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The proposed deep space exploration to the moon and later to Mars will result in astronauts receiving significant chronic exposures to space radiation (SR). SR exposure results in multiple neurocognitive impairments. Recently, our cross-species (mouse/rat) studies reported impaired associative memory formation in both species following a chronic 6-month low dose exposure to a mixed field of neutrons (1 mGy/day for a total dose pf 18 cGy). In the present study, we report neutron exposure induced synaptic plasticity in the medial prefrontal cortex, accompanied by microglial activation and significant synaptic loss in the hippocampus. In a parallel study, neutron exposure was also found to alter fluorescence assisted single synaptosome LTP (FASS-LTP) in the hippocampus of rats, that may be related to a reduced ability to insert AMPAR into the post-synaptic membrane, which may arise from increased phosphorylation of the serine 845 residue of the GluA1 subunit. Thus, we demonstrate for the first time, that low dose chronic neutron irradiation impacts homeostatic synaptic plasticity in the hippocampal-cortical circuit in two rodent species, and that the ability to successfully encode associative recognition memory is a dynamic, multicircuit process, possibly involving compensatory changes in AMPAR density on the synaptic surface.

Preeclampsia (preE) is a severe multisystem hypertensive syndrome of pregnancy associated with ischemia/hypoxia, angiogenic imbalance, apolipoprotein E (ApoE)-mediated dyslipidemia, placental insufficiency, and inflammation at the maternal–fetal interface. Our recent data further suggest that preE is associated with impaired autophagy, vascular dysfunction, and proteinopathy/tauopathy disorder, similar to neurodegenerative diseases such as Alzheimer's disease (AD), including the presence of the cis stereo-isoform of phosphorylated tau (cis P-tau), amyloid-β, and transthyretin in the placenta and circulation. This review provides an overview of the factors that may lead to the induction and accumulation of cis P-tau-like proteins by focusing on the inactivation of peptidyl-prolyl cis–trans isomerase (Pin1) that catalyzes the cis to trans isomerization of P-tau. We also highlighted the novel role of the Pin1-cis P-tau-ApoE axis in the development of preE, and propagation of cis P-tau-mediated abnormal protein aggregation (tauopathy) from the placenta to cerebral tissues later in life, leading to neurodegenerative conditions. In the case of preE, proteinopathy/tauopathy may interrupt trophoblast differentiation and induce cell death, similar to the events occurring in neurons. These events may eventually damage the endothelium and cause systemic features of disorders such as preE. Despite impressive research and therapeutic advances in both fields of preE and neurodegenerative diseases, further investigation of Pin1-cis P-tau and ApoE-related mechanistic underpinnings may unravel novel therapeutic options, and new transcriptional and proteomic markers. This review will also cover genetic polymorphisms in the ApoE alleles leading to dyslipidemia induction that may regulate the pathways causing preE or dementia-like features in the reproductive age or later in life, respectively. [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) and spinocerebellar ataxia type 3 (SCA3) are the two most prevalent polyglutamine (polyQ) neurodegenerative diseases, caused by CAG (encoding glutamine) repeat expansion in the coding region of the huntingtin (HTT) and ataxin-3 (ATXN3) proteins, respectively. We have earlier reported that the activity, but not the protein level, of an essential DNA repair enzyme, polynucleotide kinase 3'-phosphatase (PNKP), is severely abrogated in both HD and SCA3 resulting in accumulation of double-strand breaks in patients' brain genome. While investigating the mechanistic basis for the loss of PNKP activity and accumulation of DNA double-strand breaks leading to neuronal death, we observed that PNKP interacts with the nuclear isoform of 6-phosphofructo-2-kinase fructose-2,6-bisphosphatase 3 (PFKFB3). Depletion of PFKFB3 markedly abrogates PNKP activity without changing its protein level. Notably, the levels of both PFKFB3 and its product fructose-2,6 bisphosphate (F2,6BP), an allosteric modulator of glycolysis, are significantly lower in the nuclear extracts of postmortem brain tissues of HD and SCA3 patients. Supplementation of F2,6BP restored PNKP activity in the nuclear extracts of patients' brain. Moreover, intracellular delivery of F2,6BP restored both the activity of PNKP and the integrity of transcribed genome in neuronal cells derived from the striatum of the HD mouse. Importantly, supplementing F2,6BP rescued the HD phenotype in Drosophila, suggesting F2,6BP to serve in vivo as a cofactor for the proper functionality of PNKP and thereby, of brain health. Our results thus provide a compelling rationale for exploring the therapeutic use of F2,6BP and structurally related compounds for treating polyQ diseases. [ABSTRACT FROM AUTHOR]

Amino-1,8-naphthalimides are a sought-after class of materials due to their optoelectronic properties. This work demonstrates the application of CuO/CaO for a chemoselective synthesis of amino-1,8-naphthalimide fluorophores from the corresponding nitro-analogues with 100% conversion and selectivity. The reaction was completed in 10 min in isopropyl alcohol using hydrazine hydrate as a reducing agent at 80 °C. The material was characterized using XRD, FT-IR, SEM, TEM, and adsorption techniques. The product, 4-amino-1,8-naphthalimides, was characterized by using NMR (1H and 13C), LCMS, and photophysical properties were measured in DCM at 298 K.

Alzheimer's disease (AD) is the most common age-associated neurodegenerative disorder, characterized by progressive cognitive decline, memory impairment, and structural brain changes, primarily involving Aβ plaques and neurofibrillary tangles of hyperphosphorylated tau protein. Recent research highlights the significance of smaller Aβ and Tau oligomeric aggregates (AβO and TauO, respectively) in synaptic dysfunction and disease progression. Calcineurin (CaN), a key calcium/calmodulin-dependent player in regulating synaptic function in the central nervous system (CNS) is implicated in mediating detrimental effects of AβO on synapses and memory function in AD. This study aims to investigate the specific impact of CaN on both exogenous and endogenous TauO through the acute and chronic inhibition of CaN. We previously demonstrated the protective effect against AD of the immunosuppressant CaN inhibitor, FK506, but its influence on TauO remains unclear. In this study, we explored the short-term effects of acute CaN inhibition on TauO phosphorylation and TauO-induced memory deficits and synaptic dysfunction. Mice received FK506 post-TauO intracerebroventricular injection and TauO levels and phosphorylation were assessed, examining their impact on CaN and GSK-3β. The study investigated FK506 preventive/reversal effects on TauO-induced clustering of CaN and GSK-3β. Memory and synaptic function in TauO-injected mice were evaluated with/without FK506. Chronic FK506 treatment in 3xTgAD mice explored its influence on CaN, Aβ, and Tau levels. This study underscores the significant influence of CaN inhibition on TauO and associated AD pathology, suggesting therapeutic potential in targeting CaN for addressing various aspects of AD onset and progression. These findings provide valuable insights for potential interventions in AD, emphasizing the need for further exploration of CaN-targeted strategies. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is the memory‐related neurodegenerative disorder, contributing to 70% of the cases globally. Synaptic dysfunction is a well‐known early event that causes progressive cognitive decline in AD. The latest AD therapeutics on the forefront only offer a moderate symptomatic relief with significant off‐target effects. Therefore, understanding the mechanism for AD pathogenesis and developing novel therapeutic targets are urgently needed. Our lab has recently reported an anomalistic increase in phospholipase D isoform 1 (PLD1), that breakdown phospholipids in AD postmortem brain samples, compared to control subjects. Moreover, the effect of elevated PLD1 driven by amyloid‐β and tau deposits has been well‐established in wild type and in 6‐month‐old 3xTg‐AD model mice. In the present study, we assess the novel role of PLD1 in modulating cellular mechanisms involved in synaptic dysfunction in AD. Method: Here, we studied the spatial and temporal expression of PLD1 in 3xTg‐AD model mice, treated with a small molecule PLD1 inhibitor (VU0155069), in an age‐dependent manner. Furthermore, the brain‐region specific mechanisms of PLD1 were evaluated by utilizing adeno‐associated viral 2 (AAV2) vectors via intracerebroventricular route in 18‐ and 24‐month‐old wild‐type and 3xTg‐AD model mice. Following VU0155069/AAV2 administration, the mice cohorts were subjected to behavioral studies specific to learning and memory, such as Y‐maze, novel object recognition (NOR), and elevated plus maze. Synaptic dysfunctions were studied using high frequency stimulation long‐term potentiation (HFS‐LTP), by conventional electrophysiology and multi‐electrode array (MEA). Finally, the synaptic strength in frozen synaptosomal (P2) fractions was determined by previously standardized novel in vitro assay called the Fluorescence‐Assisted Single Synaptosome‐Long Term Potentiation (FASS‐LTP). Morphological changes in the synapse were assessed using ImageJ and IMARIS following Golgi‐Cox staining, a gold standard for measuring dendritic spine integrity. To deduce the underlying mechanisms, we used brain spheroids developed from human tissue to test the effects of PLD1 inhibition. Result: In WT aged mice we noted differential effects of PLD1 over expression and attenuation. Additionally, we corroborate our results with diseased aging seen in 3xTg‐AD using pharmacological and molecular approaches with AAV2 vectors. Conclusion: Our research provides a novel insight into how PLD1 contributes to progressive functional deficits associated with synaptic dysfunction by impinging on critical cellular signaling events compromised in early and late stages of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Occurrence of Multiple Primary Malignancies (MPM) in an individual is an uncommon phenomenon. It can occur synchronously or metachronously, and the incidence ranges from 1 to 16%. There has been a dramatic increase in the incidence of multiple primaries in patients in the last few years. The diagnosis and treatment of these malignancies pose a clinical challenge as there is no consensus on the optimal management of this condition. It is important to distinguish this condition from the metastasis of an existing malignancy as it can alter the treatment and prognosis of these patients. So far, there have been few case reports published in the literature on triple malignancies, and to the best of authors knowledge, no series have been published yet. Here, authors report a series of three patients (one male and two females) who developed three primary malignancies either synchronously or metachronously. The management of all the patients was decided in a multidisciplinary board based on the stage of each disease and patient tolerance. Two of these patients are alive and on regular follow-up, while one patient was lost to followup during treatment. These cases highlight the importance of evaluating and closely following up patients, as well as considering histopathological examination of lesions in unusual sites of metastasis. [ABSTRACT FROM AUTHOR]

Objective: The objective of this research is to determine whether the thermoplastic polyurethane (TPU) coated with carboxymethylcellulose chitosan has better mechanical and antibacterial action (anti-Streptococcus mutans) when utilized in intraoral simulations with synthetic saliva. Materials and Methods: The TPU sheets (n = 45) were divided into three groups. Control (n = 15) consists of as-received TPU sheets. Test 1 consists of TPU sheets coated with carboxymethyl cellulose (CMC) chitosan (CHI) (n = 15). Test 2 consists of thermoformed nano-coated TPU (n = 15). For the polyurethane sheets, CHI-CMC sheets, and thermoformed CHI-CMC sheets, scanning electron microscopy (SEM) and three-point flexural tests were conducted and assessed. The materials testing software was used to calculate the elastic modulus and tensile strength. To study the bacterial accumulation, the cut circles of the TPU aligner were placed in centrifuge tubes with 2.5 mL of bacterial suspension at a concentration of 104 or 105 CFU/mL. SEM was done to assess the presence of cell growth in all three groups. Results: According to SEM analyses of bacterial buildup, the coated TPU had minimal biofilms compared to the bare TPUs numerous biofilms. The effect of aging on coating thickness reveals that the thickness of thermoformed coated TPU films dramatically decreased over time, while the thickness of coated TPU films was maintained. When TPU is coated with CMC/CHI, the elastic modulus and tensile strength were observed to improve. Conclusion: The development of a super-hydrophilic coating by the CHI CMC coating on TPU sheets improved the coating's biocompatibility while also changing the shape of the multilayer film to prevent bacterial adhesion. The effect on the improvement in the mechanical properties diminished after the material underwent a thermoforming process. It is therefore suggested that the nanofilm be used in therapeutic applications following the thermoforming process. [ABSTRACT FROM AUTHOR]

Forty older and 60 younger adults were asked to estimate the level of discount expected in ads. Consumers were skeptical of implausible discounts. Implausible and highly plausible discounts had more influence on price perceptions than did discounts with low plausibility. (SK)