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Poongothai Venkatachalapathy,1 Sruthi Padhilahouse,1 Mohan Sellappan,1 Tharunika Subramanian,2 Shilia Jacob Kurian,3 Sonal Sekhar Miraj,3 Mahadev Rao,3 Ashwin Ashok Raut,4 Rupinder Kaur Kanwar,4 Jitendra Singh,4 Sagar Khadanga,5 Sukumar Mondithoka,5 Murali Munisamy4 1Department of Pharmacy Practice, Karpagam College of Pharmacy, Coimbatore, Tamilnadu, India; 2Karpagam Faculty of Medical Sciences and Research, Coimbatore, India; 3Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India; 4Translational Medicine Centre, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India; 5Department of General Medicine, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, IndiaCorrespondence: Murali MunisamyTranslational Medicine Centre, All India Institute of Medical Sciences, Bhopal, 462020, Madhya Pradesh, India, Tel +91-9600-883-284Email murali.tmc@aiimsbhopal.edu.inAbstract: Type 2 diabetes mellitus (T2DM) is the most common form of diabetes, and is rising in incidence with widespread prevalence. Multiple gene variants are associated with glucose homeostasis, complex T2DM pathogenesis, and its complications. Exploring more effective therapeutic strategies for patients with diabetes is crucial. Pharmacogenomics has made precision medicine possible by allowing for individualized drug therapy based on a patient’s genetic and genomic information. T2DM is treated with various classes of oral hypoglycemic agents, such as biguanides, sulfonylureas, thiazolidinediones, meglitinides, DPP4 inhibitors, SGLT2 inhibitors, α-glucosidase inhibitors, and GLP1 analogues, which exhibit various pharmacogenetic variants. Although genomic interventions in monogenic diabetes have been implemented in clinical practice, they are still in the early stages for complex polygenic disorders, such as T2DM. Precision DM medicine has the potential to be effective in personalized therapy for those suffering from various forms of DM, such as T2DM. With recent developments in genetic techniques, the application of candidate-gene studies, large-scale genotyping investigations, genome-wide association studies, and “multiomics” studies has begun to produce results that may lead to changes in clinical practice. Enhanced knowledge of the genetic architecture of T2DM presents a bigger translational potential. This review summarizes the genetics and pathophysiology of T2DM, candidate-gene approaches, genome-wide association studies, personalized medicine, clinical relevance of pharmacogenetic variants associated with oral hypoglycemic agents, and paths toward personalized diabetology.Keywords: pharmacogenomics, personalized medicine, type 2 diabetes, antidiabetic drugs

Sishir K Kamalapuram,1 Rupinder K Kanwar,1 Kislay Roy,1 Rajneesh Chaudhary,1 Rakesh Sehgal,2 Jagat R Kanwar1 1Nanomedicine Laboratory of Immunology and Molecular Biomedical Research, School of Medicine, Centre for Molecular and Medical Research, Faculty of Health, Deakin University, Geelong, VIC, Australia; 2Department of Medical Parasitology, Postgraduate Institute of Medical Education and Research, Chandigarh, India Abstract: The present study successfully developed orally deliverable multimodular zinc (Zn) iron oxide (Fe3O4)-saturated bovine lactoferrin (bLf)-loaded polymeric nanocapsules (NCs), and evaluated their theranostic potential (antitumor efficacy, magnetophotothermal efficacy and imaging capability) in an in vivo human xenograft CpG-island methylator phenotype (CIMP)-1+/CIMP2−/chromosome instability-positive colonic adenocarcinoma (Caco2) and claudin-low, triple-negative (ER−/PR−/HER2−; MDA-MB-231) breast cancer model. Mice fed orally on the Zn-Fe-bLf NC diet showed downregulation in tumor volume and complete regression in tumor volume after 45 days of feeding. In human xenograft colon cancer, vehicle-control NC diet-group (n=5) mice showed a tumor volume of 52.28±11.55 mm3, and Zn-Fe-bLf NC diet (n=5)-treated mice had a tumor-volume of 0.10±0.073 mm3. In the human xenograft breast cancer model, Zn-Fe-bLf NC diet (n=5)-treated mice showed a tumor volume of 0.051±0.062 mm3 within 40 days of feeding. Live mouse imaging conducted by near-infrared fluorescence imaging of Zn-Fe-bLf NCs showed tumor site-specific localization and regression of colon and breast tumor volume. Ex vivo fluorescence-imaging analysis of the vital organs of mice exhibited sparse localization patterns of Zn-Fe-bLf NCs and also confirmed tumor-specific selective localization patterns of Zn-Fe-bLf NCs. Dual imaging using magnetic resonance imaging and computerized tomography scans revealed an unprecedented theranostic ability of the Zn-Fe-bLf NCs. These observations warrant consideration of multimodular Zn-Fe-bLf NCs for real-time cancer imaging and simultaneous cancer-targeted therapy. Keywords: theranostic, multimodular cancer therapy, nanocapsules, nanomedicine, real-time imaging

Kislay Roy,1,* Yogesh S Patel,1,* Rupinder K Kanwar,1 Rangam Rajkhowa,2 Xungai Wang,2 Jagat R Kanwar1 1Nanomedicine-Laboratory of Immunology and Molecular Biomedical Research (NLIMBR), Centre for Molecular and Medical Research (C-MMR), School of Medicine (SoM), Faculty of Health, 2Institute for Frontier Materials (IFM), Deakin University, Waurn Ponds, VIC, Australia *These authors contributed equally to this work Abstract: This study used the Eri silk nanoparticles (NPs) for delivering apo-bovine lactoferrin (Apo-bLf) (~2% iron saturated) and Fe-bLf (100% iron saturated) in MDA-MB-231 and MCF-7 breast cancer cell lines. Apo-bLf and Fe-bLf-loaded Eri silk NPs with sizes between 200 and 300 nm (±10 nm) showed a significant internalization within 4 hours in MDA-MB-231 cells when compared to MCF-7 cells. The ex vivo loop assay with chitosan-coated Fe-bLf-loaded silk NPs was able to substantiate its future use in oral administration and showed the maximum absorption within 24 hours by ileum. Both Apo-bLf and Fe-bLf induced increase in expression of low-density lipoprotein receptor-related protein 1 and lactoferrin receptor in epidermal growth factor (EGFR)-positive MDA-MB-231 cells, while transferrin receptor (TfR) and TfR2 in MCF-7 cells facilitated the receptor-mediated endocytosis of NPs. Controlled and sustained release of both bLf from silk NPs was shown to induce more cancer-specific cytotoxicity in MDA-MB-231 and MCF-7 cells compared to normal MCF-10A cells. Due to higher degree of internalization, the extent of cytotoxicity and apoptosis was significantly higher in MDA-MB-231 (EGFR+) cells when compared to MCF-7 (EGFR-) cells. The expression of a prominent anti-cancer target, survivin, was found to be downregulated at both gene and protein levels. Taken together, all the observations suggest the potential use of Eri silk NPs as a delivery vehicle for an anti-cancer milk protein, and indicate bLf for the treatment of breast cancer. Keywords: breast cancer, silk nanoparticles, bovine lactoferrin, epidermal growth factor receptor, apoptosis

Namrata Anand,1 Rakesh Sehgal,1 Rupinder Kaur Kanwar,2 Mohan Lal Dubey,1 Rakesh Kumar Vasishta,3 Jagat Rakesh Kanwar21Department of Medical Parasitology, Postgraduate Institute of Medical Education and Research, Chandigarh, India; 2Nanomedicine-Laboratory of Immunology and Molecular Biomedical Research, School of Medicine, Centre for Molecular and Medical Research, Faculty of Health, Deakin University, Geelong, VIC, Australia; 3Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, IndiaAbstract: Toxoplasma gondii is a deadly intracellular parasite known to reside in every nucleated cell and known to cause severe complications in immunocompromised host. Standard drugs are cost effective and cause side effects, therefore, there is a necessity for a new drug molecule with immunomodulatory potential. Lactoferrin (Lf) is a natural milk protein, which has shown antimicrobial properties in its nanoformulation using alginate chitosan calcium phosphate bovine lactoferrin nanocapsules (AEC-CCo-CP-bLf-NCs). The present study was aimed to analyze and compare the effect of bovine Lf (bLf) in its native as well as nanoformulation (AEC-CCo-CP-bLf-NC) against coccidian parasite T. gondii. In vitro analysis has shown a significant increase in nitric oxide production and low parasitemia in in vitro cell culture model. In vivo BALB/c mice model have been used to develop human toxoplasmosis model. After treatment with NCs it has substantially increased the bioavailability of the protein and showed comparatively increased levels of reactive oxygen species, nitric oxide production, and Th1 cytokine which helped in parasite clearance. The mechanism of action of NCs has been clarified by immunoreactivity analysis, which showed accumulation of Lf in macrophages of various visceral organs, which is the site of parasite multiplication. Effect of NCs has significantly decreased (P

Bhasker Sriramoju, Rupinder K Kanwar, Jagat R Kanwar Nanomedicine-Laboratory of Immunology and Molecular Biomedical Research (NLIMBR), School of Medicine, Molecular and Medical Research, Faculty of Health, Deakin University, VIC, Australia Abstract: Multiple sclerosis (MS) is a chronic demyelinating neurological disorder affecting people worldwide; women are affected more than men. MS results in serious neurological deficits along with behavioral compromise, the mechanisms of which still remain unclear. Behavioral disturbances such as depression, anxiety, cognitive impairment, psychosis, euphoria, sleep disturbances, and fatigue affect the quality of life in MS patients. Among these, depression and psychosis are more common than any other neurological disorders. In addition, depression is associated with other comorbidities. Although anxiety is often misdiagnosed in MS patients, it can induce suicidal ideation if it coexists with depression. An interrelation between sleep abnormalities and fatigue is also reported among MS patients. In addition, therapeutics for MS is always a challenge because of the presence of the blood–brain barrier, adding to the lack of detailed understanding of the disease pathology. In this review, we tried to summarize various behavioral pathologies and their association with MS, followed by its conventional treatment and nanotheranostics. Keywords: demyelination, behavioral disorders, behavioral tests

Kislay Roy, Rupinder Kaur Kanwar, Jagat Rakesh Kanwar Nanomedicine-Laboratory of Immunology and Molecular Biomedical Research (NLIMBR), Centre for Molecular and Medical Research (C-MMR), Strategic Research Centre, School of Medicine (SoM), Faculty of Health, Deakin University, Waurn Ponds, VIC, Australia Abstract: Due to its severity and increasing epidemiology, arthritis needs no description. There are various forms of arthritis most of which are disabling, very painful, and common. In spite of breakthroughs in the field of drug discovery, there is no cure for arthritis that can eliminate the disease permanently and ease the pain. The present review focuses on some of the most successful drugs in arthritis therapy and their side effects. Potential new targets in arthritis therapy such as interleukin-1β, interleukin-17A, tumor necrosis factor alpha, osteopontin, and several others have been discussed here, which can lead to refinement of current therapeutic modalities. Mechanisms for different forms of arthritis have been discussed along with the molecules that act as potential biomarkers for arthritis. Due to the difficulty in monitoring the disease progression to detect the advanced manifestations of the diseases, drug-induced cytotoxicity, and problems with drug delivery; nanoparticle therapy has gained the attention of the researchers. The unique properties of nanoparticles make them highly attractive for the design of novel therapeutics or diagnostic agents for arthritis. The review also focuses on the recent trends in nanoformulation development used for arthritis therapy. This review is, therefore, important because it describes the relevance and need for more arthritis research, it brings forth a critical discussion of successful drugs in arthritis and analyses the key molecular targets. The review also identifies several knowledge gaps in the published research so far along with the proposal of new ideas and future directions in arthritis therapy. Keywords: osteoarthritis, rheumatoid arthritis, interleukin, osteopontin, nanoparticle, bovine lactoferrin

Namrata Anand,1 Rupinder K Kanwar,2 Mohan Lal Dubey,1 R K Vahishta,3 Rakesh Sehgal,1,* Anita K Verma,4 Jagat R Kanwar2,*1Department of Medical Parasitology, Postgraduate Institute of Medical Education and Research, Chandigarh, India; 2Nanomedicine Laboratory of Immunology and Molecular Biomedical Research, School of Medicine, Molecular and Medical Research Strategic Research Centre, Faculty of Health, Deakin University, Geelong, VIC, Australia; 3Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, 4Nanobiotech Laboratory, Department of Zoology, Kirorimal College, University of Delhi, Delhi, India*These authors contributed equally to this workBackground: Lactoferrin is a natural multifunctional protein known to have antitumor, antimicrobial, and anti-inflammatory activity. Apart from its antimicrobial effects, lactoferrin is known to boost the immune response by enhancing antioxidants. Lactoferrin exists in various forms depending on its iron saturation. The present study was done to observe the effect of lactoferrin, isolated from bovine and buffalo colostrum, on red blood cells (RBCs) and macrophages (human monocytic cell line-derived macrophages THP1 cells).Methods: Lactoferrin obtained from both species and in different iron saturation forms were used in the present study, and treatment of host cells were given with different forms of lactoferrin at different concentrations. These treated host cells were used for various studies, including morphometric analysis, viability by MTT assay, survivin gene expression, production of reactive oxygen species, phagocytic properties, invasion assay, and Toll-like receptor-4, Toll-like receptor-9, and MDR1 expression, to investigate the interaction between lactoferrin and host cells and the possible mechanism of action with regard to parasitic infections.Results: The mechanism of interaction between host cells and lactoferrin have shown various aspects of gene expression and cellular activity depending on the degree of iron saturation of lactoferrin. A significant increase (P0.05) change in percentage viability in the different groups of host cells treated, and no downregulation of survivin gene expression was found at 48 hours post-incubation. Upregulation of the Toll-like receptor and downregulation of the P-gp gene confirmed the immunomodulatory potential of lactoferrin protein.Conclusion: The present study details the interaction between lactoferrin and parasite host cells, ie, RBCs and macrophages, using various cellular processes and expression studies. The study reveals the possible mechanism of action against various intracellular pathogens such as Toxoplasma, Plasmodium, Leishmania, Trypanosoma, and Mycobacterium. The presence of iron in lactoferrin plays an important role in enhancing the various activities taking place inside these cells. This work provides a lot of information about targeting lactoferrin against many parasitic infections which can rule out the exact pathways for inhibition of diseases caused by intracellular microbes mainly targeting RBCs and macrophages for their survival. Therefore, this initial study can serve as a baseline for further evaluation of the mechanism of action of lactoferrin against parasitic diseases, which is not fully understood to date.Keywords: lactoferrin, phagocytosis, cytotoxicity, morphometric analysis

Ganesh Mahidhara, Rupinder K Kanwar, Kislay Roy, Jagat R Kanwar Nanomedicine-Laboratory of Immunology and Molecular Biomedical Research, School of Medicine, Molecular and Medical Research Strategic Research Centre, Faculty of Health, Deakin University, Waurn Ponds, VIC, Australia Abstract: We determined the anticancer efficacy and internalization mechanism of our polymeric–ceramic nanoparticle system (calcium phosphate nanocores, enclosed in biodegradable polymers chitosan and alginate nanocapsules/nanocarriers [ACSC NCs]) loaded with iron-saturated bovine lactoferrin (Fe-bLf) in a breast cancer xenograft model. ACSC-Fe-bLf NCs with an overall size of 322±27.2 nm were synthesized. In vitro internalization and anticancer efficacy were evaluated in the MDA-MB-231 cells using multicellular tumor spheroids, CyQUANT and MTT assays. These NCs were orally delivered in a breast cancer xenograft mice model, and their internalization, cytotoxicity, biodistribution, and anticancer efficacy were evaluated. Chitosan-coated calcium phosphate Fe-bLf NCs effectively (59%, P≤0.005) internalized in a 1-hour period using clathrin-mediated endocytosis (P≤0.05) and energy-mediated pathways (P≤0.05) for internalization; 3.3 mg/mL of ACSC-Fe-bLf NCs completely disintegrated (~130-fold reduction, P≤0.0005) the tumor spheroids in 72 hours and 96 hours. The IC50 values determined for ACSC-Fe-bLf NCs were 1.69 mg/mL at 10 hours and 1.62 mg/mL after 20 hours. We found that Fe-bLf-NCs effectively (P≤0.05) decreased the tumor size (4.8-fold) compared to the void NCs diet and prevented tumor recurrence when compared to intraperitoneal injection of Taxol and Doxorubicin. Receptor gene expression and micro-RNA analysis confirmed upregulation of low-density lipoprotein receptor and transferrin receptor (liver, intestine, and brain). Several micro-RNAs responsible for iron metabolism upregulated with NCs were identified. Taken together, orally delivered Fe-bLf NCs offer enhanced antitumor activity in breast cancer by internalizing via low-density lipoprotein receptor and transferrin receptor and regulating the micro-RNA expression. These NCs also restored the body iron and calcium levels and increased the hematologic counts. Keywords: oral delivery, Fe-bLf, miRNA, xenograft, breast cancer

Jagat R Kanwar,1 Rasika M Samarasinghe,1 Kuldeep Kumar,2 Ramesh Arya,2 Sanjeev Sharma,2 Shu-Feng Zhou,3 Sreenivasan Sasidharan,4 Rupinder K Kanwar11Nanomedicine-Laboratory of Immunology and Molecular Biomedical Research (NLIMBR), School of Medicine (SoM), Molecular and Medical Research (MMR) Strategic Research Centre, Faculty of Health, Geelong Technology Precinct (GTP), Deakin University, Waurn Ponds, VIC, Australia; 2Ayurvedic College, Paprola, Kangra, Himachal Pradesh, India; 3Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA; 4Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, Penang, MalaysiaIntroduction: Inflammatory mediators are key players in the pathogenesis of osteoarthritis (OA) and bone destruction. Conventional drugs suppress symptomatic activity and have no therapeutic influence on disease. Cissus quadrangularis and Withania somnifera are widely used for the treatment of bone fractures and wounds; however, the cellular and molecular mechanisms regulated by these herbals are still unclear.Methods: We established an in vitro OA culture model by exposing human chondrocytes to proinflammatory cytokine and interleukin (IL)-1β for 36 hours prior to treatment with the herbals: C. quadrangularis, W. somnifera, and the combination of the two herbals. Cell viability, toxicity, and gene expression of OA modifying agents were examined. In addition, expression of survivin, which is crucial for cell growth, was analyzed. In vivo work on osteotomized rats studied the bone and cartilage regenerative effects of C. quadrangularis, W. somnifera, and the combination therapy.Results: Exposure of chondrocytes to IL-1β induced significant toxicity and cell death. However, herbal treatment alleviated IL-1β induced cell toxicity and upregulated cell growth and proliferation. C. quadrangularis inhibited gene expression of cytokines and matrix metalloproteinases, known to aggravate cartilage and bone destruction, and augmented expression of survivin by inhibiting p38 MAPK. Interestingly, osteotomized rats treated with C. quadrangularis drastically enhanced alkaline phosphatase and cartilage tissue formation as compared to untreated, W. somnifera only, or the combination of both herbals.Conclusion: Our findings demonstrate for the first time the signaling mechanisms regulated by C. quadrangularis and W. somnifera in OA and osteogenesis. We suggest that the chondroprotective effects and regenerative ability of these herbals are via the upregulation of survivin that exerts inhibitory effects on the p38 MAPK signaling pathway. These findings thus validate C. quadrangularis as a potential therapeutic for rheumatic disorders.Keywords: cytokines, inflammation, osteoarthritis, Withania somnifera, alternative therapy, herbal

Kislay Roy,1 Rupinder K Kanwar,1 Subramanian Krishnakumar,2,3 Chun Hei Antonio Cheung,4 Jagat R Kanwar1 1Nanomedicine-Laboratory of Immunology and Molecular Biomedical Research (NLIMBR), Molecular and Medical Research (MMR) Strategic Research Centre, School of Medicine (SoM), Faculty of Health, Deakin University, Waurn Ponds, VIC, Australia; 2Department of Nanobiotechnology, 3Larsen & Toubro (L&T) Ocular Pathology Department, Vision Research Foundation, Kamalnayan Bajaj Institute for Research in Vision and Ophthalmology, Chennai, India; 4Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China Abstract: Endogenous survivin expression has been related with cancer survival, drug resistance, and metastasis. Therapies targeting survivin have been shown to significantly inhibit tumor growth and recurrence. We found out that a cell-permeable dominant negative survivin (SurR9-C84A, referred to as SR9) competitively inhibited endogenous survivin and blocked the cell cycle at the G1/S phase. Nanoencapsulation in mucoadhesive chitosan nanoparticles (CHNP) substantially increased the bioavailability and serum stability of SR9. The mechanism of nanoparticle uptake was studied extensively in vitro and in ex vivo models. Our results confirmed that CHNP–SR9 protected primary cells from autophagy and successfully induced tumor-specific apoptosis via both extrinsic and intrinsic apoptotic pathways. CHNP–SR9 significantly reduced the tumor spheroid size (three-dimensional model) by nearly 7-fold. Effects of SR9 and CHNP–SR9 were studied on 35 key molecules involved in the apoptotic pathway. Highly significant (4.26-fold, P≤0.005) reduction in tumor volume was observed using an in vivo mouse xenograft colon cancer model. It was also observed that net apoptotic (6.25-fold, P≤0.005) and necrotic indexes (3.5-fold, P≤0.05) were comparatively higher in CHNP–SR9 when compared to void CHNP and CHNP–SR9 internalized more in cancer stem cells (4.5-fold, P≤0.005). We concluded that nanoformulation of SR9 did not reduce its therapeutic potential; however, nanoformulation provided SR9 with enhanced stability and better bioavailability. Our study presents a highly tumor-specific protein-based cancer therapy that has several advantages over the normally used chemotherapeutics. Keywords: nanoparticle, chitosan, mucoadhesive, cytotoxicity, xenograft

Bhasker Sriramoju, Rupinder K Kanwar, Jagat R Kanwar Nanomedicine Laboratory of Immunology and Molecular Biomedical Research (NLIMBR), School of Medicine, Faculty of Health, Deakin University, Geelong, Australia Abstract: In this study, we investigated the differential actions of a dominant-negative survivin mutant (SurR9-C84A) against cancerous SK-N-SH neuroblastoma cell lines and differentiated SK-N-SH neurons. In both the cases, the mutant protein displayed dual actions, where its effects were cytotoxic toward cancerous cells and proliferative toward the differentiated neurons. This can be explained by the fact that tumorous (undifferentiated SK-N-SH) cells have a high endogenous survivin pool and upon treatment with mutant SuR9-C84A causes forceful survivin expression. These events significantly lowered the microtubule dynamics and stability, eventually leading to apoptosis. In the case of differentiated SK-N-SH neurons that express negligible levels of wild-type survivin, the mutant indistinguishably behaved in a wild-type fashion. It also favored cell-cycle progression, forming the chromosome-passenger complex, and stabilized the microtubule-organizing center. Therefore, mutant SurR9-C84A represents a novel therapeutic with its dual actions (cytotoxic toward tumor cells and protective and proliferative toward neuronal cells), and hence finds potential applications against a variety of neurological disorders. In this study, we also developed a novel poly(lactic-co-glycolic acid) nanoparticulate formulation to surmount the hurdles associated with the delivery of SurR9-C84A, thus enhancing its effective therapeutic outcome. Keywords: survivin mutant, neurological disorders, protein therapeutics, inhibitor of apoptosis protein family, poly(lactic-co-glycolic acid)

Jagat R Kanwar, Bhasker Sriramoju, Rupinder K KanwarNanomedicine Laboratory of Immunology and Molecular Biomedical Research, Centre for Biotechnology and Interdisciplinary Biosciences, Institute for Frontier Materials (IFM), Deakin University, Waurn Ponds, Victoria, AustraliaAbstract: We are now in an aging population, so neurological disorders, particularly the neurodegenerative diseases, are becoming more prevalent in society. As per the epidemiological studies, Europe alone suffers 35% of the burden, indicating an alarming rate of disease progression. Further, treatment for these disorders is a challenging area due to the presence of the tightly regulated blood–brain barrier and its unique ability to protect the brain from xenobiotics. Conventional therapeutics, although effective, remain critically below levels of optimum therapeutic efficacy. Hence, methods to overcome the blood–brain barrier are currently a focus of research. Nanotechnological applications are gaining paramount importance in addressing this question, and yielding some promising results. This review addresses the pathophysiology of the more common neurological disorders and novel drug candidates, along with targeted nanoparticle applications for brain delivery.Keywords: blood–brain barrier, neurological diseases, brain delivery, targeted nanoparticles

Kanwar JR, Samarasinghe RM, Kumar K, et al. Drug Des Devel Ther. 2015;9:2927–2940. The authors have become aware of an error in Figure 6D on page 2936. The corrected figure with the replacement figure part (Figure 6D, W. som image) is provided here. Read the original article

Introduction: Conservation agriculture (CA) is emerging as an eco-friendly and sustainable approach to food production in South Asia. CA, characterized by reduced tillage, soil surface cover through retaining crop residue or raising cover crops, and crop diversification, enhances crop production and soil fertility. Fungal communities in the soil play a crucial role in nutrient recycling, crop growth, and agro-ecosystem stability, particularly in agricultural crop fields., Methods: This study investigates the impact of seven combinations of tillage and crop residue management practices of agricultural production systems, including various tillage and crop residue management practices, on soil fungal diversity. Using the Illumina MiSeq platform, fungal diversity associated with soil was analysed., Results and Discussion: The results show that the partial CA-based (pCA) production systems had the highest number of unique operational taxonomic units (OTUs) (948 OTUs) while the conventional production system had the lowest number (665 OTUs). The major fungal phyla identified in the topsoil (0-15 cm) were Ascomycota, Basidiomycota, and Mortierellomycota, with their abundance varying across different tillage- cum -crop establishment (TCE) methods. Phylum Ascomycota was dominant in CA-based management treatments (94.9±0.62), followed by the partial CA (pCA)-based treatments (91.0 ± 0.37). Therefore, CA-based production systems play a crucial role in shaping soil fungal diversity, highlighting their significance for sustainable agricultural production., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Kumar, Choudhary, Naik, Mishra, Banra, Poonia, Mondal, Das, Rao, Kumar, Bhatt, Chaudhari, Malik and McDonald.)

Background: In the current scenario, the synthesis of nanoparticles (NPs) using environmentally benign methods has gained significant attention due to their facile processes, cost-effectiveness, and eco-friendly nature., Methods: In the present study, copper oxide nanoparticles (CuO NPs) were synthesized using aqueous extract of Coelastrella terrestris  algae as a reducing, stabilizing, and capping agent. The synthesized CuO NPs were characterized by X-ray diffraction (XRD), UV-visible spectroscopy (UV-Vis), Fourier transform infrared spectroscopy (FTIR), dynamic light scattering (DLS), and field emission scanning electron microscopy (FE-SEM) coupled with energy-dispersive X-ray spectroscopy (EDS)., Results: XRD investigation revealed that the biosynthesized CuO NPs were nanocrystalline with high-phase purity and size in the range of 4.26 nm to 28.51 nm. FTIR spectra confirmed the existence of secondary metabolites on the surface of the synthesized CuO NPs, with characteristic Cu-O vibrations being identified around 600 cm -1 , 496 cm -1 , and 440 cm -1 . The FE-SEM images predicted that the enhancement of the algal extract amount converted the flattened rice-like structures of CuO NPs into flower petal-like structures. Furthermore, the degradation ability of biosynthesized CuO NPs was investigated against Amido black 10B (AB10B) dye. The results displayed that the optimal degradation efficacy of AB10B dye was 94.19%, obtained at 6 pH, 50 ppm concentration of dye, and 0.05 g dosage of CuO NPs in 90 min with a pseudo-first-order rate constant of 0.0296 min -1 . The CuO-1 NPs synthesized through algae exhibited notable antibacterial efficacy against S. aureus with a zone of inhibition (ZOI) of 22 mm and against P. aeruginosa with a ZOI of 17 mm., Conclusion: Based on the findings of this study, it can be concluded that utilizing Coelastrella terrestris algae for the synthesis of CuO NPs presents a promising solution for addressing environmental contamination., Competing Interests: The authors have no competing interests to declare that are relevant to the content of this article., (© 2024 Khandelwal et al.)

In recent years, there has been an increasing interest in the green synthesis of metallic nanoparticles, mostly because of the evident limitations associated with chemical and physical methods. Green synthesis, commonly referred to as "biogenic synthesis," is seen as an alternative approach to produce AgNPs (silver nanoparticles). The current work focuses on the use of Asterarcys sp. (microalga) for biological reduction of AgNO 3 to produce AgNPs. The optimal parameters for the reduction of AgNPs were determined as molarity of 3 mM for AgNO 3 and an incubation duration of 24 h at pH 9, using a 20:80 ratio of algal extract to AgNO 3 . The biosynthesized Ast-AgNPs were characterised using ultraviolet-visible spectroscopy (UV-Vis), zeta potential, scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), energy-dispersive X-ray spectroscopy (EDX), and high-resolution transmission electron microscopy (HR-TEM) with selected area electron diffraction (SAED) patterns. The nanoparticles exhibited their highest absorption in the UV-visible spectra at 425 nm. The X-ray diffraction (XRD) investigation indicated the presence of characteristic peaks at certain angles: 38.30° (1 1 1), 44.40° (2 0 0), 64.64° (2 2 0), and 77.59° (3 1 1) according to the JCPDS file No. 04-0783. Based on SEM and TEM, the Ast-AgNPs had an average size of 35 nm and 52 nm, respectively. The zeta potential was determined to be - 20.8 mV, indicating their stability. The highest antibacterial effectiveness is shown against Staphylococcus aureus, with a zone of inhibition of 25.66 ± 1.52 mm at 250 μL/mL conc. of Ast-AgNPs. Likewise, Ast-AgNPs significantly suppressed the growth of Fusarium sp. and Curvularia sp. by 78.22% and 85.05%, respectively, at 150 μL/mL conc. of Ast-AgNPs. In addition, the Ast-AgNPs exhibited significant photocatalytic activity in degrading methylene blue (MB), achieving an 88.59% degradation in 120 min, revealing multiple downstream applications of Ast-AgNPs., (© 2024. The Author(s).)

A substantial percentage of kidney transplant recipients show transplant failure due to BK virus-induced nephropathy. This can be clinically controlled by the rapid and timely detection of BK virus infection in immune-compromised patients. We report a rapid (two hours from sample collection, processing, and detection), cost-effective (< 2$), highly sensitive and BKV-specific nanoLAMP (loop-mediated isothermal amplification) diagnostic methodology using novel primers and gold nanoparticles complex-based visual detection. The standardized nanoLAMP showed an analytical sensitivity of 25 copies/µl and did not cross-react with closely related JC and SV40 viruses. This nanoLAMP showed diagnostic sensitivity and specificity as 91% and 96%, respectively, taking 50 BK virus-negative (confirmed by qPCR from the plasma of healthy donors) and 57 positive BKV patient samples (confirmed by clinical parameters and qPCR assay). This simple two-step, low-cost, and quick (1-2 h/test) detection would be advantageous over the currently used diagnostic methodology. It may change the paradigm for polyomavirus infection-based failure of renal transplant., Competing Interests: Declaration of Competing Interest This was filed as an Indian Patent (202211058621) dated 13 October 2022. Apart from this, all authors declare no conflict of interest. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2024 Elsevier B.V. All rights reserved.)

The present article explores the synthesis of copper oxide nanoparticles (CuO NPs) utilizing Asterarcys quadricellulare algal extract and examines the effect of various reaction parameters on the size and morphology of the nanoparticles. The samples were thoroughly characterized using XRD, FTIR, UV-vis, FE-SEM, and EDS techniques. The XRD analysis disclosed that the size of the synthesized nanoparticles could be controlled by adjusting the reaction parameters, ranging from 4.76 nm to 13.70 nm along the highest intensity plane (111). FTIR spectroscopy provided evidence that the phytochemicals are present in the algal extract. We have compared the photocatalytic activity of biologically and chemically synthesized CuO NPs and observed that biologically synthesized CuO NPs showed better photocatalytic activity than chemically synthesized CuO NPs. The biosynthesized CuO NPs (S8) demonstrated outstanding photodegradation activity towards four different organic dyes, namely BBY, BG, EBT, and MG, with degradation percentages of 95.78%, 98.02%, 94.15%, and 96.04%, respectively. The maximum degradation efficacy of 98.02% was observed for the BG dye at optimized reaction conditions and 60 min of visible light exposure. The kinetics of the photodegradation reaction followed the pseudo-first-order kinetic model, and the rate constant ( k ) was calculated using the Langmuir-Hinshelwood model for each dye. This study provides an efficient and sustainable approach for synthesizing CuO NPs with superior photocatalytic degradation efficiency towards organic dyes., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Objective: Diabetic cardiomyopathy (DC) is one of the severe secondary complications of diabetes mellitus in humans. Vinpocetine is an alkaloid having pleiotropic pharmacological effects. The present study is designed to investigate the effect of vinpocetine in DC in rats., Methods: Rats were fed a high-fat diet for nine weeks along with single dose of streptozotocin after the second week to induce DC. The haemodynamic evaluation was performed to assess the functional status of rats using the Biopac system. Cardiac echocardiography, biochemical, oxidative stress parameters and inflammatory cytokine level were analysed in addition to haematoxylin-eosin and Masson's trichome staining to study histological changes, cardiomyocyte diameter and fibrosis, respectively. Phosphodiesterase-1 (PDE-1), transforming growth factor-β (TGF-β) and p-Smad 2/3 expression in cardiac tissues were quantified using western blot/RT-PCR., Key Finding: Vinpocetine treatment and its combination with enalapril decreased the glucose levels compared to diabetic rats. Vinpocetine improved the echocardiographic parameters and cardiac functional status of rats. Vinpocetine decreased the cardiac biochemical parameters, oxidative stress, inflammatory cytokine levels, cardiomyocyte diameter and fibrosis in rats. Interestingly, expressions of PDE-1, TGF-β and p-Smad 2/3 were ameliorated by vinpocetine alone and in combination with enalapril., Conclusions: Vinpocetine is a well-known inhibitor of PDE-1 and the protective effect of vinpocetine in DC is exerted by inhibition of PDE-1 and subsequent inhibition of the expression of TGF-β/Smad 2/3., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Uranium, naturally occurring radionuclide is chemotoxic and nephrotoxic beyond acceptable limit. The presence of uranium beyond acceptable limit in surface and ground water, adversely affecting people's health. In the present investigation, the uranium concentration in surface and ground water of Chittorgarh, Rajasthan was studied along with the physico-chemical parameters of water (n = 87). The ground water was further sub-categorised into well water, handpump water, and borewell water. The mean uranium concentration was observed at 2.5 ± 1.9 µgL -1 and 16.5 ± 1.4 µgL -1 in the surface and ground water samples, respectively. In sub-categories of ground water, the highest uranium concentration was found in borewell water (23.3 ± 17.0 µgL -1 ), followed by handpump water (13.5 ± 9.1 µgL -1 ) and well water (6.0 ± 5.5 µgL -1 ). The uranium concentration was correlated significantly with the depth of the ground water table. It also correlated significantly with electrical conductivity, total dissolved solids and nitrate concentration. 100% of surface water and 88.9% of ground water samples carried uranium concentration within the acceptable limit of WHO (30 µgL -1 ). The annual ingestion dose was found at 3.8 µSvy -1 (for males) and 2.8 µSvy -1 (for females) in surface water and 25.4 µSvy -1 (for males) and 18.5 µSvy -1 (for females) in ground water. In the sub-categories of the ground water sample, the annual ingestion dose followed the trend in males 35.8 µSvy -1 (borewell water) > 20.7 µSvy -1 (hand pump water) > 9.2 µSvy -1 (well water) and in females 26.1 µSvy -1 (borewell water) > 15.1 µSvy -1 (hand pump water) > 6.7 µSvy -1 (well water)., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Introduction: Conservation agriculture (CA) is gaining attention in the South Asia as an environmentally benign and sustainable food production system. The knowledge of the soil bacterial community composition along with other soil properties is essential for evaluating the CA-based management practices for achieving the soil environment sustainability and climate resilience in the rice-wheat-greengram system. The long-term effects of CA-based tillage- cum -crop establishment (TCE) methods on earthworm population, soil parameters as well as microbial diversity have not been well studied., Methods: Seven treatments (or scenarios) were laid down with the various tillage (wet, dry, or zero-tillage), establishment method (direct-or drill-seeding or transplantation) and residue management practices (mixed with the soil or kept on the soil surface). The soil samples were collected after 7 years of experimentation and analyzed for the soil quality and bacterial diversity to examine the effect of tillage- cum -crop establishment methods., Results and Discussion: Earthworm population (3.6 times), soil organic carbon (11.94%), macro (NPK) (14.50-23.57%) and micronutrients (Mn, and Cu) (13.25 and 29.57%) contents were appreciably higher under CA-based TCE methods than tillage-intensive farming practices. Significantly higher number of OTUs (1,192 ± 50) and Chao1 (1415.65 ± 14.34) values were observed in partial CA-based production system ( p ≤ 0.05 ). Forty-two (42) bacterial phyla were identified across the scenarios, and Proteobacteria , Actinobacteria , and Firmicutes were the most dominant in all the scenarios. The CA-based scenarios harbor a high abundance of Proteobacteria (2-13%), whereas the conventional tillage-based scenarios were dominated by the bacterial phyla Acidobacteria and Chloroflexi and found statistically differed among the scenarios ( p  ≤ 0.05). Composition of the major phyla, i.e., Proteobacteria, Actinobacteria , and Firmicutes were associated differently with either CA or farmers-based tillage management practices. Overall, the present study indicates the importance of CA-based tillage- cum -crop establishment methods in shaping the bacterial diversity, earthworms population, soil organic carbon, and plant nutrient availability, which are crucial for sustainable agricultural production and resilience in agro-ecosystem., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kumar, Choudhary, Naik, Mondal, Mishra, Poonia, Kumar, Hans, Kumar, Das, Kumar, Bhatt, Chaudhari, Malik, Craufurd, McDonald and Sherpa.)

Background: Diabetic kidney disease (DKD) is the commonest cause of end-stage renal disease (ESRD) across the world. Development of microalbuminuria is the earliest marker of DKD and predicts progressive decline in estimated glomerular filtration rate (eGFR). However, recent evidence has suggested that a significant proportion of type 2 diabetic patients have chronic kidney disease (CKD) without proteinuria., Methods: In this single-center, prospective observational study, 400 consecutive type 2 diabetic patients with either overt proteinuria (>500 mg/day) and/or renal dysfunction eGFR <60 ml/min/1.73 m 2 ) were recruited. Baseline demographic and clinical data were recorded. eGFR and proteinuria were recorded at 6 months and 1 year. Patients with proteinuric (proteinuria >0.5 g/day) and nonproteinuric phenotypes were compared for progression of renal dysfunction in terms of doubling of serum creatinine and need for dialysis., Results: In our study cohort, 106 (26.5%) were nonproteinuric. Both the groups were similar in terms of gender, duration of diabetes, comorbidities, body mass index (BMI), blood pressure control, and glycemic control. The nonproteinuric group was older (56.5 ± 2.1 vs. 54.7 ± 11.6 years, P = 0.012), had lesser prevalence of diabetic retinopathy (49 [46.2%] vs. 218 [74.1%], P < 0.001), higher hemoglobin levels (11.3 ± 1.7 vs. 10.5 ± 2.0 g/dl, P < 0.001), and higher cholesterol levels (169.3 ± 43.3 vs 157.1 ± 58.1 mg/dl, P = 0.025). The nonproteinuric phenotype had higher eGFR at baseline, 6 months, and 1 year. However, doubling of serum creatinine (10 [9.4%] vs. 48 [16.3%]) and progression to ESRD (5 [4.7%] vs. 19 [6.5%], P = 0.159) were not different between the two phenotypes., Conclusion: Nonproteinuric DKD is common. Patients with nonproteinuric DKD tend to be older with a slower decline in eGFR., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Indian Journal of Nephrology.)

Background: Hemodialysis is the most common treatment modality for patients with chronic kidney disease (CKD). Excessive daytime sleepiness and poor nighttime sleep is a common problem among these patients. Patients on maintenance hemodialysis (MHD) are regularly exposed to impaired fluid balance, which may cause overhydration of varying degree. However, the role of hydration status in sleep quality has not been explored in Indian setting. Hence, this study was undertaken to assess the factors affecting sleep quality among patients on MHD in a tertiary care hospital., Material and Methods: Patients (N = 55) were enrolled if they aged above18 years, on MHD for at least 3 months, and gave consent. The daytime sleep quality was assessed using Epworth Sleepiness Scale (ESS) and Insomnia Severity Index (ISI). The data were analyzed using SPSS version 20 and STATA software., Results: The mean age of the patients was 40.4 ± 14.7 years. The prevalence rate of predialysis fluid overload was 85.4%. The median ESS score was 7 and ISI score was 3 indicating normal daytime sleep and not significant insomnia. Multivariate regression with variables adjustment showed that interdialytic weight gain (P = 0.33), tingling sensation (P = 0.36) and numbness (P = 0.35) were significant predictive factors for quality of sleep., Conclusion: The major factors affecting sleep quality were numbness, tingling sensation, and interdialytic weight gain. Fluid overload did not play any role in sleep quality. Another study may be carried out on assessment of pattern, duration, quality of sleep in multiple dialysis sessions, and effect of optimizing fluid status on the sleep parameters., (© 2022 Wiley Periodicals LLC.)

Purpose: There is an increasing burden of kidney diseases worldwide and access to specialist care is limited. Telemedicine, has been relatively less used in developing countries like India. The current study aims to assess the feasibility and acceptance of telenephrology services at our institute, a public hospital., Methods: A total of 150 patients were selected by stratified random sampling from the list of attendees who had undergone both in-person outpatient consultation and telenephrology consultation. Patient's attitude towards, and knowledge and acceptance of telenephrology services were evaluated., Results: The average age of the study cohort was 42.52 ± 15.1 years. More than one-third (39.3%) of our patients belonged to the lower middle socioeconomic class. The median distance traveled to reach our outpatient clinic was 113.5 km (3-2249 km). Patients reported lost workdays in 54.7% cases. The majority (95%) of patients managed to consult through teleservices successfully. Ninety percent of the patients gave a satisfaction score of 4 (out of 5) or above for their tele-consultation experience. The most important perceived benefit of teleconsultation was the reduced risk of infection (40.6%) followed by economic benefits (32%). The major disadvantage (36%) was the absence of physical examination. A combination of physical and telenephrology services was the option preferred by 84% of the patients., Conclusion: In developing countries like India, with the majority of the population residing outside major cities and with limited medical access, telenephrology has a huge potential to provide quality nephrology care to the remotest parts of the country., (© 2022. The Author(s) under exclusive licence to Italian Society of Nephrology.)

Iron, an essential trace element, plays a complex role in tumour biology. While iron causes cancer clearance through toxic free radical generation, iron-induced free radical flux also acts as a cancer promoter. These fates majorly guided through cellular response towards pro-oxidant and antioxidant settings in a tumour microenvironment, designate iron-induced oxidative stress as a common yet paradoxical factor in pro-tumorigenesis as well as anti-tumorigenesis, posing a challenge to laying down iron thresholds favouring tumour clearance. Additionally, complexity of iron's association with carcinogenesis has been extended to iron-induced ROS's involvement in states of both iron deficiency and overload, conditions identified as comparable, inevitable and significant coexisting contributors as well as outcomes in chronic infections and tumorigenesis. Besides, iron overload may also develop as an unwanted outcome in certain cancer patients, as a result of symptomatic anaemia treatment owed to irrational iron-restoration therapies without a prior knowledge of body's iron status with both conditions synergistically acting towards tumour aggravation. The co-play of iron deficiency and overload along with iron's pro-tumour and antitumour roles with intersecting mechanisms, thus presents an unpredictable regulatory response loop in a state of malignancy. The relevance of iron's thresholds beyond which it proves to be beneficial against tumorigenesis hence becomes questionable. These factors pose a challenge, over establishing if iron chelation or iron flooding acts as a better approach towards antitumour therapies. This review presents a critical picture of multiple contrasting features of iron's behaviour in cancer, leading towards two conditions lying at opposite ends of a spectrum: iron deficiency and overload in chronic disease conditions including cancer, hence, validating the critical significance of diagnosis of patients' iron status prior to opting for subsequent therapies., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Enantioselective synthesis through photocatalysis is one of the highly preferred approaches towards preparation of optically active compounds. This review elaborates and critically analyzes the different strategies of photocatalytic enantioselective reactions through H-bonding, transition metal catalysis, phase-transfer catalysis (PTC), chiral Lewis acid catalysis, N-heterocyclic carbene catalysis, and amine catalysis, and also explores ion pairs. In addition, it explains the different catalysis modes with multifunctional approaches for enantioselective photocatalytic reactions., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Diabetic kidney disease (DKD) is the chief cause of renal involvement in diabetic patients. It is primarily a clinical diagnosis. Non-diabetic kidney disease (NDKD) may be missed if they are not biopsied. In this study, we describe the spectrum of NDKD and evaluate the predictors considered for planning a biopsy in diabetic patients with kidney disease., Methods: In a retrospective cohort study, diabetic patients who underwent kidney biopsy at our centre between May 2006 and July 2019 were evaluated for NDKD., Results: 321 diabetic patients who underwent kidney biopsy were analyzed. Mean age was 49.3 ± 12.4 years and 71% were males. 75.8% patients had hypertension and 25.2% had diabetic retinopathy. Based on the kidney biopsy, patients were classified as DKD-127 (39.6%), NDKD-179(55.8%) and combined DKD + NDKD-15(4.7%). Overall, the most commonly diagnosed pathology was membranous nephropathy-MN (17%), followed by IgA nephropathy (16.0%) and focal segmental glomerulosclerosis-FSGS (14.9%). In patients with DKD + NDKD, IgA nephropathy (53.3%) was predominant. 165 (51.4%) patients had a diagnosis potentially amenable to a specific therapy. On multivariate analysis, female gender [OR 2.07 (1.08-3.97), p = 0.02], absence of diabetic retinopathy [OR 7.47 (3.71-15), p < 0.001] absence of hypertension [OR 3.17 (1.56-6.45), p = 0.001] and duration of diabetes ≤ 24 months [OR 3.67(1.97-6.84), p < 0.001], were independent predictors for NDKD while the absence of nephrotic range proteinuria [OR 1.73 (0.98-3.05), p 0.05] showed a trend towards significance., Conclusion: Astute use of kidney biopsy can detect potentially treatable NDKD in a large number of diabetic patients with glomerular diseases being the predominant diagnosis. A combination of risk factors needs to be considered to guide the need for kidney biopsy in diabetic patients., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Introduction: International IgA nephropathy (IgAN) network (IIgANN) prediction tool was developed to predict risk of progression in IgAN. We attempted to externally validate this tool in an Indian cohort because the original study did not include Indian patients., Methods: Adult patients with primary IgAN were stratified to low, intermediate, higher, and highest risk groups, as per the original model. Primary outcome was reduction in estimated glomerular filtration rate (eGFR) by >50% or kidney failure. Both models were evaluated using discrimination: concordance statistics (C-statistics), time-dependent receiver operating characteristic (ROC) curves, R 2 d, Kaplan-Meier survival curves between risk groups and calibration plots. Reclassification with net reclassification improvement and integrated discrimination improvement (IDI) was used to compare the 2 models with and without race., Results: A total of 316 patients with median follow-up of 2.8 years had 87 primary outcome events. Both models with and without race showed reasonable discrimination (C-statistics 0.845 for both models, R 2 d 49.9% and 44.7%, respectively, and well-separated survival curves) but underestimated risk of progression across all risk groups. The calibration slopes were 1.234 (95% CI: 0.973-1.494) and 1.211 (95% CI: 0.954-1.468), respectively. Both models demonstrated poor calibration for predicting risk at 2.8 and 5 years. There was limited improvement in risk reclassification risk at 5 and 2.8 years when comparing model with and without race., Conclusion: IIgANN prediction tool showed reasonable discrimination of risk in Indian patients but underestimated the trajectory of disease progression across all risk groups., (© 2022 International Society of Nephrology. Published by Elsevier Inc.)

Conservation agriculture (CA), which encompasses minimum soil disturbance, residue retention either through crop residue, or cover crops and crop diversification-based crop management practices can modify the status of pest dynamics and activities under the changing climatic scenarios. CA has been advocated extensively to optimize the use of available resources, maintain the environmental quality, enhance crop productivity, and reduce the climate change impacts. Information related to the impacts of long-term CA-production systems under rice-based cropping systems on pest status is lacking, particularly in middle Indo-Gangetic Plains (MIGP). Under CA, puddling is completely avoided, and rice is directly sown or transplanted to maintain better soil health. Different sets of experimentations including farmers practice, partial CA and full CA (CA) as treatments in rice-based cropping systems, were established from 2009, 2015 and 2016 to understand the long-term impacts of CA on pest dynamics. In this study, direct and indirect effects of tillage (zero, reduced and conventional tillage), residue retention and cropping sequences on abundance and damage by pests were investigated. After 4-5 years of experimentation, populations of oriental armyworm [Mythinma (Leucania) (Pseudaletia) separata (Wlk.)] in wheat, mealybug [Brevennia rehi (Lindinger)] and bandicoot rat [Bandicota bengalensis (Gray)] in rice were found to increase abnormally in CA-based production systems. Conventionally tilled plots had a significant negative effect while residue load in zero-tilled plots had a significant positive effect on larval population build-up of M. separata. Zero tillage had a higher infestation of mealybug (52-91% infested hills) that used grassy weeds (Echinochloa colona, Echinochloa crusgalli, Cynodon dactylon, Leptochloa chinensis and Panicum repense) as alternate hosts. Cropping sequences and no disturbance of soil and grassy weeds had higher live burrow counts (4.2 and 13.7 burrows as compared to 1.47 and 7.53 burrows per 62.5 m 2 during 2019-2020 and 2020-2021, respectively) and damaged tillers (3.4%) in CA-based practices. Based on the present study, pest management strategies in CA need to be revisited with respect to tillage, residue retention on soil surface, grassy weeds in field and cropping sequences to deliver the full benefits of CA in MIGP to achieve the sustainable development goals under the climate change scenarios., (© 2022. The Author(s).)

Background: There is limited information about the incidence of metabolic acidosis (MA) after renal transplantation. This single centre prospective study aimed to delineate the incidence and risk factors of MA in the first 6 months after renal transplantation (RTX)., Design, Setting, Participants and Measurements: Patients who underwent RTX between November 2018 and July 2020 were monitored with weekly measurement of serum bicarbonate level for 6 months and those who were diagnosed with MA were evaluated further to characterize the type of MA., Results: One hundred and twenty-five patients were included in the study, 89 (71.2%) of whom developed MA. Seventy-two patients developed MA in the first month, 11 during the 2-3 months and 6 between 4 and 6 months after transplantation. Of the 89 patients, 55(61.8%) had type 1 renal tubular acidosis (T1RTA), 27 (30.3%) had type 2 RTA (T2RTA) and 7 (7.9%) type 4 RTA (T4RTA). Two patient who had T1RTA, subsequently developed high anion gap MA following severe graft rejection. On stepwise multivariate regression analysis, serum creatinine at time of diagnosis of MA [OR (95% CI): 12.02 (1.79 to 80.59), p = .01] and high tacrolimus C0 levels [OR (95% CI): 2.43 (1.0 to 5.90), p = .049], were independent risk factors for MA., Conclusion: There is a high incidence of MA in the initial 6 months post-transplant with serum creatinine and high tacrolimus C0 levels being independent risk factors., (© 2021 Asian Pacific Society of Nephrology.)

Background: Adolescents are being involved in aggressive activities nowadays. Sometimes, involvement in aggressive activities may be fatal for the victim as well as for the doer. It is a matter of great concern for all including parents, teachers, psychologists, social reformers, and others. A momentary expression of anger sometimes may spoil the future life of the adolescents., Aim and Objectives: To determine the prevalence of aggression and to identify the psychosocial risk factors associated with aggression among school-going adolescents., Methodology: The study recruited 480 school-going rural adolescents from eight government senior secondary schools in the rural block of Beri, district Jhajjar (Haryana)., Observations: The mean age of the adolescents was 14.11 ± 1.12 years; 49.4% of the adolescents were found to be aggressive. After applying binary logistic regression, there was a statistically significant relation between aggression and determinants like class, gender, occupation of the father., Conclusion and Recommendations: The study concluded that determinants like age, class of students, gender of the subject, occupation of father found a significant association with aggression. To solve this current situation, parents must give love, attention to their children and must act in an appropriate way in front of them and be role models., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Journal of Family Medicine and Primary Care.)

In chronic kidney disease (CKD) toxins accumulate in the muscles and cause fatigue, mental impairment, and muscle dysfunction (cramps). Exercise results in the opening of capillaries thereby increasing blood flow and allowing greater movement of urea and creatinine from the tissues to the vascular compartment and subsequent removal through dialysis. An experimental study of 64 CKD patients (32 each in experimental and control group), six low-intensity intra-dialytic exercises (IDE) were implemented for experimental group using video demonstration at 90 min after initiation of hemodialysis (HD) repeated thrice at an interval of 10 mins. Pre- and post-HD serum urea, creatinine, and fatigue levels were assessed at baseline, two, four and six weeks. Fatigue was measured using FACIT scale. Significant difference was found between the control and experimental group in serum urea, creatinine and fatigue levels (P = 0.007, P = 0.001, P = 0.001) at six weeks post HD. The experimental group showed a significant decrease in creatinine levels from baseline to six weeks (P = 0.04). Ninety-seven percent of patients were compliant to low-intensity IDE with patients feeling better and comfortable along with decrease in felt fatigue levels. No significant association was found between duration of illness, duration of maintenance HD and comorbidities and serum urea, serum creatinine, and fatigue levels (P = 0.5, P = 0.21, P = 0.78). The present study shows low-intensity IDE when performed regularly, was effective in decreasing serum urea, creatinine, and fatigue levels of CKD patients undergoing HD with vital signs remaining within the normal range. No overt complications were reported; hence, the exercises were safe.

Objective: To undertake a genome-wide association study (GWAS) to identify genetic variants for stroke in an Indian population., Methods: In a hospital-based case-control study, 8 teaching hospitals in India recruited 4,088 participants, including 1,609 stroke cases. Imputed genetic variants were tested for association with stroke subtypes using both single-marker and gene-based tests. Association with vascular risk factors was performed with logistic regression. Various databases were searched for replication, functional annotation, and association with related traits. Status of candidate genes previously reported in the Indian population was also checked., Results: Associations of vascular risk factors with stroke were similar to previous reports and show modifiable risk factors such as hypertension, smoking, and alcohol consumption as having the highest effect. Single-marker-based association revealed 2 loci for cardioembolic stroke (1p21 and 16q24), 2 for small vessel disease stroke (3p26 and 16p13), and 4 for hemorrhagic stroke (3q24, 5q33, 6q13, and 19q13) at p < 5 × 10 -8 . The index single nucleotide polymorphism of 1p21 is an expression quantitative trait locus ( p lowest = 1.74 × 10 -58 ) for RWDD3 involved in SUMOylation and is associated with platelet distribution width (1.15 × 10 -9 ) and 18-carbon fatty acid metabolism ( p = 7.36 × 10 -12 ). In gene-based analysis, we identified 3 genes ( SLC17A2 , FAM73A , and OR52L1 ) at p < 2.7 × 10 -6 . Eleven of 32 candidate gene loci studied in an Indian population replicated ( p < 0.05), and 21 of 32 loci identified through previous GWAS replicated according to directionality of effect., Conclusions: This GWAS of stroke in an Indian population identified novel loci and replicated previously known loci. Genetic variants in the SUMOylation pathway, which has been implicated in brain ischemia, were identified for association with stroke., (© 2021 American Academy of Neurology.)

Deteriorating soil health, diminishing soil organic carbon (SOC), development of subsurface hard compact layer and declining system productivity are barriers to achieving sustainable production in the traditional rice-wheat cropping system (TA) in the eastern Indo-Gangetic Plain of India. Conservation agriculture (CA), which favours minimum soil disturbance, crop residue retention and crop diversification could be a viable alternative to the TA to address most of those major problems. With that in mind, a long-term experiment is being implemented at ICAR-RCER, Patna, Bihar, India, with four treatments: (a) TA, (b) full CA (fCA) and (c and d) partial CA (pCA1 and pCA2), differing in crop establishment methods, cropping system and crop residue management in a randomized complete block design. Measurement of soil health parameters was carried out in the 11th year of the experiment. The results revealed a beneficial effect of CA and 46 and 40% increase in SOC concentration and stock, respectively, under fCA over TA in the 0-7.5-cm soil layer. The effect of partial CA (pCA1 and pCA2) was variable, but an increasing trend was always observed under pCA compared to TA. There was an enrichment in SOC content of aggregates under CA irrespective of size class; however, no relation was found between SOC content and aggregate diameter. The contribution of macroaggregates to SOC stock was larger (36-66%) under CA in the 0-7.5-cm soil layer. Adoption of CA improved the macroaggregate content, MWD and GMD of aggregates, and aggregation ratio. Soil macropore content was greater under fCA, whereas other parameters were similar among treatments. The impact of CA was mostly limited to 0-7.5 cm soil layer and a maximum up to 15 cm soil depth while evaluation until 60 cm soil depth was realized. The yield of rice in CA was comparable to or higher than in TA, whereas the system rice equivalent yield was always higher (38-53%) under CA than under the conventional practices. Therefore, a CA-based cropping system must be encouraged, to increase SOC status, improve aggregation stability and, consequently, sustain or increase system productivity, in order to achieve food and nutritional security in the eastern Indo-Gangetic Plain of India., Highlights: Effects of long-term conservation agriculture (CA) on soil C, aggregation and yield were evaluated.CA improved SOC concentration and stock by 46 and 40%, as well as macroaggregate SOC stock by 36-66%.Macro-aggregation and mean weight diameter improved in CA but was mostly limited to a shallow soil depth.CA can be promoted for sustainability of a rice-wheat system due to higher productivity (38-53%)., Competing Interests: None., (© 2021 The Authors. European Journal of Soil Science published by John Wiley & Sons Ltd on behalf of British Society of Soil Science.)

Abstract: The COVID-19 lockdown has not only helped in combating the community transmission of SARS-CoV-2 but also improved air quality in a very emphatic manner in most of the countries. In India, the first phase of COVID-19 lockdown came into force on March 25, 2020, which was later continued in the next phases. The purpose of this study was to investigate the result of lockdown on air quality of major metropolitan cities-Delhi, Mumbai, Kolkata, Chennai, Bengaluru, Hyderabad, Jaipur, and Lucknow-from March 25 to May 3, 2020. For this study, the concentration of six criteria air pollutants (PM 2.5 , PM 10 , CO, NO 2 , SO 2 , and O 3 ) and air quality index during the COVID-19 lockdown period was compared with the same period of the previous year 2019. The results indicate a substantial improvement in air quality with a drastic decrease in the concentration of PM 2.5 , PM 10 , CO, and NO 2 , while there is a moderate reduction in SO 2 and O 3 concentration. During the lockdown period, the maximum reduction in the concentration of PM 2.5 , PM 10 , CO, NO 2 , SO 2 , and O 3 was observed to be - 49% (Lucknow), - 57% (Delhi), - 75% (Mumbai), - 68% (Kolkata), - 48% (Mumbai), and - 29% (Hyderabad), respectively. The value of the air quality index (AQI) also dwindled significantly during the COVID-19 lockdown period. The maximum decline in AQI was observed - 52% in Bengaluru and Lucknow. The order of AQI was satisfactory > moderate > good > poor and the frequency order of prominent pollutants was O 3  > PM 10  > PM 2.5  > CO > NO 2  > SO 2 during the lockdown period in all the aforementioned metropolitan cities., Competing Interests: Conflict of interestThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© Springer Nature B.V. 2020.)

Rice-based cropping systems are the most energy-intensive production systems in South Asia. Sustainability of the rice-based cropping systems is nowadays questioned with declining natural resource base, soil degradation, environmental pollution, and declining factor productivity. As a consequence, the search for energy and resource conservation agro-techniques is increasing for sustainable and cleaner production. Conservation agriculture (CA) practices have been recommended for resource conservation, soil health restoration and sustaining crop productivity. The present study aimed to assess the different CA modules in rice-based cropping systems for energy conservation, energy productivity, and to define energy-economic relations. A field experiment consisted of four different tillage-based crop establishment practices (puddled-transplanted rice followed by (fb) conventional-till maize/wheat (CTTPR-CT), non-puddled transplanted rice fb zero-till maize/wheat (NPTPR-ZT), zero-till transplanted rice fb zero-till maize/wheat (ZTTPR-ZT), zero-till direct-seeded rice fb zero-till maize/wheat (ZTDSR-ZT)), with two residue management treatments (residue removal, residue retention) in rice-wheat and rice-maize rotations were evaluated for energy budgeting and energy-economic relations. Conservation-tillage treatments (NPTPR-ZT, ZTTPR-ZT, and ZTDSR-ZT) reduced the energy requirements over conventional tillage treatments, with the greater reduction in ZTTPR-ZT and ZTDSR-ZT treatments. Savings of energy in conservation-tillage treatments were attributed to reduced energy use in land preparation (69-100%) and irrigation (23-27%), which consumed a large amount of fuel energy. Conservation-tillage treatments increased grain and straw/stover yields of crops, eventually increased the output energy (6-16%), net energy (14-26%), energy ratio (25-33%), and energy productivity (23-34%) as compared with CTTPR-CT. For these energy parameters, the treatment order was ZTDSR-ZT ≥ ZTTPR-ZT > NPTPR-ZT > CTTPR-CT (p < 0.05). Crop residue retention reduced net energy, energy ratio, and energy productivity when compared with residue removal. Our results of energy-economic relations favored the "conservative hypothesis," which envisages that energy and monetary investments are not essentially the determinants of crop productivity. Thus, zero tillage-based crop establishments (ZTTPR-ZT, ZTDSR-ZT) in rice-based production systems could be the sustainable alternative to conventional tillage-based agriculture (CTTPR-CT) as they conserved non-renewable energy sources, reduced water requirement, and increased crop productivity.

We aimed to identify the critical molecular pathways altered upon tumor stroma interactions in retinoblastoma (RB). In vitro 2 D cocultures of RB tumor cells (Weri-Rb-1 and NCC-RbC-51) with primary bone marrow stromal cells (BMSC) was established. Global gene expression patterns in coculture samples were assessed using Affymetrix Prime view human gene chip microarray and followed with bioinformatics analyses. Key upregulated genes from Weri-Rb-1 + BMSC and NCC-RbC-51 + BMSC coculture were validated using qRT-PCR to ascertain their role in RB progression. Whole genome microarray experiments identified significant (P ≤ 0.05, 1.1 log 2 FC) transcriptome level changes induced upon coculture of RB cells with BMSC. A total of 1155 genes were downregulated and 1083 upregulated in Weri-Rb-1 + BMSC coculture. Similarly, 1865 genes showed downregulation and 1644 genes were upregulation in NCC-RbC-51 + BMSC coculture. The upregulated genes were significantly associated with pathways of focal adhesion, PI3K-Akt signalling, ECM-receptor interaction, JAK-STAT, TGF-β signalling thus contributing to RB progression. Validation of key genes by qRT-PCR revealed significant overexpression of IL8, IL6, MYC and SMAD3 in the case of Weri-Rb-1 + BMSC coculture and IL6 in the case of NCC-RbC-51 + BMSC coculture. The microarray expression study on in vitro RB coculture models revealed the pathways that could be involved in the progression of RB. The gene signature obtained in a stimulated model when a growing tumor interacts with its microenvironment may provide new horizons for potential targeted therapy in RB., (Copyright © 2020. Published by Elsevier Ltd.)

Tillage intensive cropping practices have deteriorated soil physical quality and decreased soil organic carbon (SOC) levels in rice-growing areas of South Asia. Consequently, crop productivity has declined over the years demonstrating the need for sustainable alternatives. Given that, a field experiment was conducted for six years to assess the impact of four tillage based crop establishment treatments [puddled transplant rice followed by conventional tillage in wheat/maize (CTTPR-CT), non-puddled transplant rice followed by zero-tillage in wheat/maize (NPTPR-ZT), zero-till transplant rice followed by zero-tillage in wheat/maize (ZTTPR-ZT), zero-tillage direct seeded rice followed by zero-tillage in wheat/maize (ZTDSR-ZT)], two residue management treatments [residue removal, residue retention (~33%)], and two cropping systems [rice-wheat, rice-maize] on soil aggregation, carbon pools, nutrient availability, and crop productivity. After six years of rotation, in top 0.2 m soil depth, zero-till crop establishment treatments (ZTTPR-ZT and ZTDSR-ZT) had higher ( p  < 0.05) total organic carbon (TOC) over conventional tillage treatment (CTTPR-CT). Zero-till crop establishment treatments increased very-labile C faction (C frac 1 ) by 21% followed by labile fraction (C frac 2 ) (16%), non-labile fraction (C frac 4 ) (13%) and less-labile fraction (C frac 3 ) (7%). Notably, higher passive C-pool in conservation tillage practices over CTTPR-CT suggests that conservation tillage could stabilize the recalcitrant form of carbon that persists longer in the soil. Meantime, zero-till crop establishment treatments had higher ( p  < 0.05) water stable macro-aggregates, macro-aggregates: micro-aggregates ratio and aggregate carbon content over CTTPR-CT. The treatment NPTPR-ZT significantly increased soil quality parameters over CTTPR-CT. However, the effect was not as prominent as that of ZTTPR-ZT and ZTDSR-ZT. Retention of crop residue increased ( p  < 0.05) TOC (12%) and soil available nutrients mainly available-P (16%), followed by available-K (12%), DTPA-extractable Zn (11%), and available-S (6%) over residue removal treatment. The constructive changes in soil properties following conservation tillage and crop residue retention led to increased crop productivity over conventional CTTPR-CT. Therefore, conservation tillage (particularly ZTTPR-ZT and ZTDSR-ZT) and crop residue retention could be recommended in tropical rice-based cropping systems for improving soil quality and production sustainability.

Corneal scarring refers to the loss of normal corneal tissue, replaced by fibrotic tissue (during wound repair) thereby affecting corneal transparency and vision quality. The corneal wound healing process involves a complex series of physiological events resulting in the transformation of transparent keratocytes into opaque myofibroblasts; the prominent cause of irregular extracellular matrix synthesis leading to the development of corneal opacity/hazy vision. Globally, corneal scarring/haze is one of the most prevalent causes of blindness. Ocular trauma (physical and chemical) and microbial infections induce corneal tissue damage. Although great progress has been made in the clinical management of ocular diseases, the global rates of corneal blindness remain high, nonetheless. The topical conventional modalities treating corneal wounds/injuries have inherent limitations/side effects such as low bioavailability of a therapeutic agent, upregulation of the intraocular pressure and the toxicity/allergy of the drug. These limitations/side effects rather than treating the wound, often negatively affect the healing process, especially, when applied frequently for longer periods. Recently, there has been an increasing evidence provided by the preclinical studies that nanotechnology-based drug-delivery systems can improve drug bioavailability, through controlled drug release and targeted delivery. After reviewing the epidemiology, risk factors of corneal scarring/haze and the conventional ocular medicines, we review here the different nanodrug-delivery systems and potential drug candidates including nanoherbal formulations investigated for their efficacy to heal the damaged cornea. Finally, we discuss the challenges of using these nanomedicinal platforms.

Background: The tumour microenvironment (TME) consisting of tumour cells and multiple stromal cell types regulate tumour growth, invasion and metastasis. While the concept of TME and presence of stromal cellular components is widely established in cancers, its significance in the paediatric intraocular malignancy, retinoblastoma (RB), remains unknown., Methods: The study qualitatively identified the presence of multiple stromal cellular subtypes in RB TME by immunohistochemistry., Results: Results of the study identified the presence of stromal cell types such as endothelial cells, tumour-associated macrophages, fibroblasts, cancer-associated fibroblasts, retinal astrocytes and glia in RB TME. The extent of stromal marker positivity, however, did not correlate with histopathological features of RB., Conclusions: The findings of the study convincingly suggest the presence of a stromal component in RB tumours. The interactions between stromal cells and tumour cells might be of profound importance in RB progression.