Differential requirement of Formyl Peptide Receptor 1 in macrophages and neutrophils in the host defense against Mycobacterium tuberculosis Infection.

Formyl peptide receptors (FPR), part of the G-protein coupled receptor superfamily, are pivotal in directing phagocyte migration towards chemotactic signals from bacteria and host tissues. Although their roles in acute bacterial infections are well-documented, their involvement in immunity against tuberculosis (TB) remains unexplored. This study investigates the functions of Fpr1 and Fpr2 in defense against Mycobacterium tuberculosis (Mtb), the causative agent of TB. Elevated levels of Fpr1 and Fpr2 were found in the lungs of mice, rabbits and peripheral blood of humans infected with Mtb, suggesting a crucial role in the immune response. The effects of Fpr1 and Fpr2 deletion on bacterial load, lung damage, and cellular inflammation were assessed using a TB model of hypervirulent strain of Mtb from the W-Beijing lineage. While Fpr2 deletion showed no impact on disease outcome, Fpr1-deficient mice demonstrated improved bacterial control, especially by macrophages. Bone marrow-derived macrophages from these Fpr1 -/- mice exhibited an enhanced ability to contain bacterial growth over time. Contrarily, treating genetically susceptible mice with Fpr1-specific inhibitors caused impaired early bacterial control, corresponding with increased bacterial persistence in necrotic neutrophils. Furthermore, ex vivo assays revealed that Fpr1 -/- neutrophils were unable to restrain Mtb growth, indicating a differential function of Fpr1 among myeloid cells. These findings highlight the distinct and complex roles of Fpr1 in myeloid cell-mediated immunity against Mtb infection, underscoring the need for further research into these mechanisms for a better understanding of TB immunity.

A radius valley between migrated steam worlds and evaporated rocky cores.

The radius valley (or gap) in the observed distribution of exoplanet radii, which separates smaller super-Earths from larger sub-Neptunes, is a key feature that theoretical models must explain. Conventionally, it is interpreted as the result of the loss of primordial hydrogen and helium (H/He) envelopes atop rocky cores. However, planet formation models predict that water-rich planets migrate from cold regions outside the snowline towards the star. Assuming water to be in the form of solid ice in their interior, many of these planets would be located in the radius gap contradicting observations. Here we use an advanced coupled formation and evolution model that describes the planets' growth and evolution starting from solid, moon-sized bodies in the protoplanetary disk to mature Gyr-old planetary systems. Employing new equations of state and interior structure models to treat water as vapour mixed with H/He, we naturally reproduce the valley at the observed location. The model results demonstrate that the observed radius valley can be interpreted as the separation of less massive, rocky super-Earths formed in situ from more massive, ex situ, water-rich sub-Neptunes. Furthermore, the occurrence drop at larger radii, the so-called radius cliff, is matched by planets with water-dominated envelopes. Our statistical approach shows that the synthetic distribution of radii quantitatively agrees with observations for close-in planets, but only if low-mass planets initially containing H/He lose their atmosphere due to photoevaporation, which populates the super-Earth peak with evaporated rocky cores. Therefore, we provide a hybrid theoretical explanation of the radius gap and cliff caused by both planet formation (orbital migration) as well as evolution (atmospheric escape).

CRISPR-Cas9: A Potent Gene-editing Tool for the Treatment of Cancer.

The prokaryotic adaptive immune system has clustered regularly interspaced short palindromic repeat. CRISPR-associated protein (CRISPR-Cas) genome editing systems have been harnessed. A robust programmed technique for efficient and accurate genome editing and gene targeting has been developed. Engineered cell therapy, in vivo gene therapy, animal modeling, and cancer diagnosis and treatment are all possible applications of this ground-breaking approach. Multiple genetic and epigenetic changes in cancer cells induce malignant cell growth and provide chemoresistance. The capacity to repair or ablate such mutations has enormous potential in the fight against cancer. The CRISPR-Cas9 genome editing method has recently become popular in cancer treatment research due to its excellent efficiency and accuracy. The preceding study has shown therapeutic potential in expanding our anticancer treatments by using CRISPR-Cas9 to directly target cancer cell genomic DNA in cellular and animal cancer models. In addition, CRISPR-Cas9 can combat oncogenic infections and test anticancer medicines. It may design immune cells and oncolytic viruses for cancer immunotherapeutic applications. In this review, these preclinical CRISPRCas9- based cancer therapeutic techniques are summarised, along with the hurdles and advancements in converting therapeutic CRISPR-Cas9 into clinical use. It will increase their applicability in cancer research.

Deciphering growth abilities of fusarium oxysporum f. sp. pisi under variable temperature, pH and nitrogen.

Fusarium wilt caused by Fusarium oxysporum f. sp. pisi (Fop) is an important disease and major obstacle to pea production, causing huge losses to growers. The focus of this study was on isolation followed by morphological, molecular characterization and analyzing the growth of the casual agent under variable temperature, pH and Nitrogen levels. The morphological features of radial growth, sporulation, pigmentation and mycelial characterization were examined and the variability of all isolates was presented. Molecular characterization of the fungus by ITS rDNA sequencing revealed that all 13 isolates belong to Fusarium oxysporum species. Six isolates were tested for temperature, pH and nitrogen dosage optimization studies. Seven different temperatures, viz., 21, 23, 25, 27, 29, 31, 33°C and pH values, having 3, 4, 5, 6, 7, 8, and 9 pH, as well as nitrogen dosage levels of 0 g, 3 g, 5 g, 7 g, 9 g, 11 g, and 13 g were tested against all six isolates, respectively. The results showed that all isolates exhibited the highest growth at a temperature of 25°C and the optimal temperature range for growth of Fusarium oxysporum was 23-27°C. All isolates showed the highest growth at pH5. Change in the nitrogen doses of the base ended in formation of thick, dense, fluffy mycelium of the casual agent. Six isolates were used for combination studies with seven different levels of temperatures, pH levels and nitrogen dosages. The density plots revealed the variations in the growth of the isolates with changes in temperature, pH and nitrogen levels, which can lead to mutations or genetic changes in the pathogens that could potentially introduce new threats to pea cultivation.

Exosomal miRNAs as novel avenues for breast cancer treatment.

Breast cancer is the most commonly diagnosed cancer and a leading cause of death in women worldwide. It is a heterogeneous disease, as shown by the gene expression profiles of breast cancer samples. It begins in milk-producing ducts, with a high degree of diversity between and within tumors, as well as among cancer-bearing individuals. The enhanced prevalence of breast cancer is influenced by various hormonal, lifestyle, and environmental factors, and very early onset of the disease correlates strongly with the risk of local and distant recurrence. Many subtypes are difficult to treat with conventional therapeutic modalities, and therefore, optimal management and early diagnosis are the first steps to minimizing the mortality linked with breast cancer. The use of newer methods of nanotechnology extends beyond the concept of synthesizing drug delivery mechanisms into the creation of new therapeutics, such as delivering chemotherapeutics with nanomaterial properties. Exosomes, a class of nanovesicles, are emerging as novel tools for deciphering the patient-specific proteins and biomarkers across different disease models, including breast cancer. In this review, we address the role of exosomal miRNA in breast cancer diagnosis and treatment.

Silicon nanoparticles: Synthesis, uptake and their role in mitigation of biotic stress.

In the current scenario of global warming and climate change, plants face many biotic stresses, which restrain growth, development and productivity. Nanotechnology is gaining precedence over other means to deal with biotic and abiotic constraints for sustainable agriculture. One of nature's most beneficial metalloids, silicon (Si) shows ameliorative effect against environmental challenges. Silicon/Silica nanoparticles (Si/SiO2NPs) have gained special attention due to their significant chemical and optoelectronic capabilities. Its mesoporous nature, easy availability and least biological toxicity has made it very attractive to researchers. Si/SiO2NPs can be synthesised by chemical, physical and biological methods and supplied to plants by foliar, soil, or seed priming. Upon uptake and translocation, Si/SiO2NPs reach their destined cells and cause optimum growth, development and tolerance against environmental stresses as well as pest attack and pathogen infection. Using Si/SiO2NPs as a supplement can be an eco-friendly and cost-effective option for sustainable agriculture as they facilitate the delivery of nutrients, assist plants to mitigate biotic stress and enhances plant resistance. This review aims to present an overview of the methods of formulation of Si/SiO2NPs, their application, uptake, translocation and emphasize the role of Si/SiO2NPs in boosting growth and development of plants as well as their conventional advantage as fertilizers with special consideration on their mitigating effects towards biotic stress.

Perspective on the heavy metal pollution and recent remediation strategies.

Heavy metal (HM) pollution is extremely deleterious because of the toxicity they exert on human beings, animals, and plants. HMs are recalcitrant to degradation, and hence persistent in the environment for a longer duration adding to the concern. HMs at high concentrations have adverse effects on the production of food as they affect the metabolic activity of plants. HMs have serious implications for human health, reaching the tissue via direct ingestion, dermal contact, inhalation, and adsorption. Several methods have been explored for the eradication of HMs from the environment. Conventional methods of metal removal are constrained by the processing problems, expenses, and the generation of toxic sludge, therefore more research is now focused on the use of bacteria, fungi, plants, and diatoms for the removal of metal ions from the environment. In this context, this review article sheds light on the distribution of HMs in the environment, their sources, and the ecotoxicity they exert on the environment and living beings. The sustainable remedies to decontaminate the environment and the current knowledge and strategies to minimize HM toxicity are also discussed along with the recent developments in the use of nanoparticles and diatoms for HM removal.

Alternating exosomes and their mimetics as an emergent strategy for targeted cancer therapy.

Exosomes, a subtype of the class of extracellular vesicles and nano-sized particles, have a specific membrane structure that makes them an alternative proposition to combat with cancer through slight modification. As constituents of all most all the primary body fluids, exosomes establish the status of intercellular communication. Exosomes have specific proteins/mRNAs and miRNAs which serve as biomarkers, imparting a prognostic tool in clinical and disease pathologies. They have efficient intrinsic targeting potential and efficacy. Engineered exosomes are employed to deliver therapeutic cargos to the targeted tumor cell or the recipient. Exosomes from cancer cells bring about changes in fibroblast via TGFß/Smad pathway, augmenting the tumor growth. These extracellular vesicles are multidimensional in terms of the functions that they perform. We herein discuss the uptake and biogenesis of exosomes, their role in various facets of cancer studies, cell-to-cell communication and modification for therapeutic and diagnostic use.

Current Status of Our Understanding for Brain Integrated Functions and its Energetics.

Human/animal brain is a unique organ with substantially high metabolism but it contains no energy reserve that is the reason it requires continuous supply of O2 and energy fluxes through CBF. The main source of energy remains glucose as the other biomolecules do not able to cross the blood-brain barrier. The speed of glucose metabolism is heterogeneous throughout the brain. One of the major flux consumption is Neuron-astrocyte cycling of glutamate and glutamine in glutamatergic neurons (approximately 80% of glucose metabolism in brain). The quantification of cellular glucose and other related substrate in resting, activated state can be analyzed through [18 F]FDG -positron-emission tomography (studying CMRglc) and [13 C/31P -MRS: for neuroenergetics & neurotransmitter cycling &31P-MRS: for energy induction & redox state). Merging basic in vitro studies with these techniques will help to develop new treatment paradigms for human brain diseased conditions.

Functional and antioxidant properties of cookies incorporated with foxtail millet and ginger powder.

The functional, sensory, nutritive, phytochemical and antioxidant properties of flours derived from wheat, foxtail millet and ginger along with the cookies formulated from these ingredients was studied. The foxtail millet (20, 30 and 40%) and ginger powder (5, 10 and 15%) blended wheat flours were investigated and compared to control (100% wheat flour). The increase in substitution levels of both the alternatives improved the functional properties of the composite flour and cookies formulated. Sensory analysis revealed that cookies prepared from 30% foxtail millet and 10% ginger powder had comparable scores. These were further subjected to nutritive and phytochemical analyses. The results revealed that cookies formulated using both the alternatives had reasonable proximate composition comparable to control. The substituted cookies had higher total soluble phenolic content and antioxidant capacities in terms of DPPH and ABTS scavenging potential and a strongly positive correlation was observed between the total soluble phenolic content and antioxidant capacities in composite flour and the cookies formulated from the flours. Overall the addition of foxtail millet flour (30%) and ginger powder (10%) improved the nutritional and phenolic linked antioxidant potential which can lead to shelf life extension and enhanced health benefits.

Modified benzoxazolone derivative as 18-kDa TSPO ligand.

We have synthesized six new congeners of acetamidobenzoxazolone for Translocator Protein [18 kDa, TSPO] imaging. The best in vitro binding affinity (10.8 ± 1.2 nm) for TSPO was found for N-methyl-2-(5-(naphthalen-1-yl)-2-oxobenzo[d]oxazol-3(2H)-yl)-N-phenylacetamide, (NBMP). NBMP was synthesised by Suzuki coupling reaction between 2-(5-bromo-2-oxo-1,3-benzoxazol-3(2H)-yl)-N-phenylacetamide and napthalene-1-boronic acid. Computational docking and simulation studies showed not much impact of intersubject variability on binding which is one of the major drawbacks of several TSPO ligands. These findings suggested that NBMP may become a promising marker for visualization of neuroinflammation via TSPO targeting.

Quality attributes, phytochemical profile and storage stability studies of functional ready to serve (RTS) drink made from blend of Aloe vera, sweet lime, amla and ginger.

Aloe vera based RTS formulation was prepared in this study which provides the health benefits of this wonder plant and was also appealing in terms of sensory qualities. In the present study four formulations of A. vera RTS drink with ginger, sweet lime and amla (V1, V2, V3 and V4 were developed). The developed products were subjected to physico-chemical, organoleptic and microbial analysis. The formulation V3 was found to be the most preferred variant with respect to the sensory quality. Further the blends were found to be a good source of vitamin C and other nutritional parameters. The storage stability studies carried out on the formulations showed that the physico-chemical and the sensory qualities of the RTS blends were acceptable after 60 days of storage. Microbial analysis of the RTS blends during the storage period revealed that it was free from any microbial spoilage.

Spectroscopic interaction of a coumarin derivative with bovine serum albumin.

The absorption and fluorescence spectra of the 7-diethylamino-4-methyl coumarin (DAMC) in ethanol-water (1:9 v/v) solution at varying pH values were investigated. The interaction between DAMC and bovine serum albumin (BSA) was investigated by fluorescence spectroscopy. The Stern-Volmer quenching constant, the quenching rate constant of the bimolecular reaction (kq), the binding constant, and number of binding sites are mentioned but not calculated in the paper. Moreover, in a preliminary pharmacological study, DAMC not only remarkably increased cellular apoptosis in a concentration-dependent manner but also clearly induced A549 cell cycle arrest. Thus, these coumarin derivatives merit investigation as novel potential antitumor agents with further structural modification to produce an optimal lead compound and elucidate the detailed pharmacological mechanism.

Antimalarial activity of newly synthesized chalcone derivatives in vitro.

Twenty-seven novel chalcone derivatives were synthesized using Claisen-Schmidt condensation and their antimalarial activity against asexual blood stages of Plasmodium falciparum was determined. Antiplasmodial IC(50) (half-maximal inhibitory concentration) activity of a compound against malaria parasites in vitro provides a good first screen for identifying the antimalarial potential of the compound. The most active compound was 1-(4-benzimidazol-1-yl-phenyl)-3-(2, 4-dimethoxy-phenyl)-propen-1-one with IC(50) of 1.1 µg/mL, while that of the natural phytochemical, licochalcone A is 1.43 µg/mL. The presence of methoxy groups at position 2 and 4 in chalcone derivatives appeared to be favorable for antimalarial activity as compared to other methoxy-substituted chalcones. Furthermore, 3, 4, 5-trimethoxy groups on chalcone derivative probably cause steric hindrance in binding to the active site of cysteine protease enzyme, explaining the relative lower inhibitory activity.

HIV protease inhibitors, indinavir or nelfinavir, augment antimalarial action of artemisinin in vitro.

Most malaria endemic regions are co-infested with HIV infection. Treatment of one may affect outcome of the other in co-infected individuals. HIV protease inhibitors, indinavir or nelfinavir, are important antiretroviral drugs and artemisinin is central to malaria treatment. We show these protease inhibitors augment the antimalarial activity of artemisinin against P. falciparum in vitro.

Antimalarial pharmacodynamics of chalcone derivatives in combination with artemisinin against Plasmodium falciparum in vitro.

Use of artemisinin based combination therapies (ACTs) is increasing in treatment of malaria. Their extensive and indiscriminate deployment will ultimately lead to selection of resistance. Thus, alternate ACTs are needed. We reported in vitro antimalarial potential of chalcone derivatives. A few potent chalcones were selected for their antimalarial interaction in combination with artemisinin in vitro. Combinations evaluated show synergistic or additive interactions. Chalcones act on broad range of asexual stages of the parasite. The synergistic combinations decrease hemozoin formation in parasitized erythrocytes. These combinations do not affect new permeation pathways induced in the host cells. This is the first report showing antiplasmodial interactions between artemisinin and synthetic chalcone azole derivatives. Thus, chalcones and artemisinin combinations open the possibility of novel ACTs.

Phytochemical licochalcone A enhances antimalarial activity of artemisinin in vitro.

Resistance to synthetic first-line antimalarial drugs is considered to be a major cause of increased malaria morbidity and mortality. Use of artemisinin-based combination therapies (ACTs) is being encouraged to reduce the malaria mortality in areas of falciparum resistance. Artemisinin is a natural product at times in short supply. With projected rise in demand of artemisinin there is an unmet need for alternate ACTs. Novel compounds that reduce dependence on artemisinin are required. In vitro cultures of Plasmodium falciparum provide a screen system for identifying and evaluating new drug combinations. Interactions of two phytochemicals, artemisinin and licochalcone A, has been studied against synchronized erythrocytic stages of chloroquine-sensitive 3D7 and chloroquine-resistant RKL 303 strains of P. falciparum. These two compounds in combination show synergistic antiplasmodial activity in vitro on these strains. Artemisinin but not licochalcone A interferes with hemozoin formation. Neither of the phytochemicals alone or in combination obstructs sorbitol-induced hemolysis.

In vitro activity of artemisinin in combination with clotrimazole or heat-treated amphotericin B against Plasmodium falciparum.

Currently available artemisinin-based combination therapies (ACTs) for malaria are inadequate. There remains an enormous unmet need for alternate artemisinin-based combination therapies. One of the fastest methods to identify promising artemisinin-based combination therapies is to look for synergistic or additive antimalarial interaction between artemisinin and an alternate drug against P. falciparum in vitro. Amphotericin B and clotrimazole are known drugs for treatment of human fungal infections. We repurposed clotrimazole or heat-treated amphotericin B in fixed ratio combination with artemisinin for antimalarial properties. Isobologram results show synergistic/additive interaction in both of the cases at therapeutically safe concentrations. Artemisinin, clotrimazole, and their synergistic combinations also decrease hemozoin production in parasitized erythrocytes. New permeation pathways induced in infected cells remain unaffected by drug combinations as indicated by sorbitol lysis. It would be interesting to extend the studies' in vivo system.

Synthesis of novel substituted 1,3-diaryl propenone derivatives and their antimalarial activity in vitro.

The synthesis of novel 1,3-diaryl propenone derivatives and their antimalarial activity in vitro against asexual blood stages of human malaria parasite, Plasmodium falciparum, are described. Chalcone derivatives were prepared via Claisen-Schmidt condensation of substituted aldehydes with substituted methyl ketones. Antiplasmodial IC(50) (half maximal inhibitory concentration) activity of these compounds ranged between 1.5 and 12.3 microg/ml. The chloro-series, 1,2,4-triazole substituted chalcone was found to be the most effective in inhibiting the growth of P. falciparum in vitro while pyrrole and benzotriazole substituted chalcones showed relatively less inhibitory activity. This is the first report on antiplasmodial activity of chalcones with azoles on acetophenone ring.

Antiplasmodial interactions between artemisinin and triclosan or ketoconazole combinations against blood stages of Plasmodium falciparum in vitro.

Emergence of drug-resistant Plasmodium falciparum strains to conventional first-line antimalarial drugs has compelled many countries to reorient their drug policies to adopt artemisinin-based combination therapies (ACTs) for treatment of uncomplicated malaria. This has increased the demand of artemisinin, already a scarce commodity. Synthesis of artemisinin is not yet commercially viable. Extensive use of available ACTs will invariably lead to emergence of resistance to these combinations. Thus, there is need to search for new artemisinin-based synthetic, inexpensive, synergistic combinations to reduce dependence on artemisinin. In vitro cultures of P. falciparum provide an appropriate system for identification of such new combinations. We evaluated interactions of artemisinin with triclosan or ketoconazole against blood stages of P. falciparum by a fixed-ratio isobologram method. Artemisinin shows mild synergistic interaction with triclosan and slight to marked antagonism with ketoconazole in vitro. These antiplasmodial interactions, however, require confirmation using in vivo model systems.