A physiological drop in pH decreases mitochondrial respiration, and HDAC and Akt signaling, in L6 myocytes

Exercise stimulates mitochondrial biogenesis and increases mitochondrial respiratory function and content. However, during high-intensity exercise muscle pH can decrease below pH 6.8 with a concomitant increase in lactate concentration. This drop in muscle pH is associated with reduced exercise-induced mitochondrial biogenesis, while increased lactate may act as a signaling molecule to affect mitochondrial biogenesis. Therefore, in this study we wished to determine the impact of altering pH and lactate concentration in L6 myotubes on genes and proteins known to be involved in mitochondrial biogenesis. We also examined mitochondrial respiration in response to these perturbations. Differentiated L6 myotubes were exposed to normal (pH 7.5)-, low (pH 7.0)-, or high (pH 8.0)-pH media with and without 20 mM sodium l-lactate for 1 and 6 h. Low pH and 20 mM sodium l-lactate resulted in decreased Akt (Ser473) and AMPK (T172) phosphorylation at 1 h compared with controls, while at 6 h the nuclear localization of histone deacetylase 5 (HDAC5) was decreased. When the pH was increased both Akt (Ser473) and AMPK (T172) phosphorylation was increased at 1 h. Overall increased lactate decreased the nuclear content of HDAC5 at 6 h. Exposure to both high- and low-pH media decreased basal mitochondrial respiration, ATP turnover, and maximum mitochondrial respiratory capacity. These data indicate that muscle pH affects several metabolic signaling pathways, including those required for mitochondrial function

A new experimental model for assessing drug efficacy against Trypanosoma cruzi infection based on highly sensitive in vivo imaging.

The protozoan Trypanosoma cruzi is the causative agent of Chagas disease, one of the world's major neglected infections. Although development of improved antiparasitic drugs is considered a priority, there have been no significant treatment advances in the past 40 years. Factors that have limited progress include an incomplete understanding of pathogenesis, tissue tropism, and disease progression. In addition, in vivo models, which allow parasite burdens to be tracked throughout the chronic stage of infection, have been lacking. To address these issues, we have developed a highly sensitive in vivo imaging system based on bioluminescent T. cruzi, which express a red-shifted luciferase that emits light in the tissue-penetrating orange-red region of the spectrum. The exquisite sensitivity of this noninvasive murine model has been exploited to monitor parasite burden in real time throughout the chronic stage, has allowed the identification of the gastrointestinal tract as the major niche of long-term infection, and has demonstrated that chagasic heart disease can develop in the absence of locally persistent parasites. Here, we review the parameters of the imaging system and describe how this experimental model can be incorporated into drug development programs as a valuable tool for assessing efficacy against both acute and chronic T. cruzi infections

Exploring the Efficacy of the Helen B. Landgarten Art Therapy Clinic’s Transition to Telehealth During COVID-19

This research qualitatively explores the impacts of the Helen B. Landgarten Art therapy Clinic’s transition to art therapy telehealth services during the COVID-19 pandemic. The purpose of this research was to explore the efficacy of interventions and the clinical themes that emerged as a result of telehealth art therapy services delivered to marginalized communities through the Helen B. Landgarten Art Therapy Clinic. Data that was collected includes anonymous surveys from administrators, teachers, and caregivers of those receiving services and facilitators of services, semi-structured interviews with administrators, teachers, and caregivers of those receiving services, as well as a focus group with facilitators of services. Through the analysis of data several findings suggest that art therapy telehealth can provide a safe space for engagement in mental health and be more accessible to marginalized communities. These findings potentially open new doors for further inquiry into art therapy telehealth

Quantifying Downstream, Vertical and Lateral Variation in Fluvial Deposits : Implications From the Huesca Distributive Fluvial System

Acknowledgments Author Ben Martin thanks the University of Glasgow for providing funding for this project through the ‘Stressed Environments’ scholarship fund. The SAFARI consortium (https://safaridb.com/home) are thanked for providing virtual outcrop models that have been analyzed within this paper. Two anonymous reviewers are thanked for their thorough and constructive comments on this paper.Peer reviewedPublisher PD

Biological factors that impinge on Chagas disease drug development.

Chagas disease is caused by infection with the insect-transmitted protozoan Trypanosoma cruzi, and is the most important parasitic infection in Latin America. The current drugs, benznidazole and nifurtimox, are characterized by limited efficacy and toxic side-effects, and treatment failures are frequently observed. The urgent need for new therapeutic approaches is being met by a combined effort from the academic and commercial sectors, together with major input from not-for-profit drug development consortia. With the disappointing outcomes of recent clinical trials against chronic Chagas disease, it has become clear that an incomplete understanding of parasite biology and disease pathogenesis is impacting negatively on the development of more effective drugs. In addition, technical issues, including difficulties in establishing parasitological cure in both human patients and animal models, have greatly complicated the assessment of drug efficacy. Here, we outline the major questions that need to be addressed and discuss technical innovations that can be exploited to accelerate the drug development pipeline

Host and parasite genetics shape a link between Trypanosoma cruzi infection dynamics and chronic cardiomyopathy.

Host and parasite diversity are suspected to be key factors in Chagas disease pathogenesis. Experimental investigation of underlying mechanisms is hampered by a lack of tools to detect scarce, pleiotropic infection foci. We developed sensitive imaging models to track Trypanosoma cruzi infection dynamics and quantify tissue-specific parasite loads, with minimal sampling bias. We used this technology to investigate cardiomyopathy caused by highly divergent parasite strains in BALB/c, C3H/HeN and C57BL/6 mice. The gastrointestinal tract was unexpectedly found to be the primary site of chronic infection in all models. Immunosuppression induced expansion of parasite loads in the gut and was followed by widespread dissemination. These data indicate that differential immune control of T. cruzi occurs between tissues and shows that the large intestine and stomach provide permissive niches for active infection. The end-point frequency of heart-specific infections ranged from 0% in TcVI-CLBR-infected C57BL/6 to 88% in TcI-JR-infected C3H/HeN mice. Nevertheless, infection led to fibrotic cardiac pathology in all models. Heart disease severity was associated with the model-dependent frequency of dissemination outside the gut and inferred cumulative heart-specific parasite loads. We propose a model of cardiac pathogenesis driven by periodic trafficking of parasites into the heart, occurring at a frequency determined by host and parasite genetics

Effect of Heat Shock, Pretreatment and Hsp70 Copy Number on Wing Development in Drosophila Melanogaster

Naturally Occurring Heat Shock (HS) during Pupation Induces Abnormal Wing Development in Drosophila; We Examined Factors Affecting the Severity of This Induction. the Proportion of HS-Surviving Adults with Abnormal Wings Varied with HS Duration and Intensity, and with the Pupal Age or Stage at HS Administration. Pretreatment (PT), Mild Hyperthermia Delivered Before HS, Usually Protected Development Against HS. Gradual Heating Resembling Natural Thermal Regimes Also Protected Wing Development Against Thermal Disruption. Because of the Roles of the Wings in Flight and Courtship and in View of Natural Thermal Regimes that Drosophila Experience, Both HS-Induction of Wing Abnormalities and its Abatement by PT May Have Marked Effects on Drosophila Fitness in Nature. Because PT is Associated with Expression of Heat-Inducible Molecular Chaperones Such as Hsp70 in Drosophila, We Compared Thermal Disruption of Wing Development among Hsp70 Mutants as Well as among Strains Naturally Varying in Hsp70 Levels. Contrary to Expectations, Lines or Strains with Increased Hsp70 Levels Were No More Resistant to HS-Disruption of Wing Development Than Counterparts with Lower Hsp70 Levels. in Fact, Wing Development Was More Resistant to HS in Hsp70 Deletion Strains Than Control Strains. We Suggest that, While High Hsp70 Levels May Aid Cells in Surviving Hyperthermia, High Levels May Also Overly Stimulate or Inhibit Numerous Signaling Pathways Involved in Cell Proliferation, Maturation and Programmed Death, Resulting in Developmental Failure

Assessing the Effectiveness of Curative Benznidazole Treatment in Preventing Chronic Cardiac Pathology in Experimental Models of Chagas Disease.

Chagasic heart disease develops in 30% of those infected with the protozoan parasite Trypanosoma cruzi, but can take decades to become symptomatic. Because of this, it has been difficult to assess the extent to which antiparasitic therapy can prevent the development of pathology. We sought to address this question using experimental murine models, exploiting highly sensitive bioluminescent imaging to monitor curative efficacy. Mice were inoculated with bioluminescent parasites and then cured in either the acute or chronic stage of infection with benznidazole. At the experimental endpoint (5 to 6 months postinfection), heart tissue was removed and assessed for inflammation and fibrosis, two widely used markers of cardiac pathology. Infection of BALB/c and C3H/HeN mice with distinct T. cruzi lineages resulted in greatly increased myocardial collagen content at a group level, indicative of fibrotic pathology. When mice were cured by benznidazole in the acute stage, the development of pathology was completely blocked. However, if treatment was delayed until the chronic stage, cardiac fibrosis was observed in the BALB/c model, although the protective effect was maintained in the case of C3H/HeN mice. These experiments therefore demonstrate that curative benznidazole treatment early in murine T. cruzi infections can prevent the development of cardiac fibrosis. They also show that treatment during the chronic stage can block pathology but the effectiveness varies between infection models. If these findings are extendable to humans, it implies that widespread chemotherapeutic intervention targeted at early-stage infections could play a crucial role in reducing Chagas disease morbidity at a population level