Dysfunction of complement receptors CR3 (CD11b/18) and CR4 (CD11c/18) in pre-eclampsia: a genetic and functional study.

OBJECTIVE: To study genetic variants and their function within genes coding for complement receptors in pre-eclampsia. DESIGN: A case-control study. SETTING: Pre-eclampsia is a common vascular disease of pregnancy. The clearance of placenta-derived material is one of the functions of the complement system in pregnancy. POPULATION: We genotyped 500 women with pre-eclamptic pregnancies and 190 pregnant women without pre-eclampsia, as controls, from the FINNPEC cohort, and 122 women with pre-eclamptic pregnancies and 1905 controls from the national FINRISK cohort. METHODS: The functional consequences of genotypes discovered by targeted exomic sequencing were explored by analysing the binding of the main ligand iC3b to mutated CR3 or CR4, which were transiently expressed on the surface of COS-1 cells. MAIN OUTCOME MEASURES: Allele frequencies were compared between pre-eclamptic pregnancies and controls in genetic studies. The functional consequences of selected variants were measured by binding assays. RESULTS: The most significantly pre-eclampsia-linked CR3 variant M441K (P = 4.27E-4, OR = 1.401, 95% CI = 1.167-1.682) displayed a trend of increased adhesion to iC3b (P = 0.051). The CR4 variant A251T was found to enhance the adhesion of CR4 to iC3b, whereas W48R resulted in a decrease of the binding of CR4 to iC3b. CONCLUSIONS: Results suggest that changes in complement-facilitated phagocytosis are associated with pre-eclampsia. Further studies are needed to ascertain whether aberrant CR3 and CR4 activity leads to altered pro- and anti-inflammatory cytokine responses in individuals carrying the associated variants, and the role of these receptors in pre-eclampsia pathogenesis. TWEETABLE ABSTRACT: Genetic variants of complement receptors CR3 and CR4 have functional consequences that are associated with pre-eclampsia.

Direct Observations of Particle Dynamics in Magnetized Collisionless Shock Precursors in Laser-Produced Plasmas.

We present the first laboratory observations of time-resolved electron and ion velocity distributions in magnetized collisionless shock precursors. Thomson scattering of a probe laser beam was used to observe the interaction of a laser-driven, supersonic piston plasma expanding through an ambient plasma in an external magnetic field. From the Thomson-scattered spectra we measure time-resolved profiles of electron density, temperature, and ion flow speed, as well as spatially resolved magnetic fields from proton radiography. We observe direct evidence of the coupling between piston and ambient plasmas, including the acceleration of ambient ions driven by magnetic and pressure gradient electric fields, and deformation of the piston ion flow, key steps in the formation of magnetized collisionless shocks. Even before a shock has fully formed, we observe strong density compressions and electron heating associated with the pileup of piston ions. The results demonstrate that laboratory experiments can probe particle velocity distributions relevant to collisionless shocks, and can complement, and in some cases overcome, the limitations of similar measurements undertaken by spacecraft missions.

Biermann-Battery-Mediated Magnetic Reconnection in 3D Colliding Plasmas.

Recent experiments have demonstrated magnetic reconnection between colliding plasma plumes, where the reconnecting magnetic fields were self-generated in the plasma by the Biermann-battery effect. Using fully kinetic 3D simulations, we show the full evolution of the magnetic fields and plasma in these experiments, including self-consistent magnetic field generation about the expanding plume. The collision of the two plasmas drives the formation of a current sheet, where reconnection occurs in a strongly time- and space-dependent manner, demonstrating a new 3D reconnection mechanism. Specifically, we observe a fast, vertically localized Biermann-mediated reconnection, an inherently 3D process where the temperature profile in the current sheet coupled with the out-of-plane ablation density profile conspires to break inflowing field lines, reconnecting the field downstream. Fast reconnection is sustained by both the Biermann effect and the traceless electron pressure tensor, where the development of plasmoids appears to modulate the contribution of the latter. We present a simple and general formulation to consider the relevance of Biermann-mediated reconnection in general astrophysical scenarios.

The feasibility of putrescible components of municipal solid waste for biomethane production at Hyderabad, Pakistan.

This study analyzes the feasibility of putrescible components of municipal solid waste (PCMSW) such as food waste (FW) and yard waste (YW) for methane production in Pakistan. The batch experiments have been conducted at two different inoculums to substrate ratios (ISRs) by using various inoculums under mesophilic condition. The highest methane yield of FW and YW is achieved to be 428 Nml g-1 volatile solids (VS) added and 304 Nml g-1 VS added respectively by using buffalo dung inoculum at ISR-5. While, lowest methane yield of FW and YW is obtained as 236 Nml g-1 VS added and 151Nml g-1 VS added respectively by using effluent from a continuous stirrer tank reactor as inoculum at ISR-3. The first order decay model has been introduced, which gives best fit for methane potential of PCMSW with buffalo dung inoculum. Additionally, the feasibility of PCMSW in terms of power generation potential has been analyzed. About 60.63 million m3/year energy can be generated by converting PCMSW into methane gas leading to power generation. The finding of this study concludes that the replacement of imported energy and reduction up to 1.62% in other primary energy sources would be achieved, if PCMSW are properly converted into energy through anaerobic digestion in Pakistan.

Generation and Evolution of High-Mach-Number Laser-Driven Magnetized Collisionless Shocks in the Laboratory.

We present the first laboratory generation of high-Mach-number magnetized collisionless shocks created through the interaction of an expanding laser-driven plasma with a magnetized ambient plasma. Time-resolved, two-dimensional imaging of plasma density and magnetic fields shows the formation and evolution of a supercritical shock propagating at magnetosonic Mach number M_{ms}≈12. Particle-in-cell simulations constrained by experimental data further detail the shock formation and separate dynamics of the multi-ion-species ambient plasma. The results show that the shocks form on time scales as fast as one gyroperiod, aided by the efficient coupling of energy, and the generation of a magnetic barrier between the piston and ambient ions. The development of this experimental platform complements present remote sensing and spacecraft observations, and opens the way for controlled laboratory investigations of high-Mach number collisionless shocks, including the mechanisms and efficiency of particle acceleration.

Molecular docking of the anticancer bioactive compound proceraside with macromolecules involved in the cell cycle and DNA replication.

The bioactive compounds proceraside A, frugoside and calotropin, which were extracted from the root bark of Calotropis procera (Aiton) W.T. Aiton (family Asclepiadaceae), were recently reported to inhibit the growth of inhibition against various human cancer cell lines in vitro. However, their modes of action have not been clearly defined. Therefore, we attempted an in silico approach to gain insights into their binding modes against the following selected molecular targets: CDK-2, CDK-6, topoisomerase I, BCL-2, VEGFR-2, telomere: G-quadruplex, and topoisomerase II. These targets were selected based on their key roles in cancer progression via the regulation of the cell cycle and DNA replication. Molecular-docking analyses revealed that proceraside A was the best docked ligand against all the targets, with the exception of telomere-G: quadruplex. Furthermore, it displayed the lowest binding energies and inhibition constants, and critical hydrogen bonds and hydrophobic interactions with the targets were also revealed. The present study may aid in the identification of possible targets for proceraside A, and might provide a plausible explanation for its proven anti-tumor activities. Moreover, the result of this study may further guide structure-activity relationship studies used to generate more potent target-specific inhibitors.

Target fishing of glycopentalone using integrated inverse docking and reverse pharmacophore mapping approach.

Glycopentalone isolated from Glycosmis pentaphylla (family Rutaceae) has cytotoxic and apoptosis inducing effects in various human cancer cell lines; however, its mode of action is not known. Therefore, target fishing of glycopentalone using a combined approach of inverse docking and reverse pharmacophore mapping approach was used to identify potential targets of glycopentalone, and gain insight into its binding modes against the selected molecular targets, viz., CDK-2, CDK-6, Topoisomerase I, Bcl-2, VEGFR-2, Telomere:G-quadruplex and Topoisomerase II. These targets were chosen based on their key roles in the progression of cancer via regulation of cell cycle and DNA replication. Molecular docking analysis revealed that glycopentalone displayed binding energies ranging from -6.38 to -8.35 kcal/mol and inhibition constants ranging from 0.758 to 20.90 µM. Further, the binding affinities of glycopentalone to the targets were in the order: Telomere:G-quadruplex > VEGFR-2 > CDK-6 > CDK-2 > Topoisomerase II > Topoisomerase I > Bcl-2. Binding mode analysis revealed critical hydrogen bonds as well as hydrophobic interactions with the targets. The targets were validated by reverse pharmacophore mapping of glycopentalone against a set of 2241 known human target proteins which revealed CDK-2 and VEGFR-2 as the most favorable targets. The glycopentalone was well mapped to CDK-2 and VEGFR-2 which involve six pharmacophore features (two hydrophobic centers and four hydrogen bond acceptors) and nine pharmacophore features (five hydrophobic, two hydrogen bond acceptors and two hydrogen bond donors), respectively. The present computational approach may aid in rational identification of targets for small molecules against large set of candidate macromolecules before bioassays validation.

Microbes bind complement inhibitor factor H via a common site.

To cause infections microbes need to evade host defense systems, one of these being the evolutionarily old and important arm of innate immunity, the alternative pathway of complement. It can attack all kinds of targets and is tightly controlled in plasma and on host cells by plasma complement regulator factor H (FH). FH binds simultaneously to host cell surface structures such as heparin or glycosaminoglycans via domain 20 and to the main complement opsonin C3b via domain 19. Many pathogenic microbes protect themselves from complement by recruiting host FH. We analyzed how and why different microbes bind FH via domains 19-20 (FH19-20). We used a selection of FH19-20 point mutants to reveal the binding sites of several microbial proteins and whole microbes (Haemophilus influenzae, Bordetella pertussis, Pseudomonas aeruginosa, Streptococcus pneumonia, Candida albicans, Borrelia burgdorferi, and Borrelia hermsii). We show that all studied microbes use the same binding region located on one side of domain 20. Binding of FH to the microbial proteins was inhibited with heparin showing that the common microbial binding site overlaps with the heparin site needed for efficient binding of FH to host cells. Surprisingly, the microbial proteins enhanced binding of FH19-20 to C3b and down-regulation of complement activation. We show that this is caused by formation of a tripartite complex between the microbial protein, FH, and C3b. In this study we reveal that seven microbes representing different phyla utilize a common binding site on the domain 20 of FH for complement evasion. Binding via this site not only mimics the glycosaminoglycans of the host cells, but also enhances function of FH on the microbial surfaces via the novel mechanism of tripartite complex formation. This is a unique example of convergent evolution resulting in enhanced immune evasion of important pathogens via utilization of a "superevasion site."

Statistical simulation of the magnetorotational dynamo.

Turbulence and dynamo induced by the magnetorotational instability (MRI) are analyzed using quasilinear statistical simulation methods. It is found that homogenous turbulence is unstable to a large-scale dynamo instability, which saturates to an inhomogenous equilibrium with a strong dependence on the magnetic Prandtl number (Pm). Despite its enormously reduced nonlinearity, the dependence of the angular momentum transport on Pm in the quasilinear model is qualitatively similar to that of nonlinear MRI turbulence. This demonstrates the importance of the large-scale dynamo and suggests how dramatically simplified models may be used to gain insight into the astrophysically relevant regimes of very low or high Pm.

Generation of Large-Scale Magnetic Fields by Small-Scale Dynamo in Shear Flows.

We propose a new mechanism for a turbulent mean-field dynamo in which the magnetic fluctuations resulting from a small-scale dynamo drive the generation of large-scale magnetic fields. This is in stark contrast to the common idea that small-scale magnetic fields should be harmful to large-scale dynamo action. These dynamos occur in the presence of a large-scale velocity shear and do not require net helicity, resulting from off-diagonal components of the turbulent resistivity tensor as the magnetic analogue of the "shear-current" effect. Given the inevitable existence of nonhelical small-scale magnetic fields in turbulent plasmas, as well as the generic nature of velocity shear, the suggested mechanism may help explain the generation of large-scale magnetic fields across a wide range of astrophysical objects.

Role of Ion Kinetic Physics in the Interaction of Magnetic Flux Ropes.

To explain many natural magnetized plasma phenomena, it is crucial to understand how rates of collisionless magnetic reconnection scale in large magnetohydrodynamic (MHD) scale systems. Simulations of isolated current sheets conclude such rates are independent of system size and can be reproduced by the Hall-MHD model, but neglect sheet formation and coupling to MHD scales. Here, it is shown for the problem of flux-rope merging, which includes this formation and coupling, that the Hall-MHD model fails to reproduce the kinetic results. The minimum sufficient model must retain ion kinetic effects, which set the ion diffusion region geometry and give time-averaged rates that reduce significantly with system size, leading to different global evolution in large systems.

Interactome analysis and design of inhibitors against selected protein targets of Ser/Thr protein kinase (STPK) signaling pathways in Mycobacterium tuberculosis H37Rv.

Tuberculosis continues to be a major cause of mortality worldwide despite significant advances in chemotherapy and development of the BCG vaccine. Although curable, the tuberculosis treatment period (6-9 months) presents many concerns, including patient noncompliance and the development of drug toxicity and drug resistance. This study aimed to understand the protein-protein interactions of key proteins involved in the Mycobacterium tuberculosis STPK signal transduction pathway (such as PknB, PknE, and PstP); in addition, we attempted to identify promising leads for the inhibition of protein-protein interactions. Interactome analyses revealed the interactions of these protein targets with several other proteins, including PknG and PbpA. Drug-like candidates were screened based on Lipinski's rule of five and the absorption digestion metabolism excretion toxicity. Molecular docking of the target proteins with the selected ligands identified cryptolepine HCl to be a common molecule interacting with all protein targets (with a good docking score). The generation of a pharmacophore model for cryptolepine HCl revealed three pharmacophoric regions: aromatic hydrocarbon, hydrogen bond acceptor, and hydrogen bond donor, which play important roles in its interaction with the protein targets. Therefore, cryptolepine HCl appears to be a promising drug candidate for further optimization and validation against M. tuberculosis.

Nonmodal growth of the magnetorotational instability.

We analyze the linear growth of the magnetorotational instability (MRI) in the short-time limit using nonmodal methods. Our findings are quite different from standard results, illustrating that shearing wave energy can grow at the maximum MRI rate -dΩ/dlnr for any choice of azimuthal and vertical wavelengths. In addition, by comparing the growth of shearing waves with static structures, we show that over short time scales shearing waves will always be dynamically more important than static structures in the ideal limit. By demonstrating that fast linear growth is possible at all wavelengths, these results suggest that nonmodal linear physics could play a fundamental role in MRI turbulence.

Helicity-flux-driven α effect in laboratory and astrophysical plasmas.

The constraint imposed by magnetic helicity conservation on the α effect is considered for both magnetically and flow dominated self-organizing plasmas. Direct numerical simulations are presented for a dominant contribution to the α effect, which can be cast in the functional form of a total divergence of an averaged helicity flux, called the helicity-flux-driven α (Hα) effect. Direct numerical simulations of the Hα effect are presented for two examples-the magnetically dominated toroidal plasma unstable to tearing modes, and the flow-dominated accretion disk.

Magnetic reconnection in plasma under inertial confinement fusion conditions driven by heat flux effects in Ohm's law.

In the interaction of high-power laser beams with solid density plasma there are a number of mechanisms that generate strong magnetic fields. Such fields subsequently inhibit or redirect electron flows, but can themselves be advected by heat fluxes, resulting in complex interplay between thermal transport and magnetic fields. We show that for heating by multiple laser spots reconnection of magnetic field lines can occur, mediated by these heat fluxes, using a fully implicit 2D Vlasov-Fokker-Planck code. Under such conditions, the reconnection rate is dictated by heat flows rather than Alfvènic flows. We find that this mechanism is only relevant in a high ß plasma. However, the Hall parameter ωcτei can be large so that thermal transport is strongly modified by these magnetic fields, which can impact longer time scale temperature homogeneity and ion dynamics in the system.

Magnetic reconnection between colliding magnetized laser-produced plasma plumes.

Observations of magnetic reconnection between colliding plumes of magnetized laser-produced plasma are presented. Two counterpropagating plasma flows are created by irradiating oppositely placed plastic (CH) targets with 1.8-kJ, 2-ns laser beams on the Omega EP Laser System. The interaction region between the plumes is prefilled with a low-density background plasma and magnetized by an externally applied magnetic field, imposed perpendicular to the plasma flow, and initialized with an X-type null point geometry with B=0 at the midplane and B=8 T at the targets. The counterflowing plumes sweep up and compress the background plasma and the magnetic field into a pair of magnetized ribbons, which collide, stagnate, and reconnect at the midplane, allowing the first detailed observations of a stretched current sheet in laser-driven reconnection experiments. The dynamics of current sheet formation are in good agreement with first-principles particle-in-cell simulations that model the experiments.

q-RASTR modelling for prediction of diverse toxic chemicals towards T. pyriformis.

A series of diverse organic compounds impose serious detrimental effects on the health of living organisms and the environment. Determination of the structural aspects of compounds that impart toxicity and evaluation of the same is crucial before public usage. The present study aims to determine the structural characteristics of compounds for Tetrahymena pyriformis toxicity using the q-RASTR (Quantitative Read Across Structure-Toxicity Relationship) model. It was developed using RASTR and 2-D descriptors for a dataset of 1792 compounds with defined endpoint (pIGC50) against a model organism, T. pyriformis. For the current study, the whole dataset was divided based on activity/property into the training and test sets, and the q-RASTR model was developed employing six descriptors (three latent variables) having r2, Q2F1 and Q2 values of 0.739, 0.767, and 0.735, respectively. The generated model was thoroughly validated using internationally recognized internal and external validation criteria to assess the model's dependability and predictability. It was highlighted that high molecular weight, aromatic hydroxyls, nitrogen, double bonds, and hydrophobicity increase the toxicity of organic compounds. The current study demonstrates the applicability of the RASTR algorithm in QSTR model development for the prediction of toxic chemicals (pIGC50) towards T. pyriformis.

Etiological spectrum and diagnostic challenges of short-duration fever in West Bengal (India). A cross-sectional tertiary care study.

INTRODUCTION: The scarcity of epidemiological data on acute febrile illnesses from South Asia impairs evidence-based clinical decision-making. Our study aimed to explore the etiological spectrum of short-duration fever in patients admitted to a tertiary care hospital in West Bengal, India. METHODS: We conducted a cross-sectional study from May 2021 to April 2022 involving 150 adult patients presenting with a fever lasting less than two weeks at Burdwan Medical College and Hospital (West Bengal, India). We performed comprehensive clinical assessments, including microbiological, serological, and other specific investigations, to identify the causes of the fever. RESULTS: The demographic profile predominantly included individuals aged 21-40 years, with a male-to-female ratio of 1.9:1; 60.7% of participants were from rural areas. The primary etiological agents identified were scrub typhus (25.3%), dengue (15.3%), and enteric fever (13.3%). Notably, 80% of patients presented with non-localizing symptoms, while 14.7% had respiratory symptoms. Blood cultures pinpointed Salmonella typhi and Staphylococcus aureus in a minority of cases (3.3%); malaria, primarily Plasmodium vivax, was diagnosed in 12% of the cases. CONCLUSION: Our findings highlight the complexity of diagnosing short-duration fevers, dominated by a wide range of etiological agents, with a notable prevalence of scrub typhus. These results underscore the urgent need for enhanced diagnostic facilities, including the availability of scrub typhus testing at primary healthcare centers. We recommend empirical doxycycline therapy for suspected cases and emphasize the need for further research to develop management guidelines for acute febrile illnesses. This study also highlights the importance of raising both community and clinician awareness to prevent irrational antibiotic use.

Filamentation instability of counterstreaming laser-driven plasmas.

Filamentation due to the growth of a Weibel-type instability was observed in the interaction of a pair of counterstreaming, ablatively driven plasma flows, in a supersonic, collisionless regime relevant to astrophysical collisionless shocks. The flows were created by irradiating a pair of opposing plastic (CH) foils with 1.8 kJ, 2-ns laser pulses on the OMEGA EP Laser System. Ultrafast laser-driven proton radiography was used to image the Weibel-generated electromagnetic fields. The experimental observations are in good agreement with the analytical theory of the Weibel instability and with particle-in-cell simulations.

Intuitionistic Fuzzy Weighted Least Squares Twin SVMs.

Fuzzy membership is an effective approach used in twin support vector machines (SVMs) to reduce the effect of noise and outliers in classification problems. Fuzzy twin SVMs (TWSVMs) assign membership weights to reduce the effect of outliers, however, it ignores the positioning of the input data samples and hence fails to distinguish between support vectors and noise. To overcome this issue, intuitionistic fuzzy TWSVM combined the concept of intuitionistic fuzzy number with TWSVMs to reduce the effect of outliers and distinguish support vectors from noise. Despite these benefits, TWSVMs and intuitionistic fuzzy TWSVMs still suffer from some drawbacks as: 1) the local neighborhood information is ignored among the data points and 2) they solve quadratic programming problems (QPPs), which is computationally inefficient. To overcome these issues, we propose a novel intuitionistic fuzzy weighted least squares TWSVMs for classification problems. The proposed approach uses local neighborhood information among the data points and also uses both membership and nonmembership weights to reduce the effect of noise and outliers. The proposed approach solves a system of linear equations instead of solving the QPPs which makes the model more efficient. We evaluated the proposed intuitionistic fuzzy weighted least squares TWSVMs on several benchmark datasets to show the efficiency of the proposed model. Statistical analysis is done to quantify the results statistically. As an application, we used the proposed model for the diagnosis of Schizophrenia disease.