Chickpea seed endophyte Enterobacter sp. mediated yield and nutritional enrichment of chickpea for improving human and livestock health.

Chickpeas (Cicer arietinum L.) are used as a good source of proteins and energy in the diets of various organisms including humans and animals. Chickpea straws can serve as an alternative option for forage for different ruminants. This research mainly focussed on screening the effects of adding beneficial chickpea seed endophytes on increasing the nutritional properties of the different edible parts of chickpea plants. Two efficient chickpea seed endophytes (Enterobacter sp. strain BHUJPCS-2 and BHUJPCS-8) were selected and applied to the chickpea seeds before sowing in the experiment conducted on clay pots. Chickpea seeds treated with both endophytes showed improved plant growth and biomass accumulation. Notably, improvements in the uptake of mineral nutrients were found in the foliage, pericarp, and seed of the chickpea plants. Additionally, nutritional properties such as total phenolics (0.47, 0.25, and 0.55 folds), total protein (0.04, 0.21, and 0.18 folds), carbohydrate content (0.31, 0.32, and 0.31 folds), and total flavonoid content (0.45, 027, and 0.8 folds) were increased in different parts (foliage, pericarp, and seed) of the chickpea plants compared to the control plants. The seed endophyte-treated plants showed a significant increase in mineral accumulation and improvement in nutrition in the different edible parts of chickpea plants. The results showed that the seed endophyte-mediated increase in dietary and nutrient value of the different parts (pericarp, foliage, and seeds) of chickpea are consumed by humans, whereas the other parts (pericarp and foliage) are used as alternative options for forage and chaff in livestock diets and may have direct effects on their nutritional conditions.

Immunomodulatory effects of Diospyros peregrina fruit preparation (DFP) in non-small cell lung cancer (NSCLC) by utilizing dendritic cell-mediated antigen presentation and T helper (TH) cell differentiation.

Diospyros peregrina is a dioecious plant which is native to India. It belongs to the family of Ebenaceae and is extensively used to treat various ailments, such as leucorrhoea and other uterine-related problems. Though few studies have been on D. peregrina for their anti-tumour response, little is known. Therefore, this intrigued us to understand its immunomodulator capabilities on various types of cancer extensively. Our primary focus is on NSCLC (Non-Small Cell Lung Cancer), which is ranked as the second largest form of cancer in the world, and the treatments demand non-invasive agents to target NSCLC effectively. In an objective to generate an efficient Lung Cancer Associated Antigen (LCA) specific anti-tumour immune response, LCA was presented using dendritic cells (DCs) in the presence of D. peregrina fruit preparation (DFP). Moreover, we also investigated DFP's role in the differentiation of T-helper (TH) cells. Therefore, this study aimed at better LCA presentation mediated by DFP by activating the LCA pulsed DCs and T helper cell differentiation for better immune response. DCs were pulsed with LCA for tumour antigen presentation in vitro, with and without DFP. Differentially pulsed DCs were irradiated to co-culture with autologous and allogeneic lymphocytes. Extracellular supernatants were collected for the estimation of cytokine levels by ELISA. LDH release assay was performed to test Cytotoxic T lymphocytes (CTLs) mediated lung tumour cell cytotoxicity. Thus, DFP may be a potential vaccine to generate anti-LCA immune responses to restrict NSCLC.

Cationic dextrin nanoparticles for effective intracellular delivery of cytochrome C in cancer therapy.

Intracellular protein delivery shows promise as a selective and specific approach to cancer therapy. However, a major challenge is posed by delivering proteins into the target cells. Despite the development of nanoparticle (NP)-based approaches, a versatile and biocompatible delivery system that can deliver active therapeutic cargo into the cytosol while escaping endosome degradation remains elusive. In order to overcome these challenges, a polymeric nanocarrier was prepared using cationic dextrin (CD), a biocompatible and biodegradable polymer, to encapsulate and deliver cytochrome C (Cyt C), a therapeutic protein. The challenge of endosomal escape of the nanoparticles was addressed by co-delivering the synthesized NP construct with chloroquine, which enhances the endosomal escape of the therapeutic protein. No toxicity was observed for both CD NPs and chloroquine at the concentration tested in this study. Spectroscopic investigations confirmed that the delivered protein, Cyt C, was structurally and functionally active. Additionally, the delivered Cyt C was able to induce apoptosis by causing depolarization of the mitochondrial membrane in HeLa cells, as evidenced by flow cytometry and microscopic observations. Our findings demonstrate that an engineered delivery system using CD NPs is a promising platform in nanomedicine for protein delivery applications.

NIR-Active Gold Dogbone Nanorattles Impregnated in Cationic Dextrin Nanoparticles for Cancer Nanotheranostics.

Theranostic systems, which integrate therapy and diagnosis into a single platform, have gained significant attention as a promising approach for noninvasive cancer treatment. The field of image-guided therapy has revolutionized real-time tumor detection, and within this domain, plasmonic nanostructures have garnered significant attention. These structures possess unique localized surface plasmon resonance (LSPR), allowing for enhanced absorption in the near-infrared (NIR) range. By leveraging the heat generated from plasmonic nanoparticles upon NIR irradiation, target cancer cells can be effectively eradicated. This study introduces a plasmonic gold dogbone-nanorattle (AuDB NRT) structure that exhibits broad absorption in the NIR region and demonstrates a photothermal conversion efficiency of 35.29%. When exposed to an NIR laser, the AuDB NRTs generate heat, achieving a maximum temperature rise of 38 °C at a concentration of 200 µg/mL and a laser power density of 3 W/cm2. Additionally, the AuDB NRTs possess intrinsic electromagnetic hotspots that amplify the signal of a Raman reporter molecule, making them an excellent probe for surface-enhanced Raman scattering-based bioimaging of cancer cells. To improve the biocompatibility of the nanorattles, the AuDB NRTs were conjugated with mPEG-thiol and successfully encapsulated into cationic dextrin nanoparticles (CD NPs). Biocompatibility tests were performed on HEK 293 A and MCF-7 cell lines, revealing high cell viability when exposed to AuDB NRT-CD NPs. Remarkably, even at a low laser power density of 1 W/cm2, the application of the NIR laser resulted in a remarkable 80% cell death in cells treated with a nanocomposite concentration of 100 µg/mL. Further investigation elucidated that the cell death induced by photothermal heat followed an apoptotic mechanism. Overall, our findings highlight the significant potential of the prepared nanocomposite for cancer theranostics, combining effective photothermal therapy along with the ability to image cancer cells.

miR-277 targets the proapoptotic gene-hid to ameliorate Aß42-mediated neurodegeneration in Alzheimer's model.

Alzheimer's disease (AD), an age-related progressive neurodegenerative disorder, exhibits reduced cognitive function with no cure to date. One of the reasons for AD is the accumulation of Amyloid-beta 42 (Aß42) plaque(s) that trigger aberrant gene expression and signaling, which results in neuronal cell death by an unknown mechanism(s). Misexpression of human Aß42 in the developing retina of Drosophila exhibits AD-like neuropathology. Small non-coding RNAs, microRNAs (miRNAs), post-transcriptionally regulate the expression of their target genes and thereby regulate different signaling pathways. In a forward genetic screen, we identified miR-277 (human ortholog is hsa-miR-3660) as a genetic modifier of Aß42-mediated neurodegeneration. Loss-of-function of miR-277 enhances the Aß42-mediated neurodegeneration. Whereas gain-of-function of miR-277 in the GMR > Aß42 background downregulates cell death to maintain the number of neurons and thereby restores the retinal axonal targeting defects indicating the functional rescue. In addition, gain-of-function of miR-277 rescues the eclosion- and climbing assays defects observed in GMR > Aß42 background. Thus, gain-of-function of miR-277 rescues both structurally as well as functionally the Aß42-mediated neurodegeneration. Furthermore, we identified head involution defective (hid), an evolutionarily conserved proapoptotic gene, as one of the targets of miR-277 and validated these results using luciferase- and qPCR -assays. In the GMR > Aß42 background, the gain-of-function of miR-277 results in the reduction of hid transcript levels to one-third of its levels as compared to GMR > Aß42 background alone. Here, we provide a novel molecular mechanism where miR-277 targets and downregulates proapoptotic gene, hid, transcript levels to rescue Aß42-mediated neurodegeneration by blocking cell death. These studies shed light on molecular mechanism(s) that mediate cell death response following Aß42 accumulation seen in neurodegenerative disorders in humans and provide new therapeutic targets for neurodegeneration.

Effect of substrate salinity and pH on life history traits of the bluetongue virus vector Culicoides peregrinus.

Habitat selection of Culicoides spp. (Diptera: Ceratopogonidae) is influenced by the physicochemical factors such as temperature, pH, salinity, moisture, conductivity, organic and inorganic compounds of substrates. These factors determine the life history traits of the vectors. We studied the influence of substrate salinity (0-40 parts per thousand, ppt) and pH (pH 1-13) on oviposition, egg hatching, larval survivability, and adult emergence of Culicoides peregrinus Kieffer under laboratory conditions. Most eggs (80.74%) were laid in 0 ppt and 95% in pH 7 but lowered with increased salinity and pH levels. It was observed that the females did not lay eggs in 30 ppt to 40 ppt salinity; pH 1 and pH 13 but interestingly up to 95% of the eggs were retained within the abdomen. Little effect of salinity and pH on egg hatching was observed up to 5 ppt and 10 ppt except at the extreme values of 40 ppt and pH 1, pH 13. Pupation did not occur in rearing plates with high salinities, 30 ppt and 40 ppt, although the few eggs hatched when exposed to such salinity. In low salinity (0 to 2 ppt), occurrence of adult emergence was more and then decreased with increasing salinity. Maximum emergence was seen when the rearing media was alkaline. This study deals with the suitability of breeding substrate of C. peregrinus when exposed to salinity and pH ranges. Our study suggests the ambient salinity and pH ranges to be maintained during laboratory rearing of this vector species.

Microbial Exudates as Biostimulants: Role in Plant Growth Promotion and Stress Mitigation.

Microbes hold immense potential, based on the fact that they are widely acknowledged for their role in mitigating the detrimental impacts of chemical fertilizers and pesticides, which were extensively employed during the Green Revolution era. The consequence of this extensive use has been the degradation of agricultural land, soil health and fertility deterioration, and a decline in crop quality. Despite the existence of environmentally friendly and sustainable alternatives, microbial bioinoculants encounter numerous challenges in real-world agricultural settings. These challenges include harsh environmental conditions like unfavorable soil pH, temperature extremes, and nutrient imbalances, as well as stiff competition with native microbial species and host plant specificity. Moreover, obstacles spanning from large-scale production to commercialization persist. Therefore, substantial efforts are underway to identify superior solutions that can foster a sustainable and eco-conscious agricultural system. In this context, attention has shifted towards the utilization of cell-free microbial exudates as opposed to traditional microbial inoculants. Microbial exudates refer to the diverse array of cellular metabolites secreted by microbial cells. These metabolites enclose a wide range of chemical compounds, including sugars, organic acids, amino acids, peptides, siderophores, volatiles, and more. The composition and function of these compounds in exudates can vary considerably, depending on the specific microbial strains and prevailing environmental conditions. Remarkably, they possess the capability to modulate and influence various plant physiological processes, thereby inducing tolerance to both biotic and abiotic stresses. Furthermore, these exudates facilitate plant growth and aid in the remediation of environmental pollutants such as chemicals and heavy metals in agroecosystems. Much like live microbes, when applied, these exudates actively participate in the phyllosphere and rhizosphere, engaging in continuous interactions with plants and plant-associated microbes. Consequently, they play a pivotal role in reshaping the microbiome. The biostimulant properties exhibited by these exudates position them as promising biological components for fostering cleaner and more sustainable agricultural systems.

Binding of stress-responsive OsWRKY proteins through WRKYGQK heptapeptide residue with the promoter region of two rice blast disease resistance genes Pi2 and Pi54 is important for development of blast resistance.

Molecular docking was done to investigate the interactions between five differentially expressed rice WRKY proteins when challenged with the rice blast disease caused by Magnaporthe oryzae and drought stresses applied either individually or overlapped, with the promoter region of two blast resistance genes (Pi2 and Pi54). Molecular docking was performed using the HDOCK server. Initially, the homology models for each of the five rice WRKY proteins were prepared using I-TASSER server, and then the secondary structure as well as the DNA-binding pockets were predicted using PSIPRED and BindUP servers, respectively. The molecular docking study revealed a differential binding pattern of the rice WRKYs with the two blast resistance genes. The WRKY proteins (OsWRKY88 and OsWRKY102), whose transcript levels decrease when drought and blast stresses are overlapped, interact with the two resistance genes mostly involving the residues of the zinc finger structure. On the other hand, the WRKY proteins (OsWRKY53-1 and OsWRKY113), whose transcript levels did not reduce significantly when challenged by drought and blast overlapped condition compared to individual treatment of blast, interact mostly involving the residues of the conserved WRKYGQK heptapeptide sequence. Interestingly, the protein OsWRKY74 whose transcript levels are unaffected in both individual and overlapped stresses, interacts with both the blast resistance genes involving few residues of both WRKYGQK heptapeptide and the zinc finger structure. The findings thus indicate that the interaction of OsWRKY proteins involving the conserved WRKYGQK heptapeptide sequence with the blast resistance genes Pi2 and Pi54 is important to mitigate the blast challenge in rice even during overlapping challenges of drought. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03711-y.

Palladium Nanocapsules for Photothermal Therapy in the Near-Infrared II Biological Window.

Recent developments in nanomaterials with programmable optical responses and their capacity to modulate the photothermal effect induced by an extrinsic source of light have elevated plasmonic photothermal therapy (PPTT) to the status of a favored treatment for a variety of malignancies. However, the low penetration depth of near-infrared-I (NIR-I) lights and the need to expose the human body to a high laser power density in PPTT have restricted its clinical translation for cancer therapy. Most nanostructures reported to date exhibit limited performance due to (i) activity only in the NIR-I region, (ii) the use of intense laser, (iii) need of large concentration of nanomaterials, or (iv) prolonged exposure times to achieve the optimal hyperthermia state for cancer phototherapy. To overcome these shortcomings in plasmonic nanomaterials, we report a bimetallic palladium nanocapsule (Pd Ncap)─with a solid gold bead as its core and a thin, perforated palladium shell─with extinction both in the NIR-I as well as the NIR-II region for PPTT applications toward cancer therapy. The Pd Ncap demonstrated exceptional photothermal stability with a photothermal conversion efficiency of ∼49% at the NIR-II (1064 nm) wavelength region at a very low laser power density of 0.5 W/cm2. The nanocapsules were further surface-functionalized with Herceptin (Pd Ncap-Her) to target the breast cancer cell line SK-BR-3 and exploited for in vitro PPTT applications using NIR-II light. Pd Ncap-Her caused more than 98% cell death at a concentration of just 50 µg/mL and a laser power density of 0.5 W/cm2 with an output power of only 100 mW. Flow cytometric and microscopic analyses revealed that Pd Ncap-Her-induced apoptosis in the treated cancer cells during PPTT. Additionally, Pd Ncaps were found to have reactive oxygen species (ROS) scavenging ability, which can potentially reduce the damage to cells or tissues from ROS produced during PPTT. Also, Pd Ncap demonstrated excellent in vivo biocompatibility and was highly efficient in photothermally ablating tumors in mice. With a high photothermal conversion and killing efficiency at very low nanoparticle concentrations and laser power densities, the current nanostructure can operate as an effective phototherapeutic agent for the treatment of different cancers with ROS-protecting ability.

Role of distal arginine residue in the mechanism of heme nitrite reductases.

Heme nitrite reductases reduce NO2- by 1e-/2H+ to NO or by 6e-/8H+ to NH4+ which are key steps in the global nitrogen cycle. Second-sphere residues, such as arginine (with a guanidine head group), are proposed to play a key role in the reaction by assisting substrate binding and hydrogen bonding and by providing protons to the active site for the reaction. The reactivity of an iron porphyrin with a NO2- covalently attached to a guanidinium arm in its 2nd sphere was investigated to understand the role of arginine residues in the 2nd sphere of heme nitrite reductases. The presence of the guanidinium residue allows the synthetic ferrous porphyrin to reduce NO2- and produce a ferrous nitrosyl species ({FeNO}7), where the required protons are provided by the guanidinium group in the 2nd sphere. However, in the presence of additional proton sources in solution, the reaction of ferrous porphyrin with NO2- results in the formation of ferric porphyrin and the release of NO. Spectroscopic and kinetic data indicated that re-protonation of the guanidine group in the 2nd sphere by an external proton source causes NO to dissociate from a ferric nitrosyl species ({FeNO}6) at rates similar to those observed for enzymatic sites. This re-protonation of the guanidine group mimics the proton recharge mechanism in the active site of NiR. DFT calculations indicated that the lability of the Fe-NO bond in the {FeNO}6 species is derived from the greater binding affinity of anions (e.g. NO2-) to the ferric center relative to neutral NO due to hydrogen bonding and electrostatic interaction of these bound anions with the protonated guanidium group in the 2nd sphere. The reduced {FeNO}7 species, once formed, is not affected significantly by the re-protonation of the guanidine residue. These results provide direct insight into the role of the 2nd sphere arginine residue present in the active sites of heme-based NiRs in determining the fate of NO2- reduction. Specifically, the findings using the synthetic model suggest that rapid re-protonation of these arginine residues may trigger the dissociation of NO from the {FeNO}6, which may also be the case in the protein active site.

Butyrate limits inflammatory macrophage niche in NASH.

Immune cell infiltrations with lobular inflammation in the background of steatosis and deregulated gut-liver axis are the cardinal features of non-alcoholic steatohepatitis (NASH). An array of gut microbiota-derived metabolites including short-chain fatty acids (SCFA) multifariously modulates NASH pathogenesis. However, the molecular basis for the favorable impact of sodium butyrate (NaBu), a gut microbiota-derived SCFA, on the immunometabolic homeostasis in NASH remains elusive. We show that NaBu imparts a robust anti-inflammatory effect in lipopolysaccharide (LPS) stimulated or classically activated M1 polarized macrophages and in the diet-induced murine NASH model. Moreover, it impedes monocyte-derived inflammatory macrophage recruitment in liver parenchyma and induces apoptosis of proinflammatory liver macrophages (LM) in NASH livers. Mechanistically, by histone deactylase (HDAC) inhibition NaBu enhanced acetylation of canonical NF-κB subunit p65 along with its differential recruitment to the proinflammatory gene promoters independent of its nuclear translocation. NaBu-treated macrophages thus exhibit transcriptomic signatures that corroborate with a M2-like prohealing phenotype. NaBu quelled LPS-mediated catabolism and phagocytosis of macrophages, exhibited a differential secretome which consequently resulted in skewing toward prohealing phenotype and induced death of proinflammatory macrophages to abrogate metaflammation in vitro and in vivo. Thus NaBu could be a potential therapeutic as well as preventive agent in mitigating NASH.

A taxonomic revision of the Indian species of the 'Aterinervis' group of Culicoides Latreille Subgenus Hoffmania Fox (Diptera: Ceratopogonidae).

The seven species of Culicoides spp. belonging to the Aterinervis Group of subgenus Hoffmania Fox reported from India are revised. The study is based on type material and fresh specimens trapped during the Annual Biodiversity Assessment (2nd & 4th) of Neora Valley National Park (NVNP) in the Darjeeling-Sikkim Himalaya of India. Comparative redescriptions of adult male and female of Culicoides isoregalis, C. neoregalis, C. pararegalis, C. pseudoregalis, C. quasiregalis, C. regalis and C. subregalis are provided along with the formal transfer of the nominate species, Culicoides aterinervis from subgenus Culicoides Latreille to Hoffmania. A key to the Indian species belonging to the Aterinervis group is provided along with a list of the Culicoides species present in the Darjeeling-Sikkim Himalayas.

In vitro biochemical characterization and identification of hemolytic bacteria associated with life history of Culicoides peregrinus (Diptera: Ceratopogonidae), a vector of bluetongue virus.

Gut bacterial communities in insects provide several beneficial roles like nutrition, digestion, fecundity, and survival of the host. The microbial communities of Culicoides spp. (Diptera: Ceratopogonidae) vary with parity, developmental stages, and environmental factors. Previous studies have revealed the presence of hemolytic bacteria in adult Culicoides peregrinus Kieffer (Diptera: Ceratopogonidae), an important vector of bluetongue virus (BTV). Our objectives were (i) to identify bacterial communities with hemolytic activities associated with all life stages and (ii) to compare between reared and field-collected adults including age graded females. Bacterial identification followed Sanger sequencing of 16S rRNA. In vitro biochemical characterizations including antibiotic sensitivity tests were also done. The majority of bacterial species were beta hemolytic with one, Alcaligenes faecalis, showing alpha hemolysis. Most bacterial species were observed in field-collected adults except Proteus spp. Throughout the life history of the vector, Bacillus cereus (CU6A, CU1E) and Paenibacillus sp. (CU9G) were detected indicating their possible role in blood digestion within the gut of this vector species. In vivo hemolytic activities of these culturable bacterial communities within this vector may be addressed in future. These hemolytic bacterial communities may be targeted to develop novel and effective strategies for vector control.

A Metagenomic Based Approach on Abundance and Diversity of Bacterial Communities Across the Life Stages of Culicoides peregrinus (Diptera: Ceratopogonidae) a Vector of Bluetongue Virus.

During larval rearing of Culicoides peregrinus Kieffer (Diptera: Ceratopogonidae) it was obligatory to add a small quantity of mud from larval habitat to nutrient broth in culture plates. This initiated microbial growth in rearing plates which facilitated growth and development of immature. The primary aim was to enumerate gut microbial communities across the different life stages of C. peregrinus. Amplicon sequencing of the V3-V4 hypervariable region (16S rDNA) was done on Illumina Miseq platform to detect gut bacterial communities at different life stages, while ITS regions (18S rRNA) were targeted for fungal communities of the 4th instar larvae. The major findings were: 1) Phylum Proteobacteria and Firmicutes were the most abundant throughout the life stages, along with the highest bacterial alpha diversity in the egg, 2) bacterial compositions were similar to laboratory reared and field collected adults, and 3) abundant fungal phyla associated with the larval gut were Ascomycota and Basidiomycota. Furthermore, analyses of the gut microbiome with METAGENassist might be indicative of their likely function in the natural habitat. Abundant gut-associated bacteria and/or fungal genera detected in the present study could be used as dietary supplements to establish laboratory colonies for further vectorial research. While, individual roles of the bacteria or fungi in paratransgenesis are warned for their possible utilization to frame the management strategy in upcoming works.

Silver nanostructure-modified graphite electrode for in-operando SERRS investigation of iron porphyrins during high-potential electrocatalysis.

In-operando spectroscopic observation of the intermediates formed during various electrocatalytic oxidation and reduction reactions is crucial to propose the mechanism of the corresponding reaction. Surface-enhanced resonance Raman spectroscopy coupled to rotating disk electrochemistry (SERRS-RDE), developed about a decade ago, proved to be an excellent spectroscopic tool to investigate the mechanism of heterogeneous oxygen reduction reaction (ORR) catalyzed by synthetic iron porphyrin complexes under steady-state conditions in water. The information about the formation of the intermediates accumulated during the course of the reaction at the electrode interface helped to develop better ORR catalysts with second sphere residues in the porphyrin rings. To date, the application of this SERRS-RDE setup is limited to ORR only because the thiol self-assembled monolayer (SAM)-modified Ag electrode, used as the working electrode in these experiments, suffers from stability issues at more cathodic and anodic potential, where H2O oxidation, CO2 reduction, and H+ reduction reactions occur. The current investigation shows the development of a second-generation SERRS-RDE setup consisting of an Ag nanostructure (AgNS)-modified graphite electrode as the working electrode. These electrodes show higher stability (compared to the conventional thiol SAM-modified Ag electrode) upon exposure to very high cathodic and anodic potential with a good signal-to-noise ratio in the Raman spectra. The behavior of this modified electrode toward ORR is found to be the same as the SAM-modified Ag electrode, and the same ORR intermediates are observed during electrochemical ORR. At higher cathodic potential, the signatures of Fe(0) porphyrin, an important intermediate in H+ and CO2 reduction reactions, was observed at the electrode-water interface.

Early loss of endogenous NAD+ following rotenone treatment leads to mitochondrial dysfunction and Sarm1 induction that is ameliorated by PARP inhibition.

Sarm1 is an evolutionary conserved innate immune adaptor protein that has emerged as a primary regulator of programmed axonal degeneration over the past decade. In vitro structural insights have revealed that although Sarm1 induces energy depletion by breaking down nicotinamide adenine dinucleotide+ (NAD+ ), it is also allosterically inhibited by NAD+ . However, how NAD+ levels modulate the activation of intracellular Sarm1 has not been elucidated so far. This study focuses on understanding the events leading to Sarm1 activation in both neuronal and non-neuronal cells using the mitochondrial complex I inhibitor rotenone. Here, we report the regulation of rotenone-induced cell death by loss of NAD+ that may act as a 'biological trigger' of Sarm1 activation. Our study revealed that early loss of endogenous NAD+ levels arising due to PARP1 hyperactivation preceded Sarm1 induction following rotenone treatment. Interestingly, replenishing NAD+ levels by the PARP inhibitor, PJ34 restored mitochondrial complex I activity and also prevented subsequent Sarm1 activation in rotenone-treated cells. These cellular data were further validated in Drosophila melanogaster where a significant reduction in rotenone-mediated loss of locomotor abilities, and reduced dSarm expression was observed in the flies following PARP inhibition. Taken together, these observations not only uncover a novel regulation of Sarm1 induction by endogenous NAD+ levels but also point towards an important understanding on how PARP inhibitors could be repurposed in the treatment of mitochondrial complex I deficiency disorders.

The curious case of SARM1: Dr. Jekyll and Mr. Hyde in cell death and immunity?

Sterile alpha and toll/interleukin-1 receptor motif-containing protein 1 (SARM1) was first identified as a novel ortholog of Drosophila protein CG7915 and was subsequently placed as the fifth member of the human TIR-containing adaptor protein. SARM1 holds a unique position in this family where, unlike other members, it downregulates NFκB activity in response to immunogenic stimulation, interacts with another member of the family, TRIF, to negatively regulate its function, and it also mediates cell death responses. Over the past decade, SARM1 has emerged as one of the primary mediators of programmed axonal degeneration and this robust regulation of axonal degeneration-especially in models of peripheral neuropathy and traumatic injury-makes it an attractive target for therapeutic intervention. The TIR domain of SARM1 possesses an intrinsic NADase activity resulting in cellular energy deficits within the axons, a striking deviation from its other family members of human TLR adaptors. Interestingly, the TIR NADase activity, as seen in SARM1, is also observed in several prokaryotic TIR-containing proteins where they are involved in immune evasion once within the host. Although the immune function of SARM1 is yet to be conclusively discerned, this closeness in function with the prokaryotic TIR-domain containing proteins, places it at an interesting juncture of evolution raising questions about its origin and function in cell death and immunity. In this review, we discuss how a conserved immune adaptor protein like SARM1 switches to a pro-neurodegenerative function and the evolutionarily significance of the process.

Nanotechnology Toolkit for Combating COVID-19 and Beyond.

The outbreak of SARS-CoV-2 is unlikely to be contained anytime soon with conventional medical technology. This beckons an urgent demand for novel and innovative interventions in clinical protocols, diagnostics, and therapeutics; to manage the current "disease X" and to be poised to counter its successor of like nature if one were to ever arise. To meet such a demand requires more attention to research on the viral-host interactions and on developing expeditious solutions, the kinds of which seem to spring from promising domains such as nanotechnology. Inducing activity at scales comparable to the viruses themselves, nanotechnology-based preventive measures, diagnostic tools and therapeutics for COVID-19 have been rapidly growing during the pandemic. This review covers the recent and promising nanomedicine-based solutions relating to COVID-19 and how some of these are possibly applicable to a wider range of viruses and pathogens. We also discuss the type, composition, and utility of nanostructures which play various roles specifically under prevention, diagnosis, and therapy. Further, we have highlighted the adoption and commercialization of some the solutions by large and small corporations alike, as well as providing herewith an exhaustive list on nanovaccines.

Assembly of redox active metallo-enzymes and metallo-peptides on electrodes: Abiological constructs to probe natural processes.

Redox active metallo-proteins and metallo-peptides attached to self-assembled monolayers (SAM) of thiols on Au electrodes or constituting the SAM on Au electrodes can provide unique opportunities to investigate a range of complicated biological phenomena in controlled abiological constructs. In addition to conventional biochemical tools like site-directed mutagenesis, these constructs allow control over electron transfer (ET) processes, micro solvation (SAM design), folding/misfolding and orientation of these biological entities. This article presents a review of the work done by this group in creating abiological bio-inspired SAM on Au electrodes to probe several important biological processes where redox plays or might play a major role. These include stabilisation of different morphologies of Aß peptides and which allow investigation of the reactivity of their Cu/Zn/heme-bound forms, determination of both outer-sphere and inner-sphere reorganisation energies of cytochrome c along with deciphering the role of the fluxional methionine and finally creation of bio-chemical constructs of cytochrome c oxidase which not only reduce O2 selectively to H2O efficiently but also provide key insights in O2 reduction mechanism which has aided the development of efficient artificial catalysts.

Phagocytosis and self-destruction break down dendrites of Drosophila sensory neurons at distinct steps of Wallerian degeneration.

After injury, severed dendrites and axons expose the "eat-me" signal phosphatidylserine (PS) on their surface while they break down. The degeneration of injured axons is controlled by a conserved Wallerian degeneration (WD) pathway, which is thought to activate neurite self-destruction through Sarm-mediated nicotinamide adenine dinucleotide (NAD+) depletion. While neurite PS exposure is known to be affected by genetic manipulations of NAD+, how the WD pathway coordinates both neurite PS exposure and self-destruction and whether PS-induced phagocytosis contributes to neurite breakdown in vivo remain unknown. Here, we show that in Drosophila sensory dendrites, PS exposure and self-destruction are two sequential steps of WD resulting from Sarm activation. Surprisingly, phagocytosis is the main driver of dendrite degeneration induced by both genetic NAD+ disruptions and injury. However, unlike neuronal Nmnat loss, which triggers PS exposure only and results in phagocytosis-dependent dendrite degeneration, injury activates both PS exposure and self-destruction as two redundant means of dendrite degeneration. Furthermore, the axon-death factor Axed is only partially required for self-destruction of injured dendrites, acting in parallel with PS-induced phagocytosis. Lastly, injured dendrites exhibit a unique rhythmic calcium-flashing that correlates with WD. Therefore, both NAD+-related general mechanisms and dendrite-specific programs govern PS exposure and self-destruction in injury-induced dendrite degeneration in vivo.