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Un’accurata analisi, fondata sulle evidenze morfonologiche dell’etrusco, conferma ancor oggi l’omonimia delle forme del genitivo marcate con il suffisso -ia (con varianti) aggiunto a prenomi maschili con terminazioni che selezionano tale morfo o a prenomi femminili caratterizzati dalla presenza del suffisso di mozione -i. In particolare, nel caso della tomba Regolini-Galassi, essendo impiegato, per le formule di possesso, il solo prenome in genitivo, senza “nome aggiunto” o altri elementi potenzialmente disambiguanti, permane l’indecidibilità, per quanto concerne il piano epigrafico-linuistico, sullo scioglimento di larθia come genitivo del maschile Larθ o del femminile Larθi. An accurate analysis, based on morphonological evidence, still confirms the homonymy of the Etruscan genitive forms -ia added to masculine first names with endings that select this morph or to feminine first names characterized by the presence of the gender suffix -i. In particular, in the case of the Regolini-Galassi tomb, since only the forename in genitive is used for the formulas of possession, without any “added name” or other potentially disambiguating elements, the undecidability remains, as far as the epigraphic-linguistic level is concerned, on the interpretation of larθia as genitive of the masculine Larθ or the feminine Larθi.

(1) Background: Extravasation injuries in pediatric patients can lead to significant harm if they are not promptly diagnosed and treated. However, evidence-based standardization on extravasation management remains limited, particularly for extensive wound necrosis. This case report presents the management of an 8-week-old premature patient with an extensive extravasation injury involving the right forearm and dorsum of the hand. (2) Methods: The patient was evaluated by a multidisciplinary team in our Neonatal Intensive Care Unit. Surgical intervention involved the debridement of necrotic tissues, followed by temporary coverage with an acellular dermal matrix. Definitive coverage was achieved through Meek micrografting after three weeks. Physical therapy was provided with pre- and post-rehabilitation range of motion assessed using goniometric measurements. Scar quality was evaluated using the Vancouver Scar Scale. (3) Results: The engraftment rate of the Meek micrografts was 93%, with 16 out of 226 micrografts lost. The patient achieved a Vancouver Scar Scale score of 6, indicating a moderate degree of scarring. Significant improvements in elbow, wrist, and finger joint range of motion were observed at a 1-year follow-up. (4) Conclusions: Close observation and heightened awareness of extravasation risks by trained personnel are crucial. Meek micrografting combined with dermal substitute coverage represents an innovative approach to managing extravasation wounds in pediatric patients.

Abstract Spatially encoded measurements of transient optical transmissivity became a standard tool for temporal diagnostics of free-electron-laser (FEL) pulses, as well as for the arrival time measurements in X-ray pump and optical probe experiments. The modern experimental techniques can measure changes in optical coefficients with a temporal resolution better than 10 fs. This, in an ideal case, would imply a similar resolution for the temporal pulse properties and the arrival time jitter between the FEL and optical laser pulses. However, carrier transport within the material and out of its surface, as well as carrier recombination may, in addition, significantly decrease the number of carriers. This would strongly affect the transient optical properties, making the diagnostic measurement inaccurate. Below we analyze in detail the effects of those processes on the optical properties of XUV and soft X-ray irradiated Si $${_3}$$ 3 N $$_4$$ 4 , on sub-picosecond timescales. Si $${_3}$$ 3 N $$_4$$ 4 is a wide-gap insulating material widely used for FEL pulse diagnostics. Theoretical predictions are compared with the published results of two experiments at FERMI and LCLS facilities, and with our own recent measurement. The comparison indicates that three body Auger recombination strongly affects the optical response of Si $${_3}$$ 3 N $$_4$$ 4 after its collisional ionization stops. By deconvolving the contribution of Auger recombination, in future applications one could regain a high temporal resolution for the reconstruction of the FEL pulse properties measured with a Si $${_3}$$ 3 N $$_4$$ 4 -based diagnostics tool.

Bioactive dietary polyphenols in grape (Vitis vinifera) have been used in Dietary Supplements (DSs) with the aim to prevent numerous diseases, including cardiovascular and neurodegenerative diseases, and to reduce depression and anxiety. Given prior recognition that DSs can be quality challenged from the purity, authentication, adulteration, and actual concentration of targeted bioactives, to ensure consumer health protection as well as the quality and safety of grape polyphenol-based DSs, the present investigation was aimed at establishing a comprehensive quality control (QC) approach for grape polyphenol-based DSs in support of a human clinical study. In this study, the manufactured grape seed polyphenol extract (GSPE) and trans-resveratrol (RSV) capsules and Concord Grape Juice (CGJ) along with the corresponding original drug materials were analyzed using the developed different liquid chromatography/UV-visible spectroscopy/mass spectrometry (LC/UV-Vis/MS) methods. The weight variation of GSPE and RSV capsules was also evaluated according to the US Pharmacopeia (USP) tests. The results indicate that the total identified polyphenol content in each grape seed extract (GSE) capsule/CGJ is very similar and all GSE/RSV capsules pass the content/weight uniformity test. Given the complexity of these and many botanical products from the issues of purity, quality, adulteration, consistency, and their coupling to the complex chemistry in each grape-derived botanical, quality assurance and the steps needed to ensure grape-derived DSs being well homogeneous and stable and containing the known and expected bioactives at specific concentration ranges are fundamental to any research study and in particular to a clinical trial. Each of these issues is essential to provide a solid foundation upon which clinical trials with botanicals can be conducted with the goal of realizing measurable mental health outcomes such as reducing depression and anxiety as well as understanding of their underlying biological mechanisms.

Methods for a dissolution study by ultra-high performance liquid chromatography/triple quadrupole mass spectrometry (UHPLC-QqQ/MS) analysis of grape polyphenol dietary supplements, namely, grape seed extract (GSE) and resveratrol (RSV) capsules, were developed following the guidance of United States Pharmacopeia (USP) . Two dissolution media, 0.1 N hydrochloric acid (pH 1.2) and 0.05 M acetate buffer (pH 4.6), were evaluated with dissolution apparatus (USP 1), 100 rpm rotation speed, and 900 ml dissolution medium volume. Dissolution profiling was performed over 120 min. Major phenolic compounds of gallic acid, catechin, epicatechin, and procyanidin B2 were quantitated to obtain the dissolution profile of GSE capsules, and trans-RSV was used for RSV capsules. Results indicated that the released trans-RSV for RSV capsules in both of the dissolution media meets the USP standards, and that for the GSE capsules, all the four marker compounds passed the dissolution test in the HCl medium but did not reach a 75% release within 60 min in the acetate buffer. These promising results suggest that the general USP dissolution protocols are adequate for the successful release of RSV capsules in HCl medium and acetate buffer and GSE capsules (in HCl medium), but may be inadequate for GSE capsules in acetate buffer. These results showed that under a low pH of 1.2 (simulated stomach environment), bioactive compounds were released on time from the GSE capsules and met the USP guidelines; however, under a higher pH of 4.6 (simulated duodenum environment), the same biomarkers failed, suggesting the need to further improve the dissolution of GSE over a wider range of pH environments to enhance bioavailability and efficacy.

Mitochondrial dysfunction is a key mechanism of cell death in hypoxic-ischemic brain injury. Neuronal pentraxin 1 (NP1) has been shown to play crucial roles in mitochondria-mediated neuronal death. However, the underlying mechanism(s) of NP1-induced mitochondrial dysfunction in hypoxia-ischemia (HI) remains obscure. Here, we report that NP1 induction following HI and its subsequent localization to mitochondria, leads to disruption of key regulatory proteins for mitochondrial biogenesis. Brain mitochondrial DNA (mtDNA) content and mtDNA-encoded subunit I of complex IV (mtCOX-1) expression was increased post-HI, but not the nuclear DNA-encoded subunit of complex II (nSDH-A). Up-regulation of mitochondrial proteins COXIV and HSP60 further supported enhanced mtDNA function. NP1 interaction with active Bax (Bax6A7) was increased in the brain after HI and in oxygen-glucose deprivation (OGD)-induced neuronal cultures. Importantly, NP1 colocalized with mitochondrial hexokinase II (mtHKII) following OGD leading to HKII dissociation from mitochondria. Knockdown of NP1 or SB216763, a GSK-3 inhibitor, prevented OGD-induced mtHKII dissociation and cellular ATP decrease. NP1 also modulated the expression of mitochondrial transcription factor A ( Tfam ) and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), regulators of mitochondrial biogenesis, following HI. Together, we reveal crucial roles of NP1 in mitochondrial biogenesis involving interactions with Bax[6A7] and mtHKII in HI brain injury.

Chronic stress manifests as depressive- and anxiety-like behavior while recurrent stress elicits disproportionate behavioral impairments linked to stress-induced immunological priming. The gut-brain-microbiota-axis is a promising therapeutic target for stress-induced behavioral impairments as it simultaneously modulates peripheral and brain immunological landscapes. In this study, a combination of probiotics and prebiotics, known as a synbiotic, promoted behavioral resilience to chronic and recurrent stress by normalizing gut microbiota populations and promoting regulatory T cell (Treg) expansion through modulation of ileal innate lymphoid cell (ILC)3 activity, an impact reflecting behavioral responses better than limbic brain region neuroinflammation. Supporting this conclusion, a multivariate machine learning model correlatively predicted a cross-tissue immunological signature of stress-induced behavioral impairment where the ileal Treg/T helper17 cell ratio associated to hippocampal chemotactic chemokine and prefrontal cortex IL-1β production in the context of stress-induced behavioral deficits. In conclusion, stress-induced behavioral impairments depend on the gut-brain-microbiota-axis and through ileal immune regulation, synbiotics attenuate the associated depressive- and anxiety-like behavior.

Objectives:. To determine the disease-free survival (DFS), disease-specific survival (DSS), and recurrence in patients who underwent laparoscopic low anterior rectal resection with total mesorectal excision (TME) with either high or low ligation of the inferior mesenteric artery (IMA). Background:. The level of IMA ligation during anterior rectal resection with TME is still a matter of debate, especially in terms of oncological adequacy. Methods:. Between June 2014 and December 2016, patients scheduled to undergo elective laparoscopic low anterior resection (LAR) and TME in 6 Italian nonacademic hospitals were randomized into 2 groups in the HIGHLOW Trial (ClinicalTrials.gov Identifier: NCT02153801) according to the level of IMA ligation: high ligation (HL) versus low ligation (LL). DFS, DSS, and recurrence were inquired. Recurrence was determined at 3, 6, 9, and 12 months and every 6 months thereafter. Patients and tumor characteristics as well as surgical outcomes were analyzed to identify risk factors for recurrence. Results:. One hundred ninety-six patients from the HIGHLOW trial were analyzed. Median follow-up for DFS was 40.6 (interquartile range [IQR], 6–64.7) and 40 (IQR, 7.6–67.8), while median follow-up for DSS was 41.2 (IQR, 10.7–64.7) and 42.7 (IQR, 6–67.6) in the HL and LL groups, respectively. The 3-year DFS rate of HL and LL patients was 82.2% and 82.1% (P = 0.874), respectively. The 3-year DSS for HL and LL patients was 92.1% and 93.4% (P = 0.897), respectively. There was no statistically significant difference in the local recurrence rate (2% HL vs 2.1% LL), in the regional recurrence rate (3% HL vs 2.1% LL), and in the distant recurrence rate (12.9% HL vs 13.7% LL). Multivariate analysis found conversion to open surgery (hazard ratio [HR], 3.68; P = 0.001) and higher stage of disease (HR, 7.73; P < 0.001) to be significant determinant for DFS. Conclusions:. The level of inferior mesenteric artery ligation during LAR and TME for rectal cancer does not affect DFS, DSS, and recurrence.

Introduction The worldview in relation to patient care has shifted from conquering diseases to improving overall wellbeing and quality of life. We examined treatment aspirations among people living with HIV (PLHIV). Methods In all, 2389 PLHIV were surveyed in the 25-country 2019 Positive Perspectives Study. Descriptive and multivariable analyses were used to explore attitudes towards treatment. Results Participants were from: Northern America (USA, Canada), 21.8% (520/2389); Europe, 46.8% (1119/2389); and other international regions, 31.4% (750/2389). Factors associated with some level of dissatisfaction with HIV medication among those otherwise fully satisfied with their HIV management included being on a multi-tablet regimen (AOR=2.76; 95% CI: 1.93–3.96), reporting polypharmacy (AOR=2.10; 95% CI: 1.45–3.03), and experiencing side effects from current HIV medication (AOR=2.12; 95% CI: 1.49–3.02). Of seven improvements to HIV medications assessed, the percentage ranking each attribute, as the first or second most important, was: ‘reduced long-term impact on my body’ (46.7%); ‘longer-lasting medicine so I don’t have to take it every day’ (43.1%); ‘fewer side effects’ (40.5%); ‘less HIV medicine each day but just as effective’ (25.4%); ‘less chance of affecting other medicines’ (21.6%); ‘no food restrictions/ requirements’ (14.0%); and ‘smaller pills’ (8.7%). Overall, 77.1% (1842/2389) believed ‘future advances in HIV treatment will improve my overall wellbeing’, 72.2% (1726/2389) were ‘open to taking an HIV treatment composed of fewer medicines’, while 54.7% (1306/2389) expressed openness towards longer-acting (non-daily) HIV medication. Compared to those not fully satisfied with either their HIV medication or management, those fully satisfied with both reported significantly higher prevalence of optimal treatment adherence (89.2% [372/417] vs 69.5% [763/1098]) and optimal overall health (70.3% [293/417] vs 47.8% [525/1098]) (all p

Misfolding, aggregation and deposition of α-synuclein (α-syn) are major pathologic characteristics of Parkinson’s disease (PD) and the related synucleinopathy, multiple system atrophy (MSA). The spread of α-syn pathology across brain regions is thought to play a key role in the onset and progression of clinical phenotypes. Thus, there is increasing interest in developing strategies that target and attenuate α-syn aggregation and spread. Recent studies of brain-penetrating polyphenolic acids, namely, 3-hydroxybenzoic acid (3-HBA), 3,4-dihydroxybenzoic acid (3,4-diHBA), and 3-(3-hydroxyphenyl)propionic acid (3-HPPA) that are derived from gut microbiota metabolism of dietary polyphenols, show in vitro ability to effectively modulate α-syn misfolding, oligomerization, and mediate aggregated α-syn neurotoxicity. Here we investigate whether 3-HBA, 4-hydroxybenzoic acid (4-HBA), 3,4-diHBA, or 3-HPPA interfere with α-syn spreading in a cell-based system. Using HEK293 cells overexpressing α-syn-A53T-CFP/YFP, we assessed α-syn seeding activity using Fluorescence Resonance Energy Transfer (FRET) to detect and quantify α-syn aggregation. We demonstrated that 3-HPPA, 3,4-diHBA, 3-HBA, and 4-HBA significantly attenuated intracellular α-syn seeding aggregation. To determine whether our compounds could inhibit brain-derived seeding activity, we utilized insoluble α-syn extracted from post-mortem MSA or PD brain specimens. We found that 3-HPPA effectively attenuated MSA-induced aggregation of monomer into high molecular weight aggregates capable of inducing intracellular aggregation. Outcomes from our studies suggest interactions between gut microbiome and certain dietary factors may form the basis for effective therapies that modulate pathologic α-syn propagation. Collectively, our findings provide the basis for future developments of probiotic, prebiotic, or synbiotic approaches for modulating the onset and/or progression of α-synucleinopathies.

Background: HD systems are routinely used in laparoscopic surgery, 4K ultra HD monitors are mainly available within specialized, high-volume laparoscopic centers. The higher resolution of 4K ultra HD video could upgrade the surgical performance improving intraoperative and post-operative outcomes. Methods: We performed a retrospective comparative analysis of intraoperative parameters and post-operative outcomes in a cohort of patients operated on for elective laparoscopic procedures for colo-rectal cancer during two different time frames: 2017 procedures performed using the Visera Elite full HD technology (® Olympus America, Medical) and the 2018 procedures performed the Visera 4K Ultra HD System (® Olympus America, Medical). Results: There was a statistically significant reduction in operative time in patients operated on with the 4K ultra HD technology compared to HD technology (p < 0.05). Intraoperative blood loss was significantly reduced in patients operated in 2018 (p < 0.05). There were no statistically significant differences in complication rate and postoperative outcomes between the two groups.

Chad Smith et al. show that dietary polyphenols, compounds found in grapes, enable mice to remember fearful events more effectively and map this function to the hippocampal dentate gyrus neurons. This study offers a way to identify the cellular subpopulations regulated by dietary polyphenols.

Polyphenols have partial antidepressant effect without known mechanism. Here, the authors identify two phytochemicals from bioactive dietary polyphenols, show their antidepressant effect in a rodent model of depression, and that this effect is mediated by epigenetic and anti-inflammatory mechanisms.

Background: The management of rectal cancer is multimodal and involves a multidisciplinary team of cancer specialists with expertise in medical oncology, surgical oncology, radiation oncology and radiology. It is crucial for highly specialized centers to collaborate via networks that aim to maintain uniformity in every aspect of treatment and rigorously gather patients’ data, from the first clinical evaluation to the last follow-up visit. The Advanced International Mini-Invasive Surgery (AIMS) academy clinical research network aims to create a rectal cancer registry. This will prospectively collect the data of patients operated on for non-metastatic rectal cancer in high volume colorectal surgical units through a well design pre-fashioned database for non-metastatic rectal cancer, in order to take all multidisciplinary aspects into consideration. Methods/Design: The protocol describes a multicenter prospective observational cohort study, investigating demographics, frailty, cancer-related features, surgical and radiological parameters, and oncological outcomes among patients with non-metastatic rectal cancer who are candidates for surgery with curative intent. Patients enrolled in the present registry will be followed up for 5 years after surgery. Discussion: Standardization and centralization of data collection for neoplastic diseases is a virtuous process for patient care. The creation of a register will allow the control of the quality of treatments provided and permit prospective and retrospective studies to be carried out on complete and reliable high quality data. Establishing data collection in a prospective and systematic fashion is the only possibility to preserve the enormous resource that each patient represents.

[This corrects the article DOI: 10.1371/journal.pone.0223435.].

Developing effective therapies for back pain associated with intervertebral disc (IVD) degeneration is a research priority since it is a major socioeconomic burden and current conservative and surgical treatments have limited success. Polyphenols are naturally occurring compounds in plant-derived foods and beverages, and evidence suggests dietary supplementation with select polyphenol preparations can modulate diverse neurological and painful disorders. This study tested whether supplementation with a select standardized Bioactive-Dietary-Polyphenol-Preparation (BDPP) may alleviate pain symptoms associated with IVD degeneration. Painful IVD degeneration was surgically induced in skeletally-mature rats by intradiscal saline injection into three consecutive lumbar IVDs. Injured rats were given normal or BDPP-supplemented drinking water. In-vivo hindpaw mechanical allodynia and IVD height were assessed weekly for 6 weeks following injury. Spinal column, dorsal-root-ganglion (DRG) and serum were collected at 1 and 6 weeks post-operative (post-op) for analyses of IVD-related mechanical and biological pathogenic processes. Dietary BDPP significantly alleviated the typical behavioral sensitivity associated with surgical procedures and IVD degeneration, but did not modulate IVD degeneration nor changes of pro-inflammatory cytokine levels in IVD. Gene expression analyses suggested BDPP might have an immunomodulatory effect in attenuating the expression of pro-inflammatory cytokines in DRGs. This study supports the idea that dietary supplementation with BDPP has potential to alleviate IVD degeneration-related pain, and further investigations are warranted to identify the mechanisms of action of dietary BDPP.

The aggregation and accumulation of amyloid-β plaques and tau proteins in the brain have been central characteristics in the pathophysiology of Alzheimer’s disease (AD), making them the focus of most of the research exploring potential therapeutics for this neurodegenerative disease. With success in interventions aimed at depleting amyloid-β peptides being limited at best, a greater understanding of the physiological role of amyloid-β peptides is needed. The development of amyloid-β plaques has been determined to occur 10–20 years prior to AD symptom manifestation, hence earlier interventions might be necessary to address presymptomatic AD. Furthermore, recent studies have suggested that amyloid-β peptides may play a role in innate immunity as an antimicrobial peptide. These findings, coupled with the evidence of pathogens such as viruses and bacteria in AD brains, suggests that the buildup of amyloid-β plaques could be a response to the presence of viruses and bacteria. This has led to the foundation of the antimicrobial hypothesis for AD. The present review will highlight the current understanding of amyloid-β, and the role of bacteria and viruses in AD, and will also explore the therapeutic potential of antimicrobial and antiviral drugs in Alzheimer’s disease.

Early diagnosis of Alzheimer’s disease (AD) and the identification of significant risk factors are necessary to better understand disease progression, and to develop intervention-based therapies prior to significant neurodegeneration. There is thus a critical need to establish biomarkers which can predict the risk of developing AD before the onset of cognitive decline. A number of studies have indicated that exposure to various microbial pathogens can accelerate AD pathology. Additionally, several studies have indicated that amyloid-β possess antimicrobial properties and may act in response to infection as a part of the innate immune system. These findings have led some to speculate that certain types of infections may play a significant role in AD pathogenesis. In this review, we will provide an overview of studies which suggest pathogen involvement in AD. Additionally, we will discuss a number of pathogen-associated biomarkers which may be effective in establishing AD risk. Infections that increase the risk of AD represent a modifiable risk factor which can be treated with therapeutic intervention. Pathogen-based biomarkers may thus be a valuable tool for evaluating and decreasing AD risk across the population.

As a consequence of the considerable increase in the human lifespan over the last century, we are experiencing the appearance and impact of new age-related diseases. The causal relationships between aging and an enhanced susceptibility of suffering from a broad spectrum of diseases need to be better understood. However, one specific shared feature seems to be of capital relevance for most of these conditions: the low-grade chronic inflammatory state inherently associated with aging, i.e., inflammaging. Here, we review the molecular and cellular mechanisms that link aging and inflammaging, focusing on the role of the innate immunity and more concretely on the nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, as well as how the chronic activation of this inflammasome has a detrimental effect on different age-related disorders.

The aggregation and deposition of α-synuclein (αS) are major pathologic features of Parkinson’s disease, dementia with Lewy bodies, and other α-synucleinopathies. The propagation of αS pathology in the brain plays a key role in the onset and progression of clinical phenotypes. Thus, there is increasing interest in developing strategies that attenuate αS aggregation and propagation. Based on cumulative evidence that αS oligomers are neurotoxic and critical species in the pathogenesis of α-synucleinopathies, we and other groups reported that phenolic compounds inhibit αS aggregation including oligomerization, thereby ameliorating αS oligomer-induced cellular and synaptic toxicities. Heterogeneity in gut microbiota may influence the efficacy of dietary polyphenol metabolism. Our recent studies on the brain-penetrating polyphenolic acids 3-hydroxybenzoic acid (3-HBA), 3,4-dihydroxybenzoic acid (3,4-diHBA), and 3-hydroxyphenylacetic acid (3-HPPA), which are derived from gut microbiota-based metabolism of dietary polyphenols, demonstrated an in vitro ability to inhibit αS oligomerization and mediate aggregated αS-induced neurotoxicity. Additionally, 3-HPPA, 3,4-diHBA, 3-HBA, and 4-hydroxybenzoic acid significantly attenuated intracellular αS seeding aggregation in a cell-based system. This review focuses on recent research developments regarding neuroprotective properties, especially anti-αS aggregation effects, of phenolic compounds and their metabolites by the gut microbiome, including our findings in the pathogenesis of α-synucleinopathies.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder manifesting with upper and lower neuron loss, leading to impairments in voluntary muscle function and atrophy. Mitochondrial dysfunction in metabolism and morphology have been implicated in the pathogenesis of ALS, including atypical oxidative metabolism, reduced mitochondrial respiration in muscle, and protein aggregates in the mitochondrial outer membrane. Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) plays an essential role in the regulation of mitochondrial biogenesis, the process by which existing mitochondria grow and divide. PGC-1α has been previously reported to be downregulated in the spinal cord of individuals with ALS. Towards targeting PGC-1α as a therapeutic mechanism, we have previously reported improved motor function and survival in the SOD1G93A mouse model of ALS by neuron-specific over-expression of PGC-1α under a neuron-specific enolase (NSE) promoter. As pharmacological intervention targeting PGC-1α would result in whole-body upregulation of this transcriptional co-activator, in the current study we investigated whether global expression of PGC-1α is beneficial in a SOD1G93A mouse model, by generating transgenic mice with PGC-1α transgene expression driven by an actin promoter. Actin-PGC-1α expression levels were assayed and confirmed in spinal cord, brain, muscle, liver, kidney, and spleen. To determine the therapeutic effects of global expression of PGC-1α, wild-type, actin-PGC-1α, SOD1G93A, and actin-PGC-1α/SOD1G93A animals were monitored for weight loss, motor performance by accelerating rotarod test, and survival. Overexpression of actin-PGC-1α did not confer significant improvement in these assessed outcomes. A potential explanation for this difference is that the actin promoter may not induce levels of PGC-1α relevant to disease pathophysiology in the cells that are specifically relevant to the pathogenesis of ALS. This evidence strongly supports future therapeutic approaches that target PGC-1α primarily in neurons.

Spirulina platensis contains several compounds showing nutritional and therapeutic benefits. Recently, a series of peptides able to reduce the blood pressure level and to enhance the endothelial vasorelaxation was isolated from the hydrolyzed highly water-soluble Spirulina extract (HSE). However, HSE shows critical organoleptic characteristics also having poor intestinal permeability, limiting absorption when orally delivered. This research aims to overcome the critical issues through the encapsulation of HSE in Chitosan/Mannitol—(CM)-based microparticles by spray drying. The produced powders (CM-HSE) showed good process yield (≈70%) and encapsulation efficiency (≈100%) also having good derived flow properties as well as stability up to six months storage. The microparticles constituting the spray-dried powder resulted in an amorphous micrometric state (d50 ≈ 14 µm) able to retain dark colour and unpleasant smell of raw HSE. Moreover, the in vitro permeation study by Franz cell indicated that the engineered microparticles are able to enhance the permeation of HSE through an intestinal biomimetic barrier (551.13 μg/cm2 CM-HSE vs. 315.46 μg/cm2 HSE at 270 min).

Neurodegenerative disorders constitute a group of multifaceted conditions characterized by the progressive loss of neurons and synaptic connections consequent to a combination of specific genetic predispositions and stochastic stressors. The neuropathologies observed in both Alzheimer’s and Parkinson’s disease are in part attributed to compounding intrinsic and extrinsic environmental stressors, which we propose may be limited by the administration of specific grape derived phytochemicals and their metabolized derivatives, specifically polyphenols isolated from grape botanicals. Current therapies for neurodegenerative disorders are limited as they solely target the final disease pathologies including behavioral changes, cognitive deficits, proteinopathies and neuronal loss; however, this strategy is not a sustainable approach toward managing disease onset or progression. This review discusses the application of grape derived polyphenols as an adjunctive treatment paradigm for the prevention of neuropathologies associated with Alzheimer’s disease, Parkinson’s disease and Chronic Traumatic Encephalopathy by simultaneously ameliorating two stochastic stressors that facilitate their disease pathologies: inflammation and oxidative stress. The biophysical attributes of grape-derived polyphenols buffer against redox potential dependent peripheral and neuroinflammation and down regulate the activation of inflammasomes in microglia and astrocytes, which could provide a novel mechanism through which grape-derived polyphenols simultaneously suppress risk factors across pathologically distinct neurodegenerative conditions. This approach therefore offers a prophylactic mode, not feasible through current pharmacological agents, to target activity dependent risk factors for neurodegenerative disorders that manifest over an individual’s lifetime.

We extend the list of theories featuring a rigorous interacting ultraviolet fixed point by constructing the first theory featuring a Higgs-like scalar with gauge, Yukawa and quartic interactions. We show that the theory enters a perturbative asymptotically safe regime at energies above a physical scale Λ. We determine the salient properties of the theory and use it as a concrete example to test whether scalars masses unavoidably receive quantum correction of order Λ. Having at our dispose a calculable model allowing us to precisely relate the IR and UV of the theory we demonstrate that the scalars can be lighter than Λ. Although we do not have an answer to whether the Standard Model hypercharge coupling growth toward a Landau pole at around Λ ~ 1040GeV can be tamed by non-perturbative asymptotic safety, our results indicate that such a possibility is worth exploring. In fact, if successful, it might also offer an explanation for the unbearable lightness of the Higgs.

Forthcoming

Mutations in the presenilin-1 (PS-1) gene are one cause of familial Alzheimer's disease (FAD). However, the functions of the PS-1 protein as well as how PS-1 mutations cause FAD are incompletely understood. Here we investigated if neuronal overexpression of wild-type or FAD mutant PS-1 in transgenic mice affects neurogenesis in the hippocampus of adult animals. We show that either a wild-type or an FAD mutant PS-1 transgene reduces the number of neural progenitors in the dentate gyrus. However, the wild-type, but not the FAD mutant PS-1 promoted the survival and differentiation of progenitors leading to more immature granule cell neurons being generated in PS-1 wild type expressing animals. These studies suggest that PS-1 plays a role in regulating neurogenesis in adult hippocampus and that FAD mutants may have deleterious properties independent of their effects on amyloid deposition.

In this study, we demonstrate the use of Molecular topology (MT) in an Alzheimer's disease (AD) drug discovery program. MT uses and expands upon the principles governing the molecular connectivity theory of numerically characterizing molecular structures, in the present case, active anti-AD drugs/agents, using topological descriptors to build models. Topological characterization has been shown to embody sufficient molecular information to provide strong correlation to therapeutic efficacy.We used MT to include multiple bioactive properties that allows for the identification of multi-functional single agent compounds, in this case, the dual functions of β-amyloid (Aβ) -lowering and anti-oligomerization. Using this technology, we identified and designed novel compounds in chemical classes unrelated to current anti-AD agents that exert dual Aβ lowering and anti-Aβ oligomerization activities in animal models of AD. AD is a multifaceted disease with different pathological features.Our study, for the first time, demonstrated that MT can provide novel strategy for discovering drugs with Aβ lowering and anti-aggregation dual activities for AD.

Alzheimer's disease (AD) is rapidly becoming one of the leading causes of disability and mortality in the elderly. As life-expectancy increases, an increasing number of people will rely on modern medicines to treat age-associated disorders. Among these medications, some might benefit, while others might exacerbate, the pathogenesis of AD. We screened 1,600 FDA approved drugs for β-amyloid (Aβ)-modifying activity and identified drugs that can potentially influence amyloid precursor protein processing. In this study, we focused on cardiovascular drugs and demonstrated that some hypertensive medication can differentially modulate Aβ, both in vitro and in vivo. Our study suggests that some commonly prescribed drugs might exert unintended effects and modulate AD and provides the basis for continuing investigation of the role of individual drugs on a case-by-case basis. This line of investigation will lead to the identification of common medications that are potentially beneficial or detrimental to AD as a reference for physicians to consider when prescribing the most appropriate drugs for their patients, particularly for treating chronic disorders among the growing geriatric population.

Drosophila models of tauopathies have been developed by transgenically overexpressing the disease-associated forms of tau. In this paper we report for the first time that a recently developed Grape-Seed Polyphenolic Extract (GSPE) improves the eye phenotype of a Drosophila eye model of R406W tau. GSPE-mediated improvements in this distinct in vivo neurodegeneration model for protein misfolding/aggregation suggest that GSPE may have therapeutic value in disorders involving aberrant protein aggregation.

Background: Hospital readmissions following left ventricular assist device (LVAD) remain a frequent comorbidity, associated with decreased quality of life and increased resources utilization. This study sought to determine causes, predictors, and impact on survival of hospitalizations during HeartMate 3 (HM3) support. Methods: All patients implanted with HM3 between November 2014 to December 2019 at Columbia University Irving Medical Center were consecutively enrolled in the study. Demographics and clinical characteristics from the index admission and the first outpatient visit were collected and used to estimate 1‐year and 900‐day readmission‐free survival and overall survival. Multivariable analysis was performed for subsequent readmissions. Results: Of 182 patients who received a HM3 LVAD, 167 (92%) were discharged after index admission and experienced 407 unplanned readmissions over the median follow up of 727 (interquartile range (IQR): 410.5, 1124.5) days. One‐year and 900‐day mean cumulative number of all‐cause unplanned readmissions was 0.43 (95%CI, 0.36, 0.51) and 1.13 (95%CI, 0.99, 1.29). The most frequent causes of rehospitalizations included major infections (29.3%), bleeding (13.2%), device‐related (12.5%), volume overload (7.1%), and other (28%). One‐year and 900‐day survival free from all‐cause readmission was 38% (95%CI, 31–46%) and 16.6% (95%CI, 10.3–24.4%). One‐year and 900‐day freedom from 2, 3, and ≥4 readmissions were 60.7%, 74%, 74.5% and 26.2%, 33.3%, 41.3%. One‐year and 900‐day survival were unaffected by the number of readmissions and remained >90%. Male sex, ischemic etiology, diabetes, lower serum creatinine, longer duration of index hospitalization, and a history of readmission between discharge and the first outpatient visit were associated with subsequent readmissions. Conclusions: Unplanned hospital readmissions after HM3 are common, with infections and bleeding accounting for the majority of readmissions. Irrespective of the number of readmissions, one‐year survival remained unaffected. [ABSTRACT FROM AUTHOR]