Calcium Bistriflimide-Mediated Sulfur(VI)–Fluoride Exchange (SuFEx): Mechanistic Insights toward Instigating Catalysis

We report a mechanistic investigation of calcium bistriflimide-mediated sulfur(VI)–fluoride exchange (SuFEx) between sulfonyl fluorides and amines. We determine the likely pre-activation resting state─a calcium bistriflimide complex with ligated amines─thus allowing for corroborated calculation of the SuFEx activation barrier at ∼21 kcal/mol, compared to 21.5 ± 0.14 kcal/mol derived via kinetics experiments. Transition state analysis revealed: (1) a two-point calcium-substrate contact that activates the sulfur(VI) center and stabilizes the leaving fluoride and (2) a 1,4-diazabicyclo[2.2.2]octane additive that provides Brønsted-base activation of the nucleophilic amine. Stable Ca–F complexes upon sulfonamide formation are likely contributors to inhibited catalytic turnover, and a proof-of-principle redesign provided evidence that sulfonamide formation is feasible with 10 mol % calcium bistriflimide

Rate of tau propagation is a heritable disease trait in genetically diverse mouse strains.

The speed and scope of cognitive deterioration in Alzheimer\u27s disease is highly associated with the advancement of tau neurofibrillary lesions across brain networks. We tested whether the rate of tau propagation is a heritable disease trait in a large, well-characterized cohort of genetically divergent mouse strains. Using an AAV-based model system, P301L-mutant human tau (hTau) was introduced into the entorhinal cortex of mice derived from 18 distinct lines. The extent of tau propagation was measured by distinguishing hTau-producing cells from neurons that were recipients of tau transfer. Heritability calculation revealed that 43% of the variability in tau spread was due to genetic variants segregating across background strains. Strain differences in glial markers were also observed, but did not correlate with tau propagation. Identifying unique genetic variants that influence the progression of pathological tau may uncover novel molecular targets to prevent or slow the pace of tau spread and cognitive decline

Frontliners on the move : a quantitative analysis of the prevalence of COVID-19 reinfection among healthcare workers

This study was conducted to review relevant articles and demonstrate the prevalence of coronavirus disease 2019 (COVID-19) reinfection among healthcare workers (HCWs). A systemic search was conducted on PubMed and Medline from their inception to July 17, 2021. All statistical analyses were conducted using ReviewManager 5.4.1. Studies meeting the following inclusion criteria were selected: (a) articles having HCWs with COVID-19; (b) studies describing reinfection of COVID-19; and (c) articles having a defined number of patients and controls. Three studies were selected for meta-analysis. The Newcastle- Ottawa Scale (NOS) was used to assess the quality of the cohort studies. NOS scores of 1-5 were considered high risk for bias, scores of 6-7 were deemed moderate, and scores >7 were considered low risk for bias. A random-effect model was used when heterogeneity was seen to pool the studies, and the results were reported in inverse variance (IV) and corresponding 95% confidence interval (CI). Pooled prevalence of reinfection of COVID-19 in HCWs was 3% (OR: 0.03 [-0.04, 0.01]; p=0.44; I2=4%). A non-significant prevalence was found among the healthcare professionals in terms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reinfection in Europe. The preformed antibodies were protective against reinfection. However, the waning of antibodies with respect to time was evident, varying differently in different individuals, thereby resulting in reinfection.https://www.cureus.comam2023Internal Medicin

Sodium Phenylbutyrate Controls Neuroinflammatory and Antioxidant Activities and Protects Dopaminergic Neurons in Mouse Models of Parkinson’s Disease

Neuroinflammation and oxidative stress underlie the pathogenesis of various neurodegenerative disorders. Here we demonstrate that sodium phenylbutyrate (NaPB), an FDA-approved therapy for reducing plasma ammonia and glutamine in urea cycle disorders, can suppress both proinflammatory molecules and reactive oxygen species (ROS) in activated glial cells. Interestingly, NaPB also decreased the level of cholesterol but involved only intermediates, not the end product of cholesterol biosynthesis pathway for these functions. While inhibitors of both geranylgeranyl transferase (GGTI) and farnesyl transferase (FTI) inhibited the activation of NF-κB, inhibitor of GGTI, but not FTI, suppressed the production of ROS. Accordingly, a dominant-negative mutant of p21rac, but not p21ras, attenuated the production of ROS from activated microglia. Inhibition of both p21ras and p21rac activation by NaPB in microglial cells suggests that NaPB exerts anti-inflammatory and antioxidative effects via inhibition of these small G proteins. Consistently, we found activation of both p21ras and p21rac in vivo in the substantia nigra of acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson’s disease. Oral administration of NaPB reduced nigral activation of p21ras and p21rac, protected nigral reduced glutathione, attenuated nigral activation of NF-κB, inhibited nigral expression of proinflammatory molecules, and suppressed nigral activation of glial cells. These findings paralleled dopaminergic neuronal protection, normalized striatal neurotransmitters, and improved motor functions in MPTP-intoxicated mice. Consistently, FTI and GGTI also protected nigrostriata in MPTP-intoxicated mice. Furthermore, NaPB also halted the disease progression in a chronic MPTP mouse model. These results identify novel mode of action of NaPB and suggest that NaPB may be of therapeutic benefit for neurodegenerative disorders

Medicinal plants in traumatic brain injury: Neuroprotective mechanisms revisited

Traumatic brain injury (TBI) is the most prevalent health problem affecting all age groups, and leads to many secondary problems in other organs especially kidneys, gastrointestinal tract, and heart function. In this review, the search terms were TBI, fluid percussion injury, cold injury, weight drop impact acceleration injury, lateral fluid percussion, cortical impact injury, and blast injury. Studies with Actaea racemosa, Artemisia annua, Aframomum melegueta, Carthamus tinctorius, Cinnamomum zeylanicum, Crocus sativus, Cnidium monnieri, Curcuma longa, Gastrodia elata, Malva sylvestris, Da Chuanxiong Formula, Erigeron breviscapus, Panax ginseng, Salvia tomentosa, Satureja khuzistanica, Nigella sativa, Drynaria fortune, Dracaena cochinchinensis, Polygonum cuspidatum, Rosmarinus officinalis, Rheum tanguticum, Centella asiatica, and Curcuma zedoaria show a significant decrease in neuronal injury by different mechanisms such as increasing superoxide dismutase and catalase activities, suppressing nuclear factor kappa B (NF‐κB), interleukin 1 (IL‐1), glial fibrillary acidic protein, and IL‐6 expression. The aim of this study was to evaluate the neuroprotective effects of medicinal plants in central nervous system pathologies by reviewing the available literature

Magnetic Resonance Induced Heating in a Vascular Stent

It is standard hospital practice to remove metallic objects from patients prior to MRIs. Since magnetic resonance imaging employs changing magnetic fields, even everyday items such as jewelry or keys run the risk of overheating due to induced currents leading to Joule heating. A potential problem arises, however, when the metal is subcutaneously located in the form of a medical implant. The present study evaluated this scenario by using finite element analysis to model a vascular stent under the influence of a standard MRI field. COMSOL Multiphysics software was used to conduct finite element analysis on two different stent sizes, each in the presence and absence of blood flow. The stents were modeled as stainless steel (type 316L) with internal diameters of 5mm and 8mm, length of 40mm, and wall thicknesses of 0.18mm and 0.22mm. The tests revealed that under the influence of blood cooling, the stents modeled did not overheat or cause arterial damage. Specifically, the large stent resulted in a maximum temperature of 310.807 K and the smaller stent led to 310.230 K, each after 30 minutes of heating. In the unrealistic absence of blood flow, the large and small stents reached maximum temperatures of 318.851 K and 312.297 K respectively. Ultimately, given variance in blood flow the true solutions lie somewhere in between the blood perfusion and static flow models

Combined Use of Guanfacine and N-Acetylcysteine for the Treatment of Cognitive Deficits After Traumatic Brain Injury

Traumatic Brain Injury (TBI) is a significant contributor to disability across the world. TBIs vary in severity, and most cases are designated mild TBI (mTBI), involving only brief loss of consciousness and no intracranial findings on imaging. Despite this categorization, many persons continue to report persistent cognitive changes in the months to years after injury, with particular impairment in the cognitive and executive functions of the pre-frontal cortex. For these persons, there are no currently approved medications, and treatment is limited to symptom management and cognitive or behavioral therapy. The current case studies explored the use of the alpha-2A adrenoreceptor agonist, guanfacine, combined with the antioxidant, N-acetylcysteine (NAC), in the treatment of post-TBI cognitive symptoms, based on guanfacine's ability to strengthen pre-frontal cortical function, and the open-label use of NAC in treating TBI. Two persons from our TBI clinic were treated with this combined regimen, with neuropsychological testing performed pre- and post-treatment. Guanfacine + NAC improved attention, processing speed, memory, and executive functioning with minimal side effects in both persons. These results encourage future placebo-controlled trials to more firmly establish the efficacy of guanfacine and NAC for the treatment of cognitive deficits caused by TBI