Voltage-gated calcium channels act upstream of adenylyl cyclase Ac78C to promote timely initiation of dendrite regeneration.

Most neurons are not replaced after injury and thus possess robust intrinsic mechanisms for repair after damage. Axon injury triggers a calcium wave, and calcium and cAMP can augment axon regeneration. In comparison to axon regeneration, dendrite regeneration is poorly understood. To test whether calcium and cAMP might also be involved in dendrite injury signaling, we tracked the responses of Drosophila dendritic arborization neurons to laser severing of axons and dendrites. We found that calcium and subsequently cAMP accumulate in the cell body after both dendrite and axon injury. Two voltage-gated calcium channels (VGCCs), L-Type and T-Type, are required for the calcium influx in response to dendrite injury and play a role in rapid initiation of dendrite regeneration. The AC8 family adenylyl cyclase, Ac78C, is required for cAMP production after dendrite injury and timely initiation of regeneration. Injury-induced cAMP production is sensitive to VGCC reduction, placing calcium upstream of cAMP generation. We propose that two VGCCs initiate global calcium influx in response to dendrite injury followed by production of cAMP by Ac78C. This signaling pathway promotes timely initiation of dendrite regrowth several hours after dendrite damage.

Copper-catalyzed ortho-thiocyanation of aromatic amines.

A copper-catalyzed direct ortho-Csp2-H thiocyanation of free anilines has been developed. This method employs stable and non-toxic ammonium thiocyanate as a thiocyanation source, and tert-butyl hydroperoxide as the oxidant, enabling the synthesis of ortho-thiocyanated anilines with good yields and broad substrate tolerance. Hitherto, no reports have been found in the literature for the ortho-thiocyanation of aromatic amines, making this reaction an important breakthrough in synthetic organic chemistry.

Piezoresistive sensitivity enhancement below threshold voltage in sub-5 nm node using junctionless multi-nanosheet FETs.

In this paper, the piezoresistive sensitivity is enhanced by applying uniform mechanical stress (MS) on the multi-nanosheet (NS) channels of sub-5 nm junctionless field-effect transistors. The piezoresistivity of the sensing device is boosted by narrowing channel conductivity using low gate biasing and reducing physical channel width, resulting in the maximum (∼6 times higher) sensitivity observed in the subthreshold regime compared to the ON-state condition. In addition, the sensitivity is extensively increased by ∼30.3% near the threshold voltage with horizontally multi-NS stacking due to the uniform MS distribution on the multi-NS channels, which can sense slight deflection of pressure on the circular diaphragm. These results show that the tunable sensitivity of junctionless multi-channel devices is superior to the inversion mode, a consequence of the less scattering effect, better thermal stability, and low electronic noise.

Fluoroquinolones tackling antimicrobial resistance: Rational design, mechanistic insights and comparative analysis of norfloxacin vs ciprofloxacin derivatives.

Antimicrobial resistance poses a global health concern and develops a need to discover novel antimicrobial agents or targets to tackle this problem. Fluoroquinolone (FN), a DNA gyrase and topoisomerase IV inhibitor, has helped to conquer antimicrobial resistance as it provides flexibility to researchers to rationally modify its structure to increase potency and efficacy. This review provides insights into the rational modification of FNs, the causes of resistance to FNs, and the mechanism of action of FNs. Herein, we have explored the latest advancements in antimicrobial activities of FN analogues and the effect of various substitutions with a focus on utilizing the FN nucleus to search for novel potential antimicrobial candidates. Moreover, this review also provides a comparative analysis of two widely prescribed FNs that are ciprofloxacin and norfloxacin, explaining their rationale for their design, structure-activity relationships (SAR), causes of resistance, and mechanistic studies. These insights will prove advantageous for new researchers by aiding them in designing novel and effective FN-based compounds to combat antimicrobial resistance.

Pathology, target discovery, and the evolution of XO inhibitors from the first discovery to recent advances (2020-2023).

Hyperuricemia, a disease characterized by elevation of serum uric acid level beyond 6 mg/dL. This elevation led to appearance of symptoms from joint pain to gout and from gout to difficulty in mobility of the patient. So, in this review, we have summarized the pathology of hyperuricemia, discovery of target and discovery of first XO inhibitor. At last, this review provides in-sights about the recently discovered as natural XO inhibitors, followed by design, structure activity relationship and biological activity of synthetic compounds as XO inhibitors discovered between 2020 and 2023 years. At last, the pharmacophores generated in this study will guide new researchers to design and modify the structure of novel XO inhibitors.

Recent breakthroughs on the development of electrodeionization systems for toxic pollutants removal from water environment.

Since ecosystems are becoming inherently polluted, long-term contaminant removal methods are required. Electrodeionization, in particular, has recently been demonstrated as an effective approach for eliminating ionic compounds from contaminated water sources. Being a more environmentally friendly technology is most likely the main reason for its eminence. It uses electricity to replace toxic contaminants that are conventionally used to regenerate and hence reducing the toxins associated with resin regeneration. In wastewater treatment, continuous electrodeionization system overcomes several limitations of ion exchange resins, notably ion dumping. This prospective assessment delves into the mechanism, principle, and theory of electrodeionization system. It also focused on the design and applications, particularly in the removal of toxic compounds, as well as current advances in the electrodeionization system. Recent breakthroughs in electrodeionization were comprehensively discussed. Further developments in electrodeionization systems are also projected, with improved efficiency at the time of functioning at lower costs because of reduced energy use, proving them desirable for commercial usage with a broad array of applications across the globe.

Transcriptional and secretome analysis of Rasamsonia emersonii lytic polysaccharide mono-oxygenases.

The current study is the first to describe the temporal and differential transcriptional expression of two lytic polysaccharide monooxygenase (LPMO) genes of Rasamsonia emersonii in response to various carbon sources. The mass spectrometry based secretome analysis of carbohydrate active enzymes (CAZymes) expression in response to different carbon sources showed varying levels of LPMOs (AA9), AA3, AA7, catalase, and superoxide dismutase enzymes pointing toward the redox-interplay between the LPMOs and auxiliary enzymes. Moreover, it was observed that cello-oligosaccharides have a negative impact on the expression of LPMOs, which has not been highlighted in previous reports. The LPMO1 (30 kDa) and LPMO2 (47 kDa), cloned and expressed in Pichia pastoris, were catalytically active with (kcat/Km) of 6.6×10-2 mg-1 ml min-1 and 1.8×10-2 mg-1 ml min-1 against Avicel, respectively. The mass spectrometry of hydrolysis products of Avicel/carboxy methyl cellulose (CMC) showed presence of C1/C4 oxidized oligosaccharides indicating them to be Type 3 LPMOs. The 3D structural analysis of LPMO1 and LPMO2 revealed distinct arrangements of conserved catalytic residues at their active site. The developed enzyme cocktails consisting of cellulase from R. emersonii mutant M36 supplemented with recombinant LPMO1/LPMO2 resulted in significantly enhanced saccharification of steam/acid pretreated unwashed rice straw slurry from PRAJ industries (Pune, India). The current work indicates that LPMO1 and LPMO2 are catalytically efficient and have a high degree of thermostability, emphasizing their usefulness in improving benchmark enzyme cocktail performance. KEY POINTS: • Mass spectrometry depicts subtle interactions between LPMOs and auxiliary enzymes. • Cello-oligosaccharides strongly downregulated the LPMO1 expression. • Developed LPMO cocktails showed superior hydrolysis in comparison to CellicCTec3.

Antidiabetic potential of thiazolidinedione derivatives with efficient design, molecular docking, structural activity relationship, and biological activity: an update review (2021-2023).

Thiazolidinedione has been used successfully by medicinal chemists all over the world in the development of potent antidiabetic derivatives. The few compounds with excellent antidiabetic potency that we have identified in this review could be used as a lead for further research into additional antidiabetic mechanisms. The information provided in this review regarding the design, biological activity, structure-activity relationships, and docking studies may be useful for scientists who wish to further explore this scaffold in order to fully utilize its biological potential and develop antidiabetic agents that would overcome the limitations of currently available medications for the treatment of diabetes. This review outlines the antidiabetic potential of Thiazolidinedione-based derivatives that have been published in the year 2021- till date.

A comprehensive review of synthetic and semisynthetic xanthine oxidase inhibitors: identification of potential leads based on in-silico computed ADME characteristics.

Xanthine oxidase (XO) inhibitors, both synthetic and semisynthetic, have been developed extensively over the past few decades. The increased level of XO is not only the major cause of gout but is also responsible for various conditions associated with hyperuricemia, such as cardiovascular disorders, chronic kidney disorders, diabetes, Alzheimer's disease and chronic wounds. Marketed available XO inhibitors (allopurinol, febuxostat, and topiroxostat) are used to treat hyperuricemia but they are associated with fatal side effects, which pose serious problems for the healthcare system, rising the need for new, more potent, safer compounds. This review summarizes recent findings on XO and describes their design, synthesis, biological significance in the development of anti-hyperuricemic drugs with ADME profile, structure activity relationship (SAR) and molecular docking studies. The results might help medicinal chemists to develop more efficacious XO inhibitors.

Triazole derivatives as potential xanthine oxidase inhibitors: Design, enzyme inhibition potential, and docking studies.

Considerable ingenuity has been shown in the recent years in the discovery of novel xanthine oxidase (XO) inhibitors that fall outside the purine scaffold. The triazole nucleus has been the cornerstone for the development of many enzyme inhibitors for the clinical management of several diseases, where hyperuricemia is one of them. Here, we give a critical overview of significant research on triazole-based XO inhibitors, with respect to their design, synthesis, inhibition potential, toxicity, and docking studies, done till now. Based on these literature findings, we can expect a burst of modifications on triazole-based scaffolds in the near future by targeting XO, which will treat hyperuricemics, that is, painful conditions like gout that at present are hard to deal with.

In-vitro antioxidant and anti-inflammatory potential along with p.o. pharmacokinetic profile of key bioactive phytocompounds of Snow Mountain Garlic: a comparative analysis vis-à-vis normal garlic.

Snow mountain garlic (SMG) is a trans-Himalayan medicinal plant used in the traditional medicine system for several ailments, including inflammatory arthritis. Research studies are insufficient to validate its folk medicinal applications. In the present study, the comparative abundance of its key bioactive phytocompounds, viz., S-allyl-L-cysteine (SAC), alliin, and S-methyl-L-cysteine (SMC) against normal garlic were assessed using the LC-MS/MS-MRM method. In addition, the study also explored the antioxidant and anti-inflammatory potency of crude extract of SMG and purified signature phytocompounds (i.e., SMC, SAC, and alliin) in comparison with normal garlic and dexamethasone in LPS-stimulated RAW264.7 macrophage cells. The LC-MS/MS-MRM study revealed significant differences among SMG and normal garlic, viz., alliin 22.8-fold higher in SMG, and SMC could be detected only in SMG. In the bioassays, SMG extract and purified signature phytocompounds significantly downregulated oxidative damage in activated macrophages, boosting endogenous antioxidants' activity. SMG extract-treated macrophages significantly suppressed NF-κB expression and related inflammatory indicators such as cytokines, COX-2, iNOS, and NO. Notably, the observed anti-inflammatory and antioxidant bioactivities of SMG extract were comparable to signature phytocompounds and dexamethasone. In addition, SAC being uniformly found in SMG and normal garlic, its comparative pharmacokinetics was studied to validate the pharmacodynamic superiority of SMG over normal garlic. Significantly higher plasma concentrations (Cmax), half-life (t1/2), and area under curve (AUC) of SAC following SMG extract administration than normal garlic validated the proposed hypothesis. Thus, the abundance of bioactive phytocompounds and their better pharmacokinetics in SMG extract might be underlying its medicinal merits over normal garlic.

Solar reduced graphene oxide decorated with manganese dioxide nanostructures for brackish water desalination using asymmetric capacitive deionization.

Capacitive deionization (CDI) has emerged as a low-cost, reagent-free technique for the desalination of water. This technique is based on the immobilization of dissolved ions on the electrically charged electrodes, by the electrosorption phenomenon. The electrosorption of dissolved ions by using CDI is limited for feed water having a low concentration of salts. To address this problem, we employ an asymmetric capacitive deionization (Asy-CDI) architecture having solar reduced graphene oxide decorated with manganese dioxide nanostructures (SRGO-MnO2 composite). The Asy-CDI possesses an SRGO-MnO2 composite as the cathode and SRGO as the anode with an anion exchange membrane. The cathode formed from the SRGO-MnO2 composite serves the purpose of immobilization of cations, whereas the anode formed from SRGO is responsible for anion removal. The crystal structure, chemical composition and morphology of the as-synthesized SRGO-MnO2 composite electrode materials are characterized by several techniques, confirming that the surface of SRGO is successfully loaded with α-MnO2 nanostructures. The electrochemical characterization reveals a high specific capacitance of the as-synthesized SRGO-MnO2 composite (419.9 F g-1) at 100 mV s-1. The Asy-CDI provides a higher salt adsorption capacity (40.2 mg g-1) compared to Sy-CDI (28.3 mg g-1) with feed water containing a salt concentration of 2000 mg L-1. These results indicate that the Asy-CDI may be employed as an efficient technique for the desalination of high concentration salt water.

Quinoline derivatives volunteering against antimicrobial resistance: rational approaches, design strategies, structure activity relationship and mechanistic insights.

Emergence of antimicrobial resistance has become a great threat to human species as there is shortage of development of new antimicrobial agents. So, its mandatary to combat AMR by initiating research and developing new novel antimicrobial agents. Among phytoconstituents, Quinoline (nitrogen containing heterocyclic) have played a wide role in providing new bioactive molecules. So, this review provides rational approaches, design strategies, structure activity relationship and mechanistic insights of newly developed quinoline derivatives as antimicrobial agents.

Anticonvulsant potential of Grewia tiliaefolia in pentylenetetrazole induced epilepsy: insights from in vivo and in silico studies.

Epilepsy, a chronic neurological condition, impacts millions of individuals globally and remains a significant contributor to both illness and mortality. Available antiepileptic drugs have serious side effects which warrants to explore different medicinal plants used for the management of epilepsy reported in Traditional Indian Medicinal System (TIMS). Therefore, we explored the antiepileptic potential of the Grewia tiliaefolia (Tiliaeceae) which is known for its neuroprotective properties. Aerial parts of G. tiliaefolia were subjected to extraction with increasing order of polarity viz. hexane, chloroform and methanol. Antioxidant potential of hexane, chloroform and methanol extracts of G. tiliaefolia was evaluated by 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) assay, total antioxidant capacity (TAC) assay, reducing power assay (RPA) and DNA nicking assay. Additionally, quantitative antioxidant assays were also conducted to quantify total phenolic (TPC) and total flavonoid content (TFC). As revealed by in vitro assays, methanol extract was found to contain more phenolic content. Hence, the methanol extract was further explored for its anticonvulsant potential in pentylenetetrazole (PTZ) induced acute seizures in mice. The methanol extract (400 mg/kg) significantly increased the latency to occurrence of myoclonic jerks and generalized tonic clonic seizures (GTCS). Additionally, it also reduced duration and seizure severity score associated with GTCS. The Grewia tiliaefolia methanol extract was further screened by Ultra High-Performance Liquid Chromatography (UHPLC) for presence of polyphenolic compounds, among which gallic acid and kaempferol were present in higher amount and were further analysed by in silico study to predict their possible binding sites and type of interactions these compounds show with gamma amino butyric acid (GABA) receptor and glutamate α amino-3- hydroxyl-5-methyl-4-isoxazolepropionic acid (Glu-AMPA) receptor. It was revealed that gallic acid and kaempferol had shown agonistic interaction for GABA receptor and antagonistic interaction for Glu-AMPA receptor. We concluded that G. tiliaefolia showed anticonvulsant potential possibly because of gallic acid and kaempferol possibly mediated through GABA and Glu-AMPA receptor.

Nose-to-brain drug delivery for the treatment of glioblastoma multiforme: nanotechnological interventions.

Glioblastoma multiforme (GBM) is the most aggressive malignant brain tumor with a short survival rate. Extensive research is underway for the last two decades to find an effective treatment for GBM but the tortuous pathophysiology, development of chemoresistance, and presence of BBB are the major challenges, prompting scientists to look for alternative targets and delivery strategies. Therefore, the nose to brain delivery emerged as an unorthodox and non-invasive route, which delivers the drug directly to the brain via the olfactory and trigeminal pathways and also bypasses the BBB and hepatic metabolism of the drug. However, mucociliary clearance, low administration volume, and less permeability of nasal mucosa are the obstacles retrenching the brain drug concentration. Thus, nanocarrier delivery through this route may conquer these limitations because of their unique surface characteristics and smaller size. In this review, we have emphasized the advantages and limitations of nanocarrier technologies such as polymeric, lipidic, inorganic, and miscellaneous nanoparticles used for nose-to-brain drug delivery against GBM in the past 10 years. Furthermore, recent advances, patents, and clinical trials are highlighted. However, most of these studies are in the early stages, so translating their outcomes into a marketed formulation would be a milestone in the better progression and survival of glioma patients.

Dark-field spin Hall effect of light.

While an optical system's symmetry ensures that the spin Hall effect of light (SHEL) vanishes at normal incidence, the question of how close to the normal incidence can one reliably measure the SHEL remains open. Here we report simulation and experimental results on the measurement of SHEL at $\sim 0.12^\circ$ away from normal incidence in the Fourier plane of a weakly focused beam of light, reflected at an air-glass interface. Measurement of transverse spin-shift due to $< 0.05^\circ$ polarization variation in the beam cross section along the X- and Y-directions is achieved in the dark-field region of the reflected beam. Our ability to measure the SHEL at near-normal incidence with no moving optomechanical parts and significantly improved sensitivity to phase-polarization variations is expected to enable several applications in the retro-reflection geometry including material characterization with significant advantages.

Impact of ambient temperature and thermal resistance on device performance of junctionless silicon-nanotube FET.

In this article, a comprehensive analysis of the impact of electrothermal characteristics in the junctionless silicon-nanotube (Si-NT) field-effect-transistors is carried out using the Sentaurus TCAD. The combined study of the variation in thermal contact resistance (1 × 10-9to 1 × 10-8m2W K-1), ambient temperature (300-400 K), and spacer length (5-20 nm) are performed. Significant improvements are observed in carrier temperature by 14%, lattice temperature by 13.7%, and gate leakage current from 0.787 nA to 0.218 fA due to the change in the spacer length. Further, a change in the drain current of 25.6% for thermal resistance (Rth) and of 11.62% due to ambient temperature is observed. We also show that the junctionless device suffers significantly less from self-heating effects because of the electric field intensity, which is much lower in the channel region.

A comparative study of in-vitro and in-silico anti-candidal activity and GC-MS profiles of snow mountain garlic vs. normal garlic.

AIM: The study aimed to profile the volatile phytocomposition of snow mountain garlic (SMG) compared to normal garlic and investigate the anti-Candida efficacy against clinically relevant multi-drug resistant isolates of Candida species. METHODS AND RESULTS: Herein, SMG has shown significantly superior fungicidal power at 2x-MIC dose against C. albicans and C. glabrata in killing kinetic evaluation unlike the fungistatic effect of normal garlic. GC-MS headspace-based profiling of SMG showed 5 unique volatile compounds and a 5-fold higher content of saponins than normal garlic. In an in-silico analysis, cholesta-4,6-dien-3-ol,(3-beta) was uniquely identified in SMG as a potential inhibitor with high binding affinity to the active site of exo-1,3-betaglucan synthase, an established anti-candida drug target crucial for the biofilm matrix formation, thus suggesting a plausible anti-Candida mechanism. CONCLUSION: The in-vitro and in-silico studies have demonstrated the Candida-cidal and anti-biofilm activities of SMG, distinguishing it from the Candida-static efficacy of normal garlic. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first report that identifies several phytochemical signatures of SMG along with a potential anti-Candida compound, that is cholesta-4,6-dien-3-ol,(3-beta)-, which appears worthy of detailed studies in the future to explore the utility of SMG as a fungal phytotherapy agent, especially against drug-resistant Candida sp.

Design, Synthesis, biological investigations and molecular interactions of triazole linked tacrine glycoconjugates as Acetylcholinesterase inhibitors with reduced hepatotoxicity.

Tacrine is a known Acetylcholinesterase (AChE) inhibitors having hepatotoxicity as main liability associated with it. The present study aims to reduce its hepatotoxicity by synthesizing tacrine linked triazole glycoconjugates via Huisgen's [3 + 2] cycloaddition of anomeric azides and terminal acetylenes derived from tacrine. A series of triazole based glycoconjugates containing both acetylated (A-1 to A-7) and free sugar hydroxyl groups (A-8 to A-14) at the amino position of tacrine were synthesized in good yield taking aid from molecular docking studies and evaluated for their in vitro AChE inhibition activity as well as hepatotoxicity. All the hybrids were found to be non-toxic on HePG2 cell line at 200 µM (100 % cell viability) as compared to tacrine (35 % cell viability) after 24 h of incubation period. Enzyme kinetic studies carried out for one of the potent hybrids in the series A-1 (IC50 0.4 µM) revealed its mixed inhibition approach. Thus, compound A-1 can be used as principle template to further explore the mechanism of action of different targets involved in Alzheimer's disease (AD) which stands as an adequate chemical probe to be launched in an AD drug discovery program.

Design, synthesis, and biological evaluation of isatin-indole-3-carboxaldehyde hybrids as a new class of xanthine oxidase inhibitors.

A novel series of triazole-linked isatin-indole-3-carboxaldehyde hybrids based on the febuxostat skeleton and its binding site interactions were rationally designed and synthesized as potential xanthine oxidase inhibitors. Among the synthesized hybrids, A19 showed the most potent xanthine oxidase inhibition (IC50 = 0.37 µM) with the mixed-type inhibitory scenario. Structure-activity relationship studies revealed that methoxy (OCH3 ) substitution on position 5 of the isatin nucleus and a two-carbon distance between isatin and the triazole moiety is most tolerable for the inhibitory potential. Various binding interactions of A19 with the binding site of xanthine oxidase are also streamlined by molecular docking studies, which showcase the favorable binding pattern for xanthine oxidase inhibition by the hybrid. Furthermore, molecular dynamic studies were performed that suggest the stability of the enzyme-hybrid complex. Overall, the study suggests that hybrid A19 can act as an effective hit lead for further development of potent xanthine oxidase inhibitors.