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Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare inborn metabolic disorder caused by the functional impairment of SSADH (encoded by the ALDH5A1 gene), an enzyme essential for metabolism of the inhibitory neurotransmitter γ-aminobutyric acid (GABA). In SSADHD, pathologic accumulation of GABA and its metabolite γ-hydroxybutyrate (GHB) results in broad spectrum encephalopathy including developmental delay, ataxia, seizures, and a heightened risk of sudden unexpected death in epilepsy (SUDEP). Proof-of-concept systemic SSADH restoration via enzyme replacement therapy increased survival of SSADH knockout mice, suggesting that SSADH restoration might be a viable intervention for SSADHD. However, before testing enzyme replacement therapy or gene therapy in patients, we must consider its safety and feasibility in the context of early brain development and unique SSADHD pathophysiology. Specifically, a profound use-dependent downregulation of GABAA receptors in SSADHD indicates a risk that any sudden SSADH restoration might diminish GABAergic tone and provoke seizures. In addition, the tight developmental regulation of GABA circuit plasticity might limit the age window when SSADH restoration is accomplished safely. Moreover, given SSADH expressions are cell type–specific, targeted instead of global restoration might be necessary. We therefore describe 3 key parameters for the clinical readiness of SSADH restoration: (1) rate, (2) timing, and (3) cell type specificity. Our work focuses on the construction of a novel SSADHD mouse model that allows "on-demand" SSADH restoration for the systematic investigation of these key parameters. We aim to understand the impacts of specific SSADH restoration protocols on brain physiology, accelerating bench-to-bedside development of enzyme replacement therapy or gene therapy for SSADHD patients. [ABSTRACT FROM AUTHOR]

Pathogenic variants in ALDH5A1 cause succinic semialdehyde dehydrogenase (SSADH) deficiency, with >180 cases reported worldwide. However, a nonspecific neurologic presentation and inconsistent variant nomenclature have limited diagnoses. In this study, pathogenic variants in ALDH5A1 were curated and variant prevalence assessed in the Genome Aggregation Database (gnomAD) to determine a minimum carrier frequency and to estimate disease prevalence. Stringent population variant analysis, including 98 reported disease-associated ALDH5A1 variants, indicates a pan-ethnic carrier frequency of ∼1/340, supporting a prevalence of SSADH deficiency of ∼1/460 000 worldwide, with highest carrier frequencies observed in East Asian and South Asian populations. Because heterozygous loss of function alleles are rare in gnomAD and >60% of reported disease-causing variants were missense changes that were not present in gnomAD, the pan-ethnic carrier frequency for SSADH deficiency is likely not fully represented in this study. Additional analyses to investigate the potential impact of more common ALDH5A1 variants with reduced but not deficient enzyme activity, including analysis in diverse populations, are needed to fully assess the prevalence of this ultra-rare disease. [ABSTRACT FROM AUTHOR]

We examined safety, tolerability, and efficacy of SGS-742, a γ-aminobutyric acid B (GABA-B) receptor antagonist, in patients with succinic semialdehyde dehydrogenase deficiency. This was a single-center randomized, double-blind crossover phase II clinical trial of SGS-742 versus placebo in patients with succinic semialdehyde dehydrogenase deficiency. Procedures included transcranial magnetic stimulation and the Adaptive Behavior Assessment Scale. Nineteen subjects were consented and enrolled; the mean age was 14.0 ± 7.5 years and 11 (58%) were female. We did not find a significant effect of SGS-742 on the Adaptive Behavior Assessment Scale score, motor threshold, and paired-pulse stimulation. The difference in recruitment curve slopes between treatment groups was 0.003 (P =.09). There was no significant difference in incidence of adverse effects between drug and placebo arms. SGS-742 failed to produce improved cognition and normalization of cortical excitability as measured by the Adaptive Behavior Assessment Scale and transcranial magnetic stimulation. Our data do not support the current use of SGS-742 in succinic semialdehyde dehydrogenase deficiency. Trial registry number NCT02019667. Phase 2 Clinical Trial of SGS-742 Therapy in Succinic Semialdehyde Dehydrogenase Deficiency. https://clinicaltrials.gov/ct2/show/NCT02019667 [ABSTRACT FROM AUTHOR]

Succinic semialdehyde dehydrogenase (SSADH) deficiency is an autosomal recessive disorder of γ-aminobutyric acid (GABA) degradation, resulting in elevations of brain GABA and γ-hydroxybutyric acid (GHB). Previous magnetic resonance (MR) spectroscopy studies have shown increased levels of Glx in SSADH deficiency patients. Here in this work, we measure brain GABA in a large cohort of SSADH deficiency patients using advanced MR spectroscopy techniques that allow separation of GABA from overlapping metabolite peaks. We observed significant increases in GABA concentrations in SSADH deficiency patients for all 3 brain regions that were evaluated. Although GABA levels were higher in all 3 regions, each region had different patterns in terms of GABA changes with respect to age. We also report results from structural magnetic resonance imaging (MRI) of the same cohort compared with age-matched controls. We consistently observed signal hyperintensities in globus pallidus and cerebellar dentate nucleus. [ABSTRACT FROM AUTHOR]

Background: Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a disorder of GABA degradation with use-dependent downregulation of postsynaptic GABAA/B receptors. We aim to measure the resulting cortical excitation: inhibition ratio using transcranial magnetic stimulation. Methods: In this single-center observational study, 18 subjects with SSADHD and 8 healthy controls underwent transcranial magnetic stimulation. Resting motor threshold, cortical silent period, and long-interval intracortical inhibition were measured in both groups. Resting motor threshold in focal epilepsy patients from an institutional transcranial magnetic stimulation database were also included. Results: SSADHD subjects had higher resting motor threshold than healthy controls but lower relative to focal epilepsy patients. Resting motor threshold decreased with age in all groups. Cortical silent period was longer in SSADHD subjects than in healthy controls. No difference was detected in long-interval intracortical inhibition between the 2 groups. Conclusion: Findings suggest abnormal corticospinal tract physiology in SSADHD, but with preserved developmental trajectory for corticospinal tract maturation. Defining features of these transcranial magnetic stimulation metrics in SSADHD will be better elucidated through this ongoing longitudinal study. [ABSTRACT FROM AUTHOR]

Inherited disorders of neurotransmitter metabolism are a group of rare diseases, which are caused by impaired synthesis, transport, or degradation of neurotransmitters or cofactors and result in various degrees of delayed or impaired psychomotor development. To assess the effect of neurotransmitter deficiencies on intelligence, quality of life, and behavior, the data of 148 patients in the registry of the International Working Group on Neurotransmitter Related Disorders (iNTD) was evaluated using results from standardized age‐adjusted tests and questionnaires. Patients with a primary disorder of monoamine metabolism had lower IQ scores (mean IQ 58, range 40‐100) within the range of cognitive impairment (<70) compared to patients with a BH4 deficiency (mean IQ 84, range 40‐129). Short attention span and distractibility were most frequently mentioned by parents, while patients reported most frequently anxiety and distractibility when asked for behavioral traits. In individuals with succinic semialdehyde dehydrogenase deficiency, self‐stimulatory behaviors were commonly reported by parents, whereas in patients with dopamine transporter deficiency, DNAJC12 deficiency, and monoamine oxidase A deficiency, self‐injurious or mutilating behaviors have commonly been observed. Phobic fears were increased in patients with 6‐pyruvoyltetrahydropterin synthase deficiency, while individuals with sepiapterin reductase deficiency frequently experienced communication and sleep difficulties. Patients with BH4 deficiencies achieved significantly higher quality of life as compared to other groups. This analysis of the iNTD registry data highlights: (a) difference in IQ and subdomains of quality of life between BH4 deficiencies and primary neurotransmitter‐related disorders and (b) previously underreported behavioral traits. [ABSTRACT FROM AUTHOR]

Purpose of Review: Familial hypercholesterolemia (FH) is the most common genetic metabolic disorder characterized by markedly elevated LDL-C levels from birth leading to atherosclerotic cardiovascular disease (ASCVD) and premature deaths. The purpose of this review is to share the current knowledge in the diagnosis, risk estimation, and management of patients with FH in the light of recent evidence and guideline recommendations. Recent Findings: Recent registries underscored the prevalence of FH as 1/200–250 translating to an almost 1500 million subjects suffering from FH worldwide. However, only a minority of FH patients are identified early and effectively treated. In most cases, mutations in the LDL-receptor (LDLR) gene and to a lesser degree in the apolipoprotein B-100 (APOB), proprotein convertase subtilisin/kexin type 9 (PCSK9), and the LDL-receptor adaptor protein 1 (LDLRAP1) genes cause FH. Diagnostic scores such as Dutch Lipid Clinic Network criteria using clinical manifestations are helpful in identifying FH. Traditional risk factors and high lipoprotein(a) affect the course of the disease. Vascular ultrasound imaging and coronary calcium scoring are helpful for further risk estimation of these patients. Getting to LDL-C goals is possible with currently available treatments including statins, ezetimibe, and PCSK9 inhibitors, as well as lipoprotein apheresis, lomitapide, and mipomersen in more severe phenotypes. Additionally, novel agents bempedoic acid, inclisiran, and evinacumab expanded the treatment choices for some patients with FH. Early diagnosis and initiation of LDL-C lowering are still required to achieve the greatest reduction in ASCVD morbidity and mortality in patients with FH. Summary: FH is a common genetic disorder characterized by markedly elevated LDL-C levels from birth onward, resulting in significantly increased risk for ASCVD. Despite major advances in our understanding of the disease and effective therapies, FH is still underdiagnosed and undertreated. Early initiation of LDL-C lowering by increased awareness of FH among the healthcare professionals, patients, and the public is necessary to achieve meaningful reduction in ASCVD morbidity and mortality in these patients. [ABSTRACT FROM AUTHOR]

Arterial stiffness is a non-traditional risk factor of cardiovascular disease and may explain part of the excess cardiovascular risk in chronic kidney disease patients. Successful renal transplantation (RT) may restore renal function and improve several metabolic abnormalities involved in arterial stiffness. This prospective study conducted non-invasive assessments of arterial stiffness indices [the augmentation index (AI) and pulse wave velocity (PWV)] in end-stage kidney disease (ESKD) patients before RT and 3 and 6 months after living-donor RT, alongside the effects of age and calcineurin inhibitors on arterial stiffness. The study included 26 ESKD patients (22 males and 4 females; mean age, 34.07 years; median duration of dialysis, 10 months) scheduled for RT and followed up for three visits (within 1 week before transplantation, and 3 and 6 months after transplantation). Six months after successful RT, the patients had nearly normal serum creatinine and significantly improved serum phosphate and intact parathyroid hormone levels. The pretransplant AI was 21.53% ± 13.61% which reduced significantly 6 months after RT to 16.19% ± 10.74% (P <0.05). Although there was a reduction in PWV 6 months after RT from the pre-transplant PWV, it was not significant. A significant correlation between age and the augmentation index was noted 3 and 6 months after RT. Patients on tacrolimus-based immunosuppression after RT showed significant improvements in the AI compared with patients on a cyclosporine-based regimen. RT helped to improve arterial stiffness indices, resulting in reduced cardiovascular risk., (Copyright © 2023 Copyright: © 2023 Saudi Journal of Kidney Diseases and Transplantation.)

Background: Large observational studies have shown that small, dense LDL subfractions are related to atherosclerotic cardiovascular disease. This study assessed the effects of two highly effective lipid-lowering therapies in the atherogenic subclasses of lipoproteins in subjects with ST-segment elevation myocardial infarction (STEMI). Methods: Patients of both sexes admitted with their first myocardial infarction and submitted to pharmacoinvasive strategy (N = 101) were included and randomized using a central computerized system to receive a daily dose of simvastatin 40 mg plus ezetimibe 10 mg or rosuvastatin 20 mg for 30 days. Intermediate-density lipoprotein (IDL) and low-density lipoprotein (LDL) subfractions were analysed by polyacrylamide gel electrophoresis (Lipoprint System) on the first (D1) and 30th days (D30) of lipid-lowering therapy. Changes in LDL and IDL subfractions between D1 and D30 were compared between the lipid-lowering therapies (Mann-Whitney U test). Results: The classic lipid profile was similar in both therapy arms at D1 and D30. At D30, the achievement of lipid goals was comparable between lipid-lowering therapies. Cholesterol content in atherogenic subclasses of LDL (p = 0.043) and IDL (p = 0.047) decreased more efficiently with simvastatin plus ezetimibe than with rosuvastatin. Conclusions: Lipid-lowering therapy with simvastatin plus ezetimibe was associated with a better pattern of lipoprotein subfractions than rosuvastatin monotherapy. This finding was noted despite similar effects in the classic lipid profile and may contribute to residual cardiovascular risk. Trial registration: ClinicalTrials.gov, NCT02428374, registered on 28/09/2014. [ABSTRACT FROM AUTHOR]

Background: Pyridoxine-dependent epilepsy (PDE) is due to biallelic variants in ALDH7A1 (PDE-ALDH7A1). ALDH7A1 encodes α-aminoadipic semialdehyde dehydrogenase in lysine catabolism. We investigated the gamma aminobutyric acid (GABA) metabolism and energy production pathways in human PDE-ALDH7A1 and its knock-out aldh7a1 zebrafish model. Methods: We measured GABA pathway, and tricarboxylic acid cycle metabolites and electron transport chain activities in patients with PDE-ALDH7A1 and in knock-out aldh7a1 zebrafish. Results: We report results of three patients with PDE-ALDH7A1: low paired complex I+II and complex II+III and individual complex IV activities in muscle biopsy in patient 1 (likely more severe phenotype); significantly elevated CSF glutamate in the GABA pathway and elevated CSF citrate, succinate, isocitrate and α-ketoglutarate in the TCA cycle in patient 3 (likely more severe phenotype); and normal CSF GABA pathway and TCA cycle metabolites on long-term pyridoxine therapy in patient 2 (likely milder phenotype). All GABA pathway metabolites (γ-hydroxybutyrate, glutamine, glutamate, total GABA, succinic semialdehyde) and TCA cycle metabolites (citrate, malate, fumarate, isocitrate, lactate) were significantly low in the homozygous knock-out aldh7a1 zebrafish compared to the wildtype zebrafish. Homozygous knock-out aldh7a1 zebrafish had decreased electron transport chain enzyme activities compared to wildtype zebrafish. Discussion: We report impaired electron transport chain function, accumulation of glutamate in the central nervous system and TCA cycle dysfunction in human PDE-ALDH7A1 and abnormal GABA pathway, TCA cycle and electron transport chain in knock-out aldh7a1 zebrafish. Central nervous system glutamate toxicity and impaired energy production may play important roles in the disease neuropathogenesis and severity in human PDE-ALDH7A1. [ABSTRACT FROM AUTHOR]

Epilepsy is one of the main symptoms affecting the lives of individuals with tuberous sclerosis complex (TSC), causing a high rate of morbidity. Individuals with TSC can present with various types of seizures, epilepsies, and epilepsy syndromes that can coexist or appear in relation to age. Focal epilepsy is the most frequent epilepsy type with two developmental and epileptic encephalopathies: infantile spasms syndrome and Lennox–Gastaut syndrome. Active screening and early management of epilepsy is recommended in individuals with TSC to limit its consequences and its impact on quality of life, cognitive outcome and the economic burden of the disease. The progress in the knowledge of the mechanisms underlying epilepsy in TSC has paved the way for new concepts in the management of epilepsy related to TSC. In addition, we are moving from traditional "reactive" and therapeutic choices with current antiseizure medications used after the onset of seizures, to a proactive approach, aimed at predicting and preventing epileptogenesis and the onset of epilepsy with vigabatrin, and to personalized treatments with mechanistic therapies, namely mechanistic/mammalian target of rapamycin inhibitors. Indeed, epilepsy linked to TSC is one of the only epilepsies for which a predictive and preventive approach can delay seizure onset and improve seizure response. However, the efficacy of such interventions on long-term cognitive and psychiatric outcomes is still under investigation. [ABSTRACT FROM AUTHOR]

The aim of this study was to optimize the preparation method of polymethyl methacrylate (PMMA) denture base loaded with nano silver (NAg), to more effectively and safely impart sustainable antibacterial functions. NAg solution was synthetized and mixed with acrylic acid and methyl methyacrylate (MMA) monomer in order to prepare a new type of NAg solution (NS)/polymer methyl methacrylate denture base specimens (NS/PMMA). The surface morphology, mechanical strength, antimicrobial activity, anti-aging performance, cytotoxicity and biocompatibility of NS/PMMA denture base were evaluated in comparison with specimens fabricated using traditional NAg adding methods and NAg-free denture base. The aesthetic characteristics and mechanical strength of NS/ PMMA denture base met the clinical application requirements. Meanwhile, NS/PMMA denture base showed better antibacterial activity, anti-aging properties, no cytotoxicity and displayed exceptional biocompatibility. NS/PMMA denture base thus has great potential for clinical application. [ABSTRACT FROM AUTHOR]

Numerous pathogenic bacteria are developing antibiotic resistance. Improvement from multidrug resistant (MDR) infections is a problematic issue and requires a multiple treatment with broad-spectrum antibiotics which are less efficient, more toxic and more expensive. Silver nanoparticles (AgNPs) are attracting much attention because of their potent antibacterial and anti-biofilm activities. These nanoparticles are lengthily synthesized and used as a successful broad spectrum antibacterial agent against Gram negative and Gram positive bacteria including antibiotic unwilling bacteria. Silver attacks multiple targets in the microorganism consequently decreases its ability to develop battle. Effect of coating on AgNPs constancy, toxicity on the microbial host and their antimicrobial activity was discussed. The amalgamation of AgNPs into hydrogels magnifies the antibacterial activity according to their characteristics; hydrogels work as an competent stabilizer of AgNPs and control the release of AgNPs. In the present review, the silver nanoparticles-hydrogel and their components as well as their antibacterial activities and wound healing efficacies are reviewed and discussed on the bases of constituent variabilities and characteristics. Different factors and topics are measured since there are challenges and challenging issues need to be faced and solved for expansion of new ideal antibacterial formulation. [ABSTRACT FROM AUTHOR]

Synthesis of silver nanoparticles (AgNPs) using microorganisms has gained considerable attention as an efficient alternative for conventional chemical synthesis. Earlier, we have demonstrated biosynthesis of silver nanoparticles using marine Escherichia coli VM1. Here, we investigated antibacterial, antifungal and antioxidant efficacy of the synthesized silver nanoparticles using standard techniques. The results have shown that the AgNPs synthesized using the marine Escherichia coli have potential antibacterial activity against both Gram positive (Staphylococcus aureus) and Gram negative (E. coli, Klebsiella pneumoniae, S. paratyphi, Vibrio parahaemolyticus, V. cholerae and Proteus mirabilis) pathogenic bacteria and moderate antifungal activity was observed against Aspergillus niger, Penicillium sp., Trichothecium roseum and Trichophyton rubrum. Further, in vitro antioxidant study was examined using 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity. We observed significant effect on scavenging of free radicals suggesting that the AgNPs biosynthesized using E. coli could be an efficient and eco-friendly material for biomedical applications. [ABSTRACT FROM AUTHOR]

The objective of this study was to evaluate the effects of AgNPs on Artemia salina and Allium cepa, evaluating the influence of the dilution solutions on the particle behavior. The AgNPs were synthesized by chemical reduction of AgNO3 (3 and 5 mmol L−1) with sodium borohydride and stabilized with PVA (polyvinyl alcohol) and CMC (sodium carboxymethyl cellulose). The toxicity of AgNPs was evaluated in Artemia salina (mortality) using Meyer's solution as a diluent and in Allium cepa (chromosomal aberrations) using reconstituted hard water. AgNPs showed characteristic molecular absorption bands. Particles with CMC presented hydrodynamic radius between 4 and 102 nm and with PVA between 7 and 46 nm. The studied dispersions were toxic to A. salina species. Meyer's solution, used as dilution water in the test, caused precipitation of Ag+ and also caused changes in CMC-stabilized AgNPs, changing the shape of the nanoparticles by depositing precipitates on their surface. These changes make the results of toxicity difficult to interpret. AgNPs stabilized with PVA remained unchanged. AgNPs affected cell division and caused the appearance of chromosomal aberrations on A. cepa. Higher numbers of chromosomal aberrations occurred in dispersions with smaller particle diameters (AgNPs3-PVA and AgNPs5-PVA, without dilution). In the studied conditions the dispersions were toxic to the tested organisms, the concentrations of precursors and the type of stabilizer used influenced the particle size and toxicity. In the test with A. cepa, the reconstituted hard water did not cause changes in the dispersions of AgNPs, whereas for A. salina the Meyer solution promoted aggregation of the particles and precipitation, in the dispersions stabilized with CMC, thus changing the samples. [ABSTRACT FROM AUTHOR]

Breast cancer is one of the most frequent cancer types worldwide and the first cause of cancer-related deaths in women. Although significant therapeutic advances have been achieved with drugs such as tamoxifen and trastuzumab, breast cancer still caused 627,000 deaths in 2018. Since cancer is a multifactorial disease, it has become necessary to develop new molecular therapies that can target several relevant cellular processes at once. Ion channels are versatile regulators of several physiological- and pathophysiological-related mechanisms, including cancer-relevant processes such as tumor progression, apoptosis inhibition, proliferation, migration, invasion, and chemoresistance. Ion channels are the main regulators of cellular functions, conducting ions selectively through a pore-forming structure located in the plasma membrane, protein–protein interactions one of their main regulatory mechanisms. Among the different ion channel families, the Transient Receptor Potential (TRP) family stands out in the context of breast cancer since several members have been proposed as prognostic markers in this pathology. However, only a few approaches exist to block their specific activity during tumoral progress. In this article, we describe several TRP channels that have been involved in breast cancer progress with a particular focus on their binding partners that have also been described as drivers of breast cancer progression. Here, we propose disrupting these interactions as attractive and potential new therapeutic targets for treating this neoplastic disease. [ABSTRACT FROM AUTHOR]

Paroxysmal exercise-induced neurological symptoms (PENS) encompass a wide spectrum of clinical phenomena commonly presenting during childhood and characteristically elicited by physical exercise. Interestingly, few shared pathogenetic mechanisms have been identified beyond the well-known entity of paroxysmal exercise-induced dyskinesia, PENS could be part of more complex phenotypes including neuromuscular, neurodegenerative, and neurometabolic disease, epilepsies, and psychogenetic disorders. The wide and partially overlapping phenotypes and the genetic heterogeneity make the differential diagnosis frequently difficult and delayed; however, since some of these disorders may be treatable, a prompt diagnosis is mandatory. Therefore, an accurate characterization of these symptoms is pivotal for orienting more targeted biochemical, radiological, neurophysiological, and genetic investigations and finally treatment. In this article, we review the clinical, genetic, pathophysiologic, and therapeutic landscape of paroxysmal exercise induced neurological symptoms, focusing on phenomenology and differential diagnosis. [ABSTRACT FROM AUTHOR]

22 Greinacher A, Pecci A, Kunishima S, Althaus K, Nurden P, Balduini CL, Bakchoul T. Diagnosis of inherited platelet disorders on a blood smear: a tool to facilitate worldwide diagnosis of platelet disorders. Keywords: bleeding; inherited platelet disorders; sitosterolemia; thrombocytopenia EN bleeding inherited platelet disorders sitosterolemia thrombocytopenia 573 577 5 08/03/21 20210601 NES 210601 Introduction Sitosterolemia (OMIM 210250) is a rare inherited autosomal recessive disorder of lipid metabolism, characterized by increased levels of plasma plant sterols (PS) such as stigmasterol, campesterol, and sitosterol [[1]]. Macrothrombocytopenia and stomatocytes are the typical findings in the peripheral blood smear (90%) and usually associate with other metabolic symptoms (70%) (Figure 1), indicating the presence of syndromic thrombocytopenia [[12]]. [Extracted from the article]

A profound need to explore eco-friendly methods to practice sustainable agriculture leads to the research and exploration of plant growth-promoting rhizobacteria (PGPRs). Biofilms are assemblages of microbial communities within a self-secreted exopolymeric matrix, adhering to different biotic and abiotic surfaces and performing a variety of desired and undesired functions. Biofilm formation by PGPRs is governed by effective root colonization of the host plant in providing plant growth promotion and stress management. Biofilms can also provide a suitable environment for the synthesis and entrapment of nanoparticles. Together, nanoparticles and PGPRs may contribute towards biocontrol and crop management. This review discusses the significance of biofilms in agriculture and their confluence with different types of nanoparticles for plant protection and improved crop production. [ABSTRACT FROM AUTHOR]

Terpenes and their derivatives have been used conventionally as potential dietary supplements to boost the nutritional value of endless food products. Several plant-based complex terpenoid and their derivatives have been reported for a wide range of medicinal and nutritional properties. However, their simple counterparts, whose production is relatively easy, sustainable, and economic from food-grade microbial sources, have not been studied yet for any such biological activities. The present study aimed to investigate the longevity-promoting property and neuromodulatory effects of 3,3-dimethylallyl alcohol (Prenol), one of the simplest forms of terpenoid and a constituent of fruit aroma, in the animal model Caenorhabditis elegans. Prenol supplementation (0.25 mM) augmented the lifespan of wild-type nematodes by 22.8% over the non-treated worms. Moreover, a suspended amyloid-β induced paralysis and reduced α-synuclein aggregation were observed in Prenol-treated worms. The lifespan extending properties of Prenol were correlated with ameliorated physiological parameters and increased stress (heat and oxidative) tolerance in C. elegans. In silico and gene-specific mutant studies showed that pro-longevity transcription factors DAF-16, HSF-1, and SKN-1 were involved in the improved lifespan and health-span of Prenol-treated worms. Transgenic green fluorescent protein-reporter gene expression analysis and relative mRNA quantification (using real-time PCR) demonstrated an increase in the expression of DAF-16, HSF-1, and SKN-1 transcription factors and their downstream target genes in Prenol-treated worms. Together, the findings suggest that small molecules, like Prenol, could be explored as a potential alternate to develop therapeutics against aging and age-related ailments. [ABSTRACT FROM AUTHOR]

There are about 1500 genetic metabolic diseases. A small number of treatable diseases are diagnosed by newborn screening programs, which are continually being developed. However, most diseases can only be diagnosed based on clinical symptoms or metabolic findings. The main biological fluids used are urine, plasma and, in special situations, cerebrospinal fluid. In contrast to commonly used methods such as gas chromatography and high performance liquid chromatography mass spectrometry, ex vivo proton spectroscopy ( 1 H-NMR) is not yet used in routine clinical practice, although it has been recommended for more than 30 years. Automatic analysis and improved NMR technology have also expanded the applications used for the diagnosis of inborn errors of metabolism. We provide a mini-overview of typical applications, especially in urine but also in plasma, used to diagnose common but also rare genetic metabolic diseases with 1 H-NMR. The use of computer-assisted diagnostic suggestions can facilitate interpretation of the profiles. In a proof of principle, to date, 182 reports of 59 different diseases and 500 reports of healthy children are stored. The percentage of correct automatic diagnoses was 74%. Using the same 1 H-NMR profile-targeted analysis, it is possible to apply an untargeted approach that distinguishes profile differences from healthy individuals. Thus, additional conditions such as lysosomal storage diseases or drug interferences are detectable. Furthermore, because 1 H-NMR is highly reproducible and can detect a variety of different substance categories, the metabolomic approach is suitable for monitoring patient treatment and revealing additional factors such as nutrition and microbiome metabolism. Besides the progress in analytical techniques, a multiomics approach is most effective to combine metabolomics with, for example, whole exome sequencing, to also diagnose patients with nondetectable metabolic abnormalities in biological fluids. In this mini review we also provide our own data to demonstrate the role of NMR in a multiomics platform in the field of inborn errors of metabolism., (© 2022 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.)

Barth syndrome is a rare X-linked genetic disease classically characterized by cardiomyopathy, skeletal myopathy, growth retardation, neutropenia, and 3-methylglutaconic aciduria. It is caused by mutations in the tafazzin gene localized to chromosome Xq28.12. Mutations in tafazzin may result in alterations in the level and molecular composition of the mitochondrial phospholipid cardiolipin and result in large elevations in the lysophospholipid monolysocardiolipin. The increased monolysocardiolipin:cardiolipin ratio in blood is diagnostic for the disease, and it leads to disruption in mitochondrial bioenergetics. In this review, we discuss cardiolipin structure, synthesis, and function and provide an overview of the clinical and cellular pathophysiology of Barth Syndrome. We highlight known pharmacological management for treatment of the major pathological features associated with the disease. In addition, we discuss non-pharmacological management. Finally, we highlight the most recent promising therapeutic options for this rare mitochondrial disease including lipid replacement therapy, peroxisome proliferator-activated receptor agonists, tafazzin gene replacement therapy, induced pluripotent stem cells, mitochondria-targeted antioxidants and peptides, and the polyphenolic compound resveratrol. [ABSTRACT FROM AUTHOR]

Backgrounds: Atypicalities in tactile processing are reported in autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) but it remains unknown if they precede and associate with the traits of these disorders emerging in childhood. We investigated behavioural and neural markers of tactile sensory processing in infants at elevated likelihood of ASD and/or ADHD compared to infants at typical likelihood of the disorders. Further, we assessed the specificity of associations between infant markers and later ASD or ADHD traits. Methods: Ninety-one 10-month-old infants participated in the study (n = 44 infants at elevated likelihood of ASD; n = 20 infants at elevated likelihood of ADHD; n = 9 infants at elevated likelihood of ASD and ADHD; n = 18 infants at typical likelihood of the disorders). Behavioural and EEG responses to pairs of tactile stimuli were experimentally recorded and concurrent parental reports of tactile responsiveness were collected. ASD and ADHD traits were measured at 24 months through standardized assessment (ADOS-2) and parental report (ECBQ), respectively. Results: There was no effect of infants' likelihood status on behavioural markers of tactile sensory processing. Conversely, increased ASD likelihood associated with reduced neural repetition suppression to tactile input. Reduced neural repetition suppression at 10 months significantly predicted ASD (but not ADHD) traits at 24 months across the entire sample. Elevated tactile sensory seeking at 10 months moderated the relationship between early reduced neural repetition suppression and later ASD traits. Conclusions: Reduced tactile neural repetition suppression is an early marker of later ASD traits in infants at elevated likelihood of ASD or ADHD, suggesting that a common pathway to later ASD traits exists despite different familial backgrounds. Elevated tactile sensory seeking may act as a protective factor, mitigating the relationship between early tactile neural repetition suppression and later ASD traits. [ABSTRACT FROM AUTHOR]

Central hypothyroidism might be another clinical sign of SSADH deficiency which prompts urinary organic acid screening for GHB in central hypothyroidism patients. Studies on GABA and thyroid hormone interaction might be a concept of a new therapy. [ABSTRACT FROM AUTHOR]

Metabolic epilepsies arise in the context of rare inborn errors of metabolism (IEM), notably glucose transporter type 1 deficiency syndrome, succinic semialdehyde dehydrogenase deficiency, pyruvate dehydrogenase complex deficiency, nonketotic hyperglycinemia, and mitochondrial cytopathies. A common feature of these disorders is impaired bioenergetics, which through incompletely defined mechanisms result in a wide spectrum of neurological symptoms, such as epileptic seizures, developmental delay, and movement disorders. The ketogenic diet (KD) has been successfully utilized to treat such conditions to varying degrees. While the mechanisms underlying the clinical efficacy of the KD in IEM remain unclear, it is likely that the proposed heterogeneous targets influenced by the KD work in concert to rectify or ameliorate the downstream negative consequences of genetic mutations affecting key metabolic enzymes and substrates—such as oxidative stress and cell death. These beneficial effects can be broadly grouped into restoration of impaired bioenergetics and synaptic dysfunction, improved redox homeostasis, anti‐inflammatory, and epigenetic activity. Hence, it is conceivable that the KD might prove useful in other metabolic disorders that present with epileptic seizures. At the same time, however, there are notable contraindications to KD use, such as fatty acid oxidation disorders. Clearly, more research is needed to better characterize those metabolic epilepsies that would be amenable to ketogenic therapies, both experimentally and clinically. In the end, the expanded knowledge base will be critical to designing metabolism‐based treatments that can afford greater clinical efficacy and tolerability compared to current KD approaches, and improved long‐term outcomes for patients. [ABSTRACT FROM AUTHOR]

Tacrolimus (TAC, also called FK506), a common immunosuppressive drug used to prevent allograft rejection in transplant patients, is well known to alter the functions of blood vessels. In this study, we sought to determine whether chronic treatment of TAC could inhibit the activity of big-conductance Ca2+-activated K+ (BK) channels in vascular smooth muscle cells (SMCs), leading to hypertension. Our data reveal that the activity of BK channels was inhibited in cerebral artery SMCs (CASMCs) from mice after intraperitoneal injection of TAC once a day for 4 weeks. The voltage sensitivity, Ca2+ sensitivity, and open time of single BK channels were all decreased. In support, BK channel β1-, but not α-subunit protein expression was significantly decreased in cerebral arteries. In TAC-treated mice, application of norepinephrine induced stronger vasoconstriction in both cerebral and mesenteric arteries as well as a larger [Ca2+]i in CASMCs. Chronic treatment of TAC, similar to BK channel β1-subunit knockout (KO), resulted in hypertension in mice, but did not cause a further increase in blood pressure in BK channel β1-subunit KO mice. Moreover, BK channel activity in CASMCs was negatively correlated with blood pressure. Our findings provide novel evidence that TAC inhibits BK channels by reducing the channel β1-subunit expression and functions in vascular SMCs, leading to enhanced vasoconstriction and hypertension. [ABSTRACT FROM AUTHOR]

Sitosterolemia is a rare autosomal recessively inherited lipid metabolic disorder that is characterized by hyper absorption of plant sterols from the intestinal mucosa leading to toxic levels in the blood. Four patients of age ranging from 11 to 29 years presented to the outpatient department with clinical features of hemolytic anemia. There were no features of hypercholesterolemia in any of the patients. Peripheral smear examination of all four patients showed stomatocytes and macrothrombocytopenia. Qualitative testing for plant sterols was performed in one case. Next generation sequencing revealed a compound heterozygous mutation in ABCG5 gene (c.1222C>T and c.1255C>T) in one case and homozygous mutations in ABCG5 gene (c.727C>T), (c.332G>A (p.G111E)), (c.1222C>T) in the other three cases. Ezetimibe (10 mg/day) was administered in one case, with complete resolution of symptoms. All patients were advised a low plant sterol diet and regular monitoring of hemoglobin and lipid profile. Our cases highlight a rare but important cause of hemolytic anemia that can be suspected from careful peripheral blood examination but only conclusively established by molecular genetic diagnosis. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the blood pressure (BP)–lowering effects of statins by conducting a systematic review and meta-analysis of placebo-randomized controlled trials (RCTs). Method: We conducted a meta-analysis of placebo RCTs reporting antihypertensive effects of statins therapy. We only included RCTs that did not allow for concomitant antihypertensive therapy, or clearly stated that antihypertensive therapy was fixed throughout the study period. Results: Our meta-analysis included 46 placebo RCTs, including 53 group comparisons and a total of 49,087 participants (24,589 participants in the statin groups and 24,498 participants in the placebo group). Subgroup analysis, based on use of concomitant antihypertensive, was performed. The meta-analysis showed that statin reduced systolic BP by − 1.6 mmHg (95% CI: − 2.50 to − 0.60), and diastolic BP by − 0.96 mmHg (95% CI: − 1.36 to − 0.56). Although the presence of concomitant antihypertensive therapy diluted the BP lowering effect of statins, it remained statistically significant and independent of the lipid-lowering activity. Furthermore, the BP –lowering effect of the statins was independent of the dose or type of statin (p > 0.05). Conclusion: Our results strengthen the evidence for pleiotropic effects of statins on BP that are independent of their lipid-lowering activity, supporting their beneficial role in hypertensive patients with dyslipidemia. [ABSTRACT FROM AUTHOR]

Transient receptor potential vanilloid 4 (TRPV4) is a nonselective Ca2+-permeable cation channel that is a member of the TRP channel family. It is clear that TRPV4 channels are broadly expressed in the brain. As they are expressed on the plasma membrane, they interact with other channels and play a crucial role in nervous system activity. Under some pathological conditions, TRPV4 channels are upregulated and sensitized via cellular signaling pathways, and this can cause nervous system diseases. In this review, we focus on receptors that cooperate with TRPV4, including large-conductance Ca2+-activated K+(BKca) channels, N-methyl-D-aspartate receptors (NMDARs), α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate receptors (AMPARs), inositol 1,4,5-trisphosphate receptors (IP3Rs), ryanodine receptors (RyRs), aquaporin 4 (AQP4), and other potential cooperative receptors in the brain. The data demonstrate how these channels work together to cause nervous system diseases under pathological conditions. The aim of this review was to discuss the receptors and signaling pathways related to TRPV4 based on recent data on the important physiological functions of TRPV4 channels to provide new clues for future studies and prospective therapeutic targets for related brain diseases. [ABSTRACT FROM AUTHOR]

As a ubiquitous enzyme, succinic semialdehyde dehydrogenase contributes significantly in many pathways including the tricarboxylic acid cycle and other metabolic processes such as detoxifying the accumulated succinic semialdehyde and surviving in nutrient-limiting conditions. Here the cce4228 gene encoding succinic semialdehyde dehydrogenase from Cyanothece sp. ATCC51142 was cloned and the homogenous recombinant cce4228 protein was obtained by Ni-NTA affinity chromatography. Biochemical characterization revealed that cce4228 protein displayed optimal activity at presence of metal ions in basic condition. Although the binding affinity of cce4228 protein with NAD+ was about 50-fold lower than that of cce4228 with NADP+, the catalytic efficiency of cce4228 protein towards succinic semialdehyde with saturated concentration of NADP+ is same as that with saturated concentration of NAD+ as its cofactors. Meanwhile, the catalytic activity of cce4228 was competitively inhibited by succinic semialdehyde substrate. Kinetic and structural analysis demonstrated that the conserved Cys262 and Glu228 residues were crucial for the catalytic activity of cce4228 protein and the Ser157 and Lys154 residues were determinants of cofactor preference. [ABSTRACT FROM AUTHOR]

Current guidelines state that systemic inflammation, together with endothelial dysfunction, calcification, and hypercoagulability, predispose to premature atherosclerosis in patients with inflammatory bowel disease (IBD). We assessed whether IBD can affect aortic stiffness, a well-recognized vascular biomarker and an independent risk factor for cardiovascular (CV) disease (CVD) in several populations. Recent studies reported that aortic stiffness is increased in adults with IBD compared with matched controls. This association is dependent on inflammatory burden and disease duration, and is reduced by antitumor necrosis factor therapy. Considered together, current findings suggest that increased aortic stiffness is an extraintestinal manifestation of IBD. This is clinically relevant since measuring aortic stiffness in patients with IBD could improve risk assessment, especially in those without established CVD. Moreover, effective control of inflammation could lower CV risk in patients with IBD by reducing aortic stiffness. Further longitudinal studies are needed to better clarify (i) the relationship between disease duration and irreversible changes of the arterial wall, (ii) the clinical characteristics of patients with IBD that have an increased arterial stiffness at least in part reversible, and (iii) whether arterial stiffness is useful to evaluate the efficacy of immunosuppressive therapy. [ABSTRACT FROM AUTHOR]

Background: The compilation of a list of genetic modifiers in Alzheimer's disease (AD) is an open research field. The GABAergic system is affected in several neurological disorders but its role in AD is largely understudied.Objective/methods: As an explorative study, we considered variants in genes of GABA catabolism (ABAT, ALDH5A1, AKR7A2), and APOE in 300 Italian patients and 299 controls. We introduce a recent multivariate method to take into account the individual APOE genotype, thus controlling for the effect of the discrepant allele distributions in cases versus controls. We add a genotype-phenotype analysis based on age at onset and the Mini-Mental State Evaluation score.Results: On the background of strongly divergent APOE allele distributions in AD versus controls, two genotypic interactions that represented a subtle but significant peculiarity of the AD cohort emerged. The first is between ABAT and APOE, and the second between some ALDH5A1 genotypes and APOE. Decreased SSADH activity is predicted in AD carriers of APOEɛ4, representing an additional suggestion for increased oxidative damage.Conclusion: We identified a difference between AD and controls, not in a shift of the allele frequencies at genes of the GABA catabolism pathway, but rather in gene interactions peculiar of the AD cohort. The emerging view is that of a multifactorial contribution to the disease, with a main risk factor (APOE), and additional contributions by the variants here considered. We consider genes of the GABA degradation pathway good candidates as modifiers of AD, contributing to energy impairment in AD brain. [ABSTRACT FROM AUTHOR]

Purpose: Phytosterols reduce intestinal cholesterol absorption and help to lower LDL-cholesterol. Many Chinese adults are lactose-intolerant and cannot tolerate bovine milk enriched with phytosterol. Soya-milk is a common beverage in Asia and it has beneficial effects on general health. We therefore conducted a randomized double-blind controlled trial to assess the effectiveness of a phytosterols-enriched soya drink in lowering serum LDL-cholesterol level (primary outcome) and other cardiovascular parameters (secondary outcomes). Methods: One hundred and fifty-nine normocholesterolaemic participants (85 men and 74 women; aged 19–79) were randomized to daily intake of one serving of phytosterols-enriched soya drink (N = 82), equivalent to 2 g of phytosterol per day, or a matched soya drink without phytosterols (N = 77) for 3 weeks. Adverse events, withdrawal and compliance were documented. Results: Among the treatment group (N = 82), phytosterols-enriched soya drink significantly decreased LDL-cholesterol by 5.96% (SE 1.48, 95% CI − 8.91%, − 3.00%) with a median of 6.74% compared with baseline, resulting in a significant reduction of 4.70% (95% CI − 8.89%, − 0.51%; p = 0.028) with a median of 5.20% compared with placebo (N = 77). In contrast, there were no significant changes in other lipid parameters, blood glucose, blood pressure, body weight or waist circumference. Remarkably, 95% of the participants randomized to the fortified drink reported no adverse events at all. Conclusions: Daily consumption of a phytosterols-enriched soya drink may be a simple and cost-neutral means of lowering LDL-cholesterol in individuals in China, with massive population and rising incidence of coronary heart disease (ClinicalTrials.gov identifier: NCT02881658; date of registration: 14 Aug 2016). [ABSTRACT FROM AUTHOR]

Objective: The relationship between anemia and bone disease markers was examined to a great extent in patients undergoing renal replacement therapy. The aim of this study was to investigate the relationship between bone disease markers and anemia in a cohort of adult patients without renal replacement therapy. Materials and Methods: A total of 1279 patients with stage 3b and 4 kidney disease who were admitted to the Nephrology outpatient clinic of the Kayseri Research and Training Hospital between January 1, 2014, and December 31, 2017, formed the study cohort. Logistic and linear regression models were developed to explore the adjusted effects of calcium, phosphorus, parathyroid hormone (PTH), and 25-hydroxyvitamin D concentrations on anemia. Other confounding variables were included in regression equations. Results: In the adjusted logistic regression model, it was found that the prevalence of anemia was significantly associated with calcium, phosphorus, and PTH levels. An increase of 1 mmol L-1 in serum calcium and phosphorus concentrations was associated with a 32% reduction (OR: 0.68; 95% CI: 0.51-0.91; p=0.011) and a 2.4-fold increase (OR: 2.40; 95% CI: 1.40, 4.13; p=0.002) in the prevalence of anemia, respectively. In a receiver operating characteristic analysis for identifying anemia, discriminating power of phosphorus was superior to the other bone disease markers [best cut-off value >1.23 mmol L-1, AUC 0.65 (0.624-0.677)] Conclusion: Serum calcium and phosphorus levels may contribute to the development of anemia in patients with stage 3b and 4 chronic kidney disease who are not receiving renal replacement therapy. [ABSTRACT FROM AUTHOR]

Spaceflight missions expose astronauts to increased risk of oxidative stress and inflammatory damage that might accelerate the development of asymptomatic cardiovascular disease. The purpose of this investigation was to determine whether long-duration spaceflight (4 mo) results in structural and functional changes in the carotid and brachial arteries. Common carotid artery (CCA) intimamedia thickness (cIMT), CCA distensibility and stiffness, and brachial artery endothelium-dependent and -independent vasodilation were measured in 13 astronauts (10 men, 3 women) ~180 and 60 days before launch, during the mission on ~15, 60, and 160 days of spaceflight, and within 1 wk after landing. Biomarkers of oxidative stress and inflammation were measured at corresponding times in fasting blood samples and urine samples from 24- or 48-h pools. Biomarkers of oxidative stress and inflammation increased during spaceflight, but most returned to preflight levels within 1 wk of landing. Mean cIMT, CCA stiffness, and distensibility were not significantly different from preflight at any time. As a group, neither mean endothelium-dependent nor -independent vasodilation changed from preflight to postflight, but changes within individuals in endothelial function related to some biomarkers of oxidative stress. Whereas biomarkers of oxidative stress and inflammation are elevated during spaceflight, CCA and brachial artery structure and function were not changed by spaceflight. It is unclear whether future exploration missions, with an extended duration in altered gravity fields and higher radiation exposure, may be problematic. NEW & NOTEWORTHY Carotid artery structure and stiffness did not change on average in astronauts during long-duration spaceflight (12 mo), despite increased oxidative stress and inflammation. Most oxidative stress and inflammation biomarkers returned to preflight levels soon after landing. Brachial artery structure and function also were unchanged by spaceflight. In this group of healthy middle-aged male and female astronauts, spaceflight in low Earth orbit does not appear to increase long-term cardiovascular health risk. [ABSTRACT FROM AUTHOR]

Background: Attention-Deficit Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) are two of the most frequently-observed neurodevelopmental disorders. Autistic traits are detected frequently in children who have ADHD. This study aimed to examine autism symptoms in children diagnosed with ADHD and their parents; and also, to investigate parental risk factors that increase autistic traits in children. Besides the risk factors related to pregnancy, birth and developmental history were examined. Methods: Two groups were created consisting of 66 children diagnosed with ADHD and 33 children not diagnosed with ADHD and their parents. Autism symptoms were screened with the Autism Behavior Checklist (ABC) in children, and Autism Spectrum Quotient (AQ) in parents. Also, Adult ADD/ADHD DSM-IV Based Diagnostic Screening and Rating Scale and Wender Utah Rating Scale (WURS) were used to determine ADHD symptoms in parents. Results: It was determined that there were more autism symptoms in children who were diagnosed with ADHD than in the control group without ADHD. There were more autistic symptoms in boys and the presence of Oppositional Defiant Disorder (ODD). Although there were more ADHD symptoms in the parents of children diagnosed with ADHD, it was determined that they did not differ from parents in the control group in terms of autism symptoms. It was also determined that maternal and paternal ADHD symptoms were predictive for autism symptoms in children. It was also shown that maternal smoking during pregnancy is associated with more autistic traits. Conclusion: ASD and ADHD show high levels of comorbidity. The etiology remains unclear. Both ADHD and ASD show strong hereditary transition. We found that maternal and paternal ADHD symptoms predict autism symptoms in children with ADHD. However, more studies are needed to reveal the etiology. [ABSTRACT FROM AUTHOR]

The ability of Uropathogenic Escherichia coli (UPEC) to form biofilms, can be considered an important factor that contributes to the prevalence of Urinary Tract Infections (UTIs) due to the inaccessibility of the antibiotics into the highly complex structure of the biofilm. Moreover, with the appearance of antibiotic multiresistant UPEC strains, the alternatives of treatment of UTIs are less. Silver nanoparticles (AgNPs) can be useful in the treatment of the UPEC infections due to its physicochemical properties that confer them antibacterial activity against both planktonic and biofilm structured cells. A diversity of biological methods for synthesis of AgNPs with antimicrobial activity has been widely investigated during the last decades, between these methods; the fungal-biosynthesis of AgNPs highlights as an ecofriendly, scalable and low cost method. In this study, biogenic AgNPs were synthesized with extracellular metabolites secreted by the soil fungal strain Fusarium scirpi (Ag0.5–5) by an ecofriendly, simple and efficient method. The antimicrobial activity of the biosynthesized AgNPs against UPEC was evaluated. The Minimal Inhibitory Concentration (MIC) of biogenic AgNPs over planktonic UPEC cells was 25 mg/mL, whereas a sub-MIC concentration (7.5 mg/L) was sufficient to inhibit the UPEC-biofilm formation about a 97%, or produce the disruption of an 80% of mature UPEC-biofilms demonstrating the potential of fungal-derived AgNPs to prevent UPEC infections. [ABSTRACT FROM AUTHOR]

Silver, zinc, and copper nanoparticles were reductively crystallized on thymine-containing single-stranded DNA decanucleotides, in aqueous solutions containing the corresponding metal ions and sodium borohydride, at 4 °C, pH 11.8, and 15 mM of NaCl. Iron nanoparticles were not formed under these conditions. Formation of aggregates was monitored by UV-Vis spectrophotometry, and characterized by scanning electron microscopy and dynamic light scattering. The absorption spectra for most Ag+-containing samples showed a major band centered around 425 nm and a shoulder between 500 and 600 nm, indicative of the presence of silver particles in a wide size distribution, in the 0.1–5 μm range. This was verified by micrographs and size distribution observed in scattering profiles. Silver-particle morphology indicates formation of cubic structures instead of spherical geometries. For the case of zinc and copper nanoparticles, quasi-spherical structures of approximately 100 nm were crystallized along the DNA chains by reduction reaction, and then released to the bulk solvent. Thymine residues show a higher effectiveness in nucleation of metallic cations in comparison to other DNA nucleobases, particularly in their deprotonated form, at high pH values. Adenines flanking central runs of deprotonable bases in the model oligonucletide chain affect the production of silver crystals on the DNA decamers. pH value and NaCl concentration have a significant effect on the production of silver particles, as alkaline and moderate-ionic-strength conditions are required to crystallize such structures. The tuning of size and morphology of metallic nanoparticles by the proper choice of oligonucleotide sequence and physical conditions may have interesting applications in the field of nanobiotechnology. [ABSTRACT FROM AUTHOR]

Farnesol, the sesquiterpenoid precursor of the six presently known insect juvenile hormones (JHs) was for the first time chemically identified in 1961, not in JH synthesizing glands or whole body extracts, but in excrements of the mealworm Tenebrio molitor. This finding was thought to be irrelevant and remained unexplored. In 1970, it was reported that the fall to zero of the JH titer in both prediapausing adults and in last instar larvae of the Colorado potato beetle causes severe malfunctioning of the Golgi system in the fat body, among various other effects. This endomembrane system in the cytoplasm resides at the intersection of the secretory, lysosomal, and endocytic pathways and is required for the processing of secretory proteins. Why the Golgi needs farnesol-like endogenous sesquiterpenoids (FLS) for its proper functioning has also never been further investigated. In 1999, farnesol was found to be a natural endogenous ligand for particular types of voltage-gated Ca2+ channels in mammalian cells, a finding that also remained undervalued. Only since 2014 more attention has been paid to the functional research of the "noble unknown" farnesol, in particular to its Ca2+-homeostasis-related juvenilizing and anti-apoptotic activities. Here, we introduce the term "Golgicrine activity" that addresses the secretory activity of the RER-Golgi system from its role in Ca2+-homeostasis rather than from its conventional role in mere protein secretion. Golgicrine activity attributes the so far forgotten role of farnesol-like sesquiterpenoids in proper Golgi functioning, and unites the endocrine, exocrine and enterocrine functions of these sesquiterpenoids. This out of the box view may open novel perspectives for the better understanding of particular inflammatory bowel diseases and of neurodegenerative diseases as well, because the early initiation of Alzheimer's disease may possibly result from malfunctioning of the mevalonate-farnesol-cholesterol biosynthetic pathway and thus might be a farnesol- and Ca2+-homeostasis-dependent Golgicrine issue. [ABSTRACT FROM AUTHOR]

Part of the ventral striatal division, the nucleus accumbens (NAc) drives the circuit activity of an entire macrosystem about reward like a "flagship," signaling and leading diverse conducts. Accordingly, NAc neurons feature complex inhibitory phenotypes that assemble to process circuit inputs and generate outputs by exploiting specific arrays of opposite and/or parallel neurotransmitters, neuromodulatory peptides. The resulting complex combinations enable versatile yet specific forms of accumbal circuit plasticity, including maladaptive behaviors. Although reward signaling and behavior are elaborately linked to neuronal circuit activities, it is plausible to propose whether these neuronal ensembles and synaptic islands can be directly controlled by astrocytes, a powerful modulator of neuronal activity. Pioneering studies showed that astrocytes in the NAc sense citrate cycle metabolites and/or ATP and may induce recurrent activation. We argue that the astrocytic calcium, GABA, and Glu signaling and altered sodium and chloride dynamics fundamentally shape metaplasticity by providing active regulatory roles in the synapse- and network-level flexibility of the NAc. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH) is a morbid disease characterized by progressive right ventricle (RV) failure due to elevated pulmonary artery pressures (PAP). In PAH, histologically complex vaso-occlusive lesions in the pulmonary vasculature contribute to elevated PAP. However, the mechanisms underlying dysfunction of the microvascular endothelial cells (MVECs) that comprise a significant portion of these lesions are not well understood. We recently showed that MVECs isolated from the Sugen/hypoxia (SuHx) rat experimental model of PAH (SuHx-MVECs) exhibit increases in migration/proliferation, mitochondrial reactive oxygen species (ROS; mtROS) production, intracellular calcium levels ([Ca2+]i), and mitochondrial fragmentation. Furthermore, quenching mtROS with the targeted antioxidant MitoQ attenuated basal [Ca2+]i, migration and proliferation; however, whether increased mtROS-induced [Ca2+]i entry affected mitochondrial morphology was not clear. In this study, we sought to better understand the relationship between increased ROS, [Ca2+]i, and mitochondrial morphology in SuHx-MVECs. We measured changes in mitochondrial morphology at baseline and following inhibition of mtROS, with the targeted antioxidant MitoQ, or transient receptor potential vanilloid-4 (TRPV4) channels, which we previously showed were responsible for mtROS-induced increases in [Ca2+]i in SuHx-MVECs. Quenching mtROS or inhibiting TRPV4 attenuated fragmentation in SuHx-MVECs. Conversely, inducing mtROS production in MVECs from normoxic rats (N-MVECs) increased fragmentation. Ca2+ entry induced by the TRPV4 agonist GSK1017920A was significantly increased in SuHx-MVECs and was attenuated with MitoQ treatment, indicating that mtROS contributes to increased TRPV4 activity in SuHx-MVECs. Basal and maximal respiration were depressed in SuHx-MVECs, and inhibiting mtROS, but not TRPV4, improved respiration in these cells. Collectively, our data show that, in SuHx-MVECs, mtROS production promotes TRPV4-mediated increases in [Ca2+]i, mitochondrial fission, and decreased mitochondrial respiration. These results suggest an important role for mtROS in driving MVEC dysfunction in PAH. [ABSTRACT FROM AUTHOR]

Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare autosomal recessive disorder of γ-aminobutyric acid (GABA) catabolism caused by mutations in the gene coding for succinic semialdehyde dehydrogenase (ALDH5A1). The abnormal levels of GHB detected in the brain and in all physiological fluids of SSADHD patients represent a diagnostic biochemical hallmark of the disease. Here we report on the clinical and molecular characterization of two unrelated Italian patients and the identification of two novel mutations: a 22 bp DNA duplication in exon 1, c.114_135dup, p.(C46AfsX97), and a non-sense mutation in exon 10, c.1429C > T, p.(Q477X). The two patients showed very different clinical phenotypes, coherent with their age. These findings enrich the characterization of SSADHD families and contribute to the knowledge on the progression of the disease. [ABSTRACT FROM AUTHOR]