Soil microbes: a natural solution for mitigating the impact of climate change.

Soil microbes are microscopic organisms that inhabit the soil and play a significant role in various ecological processes. They are essential for nutrient cycling, carbon sequestration, and maintaining soil health. Importantly, soil microbes have the potential to sequester carbon dioxide (CO2) from the atmosphere through processes like carbon fixation and storage in organic matter. Unlocking the potential of microbial-driven carbon storage holds the key to revolutionizing climate-smart agricultural practices, paving the way for sustainable productivity and environmental conservation. A fascinating tale of nature's unsung heroes is revealed by delving into the realm of soil microbes. The guardians of the Earth are these tiny creatures that live beneath our feet and discreetly work their magic to fend off the effects of climate change. These microbes are also essential for plant growth enhancement through their roles in nutrient uptake, nitrogen fixation, and synthesis of growth-promoting chemicals. By understanding and managing soil microbial communities, it is possible to improve soil health, soil water-holding capacity, and promote plant growth in agricultural and natural ecosystems. Added to it, these microbes play an important role in biodegradation, bioremediation of heavy metals, and phytoremediation, which in turn helps in treating the contaminated soils. Unfortunately, climate change events affect the diversity, composition, and metabolism of these microbes. Unlocking the microbial potential demands an interdisciplinary endeavor spanning microbiology, ecology, agronomy, and climate science. It is a call to arms for the scientific community to recognize soil microbes as invaluable partners in the fight against climate change. By implementing data-driven land management strategies and pioneering interventions, we possess the means to harness their capabilities, paving the way for climate mitigation, sustainable agriculture, and promote ecosystem resilience in the imminent future.

Druggable genome in attention deficit/hyperactivity disorder and its co-morbid conditions. New avenues for treatment.

Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder with only symptomatic care available. Genome-wide association (GWA) studies can provide a starting point in the search for novel drug targets and possibilities of drug repurposing. Here, we explored the druggable genome in ADHD by utilising GWA studies on ADHD and its co-morbid conditions. First, we explored whether the genes targeted by current ADHD drugs show association with the disorder and/or its co-morbidities. Second, we aimed to identify genes and pathways involved in the biological processes underlying ADHD that can be targeted by pharmacological agents. These ADHD-associated druggable genes and pathways were also examined in co-morbidities of ADHD, as commonalities in their aetiology and management may lead to novel pharmacological insights. Strikingly, none of the genes encoding targets of first-line pharmacotherapeutics for ADHD were significantly associated with the disorder, suggesting that FDA-approved ADHD drugs may act through different mechanisms than those underlying ADHD. In the examined druggable genome, three loci on chromosomes 1, 4 and 12 revealed significant association with ADHD and contained nine druggable genes, five of which encode established drug targets for malignancies, autoimmune and neurodevelopmental disorders. To conclude, we present a framework to assess the druggable genome in a disorder, exemplified by ADHD. We highlight signal transduction and cell adhesion as potential novel avenues for ADHD treatment. Our findings add to knowledge on known ADHD drugs and present the exploration of druggable genome associated with ADHD, which may offer interventions at the aetiological level of the disorder.

Cysteine Modification by Ebselen Reduces the Stability and Cellular Levels of 14-3-3 Proteins.

The 14-3-3 proteins constitute a family of adaptor proteins with many binding partners and biological functions, and they are considered promising drug targets in cancer and neuropsychiatry. By screening 1280 small-molecule drugs using differential scanning fluorimetry (DSF), we found 15 compounds that decreased the thermal stability of 14-3-3ζ Among these compounds, ebselen was identified as a covalent, destabilizing ligand of 14-3-3 isoforms ζ, ε, γ, and η Ebselen bonding decreased 14-3-3ζ binding to its partner Ser19-phosphorylated tyrosine hydroxylase. Characterization of site-directed mutants at cysteine residues in 14-3-3ζ (C25, C94, and C189) by DSF and mass spectroscopy revealed covalent modification by ebselen of all cysteines through a selenylsulfide bond. C25 appeared to be the preferential site of ebselen interaction in vitro, whereas modification of C94 was the main determinant for protein destabilization. At therapeutically relevant concentrations, ebselen and ebselen oxide caused decreased 14-3-3 levels in SH-SY5Y cells, accompanied with an increased degradation, most probably by the ubiquitin-dependent proteasome pathway. Moreover, ebselen-treated zebrafish displayed decreased brain 14-3-3 content, a freezing phenotype, and reduced mobility, resembling the effects of lithium, consistent with its proposed action as a safer lithium-mimetic drug. Ebselen has recently emerged as a promising drug candidate in several medical areas, such as cancer, neuropsychiatric disorders, and infectious diseases, including coronavirus disease 2019. Its pleiotropic actions are attributed to antioxidant effects and formation of selenosulfides with critical cysteine residues in proteins. Our work indicates that a destabilization of 14-3-3 may affect the protein interaction networks of this protein family, contributing to the therapeutic potential of ebselen. SIGNIFICANCE STATEMENT: There is currently great interest in the repurposing of established drugs for new indications and therapeutic targets. This study shows that ebselen, which is a promising drug candidate against cancer, bipolar disorder, and the viral infection coronavirus disease 2019, covalently bonds to cysteine residues in 14-3-3 adaptor proteins, triggering destabilization and increased degradation in cells and intact brain tissue when used in therapeutic concentrations, potentially explaining the behavioral, anti-inflammatory, and antineoplastic effects of this drug.

Total Synthesis of Phorbazole B.

Phorbazoles are polychlorinated heterocyclic secondary metabolites isolated from a marine sponge and several of these natural products have shown inhibitory activity against cancer cells. In this work, a synthesis of the trichlorinated phorbazole B using late stage electrophilic chlorination was developed. The synthesis relied on the use of an oxazole precursor, which was protected with an iodine in the reactive 4-position, followed by complete chlorination of all pyrrole positions. Attempts to prepare phorbazole A and C, which contain a 3,4-dichlorinated pyrrole, were unsuccessful as the desired chlorination pattern on the pyrrole could not be obtained. The identities of the dichlorinated intermediates and products were determined using NMR techniques including NOESY/ROESY, 1,1-ADEQUATE and high-resolution CLIP-HSQMBC.

Cysteine capped copper/molybdenum bimetallic nanoclusters for fluorometric determination of methotrexate via the inner filter effect.

A method is reported for the synthesis of highly luminescent copper/molybdenum bimetallic nanoclusters (Cu/Mo NCs) using cysteine as both a capping and reducing agent. The nanoclusters display bluish-green luminescence (excitation/emission peaks at 370/490 nm) and a relative quantum yield of 26%. The capped Cu/Mo NCs were used as a fluorescent probe for determination of the antineoplastic drug methotrexate (MTX) via an inner filter effect. Fluorescence intensity decreases linearly in the 50 nM to 100 µM MTX concentration range. The limit of detection is 13.7 nM. This approach has been successfully applied to the determination of MTX in spiked human urine with a typical recovery of 99%. Graphical abstract Schematic of a fluorometric method for the determination of methotrexate (MTX) which exerts a strong inner filter effect on the fluorescence of cysteine-capped copper/molybdenum nanoclusters (CuMo NCs) at the wavelength of excitation (370 nm).

Comparative Photothermal Performance among Various Sub-Stoichiometric 2D Oxygen-Deficient Molybdenum Oxide Nanoflakes and In†Vivo Toxicity.

The present study deals with photothermal therapy of solid tumors using different forms of oxygen-deficient sub-stoichiometric two-dimensional (2D) molybdenum oxide nanoflakes (α-MoO3-x ). Upon exfoliation of molybdenum oxide power using fine gridding followed by ultrasonication, bluish green molybdenum oxide (BG α-MoO3 ) was obtained. Oxygen vacancies in BG were generated upon irradiation with an intense xenon lamp. Irradiating the BG for 3 and 5 h, deep blue (B) and olive green (G) oxygen-deficient nanoflakes were obtained respectively. All exhibited high NIR absorption, making these nanomaterials suitable for photothermal therapy. All three forms were functionalized with polypyrrole (PPy@BG, PPy@B, PPy@G) to boost the photothermal stability and transduction efficiency. After functionalization and irradiation with 808 nm laser, the enhancement of temperature for BG, B, G was 50, 65, 52 °C respectively and the corresponding photothermal transduction efficiencies (PTE) were 29.32, 44.42 and 42.00 %. Each of the nanoflakes were found to be highly biocompatible and photostable both in vitro and in vivo. There was substantial decrease in the size of tumors after seven days of treatment on tumor-bearing experimental mice models.

Evaluation of Total Salivary Secretory Immunoglobulin A and Mi/fans-specific SIgA among Children having Dissimilar Caries Status.

INTRODUCTION: The occurrence of dental caries has become quite a common phenomenon nowadays. The varying levels of salivary secretory immunoglobulin A (SIgA) usually determine the progression of caries. The present study was aimed to determine the correlation between SIgA and mutans-specific antigen SIgA in children having different caries status. Scanning electron microscopic analysis was also completed to correlate the results. MATERIALS AND METHODS: This study comprised 60 subjects, who were divided into three groups depending on caries status. In all, saliva was collected to determine the level of SIgA and mutans-specific antigen SIgA using enzyme linked immunosorbent assay (ELISA). The World Health Organization (WHO) criteria and method were used to evaluate dental caries. Bradford reagent was used to evaluate the levels of protein in the antigen. Furthermore, 20 sections of enamel were randomly obtained to estimate the severity of caries development among groups. RESULTS: Categorical characteristics among all groups were compared by basic statistical analysis and Chi-squared test. Mean age (years) was found to be 9.214 ± 2.28, 9.5 ± 2.51, and 10.2 ± 2.35 in groups I, II, and III respectively. Mutans-specific IgA level (|jg/mL) was 34.63 ± 7.46, 28.24 ± 4.52, and 23.56 ± 1.62 in groups I, II, and III respectively. Total SIgA (jg/mL) was 142.53 ± 22.4, 186.10 ± 24.70, and 214.8 ± 27.56 in groups I, II, and III respectively. Caries index was 6.74 ± 2.16, 2.32 ± 0.86, and 0 ± 0 in groups I, II, and III respectively. CONCLUSION: Immunoglobulin A is dominantly present in saliva and it plays a significant role in prevention of dental caries. Hence, dental caries is more likely to develop in subjects with low level of salivary IgA (high caries index). CLINICAL SIGNIFICANCE: A low level of IgA may be associated with a high risk of developing dental caries. This association may possibly be useful in predicting the future caries status. Accordingly, suitable caries-preventive measures can be selected and employed.

Non-equivalence of Key Positively Charged Residues of the Free Fatty Acid 2 Receptor in the Recognition and Function of Agonist Versus Antagonist Ligands.

Short chain fatty acids (SCFAs) are produced in the gut by bacterial fermentation of poorly digested carbohydrates. A key mediator of their actions is the G protein-coupled free fatty acid 2 (FFA2) receptor, and this has been suggested as a therapeutic target for the treatment of both metabolic and inflammatory diseases. However, a lack of understanding of the molecular determinants dictating how ligands bind to this receptor has hindered development. We have developed a novel radiolabeled FFA2 antagonist to probe ligand binding to FFA2, and in combination with mutagenesis and molecular modeling studies, we define how agonist and antagonist ligands interact with the receptor. Although both agonist and antagonist ligands contain negatively charged carboxylates that interact with two key positively charged arginine residues in transmembrane domains V and VII of FFA2, there are clear differences in how these interactions occur. Specifically, although agonists require interaction with both arginine residues to bind the receptor, antagonists require an interaction with only one of the two. Moreover, different chemical series of antagonist interact preferentially with different arginine residues. A homology model capable of rationalizing these observations was developed and provides a tool that will be invaluable for identifying improved FFA2 agonists and antagonists to further define function and therapeutic opportunities of this receptor.

Glucose oxidase assisted visual detection of glucose using oxygen deficient α-MoO3-x nanoflakes.

An optical method is described for the quantitation of glucose by using oxygen-deficient α-MoO3-x nanoflakes. It is based on the use of glucose oxidase (GOx) which produces hydrogen peroxide on oxidation of glucose. Hydrogen peroxide then oxidizes the α-MoO3-x nanoflakes, and this results in a visible color change from blue to colorless. The color change can be measured photometrically at 740 nm. The method has a 68 nM detection limit. Graphical Abstract Mechanism of glucose detection using blue colored oxygen deficient 2D α-MoO3-x nanoflakes. Hydrogen peroxide (H2O2) is formed as a by-product in the conversion of glucose to glucono-1,5-lactone by glucose oxidase (GOx). In the presence of H2O2, the oxygen vacancies in α-MoO3-x nanoflakes are filled up, and this leads to the loss of blue color of the nanoflakes because they are converted back to colorless bulk α-MoO3.

A protocol for amide bond formation with electron deficient amines and sterically hindered substrates.

A protocol for amide coupling by in situ formation of acyl fluorides and reaction with amines at elevated temperature has been developed and found to be efficient for coupling of sterically hindered substrates and electron deficient amines where standard methods failed.

Biogenic Synthesis of Fluorescent Carbon Dots at Ambient Temperature Using Azadirachta indica (Neem) gum.

Synthesis of fluorescent Carbon Dots (CDs) from various carbonaceous materials apparently has acquired lots of interest amongst researchers as the corollary of the properties of CDs; which are subsequently getting unveiled. In this study we report the use of Azadirachta indica (Neem) Gum as a novel natural pre-cursor for synthesis of CDs at room temperature. Water soluble CDs of around 5-8 nm were obtained after treatment of the gum with ethanol and NaOH. These CDs exhibited green fluorescence in UV-light (λ = 365 nm). These CDs were found to be stable, having many bio-linkers attached on their surface, making it suitable for drug attachment and hence can serve as potential candidates for applications like drug delivery vehicles as well as for biosensors.

A green route towards highly photoluminescent and cytocompatible carbon dot synthesis and its separation using sucrose density gradient centrifugation.

An efficient, fast and green method for synthesis of Carbon dots (C-dots) using natural precursor Citrus limone under ultrasonic condition is demonstrated. Such as-synthesized C-dots were further purified using Sucrose density gradient centrifugation method (SDGC) which resulted in the separation of water-soluble, photo luminescent, monodispersed, highly photostable and chemically stable C-dot fractions (F1 and F2). They possess very small size (5-20 nm) as evidenced by High angle annular dark field-Scanning Transmission electron microscopy (HAADF-STEM) and very strong luminescence as shown by fluorescence spectroscopic studies. Cytocompatibility and bio imaging properties of both the fractions (F1 and F2) were then studied on Hep-2 cells. Quantum yield of F1 and F2 fraction was found to be 12.1 and 15 %, respectively.

Defining the molecular basis for the first potent and selective orthosteric agonists of the FFA2 free fatty acid receptor.

FFA2 is a G protein-coupled receptor that responds to short chain fatty acids and has generated interest as a therapeutic target for metabolic and inflammatory conditions. However, definition of its functions has been slowed by a dearth of selective ligands that can distinguish it from the closely related FFA3. At present, the only selective ligands described for FFA2 suffer from poor potency, altered signaling due to allosteric modes of action, or a lack of function at non-human orthologs of the receptor. To address the need for novel selective ligands, we synthesized two compounds potentially having FFA2 activity and examined the molecular basis of their function. These compounds were confirmed to be potent and selective orthosteric FFA2 agonists. A combination of ligand structure-activity relationship, pharmacological analysis, homology modeling, species ortholog comparisons, and mutagenesis studies were then employed to define the molecular basis of selectivity and function of these ligands. From this, we identified key residues within both extracellular loop 2 and the transmembrane domain regions of FFA2 critical for ligand function. One of these ligands was active with reasonable potency at rodent orthologs of FFA2 and demonstrated the role of FFA2 in inhibition of lipolysis and glucagon-like peptide-1 secretion in murine-derived 3T3-L1 and STC-1 cell lines, respectively. Together, these findings describe the first potent and selective FFA2 orthosteric agonists and demonstrate key aspects of ligand interaction within the binding site of FFA2 that will be invaluable in future ligand development at this receptor.

Extracellular ionic locks determine variation in constitutive activity and ligand potency between species orthologs of the free fatty acid receptors FFA2 and FFA3.

Free fatty acid receptors 2 and 3 (FFA2 and FFA3) are G protein-coupled receptors for short chain free fatty acids (SCFAs). They respond to the same set of endogenous ligands but with distinct rank-order of potency such that acetate (C2) has been described as FFA2-selective, whereas propionate (C3) is non-selective. Although C2 was confirmed to be selective for human FFA2 over FFA3, this ligand was not selective between the mouse orthologs. Moreover, although C3 was indeed not selective between the human orthologs, it displayed clear selectivity for mouse FFA3 over mouse FFA2. This altered selectivity to C2 and C3 resulted from broad differences in SCFAs potency at the mouse orthologs. In studies to define the molecular basis for these observations, marked variation in ligand-independent constitutive activity was identified using a [(35)S]GTPγS assay. The orthologs with higher potency for the SCFAs, human FFA2 and mouse FFA3, displayed high constitutive activity in this assay, whereas the orthologs with lower potency for the agonist ligands, mouse FFA2 and human FFA3, did not. Sequence alignments of the second extracellular loop identified single negatively charged residues in FFA2 and FFA3 not conserved between species and predicted to form ionic lock interactions with arginine residues within the FFA2 or FFA3 agonist binding pocket to regulate constitutive activity and SCFA potency. Reciprocal mutation of these residues between species orthologs resulted in the induction (or repression) of constitutive activity and in most cases also yielded corresponding changes in SCFA potency.

Gold nanorods mediated controlled release of doxorubicin: nano-needles for efficient drug delivery.

Use of cysteamine hydrochloride (Cys-HCl) protected gold nanorods (GNRs) as efficient carrier of widely used anti-cancer drug doxorubicin using folic acid as navigational molecule is presented in this work. GNRs were found to have excellent drug loading capacity of >97 %. A detailed comprehension of in vitro drug release profile under ideal physiological condition was found to obey 1st order kinetics at pH 6.8, 5.3 and 7.2, an ideal milieu for drug delivery to solid tumours.

Molecular Detection of Streptococcus mutans and Streptococcus sobrinus in Dental Plaque Samples in Children Aged Six to Nine Years.

Context Dental caries is a widespread threat, usually in children, although it has been observed at other stages of life. Various pieces of literature have confirmed the prevalence of S treptococcus mutans and S treptococcus sobrinus in the progression of the disease. However, establishing procedures to detect these species remains a challenge, posing a barrier to treatment plans. Aim The aim of this study is to detect the species in dental plaque samples from children aged six to nine years by polymerase chain reaction (PCR) and correlate their prevalence in various dentitions. Material and Methods This is an observational analytical cross-sectional study conducted in a tertiary care dental hospital. After sample isolation, microbiological processing was performed, genomic DNA was isolated, and PCR run was performed using specific primers to detect the species. SPSS for Windows Version 17 (IBM Corp., Armonk, NY) and Microsoft Excel (Microsoft Corporation, Redmond, WA, USA) were used to perform statistical analysis. A p-value of <0.05 was considered statistically significant. Results The technique could identify S. Mutans and S. Sobrinus in a short turnaround time. The frequency of S. mutans and S. sobrinus infections was higher in individuals with dental caries. Conclusions Molecular detection via PCR is a reliable, economical, and less time-consuming method for detecting S. mutans and S. sobrinus in dental plaque samples.

Synthesis and structural characterization of homochiral homo-oligomers of parent cis- and trans-furanoid-ß-amino acids.

The synthesis of homochiral homo-oligomers of cis- and trans-3-aminotetrahydrofuran-2-carboxylic acids (parent cis- and trans-furanoid-ß-amino acids, referred to as "cis-/trans-FAA") has been carried out to understand their secondary structures and their dependence on the ring heteroatom. The oligomers of two diastereomers have been shown to have a distinct left-handed helicity. The cis-FAA homo-oligomers show a 14-helix structure, in contrast to the homo-oligomers of cis-ACPC, which adopt a sheet like structure. The trans-FAA homo-oligomers were found to adopt a 12-helix structure, the same trend found in trans-ACPC homo-oligomers. With the help of ab initio calculations, the structural features of cis-ACPC and cis-FAA hexamers were compared. We believe that the more compact packing of the cis-FAA hexapeptide should be due to a more favorable interaction between the ring and the backbone amide hydrogen.

Total synthesis of (±)-sacidumlignan D.

The first total synthesis of (±)-sacidumlignan D featuring a Zn-mediated Barbier reaction and reverse Wacker oxidation to form the key γ-lactone, its diastereoselective α-methylation followed by reduction cyclization, was documented.

Introducing Tb4+ in (Ce0.09/Eu0.96)Tb0.92Mo1.1O6.93 Metal Oxide at Room Temperature and Its Use in Amyloid Defibrillation.

Tunable optical properties in nanomaterials enable a variety of applications in multidisciplinary areas. These properties are directly related to several different factors such as solvent conditions, synthesis methods, and most significantly, the oxidation states of metals participating in the absorption or emission properties. Lanthanide metals containing ABO3 perovskites are among such nanomaterials that can be tuned to a great extent by only modifying the charged states on the metals in the composition. We report a green synthesis method through sonication to synthesize ABO3 perovskites to incorporate Tb4+ into the perovskite composition at room temperature. The optical properties of the nanomaterial show emission in the entire ultraviolet-visible-near-infrared spectral regions through charge transfer between europium and terbium. The combination of cerium (C), molybdenum (M), europium (E), and terbium (T) results in a sheet-like CMET perovskite obeying hexagonal geometry. The nanomaterial is highly stable in an aqueous medium, showing finely suspended Tyndall effect due to particle size <300 nm. Owing to their wide range of emission behavior, surface charge, and aqueous stability, CMET perovskites were used to study the defibrillation of hen egg-white lysozyme (HEWL) as an amyloid model protein. The intrinsic property of the nanomaterial assists in the interaction of the fibrils with the perovskite and the emission range becomes the reporter of the defibrillation. Infrared spectroscopy shows the change in the material properties during the defibrillation. A preliminary test on the varying concentration of HEWL incubated with CMET perovskites shows linear behavior with R2 = 0.9841. The tunable emission characteristic and aqueous stability of the perovskite material make it suitable for future biological applications.

Structure-Activity Relationship Explorations and Discovery of a Potent Antagonist for the Free Fatty Acid Receptor 2.

Free fatty acid receptor 2 (FFA2) is a sensor for short-chain fatty acids that has been identified as an interesting potential drug target for treatment of metabolic and inflammatory diseases. Although several ligand series are known for the receptor, there is still a need for improved compounds. One of the most potent and frequently used antagonists is the amide-substituted phenylbutanoic acid known as CATPB (1). We here report the structure-activity relationship exploration of this compound, leading to the identification of homologues with increased potency. The preferred compound 37 (TUG-1958) was found, besides improved potency, to have high solubility and favorable pharmacokinetic properties.