Fluorescence Masking Based Multifunctional Quantum Dots’ Assay for HSP90α Interactions Detection

HSP90α is one of the most common stress proteins in cells; hence, it is a good target for developing drugs and testing systems for cancer or physical stress levels in humans. Streptavidin conjugated quantum dots (Sav-QDs) are widely used as fluorophores for biosensing to overcome chemical labelling problems. In this work, we have attempted to develop a multifunctional and robust assay for HSP90α. The detection technique was based on the masking of the fluorescence of spotted Sav-QDs on nitrocellulose chips (NC). Biotinylated ligand/antibody attaches to the spotted Sav-QD and then HSP90α is attached, which causes the masking of fluorescence. The masking of fluorescence was used to detect protein–ligand interactions, the effect of inhibitors, protein–protein interactions, and the presence of protein in the biological sample. The load of detection (LoD) of the assay lies in the nano molar range, making it a sensitive assay. The results from the experiments suggest that the used approach is promising for developing a multifunctional, robust, and sensitive assay for proteins that can be used for point-of-care detection in complex biological samples

Identification of a Thyroid Hormone Binding Site in Hsp90 with Implications for Its Interaction with Thyroid Hormone Receptor Beta

While many proteins are known clients of heat shock protein 90 (Hsp90), it is unclear whether the transcription factor, thyroid hormone receptor beta (TRb), interacts with Hsp90 to control hormonal perception and signaling. Higher Hsp90 expression in mouse fibroblasts was elicited by the addition of triiodothyronine (T3). T3 bound to Hsp90 and enhanced adenosine triphosphate (ATP) binding of Hsp90 due to a specific binding site for T3, as identified by molecular docking experiments. The binding of TRb to Hsp90 was prevented by T3 or by the thyroid mimetic sobetirome. Purified recombinant TRb trapped Hsp90 from cell lysate or purified Hsp90 in pull-down experiments. The affinity of Hsp90 for TRb was 124 nM. Furthermore, T3 induced the release of bound TRb from Hsp90, which was shown by streptavidin-conjugated quantum dot (SAv-QD) masking assay. The data indicate that the T3 interaction with TRb and Hsp90 may be an amplifier of the cellular stress response by blocking Hsp90 activity

Dynamic Phenotypic Switching and Group Behavior Help Non-Small Cell Lung Cancer Cells Evade Chemotherapy

Drug resistance, a major challenge in cancer therapy, is typically attributed to mutations and genetic heterogeneity. Emerging evidence suggests that dynamic cellular interactions and group behavior also contribute to drug resistance. However, the underlying mechanisms remain poorly understood. Here, we present a new mathematical approach with game theoretical underpinnings that we developed to model real-time growth data of non-small cell lung cancer (NSCLC) cells and discern patterns in response to treatment with cisplatin. We show that the cisplatin-sensitive and cisplatin-tolerant NSCLC cells, when co-cultured in the absence or presence of the drug, display dynamic group behavior strategies. Tolerant cells exhibit a \u27persister-like\u27 behavior and are attenuated by sensitive cells; they also appear to \u27educate\u27 sensitive cells to evade chemotherapy. Further, tolerant cells can switch phenotypes to become sensitive, especially at low cisplatin concentrations. Finally, switching treatment from continuous to an intermittent regimen can attenuate the emergence of tolerant cells, suggesting that intermittent chemotherapy may improve outcomes in lung cancer

Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Background: In an era of shifting global agendas and expanded emphasis on non-communicable diseases and injuries along with communicable diseases, sound evidence on trends by cause at the national level is essential. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) provides a systematic scientific assessment of published, publicly available, and contributed data on incidence, prevalence, and mortality for a mutually exclusive and collectively exhaustive list of diseases and injuries. Methods: GBD estimates incidence, prevalence, mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) due to 369 diseases and injuries, for two sexes, and for 204 countries and territories. Input data were extracted from censuses, household surveys, civil registration and vital statistics, disease registries, health service use, air pollution monitors, satellite imaging, disease notifications, and other sources. Cause-specific death rates and cause fractions were calculated using the Cause of Death Ensemble model and spatiotemporal Gaussian process regression. Cause-specific deaths were adjusted to match the total all-cause deaths calculated as part of the GBD population, fertility, and mortality estimates. Deaths were multiplied by standard life expectancy at each age to calculate YLLs. A Bayesian meta-regression modelling tool, DisMod-MR 2.1, was used to ensure consistency between incidence, prevalence, remission, excess mortality, and cause-specific mortality for most causes. Prevalence estimates were multiplied by disability weights for mutually exclusive sequelae of diseases and injuries to calculate YLDs. We considered results in the context of the Socio-demographic Index (SDI), a composite indicator of income per capita, years of schooling, and fertility rate in females younger than 25 years. Uncertainty intervals (UIs) were generated for every metric using the 25th and 975th ordered 1000 draw values of the posterior distribution. Findings: Global health has steadily improved over the past 30 years as measured by age-standardised DALY rates. After taking into account population growth and ageing, the absolute number of DALYs has remained stable. Since 2010, the pace of decline in global age-standardised DALY rates has accelerated in age groups younger than 50 years compared with the 1990–2010 time period, with the greatest annualised rate of decline occurring in the 0–9-year age group. Six infectious diseases were among the top ten causes of DALYs in children younger than 10 years in 2019: lower respiratory infections (ranked second), diarrhoeal diseases (third), malaria (fifth), meningitis (sixth), whooping cough (ninth), and sexually transmitted infections (which, in this age group, is fully accounted for by congenital syphilis; ranked tenth). In adolescents aged 10–24 years, three injury causes were among the top causes of DALYs: road injuries (ranked first), self-harm (third), and interpersonal violence (fifth). Five of the causes that were in the top ten for ages 10–24 years were also in the top ten in the 25–49-year age group: road injuries (ranked first), HIV/AIDS (second), low back pain (fourth), headache disorders (fifth), and depressive disorders (sixth). In 2019, ischaemic heart disease and stroke were the top-ranked causes of DALYs in both the 50–74-year and 75-years-and-older age groups. Since 1990, there has been a marked shift towards a greater proportion of burden due to YLDs from non-communicable diseases and injuries. In 2019, there were 11 countries where non-communicable disease and injury YLDs constituted more than half of all disease burden. Decreases in age-standardised DALY rates have accelerated over the past decade in countries at the lower end of the SDI range, while improvements have started to stagnate or even reverse in countries with higher SDI. Interpretation: As disability becomes an increasingly large component of disease burden and a larger component of health expenditure, greater research and developm nt investment is needed to identify new, more effective intervention strategies. With a rapidly ageing global population, the demands on health services to deal with disabling outcomes, which increase with age, will require policy makers to anticipate these changes. The mix of universal and more geographically specific influences on health reinforces the need for regular reporting on population health in detail and by underlying cause to help decision makers to identify success stories of disease control to emulate, as well as opportunities to improve. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens

Anticancer properties of nanoparticle synthesized from Cyphostemma auriculatum Roxb. on nude mice

The present study was aimed to establish the pharmacological and therapeutic properties of a green synthesized silver nanoparticles (AgNPs) in breast cancer induced by 7,12-dimethylbenzanthracene (DMBA) in nude mice. In this study, AgNPs made from Cyphostemma auriculatum Roxb. leaf extract( CA-AgNPs) were tested in a nude mice model for anticancer activity. A significant elevate changes in blood chemistry like heamoglobin, RBC, WBC,  platelets and also on blood biochemical parameters such as catalase and SOD with obtained after 28 days of treatment with carcinogen. However, these levels were restored to normal at the end of the study period treated with CA-AgNPs. The liver oxidative stress enzymes showed no significant alterations. With 15 and 30 mg/kg b.w of CA-AgNP, histopathological analysis revealed no significant abnormalities in the kidney, spleen, lungs, heart, testis, or brain. However, 30 mg/kg b.w. of CA-AgNPs caused considerable cell edema and vacuolar degeneration in the liver, which returned to normal at the conclusion of the washout period. The findings of this study suggest that green produced CA-AgNPs at low concentrations could be beneficial

Anticancer Properties of Nanoparticle Synthesized From Cyphostemma Auriculatum Roxb. on Nude Mice

The present study was aimed to establish the pharmacological and therapeutic properties of a green synthesized silver nanoparticles (AgNPs) in breast cancer induced by 7,12-dimethylbenzanthracene (DMBA) in nude mice. In this study, AgNPs made from Cyphostemma auriculatum Roxb. leaf extract( CA-AgNPs) were tested in a nude mice model for anticancer activity. A significant elevate changes in blood chemistry like heamoglobin, RBC, WBC,  platelets and also on blood biochemical parameters such as catalase and SOD with obtained after 28 days of treatment with carcinogen. However, these levels were restored to normal at the end of the study period treated with CA-AgNPs. The liver oxidative stress enzymes showed no significant alterations. With 15 and 30 mg/kg b.w of CA-AgNP, histopathological analysis revealed no significant abnormalities in the kidney, spleen, lungs, heart, testis, or brain. However, 30 mg/kg b.w. of CA-AgNPs caused considerable cell edema and vacuolar degeneration in the liver, which returned to normal at the conclusion of the washout period. The findings of this study suggest that green produced CA-AgNPs at low concentrations could be beneficial

Identification of a Thyroid Hormone Binding Site in Hsp90 with Implications for Its Interaction with Thyroid Hormone Receptor Beta

While many proteins are known clients of heat shock protein 90 (Hsp90), it is unclear whether the transcription factor, thyroid hormone receptor beta (TRb), interacts with Hsp90 to control hormonal perception and signaling. Higher Hsp90 expression in mouse fibroblasts was elicited by the addition of triiodothyronine (T3). T3 bound to Hsp90 and enhanced adenosine triphosphate (ATP) binding of Hsp90 due to a specific binding site for T3, as identified by molecular docking experiments. The binding of TRb to Hsp90 was prevented by T3 or by the thyroid mimetic sobetirome. Purified recombinant TRb trapped Hsp90 from cell lysate or purified Hsp90 in pull-down experiments. The affinity of Hsp90 for TRb was 124 nM. Furthermore, T3 induced the release of bound TRb from Hsp90, which was shown by streptavidin-conjugated quantum dot (SAv-QD) masking assay. The data indicate that the T3 interaction with TRb and Hsp90 may be an amplifier of the cellular stress response by blocking Hsp90 activity

Development of equally intelligible Telugu sentence-lists to test speech recognition in noise

<p><i>Objective</i>: To develop sentence lists in the Telugu language for the assessment of speech recognition threshold (SRT) in the presence of background noise through identification of the mean signal-to-noise ratio required to attain a 50% sentence recognition score (SRTn). <i>Design</i>: This study was conducted in three phases. The first phase involved the selection and recording of Telugu sentences. In the second phase, 20 lists, each consisting of 10 sentences with equal intelligibility, were formulated using a numerical optimisation procedure. In the third phase, the SRTn of the developed lists was estimated using adaptive procedures on individuals with normal hearing. <i>Study sample</i>: A total of 68 native Telugu speakers with normal hearing participated in the study. Of these, 18 (including the speakers) performed on various subjective measures in first phase, 20 performed on sentence/word recognition in noise for second phase and 30 participated in the list equivalency procedures in third phase. <i>Results</i>: In all, 15 lists of comparable difficulty were formulated as test material. The mean SRTn across these lists corresponded to −2.74 (SD = 0.21). <i>Conclusions</i>: The developed sentence lists provided a valid and reliable tool to measure SRTn in Telugu native speakers.</p