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The coronavirus disease 2019 (COVID-19) pandemic was caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This virus has challenged civilization and modern science in ways that few infectious diseases and natural disasters have previously, causing globally significant human morbidity and mortality and triggering economic downturns across financial markets that will be dealt with for generations. Despite this, the pandemic has also brought an opportunity for humanity to come together and participate in a shared scientific investigation. Clinically, SARS-CoV-2 is associated with lower mortality rates than other recently emerged coronaviruses, such as SARS-CoV and the Middle East respiratory syndrome coronavirus (MERS-CoV). However, SARS-CoV-2 exhibits efficient human-to-human spread, with transmission often occurring before symptom recognition; this feature averts containment strategies that had worked previ- ously for SARS-CoV and MERS-CoV. Severe COVID-19 disease is characterized by dysregulated inflammatory responses associated with pulmonary congestion and intravascular coagulopathy leading to pneumonia, vascular insults, and multiorgan disease. Approaches to treatment have combined supportive care with antivirals, such as remdesivir, with immunomodulatory medications, including corticosteroids and cytokine-blocking antibody therapies; these treatments have advanced rapidly through clinical trials. Innovative approaches to vaccine development have facilitated rapid advances in design, testing, and distribution. Much remains to be learned about SARS-CoV-2 and COVID-19, and further biomedical research is necessary, including comparative medicine studies in animal models. This overview of COVID-19 in humans will highlight important aspects of disease, relevant pathophysiology, underlying immunology, and therapeutics that have been developed to date.

Mosquito-borne diseases account for human morbidity and mortality worldwide, caused by the parasites (e.g., malaria) or viruses (e.g., dengue, Zika) transmitted through bites of infected female mosquitoes. Globally, billions of people are at risk of infection, imposing significant economic and public health burdens. As such, efficient methods to monitor mosquito populations and prevent the spread of these diseases are at a premium. One proposed technique is to apply acoustic monitoring to the challenge of identifying wingbeats of individual mosquitoes. Although researchers have successfully used wingbeats to survey mosquito populations, implementation of these techniques in areas most affected by mosquito-borne diseases remains challenging. Here, methods utilizing easily accessible equipment and encouraging community-scientist participation are more likely to provide sufficient monitoring. We present a practical, community-science-based method of monitoring mosquito populations using smartphones. We applied deep-learning algorithms (TensorFlow Inception v3) to spectrogram images generated from smartphone recordings associated with six mosquito species to develop a multiclass mosquito identification system, and flag potential invasive vectors not present in our sound reference library. Though TensorFlow did not flag potential invasive species with high accuracy, it was able to identify species present in the reference library at an 85% correct identification rate, an identification rate markedly higher than similar studies employing expensive recording devices. Given that we used smartphone recordings with limited sample sizes, these results are promising. With further optimization, we propose this novel technique as a way to accurately and efficiently monitor mosquito populations in areas where doing so is most critical.

Fungal infection of invasive nature is an alarming threat globally and a leading cause of human morbidity and mortality as they are opportunistic in nature. Rising resistance to current clinically approved marketed products for fungal infections is a major concern for humans. Dihydrofolate Reductase (DHFRase) is an essential enzyme in folate metabolic pathway responsible for DNA synthesis and is ubiquitous to all organisms, and also acts as a key target for developing antifungal drugs. In this study, potential mutant DHFRase inhibitors were screened with the help of hierarchical mode of docking of virtual library of antifungal compounds and molecular dynamic (MD) simulation. The identification of best hits was done by using the docking, binding energy prediction and further, which was supported by their predicted pharmacokinetics. MD simulation of the human DHFRase enzyme with the reference lead compound i.e. PY957 and most promising hit found i.e. ChemDiv-C390-0455 and to validate the stability of enzyme-ligand complex in best 07 retrieved hit as a potential mutant DHFRase inhibitor. The key residues Glh30, Phe34, Phe64, Phe31 of the binding pocket acknowledged as essential were found to be matching with the key interactions of the selected hit. Computed root mean square deviation (RMSD) and root mean square fluctuation (RMSF) in MD simulation of complex of DHFRase enzyme with PY957 and ChemDiv-C390-0455 were read less than 2.25[Formula: see text]Å during 100 nanoseconds simulation for both complex.

Air pollution has altered the Earth's radiation balance, disturbed the ecosystem, and increased human morbidity and mortality. Accordingly, a full-coverage high-resolution air pollutant data set with timely updates and historical long-term records is essential to support both research and environmental management. Here, for the first time, we develop a near real-time air pollutant database known as Tracking Air Pollution in China (TAP, http://tapdata.org.cn/) that combines information from multiple data sources, including ground observations, satellite aerosol optical depth (AOD), operational chemical transport model simulations, and other ancillary data such as meteorological fields, land use data, population, and elevation. Daily full-coverage PM2.5 data at a spatial resolution of 10 km is our first near real-time product. The TAP PM2.5 is estimated based on a two-stage machine learning model coupled with the synthetic minority oversampling technique and a tree-based gap-filling method. Our model has an averaged out-of-bag cross-validation R2 of 0.83 for different years, which is comparable to those of other studies, but improves its performance at high pollution levels and fills the gaps in missing AOD on daily scale. The full coverage and near real-time updates of the daily PM2.5 data allow us to track the day-to-day variations in PM2.5 concentrations over China in a timely manner. The long-term records of PM2.5 data since 2000 will also support policy assessments and health impact studies. The TAP PM2.5 data are publicly available through our website for sharing with the research and policy communities.

Foodborne parasitic diseases cause human morbidity and mortality especially in the low- & middle-income countries. This study identified the parasitic contaminated Eruca sativa & Raphanussativus cultivated in El-Kharga Oasis, Upper Egypt, as to seasonal variation and the vendors hygienepractices. A total of 270 samples of the two vegetables were purchased from public markets.Parasitic contamination was evaluated by sedimentation and flotation techniques with modifiedZiehl-Neelsen stain. The results showed that 219(81%) samples were contaminated with 13different parasites. Ascaris lumbricoides 123(25.5%) and Cryptosporidium parvum (14.9%) werethe commonest ones and the highest contamination rate was in autumn (87%) for E. sativa and inwinter (87%) for R. sativus. The contamination level was significant with the gender and washingpractices of vendors. The current data gave evidence of the seasonal dynamics of acquiring parasiticinfection due to consumption of raw vegetables, interaction, and its relevance with vendor'shygiene.

A wide variety of zoonotic viruses that can cross the interspecies barrier promote the emergence of new, potentially pandemic viruses in the human population that was often accompanied by the disappearance of existing circulating strains. Among the various reasons underlying this phenomenon is the strengthening of populational immunity by expanding the immune layer of the population and improving the means and methods of medical care. However, “Natura abhorret vacuum”, and new pathogens come to replace disappearing pathogens. In the past ten years, there have been two critical events – the pandemic spread of the swine influenza A (H1N1) pdm09 virus in 2009 and the novel SARS–CoV–2 coronavirus in 2019, providing scientists with a unique opportunity to learn more about a relationship between respiratory viruses and their pathogenesis. Together with viruses of pandemic significance, a large number of seasonal respiratory viruses circulate, which contribute to the structure of human morbidity, and co–infections aggravate the condition of the illness. In the conditions of the spread of new viruses with unexplored characteristics, in the absence of means of prevention and therapy, it is especially important to prevent the aggravation of morbidity due to mixed infections. Here we review the mutual involvement of pandemic influenza A(H1N1)pdm09 and SARS–CoV–2 coronavirus and seasonal respiratory viruses in the epidemic process, discuss some issues related to their spread, potential causes affecting the spread and severity of the morbidity. The given facts, testify to the existence of seasonality and temporal patterns of the beginning and end of the circulation of respiratory viruses. Interestingly, the beginning of the circulation of the pandemic influenza A(H1N1)pdm09 virus led to a shift in the timing and intensity of circulation of some respiratory viruses, which is probably caused by the existence of "replication conflicts" between them, and did not affect others. Co–infection with SARS–CoV–2–19 and other respiratory viruses, especially respiratory syncytial virus and rhinoviruses, was quite often observed. At the current stage, no aggravating effect of influenza on the course of COVID–19 in mixed infection has been established. Whether this is due to the mild course of influenza infection in the 2020 epidemic season, or the competitive impact of SARS–CoV–2 on influenza viruses is not yet clear. Experts are still at the stage of accumulating facts and working on creating means of effective prevention and treatment of the new coronavirus infection.

Today, one of the most common non-communicable diseases, which, according the World Health Organization experts, dominates the structure of human morbidity and mortality is osteoporosis. The aim of this study was to determine the effect of water from the hot springs of the Afyonkarahisar region on the calcium content and the levels of certain hormones in the blood of rats with experimentally induced osteoporosis. 25 female albino rats of the same age were used in the experiment. Ovaries were removed from all animals under anesthesia with ketamine (200 mg/kg) and xylazine (10 mg/kg), after which they were divided into two groups: control (10 animals) and experimental (15 animals). The animals of the control group were given tap water twice a day through an orogastric tube and they were bathed in it for 15 minutes at the same time, the water temperature was (35 ± 2) °C. The animals of the experimental group were given fresh water from the Süreyya I hot spring using the same method. Blood clinical, hematological and biochemical parameters were measured prior to the study, as well as on day 1, 7, 14, and 21 after the ovariectomy operation. The ovariectomy demonstrated inconsistence of the tested blood parameters with the standard ones. In the course of the treatment, by day 21 of the experiment, the parameters normalized, and the most noticeable changes were observed in the rats of the experimental group (p < 0.05). The results of the work performed showed that Süreyya I hot spring water contributed to a significant improvement in the clinical, hematological and biochemical blood parameters in rats with osteoporosis, therefore, it can be used for prevention and treatment of this disease in combination with other types of treatment.

With higher temperatures linked to increased human morbidity and mortality, the projected increase in the number of extreme heat events (EHEs) due to climate change poses increased risks. Although the old, individuals with pre-existing illnesses, the socially isolated, and individuals with low income or low educational status are more vulnerable to the health effects of EHEs and are targeted in public health messaging, newcomers and immigrants may be less aware of the dangers of EHEs. The impacts of EHEs on the immigrant and newcomer population are not well documented in the Canadian context and the combination of a greater number of heat events and a growing and diverse immigrant population necessitates further exploration. Framed by intersectionality and using Hamilton, Ontario, as a case example, this work explores the barriers that may affect immigrant’s awareness of EHEs.

Objectives The novel coronavirus, severe acute respiratory syndrome coronavirus 2, causing coronavirus disease 2019 (COVID-19) remains a global health threat and a significant source of human morbidity and mortality. While the virus primarily induces lung injury, it also has been reported to cause hepatic sequelae. Methods We aimed to detect the virus in formalin-fixed tissue blocks and document the liver injury patterns in patients with COVID-19 compared with a control group. Results We were able to detect viral RNA in the bronchioalveolar cell blocks (12/12, 100%) and formalin-fixed, paraffin-embedded tissue of the lung (8/8, 100%) and liver (4/9, 44%) of patients with COVID-19. Although the peak values of the main liver enzymes and bilirubin were higher in the patients with COVID-19 compared with the control group, the differences were not significant. The main histologic findings were minimal to focal mild portal tract chronic inflammation (7/8, 88%, P < .05) and mild focal lobular activity (6/8, 75%, P = .06). Conclusions We found that most patients who died of COVID-19 had evidence of mild focal hepatitis clinically and histologically; however, the virus was detected in less than half of the cases.

Background: Rheumatoid arthritis (RA) is an autoimmune disease responsible for maximum human morbidity in modern life, whereas oxidative stress is the ultimate potential biomarker for determining disease activity in patients with RA. Objective: The present study scientifically validated the effectiveness of antioxidants commonly present in different food supplements to neutralize the free radicals mediated oxidative stress in isolated peripheral blood mononuclear lymphocytes (PBML) of patients with RA. Methods: The study population included patients with Rheumatoid arthritis, RA (n =15), who fulfilled the American College of Rheumatology criteria for RA. Peripheral blood was collected, and isolated mononuclear lymphocyte cells (PBML) were pretreated with phorbol myristate acetate (PMS) and furthermore, incubated with different concentrations of Naringenin, β carotene and Nacetyl cysteine (NAC) in an ex vivo condition. The resultant cell lysate was used for further studies for the determination of other oxidative biomarkers. The increase of superoxide and nitric oxide production was observed when PBML was treated PMS. Results: Importantly, the increased oxidative stress was effectively decreased by the selected plantderived compounds β-carotene and naringenin. Conclusion: The study scientifically evaluated the efficacy of the molecules validated by one-way ANOVA, followed by Dunnett’s post hoc test of significance. Collectively, our results indicate that both β carotene and naringenin may be a promising non-toxic food supplement in attenuating the oxidative stress associated pathology in RA, meriting further pharmacological studies on other inflammatory cells like neutrophils.

According to the World Health Organization (WHO), particulate matter (PM) contamination causes around 800,000 premature deaths per year, ranking 13th in the world in terms of mortality. However, several findings revealed that the correlation is much stronger and more complicated than previously believed. PM is an element of emissions comprised of very small, acidic, organic compounds, metals, and particulate soil or dust particles or fluid droplets. The most consistent air quality component linked to human illness is PM, which is categorized by size. PM is likely to develop cardiovascular and cerebrovascular disorders due to the mechanisms of inflammation, overt and indirect coagulation activation, and direct translocation to the systemic circulation. The evidence on the cardiovascular system that shows a PM effect is strong. Coronary incidence and mortality rates in populations prone to long-term PM toxicity were significantly higher. Short-term acute emissions increase coronary incidence rates subtly within days of the pollution peak. While some evidence and associated mechanisms show a smaller outcome, the findings for PM’s cortical disease symptoms are not as promising. Respiratory infections are aggravated by exposure to PM. More analysis is needed to clarify the effects of structure, chemistry, and PM for vulnerable groups. The existing research indicates that PM toxicity causes a minor but significant increase in human morbidity and mortality. Air conditioners and particulate matter filters reduced internal heating, and cooking combustion and smoking cessation will reduce indoor PM exposure. These fundamental improvements can be beneficial to patients with acute and chronic cardiovascular and respiratory symptoms. This article provides an overview of the effects of atmospheric airborne suspended particulate matter on population morbidity and mortality. This critical review concludes with public health recommendations based on a summary of the published literature’s findings.

Vector-borne diseases (VBDs) are embedded within complex socio-ecological systems. While research has traditionally focused on the direct effects of VBDs on human morbidity and mortality, it is increasingly clear that their impacts are much more pervasive. VBDs are dynamically linked to feedbacks between environmental conditions, vector ecology, disease burden, and societal responses that drive transmission. As a result, VBDs have had profound influence on human history. Mechanisms include: (1) killing or debilitating large numbers of people, with demographic and population-level impacts; (2) differentially affecting populations based on prior history of disease exposure, immunity, and resistance; (3) being weaponized to promote or justify hierarchies of power, colonialism, racism, classism, and sexism; (4) catalyzing changes in ideas, institutions, infrastructure, technologies, and social practices in efforts to control disease outbreaks; and (5) changing human relationships with the land and environment. We use historical and archaeological evidence interpreted through an ecological lens to illustrate how VBDs have shaped society and culture, focusing on case studies from four pertinent VBDs: plague, malaria, yellow fever, and trypanosomiasis. By comparing across diseases, time periods, and geographies, we highlight the enormous scope and variety of mechanisms by which VBDs have influenced human history.

Dengue is a mosquito-borne pandemic viral infection, which transmits to humans from Female Aedes albopictis or Aedes agypti mosquitoes. It progressively deteriorates the health of infected individuals and poses a high threat of human morbidity and mortality. This paper proposes an intelligent healthcare system which identifies, monitors, and alerts dengue virus (DeV) infected individuals and other stakeholders in real-time and control the DeV infection outbreak using cloud computing, internet of things and fog computing paradigms. The proposed system uses Naive Bayesian Network (NBN) for diagnosing the possibly DeV infected individuals and generating real-time alerts for suggesting and alerting the concerned stakeholders for taking on-time necessary actions at the fog subsystem. The proposed system also uses Social Network Analysis at the cloud subsystem, to provide Global Positioning Systems (GPS)-based global risk assessment of the DeV infection on Google Maps (Google-based web map service) and control DeV infection outbreak. The analysis of the experimental results acknowledges the efficiency of the NBN-based DeV infection diagnosis, alert generation, and GPS-based risk assessment functionality, of the proposed system, via various statistical measures and experimental approaches.

Aging is the leading cause of human morbidity and death worldwide. Pyrroloquinoline quinone (PQQ) is a water-soluble vitamin-like compound that has strong anti-oxidant capacity. Beneficial effects of PQQ on lifespan have been discovered in the model organism Caenorhabditis elegans (C. elegans), yet the underlying mechanisms remain unclear. In the current study, we hypothesized that the longevity-extending effect of PQQ may be linked to autophagy and insulin/IGF1 signaling (IIS) in C. elegans. Our data demonstrate that PQQ at a concentration of 1 mM maximally extended the mean life of C. elegans by 33.1%. PQQ increased locomotion and anti-stress ability, and reduced fat accumulation and reactive oxygen species (ROS) levels. There was no significant lifespan extension in PQQ-treated daf-16, daf-2, and bec-1 mutants, suggesting that these IIS- and autophagy-related genes may mediate the anti-aging effects of the PQQ. Furthermore, PQQ raised mRNA expression and the nuclear localization of the pivotal transcription factor daf-16, and then activated its downstream targets sod-3, clt-1, and hsp16.2. Enhanced activity of the autophagy pathway was also observed in PQQ-fed C. elegans, as evidenced by increased expression of the key autophagy genes including lgg-1, and bec-1, and also by an increase in the GFP::LGG-1 puncta. Inactivation of the IIS pathway-related genes daf-2 or daf-16 by RNAi partially blocked the increase in autophagy activity caused by PQQ treatment, suggesting that autophagy may be regulated by IIS. This study demonstrates that anti-aging properties of PQQ, in the C. elegans model, may be mediated via the IIS pathway and autophagy.

Infectious diseases caused by antibiotic-resistant bacteria lead to a considerable increase in human morbidity and mortality globally. This requires to search potential actinomycete isolates from undiscovered habitats as a source of effective bioactive metabolites and to synthesis metabolite-mediated antibacterial silver nanoparticles (AgNPs). The main purpose of the present study was to identify actinomycetes isolated from Thika waste dump soils that produce bioactive metabolites to synthesize antibacterial AgNPs. The synthesis of metabolite-mediated AgNP was confirmed with visual detection and a UV-vis spectrophotometer, whereas the functional groups involved in AgNP synthesis were identified using a FTIR spectrophotometer. The antibacterial activity of the metabolite-mediated AgNPs was tested by a well diffusion assay. Identification of actinomycete isolates involved in the synthesis of antibacterial AgNPs was done based on 16S rRNA gene sequence analysis. The visual detection showed that dark salmon and pale golden color change was observed due to the formation of AgNPs by KDT32 and KGT32 metabolites, respectively. The synthesis was confirmed by a characteristic UV spectra peak at 415.5 nm for KDT32-AgNP and 416 nm for KGT32-AgNP. The FTIR spectra revealed that OH, C=C, and S-S functional groups were involved in the synthesis of KDT32-AgNP, whereas OH, C=C, and C-H were involved in the formation of KGT32-AgNP. The inhibition zone results revealed that KDT32-AgNP showed 22.0 ± 1.4 mm and 19.0 ± 1.4 mm against Escherichia coli and Salmonella typhi, whereas KGT32-AgNP showed 21.5 ± 0.7 mm and 17.0 ± 0.0 mm, respectively. KDT32 and KGT32 isolates were identified as genus Streptomyces and their 16S rRNA gene sequences were deposited in the GenBank database with MH301089 and MH301090 accession numbers, respectively. Due to the bactericidal activity of synthesized AgNPs, KDT32 and KGT32 isolates can be used in biomedical applications.

Background: Chromosomal abnormalities are the result of alterations in the number or structure of chromosomes leading to significant human morbidity and mortality. They are responsible for large proportion of miscarriages, developmental delay, disorders of sexual development, congenital malformations, and mental retardation. Objectives: The objectives of the study were to find the occurrence of chromosomal abnormalities in infants and children with various phenotypic presentations and to analyze the impact of associated risk factors for chromosomal abnormalities in children. Materials and Methods: A retrospective single-center study, based on the outcome data of chromosomal analysis of 112 children admitted to the pediatric department of our hospital over a period of 3 years, was reported. The data were collected from the electronic medical records for analysis, including maternal age, consanguinity, family history of any congenital anomalies and malformations, clinical details, and the results of chromosomal analysis. Results: A statistically significant association between the presence of dysmorphic features and chromosomal abnormalities with 3 times increased risk when compared to children with no dysmorphism (relative risk [RR] 3.06, 95% confidence interval [CI] 1.71–5.50, p=0.0002). Among the congenital anomalies, the presence of congenital heart defects had strong association and was found to be 43% higher in children with chromosomal abnormalities (RR 1.43, 95% CI 1.10–1.86, p=0.0069). Our study demonstrated a strong association for maternal age >35 years and the risk for chromosomal abnormality. It was 1.75 times more than the children born to mothers ?35 years age (RR 1.75, 95% CI 1.29–2.36, p=0.0003). Conclusion: Cytogenetics has a major role in diagnosis of chromosomal abnormalities, especially in children with dysmorphic features and congenital heart defects. The early diagnosis is important for planning and resource allocation of specialized health services directed toward the families and infants.

As cancers are one of the most important causes of human morbidity and mortality worldwide, researchers try to discover novel compounds and therapeutic approaches to decrease survival of cancer cells, angiogenesis, proliferation and metastasis. In the last decade, use of special phytochemical compounds and flavonoids was reported to be an interesting and hopeful tactic in the field of cancer therapy. Flavonoids are natural polyphenols found in plant, fruits, vegetables, teas and medicinal herbs. Based on reports, over 10,000 flavonoids have been detected and categorized into several subclasses, including flavonols, anthocyanins, flavanones, flavones, isoflavones and chalcones. It seems that the anticancer effect of flavonoids is mainly due to their antioxidant and anti inflammatory activities and their potential to modulate molecular targets and signaling pathways involved in cell survival, proliferation, differentiation, migration, angiogenesis and hormone activities. The main aim of this review is to evaluate the relationship between flavonoids consumption and cancer risk, and discuss the anti-cancer effects of these natural compounds in human cancer cells. Hence, we tried to collect and revise important recent in vivo and in vitro researches about the most effective flavonoids and their main mechanisms of action in various types of cancer cells.

Pathogen infection is the main cause of human morbidity and death. Traditional antibiotics usually sterilize bacteria in chemical ways, which tends to develop serious antibiotic resistance. Cationic polymers exhibit good bacterial inhibition with less resistance, but often face severe cytotoxicity toward normal cells. The optimization of polymeric antimicrobials for enhanced bactericidal capacity and improved biocompatibility is quite meaningful. In addition, photodynamic therapy (PDT) is a therapeutic modality with less susceptibility to develop resistance. Herein, a typical commercial polymeric antimicrobial, polyhexamethylene guanidine (PHMG) was selected for current proof-of-concept optimization due to its excellent bactericidal capacity but moderate biocompatibility. Eosin-Y (EoS) was copolymerized to afford EoS-labeled polymer conjugates, poly(2-(dimethylamino) ethyl methacrylate-co-eosin), P(DMAEMA-co-EoS), which was conjugated with PHMG to afford a novel polymeric antimicrobial, P(DMAEMA-co-EoS)-b-PHMG-b-P(DMAEMA-co-EoS), noted as PEoS-PHMG. It could efficiently kill broad-spectrum bacteria by physical damage and photodynamic therapy. Compared with PHMG, the bacterial inhibition of PEoS-PHMG was potentiated after the functionalization. Furthermore, PEoS-PHMG exhibited low cytotoxicity and minimal hemolysis, which was demonstrated by cell viability assays toward LO2 cells and RAW 264.7 cells as well as hemolytic assays against red blood cells. These results confirmed that the resultant PEoS-PHMG could act as promising alternative antibacterial materials with excellent broad-spectrum bacterial inhibition and favorable biocompatibility.

Background and objective:Atherosclerosis is one of the leading causes of human morbidity globally and reduced bioavailability of vascular nitric oxide (NO) has a critical role in the progression and development of the atherosclerotic disease. Loss of NO bioavailability, for example via a deficiency of the substrate (L-arginine) or cofactors for endothelial nitric oxide synthase (eNOS), invariably leads to detrimental vascular effects such as impaired endothelial function and increased smooth muscle cell proliferation, deficiency of the substrate (Larginine) or cofactors for eNOS. Various medicinal plants and their bioactive compounds or secondary metabolites with fewer side effects are potentially implicated in preventing cardiovascular disease by increasing NO bioavailability, thereby ameliorating endothelial dysfunction. In this review, we describe the most notable medicinal plants and their bioactive compounds that may be appropriate for enhancing NO bioavailability, and treatment of atherosclerosis.Methods:The material in this article was obtained from noteworthy scientific databases, including Web of Science, PubMed, Science Direct, Scopus and Google Scholar.Results:Medicinal plants and their bioactive compounds influence NO production through diverse mechanisms including the activation of the nuclear factor kappa B (NF-κB) signaling pathway, activating protein kinase C (PKC)-α, stimulating protein tyrosine kinase (PTK), reducing the conversion of nitrite to NO via nitrate-nitrite reduction pathways, induction of eNOS, activating the phosphatidylinositol 3-kinase (PI3K)/serine threonine protein kinase B (AKT) (PI3K/AKT/eNOS/NO) pathway and decreasing oxidative stress.Conclusion:Medicinal plants and/or their constituent bioactive compounds may be considered as safe therapeutic options for enhancing NO bioavailability and prospective preventative therapy for atherosclerosis.

Kidney stone disease (KSD) is a prevalent disorder that causes human morbidity worldwide. The etiology of KSD is heterogeneous, ranging from monogenic defect to complex interaction between genetic and environmental factors. Since mutations of genes responsible for KSD in a majority of families are still unknown, our group is identifying mutations of these genes by means of genomic and genetic analyses. In this study, we identified a novel loss-of-function mutation of PBK, encoding the PDZ binding kinase, that was found to be associated with KSD in an affected Thai family. Glycine (Gly) substituted by arginine (Arg) at position 43 (p.Gly43Arg) in PBK cosegregated with the disease in affected members of this family, but was absent in 180 normal control subjects from the same local population. Gly43 is highly evolutionarily conserved in vertebrates, and its substitution affects protein structure by alterations in H-bond forming patterns. This p.Gly43Arg substitution results in instability of the variant PBK protein as examined in HEK293T cells. The variant PBK protein (p.Gly43Arg) demonstrated decreased kinase activity to phosphorylate p38 MAPK as analyzed by immunoblotting and antibody microarray techniques. Taken together, these findings suggest a possible new mechanism of KSD associated with pathogenic PBK variation.

The severe acute respiratory syndrome-CoV-2 is an emerging viral pathogen responsible for the global coronavirus disease 2019 pandemic resulting in significant human morbidity and mortality. Based on preliminary clinical reports, hypoxic respiratory failure complicated by acute respiratory distress syndrome is the leading cause of death. Further, septic shock, late-onset cardiac dysfunction, and multiorgan system failure are also described as contributors to overall mortality. Although extracorporeal membrane oxygenation and other modalities of mechanical cardiopulmonary support are increasingly being utilized in the treatment of respiratory and circulatory failure refractory to conventional management, their role and efficacy as support modalities in the present pandemic are unclear. We review the rapidly changing epidemiology, pathophysiology, emerging therapy, and clinical outcomes of coronavirus disease 2019; and based on these data and previous experience with artificial cardiopulmonary support strategies, particularly in the setting of infectious diseases, provide consensus recommendations from American Society for Artificial Internal Organs. Of note, this is a living document, which will be updated periodically, as additional information and understanding emerges.

Background Cancer remains the leading cause of human morbidity universally. Hence, we sought to assess the in vitro antiproliferative activity of new isatin-based conjugates (5a-s) against three human cancer cell lines. Methods The antiproliferative activities of compounds 5a-s were evaluated in vitro and their ADME (absorption, distribution, metabolism and excretion) was carried out using standard protocols. Subsequently, Western blot analysis was conducted to elucidate the potential antiproliferative mechanism of compounds 5a-s. Results The in vitro antiproliferative activities of compounds 5a-s against the tested cancer cell lines ranged from 20.3 to 95.9%. Compound 5m had an IC50 value of 1.17 µM; thus, its antiproliferative potency was approximately seven-fold greater than that of sunitinib (IC50 = 8.11 µM). In-depth pharmacological testing was conducted with compound 5m to gain insight into the potential antiproliferative mechanism of this class of compounds. Compound 5m caused an increase in the number of cells in the G1 phase, with a concomitant reduction of those in the G2/M and S phases. Additionally, compound 5m significantly and dose-dependently reduced the amount of phosphorylated retinoblastoma protein detected. Compound 5m enhanced expression of B cell translocation gene 1, cell cycle-associated proteins (cyclin B1, cyclin D1, and phosphorylated cyclin-dependent kinase 1), and a pro-apoptotic protein (Bcl-2-associated X protein gene), and activated caspase-3. ADME predictions exposed the oral liability of compounds 5a-s. Conclusion Herein, we revealed the antiproliferative activity and ADME predictions of the newly-synthesized compounds 5a-s and provided a detailed insight into the pharmacological profile of compound 5m. Thus, compounds 5a-s can potentially be exploited as new antiproliferative lead compounds for cancer chemotherapeutic.

Background Arcobacter constitute emerging food- and waterborne pathogens causing gastroenteritis in humans, but the underlying mechanisms are only incompletely understood. We therefore characterized Arcobacter isolates derived from human stool samples that had been collected during a prospective prevalence study in Germany in vitro. Thirty-six bacterial isolates belonging to the species A. butzleri (n = 24), A. cryaerophilus (n = 10) and A. lanthieri (n = 2) were genotyped by ERIC-PCR, the presence of 10 putative virulence genes was assessed and cytotoxic effects on the human intestinal cell line HT-29/B6 were analyzed applying the WST-assay. Results Genotyping revealed high genetic diversity within the species A. butzleri, A. cryaerophilus and A. lanthieri. Both, A. butzleri and A. lanthieri encoded for a large number of putative virulence genes, while fewer genes were detectable in A. cryaerophilus isolates. Notably, the three cytolethal distending toxin (CDT) genes cdtA, cdtB and cdtC were abundant in both A. lanthieri isolates. Furthermore, all A. butzleri and A. lanthieri, but only one of the A. cryaerophilus isolates exerted cytotoxic effects. Conclusions Our study provides evidence for the abundance of putative virulence genes in Arcobacter isolates and prominent cytotoxic effects of A. butzleri and A. lanthieri in vitro. The presence of cdtA, cdtB, cdtC in A. lanthieri points towards CDT secretion as potential mechanism underlying cytotoxicity as opposed to A. butzleri. However, the association of the Arcobacter virulence factors detected and human morbidity should be addressed in future studies.

Oral health is an important factor of human morbidity worldwide. Yet is often neglected in occupational health despite its direct impact on the quality of life and health of workers.To discuss the role of oral health in sickness absence and presenteeism, as well as in development and work efficiency improvement processes involving governments, companies and the workers themselves.Review of full-text articles on oral health, occupational health, sickness absence and presenteeism published in English or Portuguese in the last 10 years and included in scientific databases.Oral problems accounted for 9 to 27% cases of sickness absence and 28 to 50% of presenteeism, with toothache and temporomandibular joint pain as the most frequent reasons. About 50% of workers prefer company-provided dental care, while 40% visit public and 10% other types of facilities. Despite high, the prevalence of oral diseases and orofacial pain was not associated with high rates of absenteeism, but mainly with presenteeism, this is to say, workers do not tend to miss work days, but their performance is reduced and become susceptible to more serious health problems in the future.Oral health is not dissociated from general and occupational health, and as such it must be enhanced and duly promoted in an integrated manner. Effective and comprehensive oral health promotion and prevention public policies and private sector actions in the workplace can enhance the quality of life of workers.A saúde bucal é um importante fator de morbidade humana mundial, mas frequentemente negligenciada em saúde ocupacional, apesar do impacto direto na qualidade de vida e na saúde do trabalhador. O objetivo deste artigo foi discutir o papel da saúde bucal como fator de absenteísmo e presenteísmo e nos processos de desenvolvimento e eficiência laboral por parte de governos, empresas e pelos próprios trabalhadores. Realizou-se revisão da literatura com artigos na íntegra, em inglês ou português, dos últimos 10 anos, nas bases científicas relacionando-se os temas saúde bucal, saúde ocupacional, absenteísmo e presenteísmo. Doenças bucais variaram como causas de absenteísmo entre 9 e 27%, mas de 28 a 50% como de presenteísmo. Dores dentárias e de ATM são as causas mais comuns. Entre 9 e 56% dos trabalhadores buscaram tratamentos em rede pública, e de 40 a 45%, em rede privada. Nas empresas que oferecem atendimento odontológico, 49% dos funcionários optaram pelo ambulatório da empresa, contra 40% da rede pública e 11% de outros tipos. A elevada prevalência de doenças bucais e de dor orofacial não é causa de elevados índices de absenteísmo, mas principalmente de presenteísmo. O trabalhador não se afasta, trabalha de forma deficitária e com propensão a maiores adoecimentos futuros. A saúde bucal tem importância não dissociada da saúde geral e ocupacional e, como tal, precisa ser incentivada e acompanhada de forma integrada. Políticas públicas e ações do setor privado efetivas e abrangentes na promoção e prevenção em saúde bucal no ambiente laboral podem ofertar melhor qualidade de vida aos trabalhadores.

Summary Viral infections have a large share in human morbidity and mortality. Next to vaccinations and hygiene measures, health education plays a role in preventing infections. Social scientists argue that empowerment should be included in health education, as increasing knowledge is insufficient to achieve sustainable behaviour change. Within the international education module ‘Viruskenner’, primary school students learn how to prevent virus infections by identifying health risks and developing interventions. This qualitative formative study explored to what extent Viruskenner creates conditions in which empowerment processes can arise and take place in the Netherlands and Suriname. Indicators of empowerment, as defined in the literature and placed in the attitude, social influence, and self-efficacy model, were assessed during semi-structured interviews (n = 24) with students, parents, teachers and facilitators. We conclude that Viruskenner is successful in creating conditions for empowerment processes to arise and take place, specifically in attitude and self-efficacy. According to interviewees, the module raised students’ motivation, skills and confidence to take action to improve health behaviour. Educators played a stimulating role in the participatory setting in both countries, while content relevance and community involvement differed between the Netherlands and Suriname. These outcomes could improve this module and possibly other health education programmes.

Genetic conditions contribute significantly to human morbidity and mortality. The importance of genetics is clear in the setting of pregnancy, not only to prenatal healthcare providers, but also to...

The soil bacterium Burkholderia pseudomallei is the causative agent of melioidosis and a significant cause of human morbidity and mortality in many tropical and subtropical countries. The species notoriously survives harsh environmental conditions but the genetic architecture for these adaptations remains unclear. Here we employed a powerful combination of genome-wide epistasis and co-selection studies (2,011 genomes), condition-wide transcriptome analyses (82 diverse conditions), and a gene knockout assay to uncover signals of “co-selection”—that is a combination of genetic markers that have been repeatedly selected together through B. pseudomallei evolution. These enabled us to identify 13,061 mutation pairs under co-selection in distinct genes and noncoding RNA. Genes under co-selection displayed marked expression correlation when B. pseudomallei was subjected to physical stress conditions, highlighting the conditions as one of the major evolutionary driving forces for this bacterium. We identified a putative adhesin (BPSL1661) as a hub of co-selection signals, experimentally confirmed a BPSL1661 role under nutrient deprivation, and explored the functional basis of co-selection gene network surrounding BPSL1661 in facilitating the bacterial survival under nutrient depletion. Our findings suggest that nutrient-limited conditions have been the common selection pressure acting on this species, and allelic variation of BPSL1661 may have promoted B. pseudomallei survival during harsh environmental conditions by facilitating bacterial adherence to different surfaces, cells, or living hosts.

Central nervous system (CNS) infections are a major cause of human morbidity and mortality worldwide. Even patients that survive CNS infections can have lasting neurological dysfunction resulting from immune and pathogen induced pathology. Developing approaches to noninvasively track pathology and immunity in the infected CNS is crucial for patient management and development of new therapeutics. Here, we develop novel MRI-based approaches to monitor virus-specific CD8+ T cells and their relationship to cerebrovascular pathology in the living brain. We studied a relevant murine model in which a neurotropic virus (vesicular stomatitis virus) was introduced intranasally and then entered the brain via olfactory sensory neurons – a route exploited by many pathogens in humans. Using T2*-weighted high-resolution MRI, we identified small cerebral microbleeds as the earliest form of pathology associated with viral entry into the brain. Mechanistically, these microbleeds occurred in the absence of peripheral immune cells and were associated with infection of vascular endothelial cells. We monitored the adaptive response to this infection by developing methods to iron label and track individual virus specific CD8+ T cells by MRI. Transferred antiviral T cells were detected in the brain within a day of infection and were able to reduce cerebral microbleeds. These data demonstrate the utility of MRI in detecting the earliest pathological events in the virally infected CNS as well as the therapeutic potential of antiviral T cells in mitigating this pathology.

Tick-borne diseases have expanded over the last 2 decades as a result of shifts in tick and pathogen distributions. These shifts have significantly increased the need for accurate portrayal of real-time pathogen distributions and prevalence in hopes of stemming increases in human morbidity. Traditionally, pathogen distribution and prevalence have been monitored through case reports or scientific collections of ticks or reservoir hosts, both of which have challenges that impact the extent, availability, and accuracy of these data. Citizen science tick collections and testing campaigns supplement these data and provide timely estimates of pathogen prevalence and distributions to help characterize and understand tick-borne disease threats to communities. We utilized our national citizen science tick collection and testing program to describe the distribution and prevalence of four Ixodes-borne pathogens, Borrelia burgdorferi sensu lato, Borrelia miyamotoi, Anaplasma phagocytophilum, and Babesia microti, across the continental United States. IMPORTANCE In the 21st century, zoonotic pathogens continue to emerge, while previously discovered pathogens continue to have changes within their distribution and prevalence. Monitoring these pathogens is resource intensive, requiring both field and laboratory support; thus, data sets are often limited within their spatial and temporal extents. Citizen science collections provide a method to harness the general public to collect samples, enabling real-time monitoring of pathogen distribution and prevalence.

Streptococcus pyogenes is a leading cause of human morbidity and mortality, especially in resource limited settings. The World Health Organisation has recently made a vaccine for S. pyogenes a global health priority to reduce the burden of the post-infection rheumatic heart disease. For a vaccine to be active against all relevant strains in each region, molecular characterisation of circulating S. pyogenes isolates is needed. We performed extensive comparative whole genome analyses of S. pyogenes isolates from skin and soft tissue infections in The Gambia, West Africa, where there is a high burden of such infections. To act as a comparator to this low-income country (LIC) collection of isolates, we performed genome sequencing of isolates from skin infections in Sheffield, UK, as representative high-income country (HIC) isolates. LIC isolates from The Gambia were genetically more diverse (46 emm-types in 107 isolates) compared to HIC isolates from Sheffield (23 emm-types in 142 isolates), with only 7 overlapping emm-types and with diverse genetic backgrounds. Characterisation of other molecular markers indicated some shared features, including a high prevalence of the skin infection-associated emm-pattern D and the variable fibronectin-collagen-T antigen (FCT) types FCT-3 and FCT-4. A previously unidentified FCT (FCT-10) was identified in the LIC isolates, belonging to two different emm-types. A high proportion (79/107; 73.8%) of LIC isolates carried genes for tetracycline resistance, compared to 53/142 (37.3%) HIC isolates. There was also evidence of different circulating prophages, as very few prophage-associated DNases and lower numbers of superantigens were detected in LIC isolates. Our study provides much needed insight into the genetics of circulating isolates in a LIC (The Gambia), and how they differ from those circulating in HICs (Sheffield, UK). Common molecular features may act as bacterial drivers for specific infection types, regardless of the diverse genetic background.

Mycobacterium tuberculosis(Mtb)is the causative agent of tuberculosis (TB) and is a major cause of human morbidity and mortality. Crucially,Mtbcan persist and replicate within host macrophages (MФ) and subvert multiple antimicrobial defense mechanisms. How this is achieved is incompletely understood. Previously, we reported that lipids shed by persistent mycobacteria inhibit NPC1, the lysosomal protein deficient in most cases of the rare, inherited lysosomal storage disorder Niemann-Pick disease type C (NPC). Inhibition of NPC1 leads to a drop in lysosomal calcium levels blocking phagosome-lysosome fusion and thereby leads to mycobacterial persistence.Studies of mycobacterial lineages have identified events during mycobacterial evolution that result in the acquisition of persistence. We speculated that the production of specific cell wall lipid(s) capable of inhibiting NPC1 activities could have been a critical step in the evolution of pathogenicity. In this study, we have therefore investigated whether lipid extracts from clinicalMtbstrains representative of multipleMtblineages, members of theMtbcomplex (MTBC) and selected non-tubercular mycobacteria (NTM) inhibit the NPC pathway. We have found that the ability to inhibit the NPC pathway was present in all clinical isolates studied fromMtblineages 1, 2 and 4. We also found that lipids from MTBC member,Mycobacterium bovisand the NTM,Mycobacterium abscessusandMycobacterium aviumalso inhibited the NPC pathway. However, when lipids were assayed fromMycobacterium canettii (M. canettii), a smooth tubercle mycobacterium, which is considered to resemble the common ancestor of the MTBC no inhibition of the NPC1 pathway was detected. We therefore conclude that the evolution of mycobacterial cell wall lipids that inhibit the NPC pathway evolved early and post divergence fromM. canettiirelated mycobacteria and NPC1 inhibition significantly contributes to the ability of these pathogens to persist and cause disease.Authors summaryMycobacterium tuberculosis (Mtb)actively modifies the hostile intracellular environment of host cells to create a niche in which it can persist and replicate. How this is accomplished is incompletely understood. We previously reported an unexpected phenotypic similarity between cells infected with pathogenic mycobacteria and those of the rare, neurodegenerative lysosomal storage disorder, Niemann-Pick disease type C (NPC). Mechanistically, we showed that pathogenic mycobacteria shed lipids that inhibit NCP1, the lysosomal membrane protein that is dysfunctional in NPC and thereby establish conditions that favour their survival. In this study, we have investigated the phylogenetic distribution of lipids that inhibit NPC1. We have screened lipid extracts from multiple clinical mycobacterial isolates representing differentMtblineages, other members of theMtbcomplex and non-tuberculous mycobacteria for their ability to induce NPC phenotypes. We detected activity in all of the groups tested, but not fromMycobacterium canettii, which is believed to resemble the ancestral species. These data indicate that targeting of NPC1 to achieve intracellular persistence evolved early in the evolution of theMtbcomplex, but after divergence from the presumed ancestral species.

Heritable thoracic aortic disease and familial thoracic aortic aneurysm/dissection are important causes of human morbidity/mortality, most without identifiable genetic cause. In a family with familial thoracic aortic aneurysm/dissection, we identified a missense p. (Ser178Arg) variant in PLOD1 segregating with disease, and evaluated PLOD1 enzymatic activity, collagen characteristics and in human aortic vascular smooth muscle cells, studied the effect on function. Comparison with homologous PLOD3 enzyme indicated that the pathogenic variant may affect the N-terminal glycosyltransferase domain, suggesting unprecedented PLOD1 activity. In vitro assays demonstrated that wild-type PLOD1 is capable of processing UDP-glycan donor substrates, and that the variant affects the folding stability of the glycosyltransferase domain and associated enzymatic functions. The PLOD1 substrate lysine was elevated in the proband, however the enzymatic product hydroxylysine and total collagen content was not different, albeit despite collagen fibril narrowing and preservation of collagen turnover. In VSMCs overexpressing wild-type PLOD1, there was upregulation in procollagen gene expression (secretory function) which was attenuated in the variant, consistent with loss-of-function. In comparison, si-PLOD1 cells demonstrated hypercontractility and upregulation of contractile markers, providing evidence for phenotypic switching. Together, the findings suggest that the PLOD1 product is preserved, however newly identified glucosyltransferase activity of PLOD1 appears to be affected by folding stability of the variant, and is associated with compensatory vascular smooth muscle cells phenotypic switching to support collagen production, albeit with less robust fibril girth. Future studies should focus on the impact of PLOD1 folding/variant stability on the tertiary structure of collagen and ECM interactions.

Schistosomiasis, a neglected tropical disease caused by parasitic flatworms of the genus Schistosoma, results in considerable human morbidity in sub-Saharan Africa, in particular, but also parts of the Middle East, South America, and Southeast Asia. The anti-schistosome drug praziquantel is efficacious and safe against the adult parasites of all Schistosoma species infecting humans; however, it does not prevent reinfection and the development of drug resistance is a constant concern. The need to develop an effective vaccine is of great importance if the health of many in the developing world is to be improved. Indeed, vaccination, in combination with other public health measures, can provide an invaluable tool to achieve lasting control, leading to schistosomiasis elimination. Australia has played a leading role in schistosomiasis vaccine research over many years and this review presents an overview of some of the significant contributions made by Australian scientists in this important area.

Comparative genomics of bacterial pathogens has been useful for revealing potential virulence factors. Escherichia coli is a significant cause of human morbidity and mortality worldwide but can also exist as a commensal in the human gastrointestinal tract. With many sequenced genomes, it has served as a model organism for comparative genomic studies to understand the link between genetic content and potential for virulence. To date, however, no comprehensive analysis of its complete “virulome” has been performed for the purpose of identifying universal or pathotype-specific targets for vaccine development. Here, we describe the construction of a pathotype database of 107 well-characterized completely sequenced pathogenic and nonpathogenic E. coli strains, which we annotated for major virulence factors (VFs). The data are cross referenced for patterns against pathotype, phylogroup, and sequence type, and the results were verified against all 1,348 complete E. coli chromosomes in the NCBI RefSeq database. Our results demonstrate that phylogroup drives many of the “pathotype-associated” VFs, and ExPEC-associated VFs are found predominantly within the B2/D/F/G phylogenetic clade, suggesting that these phylogroups are better adapted to infect human hosts. Finally, we used this information to propose polyvalent vaccine targets with specificity toward extraintestinal strains, targeting key invasive strategies, including immune evasion (group 2 capsule), iron acquisition (FyuA, IutA, and Sit), adherence (SinH, Afa, Pap, Sfa, and Iha), and toxins (Usp, Sat, Vat, Cdt, Cnf1, and HlyA). While many of these targets have been proposed before, this work is the first to examine their pathotype and phylogroup distribution and how they may be targeted together to prevent disease.

Venezuelan equine encephalitis virus (VEEV) is a reemerging alphavirus that can cause encephalitis resulting in severe human morbidity and mortality. Using a high-throughput cell-based screen, we identified a quinolinone compound that protected against VEEV-induced cytopathic effects. Analysis of viral replication in cells identified several quinolinone compounds with potent inhibitory activity against vaccine and virulent strains of VEEV. These quinolinones also displayed inhibitory activity against additional alphaviruses, such as Mayaro virus and Ross River virus, although the potency was greatly reduced. Time-of-addition studies indicated that these compounds inhibit the early-to-mid stage of viral replication. Deep sequencing and reverse genetics studies identified two unique resistance mutations in the nsP2 gene (Y102S/C; stalk domain) that conferred VEEV resistance on this chemical series. Moreover, introduction of a K102Y mutation into the nsP2 gene enhanced the sensitivity of chikungunya virus (CHIKV) to this chemical series. Computational modeling of CHIKV and VEEV nsP2 identified a highly probable docking alignment for the quinolinone compounds that require a tyrosine residue at position 102 within the helicase stalk domain. These studies identified a class of compounds with antiviral activity against VEEV and other alphaviruses and provide further evidence that therapeutics targeting nsP2 may be useful against alphavirus infection.

Dengue virus (DENV) is a flavivirus that causes marked human morbidity and mortality worldwide, and is transmitted to humans by Aedes aegypti mosquitoes. Habitat expansion of Aedes, mainly due to climate change and increasing overlap between urban and wild habitats, places nearly half of the world’s population at risk for DENV infection. After a bloodmeal from a DENV-infected host, the virus enters the mosquito midgut. Next, the virus migrates to, and replicates in, other tissues, like salivary glands. Successful viral transmission occurs when the infected mosquito takes another blood meal on a susceptible host and DENV is released from the salivary gland via saliva into the skin. During viral dissemination in the mosquito and transmission to a new mammalian host, DENV interacts with a variety of vector proteins, which are uniquely important during each phase of the viral cycle. Our study focuses on the interaction between DENV particles and protein components in the A. aegypti vector. We performed a mass spectrometry assay where we identified a set of A. aegypti salivary gland proteins which potentially interact with the DENV virion. Using dsRNA to silence gene expression, we analyzed the role of these proteins in viral infectivity. Two of these candidates, a synaptosomal-associated protein (AeSNAP) and a calcium transporter ATPase (ATPase) appear to play a role in viral replication both in vitro and in vivo, observing a ubiquitous expression of these proteins in the mosquito. These findings suggest that AeSNAP plays a protective role during DENV infection of mosquitoes and that ATPase protein is required for DENV during amplification within the vector., Author summary Dengue is a mosquito-borne viral disease whose incidence has increased dramatically (>30-fold) in recent years, alongside the geographical expansion of Aedes mosquitoes. Dengue is currently one of the most important neglected tropical diseases, and its transmission is strongly influenced by rainfall, temperature, urbanization and distribution of the principal mosquito vector Aedes aegypti. Vector control strategies are being implemented to reduce the expansion of this disease, but still there is a great need for better therapeutics and preventive vaccines against dengue and other flaviviruses. Flaviviruses create complex virus-host and virus-vector interactions. The interactions between viral particles and protein components in the vector are not completely understood. In this work we characterize how two mosquito proteins, “AeSNAP” and “ATPase”, influence DENV viral dissemination within A. aegypti, using both in vitro and in vivo models. These results suggest that anti-vector measures that target specific mosquito molecules may represent promising alternatives to traditional countermeasures against dengue virus spread.

Immunopathologies caused by Leishmania cause severe human morbidity and mortality. This protozoan parasite invades and persists inside host cells, resulting in disease development. Leishmania modifies the epigenomic status of the host cells, thus probably averting the host cell defense mechanism. To accomplish this, Leishmania may change the host cell chromatin structure. However, the mechanism by which the parasite changes the host cell chromatin has not been characterized. In the present study, we found that ectopically produced Leishmania histone H3, LmaH3, which mimics the secreted LmaH3 in infected cells, is incorporated into chromatin in human cells. A crystallographic analysis revealed that LmaH3 forms nucleosomes with human histones H2A, H2B and H4. We found that LmaH3 was less stably incorporated into the nucleosome, as compared to human H3.1. Consistently, we observed that LmaH3–H4 association was remarkably weakened. Mutational analyses revealed that the specific LmaH3 Trp35, Gln57 and Met98 residues, which correspond to the H3.1 Tyr41, Arg63 and Phe104 residues, might be responsible for the instability of the LmaH3 nucleosome. Nucleosomes containing LmaH3 resisted the Mg2+-mediated compaction of the chromatin fiber. These distinct physical characteristics of LmaH3 support the possibility that histones secreted by parasites during infection may modulate the host chromatin structure.

PurposeThe rapid deterioration of the earth’s natural ecosystems are increasing the risk of human morbidity and mortality worldwide. Hydrometeorological hazards are concentrating contaminants from the damaged environment and exposing large vulnerable populations to life threating illnesses and death. This study performed a retrospective health risk assessment on two recent events where such impacts unfolded, namely, the 2015 south east Equatorial Asia smoke haze disaster and the 2016 Melbourne thunderstorm asthma epidemic. The purpose of this paper is to test if the characterisation of health risk warranted earlier and more effective risk reduction activities prior to the disasters occurring.Design/methodology/approachA retrospective health risk characterisation assessment was performed combing United Nations International Strategy for Disaster Risk Health Aspect in Disaster Risk Assessment (2017) framework with a thematic and targeted word literature review to identify the level of risk knowledge prior to each event. A risk characterisation matrix was then created to characterise the health risk of each hazard event.FindingsThe 2015 south east Equatorial Asia smoke haze disaster risk assessment was characterised as “extreme” health risk and the 2016 Melbourne thunderstorm asthma epidemic was characterised as “high” health risk.Practical implicationsReaching the goals of the Sendai Framework require strategies and plans which urgently address the catastrophic level of mortality risk posed by exposure to environmental contaminants.Originality/valueInnovative approaches and partnerships are necessary to mitigate the risk from the deteriorating health of the environment and natural ecosystems, along with disaster response initiatives that reduce exposure of vulnerable people on a large scale.

Introduction Arthropod-borne viruses are important causes of human morbidity worldwide. However, the available literatur and the epidemiological data concerning the importation to Poland of globally emerging arboviral infections, such as DENV, CHIKV, WNV, or ZIKV, are scarce. Only few seroepidemiologic studies concerning WNV in animals or humans in Poland have been published. Objective The aim of this review paper is to summarize and present the current state of knowledge and the perspectives for research concerning the importation and the risk posed by the introduction to Poland of the four above-mentioned arboviral diseases. Current state of knowledge Climate change may facilitate the northward expansion of both the vectors for diseases previously unseen in Europe, as well as of the viruses themselves, resulting in autochthonous cases of diseases previously exclusively imported. Little is known about the importation of arboviral diseases to Poland because of the frequently asymptomatic or self-limiting course of the disease, lack of epidemiologic studies or effective disease reporting, as well as inadequate access to diagnostic methods. Conclusions Further epidemiologic studies in Polish travellers are necessary in order to prevent importation or introduction of the above-mentioned viruses, and to act against potential problems related to blood transfusion or organ transplantation from infected donors.

Background Probiotic consumption has dramatically grown with most products claim of gastrointestinal health and immune support. The beneficial potential of probiotic has gradually expanded to areas such as mood improvement, metabolism homeostasis and vaginal health according to scientific research advances. The positive research results provide novel and promising insight into preventing and even therapeutic methods for various human morbidity by probiotic. Scope and approach This review summarized the bidirectional relationship between the host physiology and microbiota from various animal experiments and clinical studies reported in peer-reviewed journal articles. Then the study summarized the benefits that probiotic confer to the host physiology. As a kind of food supplement, application precautions and formula suggestions were also provided for futuristic research and product development. Key Findings and Conclusions: Microbial ecosystem has a symbiotic relationship with host. The alteration in the host physiology and shift in the microbial composition in the hosts can positively or negatively impact each other. The clear and thorough comprehension of the complexity of microbiota–host crosstalk is significant for the development of probiotic intervention. Probiotic may confer various benefits ranging from traditional immune support, gastrointestinal heath even to disease control as sepsis prevention. Probiotic may function in the host mainly through competing with deleterious bacteria, beneficial metabolites and maintaining the homeostasis of gut, and new mechanisms are being discovered each year. The failed clinical study and negative results of probiotic treatment may propose the customized probiotic design for treatment. For probiotic supplement products in the market, upgrading are strongly suggested from aspects of formula innovation and clinically referred probiotic dosage.

Dengue viruses (DENV) are currently responsible for more human morbidity and mortality than any other known arbovirus, and all four DENV are known to exist in sylvatic cycles that might allow these viruses to persist if the urban (Aedes aegypti) cycle could be controlled. To determine whether DENV were being maintained in a sylvatic cycle in a forested area about 14 km southwest of Iquitos, Peru, a city in which all 4 serotypes of DENV circulate, we placed 20 DENV seronegative Aotus monkeys in cages either in the canopy or near ground level for a total of 125.6 months. Despite capturing >66,000 mosquitoes in traps that collected some of the mosquitoes attracted to these monkeys, blood samples obtained once a month from each animal were tested and found to be negative by an enzyme-linked immunosorbent assay for IgM and IgG antibodies to dengue, yellow fever, Venezuelan equine encephalitis, Oropouche, and Mayaro viruses. Although all four DENV serotypes were endemic in nearby Iquitos, the findings of this study did not support a DENV sylvatic maintenance and transmission cycle in a selected area of the Amazon rainforest in northeastern Peru.

Pathogens that express resistance to multiple drugs are becoming the norm, complicating treatment and increasing human morbidity. Acylsugars or resin glycosides from the morning glory family (Convolvulaceae) are amphipathic modulators of the efflux pumps responsible for the drug-resistant phenotype in prokaryotic and eukaryotic cells. These inhibitory effects could be used to overcome the acquired resistance to common anticancer or antimicrobial drugs by lowering the current effective therapeutic doses, thus decreasing toxic side-effects in refractory malignancies. Active chemosensitizers identified by in vitro screening methods have demonstrated the therapeutic potential of resin glycosides for further exploration as coadjuvants to avoid drug resistance and restore the clinical utility of chemotherapy in treating infections and cancer. To date, more than 20 resin glycosides have been documented as inhibitors or modulators of efflux pumps, mainly isolated from species of the genus Ipomoea. Resin glycosides have shown the ideal structural features associated with multidrug-resistant efflux pump substrates. An overview is given to the acylsugar diversity and their amphiphilicity properties for bioactivity as leads of efflux pump inhibitors for drug development.

Trichinellosis caused by parasitic nematodes of the genus Trichinella may result in human morbidity and mortality worldwide. Deciphering processes that drive species diversity and adaptation are key to understanding parasitism and developing effective control strategies. Our goal was to identify genes that are under positive selection and possible mechanisms of adaptive evolution of Trichinella spiralis genes using a comparative genomic analysis with the genomes of Brugia malayi, Trichuris suis, Ancylostoma ceylanicum, and Caenorhabditis elegans. The CODEML program derived from the PAML package was used to deduce the most probable dN/dS ratio, a measurement to detect genes/proteins undergoing adaptation. For each pair of sequences, those with a dN/dS ratio > 1 were considered positively selected genes (PSGs). Altogether, 986 genes were positively selected (p-value < 0.01). Genes involved in metabolic pathways, signaling pathways, and cytosolic DNA-sensing pathways were significantly enriched among the PSGs. Several PSGs are associated with exploitation of the host: modification of the host’s metabolism, creation of new parasite-specific morphological structures between T. spiralis and the host interface, xenobiotic metabolism to combat low oxygen concentrations and host toxicity, muscle cell transformation, cell cycle arrest, DNA repair processes during nurse cell formation, antiapoptotic factors, immunomodulation, and regulation of epigenetic processes. Some of the T. spiralis PSGs have C. elegans orthologs that confer severe or lethal RNAi phenotypes. Fifty-seven PSGs in T. spiralis were analyzed to encode differentially expressed proteins. The present study utilized an overall comparative genomic analysis to discover PSGs within T. spiralis and their relationships with biological function and organism fitness. This analysis adds to our understanding of the possible mechanism that contributes to T. spiralis parasitism and biological adaptation within the host, and thus these identified genes may be potential targets for drug and vaccine development.

Heat waves and high air temperature are associated with increased morbidity and mortality. However, the majority of research conducted on this topic is focused on high income areas of the world. Although heat waves have the most severe impacts on vulnerable populations, relatively few studies have studied their impacts in low and middle income countries (LMICs). The aim of this paper is to review the existing evidence in the literature on the impact of heat on human health in LMICs. We identified peer-reviewed epidemiologic studies published in English between January 1980 and August 2018 investigating potential associations between high ambient temperature or heat waves and mortality or morbidity. We selected studies according to the following criteria: quantitative studies that used primary and/or secondary data and report effect estimates where ambient temperature or heat waves are the main exposure of interest in relation to human morbidity or mortality within LMICs. Of the total 146 studies selected, eighty-two were conducted in China, nine in other countries of East Asia and the Pacific, twelve in South Asia, ten in Sub-Saharan Africa, eight in the Middle East and North Africa, and seven in each of Latin America and Europe. The majority of studies (92.9%) found positive associations between heat and human morbidity/mortality. Additionally, while outcome variables and study design differed greatly, most utilized a time-series study design and examined overall heath related morbidity/mortality impacts in an entire population, although it is notable that the selected studies generally found that the elderly, women, and individuals within the low socioeconomic brackets were the most vulnerable to the effects of high temperature. By highlighting the existing evidence on the impact of extreme heat on health in LMICs, we hope to determine data needs and help direct future studies in addressing this knowledge gap. The focus on LMICs is justified by the lack of studies and data studying the health burden of higher temperatures in these regions even though LMICs have a lower capacity to adapt to high temperatures and thus an increased risk.

In the review there highlighted contemporary concepts about the relation between the air pollution by the particulate matter (PM) and human morbidity and mortality rate due to cardiovascular diseases. There are considered results of the short- and long-term PM impact on the human cardiovascular system in the dependence on size, origin, chemical composition, and concentration in the air. Authors performed the formalized description of the action and possible effects of PM on vascular endothelium presented as an example of systemization. Summarizing data respective knowledge collected in the literature were used in the article as an example.

The earliest evidence of human tuberculosis can be traced to at least the early dynastic periods, when full-scaled wet-rice agriculture began or entered its early developmental stages, in circum-China countries (Japan, Korea, and Thailand). Early studies indicated that the initial spread of tuberculosis coincided with the development of wet-rice agriculture. It has been proposed that the adaptation to agriculture changed human social/living environments, coincidentally favoring survival and spread of pathogenic Mycobacterial strains that cause tuberculosis. Here we present a possible case of spinal tuberculosis evident in the remains of a young female (M191) found among 184 skeletal individuals who were Neolithic wet-rice agriculturalists from the Yangtze River Delta of China, associated with Songze culture (3900-3200 B.C.). This early evidence of tuberculosis in East Asia serves as an example of early human morbidity following the adoption of the wet-rice agriculture.

Breast cancer (BC) is a major cause of human morbidity and mortality, especially among women. Despite the important role of metabolism in the molecular pathogenesis of cancer, robust metabolic markers to enable enhanced screening and disease monitoring of BC are still critically needed. In this study, a targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) metabolic profiling approach is presented for the identification of metabolic marker candidates that could enable highly sensitive and specific detection of all-stage as well as early-stage BC. In this targeted approach, 105 metabolites from >35 metabolic pathways of potential biological relevance were reliably detected in 201 plasma samples taken from two groups of subjects (102 BC patients and 99 healthy controls). The results of our general linear model and partial least squares-discriminant analysis (PLS-DA) informed the construction of a novel 6-metabolite panel of potential biomarkers. A receiver operating characteristic (ROC) curve generated based on an improved PLS-DA model showed relatively high sensitivity (0.80), specificity (0.75), and area under the receiver-operating characteristic curve (AUROC = 0.89). Similar classification performance of the model was observed for detection of early-stage BC (AUROC = 0.87, sensitivity: 0.86, specificity: 0.75). Bioinformatics analyses revealed significant disturbances in arginine/proline metabolism, tryptophan metabolism, and fatty acid biosynthesis. Our univariate and multivariate results indicate the effectiveness of this metabolomics approach for all-stage as well as early-stage BC diagnosis; our bioinformatics results indicate affected pathways related to tumor growth, metastasis, and immune escape mechanisms. Future studies should validate these results using more samples from different locations.