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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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

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., Competing Interests: Declaration of competing interest All authors declare that they have no actual or potential competing financial interests. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Diruthenium paddlewheel complexes supported by electron-rich anilinopyridinate (Xap) ligands were synthesized in the course of the first in-depth structural and spectroscopic interrogation of monocationic [Ru 2 (Xap) 4 Cl] + species in the Ru 2 6+ oxidation state. Despite paramagnetism of the compounds, 1 H NMR spectroscopy proved highly informative for determining the isomerism of the Ru 2 5+ and Ru 2 6+ compounds. While most compounds are found to have the polar (4,0) geometry, with all four Xap ligands in the same orientation, some synthetic procedures resulted in a mixture of (4,0) and (3,1) isomers, most notably in the case of the parent compound Ru 2 (ap) 4 Cl. The isomerism of this compound has been overlooked in previous reports. Electrochemical studies demonstrate that oxidation potentials can be tuned by the installation of electron donating groups to the ligands, increasing accessibility of the Ru 2 6+ oxidation state. The resulting Ru 2 6+ monocations were found to have the expected (π*) 2 ground state, and an in-depth study of the electronic transitions by Vis/NIR absorption and MCD spectroscopies with the aid of TD-DFT allowed for the assignment of the electronic spectra. The empty δ* orbital is the major acceptor orbital for the most prominent electronic transitions. Both Ru 2 5+ and Ru 2 6+ compounds were studied by Ru K-edge X-ray absorption spectroscopy; however, the rising edge energy is insensitive to redox changes in the compounds due to the broad line shape observed for 4d transition metal K-edges. DFT calculations indicate the presence of ligand orbitals at the frontier level, suggesting that further oxidation beyond Ru 2 6+ will be ligand-centered rather than metal-centered.

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., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)

The noncanonical heme oxygenase MhuD from Mycobacterium tuberculosis binds a heme substrate that adopts a dynamic equilibrium between planar and out-of-plane ruffled conformations. MhuD degrades this substrate to an unusual mycobilin product via successive monooxygenation and dioxygenation reactions. This article establishes a causal relationship between heme substrate dynamics and MhuD-catalyzed heme degradation, resulting in a refined enzymatic mechanism. UV/vis absorption (Abs) and electrospray ionization mass spectrometry (ESI-MS) data demonstrated that a second-sphere substitution favoring the population of the ruffled heme conformation changed the rate-limiting step of the reaction, resulting in a measurable buildup of the monooxygenated meso-hydroxyheme intermediate. In addition, UV/vis Abs and ESI-MS data for a second-sphere variant that favored the planar substrate conformation showed that this change altered the enzymatic mechanism resulting in an α-biliverdin product. Single-turnover kinetic analyses for three MhuD variants revealed that the rate of heme monooxygenation depends upon the population of the ruffled substrate conformation. These kinetic analyses also revealed that the rate of meso-hydroxyheme dioxygenation by MhuD depends upon the population of the planar substrate conformation. Thus, the ruffled heme conformation supports rapid heme monooxygenation by MhuD, but further oxygenation to the mycobilin product is inhibited. In contrast, the planar substrate conformation exhibits altered heme monooxygenation regiospecificity followed by rapid oxygenation of meso-hydroxyheme. Altogether, these data yielded a refined enzymatic mechanism for MhuD where access to both substrate conformations is needed for rapid incorporation of three oxygen atoms into heme yielding mycobilin.

The measurement of carbon dioxide (CO 2 ) fluxes using the eddy covariance technique is difficult in forests in complex terrain because of the horizontal advection of CO 2 at night. This results the under- or overestimation of net ecosystem exchanges of CO 2 . We propose a technique for nighttime filtering (and correction) of CO 2 fluxes to eliminate (and replace) those significantly affected by horizontal advection: the modified moving point test method. This was developed by merging the friction velocity filtering and van Gorsel methods. It is based on an approach using moving windows for time and friction velocity, allowing a nighttime CO 2 flux correction that includes an assessment of CO 2 drainage at midnight. We tested the method using datasets from two flux towers in forests in hilly and complex terrains, where the application of generic nighttime filtering methods is difficult because CO 2 drainage is generated earlier than the time assumed by the generic methods. The method produced carbon budgets consistent with previous research results, while showing improved applicability. •We propose a nighttime CO 2 flux filtering method for hilly and complex terrain that combines the friction velocity filtering and van Gorsel methods.•This method determines the friction velocity threshold and the significance of CO 2 drainage at midnight based on an approach using moving windows for time and friction velocity.•The method produced consistent results and shows improved applicability.

MhuD is a protein found in mycobacteria that can bind up to two heme molecules per protein monomer and catalyze the degradation of heme to mycobilin in vitro. Here the Kd1 for heme dissociation from heme-bound MhuD was determined to be 7.6 ± 0.8 nM and the Kd2 for heme dissocation from diheme-bound MhuD was determined to be 3.3 ± 1.1 μM. These data strongly suggest that MhuD is a competent heme oxygenase in vivo.

Objective: To discuss the various factors which cause the common skin flap complications after radical operation for breast cancer., Methods: Two hundred sixteen patients with T1-3N0-1M0 breast cancer underwent radical surgery at The Cancer Hospital of Xingtai City, China during 1995-2003. Patey mastectomy was performed in majority of patients. Skin flaps were dissected using scalpel after injecting adrenaline containing saline into subcutaneous tissue. Diathermy was used only to stop bleeding vessels. A subset of patients who developed abnormal vascularity of skin flaps, seroma collection and flap necrosis was analyzed. Pressure garment and suction drains were used routinely. Flap necrosis < 3cm(2) was allowed to heal with secondary intention whereas larger defects were skin grafted., Results: In 56 patients, flap associated complications were noted. Abnormal vascularity, flap necrosis and seroma collection were absorbed in 34 (15.7%), 13 (6%) and 9 (4.2%) patients, respectively. Eight patients (3.7%) required skin grafting. All patients were discharged with full recovery., Conclusion: To minimize the skin flap complications after radical surgery for breast cancer, lesser use of cautery, injection of adrenaline containing solution into subcutaneous tissue, routine use of suction drains and application of pressure garment may be recommended.