scholarly journals Analysis of heat-induced protein aggregation in human mitochondria

2018 ◽  
Author(s):  
Anne Wilkening ◽  
Cornelia Rüb ◽  
Marc Sylvester ◽  
Wolfgang Voos
Keyword(s):  
Heat Stress ◽  
Mammalian Cells ◽  
Elevated Temperatures ◽  
Protein Biosynthesis ◽  
High Sensitivity ◽  
Small Subset ◽  
Loss Of Function ◽  
Mitochondrial Translation ◽  
The Impact ◽  
Induced Aggregation

AbstractAs proteins in mammalian cells exhibit optimal stability at natural temperatures, small temperature variations may cause unfolding and subsequent non-specific aggregation. As this process leads to a loss of function of the affected polypeptides as well as to further cytotoxic stress, aggregate formation has been recognized as a major pathogenic factor in human diseases. In this study we determined the impact of physiological heat stress on mammalian mitochondria on a proteomic level. The overall solubility of endogenous mitochondrial proteins was only marginally affected by a treatment at elevated temperatures. However, we identified a small subset of polypeptides that exhibited an exceptionally high sensitivity to heat stress. The mitochondrial translation elongation factor Tu (Tufm), a protein essential for organellar protein biosynthesis, was highly aggregation-prone and lost its solubility already under mild heat stress conditions. In parallel, mitochondrial translation as well as the import of cytosolic proteins was defective in heat stressed mitochondria. Both types of nascent polypeptides, derived from translation as well as from import exhibited a strong heat-induced aggregation tendency. We propose a model that a quick and specific inactivation of elongation factors may prevent an accumulation of misfolded nascent polypeptides and thereby attenuate proteotoxicity under stress.

scholarly journals The Hsp60 Protein of Helicobacter Pylori Exhibits Chaperone and ATPase Activities at Elevated Temperatures

BioChem ◽  
2021 ◽  
Vol 1 (1) ◽  
pp. 19-25
Author(s):  
Jose A. Mendoza ◽  
Julian L. Ignacio ◽  
Christopher M. Buckley
Keyword(s):  
Helicobacter Pylori ◽  
Heat Stress ◽  
Molecular Chaperone ◽  
Elevated Temperatures ◽  
Citrate Synthase ◽  
Gastric Epithelium ◽  
Acidic Conditions ◽  
H Pylori ◽  
Induced Aggregation ◽  
Hydrolysis Of

The heat-shock protein, Hsp60, is one of the most abundant proteins in Helicobacter pylori. Given its sequence homology to the Escherichia coli Hsp60 or GroEL, Hsp60 from H. pylori would be expected to function as a molecular chaperone in this organism. H. pylori is a type of bacteria that grows on the gastric epithelium, where the pH can fluctuate between neutral and 4.5, and the intracellular pH can be as low as 5.0. We previously showed that Hsp60 functions as a chaperone under acidic conditions. However, no reports have been made on the ability of Hsp60 to function as a molecular chaperone under other stressful conditions, such as heat stress or elevated temperatures. We report here that Hsp60 could suppress the heat-induced aggregation of the enzymes rhodanese, malate dehydrogenase, citrate synthase, and lactate dehydrogenase. Moreover, Hsp60 was found to have a potassium and magnesium-dependent ATPase activity that was stimulated at elevated temperatures. Although, Hsp60 was found to bind GTP, the hydrolysis of this nucleotide could not be observed. Our results show that Hsp60 from H. pylori can function as a molecular chaperone under conditions of heat stress.

scholarly journals The genetic and molecular basis for improving heat stress tolerance in wheat

aBIOTECH ◽  
2021 ◽  
Author(s):  
Lv Sun ◽  
Jingjing Wen ◽  
Huiru Peng ◽  
Yingyin Yao ◽  
Zhaorong Hu ◽  
...  
Keyword(s):  
Heat Stress ◽  
Stress Tolerance ◽  
Heat Tolerance ◽  
Genetic Basis ◽  
Molecular Mechanisms ◽  
Elevated Temperatures ◽  
New Technologies ◽  
Wheat Breeding ◽  
Heat Stress Tolerance ◽  
The Impact

AbstractWheat production requires at least ~ 2.4% increase per year rate by 2050 globally to meet food demands. However, heat stress results in serious yield loss of wheat worldwide. Correspondingly, wheat has evolved genetic basis and molecular mechanisms to protect themselves from heat-induced damage. Thus, it is very urgent to understand the underlying genetic basis and molecular mechanisms responsive to elevated temperatures to provide important strategies for heat-tolerant varieties breeding. In this review, we focused on the impact of heat stress on morphology variation at adult stage in wheat breeding programs. We also summarize the recent studies of genetic and molecular factors regulating heat tolerance, including identification of heat stress tolerance related QTLs/genes, and the regulation pathway in response to heat stress. In addition, we discuss the potential ways to improve heat tolerance by developing new technologies such as genome editing. This review of wheat responses to heat stress may shed light on the understanding heat-responsive mechanisms, although the regulatory network of heat tolerance is still ambiguous in wheat.

scholarly journals Cellular and Molecular Adaptation of Bovine Granulosa Cells and Oocytes under Heat Stress

Animals ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 110 ◽  
Author(s):  
Adnan Khan ◽  
Muhammad Zahoor Khan ◽  
Saqib Umer ◽  
Ibrar Muhammad Khan ◽  
Huitao Xu ◽  
...  
Keyword(s):  
Heat Stress ◽  
Dairy Cattle ◽  
Granulosa Cells ◽  
Elevated Temperatures ◽  
Mitigation Strategies ◽  
Future Research ◽  
Stressed Animal ◽  
Regulate Body Temperature ◽  
And Function ◽  
The Impact

Heat stress has long been recognized as a challenging issue that severely influences the reproductive functions of dairy cattle, disrupting oocyte development during fetal growth. These detrimental effects of heat stress are the result of either the hyperthermia associated with heat stress or the physiological adjustments made by the heat-stressed animal to regulate body temperature. In addition, elevated temperatures have been implicated in increasing the production of reactive oxygen species. Thus, understanding the impact of heat stress on reproductive functions, from a cellular to molecular level, might help in selecting heat-resilient dairy cattle and developing heat stress mitigation strategies. In the present paper, we have attempted to describe the changes in the reproductive system and function of dairy cattle in response to heat stress by reviewing the latest literature in this area. The review provides useful knowledge on the cellular and genetic basis of oocyte and granulosa cells in heat-stressed dairy cattle, which could be helpful for future research in this area.

scholarly journals A Single Conserved Residue Mediates Binding of the Ribonucleotide Reductase Catalytic Subunit RRM1 to RRM2 and Is Essential for Mouse Development

2015 ◽  
Vol 35 (17) ◽  
pp. 2910-2917 ◽  
Author(s):  
Julia Specks ◽  
Emilio Lecona ◽  
Andrés J. Lopez-Contreras ◽  
Oscar Fernandez-Capetillo
Keyword(s):  
Ribonucleotide Reductase ◽  
Mammalian Cells ◽  
Catalytic Subunit ◽  
Regulatory Subunit ◽  
Loss Of Function ◽  
Mouse Development ◽  
Genetic Studies ◽  
Content Type ◽  
The Impact ◽  
Rate Limiting

The ribonucleotide reductase (RNR) complex, composed of a catalytic subunit (RRM1) and a regulatory subunit (RRM2), is thought to be a rate-limiting enzymatic complex for the production of nucleotides. In humans, theRrm1gene lies at 11p15.5, a tumor suppressor region, and RRM1 expression in cancer has been shown to predict responses to chemotherapy. Nevertheless, whether RRM1 is essential in mammalian cells and what the effects of its haploinsufficiency are remain unknown. To model RNR function in mice we used a mutation previously described inSaccharomyces cerevisiae(Rnr1-W688G) which, despite being viable, leads to increased interaction of the RNR complex with its allosteric inhibitor Sml1. In contrast to yeast, homozygous mutant mice carrying theRrm1mutation (Rrm1WG/WG) are not viable, even at the earliest embryonic stages. Proteomic analyses failed to identify proteins that specifically bind to the mutant RRM1 but revealed that, in mammals, the mutation prevents RRM1 binding to RRM2. Despite the impact of the mutation,Rrm1WG/+mice and cells presented no obvious phenotype, suggesting that the RRM1 protein exists in excess. Our work reveals that binding of RRM1 to RRM2 is essential for mammalian cells and provides the first loss-of-function model of the RNR complex for genetic studies.

Influence of environmental factors on the infectivity of Echinococcus multilocularis eggs

Parasitology ◽  
1995 ◽  
Vol 110 (1) ◽  
pp. 79-86 ◽  
Author(s):  
P. Veit ◽  
B. Bilger ◽  
V. Schad ◽  
J. Schäfer ◽  
W. Frank ◽  
...  
Keyword(s):  
Relative Humidity ◽  
Echinococcus Multilocularis ◽  
Elevated Temperatures ◽  
High Sensitivity ◽  
Laboratory Conditions ◽  
Nylon Mesh ◽  
Low Concentrations ◽  
Autumn And Winter ◽  
The Impact

The sensitivity of eggs of Echinococcus multilocularis to environmental and controlled laboratory conditions was tested. Egg material was exposed and the infectivity was subsequently monitored by in vitro activation and by oral infection of the natural host, Microtus arvalis. To study the impact of environmental conditions in an endemic area of south-western Germany, eggs were sealed into bags of nylon mesh and exposed to the natural climate during various seasons. The maximal survival time of eggs was 240 days in an experiment performed in autumn and winter and 78 days in summer. A study of the tenacity of eggs under laboratory conditions revealed a high sensitivity to elevated temperatures and to desiccation. At 45 °C and 85–95% relative humidity the infectivity was lost after 3 h as well as after 4 h exposure to 43 °C suspended in water. Exposure to 27% relative humidity at 25 °C as well as exposure to 15% relative humidity at 43 °C resulted in a total loss of infectivity within 48 and 2 h, respectively. Temperatures of 4 °C and of –18 °C were well tolerated (478 days and 240 days survival, respectively), whereas exposure to –83 °C and to –196 °C quickly killed off the eggs (within 48 h and 20 h, respectively). Eggs of E. multilocularis were not killed off by exposure to various commercially available disinfectants applied according to the manufacturers' instructions and by exposure for 24 h to low concentrations of ethanol. Irradiation with 40 krad. from a 137Caesium source prevented the development of metacestodes but allowed seroconversion of infected rodents.

INFLUENCE OF GREENHOUSE SHADING AND DIFFERENT NUTRIENT MANAGEMENT PRACTICES ON ALLEVIATING HEAT STRESS, IMPROVING PLANT NUTRIENTS STATUS, FLOWERING GROWTH AND YIELD OF TOMATO

2020 ◽  
Vol 51 (4) ◽  
pp. 1001-1014
Author(s):  
Sulaiman & Sadiq
Keyword(s):  
Heat Stress ◽  
Management Practices ◽  
Nutrient Management ◽  
Block Design ◽  
Nutrient Status ◽  
Growth And Yield ◽  
Reproductive Growth ◽  
Positive Effects ◽  
Nutrition Programs ◽  
The Impact

The experiment was conducted in a greenhouse during 2017 and 2018 growing seasons to evaluate the impact of the shading and various nutrition programs on mitigating heat stress, reducing the use of chemical minerals, improving the reproductive growth and yield of tomato plant. Split-plot within Randomized Complete Block Design (RCBD) with three replications was conducted in this study. Shading factor was allocated in the main plots and the nutrition programs distributed randomly in the subplots. Results indicate that shading resulted in the decrease of daytime temperature by 5.7˚C as an average for both seasons; thus a significant increasing was found in leaf contents of macro nutrients (Nitrogen, Phosphorous, and Potassium), and micro nutrients (Iron, Zinc and Boron), except the Iron content in 2018 growing season. Furthermore, shading improved significantly the reproductive growth and tomato yield. Among the plant nutrition programs, the integrated nutrient management (INM) including the application of organic substances, bio inoculum of AMF and 50% of the recommended dose of chemical fertilizers; lead to the enhancement of nutrients content, reproductive characteristics and plant yield. Generally, combination of both shading and INM showed positive effects on plants nutrient status and persisting balance on tomato flowering growth and fruits yield.

scholarly journals Review: Impacts of shade on cattle well-being in the beef supply chain

2020 ◽  
Author(s):  
Lily N Edwards-Callaway ◽  
M Caitlin Cramer ◽  
Caitlin N Cadaret ◽  
Elizabeth J Bigler ◽  
Terry E Engle ◽  
...  
Keyword(s):  
Supply Chain ◽  
Heat Stress ◽  
Beef Cattle ◽  
Production Systems ◽  
Construction Materials ◽  
Well Being ◽  
Third Party ◽  
Ambient Temperatures ◽  
Stress Susceptibility ◽  
The Impact

ABSTRACT Shade is a mechanism to reduce heat load providing cattle with an environment supportive of their welfare needs. Although heat stress has been extensively reviewed, researched, and addressed in dairy production systems, it has not been investigated in the same manner in the beef cattle supply chain. Like all animals, beef cattle are susceptible to heat stress if they are unable to dissipate heat during times of elevated ambient temperatures. There are many factors that impact heat stress susceptibility in beef cattle throughout the different supply chain sectors, many of which relate to the production system, i.e. availability of shade, microclimate of environment, and nutrition management. The results from studies evaluating the effects of shade on production and welfare are difficult to compare due to variation in structural design, construction materials used, height, shape, and area of shade provided. Additionally, depending on operation location, shade may or may not be beneficial during all times of the year, which can influence the decision to make shade a permanent part of management systems. Shade has been shown to lessen the physiologic response of cattle to heat stress. Shaded cattle exhibit lower respiration rates, body temperatures, and panting scores compared to un-shaded cattle in weather that increases the risk of heat stress. Results from studies investigating the provision of shade indicate that cattle seek shade in hot weather. The impact of shade on behavioral patterns is inconsistent in the current body of research, some studies indicating shade provision impacts behavior and other studies reporting no difference between shaded and un-shaded groups. Analysis of performance and carcass characteristics across feedlot studies demonstrated that shaded cattle had increased ADG, improved feed efficiency, HCW, and dressing percentage when compared to cattle without shade. Despite the documented benefits of shade, current industry statistics, although severely limited in scope, indicate low shade implementation rates in feedlots and data in other supply chain sectors do not exist. Industry guidelines and third party on-farm certification programs articulate the critical need for protection from extreme weather but are not consistent in providing specific recommendations and requirements. Future efforts should include: updated economic analyses of cost versus benefit of shade implementation, exploration of producer perspectives and needs relative to shade, consideration of shade impacts in the cow-calf and slaughter plant segments of the supply chain, and integration of indicators of affective (mental) state and preference in research studies to enhance the holistic assessment of cattle welfare.

scholarly journals ATP13A2 Regulates Cellular α-Synuclein Multimerization, Membrane Association, and Externalization

2021 ◽  
Vol 22 (5) ◽  
pp. 2689
Author(s):  
Jianmin Si ◽  
Chris Van den Haute ◽  
Evy Lobbestael ◽  
Shaun Martin ◽  
Sarah van Veen ◽  
...  
Keyword(s):  
Membrane Integrity ◽  
Ubiquitin Proteasome System ◽  
Regulatory Function ◽  
Membrane Association ◽  
Loss Of Function ◽  
Atypical Form ◽  
Polyamine Transport ◽  
Independent Functions ◽  
Ubiquitin Proteasome ◽  
The Impact

ATP13A2, a late endo-/lysosomal polyamine transporter, is implicated in a variety of neurodegenerative diseases, including Parkinson’s disease and Kufor–Rakeb syndrome, an early-onset atypical form of parkinsonism. Loss-of-function mutations in ATP13A2 result in lysosomal deficiency as a consequence of impaired lysosomal export of the polyamines spermine/spermidine. Furthermore, accumulating evidence suggests the involvement of ATP13A2 in regulating the fate of α-synuclein, such as cytoplasmic accumulation and external release. However, no consensus has yet been reached on the mechanisms underlying these effects. Here, we aimed to gain more insight into how ATP13A2 is linked to α-synuclein biology in cell models with modified ATP13A2 activity. We found that loss of ATP13A2 impairs lysosomal membrane integrity and induces α-synuclein multimerization at the membrane, which is enhanced in conditions of oxidative stress or exposure to spermine. In contrast, overexpression of ATP13A2 wildtype (WT) had a protective effect on α-synuclein multimerization, which corresponded with reduced αsyn membrane association and stimulation of the ubiquitin-proteasome system. We also found that ATP13A2 promoted the secretion of α-synuclein through nanovesicles. Interestingly, the catalytically inactive ATP13A2 D508N mutant also affected polyubiquitination and externalization of α-synuclein multimers, suggesting a regulatory function independent of the ATPase and transport activity. In conclusion, our study demonstrates the impact of ATP13A2 on α-synuclein multimerization via polyamine transport dependent and independent functions.

scholarly journals POS1121 DEMOGRAPHICS, COMORBIDITIES, AND RENAL FUNCTION OF UNCONTROLLED GOUT PATIENTS WHO RECEIVED PEGLOTICASE: FINDING FROM A LARGE US CLAIMS DATABASE

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 839.2-840
Author(s):  
C. Vesel ◽  
A. Morton ◽  
M. Francis-Sedlak ◽  
B. Lamoreaux
Keyword(s):  
Kidney Function ◽  
Real World ◽  
Randomized Clinical Trials ◽  
Small Subset ◽  
Phase 3 ◽  
Claims Database ◽  
Medical Diagnoses ◽  
Ckd Stage ◽  
Before And After ◽  
The Impact

Background:NHANES data indicate that approximately 9.2 million Americans have gout,1 with a small subset having uncontrolled disease.2 Pegloticase is a PEGylated recombinant uricase enzyme indicated for treating uncontrolled gout that markedly reduces serum uric acid levels (sUA)3 and resolves tophi in treatment responders.4 Despite pegloticase availability in the US for many years, real world demographics of pegloticase users in the treatment of uncontrolled gout have not been previously reported in a population-based cohort.Objectives:This study utilized a large US claims database to examine demographics and co-morbidities of uncontrolled gout patients treated with pegloticase. Kidney function before and after pegloticase treatment and concomitant therapy with immunomodulators were also examined.Methods:The TriNetX Diamond database includes de-identified data from 4.3 million US patients with gout (as of September 2019), including demographics, medical diagnoses, laboratory values, procedures (e.g. infusions, surgeries), and pharmacy data. Patients who had received ≥1 pegloticase infusion were included in these analyses. The number of infusions was evaluated for a subgroup of patients who were in the database ≥3 months before and ≥2 years after the first pegloticase infusion (i.e. first infusion prior to September 2017) to ensure only complete courses of therapy were captured. In this subpopulation, kidney function before and after pegloticase therapy was examined, along with the presence of immunomodulation prescriptions (methotrexate, mycophenolate mofetil, azathioprine, leflunomide) within 60 days prior to and 14 days after the first pegloticase infusion.Results:1494 patients treated with pegloticase were identified. Patients were 63.1 ± 14.0 years of age (range: 23–91), mostly male (82%), and white (76%). Mean sUA prior to pegloticase was 8.7 ± 2.4 mg/dL (n=50), indicating uncontrolled gout in the identified population. The most commonly reported comorbidities were chronic kidney disease (CKD, 48%), essential hypertension (71%), type 2 diabetes (39%), and cardiovascular disease (38%), similar to pegloticase pivotal Phase 3 trial populations. In patients with pre-therapy kidney function measures (n=134), pre-treatment eGFR averaged 61.2 ± 25.7 ml/min/1.73 m2, with 44% having Stage 3-5 CKD. In patients with complete therapy course capture and pre- and post-therapy eGFR measures (n=48), kidney function remained stable (change in eGFR: -2.9 ± 18.2 ml/min/1.73 m2) and CKD stage remained the same or improved in 81% of patients. In 791 patients with complete treatment course capture, patients had received 8.7 ± 13.8 infusions (median: 3, IQR: 2-10). Of these, 189 (24%) patients received only 1 pegloticase infusion and 173 (22%) received ≥12 infusions. As the data cut-off for this analysis pre-dated emerging data on the use of immunomodulation as co-therapy, only 19 of 791 (2%) patients received immunomodulation co-therapy with pegloticase.Conclusion:This relatively large group of patients with uncontrolled gout treated with pegloticase had similar patient characteristics of those studied in the phase 3 randomized clinical trials. Patients with uncontrolled gout are significantly burdened with systemic co-morbid diseases. The majority of patients had stable or improved kidney function following pegloticase treatment. As these results reflect patients initiating treatment prior to 2018, before co-treatment with immunomodulation was introduced, this cohort only included a small percentage of patients who were co-treated with an immunomodulator. Future studies using more current datasets are needed to evaluate real world outcomes in patients treated with pegloticase/immunomodulator co-therapy and to evaluate the impact of systemic co-morbid diseases.References:[1]Chen-Xu M, et al. Arthritis Rheumatol 2019 71:991-999.[2]Fels E, Sundy JS. Curr Opin Rheumatol 2008;20:198-202.[3]Sundy J, et al. JAMA 2011;306:711-720.[4]Mandell BF, et al. Arthritis Res Ther 2018;20:286.Disclosure of Interests:Claudia Vesel Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Allan Morton Speakers bureau: Sanofi, Amgen, and Horizon, Megan Francis-Sedlak Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Brian LaMoreaux Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc.

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