49 research outputs found
Phase stability in nanoscale material systems: extension from bulk phase diagrams
Phase diagrams of multi-component systems are critical for the development and engineering of material alloys for all technological applications. At nano dimensions, surfaces (and interfaces) play a significant role in changing equilibrium thermodynamics and phase stability. In this work, it is shown that these surfaces at small dimensions affect the relative equilibrium thermodynamics of the different phases. The CALPHAD approach for material surfaces (also termed ânano-CALPHADâ) is employed to investigate these changes in three binary systems by calculating their phase diagrams at nano dimensions and comparing them with their bulk counterparts. The surface energy contribution, which is the dominant factor in causing these changes, is evaluated using the spherical particle approximation. It is first validated with the AuâSi system for which experimental data on phase stability of spherical nano-sized particles is available, and then extended to calculate phase diagrams of similarly sized particles of GeâSi and AlâCu. Additionally, the surface energies of the associated compounds are calculated using DFT, and integrated into the thermodynamic model of the respective binary systems. In this work we found changes in miscibilities, reaction compositions of about 5 at%, and solubility temperatures ranging from 100â200 K for particles of sizes 5 nm, indicating the importance of phase equilibrium analysis at nano dimensions
Methylphenidate Exposure Induces Dopamine Neuron Loss and Activation of Microglia in the Basal Ganglia of Mice
Background: Methylphenidate (MPH) is a psychostimulant that exerts its pharmacological effects via preferential blockade of the dopamine transporter (DAT) and the norepinephrine transporter (NET), resulting in increased monoamine levels in the synapse. Clinically, methylphenidate is prescribed for the symptomatic treatment of ADHD and narcolepsy; although lately, there has been an increased incidence of its use in individuals not meeting the criteria for these disorders. MPH has also been misused as a cognitive enhancer and as an alternative to other psychostimulants. Here, we investigate whether chronic or acute administration of MPH in mice at either 1 mg/kg or 10 mg/kg, affects cell number and gene expression in the basal ganglia. Methodology/Principal Findings: Through the use of stereological counting methods, we observed a significant reduction (~20%) in dopamine neuron numbers in the substantia nigra pars compacta (SNpc) following chronic administration of 10 mg/kg MPH. This dosage of MPH also induced a significant increase in the number of activated microglia in the SNpc. Additionally, exposure to either 1 mg/kg or 10 mg/kg MPH increased the sensitivity of SNpc dopaminergic neurons to the parkinsonian agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Unbiased gene screening employing Affymetrix GeneChipŸ HT MG-430 PM revealed changes in 115 and 54 genes in the substantia nigra (SN) of mice exposed to 1 mg/kg and 10 mg/kg MPH doses, respectively. Decreases in the mRNA levels of gdnf, dat1, vmat2, and th in the substantia nigra (SN) were observed with both acute and chronic dosing of 10 mg/kg MPH. We also found an increase in mRNA levels of the pro-inflammatory genes il-6 and tnf-α in the striatum, although these were seen only at an acute dose of 10 mg/kg and not following chronic dosing. Conclusion: Collectively, our results suggest that chronic MPH usage in mice at doses spanning the therapeutic range in humans, especially at prolonged higher doses, has long-term neurodegenerative consequences
Acute NMDA toxicity in cultured rat cerebellar granule neurons is accompanied by autophagy induction and late onset autophagic cell death phenotype
<p>Abstract</p> <p>Background</p> <p>Autophagy, an intracellular response to stress, is characterized by double membrane cytosolic vesicles called autophagosomes. Prolonged autophagy is known to result in autophagic (Type II) cell death. This study examined the potential role of an autophagic response in cultured cerebellar granule neurons challenged with excitotoxin N-methyl-D-aspartate (NMDA).</p> <p>Results</p> <p>NMDA exposure induced light chain-3 (LC-3)-immunopositive and monodansylcadaverine (MDC) fluorescent dye-labeled autophagosome formation in both cell bodies and neurites as early as 3 hours post-treatment. Elevated levels of Beclin-1 and the autophagosome-targeting LC3-II were also observed following NMDA exposure. Prolonged exposure of the cultures to NMDA (8-24 h) generated MDC-, LC3-positive autophagosomal bodies, concomitant with the neurodegenerative phase of NMDA challenge. Lysosomal inhibition studies also suggest that NMDA-treatment diverted the autophagosome-associated LC3-II from the normal lysosomal degradation pathway. Autophagy inhibitor 3-methyladenine significantly reduced NMDA-induced LC3-II/LC3-I ratio increase, accumulation of autophagosomes, and suppressed NMDA-mediated neuronal death. ATG7 siRNA studies also showed neuroprotective effects following NMDA treatment.</p> <p>Conclusions</p> <p>Collectively, this study shows that autophagy machinery is robustly induced in cultured neurons subjected to prolonged exposure to excitotoxin, while autophagosome clearance by lysosomal pathway might be impaired. Our data further show that prolonged autophagy contributes to cell death in NMDA-mediated excitotoxicity.</p
Manganese exposure in juvenile C57BL/6 mice increases glial inflammatory responses in the substantia nigra following infection with H1N1 influenza virus.
Infection with Influenza A virus can lead to the development of encephalitis and subsequent neurological deficits ranging from headaches to neurodegeneration. Post-encephalitic parkinsonism has been reported in surviving patients of H1N1 infections, but not all cases of encephalitic H1N1 infection present with these neurological symptoms, suggesting that interactions with an environmental neurotoxin could promote more severe neurological damage. The heavy metal, manganese (Mn), is a potential interacting factor with H1N1 because excessive exposure early in life can induce long-lasting effects on neurological function through inflammatory activation of glial cells. In the current study, we used a two-hit model of neurotoxin-pathogen exposure to examine whether exposure to Mn during juvenile development would induce a more severe neuropathological response following infection with H1N1 in adulthood. To test this hypothesis, C57BL/6 mice were exposed to MnCl2 in drinking water (50 mg/kg/day) for 30 days from days 21-51 postnatal, then infected intranasally with H1N1 three weeks later. Analyses of dopaminergic neurons, microglia and astrocytes in basal ganglia indicated that although there was no significant loss of dopaminergic neurons within the substantia nigra pars compacta, there was more pronounced activation of microglia and astrocytes in animals sequentially exposed to Mn and H1N1, as well as altered patterns of histone acetylation. Whole transcriptome Next Generation Sequencing (RNASeq) analysis was performed on the substantia nigra and revealed unique patterns of gene expression in the dual-exposed group, including genes involved in antioxidant activation, mitophagy and neurodegeneration. Taken together, these results suggest that exposure to elevated levels of Mn during juvenile development could sensitize glial cells to more severe neuro-immune responses to influenza infection later in life through persistent epigenetic changes
The Acceptability Among Health Researchers and Clinicians of Social Media to Translate Research Evidence to Clinical Practice: Mixed-Methods Survey and Interview Study
Background: Establishing and promoting connections between health researchers and health professional clinicians may help translate research evidence to clinical practice. Social media may have the capacity to enhance these connections.
Objective: The aim of this study was to explore health researchersâ and cliniciansâ current use of social media and their beliefs and attitudes towards the use of social media for communicating research evidence.
Methods: This study used a mixed-methods approach to obtain qualitative and quantitative data. Participation was open to health researchers and clinicians. Data regarding demographic details, current use of social media, and beliefs and attitudes towards the use of social media for professional purposes were obtained through an anonymous Web-based survey. The survey was distributed via email to research centers, educational and clinical institutions, and health professional associations in Australia, India, and Malaysia. Consenting participants were stratified by country and role and selected at random for semistructured telephone interviews to explore themes arising from the survey.
Results: A total of 856 participants completed the questionnaire with 125 participants declining to participate, resulting in a response rate of 87.3%. 69 interviews were conducted with participants from Australia, India, and Malaysia. Social media was used for recreation by 89.2% (749/840) of participants and for professional purposes by 80.0% (682/852) of participants. Significant associations were found between frequency of professional social media use and age, gender, country of residence, and graduate status. Over a quarter (26.9%, 229/852) of participants used social media for obtaining research evidence, and 15.0% (128/852) of participants used social media for disseminating research evidence. Most participants (95.9%, 810/845) felt there was a role for social media in disseminating or obtaining research evidence. Over half of the participants (449/842, 53.3%) felt they had a need for training in the use of social media for professional development. A key barrier to the professional use of social media was concerns regarding trustworthiness of information.
Conclusions: A large majority of health researchers and clinicians use social media in recreational and professional contexts. Social media is less frequently used for communication of research evidence. Training in the use of social media for professional development and methods to improve the trustworthiness of information obtained via social media may enhance the utility of social media for communicating research evidence. Future studies should investigate the efficacy of social media in translating research evidence to clinical practice
Methylphenidate Exposure Induces Dopamine Neuron Loss and Activation of Microglia in the Basal Ganglia of Mice
Background: Methylphenidate (MPH) is a psychostimulant that exerts its pharmacological effects via preferential blockade of the dopamine transporter (DAT) and the norepinephrine transporter (NET), resulting in increased monoamine levels in the synapse. Clinically, methylphenidate is prescribed for the symptomatic treatment of ADHD and narcolepsy; although lately, there has been an increased incidence of its use in individuals not meeting the criteria for these disorders. MPH has also been misused as a ââcognitive enhancerâ â and as an alternative to other psychostimulants. Here, we investigate whether chronic or acute administration of MPH in mice at either 1 mg/kg or 10 mg/kg, affects cell number and gene expression in the basal ganglia. Methodology/Principal Findings: Through the use of stereological counting methods, we observed a significant reduction (,20%) in dopamine neuron numbers in the substantia nigra pars compacta (SNpc) following chronic administration of 10 mg/kg MPH. This dosage of MPH also induced a significant increase in the number of activated microglia in the SNpc. Additionally, exposure to either 1 mg/kg or 10 mg/kg MPH increased the sensitivity of SNpc dopaminergic neurons to the parkinsonian agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Unbiased gene screening employing Affymetrix GeneChipH HT MG-430 PM revealed changes in 115 and 54 genes in the substantia nigra (SN) of mice exposed to 1 mg/kg and 10 mg/kg MPH doses, respectively. Decreases in the mRNA levels of gdnf, dat1, vmat2, and th in the substantia nigr
The global burden of cancer attributable to risk factors, 2010-19 : a systematic analysis for the Global Burden of Disease Study 2019
Background Understanding the magnitude of cancer burden attributable to potentially modifiable risk factors is crucial for development of effective prevention and mitigation strategies. We analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 to inform cancer control planning efforts globally. Methods The GBD 2019 comparative risk assessment framework was used to estimate cancer burden attributable to behavioural, environmental and occupational, and metabolic risk factors. A total of 82 risk-outcome pairs were included on the basis of the World Cancer Research Fund criteria. Estimated cancer deaths and disability-adjusted life-years (DALYs) in 2019 and change in these measures between 2010 and 2019 are presented. Findings Globally, in 2019, the risk factors included in this analysis accounted for 4.45 million (95% uncertainty interval 4.01-4.94) deaths and 105 million (95.0-116) DALYs for both sexes combined, representing 44.4% (41.3-48.4) of all cancer deaths and 42.0% (39.1-45.6) of all DALYs. There were 2.88 million (2.60-3.18) risk-attributable cancer deaths in males (50.6% [47.8-54.1] of all male cancer deaths) and 1.58 million (1.36-1.84) risk-attributable cancer deaths in females (36.3% [32.5-41.3] of all female cancer deaths). The leading risk factors at the most detailed level globally for risk-attributable cancer deaths and DALYs in 2019 for both sexes combined were smoking, followed by alcohol use and high BMI. Risk-attributable cancer burden varied by world region and Socio-demographic Index (SDI), with smoking, unsafe sex, and alcohol use being the three leading risk factors for risk-attributable cancer DALYs in low SDI locations in 2019, whereas DALYs in high SDI locations mirrored the top three global risk factor rankings. From 2010 to 2019, global risk-attributable cancer deaths increased by 20.4% (12.6-28.4) and DALYs by 16.8% (8.8-25.0), with the greatest percentage increase in metabolic risks (34.7% [27.9-42.8] and 33.3% [25.8-42.0]). Interpretation The leading risk factors contributing to global cancer burden in 2019 were behavioural, whereas metabolic risk factors saw the largest increases between 2010 and 2019. Reducing exposure to these modifiable risk factors would decrease cancer mortality and DALY rates worldwide, and policies should be tailored appropriately to local cancer risk factor burden. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.Peer reviewe
Concurrent Simulation of Plasma Reactors
This paper summarizes the computational techniques behind a novel concurrent simulation method used for studying the neutral flow inside plasma reactors. The technique is intended to cope with low pressure flow (less than 1.5 Torr) in realistic three-dimensional geometries. It is based on the Direct Simulation Monte Carlo method to accurately model rarefied gas flow. The concurrent formulation operates on a broad variety of shared-memory multiprocessors, multicomputers, and networked workstations. INTRODUCTION Plasma processing equipment accounts for approximately 20 percent of the setup cost for a new semiconductor manufacturing plant. The cost of these production facilities is escalating, as are the research and development costs of introducing each new generation of processing technology. One of the key pieces of equipment in microelectronics manufacturing is the plasma reactor, used in 30 to 40 percent of processing steps. It is widely recognized that the development of computati..
Sitagliptin 100 mg vs glimepiride 1â3 mg as an add-on to insulin and metformin in type 2 diabetes (SWIM)
Objective: To compare the effect of sitagliptin (100 mg) vs glimepiride (1â3 mg) as add-on therapy in Indian type 2 diabetes (T2DM) patients on treatment with insulin and metformin (SWIM study).
Research design and methods: This 24-week, controlled, open-label study randomized T2DM patients (n = 440) receiving a stable dose of metformin and insulin combination therapy to sitagliptin (100 mg) or glimepiride (1â3 mg) as add-on therapy. Baseline HbA1c was â„7.3% and â€8.5%. After a 6-week titration period for glimepiride (dose titrated every 2 weeks by 1 mg up to a maximum of 3 mg daily), patients were continued for 18 weeks on their respective tolerable doses of glimepiride (ranging from 1 mg to 3 mg) or sitagliptin (100 mg) along with metformin and insulin.
Results: Greater reductions in HbA1c and TDD of insulin were achieved with sitagliptin compared to glimepiride. HbA1c targets and reductions in TDD were achieved by more patients on sitagliptin than on glimepiride. Reductions in both body weight and BMI were also noted among patients on sitagliptin when compared to those on glimepiride, and more hypoglycemic events occurred with glimepiride treatment than with sitagliptin.
Conclusions: Sitagliptin (100 mg), when compared to glimepiride (1â3 mg), bestowed beneficial effects to T2DM patients in terms of achieving greater glycemic control and also brought significant reductions in total daily dose of insulin required, bodyweight, BMI and hypoglycemic events. Overall, the results suggest that sitagliptin (100 mg) is a superior agent over glimepiride (1â3 mg) as an add-on to insulinâmetformin therapy among Asian Indians with T2DM