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Table grape viticulture, due to the impact of climate change, will have to face many challenges in the coming decades, including resistance to pathogens and physiological disorders. Our attention was focused on fruit cracking due to its ubiquitous presence in several species. This study explores the effects of three different treatments on the epidermis and cuticle of table grape berries by evaluating the impact of the girdling technique on various fruit quality parameters, including cuticle thickness, sugar content, acidity, color, bunch weight, and rheological properties. The treatments were (1) calcium chloride (CaCl2), (2) calcium chloride + salicylic acid (CaCl2 + SA), and (3) calcium chloride + Ascophyllum nodosum (CaCl2 + AN), with and without girdling, plus an untreated control. This research was conducted over the 2021–2022 growing season in a commercial vineyard in Licodia Eubea, Sicily, Italy. The results indicate significant variations in cuticle thickness and other qualitative traits throughout the growth and ripening phases, with notable differences depending on the treatment used. This study's findings suggest that specific treatments can influence the structural integrity of the grape cuticle, potentially impacting the fruit's susceptibility to cracking and overall marketability. The findings provide valuable insights into the role of chemical treatments and cultural techniques in enhancing fruit quality and resistance to environmental stresses in table grape cultivation. [ABSTRACT FROM AUTHOR]

Inhibitors of monoamine oxidases (MAOs) are of interest for the treatment of neurodegenerative disorders and other human pathologies. In this frame, the present work describes different synthetic strategies to obtain MAO inhibitors via the coupling of the aminocoumarin core with arylsulfonyl chlorides followed by copper azide-alkyne cycloaddition, leading to coumarin–sulfonamide–nitroindazolyl–triazole hybrids. The nitration position on the coumarin moiety was confirmed through nuclear magnetic resonance spectroscopy and molecular electron density theory in order to elucidate the molecular mechanism and selectivity of the electrophilic aromatic substitution reaction. The coumarin derivatives were evaluated for their inhibitory potency against monoamine oxidases and cholinesterases. Molecular docking calculations provided a rational binding mode of the best compounds in the series with MAO A and B. The work identified hybrids 14a–c as novel MAO inhibitors, with a selective action against isoform B, of potential interest to combat neurological diseases. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disorder. While there are five FDA-approved drugs for treating this disease, each has only modest benefits. To design new and more effective therapies for ALS, particularly for sporadic ALS of unknown and diverse etiologies, we must identify key, convergent mechanisms of disease pathogenesis. This review focuses on the origin and effects of glutamate-mediated excitotoxicity in ALS (the cortical hyperexcitability hypothesis), in which increased glutamatergic signaling causes motor neurons to become hyperexcitable and eventually die. We characterize both primary and secondary contributions to excitotoxicity, referring to processes taking place at the synapse and within the cell, respectively. 'Primary pathways' include upregulation of calcium-permeable AMPA receptors, dysfunction of the EAAT2 astrocytic glutamate transporter, increased release of glutamate from the presynaptic terminal, and reduced inhibition by cortical interneurons—all of which have been observed in ALS patients and model systems. 'Secondary pathways' include changes to mitochondrial morphology and function, increased production of reactive oxygen species, and endoplasmic reticulum (ER) stress. By identifying key targets in the excitotoxicity cascade, we emphasize the importance of this pathway in the pathogenesis of ALS and suggest that intervening in this pathway could be effective for developing therapies for this disease. [ABSTRACT FROM AUTHOR]

This review deals with major diseases caused by fungi and oomycetes in the citrus supply chain, including post-harvest fruit diseases, and summarizes the strategies and techniques that may be adopted to prevent the damages and losses they cause. Its scope is to highlight the contribute that smart technologies provide towards new solutions for sustainable and safe management strategies of these diseases. Particular attention is given to the application of biopesticides, natural substances, resistance inducers and biostimulants to prevent fruit rots. The review focuses also on mycotoxins and mycotoxigenic fungi that contaminate fresh fruit and food products derived from citrus fruit, an aspect that has been little investigated and regulated so far. An additional relevant aspect addressed by the review is the early detection and routine diagnosis of fungal and oomycete pathogens that threat the international trade and long-distance shipment of citrus fruit, with a particular emphasis on quarantine pathogens. In this respect, the opportunities offered by new practical, rapid, sensitive and robust molecular diagnostic methods are briefly discussed. [ABSTRACT FROM AUTHOR]

Background. Adolescence is a critical phase of development characterized by numerous physical, psychological and social changes. During this stage, individuals may engage in experimentation and risky behavior, leading to increased vulnerability to addiction. This article aims to present the results of a survey based on the HBSC (Health Behavior in School-aged Children) surveillance model in a province of Southern Italy for primary and secondary school students. Methods. We conducted a prospective study from March 2020 to April 2023 through the administration of a questionnaire to students of the healthcare faculties of the University of Messina and primary and secondary school students, composed of 19 items and based on HBSC surveillance. Results. We collected a total of 664 questionnaires. We found that smoking habits increase with age: approximately 31% of secondary school students declare they are real smokers compared to 40% of HCP students. At least once, in the three study groups, students experienced alcohol consumption at different rates, with younger students having a greater propensity to drink than older students. Fortunately, in our sample, no middle school students had tried cannabis. At the same time there is a surprising decrease in gambling in all categories compared to national data. Conclusions. The presence of addictive behaviors in our sample was found to be widespread despite being in line with the national trend. Furthermore, we have observed a reduction in recent years which needs to be investigated to assess the reasons. Primary prevention is probably the main weapon in the hands of politicians and must be applied early in school and community settings to reduce prevalence. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases such as Alzheimer's disease (AD) are multifactorial with several different pathologic mechanisms. Therefore, it is assumed that multitargeted-directed ligands (MTDLs) which interact with different biological targets relevant to the diseases, might offer an improved therapeutic alternative than using the traditional "one-target, one-molecule" approach. Herein, we describe new benzothiazole-based derivatives as a privileged scaffold for histamine H3 receptor ligands (H3R). The most affine compound, the 3-(azepan-1-yl)propyloxy-linked benzothiazole derivative 4b, displayed a Ki value of 0.012 μM. The multitargeting potential of these H3R ligands towards AChE, BuChE and MAO-B enzymes was evaluated to yield compound 3s (pyrrolidin-1-yl-(6-((5-(pyrrolidin-1-yl)pentyl)oxy)benzo[d]thiazol-2-yl)methanone) as the most promising MTDL with a Ki value of 0.036 μM at H3R and IC50 values of 6.7 µM, 2.35 µM, and 1.6 µM towards AChE, BuChE, and MAO-B, respectively. These findings suggest that compound 3s can be a lead structure for developing new multi-targeting anti-AD agents. [ABSTRACT FROM AUTHOR]

The antimicrobial activity, surface features, wettability, and adhesion of photocatalytic xerogel AquaSun deposited on shipbuilding steel in comparison to those of a commercial antifouling paint are investigated. The antimicrobial activity of AquaSun deposited on a steel substrate pretreated with primer and tiecoat paint exposed to a microbial consortium composed of Bacillus aquimaris and Pseudomonas poae is significant and of broad scope. Taking into account the low cost, high stability, and lack of ecotoxicity of this hybrid sol–gel coating, these results are promising en route to developing novel antibacterial coatings of broad applicability. [ABSTRACT FROM AUTHOR]

Identifying genetic modifiers of familial amyotrophic lateral sclerosis (ALS) may reveal targets for therapeutic modulation with potential application to sporadic ALS. GGGGCC (G4C2) repeat expansions in the C9orf72 gene underlie the most common form of familial ALS, and generate toxic arginine-containing dipeptide repeats (DPRs), which interfere with membraneless organelles, such as the nucleolus. Here we considered senataxin (SETX), the genetic cause of ALS4, as a modifier of C9orf72 ALS, because SETX is a nuclear helicase that may regulate RNA–protein interactions involved in ALS dysfunction. After documenting that decreased SETX expression enhances arginine-containing DPR toxicity and C9orf72 repeat expansion toxicity in HEK293 cells and primary neurons, we generated SETX fly lines and evaluated the effect of SETX in flies expressing either (G4C2)58 repeats or glycine-arginine-50 [GR(50)] DPRs. We observed dramatic suppression of disease phenotypes in (G4C2)58 and GR(50) Drosophila models, and detected a striking relocalization of GR(50) out of the nucleolus in flies co-expressing SETX. Next-generation GR(1000) fly models, that show age-related motor deficits in climbing and movement assays, were similarly rescued with SETX co-expression. We noted that the physical interaction between SETX and arginine-containing DPRs is partially RNA-dependent. Finally, we directly assessed the nucleolus in cells expressing GR-DPRs, confirmed reduced mobility of proteins trafficking to the nucleolus upon GR-DPR expression, and found that SETX dosage modulated nucleolus liquidity in GR-DPR-expressing cells and motor neurons. These findings reveal a hitherto unknown connection between SETX function and cellular processes contributing to neuron demise in the most common form of familial ALS. [ABSTRACT FROM AUTHOR]

Increasing the economic and environmental sustainability of irrigated agriculture is a vital challenge for the Mediterranean crop production sector. This study explores the effects of the adoption of reclaimed water (RW) as source of irrigation in conjunction with the application of deficit irrigation strategies in an olive orchard (different genotypes) located within the "Valle dei Margi" farmhouse (Eastern Sicily). Specifically, the RW was obtained in situ by treating the wastewater coming from the farmhouse throughout a nature-based treatment wetland system (TW). The effects of RW on crop water status (CWS) was assessed by conducting plant-based measurements (i.e., leaf water potential, Ψ; and leaves' relative water content, RWC) and determining satellite-based biophysical indicators. An economic and environmental evaluation of the proposed sustainable irrigation practices was carried out using the life cycle assessment (LCA) approach. The RW quality showed high variability due to fluctuations in the number of customers at the farmhouse during the COVID-19 pandemic period. A strong impact on the variation in Ψ was observed among the olive orchard under the different water regimes, evidencing how CWS performances are conditioned by the genotype. However, no differences in leaves' RWC and in satellite-based biophysical indicators were detected. Finally, the results of the LCA analysis underlined how the use of RW may permit us to obtain important economic and environmental gains, representing an added value for olive growing for operating in accordance to more sustainable development models. [ABSTRACT FROM AUTHOR]

Background. Many studies have shown that the stress level among healthcare university students is often as high as in workers who experience burnout. Our study investigated if it is possible to observe the burnout syndrome in these kind of students, able to significantly alter the quality of life, their approach to daily activities and relationship life. Methods. The study was conducted through the administration of an anonymous questionnaire, distributed online through messaging apps, during the breaks between lessons. It was formulated using the perceived stress scale (PSS) in its short formula in order to evaluate feelings and thoughts and the WHOQOL-AGE, in order to evaluate the quality of life. Results. The sample consisted of 292 university students aged between 18 and 49, with an average age of 22,42 ± 4,65. 16.4% does not often feel able to control the important things in life, 42.8% is often unable to manage personal problems. The PSS score of all our university students showed a high stress level in 6.2%, an average stress level in 57.2% and low stress level in 36.6%. The WHOQOL score shows that 42% had a high quality of life and only 4% had a poor quality of life, 54% had an intermediate quality of life and half of the sample was unsatisfied with the way he felt every day. Conclusions. Many students (63.4%) are subjected to stress study-related, even if does not affect their quality of live, therefore not perceiving it as negative. There is a gender difference: females have a higher level of stress than men. Two thirds of the sample has an average or high stress level; only a third has a low grade. Stress prevention in young university students must begin through a new way of teaching, even if a certain amount of stress studyrelated is stimulant. [ABSTRACT FROM AUTHOR]

Climate change, desertification, salinisation of soils and the changing hydrology of the Earth are creating or modifying microbial habitats at all scales including the oceans, saline groundwaters and brine lakes. In environments that are saline or hypersaline, the biodegradation of recalcitrant plant and animal polysaccharides can be inhibited by salt‐induced microbial stress and/or by limitation of the metabolic capabilities of halophilic microbes. We recently demonstrated that the chitinolytic haloarchaeon Halomicrobium can serve as the host for an ectosymbiont, nanohaloarchaeon 'Candidatus Nanohalobium constans'. Here, we consider whether nanohaloarchaea can benefit from the haloarchaea‐mediated degradation of xylan, a major hemicellulose component of wood. Using samples of natural evaporitic brines and anthropogenic solar salterns, we describe genome‐inferred trophic relations in two extremely halophilic xylan‐degrading three‐member consortia. We succeeded in genome assembly and closure for all members of both xylan‐degrading cultures and elucidated the respective food chains within these consortia. We provide evidence that ectosymbiontic nanohaloarchaea is an active ecophysiological component of extremely halophilic xylan‐degrading communities (although by proxy) in hypersaline environments. In each consortium, nanohaloarchaea occur as ectosymbionts of Haloferax, which in turn act as scavenger of oligosaccharides produced by xylan‐hydrolysing Halorhabdus. We further obtained and characterised the nanohaloarchaea–host associations using microscopy, multi‐omics and cultivation approaches. The current study also doubled culturable nanohaloarchaeal symbionts and demonstrated that these enigmatic nano‐sized archaea can be readily isolated in binary co‐cultures using an appropriate enrichment strategy. We discuss the implications of xylan degradation by halophiles in biotechnology and for the United Nation's Sustainable Development Goals. [ABSTRACT FROM AUTHOR]

This study identified secondary metabolites produced by Alternaria alternata, Colletotrichum gloeosporioides, and Penicillium digitatum in fruits of two blood orange cultivars before harvest. Analysis was performed by UHPLC–Q-TOF-MS. Three types of fruits were selected, asymptomatic, symptomatic showing necrotic lesions caused by hail, and mummified. Extracts from peel and juice were analyzed separately. Penicillium digitatum was the prevalent species recovered from mummified and hail-injured fruits. Among 47 secondary metabolites identified, 16, 18, and 13 were of A. alternata, C. gloeosporioides, and P. digitatum, respectively. Consistently with isolations, indicating the presence of these fungi also in asymptomatic fruits, the metabolic profiles of the peel of hail-injured and asymptomatic fruits did not differ substantially. Major differences were found in the profiles of juice from hail-injured and mummified fruits, such as a significant higher presence of 5,4-dihydroxy-3,7,8-trimethoxy-6C-methylflavone and Atrovenetin, particularly in the juice of mummified fruits of the Tarocco Lempso cultivar. Moreover, the mycotoxins patulin and Rubratoxin B were detected exclusively in mummified fruits. Patulin was detected in both the juice and peel, with a higher relative abundance in the juice, while Rubratoxin B was detected only in the juice. These findings provide basic information for evaluating and preventing the risk of contamination by mycotoxins in the citrus fresh fruit supply chain and juice industry. [ABSTRACT FROM AUTHOR]

Extremely halophilic representatives of the phylum Candidatus Nanohaloarchaeota (members of theDPANNsuperphyla) are obligately associated with extremely halophilic archaea of the phylum Halobacteriota (according to the GTDB taxonomy). Using culture-independent molecular techniques, their presence in various hypersaline ecosystems around the world has been confirmed over the past decade. However, the vast majority of nanohaloarchaea remain uncultivated, and thus their metabolic capabilities and ecophysiology are currently poorly understood. Using the (meta)genomic, transcriptomic, and DNA methylome platforms, the metabolism and functional prediction of the ecophysiology of two novel extremely halophilic symbiotic nanohaloarchaea (Ca. Nanohalococcus occultus and Ca. Nanohalovita haloferacivicina) stably cultivated in the laboratory as members of a xylose-degrading binary culture with a haloarchaeal host, Haloferax lucentense, was determined. Like all known DPANN superphylum nanoorganisms, these new sugar-fermenting nanohaloarchaea lack many fundamental biosynthetic repertoires, making them exclusively dependent on their respective host for survival. In addition, given the cultivability of the new nanohaloarchaea, we managed to discover many unique features in these new organisms that have never been observed in nano-sized archaea both within the phylum Ca. Nanohaloarchaeota and the entire superphylum DPANN. This includes the analysis of the expression of organism-specific non-coding regulatory (nc)RNAs (with an elucidation of their 2D-secondary structures) as well as profiling of DNA methylation. While some ncRNA molecules have been predicted with high confidence as RNAs of an archaeal signal recognition particle involved in delaying protein translation, others resemble the structure of ribosome-associated ncRNAs, although none belong to any known family. Moreover, the new nanohaloarchaea have very complex cellular defense mechanisms. In addition to the defense mechanism provided by the type II restriction-modification system, consisting of Dcm-like DNA methyltransferase and Mrr restriction endonuclease, Ca. Nanohalococcus encodes an active type I-D CRISPR/Cas system, containing 77 spacers divided into two loci. Despitetheir diminutive genomes and as part of their host interaction mechanism, the genomes of new nanohaloarchaea do encode giant surface proteins, and one of them (9,409 amino acids long) is the largest protein of any sequenced nanohaloarchaea and the largest protein ever discovered in cultivated archaea. [ABSTRACT FROM AUTHOR]

X-linked spinal and bulbar muscular atrophy (SBMA; Kennedy's disease) is a rare neuromuscular disorder characterized by adult-onset proximal muscle weakness and lower motor neuron degeneration. SBMA was the first human disease found to be caused by a repeat expansion mutation, as affected patients possess an expanded tract of CAG repeats, encoding polyglutamine, in the androgen receptor (AR) gene. We previously developed a conditional BAC fxAR121 transgenic mouse model of SBMA and used it to define a primary role for skeletal muscle expression of polyglutamine-expanded AR in causing the motor neuron degeneration. Here we sought to extend our understanding of SBMA disease pathophysiology and cellular basis by detailed examination and directed experimentation with the BAC fxAR121 mice. First, we evaluated BAC fxAR121 mice for non-neurological disease phenotypes recently described in human SBMA patients, and documented prominent non-alcoholic fatty liver disease, cardiomegaly, and ventricular heart wall thinning in aged male BAC fxAR121 mice. Our discovery of significant hepatic and cardiac abnormalities in SBMA mice underscores the need to evaluate human SBMA patients for signs of liver and heart disease. To directly examine the contribution of motor neuron-expressed polyQ-AR protein to SBMA neurodegeneration, we crossed BAC fxAR121 mice with two different lines of transgenic mice expressing Cre recombinase in motor neurons, and after updating characterization of SBMA phenotypes in our current BAC fxAR121 colony, we found that excision of mutant AR from motor neurons did not rescue neuromuscular or systemic disease. These findings further validate a primary role for skeletal muscle as the driver of SBMA motor neuronopathy and indicate that therapies being developed to treat patients should be delivered peripherally. [ABSTRACT FROM AUTHOR]

Financial sanctions, alongside economic sanctions, are components of the toolkit used by governments as part of international diplomacy. The use of sanctions, especially financial, has increased over the last 70 years. Financial sanctions have been particularly important whenever the goals of the sanctioning countries were related to democracy and human rights. Financial sanctions restrict entities—countries, businesses, or even individuals—from purchasing or selling financial assets, or from accessing custodial or other financial services. They can be imposed on a sanctioned entity's ability to access the infrastructures that are in place to execute international payments, irrespective of whether such payments underpin financial or real activity. This article explains how financial sanctions can be designed to limit access to the international payment system and, in particular, the SWIFT network, and provides some recent examples. [ABSTRACT FROM AUTHOR]

Introduction: Clinical presentation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in old adults from Southern Italy is little known. This study aims to investigate the mortality risk related to risk factors, therapy and clinical course and to suggest prognostic indicators based on day-to-day follow-up of clinical and laboratory findings. Material and methods: It was designed as a retrospective longitudinal cohort study of adult SARS-CoV-2 patients admitted at Partinico COVID Hospital in Palermo, Southern Italy. Patients were recruited between 4 March and 25 April and followed up until 31 May 2020, day-to-day until death or hospital discharge. Clinical data, laboratory tests and treatment data were extracted from medical records and epidemiologic information was obtained by clinical history and the medical interview. Results: Forty-seven patients (median age = 75 IQR: 59.50–86.00) were followed up during a 87 days observation period, accounting for a total of 1,035 person days. At the end of follow-up, 28 (60%) patients were discharged and 19 (40%) died, so that the estimated incidence density rate was 0.018 deaths per day (18 SARS-CoV-2-related deaths per 1,000 patient days). Diabetes (HR = 8.13, 95% CI: 1.91–34.67), chronic kidney failure (HR = 5.86, 95% CI: 1.36–25.21), dementia (HR = 7.84, 95% CI: 1.80–34.20), and neutrophil/lymphocyte ratio > 7 (HR = 10.37, 95% CI: 2.24–48.14) were found as significant prognostic factors. Conclusions: The joint evaluation of dementia, diabetes, chronic kidney failure and neutrophil/lymphocyte ratio showed an optimal prognostic value already in the first week of follow-up. The day-to-day follow-up provides essential information for clinical monitoring and treatment of the disease in a hospital setting and improves the disease’s home management, especially for older patients with frailty. [ABSTRACT FROM AUTHOR]

The aim of this study was to determine the effectiveness of a Super absorbent polymer (SAP) containing copper (SAP-Cu) in controlling mal secco disease (MSD) of lemon caused by the fungus Plenodomus tracheiphilus. Super absorbent polymer containing copper was characterized by atomic absorption spectrometry (AAS) and UV-VIS spectroscopy. In vitro tests were performed to determine the inhibitory effects of SAP-Cu against the pathogen on both potato-dextrose-agar medium and naturally infected lemon cuttings. Super absorbent polymer was able to absorb up to about 200 and 30 times its weight of ionized water and copper (II) sulfate solution (Cu2C ions at the concentration 236 mM), respectively. The distribution of copper released on twigs after 24 h of contact with SAP-Cu was determined by secondary ion mass spectrometry with time-of-flight analyzer (ToF-SIMS). Super absorbent polymer containing copper significantly inhibited the viability of P. tracheiphilus in lemon twigs. Overall, the results of this study showed that the SAP could be a suitable carrier of antifungal compounds. [ABSTRACT FROM AUTHOR]

The article reports that in March 2020, at the onset of the COVID-19 pandemic, investors redeemed their shares en masse from both domestic and offshore dollar-denominated prime money market funds (MMFs). Relative to the size of the prime MMF industry, the run was remarkably similar to the run that took place in September 2008, during the global financial crisis, notwithstanding the starkly different natures of the shocks that precipitated the two episodes.

Isolation techniques supplemented by sequencing of DNA from axenic cultures have provided a robust methodology for the study of Phytophthora communities in agricultural and natural ecosystems. Recently, metabarcoding approaches have emerged as new paradigms for the detection of Phytophthora species in environmental samples. In this study, Illumina DNA metabarcoding and a conventional leaf baiting isolation technique were compared to unravel the variability of Phytophthora communities in different environments. Overall, 39 rhizosphere soil samples from a natural, a semi-natural and a horticultural small-scale ecosystem, respectively, were processed by both baiting and metabarcoding. Using both detection techniques, 28 out of 39 samples tested positive for Phytophthora. Overall, 1,406,613 Phytophthora internal transcribed spacer 1 (ITS1) sequences and 155 Phytophthora isolates were obtained, which grouped into 21 taxa, five retrieved exclusively by baiting (P. bilorbang; P. cryptogea; P. gonapodyides; P. parvispora and P. pseudocryptogea), 12 exclusively by metabarcoding (P. asparagi; P. occultans; P. psycrophila; P. syringae; P. aleatoria/P. cactorum; P. castanetorum/P. quercina; P. iranica-like; P. unknown sp. 1; P. unknown sp. 2; P. unknown sp. 3; P. unknown sp. 4; P. unknown sp. 5) and four with both techniques (P. citrophthora, P. multivora, P. nicotianae and P. plurivora). Both techniques complemented each other in describing the variability of Phytophthora communities from natural and managed ecosystems and revealing the presence of rare or undescribed Phytophthora taxa. [ABSTRACT FROM AUTHOR]

Both sleep-wake behavior and circadian rhythms are tightly coupled to energy metabolism and food intake. Altered feeding times in mice are known to entrain clock gene rhythms in the brain and liver, and sleep-deprived humans tend to eat more and gain weight. Previous observations in mice showing that sleep deprivation (SD) changes clock gene expression might thus relate to altered food intake, and not to the loss of sleep per se. Whether SD affects food intake in the mouse and how this might affect clock gene expression is, however, unknown. We therefore quantified (i) the cortical expression of the clock genes Per1, Per2, Dbp, and Cry1 in mice that had access to food or not during a 6 h SD, and (ii) food intake during baseline, SD, and recovery sleep. We found that food deprivation did not modify the SD-incurred clock gene changes in the cortex. Moreover, we discovered that although food intake during SD did not differ from the baseline, mice lost weight and increased food intake during subsequent recovery. We conclude that SD is associated with food deprivation and that the resulting energy deficit might contribute to the effects of SD that are commonly interpreted as a response to sleep loss. [ABSTRACT FROM AUTHOR]

Pathogenic variants in SETX cause two distinct neurological diseases, a loss-of-function recessive disorder, ataxia with oculomotor apraxia type 2 (AOA2), and a dominant gain-of-function motor neuron disorder, amyotrophic lateral sclerosis type 4 (ALS4). We identified two unrelated patients with the same de novo c.23C > T (p.Thr8Met) variant in SETX presenting with an early-onset, severe polyneuropathy. As rare private gene variation is often difficult to link to genetic neurological disease by DNA sequence alone, we used transcriptional network analysis to functionally validate these patients with severe de novo SETX-related neurodegenerative disorder. Weighted gene co-expression network analysis (WGCNA) was used to identify disease-associated modules from two different ALS4 mouse models and compared to confirmed ALS4 patient data to derive an ALS4-specific transcriptional signature. WGCNA of whole blood RNA-sequencing data from a patient with the p.Thr8Met SETX variant was compared to ALS4 and control patients to determine if this signature could be used to identify affected patients. WGCNA identified overlapping disease-associated modules in ALS4 mouse model data and ALS4 patient data. Mouse ALS4 disease-associated modules were not associated with AOA2 disease modules, confirming distinct disease-specific signatures. The expression profile of a patient carrying the c.23C > T (p.Thr8Met) variant was significantly associated with the human and mouse ALS4 signature, confirming the relationship between this SETX variant and disease. The similar clinical presentations of the two unrelated patients with the same de novo p.Thr8Met variant and the functional data provide strong evidence that the p.Thr8Met variant is pathogenic. The distinct phenotype expands the clinical spectrum of SETX-related disorders. [ABSTRACT FROM AUTHOR]

Late blight caused by the oomycete Phytophthora infestans is a disease of potato and tomato of worldwide relevance and is widespread throughout Europe and the Mediterranean region. While pathogen populations in northern Europe have been sampled and characterized for many years, the genetic structure of populations from southern Europe, including Italy, has been less studied. Between 2018 and 2019, we collected 91 samples of P. infestans from potato and tomato crops in Italy, Algeria, and Tunisia on FTA cards and genotyped them using 12‐plex microsatellites. These samples were compared to genotypes of P. infestans previously collected within the framework of the EuroBlight network and from published sources. Four clonal lineages were identified: 13_A2 (Blue 13), 2_A1, 23_A1, and 36_A2. Two other isolates collected could not be matched to any currently known clonal lineage. The 13_A2 and 36_A2 lineages were found exclusively in southern Italy and Algeria, while 2_A1 was only found in Algeria. This is the first report of the 36_A2 lineage in Italy. Two isolates from Solanum nigrum were 13_A2, suggesting this weed host could be a reservoir of inoculum. The 23_A1 lineage was found widely on infected tomato crops in Italy and is the same as the lineage US‐23 that is widespread in North America. Differences in genotypes across the country suggests that there may be different sources of introduction into Italy, possibly via infected seed tubers from other countries in Europe, tubers for consumption from North Africa, or tomatoes. [ABSTRACT FROM AUTHOR]

Background: Senataxin (SETX) is a DNA/RNA helicase critical for neuron survival. SETX mutations underlie two inherited neurodegenerative diseases: Ataxia with Oculomotor Apraxia type 2 (AOA2) and Amyotrophic Lateral Sclerosis type 4 (ALS4). Methods: This review examines SETX key cellular processes and we hypothesize that SETX requires SUMO posttranslational modification to function properly. Results: SETX is localized to distinct foci during S‐phase of the cell cycle, and these foci represent sites of DNA polymerase/RNA polymerase II (RNAP) collision, as they co‐localize with DNA damage markers 53BP1 and H2AX. At such sites, SETX directs incomplete RNA transcripts to the nuclear exosome for degradation via interaction with exosome component 9 (Exosc9), a key component of the nuclear exosome. These processes require SETX SUMOylation. SETX was also recently localized within stress granules (SGs), and found to regulate SG disassembly, a process that similarly requires SUMOylation. Conclusion: SETX undergoes SUMO modification to function at S‐phase foci in cycling cells to facilitate RNA degradation. SETX may regulate similar processes in non‐dividing neurons at sites of RNAP II bidirectional self‐collision. Finally, SUMOylation of SETX appears to be required for SG disassembly. This SETX function may be crucial for neuron survival, as altered SG dynamics are linked to ALS disease pathogenesis. In addition, AOA2 point mutations have been shown to block SETX SUMOylation. Such mutations induce an ataxia phenotype indistinguishable from those with SETX null mutation, underscoring the importance of this modification. [ABSTRACT FROM AUTHOR]

The graphene-based Field Effect Transistors (GFETs), due to their multi-parameter characteristics, are growing rapidly as an important detection component for the apt detection of disease biomarkers, such as DNA, in clinical diagnostics and biomedical research laboratories. In this paper, the non-equilibrium Green function (NEGF) is used to create a compact model of GFET in the ballistic regime as an important building block for DNA detection sensors. In the proposed method, the self-consistent solutions of two-dimensional Poisson's equation and NEGF, using the nearest neighbor tight-binding approach on honeycomb lattice structure of graphene, are modeled as an efficient numerical method. Then, the eight parameters of the phenomenological ambipolar virtual source (AVS) circuit model are calibrated by a least-square curve-fitting routine optimization algorithm with NEGF transfer function data. At last, some parameters of AVS that are affected by induced charge and potential of DNA biomolecules are optimized by an experimental dataset. The new compact model response, with an acceptable computational complexity, shows a good agreement with experimental data in reaction with DNA and can effectively be used in the plan and investigation of GFET biosensors. [ABSTRACT FROM AUTHOR]

This study was aimed at testing the integrated use of a natural biostimulant based on seaweed (Ascophyllum nodosum) and plant (alfalfa and sugarcane) extracts and reduced dosages of the conventional synthetic fungicide Imazalil (IMZ) to manage postharvest rots of orange fruits. The following aspects were investigated: (i) the effectiveness of postharvest treatment with natural biostimulant alone or in mixture with IMZ at a reduced dose against green mold caused by Penicillium digitatum ; (ii) the differential expression of defense genes in orange fruits treated with the natural biostimulant both alone and in combination with a reduced dose of IMZ; (iii) the persistence of the inhibitory activity of both biostimulant and the mixture biostimulant/IMZ against green mold; and (iv) the residue level of fungicide in citrus peel when applied alone or in combination with the biostimulant. Treatments with the chemical plant resistance-inducer potassium phosphite, alone or with a reduced dose of IMZ, were included for comparison. The mixture of natural biostimulant and IMZ at a low dose consistently reduced the incidence and severity of fruit green mold and induced a significant increase of the expression level of β-1,3-glucanase-, peroxidase (PEROX)-, and phenylalanine ammonia-lyase (PAL)-encoding genes in fruit peel, suggesting that the natural biostimulant elicits a long-lasting resistance of citrus fruits to infections by P. digitatum. Interestingly, the residual concentration of IMZ in fruits treated with the biostimulant/fungicide mixture was significantly lower than that of IMZ in fruits treated only with the fungicide at the same dose and by far below the threshold values set by the European Union. This study laid the foundations for (i) conceiving a practical and more eco-friendly alternative to the conventional postharvest management of green mold of citrus fruits, based almost exclusively on the use of synthetic fungicide IMZ, alone or mixed with potassium phosphite and (ii) providing a better insight into the mechanisms of disease resistance induction by biostimulants. [ABSTRACT FROM AUTHOR]

Post-harvest fungal diseases of plant products are a serious concern leading to economic losses and health risks. Moreover, the use of synthetic chemical fungicides to prevent these diseases is limited due to toxic residues. This study aimed at determining the effective dose of extracts of Tricho-derma asperellumIMI393899 (TE1) andTrichoderma atrovirideTS (TE2) in inhibiting the contamination by mycotoxigenic fungi on different plant matrices. Extracts were tested on tomatoes contaminated by Fusarium verticillioides and Fusarium graminearum, wheat contaminated by Penicillium verrucosum and maize contaminated by Aspergillus flavus. The efficacy of extracts was evaluated at two time intervals after treatment, 4 and 11 days for tomato, and 10 and 20 days for both wheat and maize.Both extracts showed a significant inhibitory activity on mycotoxigenic pathogens and significantly reduced Log CFU/g compared to the control. Moreover, the extracts reduced mycotoxin production in a dose dependent manner and with a long-lasting effect. The ochratoxin A was reduced by both extracts but only the extract TE2 was effective in reducing aflatoxins, whereas TE1 treatment increased their synthesis. [ABSTRACT FROM AUTHOR]

This article discusses the occurrence of bleeding stem cankers and root rot in Morus alba, Pistacia atlantica, and Sterculia diversifolia trees in urban parks and gardens in eastern Sicily. The researchers isolated a homothallic Phytophthora species from the affected trees and confirmed its identity as Phytophthora multivora through phylogenetic analysis. The pathogenicity of the isolates was tested on saplings of the three tree species, resulting in leaf chlorosis and stem gummosis. This is the first report of P. multivora from Morus alba and as a pathogen of Pistacia atlantica and Sterculia diversifolia worldwide. The study emphasizes the importance of surveys in urban green areas. [Extracted from the article]

A cryogen-free portable 3 T high-temperature superconducting magnet for an electromagnetic property measurement system has been developed to serve as a user facility at the Korea Basic Science Institute. The metallic insulation method was adopted to reduce the charging delay without sacrificing the self-protecting feature. A genetic-algorithm-aided optimized design was carried out to minimize the superconducting tape consumption while satisfying several design constraints. After the design, the compact high-temperature superconducting magnet composed of eight double-pancake coil modules was wound with high-temperature superconducting tape and stainless steel tape, and integrated with a two-stage cryo-cooler. The 3 T magnet was successfully cooled to approximately 20 K with a cryo-cooler and reached the target field of 3 T without any problems. Long-term measurements and a range of other tests were also implemented to verity the performance of the magnet. Test results demonstrated the feasibility of a cryogen-free portable high-temperature superconducting magnet system for electromagnetic property measurement experiments. [ABSTRACT FROM AUTHOR]

Decline of protein quality control in neurons contributes to age-related neurodegenerative disorders caused by misfolded proteins. 4EBP1 is a key node in the regulation of protein synthesis, as activated 4E-BP1 represses global protein translation. Overexpression of 4E-BP1 mediates the benefits of dietary restriction and can counter metabolic stress, and 4E-BP1 disinhibition on mTORC1 repression may be neuroprotective; however, whether 4E-BP1 overexpression is neuroprotective in mammalian neurons is yet to be fully explored. To address this question, we generated 4E-BP1-overexpressing transgenic mice and confirmed marked reductions in protein translation in 4E-BP1-overexpressing primary neurons. After documenting that 4E-BP1-overexpressing neurons are resistant to proteotoxic stress elicited by brefeldin A treatment, we exposed primary neurons to three different Parkinson's disease (PD)-linked toxins (rotenone, maneb, or paraquat) and documented significant protection in neurons from newborn male and female 4E-BP1-OE transgenic mice. We observed 4E-BP1-dependent upregulation of genes encoding proteins that comprise the mitochondrial unfolded protein response, and noted 4E-BP1 overexpression required activation of the mitochondrial unfolded protein response for neuroprotection against rotenone toxicity. We also tested whether 4E-BP1 could prevent a-synuclein neurotoxicity by treating 4E-BP1- overexpressing primary neurons with a-synuclein preformed fibrils, and we observed marked reductions in a-synuclein aggregation and neurotoxicity, thus validating that 4E-BP1 is a powerful suppressor of PD-linked pathogenic insults. Our results indicate that increasing 4E-BP1 expression or enhancing 4E-BP1 activation can robustly induce the mitochondrial unfolded protein response and thus could be an appealing strategy for treating a variety of neurodegenerative diseases, including especially PD. [ABSTRACT FROM AUTHOR]

Decoding the mechanisms of plant defense against plant pathogens in a scenario where antagonistic activity and the plant growth-promoting effects of useful organisms intervene simultaneously is a new frontier of plant pathology. Here, we demonstrated that (i) two selected strains of Trichoderma asperellum and Trichoderma atroviride promoted tomato (Solanum lycopersicum) growth and reduced the severity of disease caused by the oomycete Phytophthora nicotianae and (ii) the genetic patterns of the components of the experimental model system tomato– Trichoderma spp.– P. nicotianae were differentially expressed. The beneficial effects in both the promotion of the growth of host plant and the biological control of the pathogen by two selected strains of different Trichoderma species were tested both in planta and in vitro. In both respects, T. atroviride demonstrated to be more effective than T. asperellum. Additionally, the simultaneous transcriptional reprogramming of several plant defense-related genes, pathogen effectors, and mycoparasitism-related genes in tomato, P. nicotianae , and Trichoderma spp., respectively, was evaluated during the three-component interaction. Results support the hypothesis that Trichoderma spp. elicit the expression of plant defense-related genes. As expected, a mycoparasitism-related gene was significantly up-regulated in Trichoderma -colonizing tomato plants infected by P. nicotianae. Finally, a marked up-regulation of the genes encoding two necrosis-inducing effectors was observed in P. nicotianae infecting tomato plants colonized by Trichoderma. In conclusion, this study is a contribution toward understanding the genetic pathways related with the ability of Trichoderma spp. to counteract the challenge of P. nicotianae infections on tomato. Additionally, the experiments revealed the beneficial effects in the tomato growth promotion of a new T. atroviride strain and its good antagonistic effectiveness in the biological control of root and crown rot incited by P. nicotianae , confirming that Trichoderma spp. can be a powerful tool in integrated pest management strategies of Phytophthora diseases of horticultural crops. [ABSTRACT FROM AUTHOR]

Nano-sized archaeota, with their small genomes and limited metabolic capabilities, are known to associate with other microbes, thereby compensating for their own auxotrophies. These diminutive and yet ubiquitous organisms thrive in hypersaline habitats that they sharewith haloarchaea. Here, we reveal the genetic and physiological nature of a nanohaloarchaeon–haloarchaeon association, with both microbes obtained from a solar saltern and reproducibly cultivated together in vitro. The nanohaloarchaeon Candidatus Nanohalobium constans LC1Nh is an aerotolerant, sugar-fermenting anaerobe, lacking key anabolic machinery and respiratory complexes. The nanohaloarchaeon cells are found physically connected to the chitinolytic haloarchaeon Halomicrobium sp. LC1Hm. Our experiments revealed that this haloarchaeon can hydrolyze chitin outside the cell (to produce the monosaccharide N-acetylglucosamine), using this betaglucan to obtain carbon and energy for growth. However, LC1Hm could not metabolize either glycogen or starch (both alpha-glucans) or other polysaccharides tested. Remarkably, the nanohaloarchaeon’s ability to hydrolyze glycogen and starch to glucose enabled growth of Halomicrobiumsp. LC1Hm in the absence of a chitin. These findings indicated that the nanohaloarchaeon–haloarchaeon association is both mutualistic and symbiotic; in this case, each microbe relies on its partner’s ability to degrade different polysaccharides. This suggests, in turn, that other nano-sized archaeota may also be beneficial for their hosts. Given that availability of carbon substrates can vary both spatially and temporarily, the susceptibility of Halomicrobium to colonization by Ca. Nanohalobium can be interpreted as a strategy to maximize the long-term fitness of the host. [ABSTRACT FROM AUTHOR]

Some species of Cnidarians, well known venomous organisms, are able to induce serious health problems as well as economic and social trouble. A lot of data show that cnidarian venoms can be cytotoxic to cultured cells. Therefore, a priority of the research is to find tools which could counteract the damaging activity of venoms. In this connection, the modulatory effects exerted by extracts of plants Ananas comosus (L.) and Carica papaya (L.) on cytotoxicity of heterotrichous microbasic eurytele nematocysts isolated from the jellyfish Pelagia noctiluca was evaluated. The nematocyst extract induced strong cytotoxicity at highest tested doses with reduction of cell survival below 40% and IC50 value of 40×103 nematocysts/mL. Both plant extracts significantly improved the survival of cells, so that the IC50 resulted 74×103 and 100×103 nematocysts/mL in the presence of A. comosus and C. papaya extracts, respectively, both used at 10 and 100 μg/mL. Taking into account that heterotrichous microbasic eurytele nematocysts are present mainly in tentacles, which Pelagia noctiluca utilizes both for predation and defence, this result is particularly interesting from both ecological and sanitary point of view and demonstrates the potential of these plants extracts against cnidarian venoms. [ABSTRACT FROM AUTHOR]

Background: Although Huntington's disease (HD) is caused by a single dominant gene, it is clear that there are genetic modifiers that may influence the age of onset and disease progression.Objectives: We sought to investigate whether new inflammation-related genetic variants may contribute to the onset and progression of HD.Methods: We first used postmortem brain material from patients at different stages of HD to look at the protein expression of toll-like receptor 4 (TLR4) and triggering receptor expressed on myeloid cells 2 (TREM2). We then genotyped the TREM2 R47H gene variant and 3 TLR4 single nucleotide polymorphisms in a large cohort of HD patients from the European Huntington's Disease Network REGISTRY.Results: We found an increase in the number of cells expressing TREM2 and TLR4 in postmortem brain samples from patients dying with HD. We also found that the TREM2 R47H gene variant was associated with changes in cognitive decline in the large cohort of HD patients, whereas 2 of 3 TLR4 single nucleotide polymorphisms assessed were associated with changes in motor progression in this same group.Conclusions: These findings identify TREM2 and TLR4 as potential genetic modifiers for HD and suggest that inflammation influences disease progression in this condition. © 2019 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Autophagy, particularly with BECN1, has paradoxically been highlighted as tumor promoting in Ras-driven cancers, but potentially tumor suppressing in breast and ovarian cancers. However, studying the specific role of BECN1 at the genetic level is complicated due to its genomic proximity to BRCA1 on both human (chromosome 17) and murine (chromosome 11) genomes. In human breast and ovarian cancers, the monoallelic deletion of these genes is often co-occurring. To investigate the potential tumor suppressor roles of two of the most commonly deleted autophagy genes in ovarian cancer, BECN1 and MAP1LC3B were knocked-down in atypical (BECN1+/+ and MAP1LC3B+/+) ovarian cancer cells. Ultra-performance liquid chromatography mass-spectrometry metabolomics revealed reduced levels of acetyl-CoA which corresponded with elevated levels of glycerophospholipids and sphingolipids. Migration rates of ovarian cancer cells were increased upon autophagy gene knockdown. Genomic instability was increased, resulting in copy-number alteration patterns which mimicked high grade serous ovarian cancer. We further investigated the causal role of Becn1 haploinsufficiency for oncogenesis in a MISIIR SV40 large T antigen driven spontaneous ovarian cancer mouse model. Tumors were evident earlier among the Becn1+/- mice, and this correlated with an increase in copy-number alterations per chromosome in the Becn1+/- tumors. The results support monoallelic loss of BECN1 as permissive for tumor initiation and potentiating for genomic instability in ovarian cancer. Author summary: Life requires an excellent trash and recycling system. One system mammalian cells rely upon is called autophagy. Autophagy clears cells of larger forms of debris and is critical for normal cell function. We previously found that ovarian cancer cells are unable to execute normal cellular recycling during periods of stress, due to losses in core autophagy genes. Since autophagy has previously been implicated as a cancer cell survival factor, we directly investigated the impact of autophagy gene loss in ovarian cancer models. We discovered a reduction in autophagy proteins disabled normal genome quality control during cell division, leading to genomic instability. We document here for the first time whether reducing an autophagy gene in mice influences ovarian tumor formation. We found earlier ovarian tumors in autophagy deficient mice compared with control mice. We conclude that serous ovarian carcinomas, which rank among the most genetically altered cancers, gain their hallmark genomic instability in part by losing autophagy genes. [ABSTRACT FROM AUTHOR]

Inhibition of mammalian target of rapamycin complex I (mTORC1) by rapamycin improves cardiac function in both aging and heart failure. While the protective mechanisms are not fully understood in mammals, they are presumably mediated through metabolic regulation and suppression of protein translation by reduced phosphorylation of 4EBP1, a target of mTORC1. Using transverse aortic constriction (TAC) and Gαq overexpression-induced heart failure models, we examined the effect of cardiac-specific heterozygous deletion (het) of Raptor, a component of mTORC1, and cardiac-specific transgenic overexpression of wild type or phosphorylation site mutant 4EBP1. In wild-type mice with TAC-induced heart failure, quantitative shotgun proteomics revealed decreased abundance of proteins of mitochondrial metabolism and increased abundance of proteins in oxidative stress response, ubiquitin, and other pathways. The Raptor het ameliorated both TAC- and Gαq overexpression-induced heart failure and the associated proteomic remodeling, especially those pathways involved in mitochondrial function, citric acid cycle, and ubiquitination. In contrast, transgenic overexpression of either wild type or mutant 4EBP1 aggravated TAC and Gαq, consistent with reduced adaptive hypertrophy by suppression of protein translation, in parallel with adverse remodeling of left ventricular proteomes. Partial mTORC1 inhibition by Raptor heterozygous deletion ameliorates heart failure and is associated with better preservation of the mitochondrial proteome; however, this effect does not appear to be mediated through suppression of protein translation by increased 4EBP1. Increased activity of 4EBP1 reduced adaptive hypertrophy and aggravated heart failure, suggesting that protein translation is essential for adaptive hypertrophy in pressure overload. [ABSTRACT FROM AUTHOR]

Skeletal muscle has recently arisen as a regulator of central nervous system (CNS) function and aging, secreting bioactive molecules known as myokines with metabolism-modifying functions in targeted tissues, including the CNS. Here, we report the generation of a transgenic mouse with enhanced skeletal muscle lysosomal and mitochondrial function via targeted overexpression of transcription factor E-B (TFEB). We discovered that the resulting geroprotective effects in skeletal muscle reduce neuroinflammation and the accumulation of tau-associated pathological hallmarks in a mouse model of tauopathy. Muscle-specific TFEB overexpression significantly ameliorates proteotoxicity, reduces neuroinflammation, and promotes transcriptional remodeling of the aged CNS, preserving cognition and memory in aged mice. Our results implicate the maintenance of skeletal muscle function throughout aging in direct regulation of CNS health and disease and suggest that skeletal muscle originating factors may act as therapeutic targets against age-associated neurodegenerative disorders. [Display omitted] • Increased TFEB expression modifies aging hallmarks in skeletal muscle • Muscle-TFEB reduces neuroinflammation during aging and neurodegeneration • Neuroprotective muscle-to-brain signaling is activated in a sex-biased manner Matthews et al. demonstrate that activation of the muscle-to-brain axis in vivo promotes robust neuroprotective effects during aging and neurodegenerative disease. These benefits are associated with transcriptional remodeling of the hippocampus and sex-biased modulation of classical pathways known to decline with age, including synaptic plasticity, mitochondrial function, and ribosomal metabolism. [ABSTRACT FROM AUTHOR]

In article number 2300626, Mario Pagliaro, Annamaria Visco, Rosaria Ciri Minna, and co-workers show that, when exposed to a microbial consortium composed of I Bacillus aquimaris i and I Pseudomonas poae i , the photocatalytic xerogel AquaSun deposited on shipbuilding steel exerts significant antimicrobial activity of broad scope. Antibacterial Properties of AquaSun Sol-Gel Coating These results are promising en route to developing novel antimicrobial coatings of broad applicability. [Extracted from the article]

Intravitreal injection of antisense oligonucleotides targeting mutated Ataxin-7 improves visual function in a mouse model of spinocerebellar ataxia type 7. Improving vision in spinocerebellar ataxia: Spinocerebellar ataxia type 7 (SCA7) is a genetic disorder caused by mutations in the ATAXIN-7 gene. SCA7 is characterized by impairments in coordination, balance, and speech and by retinal degeneration that results in complete blindness. Here, Niu et al. developed a strategy for treating visual impairments in SCA7 by inhibiting the mutated Ataxin-7 in the retina using antisense oligonucleotides (ASOs). Intravitreal injection of ASOs specifically targeting the mutated Ataxin-7 reduced protein expression in the retina and ameliorated pathology and vision loss in a SCA7 mouse model. The results suggest that ASOs targeting ATAXIN-7 might be effective in treating retinal degeneration in patients with SCA7. Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant neurodegenerative disorder characterized by cerebellar and retinal degeneration, and is caused by a CAG-polyglutamine repeat expansion in the ATAXIN-7 gene. Patients with SCA7 develop progressive cone-rod dystrophy, typically resulting in blindness. Antisense oligonucleotides (ASOs) are single-stranded chemically modified nucleic acids designed to mediate the destruction, prevent the translation, or modify the processing of targeted RNAs. Here, we evaluated ASOs as treatments for SCA7 retinal degeneration in representative mouse models of the disease after injection into the vitreous humor of the eye. Using Ataxin-7 aggregation, visual function, retinal histopathology, gene expression, and epigenetic dysregulation as outcome measures, we found that ASO-mediated Ataxin-7 knockdown yielded improvements in treated SCA7 mice. In SCA7 mice with retinal disease, intravitreal injection of Ataxin-7 ASOs also improved visual function despite initiating treatment after symptom onset. Using color fundus photography and autofluorescence imaging, we also determined the nature of retinal degeneration in human SCA7 patients. We observed variable disease severity and cataloged rapidly progressive retinal degeneration. Given the accessibility of neural retina, availability of objective, quantitative readouts for monitoring therapeutic response, and the rapid disease progression in SCA7, ASOs targeting ATAXIN-7 might represent a viable treatment for SCA7 retinal degeneration. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis type 4 (ALS4) is a rare, early-onset, autosomal dominant form of ALS, characterized by slow disease progression and sparing of respiratory musculature. Dominant, gain-of-function mutations in the senataxin gene (SETX) cause ALS4, but the mechanistic basis for motor neuron toxicity is unknown. SETX is a RNA-binding protein with a highly conserved helicase domain, but does not possess a low-complexity domain, making it unique among ALS-linked disease proteins. We derived ALS4 mouse models by expressing two different senataxin gene mutations (R2136H and L389S) via transgenesis and knock-in gene targeting. Both approaches yielded SETX mutant mice that develop neuromuscular phenotypes and motor neuron degeneration. Neuropathological characterization of SETX mice revealed nuclear clearing of TDP-43, accompanied by TDP-43 cytosolic mislocalization, consistent with the hallmark pathology observed in human ALS patients. Postmortem material from ALS4 patients exhibited TDP-43 mislocalization in spinal cord motor neurons, and motor neurons from SETX ALS4 mice displayed enhanced stress granule formation. Immunostaining analysis for nucleocytoplasmic transport proteins Ran and RanGAP1 uncovered nuclear membrane abnormalities in the motor neurons of SETX ALS4 mice, and nuclear import was delayed in SETX ALS4 cortical neurons, indicative of impaired nucleocytoplasmic trafficking. SETX ALS4 mice thus recapitulated ALS disease phenotypes in association with TDP-43 mislocalization and provided insight into the basis for TDP-43 histopathology, linking SETX dysfunction to common pathways of ALS motor neuron degeneration. [ABSTRACT FROM AUTHOR]

Patients with chronic mountain sickness (CMS) suffer from hypoxemia, erythrocytosis, and numerous neurologic deficits. Here we used induced pluripotent stem cell (iPSC)-derived neurons from both CMS and non-CMS subjects to study CMS neuropathology. Using transmission electron microscopy, we report that CMS neurons have a decreased mitochondrial volume density, length, and less cristae membrane surface area. Real-time PCR confirmed a decreased mitochondrial fusion gene optic atrophy 1 (OPA1) expression. Immunoblot analysis showed an accumulation of the short isoform of OPA1 (S-OPA1) in CMS neurons, which have reduced ATP levels under normoxia and increased lactate dehydrogenase (LDH) release and caspase 3 activation after hypoxia. Improving the balance between the long isoform of OPA1 and S-OPA1 in CMS neurons increased the ATP levels and attenuated LDH release under hypoxia. Our data provide initial evidence for altered mitochondrial morphology and function in CMS neurons, and reveal increased cell death under hypoxia due in part to altered mitochondrial dynamics. NEW & NOTEWORTHY Induced pluripotent stem cell-derived neurons from chronic mountain sickness (CMS) subjects have altered mitochondrial morphology and dynamics, and increased sensitivity to hypoxic stress. Modification of OPA1 can attenuate cell death after hypoxic treatment, providing evidence that altered mitochondrial dynamics play an important role in increased vulnerability under stress in CMS neurons. [ABSTRACT FROM AUTHOR]

Huntington disease (HD) is a progressive autosomal dominant neurodegenerative disorder in which patients typically present with uncontrolled involuntary movements and subsequent cognitive decline. In 1993, a CAG trinucleotide repeat expansion in the coding region of the huntingtin (HTT) gene was identified as the cause of this disorder. This extended CAG repeat results in production of HTT protein with an expanded polyglutamine tract, leading to pathogenic HTT protein conformers that are resistant to protein turnover, culminating in cellular toxicity and neurodegeneration. Research into the mechanistic basis of HD has highlighted a role for bioenergetics abnormalities stemming from mitochondrial dysfunction, and for synaptic defects, including impaired neurotransmission and excitotoxicity. Interference with transcription regulation may underlie the mitochondrial dysfunction. Current therapies for HD are directed at treating symptoms, as there are no disease‐modifying therapies. Commonly prescribed drugs for involuntary movement control include tetrabenazine, a potent and selective inhibitor of vesicular monoamine transporter 2 that depletes synaptic monoamines, and olanzapine, an atypical neuroleptic that blocks the dopamine D2 receptor. Various drugs are used to treat non‐motor features. The HD therapeutic pipeline is robust, as numerous efforts are underway to identify disease‐modifying treatments, with some small compounds and biological agents moving into clinical trials. Especially encouraging are dosage reduction strategies, including antisense oligonucleotides, and molecules directed at transcription dysregulation. Given the depth and breadth of current HD drug development efforts, there is reason to believe that disease‐modifying therapies for HD will emerge, and this achievement will have profound implications for the entire neurotherapeutics field. [ABSTRACT FROM AUTHOR]

Autophagy is the major cellular pathway by which macromolecules are degraded, and amino acid depletion powerfully activates autophagy. MAP4K3, or germinal-center kinase-like kinase, is required for robust cell growth in response to amino acids, but the basis for MAP4K3 regulation of cellular metabolic disposition remains unknown. Here we identify MAP4K3 as an amino acid-dependent regulator of autophagy through its phosphorylation of transcription factor EB (TFEB), a transcriptional activator of autophagy, and through amino acid starvation-dependent lysosomal localization of MAP4K3. We document that MAP4K3 physically interacts with TFEB and MAP4K3 inhibition is sufficient for TFEB nuclear localization, target gene transactivation, and autophagy, even when mTORC1 is activated. Moreover, MAP4K3 serine 3 phosphorylation of TFEB is required for TFEB interaction with mTORC1-Rag GTPase-Ragulator complex and TFEB cytosolic sequestration. Our results uncover a role for MAP4K3 in the control of autophagy and reveal MAP4K3 as a central node in nutrient-sensing regulation. [ABSTRACT FROM AUTHOR]

Preconditioning (PC) is a cell adaptive response to oxidative stress and, with regard to neurons, can be considered as a neuroprotective strategy. The aim of the present study was to verify how neuronal‐like differentiated SH‐SY5Y cells adapt to a mild and transient H2O2‐induced oxidative stress and, hence, whether may be considered as more sensitive cell model to study PC pathways. A first screening allowed to define H2O2 concentrations for PC (10μM‐50μM), applied before damage(100μM H2O2). Cell viability measured 24 hours after 100μM H2O2–induced damage was ameliorated by 24‐hour pre‐exposure to low‐concentration H2O2 (10μM‐30μM) with cell size as well restored. Markers for apoptosis (Bcl‐2 and Bad), inflammation (iNOS), and redox system (MnSOD) were also determined, showing that, in cells pre‐exposed to 10μM H2O2 and then submitted to 100μM H2O2, Bcl‐2 levels were higher, Bad and iNOS levels were lower than those observed in damaged cells, and MnSOD levels were unchanged. Such findings show that (1) neuronal‐like differentiated SH‐SY5Y cells are a suitable model to investigate PC response and more sensitive to the effect of a mild and transient H2O2‐induced oxidative stress with respect to other neuronal cells; (2) 10μM H2O2–induced PC is mediated by apoptotic and inflammatory pathways, unlike antioxidant system; (3) such neuroprotective strategy and underlying signals proven in neuronal‐like differentiated SH‐SY5Y cells may contribute to understand in vivo PC mechanisms and to define a window for pharmacological intervention, namely, related to ischemic brain damage. Significance of the study: Neuronal‐like differentiated SH‐SY5Y cells are a suitable model to investigate PC, an endogenous neuroprotective response to a mild and transient H2O2‐induced oxidative stress, elicited by 24‐hour exposure to very low H2O2 concentrations and mediated by both apoptotic and inflammatory pathways. This model reflects in vivo PC mechanisms occurring after brain trauma and provides novel information about pathways and time of protection useful for an appropriate pharmacological intervention. [ABSTRACT FROM AUTHOR]

Covering two-thirds of our planet, the global deep ocean plays a central role in supporting life on Earth. Among other processes, this biggest ecosystem buffers the rise of atmospheric CO2. Despite carbon sequestration in the deep ocean has been known for a long time, microbial activity in the meso- and bathypelagic realm via the "assimilation of bicarbonate in the dark" (ABD) has only recently been described in more details. Based on recent findings, this process seems primarily the result of chemosynthetic and anaplerotic reactions driven by different groups of deep-sea prokaryoplankton. We quantified bicarbonate assimilation in relation to total prokaryotic abundance, prokaryotic heterotrophic production and respiration in the meso- and bathypelagic Mediterranean Sea. The measured ABD values, ranging from 133 to 370 μg Cm-3 d-1, were among the highest ones reported worldwide for similar depths, likely due to the elevated temperature of the deepMediterranean Sea (13-14°C also at abyssal depths). Integrated over the dark water column (≥200m depth), bicarbonate assimilation in the deep-sea ranged from 396 to 873mg C m-2 d-1. This quantity of produced de novo organic carbon amounts to about 85-424% of the phytoplankton primary production and covers up to 62% of deep-sea prokaryotic total carbon demand. Hence, the ABD process in the meso- and bathypelagic Mediterranean Sea might substantially contribute to the inorganic and organic pool and significantly sustain the deep-sea microbial food web. To elucidate the ABD key-players, we established three actively nitrifying and CO2-fixing prokaryotic enrichments. Consortia were characterized by the co-occurrence of chemolithoautotrophic Thaumarchaeota and chemoheterotrophic proteobacteria. One of the enrichments, originated from Ionian bathypelagic waters (3,000m depth) and supplemented with low concentrations of ammonia, was dominated by the Thaumarchaeota "low-ammonia-concentration" deep-sea ecotype, an enigmatic and ecologically important group of organisms, uncultured until this study. [ABSTRACT FROM AUTHOR]

The article reports on the activation of peroxisome proliferator–activated receptors (PPARs) by the U.S. Food and Drug Administration-approved drug bexarotene promoting neuroprotective in cellular models of Huntington's disease (HD), a progressive neurodegenerative disorder. Mitochondrial and protein quality control in cellular models of HD was examined.