The main objective of this work is the assessment of the annual number of hospital admissions for respiratory disease (HARD) due to the exposure to in-healable particulate matter (PM10), within the greater Athens area (GAA), Greece. Towards this aim, the time series of the particulate matter with aerodynamic diameter less than 10μm (PM10) recorded in six monitoring stations located in the GAA, for a 13-year period 2001-2013, is used. Initially, a descriptive statistical treatment of PM10 concentrations took place. Furthermore, the AirQ2.2.3 software developed by the WHO was used to evaluate adverse health effects by PM10 in the GAA during the examined period. The results show that, during the examined period PM10 concentrations present a significant decreasing trend. Also, the mean annual HARD cases per 100,000 inhabitants ranged between 20 (suburban location) and 40 (city centre location). Approximately 70% of the annual HARD cases are due to city centre residents. In all examined locations, a declining trend in the annual number of HARD cases is appeared. Moreover, a strong relation between the annual number of HARD cases and the annual number of days exceeding the European Union daily PM10 threshold value was found.

Leishmaniasis is the third most common vector-borne disease and a very important protozoan infection. Cutaneous leishmaniasis is one of the most common types of leishmaniasis infectious diseases with up to 2 million occurrences of new cases each year worldwide. A dynamic transmission multivariate time series model was applied to the data to account for overdispersion and evaluate the effects of three environmental layers as well as seasonality in the data. Furthermore, ecological niche modeling was used to investigate the geographical suitable conditions for cutaneous leishmaniasis using temperature, precipitation and altitude as environmental layers, together with the leishmaniasis presence data. A retrospective analysis of the cutaneous leishmaniasis spatial data in Afghanistan between 2003 and 2009 indicates a steady increase from 2003 to 2007, a small decrease in 2008, then another increase in 2009. An upward trend and regularly repeating patterns of highs and lows was observed related to the months of the year which suggests seasonality effect in the data. Two peaks were observed in the disease occurrence-- January to March and September to December -- which coincide with the cold period. Ecological niche modelling indicates that precipitation has the greatest contribution to the potential distribution of leishmaniasis.

A high intake of carbohydrates, associated with obesity, is one of the major causes of fatty liver disease in humans. This study investigated how high carbohydrate intake induces fatty liver disease in Blunt snout bream (Megalobrama amblycephala). Blunt snout bream were fed a high-carbohydrate diet (HCBD) for 60 days. Their growth indices were evaluated, and the transcriptomes, metabolites, biochemistry, and histology of their blood and livers were analyzed. The final weight, weight gain, specific growth rate, and feed conversion ratio were all higher in the HCBD group than in the control group, but not significantly so (P > 0.05). The hepatosomatic index (HSI) differed significantly in the two groups (P < 0.05), and the metabolomics results showed that a high carbohydrate intake induced significant increases in plasma α/β-glucose, succinate, and tyrosine, which could increase hepatic glycogen and triglyceride. Low levels of betaine were also found in the livers of the HCBD group. The histology and blood biochemistry results suggested abnormal liver, with excessive lipid accumulation and liver damage. A transcriptome analysis and quantitative reverse transcription–PCR (RT–qPCR) indicated that the expression of the factors INSR, IRS, PI3K, PDK, AKT, ACC, IL6, AP1, ChREBP-MLX, PEPCK, and FBP in the insulin signaling pathway was significantly upregulated and that of SOCS3, GSK3β, and AMPK significantly downregulated in the HCBD. This pattern is associated with the nonalcoholic fatty liver disease (NAFLD) pathway. This study extends our understanding of how high carbohydrate causes increased fat deposition in the liver, enhanced glycolysis (α/β-glucose) in the plasma, and reduced betaine in the liver. This leads to activation of hepatocyte insulin resistance and lipogenesis by regulating the expression of genes related to fatty liver disease.

Background: The COVID-19 outbreak has accelerated the huge difference between medical care and disease prevention in Chinese medical institutions. This study aimed to investigated the relationship between the symbiotic units, environments, models, and effects of the integration of medical and disease prevention. Methods: This cross-sectional study involved 762 employees of public hospitals in 11 cities in Zhejiang Province by random stratified sampling. We analyzed the influence paths of elements in the mechanism of integration of medical and disease prevention and the mediating effect of symbiotic models among symbiotic units, symbiotic environments, and effects for on this integration. Results: The path coefficient of symbiotic unit on the symbiosis model was 0.46 (p&lt;.001), the path coefficient of symbiotic environment on symbiosis model was 0.52 (p&lt;.001). The path coefficient of the symbiotic unit and environment was 0.91 (p&lt;.001). The symbiotic models exhibited a partial mediation effect between symbiotic units and the effect of this integration. Sobel test = 3.27, β = 0.152, and the mediating effect accounted for 34.6%. Conclusions: It is suggested that Health policy-makers and public hospital managers should provide sufficient symbiotic units, establish collaborative symbiotic models, and improve the effects of integration of medical and disease prevention in public hospitals.

Crohn's disease (CD) results from an aberrant immune response against commensal microbiota in genetically susceptible hosts. However, the nature of immune defects, the microflora involved, and genetic susceptibility remain incompletely defined and controversial. This review seeks to describe the present state of association between CD and renal disease; moreover, we highlight the convergence of CD with amyloidosis that can trigger sustained inflammation, producing the pathological alteration observed in both diseases. The following MESH terms were searched in PubMed, PubMed Central (PMC), and Web of Science: “Crohn´s disease” and “renal disease.” The R RISmed package was used for PubMed and PMC. The abnormal humoral immune response is described along with alterations in immune cell migration mechanisms in CD during inflammation.

Nearly half a century has passed since the discovery of cytoplasmic inheritance of human chloramphenicol resistance. The inheritance was then revealed to take place maternally by mitochondrial DNA (mtDNA). Later, a number of mutations in mtDNA were identified as a cause of severe inheritable metabolic diseases with neurological manifestation, and the impairment of mitochondrial functions has been probed in the pathogenesis of a wide range of illnesses including neurodegenerative diseases. Recently growing number of preclinical studies has revealed that animal behaviors are influenced by the impairment of mitochondrial functions and possibly by the loss of mitochondrial stress resilience. Indeed, as high as 54% of patients with one of the most common primary mitochondrial diseases, mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome, present psychiatric symptoms including cognitive impairment, mood disorder, anxiety, and psychosis. Mitochondria are multifunctional organelles which produce cellular energy and play a major role in other cellular functions including homeostasis, cellular signaling, and gene expression, among other. Mitochondrial functions are observed to be compromised and to become less resilient under continuous stress. Meanwhile, stress and inflammation have been linked to the activation of the tryptophan (Trp)-kynurenine (KYN) metabolic system, which observably contributes to development of pathological conditions including neurological and psychiatric disorders. This narrative review discusses the functions of mitochondria and the Trp-KYN system, the interaction of the Trp-KYN system with mitochondria, and the current understanding of the involvement of mitochondria and the Trp-KYN system in preclinical and clinical studies of major neurological and psychiatric diseases.

Over the last decade, advances in our understanding about the genetic architecture of complex traits and common diseases, have increased our ability to perform susceptibility genetic testing for diseases in asymptomatic individuals. These technological developments raise complex ethical, legal and social considerations. Here we discuss a series of ethical issues associated with susceptibility genetic testing for Alzheimer's and Parkinson's disease. These include, amongst others, informed consent, disclosure of results and unexpected findings, mandatory screening, privacy and confidentiality, and stigma and genetic discrimination. As knowledge of the genetic basis of these diseases continues growing, and as genetic testing becomes more widespread, we anticipate that it will become increasingly important for scientists and clinicians to engage in the conversation about the ethical, social and policy implications of these technologies.

The Neurodegenerative Diseases are, according to recent studies, one of the main causes of disability and death worldwide. Interest in molecular genetics has started to have an exponential growth thanks to numerous advancements in tech, shifts in the understanding of the disease as a phenomenon, and the change of perspective regarding gene editing and the upsides of this action. The aim of this paper is to analyse the newest approaches in genetics and molecular sciences regarding four of the most important neurodegenerative disorders: Alzheimer’s Disease, Parkinson’s Disease, Huntington’s Disease and Amyotrophic Lateral Sclerosis. We intend through this review to focus on the newest treatment, diagnosis and predictions plans regarding this large group of diseases, in order to obtain a better accuracy analysing and spotting the emerging signs that could lead to a better outcome in order to increase both the quality and the life span of the patient. Moreover, this review could provide future evidence of possible novelty therapies that target the specific genes and could be useful to be taken into consideration when the classical approaches fail to shed light.

Intracellular aggregates of the alpha-synuclein protein result in cell loss and dysfunction in Parkinson’s disease and atypical parkinsonism, such as multiple system atrophy and dementia with Lewy bodies. Each of these neurodegenerative conditions, known collectively as alpha-synucleinopathies, may be characterized by a different suite of molecular triggers that initiate pathogenesis. The mechanisms whereby alpha-synuclein aggregates in turn mediate cytotoxicity also remain to be fully elucidated. However, recent studies have implicated the cell-to-cell spread of alpha-synuclein as the major mode of disease propagation between brain regions during disease progression. Here, we review the current evidence for different modes of alpha-synuclein cellular release, movement and uptake, including exocytosis, exosomes, tunnelling nanotubes, glymphatic flow and endocytosis. A more detailed understanding of the major modes by which alpha-synuclein pathology spreads throughout the brain may provide new targets for therapies that halt the progression of disease.

The rising global incidence of acute and chronic kidney diseases has increased the demand for renal replacement therapy. This issue, compounded with the limited availability of viable kidneys for transplantation, has propelled the search for alternative strategies to address the growing health and economic burdens associated with these conditions. In the search for such alternatives, significant efforts have been devised to augment the current and primarily supportive management of renal injury with novel regenerative strategies. For example, gene- and cell-based approaches that utilize recombinant peptides/proteins, gene, cell, organoid, and RNAi technologies have shown promising outcomes primarily in experimental models. Supporting research has also been conducted to improve our understanding of the critical aspects that facilitate the development of efficient gene- and cell-based techniques that the complex structure of the kidney has traditionally limited. This manuscript is intended to communicate efforts that have driven the development of such therapies by identifying the vectors and delivery routes needed to drive exogenous transgene incorporation that may support the treatment of acute and chronic kidney diseases.

Aleutian mink disease virus (AMDV) is known to cause the most significant disease in the mink industry. It is globally widespread and manifested as a deadly plasmacytosis and hyperglobulinemia. So far, measures to control viral spread have been limited to manual serological testing for AMDV-positive mink. Further, due to the persistent nature of this virus, attempts to eradicate Aleutian disease (AD) have largely failed. Therefore, effective strategies to control viral spread are of crucial importance for wildlife protection. One potentially key tool in the fight against this disease is by immunization of mink against AMDV. Throughout many years, several researchers have tried to develop AMDV vaccines and demonstrated varying degrees of protection in mink by those vaccines. Despite these attempts, there are currently no vaccines available against AMDV, allowing the continuation of the spread of Aleutian disease. Herein, we summarize previous AMDV immunization attempts in mink as well as other preventative measures with the purpose to shed light on future studies designing such a potentially crucial preventative tool against Aleutian disease.

Ulcerative colitis (UC) is one of the two disorders known as inflammatory bowel diseases (IBD) along with Crohn’s disease (CD), with complex pathogenesis, requiring costly invasive investigations. Objective: to examine the most recent biomarkers proposed for UC diagnosis; to establish the strategy used to make the differential diagnosis between UC and CD relying on these biomarkers, also adding the benefit of finding new non-invasive tools in managing this condition. The search was performed in a single database (Web of Science) using the specific keywords „ulcerative colitis”, „biomarkers” and „diagnosis” for the last five years. Study eligibility criteria: clinical trials on adults and pediatric patients with ulcerative colitis compared with Crohn’s disease. Results: We selected 57 studies, randomized controlled trials (RCTs) and clinical case series (CCS), summarizing the latest most specific biomarkers in diagnosis of UC. Limitations: we considered RCTs and CCS from one database, limited to the search topics. Our findings indicate a important number of potential biomarkers with diagnostic value, which bring the advantage of a non-invasive method to approach this challenging disorder.

Tomato (Solanum lycopersicum L.) is a valuable horticultural crop grown and consumed worldwide. Optimum production is hindered by several factors of which Verticillium dahliae, the cause of Verticillium wilt, is one of the major biological constraints in temperate production regions. V. dahliae is difficult to manage because it is a vascular pathogen, has a broad host range and worldwide distribution, and can persist in soil for years. Understanding the pathogen virulence and genetic diversity, host resistance, and plant-pathogen interactions can ultimately inform the development of integrated strategies to manage the disease. In recent years, considerable research has focused on providing new insight into these processes as well as the development and integration of environment-friendly management approaches. In this review, we discuss and summarize the recent findings on the race and population structure of V. dahliae; pathogenicity factors; host genes, proteins, and enzymes involved in defense; the emergent management strategies, and recent approaches to managing Verticillium wilt in tomatoes.

Cannabidiol is a well-known non-psychotropic phytocannabinoid from Cannabis sativa, which exerts a broad range of neuropharmacological activities in the central nervous systems. Over the past years, compelling evidence from preclinical and clinical studies support therapeutic potentials of cannabidiol in various neurological disorders, including neurodegenerative diseases. Neurodegenerative diseases are characterized by the accumulation of misfolded or aggregated protein due to the defective protein homeostasis or proteostasis network, termed as proteinopathies. Because of its role in the protein homeostasis network, cannabidiol could be a potent molecule to revert not only age-associated neurodegeneration but also other protein misfolding disorders. In this review, we discuss the potentiality of cannabidiol as a pharmacological modulator of the proteostasis network, highlighting its neuroprotective and aggregates clearing system inducing potentials in the neurodegenerative diseases.

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the two most common neurodegenerative diseases in elderly. The key histopathological features of these diseases are the presence of abnormal protein aggregates and the progressive and irreversible loss of neurons in specific brain regions. The exact mechanisms underlying the etiopathogenesis of AD or PD remain unknown, but there is extensive evidence indicating that excessive generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) along with a depleted antioxidant system, mitochondrial dysfunction, and intracellular Ca2+ dyshomeostasis play a vital role in the pathophysiology of these neurological disorders. Due to an improvement in life expectancy, the incidence of age-related neurodegenerative diseases has significantly increased. However, there is no effective protective treatment or therapy available but rather only very limited palliative treatment. Therefore, there is an urgent need for the development of preventive strategies and disease-modifying therapies to treat AD/PD. Because dysregulated Ca2+ metabolism drives oxidative damage and neuropathology in these diseases, the identification or development of compounds capable of restoring Ca2+ homeostasis and signaling may provide a neuroprotective avenue for the treatment of neurodegenerative diseases. In addition, a set of strategies to control mitochondrial Ca2+ homeostasis and signaling has been reported, including decreased Ca2+ uptake through voltage-operated Ca2+ channels (VOCCs). In this article, we review the modulatory effects of several heterocyclic compounds on Ca2+ homeostasis and trafficking, and their ability to regulate compromised mitochondrial function and associated free radical production during the onset and progression of AD or PD. This comprehensive review also describes the chemical synthesis of the heterocycles and summarizes the clinical trial outcomes.

Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common neurodegenerative disorders related to aging. Though several risk factors are shared between these two diseases, the exact relationship between these two diseases is still unknown. In this paper, we analyzed how these diseases relate to each other from a genomics viewpoint. Using an extensive literature search, we accumulated the list of genes from the major genome-wide association (GWAS) studies. However, we found only one gene (HLA-DRB5) reported in these GWAS studies that are common between AD and PD. We also listed all the miRNAs that have been previously reported for AD and PD. Here we found 15 different miRNAs that were reported in both diseases. In order to get better insights, we predicted the gene coexpression network for both AD and PD. Network analysis on these networks show six clusters of genes related to AD and four clusters of genes related to PD.

As a conceptual model of disease mechanisms, a disease map integrates available knowledge and is applied for data interpretation, predictions and hypothesis generation. It is possible to model disease mechanisms on different levels of granularity and adjust the approach to the goals of a particular project. This rich environment together with requirements for high-quality network reconstruction makes it challenging for new curators and groups to be quickly introduced to the development methods. In this review, we offer a step-by-step guide for developing a disease map within its mainstream pipeline that involves using the CellDesigner tool for creating and editing diagrams and the MINERVA Platform for online visualisation and exploration. We also describe how the Neo4j graph database environment can be used for managing and querying efficiently such a resource. For assessing the interoperability and reproducibility we apply FAIR principles.

A synoptic review of plant disease epidemics and outbreaks was made using two complementary approaches. The first approach involved reviewing scientific literature published in 2021, in which quantitative data related to new plant disease epidemics or outbreaks were obtained via surveys or similar methodologies. The second approach involved retrieving new records added in 2021 to the CABI Distribution Database, which contains over a million global geographic records of organisms from over 50,000 species. The literature review retrieved 186 articles, describing studies in 62 categories (pathogen species/species complexes) across >40 host species on 6 continents. Pathogen species with >5 articles were: Bursaphelenchus xylophilus, Candidatus Liberibacter asiaticus, cassava mosaic viruses, citrus tristeza virus, Erwinia amylovora, Fusarium spp. complexes, Fusarium oxysporum f. sp. cubense, Magnaporthe oryzae, maize lethal necrosis co-infecting viruses, Meloidogyne spp. complexes, Pseudomonas syringae pvs, Puccinia striiformis f. sp. tritici, Xylella fastidiosa, and Zymoseptoria tritici. Automated searches of the CABI Distribution Database identified 617 distribution records new in 2021 of 283 plant pathogens. A further manual review of these records confirmed 15 pathogens reported in new locations: apple hammerhead viroid, apple rubbery wood viruses, Aphelenchoides besseyi, Biscogniauxia mediterranea, Ca. Liberibacter asiaticus, citrus tristeza virus, Colletotrichum siamense, cucurbit chlorotic yellows virus, Erwinia rhapontici, Erysiphe corylacearum, Fusarium oxysporum f. sp. cubense Tropical Race 4, Globodera rostochiensis, Nothophoma quercina, potato spindle tuber viroid, and tomato brown rugose fruit virus. Of these, 4 pathogens had at least 25% of all records reported in 2021. We assessed two of these pathogens – tomato brown rugose fruit virus and cucurbit chlorotic yellows virus – to be actively emerging in/spreading to new locations. Although three important pathogens – Ca. Liberibacter asiaticus, citrus tristeza virus and Fusarium oxysporum f. sp. cubense – were represented in the results of both our literature review and our interrogation of the CABI Distribution Database, in general our dual approaches revealed distinct sets of plant disease outbreaks and new records, with little overlap.

Humans are a vision-dominated species, and what we see depends on where we look. Therefore, eye movements (EM) are essential to our interactions with the environment, and experimental findings show EM is affected in neurodegenerative disorders (ND). It could be a reason for some cognitive and movement disorders in ND. Therefore, we aim to determine if changes in EM-evoked responses can tell us about ND, such as Alzheimer’s (AD) and Parkinson’s Disease (PD) progression in different stages. In the present review, we have analyzed the results of neurological, psychological, and EM (saccades, antisaccades, pursuit) tests to predict disease progression with Machine Learning (ML) methods. Described predictive algorithms are using various approaches, including Granular Computing, Naive Bayes, Decision Trees/Tables, Logistic Regression, C-/LinearSVC, KNC, and Random Forest. We demonstrated that EM is a robust biomarker for assessing symptom progression in PD and AD. There are also navigation problems in 3D space in both diseases. Consequently, we investigated EM experiments in the virtual space and how they may help find neurodegeneration-related brain changes. In conclusion: EM parameters with clinical symptoms are powerful precision instruments that, in addition to predictions of ND progression with the help of ML, could be used to indicate the different preclinical stages of both diseases.

Alfalfa (Medicago sativa L.) is one of the most important forage crops in the world. In Bolivia it is cultivated in different parts of the High Andes and in the Interandean Valleys. The species is affected by several fungal diseases which reduce production, but before 2016 hardly any mention had been made of virus disease in the region. The aims of the present work were: 1) to describe the symptomology of this apparent viral disease, and ii) determine its effects on the yield of different alfalfa cultivars available from the CIF-UMSS. In 2016, a plot was established at Tiquipaya (Dept. of Cochabamba) (altitude 2480 m) was planted with 12 alfalfa cultivars. Disease incidence values were estimated and the area under the disease progress curves (AUDPC) calculated. The disease progress curves themselves were analyzed using logit functions for polycyclic diseases, and yields were determined. Disease symptoms included deformation of the folioles, thickened veins, the presence of vein enations and papillae on the abaxial leaves, reduced plant size - all symptoms of infection apparently caused by Alfalfa Dwarf Virus. The different cultivars returned different incidence values. They also returned different apparent infection rates ranging from 0.072/day for Cóndor, to 0.113/day for Tamborada. The different cultivars returned different dry weight yields, with yields inversely related to the AUDPC. In conclusion, based on the foliar symptoms registered, the viral disease is associated with the Alfalfa Dwarf Virus. The twelve cultivars evaluated presented different incidence levels of the viral disease.

Latest evidence revealed a possible association between Parkinson’s disease (PD) and periodontitis. We explored the causal relationship of this association through two-sample Mendelian randomization (MR) in European ancestry populations. To this end, we used openly accessible data of genome-wide association studies (GWAS) on PD and periodontitis. As instrumental variables for periodontitis, seventeen single-nucleotide polymorphisms (SNPs) from a GWAS of periodontitis (1817 periodontitis cases vs. 2215 controls) and forty-five SNPs from a GWAS of PD (20,184 cases and 397,324 controls). Eight non-overlapping SNPs of periodontitis from an additional GWAS assisted in the validation of association being studied. Multiple approaches of MR were carried-out. There was no evidence of genetic liability of periodontitis being associated with a higher risk of PD (B= -0.0003, Standard Error [SE] 0.0003, P = 0.26). The eight independent SNPs (B= -0.0000, SE 0.0001, P = 0.99) validated this outcome. We found no association of genetically primed PD towards periodontitis (B= -0.0001, SE 0.0001, P = 0.19). This MR study found no conclusive evidence to support a bidirectional causal genetic liability between PD and periodontitis. Further GWAS studies are needed to confirm the consistency of these results.

Recent studies supported a clinical association between Parkinson’s Disease (PD) and periodontitis. Hence, investigating possible protein interactions between these two conditions is of interest. In this study, we conducted a protein-protein network interaction analysis with recognized genes encoding proteins for PD and periodontitis. Genes of interest were collected via GWAS database. Then, we conducted a protein interaction analysis using STRING database, with a highest confidence cut-off of 0.9. Our protein network casted a comprehensive analysis of potential protein-protein interactions between PD and periodontitis. This analysis may underpin valuable information for new candidate molecular mechanisms between PD and periodontitis and may serve new potential targets for research purposes. These results should be carefully interpreted giving the limitations of this approach.

RNA epigenetics is perhaps the most recent aspect of interest for translational epigeneticists. RNA modifications create such an extensive network of epigenetically driven combination whose role in physiology and pathophysiology is still far from being elucidated. Not surprisingly, some of the players determining changes into RNA structure are in common with those involved in DNA and chromatin structure regulation, while other molecules seem very specific to RNA. It is envisaged, then, that new small molecules, acting selectively on RNA epigenetic changes, will be reported soon, opening new therapeutic interventions based on the correction of the RNA epigenetic landscape. In this review, we shall summarize some aspects of RNA epigenetics limited to those in which the potential clinical translatability to cardiovascular disease is emerging.

The global population is currently experiencing the impact of the SARS-CoV-2 coronavirus, which has caused the Coronavirus Disease 2019 (COVID-19) pandemic. By our profound comprehension of COVID-19, encompassing the involvement sequence of the respiratory tract, gastrointestinal system, and cardiovascular apparatus, the multiorgan symptoms of this infectious disease have been discerned. Metabolic-associated fatty liver disease (MAFLD) is a pervasive public health concern, intricately linked with metabolic dysregulation and estimated to afflict one-fourth of the global adult population. The burgeoning focus on the association between COVID-19 and metabolic dysfunction-associated fatty liver disease (MAFLD) is justified by the potential role of the latter as a risk factor for both SARS-CoV-2 infection and the subsequent emergence of severe COVID-19 symptoms. Investigations have suggested that changes in both innate and adaptive immune responses among metabolic dysfunction-associated fatty liver disease (MAFLD) patients may play a role in determining the severity of COVID-19. The remarkable similarities observed in the cytokine pathways implicated in both diseases imply the existence of shared mechanisms governing the chronic inflammatory responses characterizing these conditions. The effect of metabolic dysfunction-associated fatty liver disease (MAFLD) on the severity of COVID-19 illness remains uncertain, as indicated by conflicting results in cohort investigations.

Despite all scientific efforts and many protracted and expensive clinical trials, no new drug has been approved by FDA for treatment of Alzheimer disease (AD) since 2003. Indeed, more than 200 investigational programs have failed or have been abandoned in the last decade. The most probable explanations for failures of disease-modifying treatments (DMTs) for AD may include late initiation of treatments during the course of AD development, inappropriate drug dosages, erroneous selection of treatment targets, and mainly an inadequate understanding of the complex pathophysiology of AD, which may necessitate combination treatments rather than monotherapy. Clinical trials’ methodological issues have also been criticized. Current drug-development research for AD is aimed to overcome these drawbacks. Preclinical and prodromal AD populations, as well as traditionally investigated populations representing all the clinical stages of AD, are included in recent trials. Systematic use of biomarkers in staging preclinical and prodromal AD and of a single primary outcome in trials of prodromal AD are regularly integrated. The application of amyloid, tau, and neurodegeneration biomarkers, including new biomarkers—such as Tau positron emission tomography, neurofilament light chain (blood and CSF biomarker of axonal degeneration) and neurogranin (CSF biomarker of synaptic functioning)—to clinical trials allows more precise staging of AD. Additionally, use of the Bayesian statistics, modifiable clinical trial designs, and clinical trial simulators enrich the trial methodology. Besides, combination therapy regimens are currently assessed in clinical trials. The abovementioned diagnostic and statistical advances, which have been recently integrated in clinical trials, are consequential to the recent failures of studies of disease-modifying treatments. Their experiential rather than theoretical origins may better equip potentially successful drug-development strategies.

Background: Senescence is a cellular ageing process in all multicellular organisms. It is characterized by a decline in cellular functions and proliferation, resulting in increased cellular damage and death. This condition plays an essential role in the ageing process and significantly contributes to the development of age-related complications. On the other hand, ferroptosis is a systemic cell death characterized by excessive iron accumulation followed by the generation of reactive oxygen species (ROS). Oxidative stress is a common trigger of this condition and may be induced by various factors such as toxins, drugs, and inflammation. Ferroptosis is linked to numerous illnesses, including cardiovascular disease, neurodegeneration, and cancer. Relevance of these conditions to ageing and disease: Senescence is believed to contribute to the decline in tissue and organ function that occurs with ageing. It has also been linked to the development of age-related pathologies, such as cardiovascular diseases, diabetes, and cancer. In particular, senescent cells have been shown to produce inflammatory cytokines and other pro-inflammatory molecules that can contribute to these conditions. On the other hand, ferroptosis has been linked to the development of various health disorders, including neurodegeneration, cardiovascular disease, and cancer [1]. It is known to play a role in developing these diseases by promoting the death of damaged or diseased cells and contributing to the inflammation often associated with them. Both senescence and ferroptosis are complex processes that are still not fully understood. Further research is needed to thoroughly understand the role of these processes in ageing and disease, and to identify potential interventions to target these processes to prevent or treat age-related conditions. Objectives: This systematic review aims to assess the potential mechanisms underlying the link connecting senescence, ferroptosis, ageing, and disease.

Crohn's disease (CD) results from an aberrant immune response against the commensal microbiota in genetically susceptible hosts. However, the nature of the immune defects, the microflora involved and the genetic susceptibility remain incompletely defined and controversial. Extraintestinal manifestations occur in up to 25-35% of patients and generally precede the onset of gastrointestinal symptoms, which are often of a colonic nature and are influenced by disease activity. Renal manifestations can be considered dependent on the same immune mechanism that determines inflammatory bowel disease in CD. This review seeks to describe the current state of association between CD and kidney disease.

Neurological disorders, such as amyotrophic lateral sclerosis, Parkinson’s disease, and Alzheimer’s disease, are commonly associated with persistent neuro-inflammation, and there is an urgent need to discover new therapeutic agents that may target the various pathways involved in neurodegeneration. In this study, we investigated the therapeutic potential of folecitin, a flavonoid isolated from Hypericum oblongifolium, against lipopolysaccharide (LPS)-induced oxidative stress associated with neurodegeneration, amyloidogenic Aβ production pathway, and memory dysfunction in mice. LPS was administered i.p. at 250 µg/kg/day for 3 weeks, followed by the administration of folecitin at a dose of 30 mg/kg/day for the last two weeks. A Western blot technique was used to assess the expression of different proteins involved in oxidative stress, neurodegeneration, and neuronal synapse. Results indicated that folecitin significantly reduced LPS-induced apoptotic neurodegeneration, including the expression of BAX, Caspase-3, and PARP-1 proteins, inhibited BACE1, and the amyloidogenic Aβ production pathway. Folecitin improved both pre- and post-neuronal synapse, as well as memory dysfunction. Furthermore, folecitin significantly activated endogenous antioxidant proteins such as Nrf-2 and HO-1 via stimulating the phosphorylation of Akt proteins. These findings suggest that folecitin may be a suitable lead to design new drugs for neurotoxin-triggered neurodegenerative disorders.

Human pigmentation has been largely associated with different disease prevalence among populations, but most of these studies are observational and inconclusive. Known to be genetically determined, pigmentary traits have been largely studied by GWAS, mostly in Caucasian ancestry cohorts from North Europe, identifying robustly, several loci involved in many of the pigmentary traits. Here, we conduct a detailed analysis of 13 pigmentary-related traits in a South European cohort of Caucasian ancestry (n=20,000). We observed fair phototype strongly associated with non-melanoma skin cancer and other dermatoses and confirmed by PRS-approach the shared genetic basis with skin and eye diseases, such as melanoma (OR=0.95), non-melanoma skin cancer (OR=0.93), basal cell carcinoma (OR=0.97) and darker phototype with vitiligo (OR=1.02), and cataracts (OR=1.04). Detailed genetic analyses revealed 37 risk loci associated with 10 out of 13 analyzed traits, and 16 fine-mapped genes significantly associated with at least two pigmentary traits. Some of them widely reported, such as MC1R, HERC2, OCA2, TYR, TYRP1, SLC45A2, and unveiling three new candidates RP11-1084J3.4, C1QTNF3 and C17orf112, not reported in GWAS Catalog. These results highlight the importance of phototype assessment as a genetic proxy of skin functionality when evaluating disease screening in mixed populations.

A nutritional approach could be a promising strategy to prevent or slow the progression of neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease, since there is no effective therapy for these diseases so far. The beneficial effects of omega-3 fatty acids are now well established by a plethora of studies through their involvement in multiple biochemical functions, including synthesis of antinflammatory mediators, cell membrane fluidity, intracellular signalling and gene expression. This systematic review will consider epidemiological studies and clinical trials that assessed the impact of supplementation or dietary intake of omega-3 polyunsaturated fatty acids on neurodegenerative diseases such as Parkinson’s and Alzheimer’s diseases. Indeed, treatment with omega-3 fatty acids, being safe and well tolerated, represent a valuable and biologically plausible tool in the management of neurodegenerative diseases in their early stages.

Beyond their significant contribution to the dietary and industrial supplies, marine algae are considered to be a potential source of some unique metabolites with diverse health benefits. The pharmacological properties, such as antioxidant, anti-inflammatory, cholesterol homeostasis, protein clearance and anti-amyloidogenic potentials of algal metabolites endorse their protective efficacy against oxidative stress, neuroinflammation, mitochondrial dysfunction, and impaired proteostasis which are known to be implicated in the pathophysiology of neurodegenerative disorders and the associated complications after cerebral ischemia and brain injuries. As was evident in various preclinical studies, algal compounds conferred neuroprotection against a wide range of neurotoxic stressors, such as oxygen/glucose deprivation, hydrogen peroxide, glutamate, amyloid β, or 1-methyl-4-phenylpyridinium (MPP+) and, therefore, hold therapeutic promise for brain disorders. While a significant number of algal compounds with promising neuroprotective capacity have been identified over the last decades, a few of them have had access to clinical trials. However, the recent approval of an algal oligosaccharide, sodium oligomannate, for the treatment of Alzheimer's disease enlightened the future of marine algae-based drug discovery. In this review, we briefly outline the pathophysiology of neurodegenerative diseases and brain injuries for identifying the targets of pharmacological intervention, and then review the literature on the neuroprotective potentials of algal compounds along with the underlying pharmacological mechanism, and present an appraisal on the recent therapeutic advances. We also propose a rational strategy to facilitate algal metabolites-based drug development.

In this age of mass media and, in particular, social media-driven perception of reality, coupling disease and prophylactic opinion dynamics models can provide better insights into disease evolution than using a disease model alone. We develop in this work two disease-opinion dynamics models based on the epidemiology of the new coronavirus disease (COVID-19) and the availability or not of imperfect vaccines. We assume that susceptibility to infection decreases with the level of prophylactic attitude (personal hygiene, social distancing), and changes in prophylactic attitudes of susceptible individuals occur in response to perceived disease prevalence and vaccination coverage and efficacy in the population. We derive and discuss the disease-free equilibriums and reproduction numbers in the introduced models. We further assess the impacts of the distribution of opinions at disease introduction, the ability to detect presymptomatic, asymptomatic and symptomatic positive COVID-19 cases, the behavioural responses to the outbreak and the introduction of vaccination, and the effects of distortions of disease prevalence by public policy and mass media on disease dynamics. The insights highlighted from the proposed models are expected to make informative contributions to public policy in a context of opinion fluxes in response to perceived disease prevalence.

Hypoxia is one of the most common pathological conditions which results from ischemic injury, trauma, inflammatory conditions, tumors, The adaptation of the body to hypoxia is a phenomenon that is of great importance both in normal conditions and in Most of the cellular response’ reactions to hypoxia is associated with a family of transcription factors called hypoxia-inducible factors (HIF). They induce the expression of a wide range of genes that help cells adapt to a hypoxic HIF functions are currently being extensively studied. In 2019, William G. Kaelin and Gregg Semenza from the USA and Sir Peter J. Ratcliffe from the UK received the Nobel Prize in Physiology or Medicine for the discovery of the basic mechanisms of adaptation to hypoxia and investigation of the role of HIF factor in the regulation of the hormone erythropoietin Based on its pivotal physiological importance, the HIF factor attracts more and more attention as a new potential target for treating a large number of diseases associated with Most of the experimental work dealing with the HIF factor is focused on its role in liver and However, increasing amount of experimental results clearly demonstrates that the HIF factor-based response represents an universal adaptation mechanism for all kinds of tissues, including the nervous system where HIF is critical for regulating neurogenesis, nerve cell differentiation, and neuronal This review provides actual overview about the complex role of HIF-1 in the adaptation of nerve cells to hypoxia with the focus on its potential role by various neuronal

Leptospirosis is an important zoonotic disease, causing about 60,000 deaths annually. One of the reasons for the severe course of leptospirosis is a cytokine storm, which develops as a result of an excessive immune response. The gut microbiota that resides in the gastrointestinal tract provides essential health benefits to its host, particularly by regulating immune homeostasis and a bidirectional relationship with many internal organs. A change in the gut microbiota can be caused not only by antibiotics, but also by infectious agents such as the coronavirus or the flu virus. It is known that L. interrogans can change the microbiota of mice. Thus, gut dysbiosis in leptospirosis can affect the clinical course of the disease, through the gut–organ axis. Modulation of intestinal microbiota by probiotics and/or fecal microbiota transplantation in leptospirosis may become an important area of scientific research.

Rice is consumed as a staple food by majority of the people in the world and failure in rice crop, due to any reason, poses a severe threat of starvation. Rice blast, caused by a fungus blast has been ranked among the most important plant diseases. It is by far the most threatening disease of ric crop and it is found wherever rice is grown. All of the rice blast disease management strategies that have been employed have limited success and rice blast has never been eliminated from a region in which rice is grown. Hence there is need to look for the best remedy in terms of effectiveness and organic nature of the method etc. This study was aimed to determine the plant growth promoting and biopesticidal effects of bioactive components present in a mixture of Piper caninum and Piper betle var. Nigra leaf extracts. . The extracts were applied in the field to determine their inhibition effects against blast disease, growth and yield improvement.. Extract of both the plants promoted plant growth and exhibited antifungal activity against rice blast fungus, Pyricularia oryzae. However the synergistic effect of the mixture of the two extracts exhibited greater effects than an effect of a single extract. . All treatments reduced the intensity of blast disease on week 15 with disease intensity by 7.90%. The extracts could increase plant height, the numbers of tillers, number of leaves, number of grains per panicle number of heads per panicle, and the full-grain weight hill.. The highest potential yield (t/ha) was observed in the 2% extract treatment, and all treatment results significantly differed from that of the control. The potential grain yield was 3.23 t/ha in the control, while that in the treatment ranged from 3.81 t/ha to 5.61 t/ha. The high grain yield observed with the treatment was caused by the low intensity of blast disease.

Healthy life style is associated with decreased risk of chronic kidney disease (CKD) and mortality in the general population. However, there is no definitive evidence on the benefits of physical activity and other health-related behaviors in the early-stage CKD. This study aimed to explore the association between health-related behaviors and end-stage renal disease (ESRD) and mortality in the early stages of CKD. The National Health Insurance Service (NHIS) database from January 1st, 2009 to December 31st, 2016 was used to screen 83,470 subjects with early stage CKD. Cox proportional hazard regression analysis was used to evaluate the association between health-related behaviors and ESRD and death. Kaplan-Meier curves for mortality and ESRD were plotted according to the physical activity, smoking status and alcohol consumption pattern. Risk of death decreased significantly in subjects who engaged in sufficient physical activity (adjusted Hazard Ratio (HR) 0.73; 95% CI: 0.64-0.83; p < 0.001). Risk of ESRD and death increased significantly in the current smoker with adjusted HR of 1.44 (95% CI: 1.06-1.95; p < 0.02) and 1.61 (95% CI: 1.44-1.80; p < 0.001) respectively. Therefore, systematic interventions to encourage physical activity and smoking cessation need to be actively considered in the early stages of CKD.

Initially, renal resistive index (RRI) was investigated to improve diagnosis in kidney diseases, but failed to meet this goal. Recently many papers highlighted the prognostic significance of RRI in chronic kidney disease, in the estimation of revascularization success of renal artery stenoses or the evolution of the graft and recipients in renal transplantation. Moreover, RRI gained importance in prediction of acute kidney injury in critically ill patients. Along with RRI study in renal pathology have been revealed correlations of this index with parameters of systemic circulation. The theoretical and experimental premises of this connection were reconsidered, and studies for analyzing the link between RRI and arterial stiffness, central and peripheral pressure or left ventricular flow were conducted with this purpose. A high amount of data is currently indicating that RRI is influenced more by pulse pressure and vascular compliance than by renal vascular resistance – assuming that RRI reflects the complex interplay between systemic circulation and renal microcirculation and should be considered as a marker of systemic cardiovascular risk beyond its prognostic relevance for kidney disease. In this review we will go through clinical research that revealed the implications of RRI in renal and cardiovascular disease.

Background: Crohn’s and Ulcerative Colitis Questionnaire-32 (CUCQ-32) is a validated questionnaire to measure the quality of life (QoL) in inflammatory bowel disease (IBD). However, it does not have stoma specific questions and can be lengthy. This study aimed to validate a subset of the CUCQ-32 that would be suitable for patients with a stoma. Methods: Baseline data were collected from a cohort of patients with acute ulcerative colitis who were participating in the CONSTRUCT multi-centre clinical trial. A subset of the CUCQ-32 questions was selected by stepwise regression. Further validation was examined using data from the UK IBD biological therapies audit. Construct validity was carried out using the EuroQol 5 dimensions (EQ5D) questionnaire, Simple Clinical Colitis Activity Index (SCCAI) and the Harvey-Bradshaw Index (HBI). Literature review and an expert focus group identified supplementary questions to cover patients with a stoma. Test-retest analysis was done during the patients’ second follow up visits. Results: Using the data from 124 patients, a short version questionnaire (CUCQ-12) was developed. Further validation using data from 484 patients with IBD as part of the UK IBD biological therapies audit. Using the data from 61 patients with a stoma, we identified 5 stoma specific questions for the CUCQ-12+. The CUCQ-12+ demonstrated excellent internal consistency (Cronbach’s α= 0.86); established effective reproducibility (intra-class correlation coefficient= 0.74); correlated well with the EQ5D (r= - 0.48), HBI (r= 0.45) and SCCAI (r= 0.43); and represented good responsiveness statistics (>0.5). Conclusions: CUCQ-12+ is a valid and reliable QoL measure that can be used for all patients with IBD in clinical practice including patients with a stoma.

The outbreak of Coronavirus disease 2019 (COVID-19) has posed a significant concern in many countries due to the rapid rate of transmission between humans. Taking advantage of the experience of the last epidemics in 2002 Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and 2012 Middle East Respiratory Syndrome Coronavirus (MERS-CoV), some regions of the world were well- prepared for the new outbreak. However, other countries needed to be adapted to the situation promptly. Many management strategies were established, and some restrictions were introduced in some regions. In this review, we aimed to determine countries’ public responses to the epidemic of COVID-19 and how they developed administrative approaches towards the outbreak.

GM2 gangliosidoses are a group of pathologies characterized by GM2 ganglioside accumulation into the lysosome due to mutations on the genes encoding for the β-hexosaminidases subunits or the GM2 activator protein. Three GM2 gangliosidoses have been described: Tay-Sachs disease, Sandhoff disease, and the AB variant. Central nervous system dysfunction is the main characteristic of GM2 gangliosidoses patients that include neurodevelopment alterations, neuroinflammation, and neuronal apoptosis. Currently, there is not approved therapy for GM2 gangliosidoses, but different therapeutic strategies have been studied including hematopoietic stem cell transplantation, enzyme replacement therapy, substrate reduction therapy, pharmacological chaperones, and gene therapy. The blood-brain barrier represents a challenge for the development of therapeutic agents for these disorders. In this sense, alternative routes of administration (e.g. intrathecal or intracerebroventricular) have been evaluated, as well as the design of fusion peptides that allow the protein transport from the brain capillaries to the central nervous system. In this review, we outline the current knowledge about clinical and physiopathological findings of GM2 gangliosidoses, as well as the ongoing proposals to overcome some limitations of the traditional alternatives by using novel strategies such as molecular Trojan horses or advanced tools of genome editing.

The effective management of Fusarium wilt of bananas (FW) depends on the knowledge of the disease dynamics in time and space. The objectives of this work were: To estimate disease intensity and impact, and to investigate the spatial and temporal dynamic of FW. Fields planted with Silk (n = 10), Pome (n = 17) or Cavendish (n = 3) banana subgroups were surveyed in Brazil, totaling 95 ha. In each field, all plants were visually assessed and diseased plants were georeferenced. The incidence of FW and the impact of the disease on yield on a regional scale were estimated. Spatial patterns were analyzed using quadrat- and distance-based methods. FW incidence ranged from 0.09 to 41.42%, being higher in Silk fields (median = 14.26%). Impacts of epidemics on yield ranged from 18.4 to 8,192.5 kg.ha-1.year-1, with a median of 935.2 kg.ha-1.year-1. The higher economic impact of the disease was observed on Silk cultivar with a median loss of US$ 910.5 ha-1.year-1. Overall, estimated losses increased on average by US$ 109.8 ha-1.year-1 at each 1% of incidence. Aggregation of FW was detected by all analytical methods in 13 fields (1 of Cavendish, 11 of Pome and 1 of Silk). In the other 17 fields, at least one analytical method did not reject the null hypothesis of randomness. One field (5 ha), composed of six plots, was selected for spatial and temporal studies during two years with bi-monthly assessments. A sigmoidal curve represented the FW progress and the Gompertz model best fitted disease progress. The level of aggregation varied over time, and evidence of secondary infection to neighboring and distant plants were detected. FW is a widespread problem in Brazil and yield losses can be of high magnitude. Epidemiology-based management strategies can now be better established.

Fumaric acid esters (FAEs) are small molecules with anti-oxidative, anti-inflammatory and immune-modulating effects. Dimethyl fumarate (DMF) is the best characterised FAE and is approved and registered for the treatment of psoriasis and Relapsing-Remitting Multiple Sclerosis (RRMS). Psoriasis and RRMS share an immune-mediated aetiology, driven by severe inflammation and oxidative stress. DMF, as well as monomethyl fumarate and diroximel fumarate, are commonly prescribed first-line agents with favourable safety and efficacy profiles. The potential benefits of FAEs against other diseases that appear pathogenically different but share the pathologies of oxidative stress and inflammation are currently investigated.

Scientists have observed amyotrophic lateral sclerosis (ALS) disease clusters around certain lakes in the regions of northern New England and northern Ohio. A Parkinson’s disease cluster has also been observed in Vancouver. Cyanobacteria toxin exposure has been considered as a potential risk factor to explain this association. It is reported here that these regions have several commonalities in their environment, including a notable geologic history, the presence of abundant glacial sediments, and possible mineral and bentonite exposures. The possible association with and significance of these risk factors in ALS and Parkinson’s disease is discussed.

Background: Meniere's disease (MD) has been recently linked to gluten assumption. Approximately 75% of MD patients show positive skin test to food and about 50% of the positive responses are specific to the gliadin acid extract fraction. Aim of this study was to investigate the humoral immune responses to wheat antigens and related autoantigens in MD patients. Methods. We assessed the reactivity of sera from 28 patients with definite MD and 100 healthy controls against a repertoire of 51 antigens usually associated with immune reaction to gluten. Results. MD patients showed an increase of anti-wheat IgA, anti-cerebellar peptide IgA and anti-glutamic acid decarboxylase (GAD) 65 IgM compared to healthy controls. In particular, the increase of anti-wheat IgA and GAD 65 IgM has been confirmed in a subgroup of MD patients symptomatically responding to a gluten free diet (GFD). Conclusion. In MD patients, an increase of the antibody production against gluten biomarkers was observed; in particular, anti-wheat IgA seems to be associated to clinical response to GFD.

The lumpy skin disease virus (LSDV) is an animal virus and a member of the Poxviridae family, which causes lumpy skin disease (LSD) in livestock animals like cows and buffaloes. LSD is an important transboundary disease of economic importance that was first discovered in 1929 in Zambia. LSDV has been prevalent in African countries, where several outbreaks have been reported previously. However, the virus has spread rapidly across the Middle East in the past two decades, reaching Russia and, recently, the Asian subcontinent. With the unprecedented cluster outbreaks reported across Asian countries, LSDV is certainly undergoing an epidemiological shift and expanding its geographical footprint globally. The recent LSD outbreaks have gained attention from global regulatory authorities and raised serious concerns among epidemiologists and veterinary researchers. Although there is no dearth of knowledge about LSDV, the disease lacks networked global surveillance and management, consequently making the current statistics deficient, fragmented, and unreliable. Hence, recurrent LSD outbreaks seriously threaten the global livestock industry. This review provides recent insights into LSDV by augmenting latest literature associated with its epidemiology, pathogenesis, transmission, currently-available intervention strategies, and economic implications on the dairy industries. The review also critically examines the changing epidemiological footprint of LSD and speculates on the possible reasons contributing to the ongoing multi-country LSD outbreak.

Alzheimer’s disease (AD) is an irreversible neurodegenerative disease characterized by progressive cognitive decline. The two cardinal neuropathological hallmarks of AD include buildup of cerebral β amyloid (Aβ) plaques and neurofibrillary tangles of hyperphosphorylated tau. The current disease-modifying treatments are still not effective enough to lower the rate of cognitive decline. The paucity of early detection and disease progression biomarkers also seems to present a major obstacle to AD drug development. The current established readouts based on expression levels of amyloid beta, tau and phospho tau have shown many discrepancies in patient samples when linked to disease progression. There is an urgent need to identify diagnostic and disease progression biomarkers from blood, CSF or other biofluids that can facilitate early detection of the disease and provide pharmacodynamic readouts for new drugs being tested in clinical trials. Advances in proteomic approaches using state-of-the-art mass spectrometry, are now being increasingly applied to study AD disease mechanisms, identify drug targets and novel disease biomarkers. In this report, we describe applications of the quantitative proteomic approaches for understanding AD pathophysiology, summarize the current knowledge gained from proteomic investigations of AD and discuss development and validation of new predictive and diagnostic disease biomarkers.

Neurodegenerative diseases are multifactorial, initiated by a series of the causative complex which develops into a certain clinical picture. The pathogenesis and disease course vary from patient to patient. Thus, it should be likewise to the treatment. Peripheral biomarkers are to play a central role for tailoring a personalized therapeutic plan for patients who suffered from neurodegenerative diseases such as Alzheimer’s diseases, Parkinson’s disease, and multiple sclerosis, among others. Nevertheless, the use of biomarkers in clinical practice is still underappreciated and data presented in biomarker research for clinical use is still uncompelling, compared to abundant data available for drug research and development. So is the case with kynurenines (KYNs) and the kynurenine pathway (KP) enzymes which have been associated with a wide range of diseases including cancer, autoimmune diseases, inflammatory diseases, neurologic diseases, and psychiatric disorders. This review article discusses current knowledge of the KP alteration observed in the central nervous system as well as the periphery, its involvement in pathogenesis and disease progression, and emerging evidence of roles of microbiota to the gut-brain axis, searching for practical peripheral biomarkers which ensure personalized treatment plans for neurodegenerative diseases.

Kidney disease is a significant health problem worldwide, affecting an estimated 10% of the global population. Kidney disease encompasses a diverse group of disorders that vary in their underlying pathophysiology, clinical presentation, and outcomes. These disorders include acute kidney injury (AKI), chronic kidney disease (CKD), glomerulonephritis, nephrotic syndrome, polycystic kidney disease, diabetic kidney disease, and many others. Despite their distinct etiologies, these disorders share a common feature of immune system dysregulation and metabolic disturbances. The immune system and metabolic pathways are intimately connected and interact to modulate the pathogenesis of kidney diseases. The dysregulation of immune responses in kidney diseases includes a complex interplay between various immune cell types, including resident and infiltrating immune cells, cytokines, chemokines, and complement factors. These immune factors can trigger and perpetuate kidney inflammation, causing renal tissue injury and progressive fibrosis. In addition, metabolic pathways play critical roles in the pathogenesis of kidney diseases, including glucose and lipid metabolism, oxidative stress, mitochondrial dysfunction, and altered nutrient sensing. Dysregulation of these metabolic pathways contributes to the progression of kidney disease by inducing renal tubular injury, apoptosis, and fibrosis. Recent studies have provided insights into the intricate interplay between immune and metabolic pathways in kidney diseases, revealing novel therapeutic targets for the prevention and treatment of kidney diseases. Potential therapeutic strategies include modulating immune responses through targeting key immune factors or inhibiting pro-inflammatory signaling pathways, improving mitochondrial function, and targeting nutrient-sensing pathways such as mTOR, AMPK, and SIRT1. This review highlights the importance of the interplay between immune and metabolic pathways in kidney diseases and the potential therapeutic implications of targeting these pathways.

Stress mechanisms have long been associated with neuronal loss and neurodegenerative diseases. The origin of cell stress and neuronal loss likely stems from multiple pathways. These include (but are not limited to) bioenergetic failure, neuroinflammation, and loss of proteostasis. Cells have adapted compensatory mechanisms to overcome stress and circumvent death. One mechanism is mitophagy. Recent studies have implicated mitophagy in several neurodegenerative diseases and clinical trials are underway which target mitophagy pathways. Here, we review mitophagy pathways, the role of mitophagy in neurodegeneration, potential therapeutics, and the need for further study.

Background: Several preventive strategies to reduce dyslipidaemia, have been suggested of which dietary modification features as an important one. Addition of almonds in our daily diets has been proposed to beneficially impact the lipid profile. This review critically examines the available evidence assessing the effect of almonds on dyslipidaemia in the South Asian (particularly Indian) context. Methods: An extensive review comprising of epidemiological studies, clinical trials, meta-analyses and systematic reviews was conducted from published literature from across the world. Studies examining the effect of almonds on different aspects of dyslipidaemia viz. high LDL-C, low HDL-C, triglyceridaemia, high total cholesterol levels have been included. Results: Dyslipidaemia is a major risk factor for coronary heart disease and strategies to manage dyslipidaemia have been shown to reduce the incidence of CVD. Although there are proven pharmacological therapies to help manage this condition, there are not many nutritional interventions which can impact dyslipidaemia. Almonds have been shown to reduce LDL-C which is a known risk factor for CHD, in several studies and the effect of almonds has been well documented in systematic reviews and meta-analysis of clinical trials. Conclusions: Addition of almonds in the diet has been shown to not only to reduce LDL-C levels, but also to maintain HDL-C levels. This review informs about the use of this simple nutritional strategy which may help manage known major risk factors for heart disease such as high LDL-C and low HDL-C levels especially in the context of South Asians.

Studies have shown increased nontuberculous mycobacterial pulmonary disease (NTM) incidence with inhaled corticosteroid (ICS) use in patients with chronic respiratory diseases; however, this association in chronic obstructive pulmonary disease (COPD) remains insufficiently studied. Using a nationwide population-based database of the Korean National Health Insurance Service, newly diagnosed COPD patients (20052018) treated with inhaled bronchodilators were selected. An NTM case was defined by the presence of the first diagnostic code following inhaled bronchodilator use. Results indicated that ICS users did not have an increased risk of NTM disease compared to non-ICS users (hazard ratio [HR], 1.121; 95% confidence interval [CI], 0.9501.323; p = 0.1755). The highest quartile of the cumulative ICS dose was associated with the development of NTM (1.200, 0.9501.323, p = 0.0497). Medium (1.229, 1.0081.499, p = 0.0410) and high daily doses of ICS (1.637, 1.2412.160, p = 0.0005) were associated with an increased risk of NTM disease. There was no difference in the risk of NTM according to ICS type. ICS use may not increase the risk of developing NTM disease in patients with COPD. However, physicians should weigh the potential benefits and risks of ICS, especially when using high doses and prolonged durations.

The number one leading cause of death in 2017 for Americans was cardiovascular disease, and health disparities can exacerbate risks. This study evaluates the 2018 Behavioral Risk Factor Surveillance System (n=437,436) to estimate population risks for behavioral, socio-economic, psychological, and biological factors. A general linear model with a quasi-binomial link function indicated higher risks for the following groups: smokers, individuals with higher body-mass index scores, persons unable to work, individuals with depression, workers who missed more days due to mental issues, the elderly, those in race categories “indigenous Americans, Alaskan non-Hispanics” or “other, non-Hispanic,” and individuals with lower income. The results confirm previous studies and raise more questions about drinking and cardiovascular disease. Policy and ethical considerations are also discussed.

Lyme carditis (LC) is a manifestation of the early disseminated stage of Lyme disease and often presents as high-degree atrioventricular (AV) block. High-degree AV block in LC can be treated with antibiotics, usually resolving with highly favourable prognosis, thus preventing the unnecessary implantation of permanent pacemakers. We present a systematic approach to the diagnosis and management of LC that implements the Suspicious Index in Lyme Carditis (SILC) risk stratification score.

The last 20 years have seen a surge in scientific activity and promising results in the study of aging and longevity. Many researchers have focused on telomeres, which are composed of a series of TTAGGG repeat nucleotide sequences at the ends of each chromosome. Measurements of the length of these telomere strands show that they decrease in length with increasing age, leading many authors to propose that when the length of these telomere strands decreases sufficiently, the cells enter into a state of replicative senescence, eventually leading to disease and death. These ideas are supported by evidence that short telomere length is correlated with increased mortality. In this paper, we extend this idea to make an actual calculation of the predicted mortality rate caused by short telomere length induced senescence (STLIS). We derive a simple equation for the mathematical relationship between telomere length and mortality rate. Using only 3 parameters based on telomere length measurement data of Canadians, we have calculated both the magnitude and the age dependence of the mortality rate, for both men and women. We show that these calculated data are in good quantitative agreement with the actual number of Canadians that die. This agreement provides strong evidence (but not proof) that the mechanism of STLIS plays an important role in the major diseases of aging (e.g., cardiovascular disease, many cancers, and diabetes mellitus) which dominate human mortality. This result represents significant progress in our understanding the factors behind the cause of aging.

Sacrococcygeal pilonidal disease is a chronic inflammatory condition with an incidence of 26:100,000 in the United States. However, its etiology and optimal treatment remain controversial. We included 129 and 74 patients with simple and complex sacrococcygeal pilonidal disease, respectively. The primary outcome was pilonidal sinus recurrence after unroofing curettage. Secondary outcomes were pain scores, time to return to work/school, and time to complete recovery. At a median follow-up of 53 months, the recurrence rate was 4.9% in all patients, not significantly higher in subjects with the complex disease. Duration of surgery (15.4 vs. 12.2 min), time to return to school/work (9.8 vs. 7.7 days), and complete healing time (44 vs. 36 days) were longer in patients with the complex disease. Postoperative complication rates, pain scores, and quality of life scores between the two groups did not differ. Unroofing curettage may be a good first-choice treatment for both simple and complex sacrococcygeal pilonidal disease.

There is limited data on pregnancy outcomes in Pompe Disease (PD) resulting from deficiency of the lysosomal enzyme acid alpha-glucosidase. Late-onset PD is characterized by progressive proximal muscle weakness and decline of respiratory function secondary to the involvement of the respiratory muscles. In a cohort of twenty-five females, the effects of both PD on the course of pregnancy and the effects of pregnancy on PD were investigated. Reproductive history, course of pregnancy, use of Enzyme replacement therapy (ERT), PD symptoms, and outcomes of each pregnancy were obtained through a questionnaire. Among 20 subjects that reported one or more pregnancies, one subject conceived while on ERT and continued therapy through two normal pregnancies with worsening of weakness during pregnancy and improvement postpartum. While fertility was not affected, pregnancy may worsen symptoms, or cause initial symptoms to arise. Complications with pregnancy or birth were not higher, except for an increase in the rate of stillbirths (3.8% compared to the national average of 0.2-0.7%). Given small sample size and possible bias of respondents being only women who have been pregnant, further data may be needed to better analyze the effects of pregnancy on PD, and the effects of ERT on pregnancy outcomes.

Growing evidence from neurodegenerative disease research supports an early pathogenic role for mitochondrial dysfunction in affected neurons that precedes morphological and functional deficits. Resulting oxidative stress and respiratory malfunction contribute to neuronal toxicity and may enhance the vulnerability of neurons to continued assault by aggregation-prone proteins. Consequently, targeting mitochondria with antioxidant therapy may be a non-invasive, inexpensive, and viable means of strengthening neuronal health and slowing disease progression, thereby extending quality of life. We review the pre-clinical and clinical findings available to date of the natural bioactive phenol resveratrol and two synthetic mitochondrial-targeted antioxidants MitoQ and SkQ.

Even though Alzheimer’s disease (AD) is of significant interest to the scientific community, its pathogenesis is very complicated and not well-understood. A great deal of progress has been made in AD research recently and with the advent of these new insights more therapeutic benefits may be identified that could help patients around the world. Much of the research in AD thus far has been very neuron-oriented; however, recent studies suggest that glial cells, i.e., microglia, astrocytes, oligodendrocytes, and oligodendrocyte progenitor cells (NG2 glia), are linked to the pathogenesis of AD and may offer several potential therapeutic targets against AD. In addition to a number of other functions, glial cells are responsible for maintaining homeostasis (i.e., concentration of ions, neurotransmitters, etc.) within the central nervous system (CNS) and are crucial to the structural integrity of neurons. This review explores the: (i) role of glial cells in AD pathogenesis; (ii) complex functionalities of the components involved; and (iii) potential therapeutic targets that could eventually lead to a better quality of life for AD patients

Experimental and epidemiological evidence has shown that modifications of the intrauterine environment can have deleterious consequences for individuals, expressed as an increased risk of suffering non-communicable pathologies in adult life, which is known as the hypothesis of the early origin of diseases or programming fetal. On the other hand, changes in gene expression patterns through epigenetic modifications can be the basis for long-term maintenance of the effects of fetal programming. In this sense, epigenetics comprises the study of intrauterine disturbances, which develop diseases in the adult, including Celiac Disease (CD). In addition, early feeding practices could influence the risk of CD development, such as breastfeeding timing and duration and age at gluten introduction in the diet. Gluten acts as a trigger for CD in genetically predisposed subjects, although approximately 30% of the world population has HLA DQ2 or DQ8, the prevalence of the disease is only 1-3%. It is not known what factors act to modify the risk of disease in genetically at risk subjects. Taking into account all these considerations, the aim of the current review is to elucidate the role of early programming and the effect of early nutrition on the development and progression of CD.

Results: A total of 6270 individuals were assessed (1615 severe and 4655 non-severe patients). The median age was 63 (95% CI: 49-74) and 47 (95% CI: 19-63) years in the severe and non-severe groups, respectively. Moreover, about 41% of patients had comorbidities. Severity was higher in patients with history of cerebrovascular disease: OR 4.85 (95% CI: 3.11-7.57). The odds of being in severe group increase by 4.81(95% CI: 3.43-6.74) for history of cardiovascular disease (CVD). This was 4.19 (95% CI: 2.84-6.19) for chronic lung disease and 3.18, 95% CI: 2.09-4.82 for cancer .The odds ratio of a diabetes and hypertension were 2.61 (95% CI: 2.02-3.3), and 2.37( 95% CI: 1.80-3.13) respectively.

Ursolic and oleanolic acids are secondary plant metabolites that are known to be involved in the plant defence system against water loss and pathogens. Nowadays these triterpenoids are also regarded as potential pharmaceutical compounds and there is mounting experimental data that either purified compounds or triterpenoid-enriched plant extracts exert various beneficial effects, including anti-oxidative, anti-inflammatory and anticancer, on model systems of both human or animal origin. Some of those effects have been linked to the ability of ursolic and oleanolic acids to modulate intracellular antioxidant systems and also inflammation- and cell death-related pathways. Therefore, our aim was to review the current knowledge about the distribution of ursolic and oleanolic acids in plants, bioavailability and pharmacokinetic properties of these triterpenoids and their derivatives, and to discuss their neuromodulatory effects in vitro and in vivo.

Leukotrienes are proinflammatory mediators that participate in the process of atherogenesis and contribute to the development of symptomatic peripheral arterial disease. The aim was to evaluate the relationship between leukotriene E4 (LTE4) and B4 (LTB4) with parameters reflecting endothelial vascular function in patients with chronic lower limb ischemia. This prospective observational study enrolled 50 consecutive patients undergoing endovascular treatment due to chronic lower limb ischemia (Rutherford 3). All participants were followed-up for one year (after 1, 3, 6 and 12 months), with a sequential assessment of urinary LTE4 and LTB4, as well as measures of endothelial and vascular function: Flow-Mediated Dilatation (FMD), Intima-Media Thickness (IMT), corrected Augmentation Index (AI75), Shear Rate (SR), Ankle-Brachial Index (ABI), Toe-Brachial Index (TBI). There was a significant relationship between LTE4 and measures of vascular function: FMD (R2 = 0.69, P&lt;0.001), IMT (R2=0.12, P&lt;0.01), AI75 (R2=0.43, P&lt;0.001), SR (R2=0.48, P&lt;0.001). Similar findings were noted for LTB4: FMD (R2=0.47, p&lt;0.001), IMT (R2=0.23, P&lt;0.001), AI75 (R2=0.61, P&lt;0.001) and SR (R2=0.33, P&lt;0.001). Alterations in parameters were significantly related: ΔLTE4 vs ΔFMD(R2=0.63, P&lt;0.001), ΔSR (R2=0.42, P&lt;0.001) and ΔLTB4 vs AI75(R2=0.40, P&lt;0.001), SR(R2=0. 29, P&lt;0.001). We conclude, that increasing concentrations of LTE4 and LTB4 are associated with impairment of vascular and endothelial function, which may lead to worse endovascular treatment clinical outcomes.

Introduction: Epilepsy is one of the most common neurological diseases. Epilepsy poses a significant burden on the quality of life of affected individuals and their families. The aim of this study was to determine the psychiatric disorders in epileptic patients. Methods and Materials: This descriptive-analytical study was conducted in 2017 with a simple random sampling method on patients with epilepsy who admitted to the neurology department. Results: Among the 150 examined patients, 88 (58.7%) were female and 63(42%) had epilepsy more than 10 years. The most common psychiatric disorder among epileptic patients was depression (68 patients = 45.3%) and anxiety (65 patients = 43.3%) patients. Conclusion: Most of patients had more than 10 years history of epilepsy. Also, Anxiety and depression were the most common symptoms in epileptic patients. It need to more study to determine the psychiatric disorders in epileptic patients.

Interest in organic foods is increasing at a moment when humanity is facing a range of health challenges including the concern that some conventionally produced foods may pose possible adverse effects on human and livestock health. With the increasing human population, intensive production is increasingly trending towards high-input systems that aim to close yield gaps, increase crop yields, and develop new crop varieties with higher yield potential and tolerance to biotic and abiotic stresses, all within the context of incorporating specific traits to satisfy consumer demand. Potato (Solanum tuberosum L.) is one of the most consumed foods under different cultural diets, however its production faces some challenges related to soilborne diseases, marketable yield and quality, sugars and dry matter content of the produced tubers, tuber content in terms of nitrate, minerals, vitamins, bioactive compounds and antioxidants, and consumer appreciation regarding the sensory characteristics of tubers and processed products. Different studies have been investigating some of these challenges, with sometimes straightforward and sometimes connflicting results. This variability in research results indicates the general non-transferability of the results from one location to another under the same management practices in addition to differences in plant material. This review compares some characteristics of raw or boiled potato and processed products from potato tubers grown organically and conventionally. Ideally, such information may be of benefit in decision making by consumers in their dietary choices, by potato growers in their selection of crop management practices, and by scientists looking at potential areas for future research on potatoes.

Concomitant neuropathological hallmarks of Alzheimer’s Disease (AD) are common in the brains of people with Parkinson’s disease (PD). Furthermore, AD biomarkers are associated with cognitive decline and dementia in PD patients during life. Here, we highlight the considerable overlap between AD and PD, emphasizing neuropathological, biomarker, and mechanistic studies. We suggest that precision medicine approaches may successfully identify PD patients most likely to develop concomitant AD. The ability to identify PD patients at high risk for future concomitant AD in turn provides an ideal cohort for trials of AD-directed therapies in PD patients, aimed at delaying or preventing cognitive symptoms.

Assessment of cardiac function is the leading parameter when evaluating the state of the cardiovascular system of patients undergoing chronic hemodialysis. The aim of the paper: to assess the state of the cardiovascular system of these patients using new sensitive echocardiography and Doppler techniques and thus advance the prevention of cardiovascular disease.Method: Twenty children with end-stage renal insufficiency on chronic hemodialysis and twenty healthy controls underwent echocardiographic monitoring using standard Doppler and tissue Doppler imaging. Structural and functional changes in the left ventricle were evaluated.Results: Patients on hemodialysis had significantly greater left ventricular mass indices compared to the controls (p<0.001). The patients on hemodialysis had preserved systolic function – their fractional shortening, ejection fraction and Sm (systolic myocardial velocity) did not differ significantly compared to the controls (p>0.05). Early diastolic function in children on hemodialysis was also preserved: the E/A and Em/Am ratio did not differ significantly from the control group (p>0.05). Children on hemodialysis exhibited impaired late diastolic function (compliance index), that is, considerably higher E/Em compared to controls (p<0.00). Myocardial Performance Index values showed statistically significant elevation in children on hemodialysis compared to the control group (p<0.001).Conclusion: Tissue Doppler in tandem with conventional Pulsed Doppler can provide additional information on left ventricular filling pressures (E/Em) in children on hemodialysis. It is therefore recommended to perform routine measuring of Em waves and the E/Em ratio, not only in order to evaluate myocardial relaxation and ventricular filling pressures, but primarily to stratify risk and provide a prognosis.

Marine wildlife and aquaculture species can accumulate large amounts of microplastic particles (&lt;1 mm), threatening the health of marine populations and ecosystems and posing a risk to food safety and human health. The uptake of chemicals from microplastics seems to decrease the immune capacity of bivalves and corals to fight pathogenic bacteria, thereby increasing their vulnerability to disease. Moreover, major pathogens of bivalves, fish, and humans, including several Vibrio species, have been shown to be specifically enriched in the microbial communities adhered to marine microplastic debris (MMD). Microplastics can therefore serve as an important vector for and regulator of pathogen transmission and disease dynamics. Here, we outline a theoretical, three-perspective approach for studying the relationship between MMD and disease. First, we provide a framework for retrospective analysis of MMD and pathogen loads in marine animal tissues to assess the relationships between them, their bioaccumulation over time, and their relationship to other environmental variables. The results from such an analysis can be used to decide whether a compound or pathogen should be considered an emerging substance or organism. Second, we describe an experimental design for testing the effect of a variety of microplastics on in vivo pathogen removal (i.e., the phagocytic activity of hemocytes) and infection intensity in two study model species (oysters and zebrafish). Finally, we create a theoretical susceptible-infected microplastic particle and pathogen transmission model for bivalves and fish. Overall, the experiments and models we propose will pave the way for future research designed to assess the role of MMD as a vector for marine and human pathogens. This multi-faceted approach needs to be an urgent priority of the EU Strategic Research Innovation Agenda for addressing marine disease challenges related to MMD.

Lyme disease and associated co-infections are increasing worldwide and approximately 20% of individuals develop chronic Lyme disease (CLD)/Post-Treatment Lyme Disease Syndrome (PTLDS) despite early antibiotics. A 7–8-week protocol of double dose dapsone combination therapy (DDDCT) for CLD/PTLDS results in symptom remission in approximately 50% of patients for one year or longer, with published culture studies indicating higher doses of dapsone demonstrate efficacy against resistant biofilm forms of Borrelia burgdorferi. The purpose of this study was therefore to evaluate higher doses of dapsone in the treatment of resistant CLD/PTLDS and associated co-infections. Twenty-five patients with a history of Lyme and associated co-infections, most of whom had ongoing symptoms despite several courses of DDDCT, took one or more courses of high dose pulsed dapsone combination therapy (200 mg dapsone X 3-4 days and/or 200 mg BID x 4 days), depending on persistent symptoms. The majority of patients noticed sustained improvement in 8 major Lyme symptoms, including fatigue, pain, headaches, neuropathy, insomnia, cognition, and sweating, where dapsone dosage, not just treatment length, positively affected outcomes. High dose pulsed dapsone combination therapy may represent a novel therapeutic approach for the treatment of resistant CLD/PTLDS, and should be confirmed in randomized, controlled clinical trials.

Although originally multi-ethnic in its structure, nowadays the Calabria region of southern Italy represents an area with a low genetic heterogeneity and a high level of consanguinity that allows rare mutations to be maintained due to the founder effect. A complex research methodology ranging from clinical activity to genealogical reconstruction of families/populations along the centuries, creation of databases, and molecular/genetic research, has been modelled on the characteristics of the Calabrian population for more than three decades. This methodology allows to the identification of several novel genetic mutations or variants associated with neurodegenerative diseases. In addition, in this population it has been reported a higher prevalence of several hereditary neurodegenerative diseases such as Alzheimer’s disease, Frontotemporal dementia, Parkinson’s disease, Niemann Pick type C disease, Spino-cerebellar ataxia, Creutzfeldt–Jakob disease and Gerstmann Straussler Scheincker disease. Thus, Calabria constitutes a model for the study of neurodegenerative diseases, a sort of "outdoor laboratory" useful for the advancement of knowledge in this field. Here, we summarize and discuss some results of research data supporting the view that Calabria is a genetic isolate and could represent a useful model for the study and characterization of neurodegenerative diseases.

: Cattle farming is an ancient practice, with roots in the early Neolithic era that has retained its status in the food industry today, with global beef market revenue amounting to $385.7B, as of 2018. Hence, cattle maintenance is naturally essential to cater to nutritional requirements of modern civilization. This extensive review aims to provide a holistic overview of cattle microbiome, analysing the native microbial composition within respiratory tract, gastrointestinal tract, reproductive tract, and skin. The dysbiosis associated with various diseases such as bovine respiratory disease, bovine digital dermatitis, mastitis, Johne's disease, uterine diseases (metritis and endometritis) and metabolic disorders (ruminal acidosis and ketosis) has been discussed. Moreover, various non-antibiotic microbial therapies including phage therapy, prebiotics and probiotics have been examined as potential means to reduce disease-associated dysbiosis. In general, this review highlights the importance of the microbiome in maintenance of health in cattle and its potential in alleviating bovine diseases, with an aim to enhance cattle health and production.

Congenital Disorders of Glycosylation (CDG) are a heterogenous group of primarily autosomal recessive mendelian diseases caused by disruptions in the synthesis of lipid linked oligosaccha-rides and their transfer to proteins. CDGs affect multiple organ systems and vary in presentation, even within families. Here we describe a chemically induced mouse mutant, tvrm76, with early onset photoreceptor degeneration. The recessive mutation was mapped to Chromosome 9 and as-sociated with a missense mutation in the Dpagt1 gene encoding UDP-N-acetyl-D-glucosamine:dolichyl-phosphate N-acetyl-D-glucosaminephosphotransferase (EC 2.7.8.15). The mutation is predicted to cause a substitution of aspartic acid with glycine at residue 166 of DPAGT1. Increased expression of Ddit3, and elevated levels of HSPA5 (BiP) sug-gest the presence of early-onset endoplasmic reticulum (ER) stress. These changes were associated with induction of photoreceptor apoptosis in tvrm76 retinas. Mutations in human DPAGT1 cause Myasthenic Syndrome 13 and severe forms of Congenital Disorder of Glycosylation Type Ij. In contrast, Dpagt1tvrm76 homozygous mice present with congenital photoreceptor degeneration without overt muscle or muscular junction involvement. Our results suggest the possibility of DPAGT1 mutations in human patients that present primarily with retinitis pigmentosa with little or no muscle disease. Variants in DPAGT1 should be considered when evaluating cases of non-syndromic retinal degeneration.

The association between angiotensin-converting enzyme insertion/deletion (ACE I/D) polymorphisms and plasma ACE levels may allow for the optimization of a preventive intervention to reduce cardiovascular morbidity and mortality in the chronic kidney disease (CKD) population. In this study, we aimed to analyze the association between ACE I/D polymorphism and cardiovascular mortality risk among non-hemodialyzed chronic kidney disease patients. This cross-sectional study examined 70 patients of Javanese ethnic origin with stable CKD who did not receive hemodialysis. ACE I/D polymorphisms, plasma ACE levels, atherosclerotic cardiovascular disease (ASCVD) risk, and cardiovascular mortality risk were investigated. As per our findings, the I allele was found to be more frequent (78.6) than the D allele (21.4), and the DD genotype was less frequent than the II genotype (4.3 vs. 61.4). The ACE I/D polymorphism had a significant direct positive effect on plasma ACE levels (path coefficient = 0.302, p = 0.021). Similarly, plasma ACE levels had a direct and significant positive effect on the risk of atherosclerotic cardiovascular disease (path coefficient = 0.410, p = 0.000). Moreover, atherosclerotic cardiovascular disease risk had a significant positive effect on cardiovascular mortality risk (path coefficient = 0.918, p = 0.000). The ACE I/D polymorphism had no direct effect on ASCVD and cardiovascular mortality risk. However, our findings show that the indirect effects of high plasma ACE levels may be a factor in the increased risk of ASCVD and cardiovascular mortality in Javanese CKD patients.

PSD-95 (Dlg4) is an ionotropic glutamate receptor scaffolding protein essential in synapse stability and neurotransmission. PSD-95 levels are reduced during aging and in neurodegenerative diseases like Huntington’s disease (HD), and it is believed to contribute to synaptic dysfunction and behavioral deficits. However, the mechanism responsible for PSD-95 dysregulation under these conditions is unknown. The Heat Shock transcription Factor 1 (HSF1), canonically known for its role in protein homeostasis, is also depleted in both aging and HD. Synaptic protein levels, including PSD-95, are influenced by alterations in HSF1 levels and activity, but the direct regulatory relationship between PSD-95 and HSF1 has yet to be determined. Here, we showed that HSF1 chronic or acute depletion in cell lines and mice decreased PSD-95 expression. Furthermore, HSF1(+/-) mice had reduced PSD-95 synaptic puncta that paralleled a loss in thalamo-striatal excitatory synapses, an important circuit disrupted early in HD. We demonstrated that HSF1 binds to regulatory elements present in the PSD-95 gene and directly regulates PSD-95 expression. HSF1 DNA-binding on the PSD-95 gene was disrupted in an age-dependent manner in WT mice and worsened in HD cells and mice, leading to reduced PSD-95 levels. These results demonstrate a direct role of HSF1 in synaptic gene regulation that has important implications in synapse maintenance in basal and pathological conditions.

Biologists seek to identify a small number of significant features that are important, non-redundant, and relevant from diverse omics data. For example, statistical methods like LIMMA and DEseq distinguish differentially expressed genes between a case and control group from the transcript profile. Researchers also apply various column subset selection algorithms on genomics datasets for a similar purpose. Unfortunately, genes selected by such statistical or machine learning methods are often highly co-regulated, making their performance inconsistent. Here, we introduce a novel feature selection algorithm that selects highly disease-related and non-redundant features from a diverse set of omics datasets. We successfully applied this algorithm to three different biological problems: a) disease to normal sample classification, b) multiclass classification of different disease samples, and c) disease subtypes detection. Considering classification ROC-AUC, False-positive, and False-negative rates, our algorithm outperformed other gene selection and differential expression (DE) methods for all six types of cancer datasets from TCGA considered here for binary and multiclass classification problems. Moreover, genes picked by our algorithm improved the disease subtyping accuracy for four different cancer types over the state-of-the-art methods. Hence, we posit that our proposed feature reduction method can support the community to solve various problems, including the selection of disease-specific biomarkers, precision medicine design, and disease sub-type detection.

Exercise can be hypothesized to play an important role in NAFLD treatment by changing the oral bacterial flora and in the mechanism underlying periodontal disease. We performed salivary component analysis before and after an exercise regimen, and genome analysis of the oral bacterial flora to elucidate the underlying mechanism. Obese middle-aged men with NAFLD and periodontal disease were allocated to 12-week exercise (n=49) or dietary restriction (n=21) groups. We collected saliva to compare the oral microflora; performed predictive analysis of metagenomic functions; and measured the salivary immunoglobulin A, cytokine, bacterial lipopolysaccharide (LPS), and lactoferrin concentrations. The exercise group showed improvements in clinical indices of oral environment. Salivary component analysis revealed significant reductions in LPS, and lactoferrin during the exercise regimen. Diversity analysis of oral bacterial flora revealed higher alpha- and beta-diversity after the exercise regimen. Analysis of the microbial composition revealed that the numbers of Campylobacter (+83.9%), Corynebacterium (+142.3%), Actinomyces (+75.9%), and Lautropia (+172.9%) were significantly higher and that of Prevotella (−28.3%) was significantly lower. The findings suggest that an exercise regimen improves the oral environment of NAFLD patients by increasing the diversity of the oral microflora and reducing the number of periodontal bacteria that produce LPS and its capability.

Coronavirus disease 2019 (COVID-19) since its declaration as a pandemic by world health organization (WHO) has spread across the various continent with little known about the most effective public health response for containing and mitigating the transmission of the epidemic. It is important to state that some authors have published on the lessons learned from transmission and management of COVID-19 infection but only a few considered it from the Africa perspective. Despite the late arrival of the pandemic in Africa and the notion that the virus may not thrive because of the high temperature in the continent; today the narrative has changed with the number of infected patients increasing daily. Herein, the authors have shared their perspectives and opinions on the dynamics and response to COVID-19 from Africa context to create more awareness and approach in mitigating the spread of the virus should the continent becomes the epicenter of COVID-19.

Alzheimer’s and Parkinson's diseases (AD and PD) are amongst top of the prevalent neurodegenerative disease. One-third of PD patients are diagnosed with dementia, a pre-symptom of AD, but the underlying mechanism is elusive. Amyloid beta (Aβ) and α-synuclein are two of the most investigated proteins, whose pathological aggregation and spreading are crucial to the pathogenesis of AD and PD, respectively. Transcriptomic studies of the mammalian central nervous system shed light on gene expression profiles at molecular levels, regarding the complexity of neuronal morphologies and electrophysiological inputs/outputs. In the last decade, the booming of the single-cell RNA sequencing technique helped to understand gene expression patterns, alternative splicing, novel transcripts, and signal pathways in the nervous system at single-cell levels, providing insight for molecular taxonomy and mechanistic targets of the degenerative nervous system. Here, we re-visited the cell-cell transmission mechanisms of Aβ and α-synuclein in medi-ating disease propagation, and summarized recent single-cell transcriptome sequencing from different perspectives and discussed its understanding of neurodegenerative diseases.

Vitamin C is important in preventing and slowing the progression of many diseases. There is significant evidence linking periodontal disease and vitamin C. We aimed to systematically review studies addressing the relationship between vitamin C and periodontal disease and the preventive ability of vitamin C against periodontal disease. Electric searches were performed using PubMed, EMBASE, Cochrane Library, and Web of Science. Studies addressing the relationships between periodontal disease and vitamin C in adults aged over 18 years were included. Quality assessment was done using Critical Appraisal Skills Program guideline and GRADE-CERQual. Seventy hundred and sixteen articles were retrieved and fifteen articles (7 cross-sectional studies, 2 case-control studies, 2 cohort studies, and 4 randomized controlled trial [RCT]) were selected by reviewing all articles. Vitamin C intake and blood level were negatively related to periodontal disease in all 7 cross-sectional studies. Subjects who suffer from periodontitis presented lower vitamin C intake and lower blood vitamin C level than subjects without periodontal disease in the two case-control studies. Patients with lower dietary intake or lower blood level of vitamin C showed greater progression of periodontal disease than did the controls. Intervention using vitamin C administration improved gingival bleeding in gingivitis but not in periodontitis. Alveolar bone absorption was also not improved. The present systematic review suggested that vitamin C contributes to reduced risk of periodontal disease.

Cardiovascular disease is the first leading cause of death in the world. Patients with cardiovascular disease may experience various problems, including physiological and psychological problems. Apart from pharmacological therapy, complementary therapy is necessary as a support to conventional medicine. This review aims to describe complementary and alternative therapies for pain and anxiety in patients with cardiovascular disease. This review utilized data from ProQuest, ScienceDirect, and PubMed with search keywords of "Complementary" AND "Nursing" AND "Pain" AND "Anxiety" AND "Coronary artery disease". Ten articles that met the inclusion criteria were analyzed. The results show that nursing actions increasingly develop along with the patient needs. One form of holistic nursing action is complementary and alternative therapy (CAT) that consists of three categories: body-based methods, mind therapies, and sensory therapies. CAT has positive impacts on patients with heart disease. It can reduce anxiety and pain, lower blood pressure, and improve the quality of life. This review also shows that CAT has a positive impact on the recovery of patients with heart disease. Proper therapeutic management should be implemented to reduce the risks of physiological and psychological problems in patients.

Oxysterols have been implicated in the pathogenesis of cardiovascular diseases. Serum levels of oxysterols could be positively correlated with cholesterol absorption and synthesis. However, physiological regulation of various serum oxysterols is largely unknown. The aim of this study was to investigate the relationship between clinical factors and cholesterol metabolism markers, and identify oxysterols associated with cholesterol absorption and synthesis in patients with coronary artery disease. Subjects (n=207) who underwent coronary stenting between 2011 and 2013 were studied cross-sectionally. We measured lipid profiles including serum oxysterols. As for the serum biomarkers of cholesterol synthesis and absorption, oxysterol levels were positively correlated with campesterol and lathosterol. Covariance structure analysis revealed that dyslipidemia and statin usage had a positive correlation with “cholesterol absorption”. Statin usage also had a positive correlation with “cholesterol synthesis” Several oxysterols associated with cholesterol absorption and/or synthesis. In conclusion, we elucidated the potential clinical factors that may affect cholesterol metabolism, and the associations between various oxysterols with cholesterol absorption and/or synthesis in patients with coronary artery disease.

Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic Lateral Sclerosis are heterogeneous, progressive diseases with frequently overlapping symptoms characterized by a loss of neurons. Studies suggested relations between neurodegenerative diseases for many years, e.g., regarding the aggregation of toxic proteins or triggering endogenous cell death pathways. Within this study, publicly available genomic, transcriptomic and proteomic data were gathered from 188 studies and more than one million patients to detect shared genetic patterns between the neurodegenerative diseases and the analyzed omics-layers within conditions. The results show a remarkably high number of shared genes between the transcriptomic and proteomic levels for all diseases while showing a significant relation between genomic and proteomic data only in some cases. A set of 139 genes was found to be differentially expressed in several transcriptomic experiments of all four diseases. These 139 genes showed overrepresented GO-Terms and pathways mainly involved in stress response, cell development, cell adhesion, and the cytoskeleton. Furthermore, the overlap of two and three omics-layers per disease were used to search for overrepresented pathways and GO-Terms. Taken together, we could confirm the existence of many relations between Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic Lateral Sclerosis on the transcriptomic and proteomic level by analyzing the pathways and GO-Terms arising in these intersections. The significance of the connection between the transcriptomic and proteomic data for all four analyzed neurodegenerative diseases showed that exploring these omics-layers simultaneously holds new insights that do not emerge from analyzing these omics-layers separately. Our data therefore suggests addressing human patients with neurodegenerative diseases as complex biological systems by integrating multiple underlying data sources.

The activity of the mitochondrial Permeability Transition Pore, mPTP, a highly regulated multi-component mega-channel, is enhanced in aging and in aging-driven degenerative diseases. mPTP activity accelerates aging by releasing large amounts of cell-damaging Reactive Oxygen Species, Ca2+ and NAD+. The various pathways that control the channel activity, directly or indirectly, can therefore either, inhibit, or accelerate aging, retards, or enhance the progression of aging-driven degenerative diseases, and determine lifespan and healthspan. Autophagy, a catabolic process that removes and digests damaged proteins and organelles protects the cell against aging and disease. However, the protective effect of autophagy depends on mTORC2/SKG1 inhibition of mPTP. Autophagy is inhibited in aging cells. Mitophagy, a specialized form of autophagy, which retards aging by removing mitochondrial fragments with activated mPTP, is also inhibited in aging cells, and this inhibition leads to increased mPTP activation, which is a major contributor to neurodegenerative diseases, such as Alzheimer’s and Parkinson’s Diseases. The Increased activity of mPTP in aging turns autophagy/mitophagy into a destructive process leading to cell aging and death. Several drugs and lifestyle modifications that enhance healthspan and lifespan enhance autophagy and inhibit the activation of mPTP. Therefore, elucidating the intricate connections between pathways that activate and inhibit mPTP, in the context of aging and degenerative diseases, could enhance the discovery of new drugs and lifestyle modifications that slow aging and degenerative disease.

Background Epidemiological studies have associated plasma galectin-4 (Gal-4) levels with prevalent and incident diabetes, and with increased risk of coronary artery disease, but data regarding possible associations with stroke are lacking. Methods We tested Gal-4 association with prevalent stroke in a population-based cohort, and whether Gal-4 increases after ischemic stroke in mice fed a high-fat diet (HFD). Results Gal-4 was higher in subjects with compared to without prevalent ischemic stroke, and was associated with prevalent ischemic stroke (odds ratio 1.52; 95% confidence interval 1.01-2.30; p=0.048) adjusted for age, sex and covariates of cardiometabolic health. Plasma Gal-4 increased after stroke in both controls and HFD-fed mice, but HFD exposure was devoid of impact in Gal-4 levels. Conclusions This study demonstrates higher plasma Gal-4 levels in both a stroke mouse model and individuals with prevalent stroke.

Trees provide key ecosystem services, but the health and sustainability of these plants is under increasing biotic and abiotic threat, including from the growing incidences of non-native invasive plant pests (including pathogens). The island of Ireland (Ireland and Northern Ireland) is generally accepted to have a high plant health status, in part due to its island status and because of the national and international regulations aimed at protecting plant health. To establish a baseline of the current pest threats to tree health for the island of Ireland, the literature and unpublished sources were reviewed to produce a dataset of pests of trees on the island of Ireland. The dataset contains 396 records of pests of trees on the island of Ireland, the majority of pests being arthropods and fungi, and indicating potentially more than 44 non-native pest introductions. The reliability of many (378) of the records was judged to be high, therefore the dataset provides a robust assessment of the state of pests of trees recorded on the island of Ireland. We analyse this dataset and review the history of plant pest invasions, including (i) discussion on notable native and non-native pests of trees, (ii) pest interceptions at borders and (iii) pests and climate change. The dataset establishes an important baseline for the knowledge of plant pests on the island of Ireland, and will be a valuable resource for future plant health research and policy making.

Coronavirus disease (COVID-19) is an infectious disease caused by a new virus which causes respiratory illness. Older adults and people who have previous chronic medical conditions are at higher risk for more serious complications from COVID-19.Hypovitaminosis D is attributed to the increased risk of lung injury and acute respiratory distress syndrome (ARDS) as well as diabetes, Cardiovascular event and associated comorbidities, which are the main causes of severe clinical problem in COVID-19 patients. Considering the protective role of vitamin D through modulating the innate and adaptive immune system as well as inhibition of Renin Angiotensin System (RAS), vitamin D supplementation might boost the immune system of COVID-19 patients and reduce severity of the disease in vitamin D deficient individuals.

The oral cavity is environment to a diverse range of organisms that make up an essential element of the human microbiota. There are 50-1000 kinds of microorganisms capable of colonizing the mouth. The entamoeba parasites have at minimum 7 species (E. histolytica, E. dispar, E. moshkovskii, E. coli, E. polecki E. hartmann, E. gingivalis). These parasites are parasitic single-celled organisms and Entamoeba gingivalis was the first amoeba to be described in 1849 that was capable of existing in humans. It was shown that only Entamoeba gingivalis is able to colonize the oral cavity. The aim of this study was to evaluate prevalence of E. Gingivalis in periodontal disease using two electronic database search engines. In order to have a broader view of the subject, a comprehensive manual search was conducted on these content aggregators and the initial search resulted in 277 articles using the keywords „Entamoeba gingivalis”, „periodontitis”, „E. gingivalis”, „periodontal disease”, „prevalence”, and „incidence”, in different combinations. The results showed that 755 cases were infected with Entamoeba gingivalis out of a total number of 1,729 patients diagnosed with periodontal disease indicating a global prevalence of 43%. When comparing different stages of periodontal diseases results revealed that the prevalence in patients with gingivitis was 58% while in periodontitis group the prevalence was 44%. Overall prevalence of Entamoeba Gingivalis based on gender was 43 % in female patients whilst in male patients was 47%. Based on the results it can be concluded that the higher incidence of Entamoeba Gingivalis in people with periodontal disease compared to healthy people is more than just a sign of the disease; it may also be linked to the severity of the condition and its propensity to progress.

Background and Objectives: Vision impairments and related blindness are major public health problems. Prevalence of eye disease and barriers to optimal care markedly vary among different geographic areas. In the Abruzzo region (Central Italy), an epidemiological surveillance on the state of ocular health in the population aged over 50 years was performed in 2019. Materials and Methods: Participants were sampled to be representative of the region inhabitants. Data were collected through a telephone interview and an eye examination. Prevalence of cataract, glaucoma, retinopathy, maculopathy was assessed. The Cohen’s kappa (k) was used to measure the agreement between presence of eye disease and awareness of the disease by the participants. Results: Overall, 983 people with mean age of 66.0±9.5 years were included in the study. The prevalence of cataract, glaucoma, maculopathy, and retinopathy was 52.6%, 5.3%, 5.6%, and 29.1%, respectively. Among the total of affected people, those aware of their condition were 21.8% (k=0.12, slight agreement) for cataract, 65.4% (k=0.78, substantial agreement) for glaucoma, 7.1% (k=0.10, slight agreement) for maculopathy, and 0% for retinopathy (k=-0.004, agreement lower than that expected by chance). Refractive defects were corrected in the vast majority of participants. Conclusion: In the Abruzzo region, about two third of citizens aged 50 years or over suffer from cataract, glaucoma, retinopathy or maculopathy, which are recognized as leading causes of blindness. Many people with eye disease do not know they have it. These data can be used by clinicians and policymakers to undertake clinical, political, and social actions.

Asians are known to more likely than Westerners develop fatty liver and lifestyle-related diseases despite their weight. However, the relationship between fat accumulation and lifestyle-related diseases in non-obese Asians is unknown. Therefore, this study aimed to analyze visceral fat and hepatic fat in participants with a normal body mass index (BMI) and examine their characteristics during a medical checkup. This cross-sectional study was conducted on 663 of 1,142 patients who underwent abdominal ultrasonography and who had an alcohol intake (converted to ethanol) of <30 g/day for males and <20 g/day for females and a BMI of <25 kg/m2 during a health checkup. Participants were classified into four groups: group A, visceral fat accumulation (VFA) (−) and fatty liver (FL) (−) (n = 549); group B, VFA (+) and FL(−) (n = 32); group C, VFA (−) and FL (+) (n = 58); and group D, VFA (+) and FL (+) (n = 24). The frequencies of lifestyle-related disease complications, liver function tests, and liver fibrosis were evaluated among the four groups. Compared with group A (control), groups B, C, and D had higher number of males; BMI; abdominal circumference, ALT, AST, γ-GTP, triglyceride, uric acid, fasting blood sugar levels; and incidence of hyperlipidemia. Groups C and D had higher ALT, HbA1c, cholinesterase, and triglyceride levels; FIB4 index; and number of patients with diabetes mellitus (DM) than groups A and B; however, there was no difference between groups A and B. FL is a risk factor of DM and liver fibrosis in non-obese Japanese individuals; however, VFA only is not a risk factor of DM and liver fibrosis.

Covid-19 has given a halt to all the activities in the world. Europe was most affected, followed by the United States of America. It has taken more than 350000 lives until now. In this study, we have assessed the severity of Covid-19 by analyzing the mortality rate of Covid-19 and other chronic diseases. The Covid-19 data and “death rate” data caused by other diseases were downloaded from the world health organization (WHO) website. A normalized method was used to see the mortality rate of Covid-19 in comparison to other diseases. The deaths caused by Covid-19 in April 2020 have overtaken the average number of deaths caused by Cancer, Cardiovascular diseases, and other diseases in Belgium, the United Kingdom (UK), Spain, France, and Ireland. Covid-19 was found to be strongly correlated with non-communicable respiratory diseases and Cancer with correlation coefficients 0.73 and 0.67 respectively. The severity of Covid-19 in the United States of America (USA) was moderate. The severity of Covid-19 in Asian countries was found to be low. Europe showed the highest diversity in the mortality rate of Covid-19. On average, except for a few European countries, Cardiovascular diseases, cancer, and non-communicable respiratory diseases were still more lethal and caused more deaths than Covid-19.

The pervasiveness of cardiovascular disease and physician misdiagnosis creates the urgent need for artificial intelligence models to improve diagnosis accuracy. The first objective of this study was to train machine learning models on publicly available data sets containing simple medical information of patients to diagnose cardiovascular disease. The Multilayer Perceptron (MLP) assembled for this task performed optimally with an F1 score of 0.8968. This prompted the creation of an open-source, automated cardiovascular disease diagnosis tool, powered by the MLP. The second objective of this study was to employ a meta-learning methodology called Local Interpretable Model-Agnostic Explanations (LIME) to understand the impact of different features on the model's diagnosis in the form of marginal probabilities. K-Means Clustering was employed to segment the data into ten clusters, after which each data example was passed through LIME. The resulting histograms depict the complex relationship between feature, cluster, and impact on diagnosis. A series of P-values with contrasting orders of magnitude shows the nuances in the MLP's understanding of patients from different clusters. The results of meta-learning analysis reveal that the most important features for cardiovascular disease diagnosis are fasting blood sugar, type of chest pain, and slope of the ST segment on an electrocardiogram. Future experiments should replicate the novel methodology introduced in this study on data sets containing more specialized medical features in order to gain practical medical insights about different types of cardiovascular disease represented by each cluster. Finally, feature engineering pathways should be explored with consideration of these results to create versatile diagnosis models not only for cardiovascular disease, but adaptable to other diseases as well.

Celiac disease (CeD) is a complex immune-mediated inflammatory condition triggered by ingestion of gluten in genetically predisposed individuals. Literature suggests that alterations in gut microbiota composition and function precede the onset of CeD. Considering that microbiota is partly determined by host genetics, we speculate that the genetic makeup of CeD patients could elicit disease development through alterations in the intestinal microbiota. To evaluate potential causal relationships between gut microbiota and CeD, we performed a Two-Sample Mendelian Randomization analysis (2SMR). Exposure data were obtained from the raw results of a previous Genome Wide Association Study (GWAS) of gut microbiota, and outcome data from summary statistics of CeD GWAS and Immunochip studies. We have identified a number of putative associations between gut microbiota SNPs associated with CeD. Regarding bacterial composition, most of the associated SNPs are related to Firmicutes phylum, whose relative abundance has been previously reported to be altered in CeD patients. In terms of functional units, we have linked a number of SNPs to several bacterial metabolic pathways that seem to be related to CeD. Overall, this study represents the first 2SMR approach to elucidate the relationship between microbiome and CeD.

MicroRNAs (miRNAs) are small endogenous RNAs that regulate gene expression post-transcriptionally by targeting either the 3′ untranslated or coding regions of genes. They have been reported to play key roles in a wide range of biological processes. The recent remarkable developments of transcriptomics technologies, especially next-generation sequencing technologies and advanced bioinformatics tools, allow more in-depth exploration of messenger RNAs (mRNAs) and non-coding RNAs (ncRNAs) including miRNAs. These technologies have offered great opportunities for a deeper exploration of miRNA involvement in farm animal diseases, as well as livestock productivity and welfare. In this review, we provide an overview of the current knowledge of miRNA roles in farm animal diseases with a particular focus on diseases of economic importance. In addition, we discuss the steps and future perspectives of using miRNAs as biomarkers and molecular therapy for livestock disease management as well as the challenges and opportunities for understanding the regulatory mechanisms of miRNAs related to disease pathogenesis.

The study of neurodegenerative diseases using pluripotent stem cells requires new methods to assess neurodevelopment and neurodegeneration of specific neuronal subtypes. The cholinergic system, characterized by its use of the neurotransmitter acetylcholine, is one of the first to degenerate in Alzheimer’s disease and is also affected in frontotemporal dementia. We developed a differentiation protocol to generate basal forebrain cholinergic neurons (BFCNs) from induced pluripotent stem cells (iPSCs) aided by the use of small molecule inhibitors and growth factors. Ten iPSC lines were successfully differentiated into BFCNs using this protocol. The neuronal cultures were characterised through RNA and protein expression, and functional analysis of neurons was confirmed by whole-cell patch clamp. We have developed a reliable protocol using only small molecule inhibitors and growth factors, while avoiding transfection or cell sorting methods, to achieve a BFCN culture that expresses the characteristic markers of cholinergic neurons.

Hypertrophic cardiomyopathy (HCM) is a common inherited heart disorder complicated by left ventricle outflow tract (LVOT) obstruction, which can be treated with surgical myectomy. To date, no reliable biomarkers for LVOT obstruction exist. To determine whether metabolomic biomarkers for obstruction can be identified, we conducted metabolomic profiling on plasma samples of 18 HCM patients before and after undergoing surgical myectomy to measure changes in the plasma metabolome in the postoperative state. Plasma was collected approximately 4 weeks before surgery at the preoperative visit and approximately 3 months after the surgery at the postoperative visit. We found that 215 metabolites were altered in the postoperative state (p-value &lt; 0.05). Identified metabolites that were significantly reduced post-myectomy included metabolites of heme, such as bilirubin, and phenylacetylglutamine, a biomarker of urea cycle disorders, which suggests that liver and kidney function are improved in the postoperative state. Markers of arginine metabolism such as homoarginine and dimethylarginine are also decreased in the postoperative state, suggestive of reduction in nitric oxide production, inflammation and heart failure after surgery. 3-hydroxybutyrate (BHBA) was also decreased, suggesting possible increased fatty acid utilization and a return to normal heart function. 12 of these metabolites were notably significant after adjusting for multiple comparisons (q-value &lt; 0.05), including bilirubin, PFOS, PFOA, 3,5-dichloro-2,6-dihydroxybenzoic acid, 2-hydroxylaurate, trigonelline and 6 unidentified compounds, which support improved kidney and liver function and increased lean soft tissue mass. These findings suggest improved organ metabolic function after surgical relief of LVOT obstruction in HCM and further underscore the beneficial systemic effects of surgical myectomy.

Necroptosis is a caspases-independent form of programmed cell death exhibiting intermediate features between necrosis and apoptosis. Albeit some physiological roles during embryonic development, tissue homeostasis and innate immune response are documented, necroptosis is mainly considered a pro-inflammatory cell death. Key actors of necroptosis are the receptor-interacting-protein-kinases, RIPK1 and RIPK3, and their target, the mixed-lineage-kinase-domain-like protein, MLKL. The intestinal epithelium has one of the highest rates of cellular turnover in a process that is tightly regulated. Altered necroptosis at the intestinal epithelium leads to uncontrolled microbial translocation and deleterious inflammation. Indeed, necroptosis has been associated to chronic inflammatory diseases and cancer. Drugs that inhibit necroptosis could, therefore, be used therapeutically for the treatment of these diseases, and researches to develop such inhibitors are already underway. In this Review, we outline pathways for necroptosis and its role in chronic inflammation and cancer. We also discuss current and developing therapies that target necroptosis machinery.

The Impact of Event Scale-Revised (IES-R) is the most popular measure of post-traumatic stress disorder (PTSD), which has been recently validated in Arabic. This instrumental study aimed to determine optimal cutoff scores of the IES-R and its subscales in Arab samples of psychiatric patients (N = 168, 70.8% females) and healthy adults (N = 992, 62.7% females) from Saudi Arabia during the COVID-19 pandemic as an ongoing collective traumatic event. Based on a cutoff score of 14 of the Depression Anxiety Stress Scale 8-items (DASS-8), receiver operator curve (ROC) analysis revealed two optimal points of 39.5 and 30.5 for the IES-R in the samples (area under the curve (AUC) = 0.86 &amp; 0.91, p values = 0.001, 95% CI: 0.80-0.92 &amp; 0.87 to 0.94, sensitivity = 0.85 &amp; 0.87, specificity = 0.73 &amp; 0.83, Youden index = 0.58 &amp; 0.70, respectively). Different cutoffs were detected for the six subscales of the IES-R, with numbing and avoidance expressing the lowest predictivity for distress. Meanwhile, hyperarousal followed by the irritability expressed stronger predictive capacity for distress than all subscales in both samples. In path analysis, pandemic-related irritability resulted from direct and indirect effects of key PTSD symptoms (intrusion, hyperarousal, and numbing). Irritability contributed to traumatic symptoms of sleep disturbance in both samples while the opposite was not true. The findings suggest usefulness of the IES-R at a score of 30.5 for detecting adults prone to trauma related distress, with higher scores needed for screening in psychiatric patients. Various PTSD symptoms may induce dysphoric mood, which represents a considerable burden that may induce circadian misalignment and more noxious psychiatric problems/ co-morbidities (sleep disturbance) in both healthy and diseased groups.

Pulmonary arterial hypertension is a rare disease with high mortality despite recent therapeutic advances. The disease is caused by both genetic and environmental factors, and likely gene x environment interactions. While PAH can manifest across the lifespan, pediatric-onset disease is particularly challenging because it is frequently associated with a more severe clinical course and comorbidities including lung/heart developmental anomalies. In light of these differences, it is perhaps not surprising that emerging data from genetic studies of pediatric-onset PAH indicate that the genetic basis is different than that of adults. There is a greater genetic burden in children, with rare genetic factors contributing to at least 36% of pediatric-onset idiopathic PAH (IPAH) compared to ~11% of adult-onset IPAH. De novo variants are frequently associated with PAH in children, and contribute to at least 15% of all pediatric cases. The standard of medical care for pediatric PAH patients is based on extrapolations from adult data. However, the increased etiologic heterogeneity, poorer prognosis and increased genetic burden for pediatric-onset PAH calls for a dedicated pediatric research agenda to improve molecular diagnosis and clinical management. A genomics-first approach will improve the understanding of pediatric PAH and how it is related to other rare pediatric genetic disorders.

Ten-eleven translocation (TET) enzymes are implicated in DNA demethylation through dioxygenase activity, which converts 5-methylcytosine to 5-hydroxymethylcytosine (5-hmC). However, the specific roles of TET enzymes and 5-hmC levels in head and neck squamous cell carcinoma (HNSCC) have not yet been evaluated. In this study, we analyzed 5-hmC levels and TET mRNA expression in a well-characterized dataset of 117 matched pairs of HNSCC tissues and normal tissues. 5-hmC levels and TET mRNA expression were examined via enzyme-linked immunosorbent assay and quantitative real-time PCR, respectively. 5-hmC levels were evaluated according to various clinical characteristics and prognostic implications. Notably, we found that 5-hmC levels were significantly correlated with tumor stage (P = 0.032) and recurrence (P = 0.018). Univariate analysis revealed that low levels of 5-hmC were correlated with poor disease-free survival (DFS; log-rank test, P = 0.038). The expression of TET family genes was not associated with outcomes. In multivariate analysis, low levels of 5-hmC were evaluated as a significant independent prognostic factor of DFS (hazard ratio: 2.352, 95% confidence interval: 1.136–4.896; P = 0.021). Taken together, our findings showed that reduction of TET family gene expression and subsequent low levels of 5-hmC may affect the development of HNSCC.

Celiac disease (CD) is an autoimmune disorder triggered by the ingestion of gluten and affects approximately 1% of the global population. Currently, the only treatment available is lifelong strict adherence to a gluten-free diet (GFD). Chronic diseases such as CD affect patients and their family members’ quality of life (QoL); particularly parents and caregivers who play an essential role in the child’s care and treatment. A higher level of psychological distress has been found in the parents of children with chronic ailments due to limited control over the child’s daily activities and the child’s illness. In this context, the validation of a specific questionnaire of QoL is a valuable tool to evaluate the difficulties faced by parents or caregivers of children with this chronic illness. A specific questionnaire for this population can elucidate the reasons for stress in their daily lives as well as the physical, mental, emotional, and social impact caused by CD. Therefore, this study aimed to develop and validate a specific questionnaire to evaluate the QoL of parents and caregivers of children and adolescents with CD. The study was developed in six steps: (i) development of the CD parent/caregiver QoL questionnaire (CDPC-QoL); (ii) subjective evaluation; (iii) validation of the questionnaire by the Delphi method; (iv) evaluation of the internal consistency and reproducibility of the CDPC-QoL; (v) application of the questionnaire to Brazilian CD parents or caregivers; and (vi) statistical analysis. Overall results showed that a higher family income resulted in a higher score of the worries domain. In addition, having another illness besides CD decreased the QoL (except in the worries domain). The other variables studied did not present a statistically significant impact on the QoL, which was shown to be low in all aspects. Knowledge of the QoL is important to help implement effective strategies to improve celiac patients’ quality of life and reduce their physical, emotional, and social burden.

We aim to investigate if serum levels of microRNAs: miR-126, mir-197 and mir-223, previously implicated in cardiometabolic disease, are reproducibly associated with incident-diabetes (inc-DM), incident-cardiovascular disease (inc-CVD) and with carotid atherosclerosis (measured for the maximum thickness of the intima-media of the carotid bulb (IMT)). The microRNAs were measured, one: in serum of 553 subjects from the baseline exam of the Swedish prospective cohort, Malmö Diet and Cancer Study (MDC-CC), with 169 subjects who developed CVD and 140 DM (16 years follow-up) and, two: in 1221 subjects from the Malmö Offspring Study (MOS), with 14 de-veloped CVD and 12 DM (3.7 years follow-up). Multivariate logistic and linear regression models were used to investigate the relationship of serum-concentrations of the microRNAs and inc-DM, inc-CVD, IMT-bulb respectively. In MDC-CC, miR-126 showed significant positive association with inc-DM (p= 0.01) whereas in fully adjusted model, the association was borderline significant (p= 0.05). The results were not replicated in MOS. There was no consistent significant association between the microRNAs with IMT or inc-CVD in any cohort. Our results do not support previous reports on significant associations between these microRNAs and the risk of CMD, as they were not reproducible in our cohorts. In addition, the directionality of any associations found were not consistent with those previously reported.