Correlative chemical imaging identifies amyloid peptide signatures of neuritic plaques and dystrophy in human sporadic Alzheimer's disease

OBJECTIVE: Alzheimer's disease (AD) is the most common neurodegenerative disease. The predominantly sporadic form of AD (sAD) is age-related, but the underlying pathogenic mechanisms remain not fully understood. Current efforts to combat the disease focus on the main pathological hallmarks, in particular beta-amyloid (Aβ) plaque pathology. According to the amyloid cascade hypothesis, Aβ is the critical early initiator of AD pathogenesis. Plaque pathology is very heterogeneous, where a subset of plaques, neuritic plaques, are considered most neurotoxic rendering their in depth characterization essential to understand Aβ pathogenicity. METHODS: To delineate the chemical traits specific to neuritic plaque types, we investigated senile Aβ pathology in post mortem human sporadic AD brain using advanced correlative biochemical imaging based on immunofluorescence microscopy and mass spectrometry imaging (MSI). RESULTS: Immunostaining-guided MSI identified distinct Aβ signatures of neuritic plaques characterized by increased Aβ 1-42(ox) and Aβ2-42. Moreover, correlation with a marker of dystrophy (reticulon 3, RTN3) identified key Aβ species that both delineate neuritic plaques and display association with neuritic dystrophy. CONCLUSION: Together these correlative imaging data shed light on the complex biochemical architecture of neuritic plaques and associated dystrophic neurites. These in turn are obvious targets for disease-modifying treatment strategies, as well as novel biomarkers of Aβ pathogenicity

Chemical traits of cerebral amyloid angiopathy in familial British-, Danish-, and non-Alzheimerʼs dementias

Familial British dementia (FBD) and familial Danish dementia (FDD) are autosomal dominant forms of dementia caused by mutations in the integral membrane protein 2B (ITM2B, also known as BRI2) gene. Secretase processing of mutant BRI2 leads to secretion and deposition of BRI2-derived amyloidogenic peptides, ABri and ADan that resemble APP/β-amyloid (Aβ) pathology, which is characteristic of Alzheimer's disease (AD). Amyloid pathology in FBD/FDD manifests itself predominantly in the microvasculature by ABri/ADan containing cerebral amyloid angiopathy (CAA). While ABri and ADan peptide sequences differ only in a few C-terminal amino acids, CAA in FDD is characterized by co-aggregation of ADan with Aβ, while in contrast no Aβ deposition is observed in FBD. The fact that FDD patients display an earlier and more severe disease onset than FBD suggests a potential role of ADan and Aβ co-aggregation that promotes a more rapid disease progression in FDD compared to FBD. It is therefore critical to delineate the chemical signatures of amyloid aggregation in these two vascular dementias. This in turn will increase the knowledge on the pathophysiology of these diseases and the pathogenic role of heterogenous amyloid peptide interactions and deposition, respectively. Herein, we used matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) in combination with hyperspectral, confocal microscopy based on luminescent conjugated oligothiophene probes (LCO) to delineate the structural traits and associated amyloid peptide patterns of single CAA in postmortem brain tissue of patients with FBD, FDD as well as sporadic CAA without AD (CAA+) that show pronounced CAA without parenchymal plaques. The results show that CAA in both FBD and FDD consist of N-terminally truncated- and pyroglutamate-modified amyloid peptide species (ADan and ABri), but that ADan peptides in FDD are also extensively C-terminally truncated as compared to ABri in FBD, which contributes to hydrophobicity of ADan species. Further, CAA in FDD showed co-deposition with Aβ x-42 and Aβ x-40 species. CAA+ vessels were structurally more mature than FDD/FBD CAA and contained significant amounts of pyroglutamated Aβ. When compared with FDD, Aβ in CAA+ showed more C-terminal and less N-terminally truncations. In FDD, ADan showed spatial co-localization with Aβ3pE-40 and Aβ3-40 but not with Aβx-42 species. This suggests an increased aggregation propensity of Aβ in FDD that promotes co-aggregation of both Aβ and ADan. Further, CAA maturity appears to be mainly governed by Aβ content based on the significantly higher 500/580 patterns observed in CAA+ than in FDD and FBD, respectively. Together this is the first study of its kind on comprehensive delineation of Bri2 and APP-derived amyloid peptides in single vascular plaques in both FDD/FBD and sporadic CAA that provides new insight in non-AD-related vascular amyloid pathology. (Figure presented.

The Impact of Climate Change on Biodiversity in Nepal: Current Knowledge, Lacunae, and Opportunities

Nepal has an extreme altitudinal range from 60–8850m with heterogeneous topography and distinct climatic zones. The country is considered a biodiversity hotspot, with nearly a quarter of the land area located in protected areas. Nepal and the surrounding Himalayan region are particularly vulnerable to climate change because of their abrupt ecological and climatic transitions. Tens of millions of people rely on the region’s ecosystem services, and observed and modeled warming trends predict increased climate extremes in the Himalayas. To study the ecological impacts of climate change in Nepal and inform adaptation planning, we review the literature on past, present, and predicted future climatic changes and their impacts on ecological diversity in Nepal. We found few studies focusing on organisms, while research on species and communities was more common. Most studies document or predict species range shifts and changes in community composition. Results of these few investigations highlight major lacunae in research regarding the effects of changing climate on species comprising the Himalayan biota. Further empirical work is needed at all levels of biological organization to build on information regarding direct ecological impacts of climatic changes in the region. Countries face an ever-increasing threat of climate change, and Nepal has strong physiographic, elevational, and climatic gradients that could provide a useful model for studying the effects of climate change on a mountainous, and highly biodiverse, area

Alcohol use and burden for 195 countries and territories, 1990-2016 : a systematic analysis for the Global Burden of Disease Study 2016

Background Alcohol use is a leading risk factor for death and disability, but its overall association with health remains complex given the possible protective effects of moderate alcohol consumption on some conditions. With our comprehensive approach to health accounting within the Global Burden of Diseases, Injuries, and Risk Factors Study 2016, we generated improved estimates of alcohol use and alcohol-attributable deaths and disability-adjusted life-years (DALYs) for 195 locations from 1990 to 2016, for both sexes and for 5-year age groups between the ages of 15 years and 95 years and older. Methods Using 694 data sources of individual and population-level alcohol consumption, along with 592 prospective and retrospective studies on the risk of alcohol use, we produced estimates of the prevalence of current drinking, abstention, the distribution of alcohol consumption among current drinkers in standard drinks daily (defined as 10 g of pure ethyl alcohol), and alcohol-attributable deaths and DALYs. We made several methodological improvements compared with previous estimates: first, we adjusted alcohol sales estimates to take into account tourist and unrecorded consumption; second, we did a new meta-analysis of relative risks for 23 health outcomes associated with alcohol use; and third, we developed a new method to quantify the level of alcohol consumption that minimises the overall risk to individual health. Findings Globally, alcohol use was the seventh leading risk factor for both deaths and DALYs in 2016, accounting for 2.2% (95% uncertainty interval [UI] 1.5-3.0) of age-standardised female deaths and 6.8% (5.8-8.0) of age-standardised male deaths. Among the population aged 15-49 years, alcohol use was the leading risk factor globally in 2016, with 3.8% (95% UI 3.2-4-3) of female deaths and 12.2% (10.8-13-6) of male deaths attributable to alcohol use. For the population aged 15-49 years, female attributable DALYs were 2.3% (95% UI 2.0-2.6) and male attributable DALYs were 8.9% (7.8-9.9). The three leading causes of attributable deaths in this age group were tuberculosis (1.4% [95% UI 1. 0-1. 7] of total deaths), road injuries (1.2% [0.7-1.9]), and self-harm (1.1% [0.6-1.5]). For populations aged 50 years and older, cancers accounted for a large proportion of total alcohol-attributable deaths in 2016, constituting 27.1% (95% UI 21.2-33.3) of total alcohol-attributable female deaths and 18.9% (15.3-22.6) of male deaths. The level of alcohol consumption that minimised harm across health outcomes was zero (95% UI 0.0-0.8) standard drinks per week. Interpretation Alcohol use is a leading risk factor for global disease burden and causes substantial health loss. We found that the risk of all-cause mortality, and of cancers specifically, rises with increasing levels of consumption, and the level of consumption that minimises health loss is zero. These results suggest that alcohol control policies might need to be revised worldwide, refocusing on efforts to lower overall population-level consumption.Peer reviewe

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Burkholderia gladioli strain NGJ1 deploys a prophage tail-like protein for mycophagy

Fungal pathogens are responsible for approximately two third of the infectious plant diseases. Historically they have been associated with several devastating famines, causing death and disabilities in humans. Mostly fungal diseases are being controlled by using fungicides which otherwise have adverse side effects on the health of consumers as well as environment. Due to extensive usages, pathogens have evolved resistance against most of the commonly used fungicides and rendered them ineffective. Controlling fungal disease in a sustainable and eco-friendly fashion remains a challenge. The antifungal biocontrol agents are being considered as potent, alternative and ecofriendly approach to manage fungal diseases. In our recent work, we have identified a rice associated bacterium; Burkholderia gladioli strain NGJ1 which demonstrates broad spectrum fungal eating (mycophagous) property. We determined that the bacterium utilizes its type III secretion system (Injectisome) machinery to deploy a prophage tail-like protein (Bg_9562) into fungal cells to devour them. The purified Bg_9562 protein from over-expressing recombinant E. coli strain demonstrates broad spectrum antifungal activity. Overall our study opens up a new opportunity to exploit prophage tail-like protein as potent antifungal compound to control plant as well as animal fungal diseases

Microwave-Assisted Synthesis of 3,5-Dibenzyl-4-amino-1,2,4-triazole and its Diazo Ligand, Metal Complexes Along with Anticancer Activity

Synthesis of 3,5-dibenzyl-4-amino-1,2,4-triazole was accomplished via a conventional method as well as microwave irradiation method, followed by diazotization and coupling with 2,4-pentanedione. The dinucleating ligand was isolated and complexed with Ni(II), Cu(II) and Ru(III) chlorides. These complexes were screened on Jurkat, Raji & PBMC cell lines for anticancer activity. Ruthenium complexes showed potential anticancer activities

Evaluation of the clinicoradiological profile in cases of allergic bronchopulmonary aspergillosis: An original research

Introduction: A complicated hypersensitive reaction to inhaled fungal antigens results in allergic bronchopulmonary aspergillosis (ABPA), an immunologic pulmonary disease. ABPA complicates nearly 2% of instances of persistent asthma as well as nearly 10% of chronic cases of steroid-dependent asthma, and it occurs most frequently in immunocompetent patients. The purpose of the current research was to analyze the radiological and clinical features of the participants as well as the serological association of ABPA. Materials and Methods: From April 2020 to April 2021, a retrospective investigation was conducted. The study included patients based on the International Society for Human and Animal Mycology's criteria for ABPA confirmation. Analysis was done on the demographic information and pathological and radiological test results of the patients. The patients' pre-bronchodilator and post-bronchodilator spirometry was compared, and asthmatic control was estimated. Results: A total of 50 patients were investigated at in this study. Demographic findings indicated young subjects and aa female predominance. Cough was the most prevalent symptom in 84% of patients. Asthma of the bronchi was a risk factor for all of the patients. The mean serum immunoglobulin E level and the mean absolute eosinophil count were 533 cells/L and 2269 UI/mL, respectively. Spirometry results from the study's participants indicated an obstructive pattern in about 80% of cases. The most typical radiological abnormality observed was bronchiectasis, followed by parenchymal opacities. Conclusion: In conclusion, when treating asthma that is challenging to control, the diagnosis of ABPA must be taken into account. Delay in diagnosis might result in declining lung function, worsening asthma control, possibly irreversible alterations, greater treatment costs, and declined quality of life