficiencias en el inglés, prácticas de revisión conscientes de prejuicios, disponibilidad de recursos o servicios de traducción y edición, la publicación de resúmenes o traducciones en idiomas adicionales al inglés y la disponibilidad de licencias que permitan a los autores (u otros académicos) traducir su trabajo y publicarlo en otro lugar. También contactamos directamente a un subconjunto de revistas para comprobar si la información que aparece en las instrucciones para autores refleja con exactitud sus políticas y los ajustes que harían. Comprobamos que las revistas y los editores han avanzado poco en el reconocimiento o reducción de barreras lingüísticas y en la promoción de igualdad lingüística. Al contrario de nuestras predicciones, las revistas asociadas a sociedades científicas no parecen tener políticas más inclusivas en comparación con las revistas que no pertenecen a ninguna sociedad. Muchas políticas carecen de transparencia y claridad, lo que puede generar incertidumbre, dar lugar a rechazos evitables de manuscritos y exigir tiempo y esfuerzo adicionales tanto a los futuros autores como a los editores de las revistas. También destacamos ejemplos de políticas equitativas y resumimos las medidas que las revistas pueden adoptar para empezar a aliviar los obstáculos de publicación científica.

Clinico-epidemiological Characteristics of Asymptomatic and Symptomatic COVID-19-Positive Patients in Bangladesh.

As of August 15, 2020, Bangladesh lost 3591 lives since the first Coronavirus disease 2019 (COVID-19) case announced on March 8. The objective of the study was to report the clinical manifestation of both symptomatic and asymptomatic COVID-19-positive patients. An online-based cross-sectional survey was conducted for initial recruitment of participants with subsequent telephone interview by the three trained physicians in 237 adults with confirmed COVID-19 infection in Bangladesh. The study period was 27 April to 26th May 2020. Consent was ensured before commencing the interview. Collected data were entered in a pre-designed case record form and subsequently analyzed by SPSS 20.0. The mean±SD age at presentation was 41.59±13.73 years and most of the cases were male (73.0%). A total of 90.29% of patients reside in urban areas. Among the positive cases, 13.1% (n=31) were asymptomatic. Asymptomatic cases were significantly more common in households with 2 to 4 members (p=0.008). Both symptomatic and asymptomatic patients shared similar ages of presentation (p=0.23), gender differences (p=0.30) and co-morbidities (p=0.11). Only 5.3% of patients received ICU care during their treatment. The most frequent presentation was fever (88.3%), followed by cough (69.9%), chest pain (34.5%), body ache (31.1%), and sore throat (30.1%). Thirty-nine percent (n=92) of the patients had co-morbidities, with diabetes and hypertension being the most frequently observed. There has been an upsurge in COVID-19 cases in Bangladesh. Patients were mostly middle-aged and male. Typical presentations were fever and cough. Maintenance of social distancing and increased testing are required to meet the current public health challenge.

Mortality Attributable to Ambient Air Pollution: A Review of Global Estimates.

Since the publication of the first epidemiological study to establish the connection between long-term exposure to atmospheric pollution and effects on human health, major efforts have been dedicated to estimate the attributable mortality burden, especially in the context of the Global Burden of Disease (GBD). In this work, we review the estimates of excess mortality attributable to outdoor air pollution at the global scale, by comparing studies available in the literature. We find large differences between the estimates, which are related to the exposure response functions as well as the number of health outcomes included in the calculations, aspects where further improvements are necessary. Furthermore, we show that despite the considerable advancements in our understanding of health impacts of air pollution and the consequent improvement in the accuracy of the global estimates, their precision has not increased in the last decades. We offer recommendations for future measurements and research directions, which will help to improve our understanding and quantification of air pollution-health relationships.

Single-Molecule Human Nucleosome Spontaneously Ruptures under the Stress of Compressive Force: A New Perspective on Gene Stability and Epigenetic Pathways.

Force manipulation on the biological entities from living cells to protein molecules has revealed many mechanical details of cell biology from resolving folding and unfolding pathways to finding molecular interaction forces. A nucleosome is the basic repeating unit of chromatin where the histone octamer is wrapped by DNA, important for gene stability and regulation. How the inner side of the DNA gets accessed by other DNA binding molecules has been a puzzle that has been intensively studied and debated, important to epigenetics, gene stability, and regulations. Here we report our observation of spontaneous ruptures of human nucleosomes under pico-Newton (pN) compressive force. The amplitude of the compressive force, a squeezing rather than pulling force, involved in our experiment is tens of pN, which can be thermally available by biological force fluctuation at room temperature and under physiological conditions. This kind of structural rupture can loosen up the DNA around the histone, which in turn makes the DNA accessible to transcription and epigenetic modifications.

Preferences of cancer patients as a guide to cancer prevention: a retrospective willingness to pay study in Nepal.

OBJECTIVE: In developing countries, like Nepal, with no population-based cancer registry and low level of awareness, it is difficult to communicate the significance of cancer preventative measures to the general population. Only patients, who have faced or facing the economic and mental burden of cancer, can better understand the importance of early diagnosis. This led us to study the retrospective preference of cancer patients in valuing an annual comprehensive cancer screening program in Nepal. STUDY DESIGN: This is a primary survey-based study of 600 diagnosed cancer patients (aged 18+ years) randomly sampled from five hospitals of Nepal during December 2015-February 2016. METHODS: Using the contingent valuation estimation methods, we modelled patients' willingness to pay (WTP) for early cancer screening through the Structural Equation Modelling framework. RESULTS: About 59% of our sampled patients did not receive education and 65% earned below $100/month. Among other findings, we saw that the Risk of re-occurrence impacted WTP through two opposing channels. The direct effect of Risk of re-occurrence on WTP was positive (ß = 0.20; p < 0.05), but higher the risk of cancer relapses, the higher was the Pessimism among patients, which indirectly impacted WTP negatively (ß = -0.16; p < 0.1). In addition, we found the effect of Income on WTP to be positive (ß = 0.15; p < 0.05), whereas, one belonging to the backward Dalit section of the society had lower WTP for screening. CONCLUSION: Cancer patients value the importance of early diagnosis with multiple psychosocial factors impacting this preference. This direct account of patients could be used as evidence in policymaking.

Convolutional LSTM: a deep learning approach to predict shoulder joint reaction forces.

We developed a Convolutional LSTM (ConvLSTM) network to predict shoulder joint reaction forces using 3D shoulder kinematics data containing 30 different shoulder activities from eight human subjects. We considered simulation outcomes from the AnyBody musculoskeletal model as the baseline force dataset to validate ConvLSTM model predictions. Results showed a good correlation (>80% accuracy, r ≥ 0.82) between ConvLSTM predicted and AnyBody estimated force values, the generalization of the developed model for novel task type (p-value = 0.07 ∼ 0.33), and a better prediction accuracy for the ConvLSTM model than conventional CNN and LSTM models.

Pathological Sequelae Associated with Skeletal Muscle Atrophy and Histopathology in G93A*SOD1 Mice.

Amyotrophic lateral sclerosis (ALS) is a complex systemic disease that primarily involves motor neuron dysfunction and skeletal muscle atrophy. One commonly used mouse model to study ALS was generated by transgenic expression of a mutant form of human superoxide dismutase 1 (SOD1) gene harboring a single amino acid substitution of glycine to alanine at codon 93 (G93A*SOD1). Although mutant-SOD1 is ubiquitously expressed in G93A*SOD1 mice, a detailed analysis of the skeletal muscle expression pattern of the mutant protein and the resultant muscle pathology were never performed. Using different skeletal muscles isolated from G93A*SOD1 mice, we extensively characterized the pathological sequelae of histological, molecular, ultrastructural, and biochemical alterations. Muscle atrophy in G93A*SOD1 mice was associated with increased and differential expression of mutant-SOD1 across myofibers and increased MuRF1 protein level. In addition, high collagen deposition and myopathic changes sections accompanied the reduced muscle strength in the G93A*SOD1 mice. Furthermore, all the muscles in G93A*SOD1 mice showed altered protein levels associated with different signaling pathways, including inflammation, mitochondrial membrane transport, mitochondrial lipid uptake, and antioxidant enzymes. In addition, the mutant-SOD1 protein was found in the mitochondrial fraction in the muscles from G93A*SOD1 mice, which was accompanied by vacuolized and abnormal mitochondria, altered OXPHOS and PDH complex protein levels, and defects in mitochondrial respiration. Overall, we reported the pathological sequelae observed in the skeletal muscles of G93A*SOD1 mice resulting from the whole-body mutant-SOD1 protein expression.

Mitochondrial dysfunction and autophagy activation are associated with cardiomyopathy developed by extended methamphetamine self-administration in rats.

The recent rise in illicit use of methamphetamine (METH), a highly addictive psychostimulant, is a huge health care burden due to its central and peripheral toxic effects. Mounting clinical studies have noted that METH use in humans is associated with the development of cardiomyopathy; however, preclinical studies and animal models to dissect detailed molecular mechanisms of METH-associated cardiomyopathy development are scarce. The present study utilized a unique very long-access binge and crash procedure of METH self-administration to characterize the sequelae of pathological alterations that occur with METH-associated cardiomyopathy. Rats were allowed to intravenously self-administer METH for 96 h continuous weekly sessions over 8 weeks. Cardiac function, histochemistry, ultrastructure, and biochemical experiments were performed 24 h after the cessation of drug administration. Voluntary METH self-administration induced pathological cardiac remodeling as indicated by cardiomyocyte hypertrophy, myocyte disarray, interstitial and perivascular fibrosis accompanied by compromised cardiac systolic function. Ultrastructural examination and native gel electrophoresis revealed altered mitochondrial morphology and reduced mitochondrial oxidative phosphorylation (OXPHOS) supercomplexes (SCs) stability and assembly in METH exposed hearts. Redox-sensitive assays revealed significantly attenuated mitochondrial respiratory complex activities with a compensatory increase in pyruvate dehydrogenase (PDH) activity reminiscent of metabolic remodeling. Increased autophagy flux and increased mitochondrial antioxidant protein level was observed in METH exposed heart. Treatment with mitoTEMPO reduced the autophagy level indicating the involvement of mitochondrial dysfunction in the adaptive activation of autophagy in METH exposed hearts. Altogether, we have reported a novel METH-associated cardiomyopathy model using voluntary drug seeking behavior. Our studies indicated that METH self-administration profoundly affects mitochondrial ultrastructure, OXPHOS SCs assembly and redox activity accompanied by increased PDH activity that may underlie observed cardiac dysfunction.