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Abstract: Alzheimer's Disease (AD), affecting a large population worldwide, is characterized by the old population's loss of memory and learning ability. Cholinergic deficiency is associated with AD, and various cholinesterase inhibitors have been developed to treat AD, including naturally-derived inhibitors, synthetic analogs, and hybrids. Acetylcholinesterase (AChE) has obtained a re-newed interest as a therapeutic target in Alzheimer's disease (AD) due to increased neural cells' function by increasing the concentration of acetylcholine. In this review, we reported the recent de-velopment of novel heterocyclic compounds such as coumarin-benzotriazole hybrids, carbazole de-rivatives, tacrine conjugates, N-benzyl-piperidine-aryl-acyl hydrazones hybrid, spiropyrazoline de-rivatives, coumarin-dithiocarbamate hybrids, etc., as AChE inhibitors for the treatment of Alz-heimer disease. All the bioactive compounds show an effect on different cells and interact simulta-neously with the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE with a nar-row range of IC50 values from 0.4 nm to 88.21 μm using Ellman’s in vitro AChE assay method and show high BBB permeability in vitro. In addition, the in vitro fluorescence assay study using Am-plex Red assay kits revealed that all the compounds could inhibit self-induced β-amyloid (Aβ) ag-gregation with the highest inhibition range from 31.4 to 82%. Furthermore, most of the compounds show a low toxicity profile during in vivo studies. The results suggest that all the compounds consti-tute promising leads for the AChE targeted approach for Alzheimer’s disease.

Traumatic brain injury (TBI) is a leading cause of mortality and chronic disability worldwide TBI involves an initial primary phase triggered by an impactful force to the brain and a subsequent secondary pathological phase. The secondary phase is characterized by key cellular events such as the release of calcium ions (Ca2+) and a cascade of inflammatory events such as the impairment of mitochondrial function, increase in oxidative stress, activation of glial cells, and impairment of the blood-brain barrier (BBB) causing paracellular leakage. There is no FDA-approved drug for TBI, but current treatment strategies rely on the delivery of small and macromolecular therapies to the brain, and these are severely restricted by the BBB, poor retention, off-target toxicity, and by the complex pathology of TBI. Therefore, there is a growing need for novel therapeutics for the diagnosis and treatment of TBI with effective delivery tactics and treatment paradigms such as nano-engineering nanoparticles (NPs). Nanoparticles sizes range between 1-100 nm and are engineered to form distinct materials such as lipids, organic polymers, and silica and metals complexes providing NPs with characteristics that can mitigate TBI secondary events like BBB breakage, neuroinflammation, oxidative stress, and mitochondrial dysfunction, leading to mitigation of TBI pathology. Limitations of NP technology in the treatment of TBI are related to bioavailability, toxicity load and proinflammatory activity of NPs in the brain. In this chapter, we discuss nanoparticles (NPs) as novel strategies for the treatment of TBI and explore their synthesis, mechanisms of action, and limitations. Understanding the mechanisms and complications of NPs as novel therapeutic strategies will help guide and improve the design of future TBI therapies.

Background: Pyrimidine derivative has evinced its biological importance in targeting lung cancer by inhibiting neutrophil elastase. Methods: All THPM derivatives were synthesized by the grindstone method at ambient temperature followed by molecular docking study for efficient binding interaction of THPM compounds by targeting human neutrophil elastase (HNE) (PDB ID: 5A0A) and In-silico ADMET study using PkCSM. Moreover, all synthesized compounds were characterized by spectroscopy techniques and screened for anti-cancer activity using in vitro HNE assay kit. Results: We reported a one-pot solvent-free mechanochemical approach for synthesizing tetrahydropyrimidine (THPM) derivatives from various aromatic aldehydes, ethyl cyanoacetate, and urea followed by in silico study and evaluation against human neutrophil elastase (HNE) for treatment of lung cancer. We calibrated the best molecules that bound to specific targets more efficiently using a molecular docking approach and provided the desired efficacy. In-silico ADMET studies revealed that all best-scored compounds had drug-like characteristics for potential use as human neutrophil elastase inhibitors (HNE) in lung cancer treatment. Additionally, the in vitro studies revealed that compounds 1, 2, and 8 show potent HNE inhibitory activity for lung cancer treatment. Conclusion: In a nutshell, the tetrahydropyrimidine (THPM) scaffold and its derivatives may serve as potential HNE inhibitors for the development of a promising anti-cancer agent.

Background: Quinoline derivatives have evinced their biological importance in targeting bacteria by inhibiting Dihydrofolate reductase. H2SO4 was successfully applied as an acid catalyst for a green, efficient, and one-pot solvent-free synthesis of quinoline derivatives using sonochemistry approach from various aromatic amines and glycerol with affording yield up to 96% within 6-10 min. Objective: In this study, the synthesis, characterization, and biological assessment of fifteen quinoline derivatives (1-15) as potential DHFR inhibitors were carried out. The target compounds were docked to study the molecular interactions and binding affinities with the 1DLS enzyme. Methods: The synthesized molecules were characterized using IR, MASS, and 1H and 13C NMR. The In-silico molecular docking study was carried out through target Human Dihydrofolate Reductase (DHFR) retrieved from a protein data bank having PDB ID: 1DLS and the antimicrobial activity of all synthesized compounds were tested against Human Dihydrofolate Reductase(DHFR) enzyme by using in-vitro DHFR assay kit. Results: The molecular docking results revealed that compounds 2 and 6 have the lowest binding energy and good binding affinity with the DHFR enzyme. In-silico ADMET predictions revealed that all best-scored compounds had good absorption and drug-like properties for potential use as DHFR inhibitors to treat bacterial infection. The in vitro studies revealed that compounds 2 and 6 show potent DFHR inhibitory activity against gram-positive and gram-negative with IC50 = 12.05 ± 1.55 μM and 10.04 ± 0.73 μM, respectively. While compounds 12, 13, and 15 exhibited moderate antimicrobial activity through DHFR inhibition with IC50= 16.33 ± 0.73 μM, 17.02 ± 1.55 μM, and 18.04 ± 1.05 μM, respectively. Conclusion: This environmentally benign sonochemistry-based approach for synthesizing quinoline derivatives could be affordable for large-scale production and become a potential lead candidate for developing a new quinoline-based antimicrobial agent.

Abstract: Parkinson’s disease is a relatively common neurological disorder with incidence increasing with age. Since current medications only relieve the symptoms and do not change the course of the disease, therefore, finding disease-modifying therapies is a critical unmet medical need. However, significant progress in understanding how genetics underpins Parkinson's disease (PD) has opened up new opportunities for understanding disease pathogenesis and identifying possible therapeutic targets. One such target is leucine-rich repeat kinase 2 (LRRK2), an elusive enzyme implicated in both familial and idiopathic PD risk. As a result, both academia and industry have promoted the development of potent and selective inhibitors of LRRK2. In this review, we have summarized recent progress in the discovery and development of LRKK2 inhibitors as well as the bioactivity of several small-molecule LRRK2 inhibitors that have been used to inhibit LRRK2 kinase activity in vitro or in vivo.

In the present investigation, emphasis was placed on the efficacy of lipopolysaccharide (LPS) extracted from the plant beneficial rhizobacterium Alcaligenes faecalis MSS8 for the induction of disease resistance by enhancing immune response in plants against phytopathogen Fusarium oxysporum f. sp. lycopersici (FOL). Characterization and proficiency of the rhizobacterial LPS for the induced defense response in plant against FOL was revealed by the gel activity staining of Peroxidase (PO) and Polyphenol oxidase (PPO) isoforms as compared to the untreated and only FOL treated plants. It has been observed that after 48 h of FOL challenge inoculation, in the LPS pretreated plant there was significant induction of PO and PPO isoforms. Furthermore, RT-PCR analysis for the study of relative gene expression of pathogenesis related (PR) proteins confirms the result of gel activity staining. It has been observed that expression level of LeChi9, LeGluB, LePR1a was significantly upregulated in LPS treated plants 24 h after FOL inoculation and maximum level was observed at 48 h as compared to the control and FOL treated plants. This clearly indicates the role of LPS extracted from A. faecalis as a potential biocontrol agent against fusarium wilt.

Small bowel neoplasms are rare, accounting for only 3%-6% of all gastrointestinal neoplasms. Carcinoid tumors represent a large portion of these (20%-30%), making them the second most common small bowel malignancy after adenocarcinoma. Gastrointestinal carcinoids constitute 70% of all neuroendocrine tumors, and out of those, 42% originate in the small bowel. They are predominantly seen in older patients around the age of 65 years. From 1973 to 2004, there has been more than a fourfold increase in the incidence of carcinoid tumors. This can be probably due to increased diagnostic accuracy rather than an actual increase in the number of new cases. The workup of a suspicious case of gastrointestinal bleeding consists of esophagogastroduodenoscopy and/or colonoscopy, and other imaging tests including video capsule endoscopy and balloon-assisted endoscopy. Management of the tumors is dependent on the size and location of the lesion. Treatment options include surgery, endoscopic removal of tumors, and various immunotherapy and chemotherapeutic agents.

Providencia rettgeri MSS2, a novel gamma proteobacterium, isolated from the rhizospheric soil of tomato plant in Gujarat, India has in vitro biocontrol activity against Fusarium oxysporum f. sp. lycopersici (FOL), causative agent of fusarium wilt in tomato plant. It also has a strong root colonization potential which was confirmed by SEM analysis. Talc-based bioformulation of MSS2 was applied under pot trials to study the mechanism of induced resistance against FOL by enhancement of defense enzymes and total phenolics in tomato. Results of the study showed an increase in the defense enzymes like peroxidase (PO) and polyphenoloxidase (PPO), maximum increase of these enzymes was observed on the 6th day of pathogen challenge. Enzyme activity was found to be increased by 1.2 fold in the plants pretreated with MSS2 and challenged with FOL as compared to only pathogen treated plants. Activity of phenylalanine ammonium lyase (PAL) was also found to increase in plants pretreated with MSS2 challenge inoculated by FOL. Increase in total phenolics upto 1.7 fold was found in the plants treated with MSS2 challenge inoculated by FOL than untreated plants. Zymographic study for both defense enzymes showed induction of isoform PO2, PPO1 and PPO4 in the rhizobacterial treated plant challenged with pathogen than with untreated and pathogen control plants. Plant root colonizing ability of the rhizobacteria P. rettgeri MSS2 helps in the significant induction of enhanced plant defense response against phytopathogen FOL.

Plant growth promoting Bacillus subtilis MSS9 and Bacillus licheniformis MSS14 were isolated from the tomato rhizosphere. These isolates were capable of inhibiting the fungal pathogen, Fusarium oxysporum f. sp. lycopersici causing fusarium wilt in tomato, tested by dual culture method and by mycolytic enzyme production. The isolates have the capacity to form biofilm on the microtitre plate. Scanning electron microscopy revealed good colonization capacity of Bacillus licheniformis MSS14 on tomato plant root as compared to Bacillus subtilis MSS9, pot experiments were also analyzed to study the effects of both rhizobacterial cultures on pathogen development and plant growth. It was observed that MSS14 reduces the incidence of Fusarium oxysporum f. sp. lycopersici in tomato and there was significant increase in vegetative parameters like root length, shoot length, plant wet weight, dry weight and chlorophyll content after which indicates that the root colonization property of the culture MSS14 helps in enhancing the biocontrol capacity against pathogen than that of MSS9.

Tomato is a popular vegetable widely grown in the tropics, which is mainly attacked by fusarium wilt incited by Fusarium oxysporum f. sp. lycopersici (FOL). In the present scenario, an ecofriendly ...

Two fungal species A. niger and A. parasiticus isolated from agriculture field were used in the present study. These two fungal isolates were studied for the siderophore production on the modified CAS agar medium. On daily observation it was observed that the growth was increased along with the production indicating the change in colour of CAS dye from blue to purplish red by A. niger and Yellow by A. parasiticus . Quantitative determination of siderophore production was further studied using liquid medium. After 10 days of incubation A. niger and A. parasiticus produce 80% and 73% units of siderophore. Chemical determination showed that both the fungal isolates showed hydroxamate type of siderophore. Optimization of type of inoculum showed that block inoculum produced maximum siderophore compared to loop and monosporic inoculation in both the fungal isolates. Neutral pH 7.0 showed maximum siderophore production in both the isolates. Decrease in iron concentration increases the siderophore production by the fungal isolates. Maximum siderophore production 80% and 74% units was observed in A. niger and A. parasiticus respectively when there was no addition of iron in the medium. Pot studies were carried out to observe the effect of fungal inoculum on mungbean plant. Inoculation with fungal isolates showed increase in number of leaves, number of branches, number of lateral roots, plant height, fresh weight and dry weight of plant compared to control. Thus both the fungal isolates proved to be potential bioinoculant for improving the growth of mungbean plant.

Susceptibility to abacavir hypersensitivity (ABH) in HIV-1-positive patients is strongly linked to the carriage of HLA-B*57:01 and the potential mechanism includes drug-specific activation of cytokine producing CD8 T cells exclusively in individuals carrying HLA-B*57:01. Here, we report a detailed characterization of abacavir-induced functional response of CD8 T cells in HLA-B*57:01pos individuals. Peripheral blood mononuclear cells (PBMNCs) from HLA-B*57:01pos ABHpos and HLA-B*57:01neg ABHneg individuals were stimulated with abacavir. Multicolor flow cytometry was performed to assess the cytokine (IFNγ) production and degranulation (CD107a expression) after 6-18 hr culture and to enumerate proliferating CD4/CD8 T cells by culturing carboxyfluorescein diacetate succinimidyl ester-loaded PBMNCs for 7 days. CD8 T cells from HLA-B*57:01pos ABHpos individuals were multifunctional: proliferating, IFNγ producing, degranulating (CD107apos ), and both degranulating and IFNγ producing (CD107apos IFNγpos ). Degranulating CD8 T cells in general and both degranulating and IFNγ producing CD8 T cells in particular dominated abacavir-specific immune response. All functional responses were partially blocked by addition of HLA-B*57:01-reactive Bw4 mAb, but not by non-HLA-B*57:01-reactive Bw6 mAb. In conclusion, the study demonstrates that abacavir-specific CD8 T-cell-restricted immune response in HLA-B*57:01pos ABHpos HIV-1 patients has multiple effector and proliferating functions, where the primary effector response appears to be the release of cytolytic granules. The findings have implications for immunotherapy of HLA-related drug hypersensitivities.

Neural Network modeling as computational tool has been widely used in many practical problems in the field of communication. This paper proposes the use of neural network modeling to microstrip antenna. The same has been developed for equilateral triangular microstrip antenna which is used on suspended air as well as glass epoxy suspended substrates. Using proposed model, frequencies calculated over wide range and for increasing substrate thickness give closer agreement with the simulated data obtained using IE3D simulations. At some frequencies and substrate thickness, measurements have also been carried out to validate the proposed model. A good agreement between simulated, measured, and calculated results is observed with % error of less than 2%.

Tomato is a popular vegetable widely grown in the tropics, which is mainly attacked by fusarium wilt incited by Fusarium oxysporum f. sp. lycopersici (FOL). In the present scenario, an ecofriendly alternative strategy such as use of fungi from rhizosphere is being explored to combat the phytopathogen invasion. This study was carried out to evaluate the efficacy of Trichoderma asperellum MSST to promote the growth and yield parameters of tomato S-22, a susceptible variety. This study was also undertaken to manage fusarium wilt disease under in vitro and in vivo conditions. Significant increase in vegetative parameters like root length, shoot length, plant weight and chlorophyll content 60 days after sowing (DAS) was observed. There was reduction in the incidence of fusarium wilt in tomato up to 85%. Increase in the level of total phenol, peroxidase, polyphenoloxidase and phenylalanine ammonium lyase activity at 10th day of pathogen inoculation showed enhancement of plant defence mechanism by T. asperellum MSST against FOL. Overall study revealed that isolate MSST was proven to be potential biocontrol agent showing induced resistance against FOL.

Introduction Chronic graft versus host disease is the major cause of poor outcomes after allogeneic hematopoietic cell transplantation (HCT). Clinically significant moderate-severe chronic GvHD (cGvHD) rarely shows a sustained complete response to immunosuppressive drugs and non-responders either die or suffer long-term. Early and accurate prediction of ensuing cGvHD can help identify high risk patients to make preemptive treatment possible. In the present study, we retrospectively analyzed the transcriptome of immunity related genes at one month post-transplant with the aim to identify a potential early and accurate predictor of clinically significant cGvHD. Methods An adult retrospective cohort of 73 human leukocyte antigen (HLA) matched myeloablative allogeneic HCT recipients were included. All patients received 4.5 mg/kg antithymocyte globulin as GvHD prophylaxis. Diagnosis of cGvHD was based on National Institutes of Health consensus criteria with the median day of diagnosis being 126 days. Total RNA extracted from cryopreserved peripheral blood mononuclear cells at one month post-transplant was used to run a gene expression CodeSet profiling of 594 immunity related genes including 15 internal reference genes using Nanostring Technology. Benjamini Hochberg procedure was used to calculate the P value and the false discovery rate (FDR) of differentially expressed genes. Results A set of 12 differentially expressed genes with a Benjamini Hochberg P-value (BHP) of 7 in this panel of 12 genes was able identify patients with high risk of developing mod-severe cGVHD with a sensitivity of 79% and specificity of 88% (AUC = 0.88, P Conclusion The robust and rapid technique of Nanostring based transcriptome profiling identified a gene panel consisting of 12 genes for an early prediction of moderate-severe cGVHD (one month) with high sensitivity and specificity. A precision medicine approach of preemptive treatment of cGVHD can be possible using this study leading to improved outcomes of HCT.

In an environment consisting of harmful microorganisms, survival of plants mainly depends on efficient microbial recognition and rapid defense mechanisms. After infection with a necrotizing pathogen, many plants develop resistance against attack by phytopathogens. This resistance is regarded as systemic acquired resistance, which is a key portion of plant defense against pathogen infection. Induction of acquired resistance in plants occurs mainly by enhancement of the levels of pathogenesis-related proteins and salicylic acid. Some groups of plant-growth-promoting rhizobacteria are involved in an indirect mechanism, either by their antagonistic effect against phytopathogens or by induced systemic resistance (ISR) mechanisms in plants. ISR has been studied with respect to the underlying signaling pathways and to its application in crop protection. The signaling pathway regulating ISR functions independently of salicylic acid, and is mainly dependent on the plant hormones jasmonic acid and ethylene. Apart from these, NPR1, a defensive regulatory protein, is also involved in both systemic and acquired resistance in plants. In this chapter, the molecular and genetic relationship between basal resistance and induced resistance is highlighted.

Introduction:Graft versus host disease (GvHD) is the most common and debilitating complication of allogeneic hematopoietic cell transplantation (HCT). Among the two clinically significant forms, moderate-severe chronic GvHD (cGvHD) is more difficult to treat than grade 2-4 acute GvHD (aGvHD). Chronic GvHD rarely shows a sustained complete response to immunosuppressive drugs and non-responders either die or suffer long-term. However, if an early and accurate prediction of ensuing cGvHD is posiible, then the high risk patients can be identified and treated preemptively. In the present investigation, we retrospectively analyzed the transcriptome of immunity related genes at one month post-transplant with the aim to identify a potential early and accurate predictor of clinically significant cGvHD. Methods:A cohort of 73 HLA matched first allogeneic HCT recipients with moderate-severe cGvHD (n = 31) and no chronic GvHD (n = 42) were included in the study. All patients received similar myeloablative conditioning regimens along with 4.5 mg/kg antithymocyte globulin as GvHD prophylaxis. The diagnosis of cGvHD was based on National Institutes of Health consensus criteria and median day of diagnosis in our cohort was 126 days. Total RNA was extracted from cryopreserved peripheral blood mononuclear cells (PBMNCs) at one month post-transplant. Gene expression CodeSet profiling of 594 immunity related genes including 15 internal reference genes was performed using Nano string Technology Immunology panel. Differential gene expression and receiver operating characteristic (ROC) analyses was performed using R statistical packages and GraphPad PRISM software. Benjamini Hochberg procedure was used to calculate the P value and the false discovery rate (FDR). Differentially expressed genes with a Benjamini Hochberg P value (BHP) of Results:A gene panel consisting of immunity related 12 genes was identified at one month post-transplant whose transcriptome profile was significantly different between patients that developed moderate-severe cGvHD compared to the patients who did not develop cGvHD. The identified gene panel included highly upregulated T cell activation and proliferation markers like CD3D (BHP=0.005), CD3E (BHP=0.01), CCR7 (BHP=0.005), CD5 (BHP=0.006); TNF receptor superfamily markers like B- and T-lymphocyte attenuator-BTLA (BHP=0.004), CD27 (BHP=0.004), CD40LG (BHP=0.005); and Costimulatory signaling molecules like Inducible T-cell Co-stimulator ICOS (BHP=0.001), CD28 (BHP=0.006) in patients with cGVHD. A gene score of >7 in this panel of 12 genes was able to differentiate patients with high risk of developing mod-severe cGvHD with a sensitivity of 79% and specificity of 88% (AUC = 0.88, P Conclusions:The cGvHD gene panel consisting of 12 genes from multiple immune regulatory pathways identified in the present study provided an early prediction of moderate-severe cGvHD (one month) with high sensitivity and specificity. The robust and rapid technique of nanostring based transcriptome profiling has the potential to be implemented in the clinic. Differentiating patients at high risk of mod-severe cGvHD can help develop new strategies for preemptive therapy and pave the way towards precision medicine leading to improved outcomes of HCT. Disclosures No relevant conflicts of interest to declare.

The world of halophilic bacteria is quite diverse. We find representatives of three domains of life, archaea, bacteria and eukarya that are adapted to salt concentration upto saturation. The micro-organisms able to grow upto NaCl concentration (>300 g/l) are found all over the small subunit rRNA based tree of life. Their metabolic diversity is high as well encompassing oxygenic and anoxygenic phototrophs, aerobic heterotrophs, denitrifiers, sulfate reducers, fermenters and methanogens. The proteins of halophilic bacteria are magnificently engineered to function in a milieu containing 2–5 M salt. The proteins and encoding genes of halophiles represent a valuable repository and resource for reconstruction and visualizing processes of habitat selection and adaptive evolution. Search for new enzymes endowed with novel activities and enhanced stability continues to be desirable character for important commercial production. These poly extremophiles are excellent source of enzymes and metabolites possessing inherent ability to function in extreme conditions viz high salt, alkaline pH and facilitating catalysis for biotechnological application in food processing, industrial bioconversion and bioremediation. In brief, we have just begun to realize the great potential and true extent of diversity and suitable industrial applications possible from halophiles.