Circulating renin-angiotensin systems mediated feedback controls over the mean-arterial pressure.

The renin-angiotensin systems play pivotal role in cardiovascular physiology through its effects on regulating blood pressure and electrolyte homeostasis. Components of circulating RAS (cRAS) that include precursor angiotensinogen, two critical enzymes (renin and angiotensin-converting enzyme, ACE), their bioactive products, angiotensin- I, II together with its receptors (AT1R and AT2R) essentially determine this homeostasis. Most classical studies, however, showed the deleterious role of cRAS in elevating the blood pressure. Contemporary discovery of non-canonical components of the RAS has challenged this classic hypothesis that it can only exert deleterious effects on the cardiovascular systems. Using the classic cRAS model, we have designed in-silico experiments to test the hypothesis that AT2R-mediated feedback effects play pivotal role for maintaining the normal variation of the mean-arterial pressure (MAP).Beside the AT2R-mediation of downstream singling pathways consisting of several non-canonical RAS components, this study first time illustrated AT2R mediated feedback controls over the blood pressure regulation: one that impedes AT1R activity, and the other that downregulates renin. It has been shown that relatively stronger suppression of renin activity significantly contributes in maintaining the normal MAP and that tight AT2R-mediated regulation is relaxed in hyper-and hypotension. This control mechanism is noted to be robustly maintained with the MAP variations through an established linear steady-state relationship among renin, angiotensin I and angiotensin II. This examination suggests that AT2R-mediated downregulation of renin activities potentially counteracts the AT1R-mediated deleterious actions of Ang II. This study, therefore, provides a solid ground for considering different AT2 receptor adaptor protein and direct agonism at AT2R that can cause greater effects along with contemporary approaches of blocking AT1R mediation to attenuate hypertension or other cardiovascular disorders.

Changes in the associations between malaria incidence and climatic factors across malaria endemic countries in Africa and Asia-Pacific region.

Empirical evidence supporting the associations between malaria incidence and climatic factors has remained controversial, buffering the progress in the Global Malaria Program that aims to eliminate 90% of the world malaria burden by 2030. This study has aimed to evaluate the nature and extent at which these relations are maintained across all the malaria endemic countries of Africa and Asia-Pacific region. We have utilized the last two decades of malaria incidence, annual minimum temperature, and annual precipitation time series data (2000-2020) for the two most malaria-impacted regions. These data were fitted in the generalized linear model and the mixed effects model. The results showed that there exists a large heterogeneity in malaria incidence across the countries, and between the regions. Last two decadal tendencies showed significant reductions in the disease burden in almost all the countries in the Asia Pacific, with several exceptions or relatively slowed reductions in the Africa. We found significant changes in the positive linear associations between malaria incidence, annual minimum temperature, and annual precipitation across African countries. Many Asia-Pacific countries namely Bangladesh, Bhutan, Indonesia, South Korea, Nepal, Thailand, Vietnam showed negative effects in the associations with the annual precipitation. This study indicates that increasing temperature within the range of 12-30 °C can generate positive effects on malaria incidence, but the nature and extent of precipitation effects vary across countries and at a large regional scale.

Ecological risk assessment of organochlorine pesticide mixture in South China Sea and East China Sea under the effects of seasonal changes and phase-partitioning.

Organochlorine pesticides (OCPs), chlorinated hydrocarbon derivatives extensively used in agriculture and chemical industry, have been banned for several decades in most developed countries. However, OCPs act as persistent organic pollutants due to their semi-volatility nature, high ability for wide range transportation and faster bioaccumulation, and thus it has remained as a topical global concern. This study focuses on OCP distributions, sources and associated ecological risks in the globally important OCP source-sink regions of South China Sea (SCS) and East China Sea (ECS). Given the co-exposure of multiple OCPs that undermine the classical risk assessment of single OCP species, a two-tier mixture risk assessment approach has been employed with explicit consideration of seasonal changes and phase-partitioning effects. The results indicate existence of multiple sources varied across the seasons and between the dissolved and particulate phases. Potential sources include the current-use of lindane or historical use of technical HCH, input of technical DDTs, long-range atmospheric transport, and deposition of HCB from land surfaces. There are no wide high-risk zones. Dissolved HCB and DDTs have posed low-to-medium levels of risks broadly distributed across the seasons. Relatively greater risks are observed in summer in the both dissolved and particulate phases. The study has shown the importance of considering mixture risk assessments with the effects of phase-partitioning and seasonal changes for efficient oceanic risk management.

Phase partitioning effects on seasonal compositions and distributions of terrigenous polycyclic aromatic hydrocarbons along the South China Sea and East China Sea.

Polycyclic aromatic hydrocarbons (PAHs) have posed serious risk to marine ecosystems due to their carcinogenic properties, and persistence in the environment and elevated bioaccumulation. It, therefore, becomes essential to examine spatial distribution, composition, and sources of PAHs. In this study, we have examined these PAH variations in the South China Sea (SCS) and East China Sea (ECS), that are experiencing rapid population and economic growth by the surrounding developing countries. It revealed high seasonal variations that significantly differ between dissolved and particulate PAHs concentrations. Spatial variations of PAHs across sites remain relatively insignificant. Persistently high particulate concentrations of the Naphthalene (Nap) were observed, whereas the dissolved concentrations of Fluorene (Flu) and Phenanthrene (Phen) remained prevalent across all the seasons. The result of non-metric multidimensional scaling (NMDS) strongly reflects the weak dispersions of PAHs across the seasons and the contrasting effects of the phase partitioning. Principal component analysis indicates that the primary source of PAH contamination is coal tar or petroleum distillation. However, estimated risk quotient (RQ) values of both the dissolved and particulate PAHs in all the seasons are far below the high-risk levels, while dissolved PAHs displayed relatively higher values. This study signifies the importance of phase petitioning for PAHs monitoring and potential risk assessments.

Mutation-Induced Long-Range Allosteric Interactions in the Spike Protein Determine the Infectivity of SARS-CoV-2 Emerging Variants.

The emergence of a variety of highly transmissible SARS-CoV-2 variants, the causative agent of COVID-19, with multiple spike mutations poses serious challenges in overcoming the ongoing deadly pandemic. It is, therefore, essential to understand how these variants gain enhanced ability to evade immune responses with a higher rate of spreading infection. To address this question, here we have individually assessed the effects of SARS-CoV-2 variant-specific spike (S) protein receptor-binding domain (RBD) mutations E484K, K417N, L452Q, L452R, N501Y, and T478K that characterize and differentiate several emerging variants. Despite the hundreds of apparently neutral mutations observed in the domains other than the RBD, we have shown that each RBD mutation site is differentially engaged in an interdomain allosteric network involving mutation sites from a distant domain, affecting interactions with the human receptor angiotensin-converting enzyme-2 (ACE2). This allosteric network couples the residues of the N-terminal domain (NTD) and the RBD, which are modulated by the RBD-specific mutations and are capable of propagating mutation-induced perturbations between these domains through a combination of structural changes and effector-dependent modulations of dynamics. One key feature of this network is the inclusion of compensatory mutations segregated into three characteristically different clusters, where each cluster residue site is allosterically coupled with specific RBD mutation sites. Notably, each RBD mutation acted like a positive allosteric modulator; nevertheless, K417N was shown to have the largest effects among all of the mutations on the allostery and thereby holds the highest binding affinity with ACE2. This result will be useful for designing the targeted control measure and therapeutic efforts aiming at allosteric modulators.