Both heat-sensitive TRPV4 and cold-sensitive TRPM8 ion channels regulate microglial activity.

Microglia, the brain-resident macrophages, perform a myriad of functions directed towards development of neural circuits, and their maintenance. A plethora of ion channels aid in microglial activities that are critical for overall brain functioning. Notably, different functions of microglial cells are sensitive to minute temperature changes, as well as mechanical forces. Therefore, among all the players involved in the regulation of microglial functions, thermosensitive TRP ion channels are potentially important. In this study, we report the endogenous and functional presence of a heat-sensitive ion channel TRPV4 and a cold-sensitive ion channel TRPM8 in primary rat microglia and microglial cell line, N9. We demonstrate that pharmacological modulations of both these channels affect intracellular Ca2+-levels, cellular morphology, migration, and motility. Thus, TRPV4 and TRPM8 act as potential regulators of microglial activities. These findings may have broad implications in understanding neuro-glia interactions in neurodevelopmental and neurodegenerative pathologies with overall bio-medical applications.

Function and regulation of thermosensitive ion channel TRPV4 in the immune system.

Transient receptor potential vanilloid sub-type 4 (TRPV4) is a six transmembrane protein that acts as a non-selective Ca2+ channel. Notably, TRPV4 is present in almost all animals, from lower eukaryotes to humans and is expressed in diverse tissue and cell types. Accordingly, TRPV4 is endogenously expressed in several types of immune cells that represent both innate and adaptive immune systems of higher organism. TRPV4 is known to be activated by physiological temperature, suggesting that it acts as a molecular temperature sensor and thus plays a key role in temperature-dependent immune activation. It is also activated by diverse endogenous ligands, lipid metabolites, physical and mechanical stimuli. Both expression and function of TRPV4 in various immune cells, including T cells and macrophages, are also modulated by multiple pro- and anti-inflammatory compounds. The results from several laboratories suggest that TRPV4 is involved in the immune activation, a phenomenon with evolutionary significance. Because of its diverse engagement in the neuronal and immune systems, TRPV4 is a potential therapeutic target for several immune-related disorders.

Critical aspects of neurodevelopment.

Organisms have the unique ability to adapt to their environment by making use of external inputs. In the process, the brain is shaped by experiences that go hand-in-hand with optimisation of neural circuits. As such, there exists a time window for the development of different brain regions, each unique for a particular sensory modality, wherein the propensity of forming strong, irreversible connections are high, referred to as a critical period of development. Over the years, this domain of neurodevelopmental research has garnered considerable attention from many scientists, primarily because of the intensive activity-dependent nature of development. This review discusses the cellular, molecular, and neurophysiological bases of critical periods of different sensory modalities, and the disorders associated in cases the regulators of development are dysfunctional. Eventually, the neurobiological bases of the behavioural abnormalities related to developmental pathologies are discussed. A more in-depth insight into the development of the brain during the critical period of plasticity will eventually aid in developing potential therapeutics for several neurodevelopmental disorders that are categorised under critical period disorders.

Tunnelling nanotubes between neuronal and microglial cells allow bi-directional transfer of α-Synuclein and mitochondria.

Tunnelling Nanotubes (TNTs) facilitate contact-mediated intercellular communication over long distances. Material transfer via TNTs can range from ions and intracellular organelles to protein aggregates and pathogens. Prion-like toxic protein aggregates accumulating in several neurodegenerative pathologies, such as Alzheimer's, Parkinson's, and Huntington's diseases, have been shown to spread via TNTs not only between neurons, but also between neurons-astrocytes, and neurons-pericytes, indicating the importance of TNTs in mediating neuron-glia interactions. TNT-like structures were also reported between microglia, however, their roles in neuron-microglia interaction remain elusive. In this work, we quantitatively characterise microglial TNTs and their cytoskeletal composition, and demonstrate that TNTs form between human neuronal and microglial cells. We show that α-Synuclein (α-Syn) aggregates increase the global TNT-mediated connectivity between cells, along with the number of TNT connections per cell pair. Homotypic TNTs formed between microglial cells, and heterotypic TNTs between neuronal and microglial cells are furthermore shown to be functional, allowing movement of both α-Syn and mitochondria. Quantitative analysis shows that α-Syn aggregates are transferred predominantly from neuronal to microglial cells, possibly as a mechanism to relieve the burden of accumulated aggregates. By contrast, microglia transfer mitochondria preferably to α-Syn burdened neuronal cells over the healthy ones, likely as a potential rescue mechanism. Besides describing novel TNT-mediated communication between neuronal and microglial cells, this work allows us to better understand the cellular mechanisms of spreading neurodegenerative diseases, shedding light on the role of microglia.

Nanocomposite-based smart fertilizers: A boon to agricultural and environmental sustainability.

Fertilizers are indispensable agri-inputs to accomplish the growing food demand. The injudicious use of conventional fertilizer products has resulted in several environmental and human health complications. To mitigate these problems, nanocomposite-based fertilizers are viable alternative options. Nanocomposites, a novel class of materials having improved mechanical strength, barrier properties, and mechanical and thermal stability, are suitable candidates to develop eco-friendly slow/controlled release fertilizer formulations. In this review, the use of different nanocomposite materials developed for nutrient management in agriculture has been summarized with a major focus on their synthesis and characterization techniques, and application aspects in plant nutrition, along with addressing constraints and future opportunities of this domain. Further detailed studies on nanocomposite-based fertilizers are required to evaluate the cost-effective synthesis methods, in-depth field efficacy, environmental fate, stability, etc. before commercialization in the field of agriculture. The present review is expected to help the policy makers and all the stakeholders in the large-scale commercialization and application of nanocomposite-based smart fertilizer products with greater societal acceptance and environmental sustainability in near future.

Nitrification and urease inhibitors mitigate global warming potential and ammonia volatilization from urea in rice-wheat system in India: A field to lab experiment.

The efficacy of alternative nitrogenous fertilizers for mitigating greenhouse gas and ammonia emissions from a rice-wheat cropping system in northern India was addressed in a laboratory incubation experiment using soil from a 10-year residue management field experiment (crop residue removal, CRR, vs. incorporation, CRI). Neem coated urea (NCU), standard urea (U), urea ammonium sulfate (UAS), and two alternative fertilizers, urea + urease inhibitor NBPT (UUI) and urea + urease inhibitor NBPT + nitrification inhibitor DMPSA (UUINI) were compared to non-fertilized controls for four weeks in incubation under anaerobic condition. Effects of fertilizers on global warming potential (GWP) and ammonia volatilization were dependent on residue treatment. Relative to standard urea, NCU reduced GWP by 11 % in CRI but not significantly in CRR; conversely, UAS reduced GWP by 12 % in CRR but not significantly in CRI. UUI and UUINI reduced GWP in both residue treatments and were more effective in CRI (21 % and 26 %) than CRR (15 % and 14 %). Relative to standard urea, NCU increased ammonia volatilization by 8 % in CRI but not significantly in CRR. Ammonia volatilization was reduced most strongly by UUI (40 % in CRI and 37 % in CRR); it was reduced 28-29 % by UUINI and 12-15 % by UAS. Overall, the urease inhibitor, alone and in combination with the nitrification inhibitor, was more effective in mitigating greenhouse gas and ammonia emissions than NCU. However, these products need to be tested in field settings to validate findings from the controlled laboratory experiment.

Enhancing cation and anion exchange capacity of rice straw biochar by chemical modification for increased plant nutrient retention.

Biochar, a potential alternative of infield crop residue burning, can prevent nutrient leaching from soil and augment soil fertility. However, pristine biochar contains low cation (CEC) and anion (AEC) exchange capacity. This study developed fourteen engineered biochar by treating a rice straw biochar (RBC-W) first separately with different CEC and AEC enhancing chemicals, and then with their combined treatments to increase CEC and AEC in the novel biochar composites. Following a screening experiment, promising engineered biochar, namely RBC-W treated with O3-HCl-FeCl3 (RBC-O-Cl), H2SO4-HNO3-HCl-FeCl3 (RBC-A-Cl), and NaOH-Fe(NO3)3(RBC-OH-Fe), underwent physicochemical characterization and soil leaching-cum nutrient retention studies. RBC-O-Cl, RBC-A-Cl, and RBC-OH-Fe recorded a spectacular rise in CEC and AEC over RBC-W. All the engineered biochar remarkably reduced the leaching of NH4+-N, NO3- -N, PO43--P and K+ from a sandy loam soil and increased retention of these nutrients. RBC-O-Cl at 4.46 g kg-1 dosage emerged as the most effective soil amendment increasing the retention of above ions by 33.7, 27.8, 15.0, and 5.74 % over a comparable dose of RBC-W. The engineered biochar could thus enhance plants' nutrient use efficiency and reduce the use of costly chemical fertilizers that are harmful to environmental quality.

Hydrogel-Mediated Release of TRPV1 Modulators to Fine Tune Osteoclastogenesis.

Bone defects, including bone loss due to increased osteoclast activity, have become a global health-related issue. Osteoclasts attach to the bone matrix and resorb the same, playing a vital role in bone remodeling. Ca2+ homeostasis plays a pivotal role in the differentiation and maturation of osteoclasts. In this work, we examined the role of TRPV1, a nonselective cation channel, in osteoclast function and differentiation. We demonstrate that endogenous TRPV1 is functional and causes Ca2+ influx upon activation with pharmacological activators [resiniferatoxin (RTX) and capsaicin] at nanomolar concentration, which enhances the generation of osteoclasts, whereas the TRPV1 inhibitor (5'-IRTX) reduces osteoclast differentiation. Activation of TRPV1 upregulates tartrate-resistant acid phosphatase activity and the expression of cathepsin K and calcitonin receptor genes, whereas TRPV1 inhibition reverses this effect. The slow release of capsaicin or RTX at a nanomolar concentration from a polysaccharide-based hydrogel enhances bone marrow macrophage (BMM) differentiation into osteoclasts whereas release of 5'-IRTX, an inhibitor of TRPV1, prevents macrophage fusion and osteoclast formation. We also characterize several subcellular parameters, including reactive oxygen (ROS) and nitrogen (RNS) species in the cytosol, mitochondrial, and lysosomal profiles in BMMs. ROS were found to be unaltered upon TRPV1 modulation. NO, however, had elevated levels upon RTX-mediated TRPV1 activation. Capsaicin altered mitochondrial membrane potential (ΔΨm) of BMMs but not 5'-IRTX. Channel modulation had no significant impact on cytosolic pH but significantly altered the pH of lysosomes, making these organelles less acidic. Since BMMs are precursors for osteoclasts, our findings of the cellular physiology of these cells may have broad implications in understanding the role of thermosensitive ion channels in bone formation and functions, and the TRPV1 modulator-releasing hydrogel may have application in bone tissue engineering and other biomedical sectors.

TRPV4 acts as a mitochondrial Ca2+-importer and regulates mitochondrial temperature and metabolism.

TRPV4 is associated with the development of neuropathic pain, sensory defects, muscular dystrophies, neurodegenerative disorders, Charcot Marie Tooth and skeletal dysplasia. In all these cases, mitochondrial abnormalities are prominent. Here, we demonstrate that TRPV4, localizes to a subpopulation of mitochondria in various cell lines. Improper expression and/or function of TRPV4 induces several mitochondrial abnormalities. TRPV4 is also involved in the regulation of mitochondrial numbers, Ca2+-levels and mitochondrial temperature. Accordingly, several naturally occurring TRPV4 mutations affect mitochondrial morphology and distribution. These findings may help in understanding the significance of mitochondria in TRPV4-mediated channelopathies possibly classifying them as mitochondrial diseases.