37495 research outputs found
Sort by
Computational Molecular Docking of Fluorinated Morphine Derivatives for Improved Pain Management
No full textThe opioid epidemic impacts 60 million people worldwide every year. Morphine, a commonly prescribed opioid, binds to the μ-opioid receptor (MOR) in the body via protonation of its tertiary amino group and the MOR. An unfortunate side effect of this binding process is its non-selectivity in both peripheral and central tissues. While activation within inflamed peripheral tissues results in pain relief, activation within central tissues results in the unwanted and addictive side effects of opioids. Because there is a discrepancy in pH between healthy (central) and inflamed (peripheral) tissue, selective binding within the inflamed tissues could provide pain relief without addictive properties. Fluorination of the morphine molecule reduces its pKa, promoting selective protonation and receptor binding in the lower pH environment of inflamed tissues while avoiding activation within the CNS. Additionally, removal of the C and D rings alters steric properties, improving receptor fit and binding efficiency by increasing molecular flexibility. The aim of this study is to further assess these derivatives using molecular docking simulations conducted in Rowan, a graphical interface for AutoDock Vina that allows visualization and evaluation of ligand-receptor interactions. Docking simulations were performed using a manually defined binding pocket. Specific ligands modeled included protonated models of morphine, morphine BC1, morphine BC2, and morphine BC3 derivatives. Out of the different ligands, protonated models of morphine BC2 and BC3 demonstrated the best docking affinity with the least ligand strain. These docking results provide critical groundwork for selecting derivatives with optimal receptor complementarity to guide future synthesis of non-addictive opioid analogs
The Erosion of Credibility: How Government Control Shapes Distrust in Journalism
No full textIn the past few months, talk show hosts have been canceled for speaking out against the president, deepfakes and AI have become more accessible, there has been an increase in propaganda and state-sponsored media, and through all this, we have seen a continuous increase in government control. All of these factors offer potential explanations as to why there has been an increased distrust and loss of respect regarding journalism throughout the United States in recent years. This research aims to demonstrate that when the government heavily monitors and controls the country, Americans are less likely to trust the media and journalists. This paper will examine the growing issue of media distrust, with a primary focus on how government control of the press contributes to a heightened lack of trust in journalistic credibility. The data for this research were obtained from the American National Election Survey. These trends will be shown by analyzing political affiliation, government trust, and media trust/consumption, alongside comparisons of governmental control of the media over time. The findings have shown that with greater government control over the country, people trust the media and journalists less, fearing repercussions from the government for expressing their own thoughts and opinions. This information is vital to study to grasp the urgency of this matter and understand the consequences of the American people not having a reliable way to obtain information
Kind Kids, Healthy Teens: Child Prosociality and Fruit and Vegetable Intake
No full textIntroduction Prosocial behaviors (i.e., being kind, caring, and cooperative) are believed to shape health and well-being starting in childhood. Yet, limited research has examined their long-term impact on health outcomes later in life. This study examined associations between childhood prosocial behaviors and fruit and vegetable consumption patterns across adolescence. Methods Participants were from the United Kingdom Millennium Cohort Study (N=6,265). Caregivers reported children’s prosocial behaviors using the Strengths and Difficulties Questionnaire at ages 5 (2005–2007), 7 (2007–2009), and 11 (2011–2013) years. In 2024, Poisson regression was conducted to assess the associations between prosocial behaviors at age 5 years and sustained healthy levels of self-reported fruit and vegetable consumption across ages 14 (2014–2016) and 17 (2017–2019) years, defined as eating ≥2 portions of each daily. To evaluate heterogeneity by developmental stage, secondary analyses considered associations with prosocial behaviors at ages 7 and 11 years. All analyses adjusted for relevant confounders. Results More engagement in prosocial behaviors at age 5 years was associated with a greater likelihood of sustaining healthy fruit and vegetable consumption over time (adjusted prevalence ratio per 1 SD=1.14; 95% CI=1.02, 1.27). Comparable associations were observed with prosocial behaviors at ages 7 (adjusted prevalence ratio per 1 SD=1.12; 95% CI=1.03, 1.23) and 11 (adjusted prevalence ratio per 1 SD=1.13; 95% CI=1.03, 1.24) years. Conclusions Greater engagement in prosocial behaviors was related to healthy fruit and vegetable consumption patterns across adolescence with comparable associations when prosocial behaviors were measured at ages 5, 7, and 11 years. These findings suggest fostering prosociality throughout childhood may be a novel intervention strategy to promote healthy eating
AI-Based Mapping of Offshore Wind Energy Around the Korean Peninsula Using Sentinel-1 SAR and Numerical Weather Prediction Data
No full textOffshore wind farm projects are being promoted in the seas surrounding the Korean Peninsula to secure renewable energy. To support site selection, offshore wind resource maps were generated using deep neural networks trained on Sentinel-1 SAR imagery, numerical weather prediction data, offshore wind observations, sea surface temperature, and bathymetry. The deep neural network (DNN) framework consisted of six sub-models targeting eastward and northward wind components across three regions—the Yellow Sea, Korea Strait, and East Sea—to account for spatial heterogeneity. The proposed models outperformed existing approaches, achieving mean absolute errors (MAE) ranging from 1.31 to 1.69 m/s and correlation coefficients (CC) between 0.827 and 0.913. These DNN models were then applied to produce offshore wind energy maps at a 150 m resolution, effectively capturing seasonal and regional variability. The resulting high-resolution maps provide valuable insights for evaluating the suitability of existing wind farm sites and identifying potential new candidates
Abnormalities in Sensorimotor Brain Function are Related to Chronicity of Low Back Pain
No full textMaladaptive plasticity in the brain may contribute to chronic low back pain (LBP) and underlie the altered postural control of the lumbopelvic musculature that is evident in some individuals with LBP. We recently described an MRI-compatible leg-raise paradigm to measure brain activity associated with lumbopelvic postural control. The objective of this study was to compare brain function in young adults with and without a history of LBP and to determine relationships between brain function, pain, and postural control characteristics. We recruited 55 participants with a history of LBP, who were asymptomatic when studied, and 30 healthy controls. Postural control during leg-raise tasks were quantified using electromyography and ground reaction forces. Group differences in movement-related brain activation during the leg-raise tasks were assessed with fMRI and associations among brain activation, postural control, and pain characteristics were examined. Compared with controls, participants with LBP had greater activation in the angular gyri, posterior cingulate cortices; and greater peak signal change in the right angular gyrus, right pre-central gyrus, and left globus pallidus. Abnormal postural control was associated with greater activation in right pre-central gyrus and left posterior cingulate cortex. Worse pain characteristics associated with less activation in left posterior cingulate cortex and more activation in right angular gyrus. Pathological changes in movement-related brain function are evident early in the time-course of LBP, persist between symptomatic episodes, and associate with clinical characteristics. These findings suggest biomarkers of dysfunction in pain-related circuits associated with LBP and have implications for pathophysiology of this condition
Hepatocyte-Specific LRP1 Silencing Exacerbates Brain Amyloidosis Without Compensatory LDL Receptor Family Involvement
No full textBackground
LDL receptor related protein 1 (LRP1) is a major hepatic receptor involved in lipoprotein metabolism, protease degradation, transmembrane receptor modulation, and clearance of excess protein, such as Aβ. Decreased expression of LRP1 due to liver injury can impair receptor-mediated clearance, increasing Aβ availability in the periphery. We investigated the effects of hepato-specific silencing of LRP1 on Aβ deposition in the brain. Additionally, other LDL family members (LRP5, LRP6, and LDLR) that may participate in Aβ clearance were monitored in the liver to ensure non-compensatory effects of LRP1 silencing. Method
4-month-old male double transgenic (APP/PS1) AD mice were injected with adeno-associated virus 8 (AAV8) containing microRNA targeting LRP1 (LRP1-silenced) or LacZ (control). (n = 6-7 per group). Organs were harvested 12- and 28-weeks post injection, homogenized and assayed using western blotting. Western blots of liver homogenates were probed for LDL receptor related proteins (LDLR, LRP1, LRP5, LRP6), receptors involved in Aβ clearance (RAGE, MDR1), and AD biomarkers (APOE). Beta-actin and GDH were used as loading controls. Brain and liver Aβ were quantified using sandwich enzyme-linked immunosorbent assays (ELISA). Result
Hepatic LRP1 was silenced \u3e80% in both 12- and 28-week mouse samples (p≤0.05) compared to AAV8 LacZ control. Hepato-specific LRP1 silencing significantly increased TBS-soluble mouse (mAβ42) and human (hAβ42) amyloid beta levels in the brain and hAβ42 in the periphery (p≤0.05). No significant change in hepatic MDR1 or APOE expression was observed. Hepatic APP showed a non-significant increasing trend in expression with LRP1 silencing. Hepatic LDL receptor family proteins did not show significant changes at 12- or 28-weeks. Conclusion
Hepatic LRP1-mediated clearance of peripheral Aβ plays an important role in mitigating brain amyloidosis. Hepatic downregulation of LRP1 in AD mice correlates with increased brain amyloidosis that is neither the result of compensation in other hepatic LDL receptors nor changes in receptors involved in Aβ clearance. Hepatic LRP1 specifically may hold promise as a therapeutic target, especially in conditions resulting in liver damage and hepatic LRP1 reduction such as obesity and alcoholism, known modifiable risk factors for AD
Selenium Nanoparticles as Versatile Delivery Tools
No full textSelenium nanoparticles (SeNPs) have emerged as promising metal-based nanoparticles for drug delivery due to their unique physicochemical properties, intrinsic bioactivity, and biocompatibility. SeNPs offer a lower toxicity, higher bioavailability, and flexibility to be customized for surface chemistry compared to traditional selenium compounds. Advances in synthetic strategies, including chemical reduction, green biosynthesis, and surface functionalization with polymers, peptides, or ligands, have improved their stability, targeting capability, and circulation time. SeNP-based systems have demonstrated unique anticancer, antimicrobial, and anti-inflammatory activities, as they can function as drug carriers and active therapeutic agents. The surface of SeNPs has been functionalized with ligands such as Arginylglycylaspartic acid (RGD) peptides, hyaluronic acid, or chitosan to enhance their receptor-mediated targeting abilities in tumor tissues. In addition, SeNPs have shown a synergistic effect in the presence of drugs such as doxorubicin and paclitaxel. Even though SeNPs have demonstrated significant potential in pre-clinical investigations, their use in clinical studies has not been expanded due to several limiting challenges, including large-scale production, long-term safety, pharmacokinetic properties, and regulations required for FDA approval. Continued research into optimizing formulation strategies and expanding in vivo validation will be critical to translating SeNP-based drug delivery systems into clinical applications. In this review, we focus on the methods for synthesizing SeNPs, their physicochemical properties, the structure of ligands attached to SeNPs for drug delivery applications, and the specific biological targets of functionalized SeNPs
GPU-accelerated Effective Hamiltonian Calculator
No full textEffective Hamiltonian calculations for large quantum systems can be both analytically intractable and numerically expensive using standard techniques. In this manuscript, we present numerical techniques inspired by Nonperturbative Analytical Diagonalization (NPAD) and the Magnus expansion for the efficient calculation of effective Hamiltonians. While these tools are appropriate for a wide array of applications, we here demonstrate their utility for models that can be realized in circuit-QED settings. Our numerical techniques are available as an opensource Python package, qCHeff, which is available on GitHub (https://github.com/ NVlabs/qCHeff) and PyPI (https://pypi.org/ project/qcheff/). We use the CuPy library for GPU-acceleration and report up to 15x speedup on GPU over CPU for NPAD, and up to 42x speedup for the Magnus expansion (compared to QuTiP), for large system sizes
Brain Delivery of Erythropoietin Results in a Significant Reduction of Brain Aβ and Spatial Memory Deficits in the APP Knock-in Mouse Model
Get PDFBackground
Although novel treatments for Alzheimer’s disease (AD) have begun to show modest therapeutic effects, agents that target hallmark AD pathology and offer neuroprotection are desired. Erythropoietin (EPO) is a glycoprotein hormone with neuroprotective effects but is faced with challenges including limited brain uptake and increased hematopoietic side effects with long-term dosing. Therefore, EPO has been modified and bound to a chimeric transferrin receptor monoclonal antibody (cTfRMAb); the latter shuttles EPO past the blood-brain barrier (BBB) into brain parenchyma and reduces its plasma exposure and potential for side effects. Our study sought to characterize the safety and pharmacokinetics (PK) of modified EPO following chronic dosing in healthy mice, and then utilize the optimized dose in mitigating hallmark AD pathologies in APP-SAA knock-in (KI) mice, a model that recapitulates Aβ pathology in the absence of APP overexpression, in vivo. Methods
For the PK and safety study, a multidose design was employed with 10-week-old C57BL/6 male mice (n = 4-5/dose) receiving doses ranging from 1- to 20-mg/kg SQ for 4 weeks, aimed to evaluate the dose-dependent plasma concentrations, and metabolic and hematologic safety of the modified EPO. The dose that resulted in the highest safety and sustained plasma exposure was dosed SQ to 5.5-month-old male APP-SAA KI mice (n = 6) for 14 weeks. Control APP-SAA KI mice (n = 5) received vehicle. The effect of modified EPO on Aβ load by immunoassays, and spatial memory via Y-maze test, were assessed. Results
The 1mg/kg dose resulted in no adverse effects and sustained plasma exposure which are conducive to longitudinal dosing. APP-SAA KI mice treated with the modified EPO had a remarkable (70-80%, p\u3c0.001) reduction in 6E10-positive-Aβ plaque area and number in the brain. Aggregated Aβ measured by ELISA was also significantly lower (p\u3c0.05) with modified EPO treatment. Modified EPO increased the discrimination index for the novel arm (p\u3c0.05), suggesting an improvement in spatial memory recall of the reinforced arm of the maze. Conclusions
These findings provide essential data for dose optimization for longitudinal studies using cTfRMAb-based therapeutics, and specifically modified EPO used herein, and illustrate the therapeutic potential of the brain-penetrating cTfRMAb-EPO in a novel AD mouse model devoid of APP overexpression
Restitution of Jewish Property in Northern Transylvania During the Early Postwar Years
Get PDFThe restitution of Jewish property in the multiethnic region of Northern Transylvania faced numerous challenges during the first post-Holocaust years as a result of the complicated wartime history, postwar demographics, legal status, interethnic dynamics, and occasional violence. Having the lowest rate of survival among all Jewish communities in Romania, most of the region’s Jews died during the deportation and did not return to their native places to claim their properties. This impacted the extent of restitution of individual private property. Some of the Aryanized property was restituted to the Jewish survivors or their heirs because the wartime beneficiaries fled the country or renounced posession since they were afraid of potential negative consequences. Part of the restitution took place through court litigation and this gives researchers a chance to assess the extent of Jewish success in obtaining restitution. The Supreme Court decisions in restitution cases show that the Jewish plaintiffs were completely successful in their litigation based on law 645/1945 that cancelled the transactions with property Aryanized during the Hungarian rule of Northern Transylvania. This was a much higher success rate, compared to the general share of success for Jewish litigation at the entire country level – around 66 %