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Introduction: Millets are nutritionally superior and climate-resilient short-duration crops and hold a prominent place in cropping sequences around the world. They have immense potential to grow in a marginal environment due to diverse adaptive mechanisms., Methods: An experiment was conducted in an organic production system in the North Eastern Himalayan foothills of India for 3 consecutive years by evaluating high-yielding varieties (HYVs) of different millets, viz., finger millet, foxtail millet, little millet, barnyard millet, proso millet, and browntop millet, along with local landraces of finger millets ( Sikkim-1 and Sikkim-2; Nagaland-1 and Nagaland-2 ) to identify stable, high-yielding, and nutritionally superior genotypes suited for the region., Results: Among the various millets, finger millet, followed by little millet and foxtail millet, proved their superiority in terms of productivity (ranging between 1.16 and 1.43 Mg ha -1 ) compared to other millets. Among different varieties of finger millets, cv. VL Mandua 352 recorded the highest average grain yield (1.43 Mg ha -1 ) followed by local landraces, Nagaland-2 (1.31 Mg ha -1 ) and Sikkim-1 (1.25 Mg ha -1 ). Root traits such as total root length, root volume, average diameter of roots, and root surface area were significantly higher in finger millet landraces Nagaland-1, Nagaland - 2 , and Sikkim-1 compared to the rest of the millet genotypes. The different millets were found to be rich sources of protein as recorded in foxtail millet cv. SiA 3088 (12.3%), proso millet cv. TNAU 145 (11.5%), and finger millet landraces, Sikkim-1 and Nagaland-2 (8.7% each). Finger millet landrace Sikkim-2 recorded the highest omega-6 content (1.16%), followed by barnyard millet cv. VL 207 (1.09%). Barnyard millet cv. VL 207 recorded the highest polyunsaturated fatty acid (PUFA) content (1.23%), followed by foxtail millet cv. SiA 3088 (1.09%). The local finger millet landraces Sikkim-1 and Sikkim - 2 recorded the highest levels of histidine (0.41%) and tryptophan (0.12%), respectively. Sikkim-1 and Nagaland-2 recorded the highest level of thiamine (0.32%) compared to the HYVs., Conclusion: These findings indicate that finger millet has great potential in the organic production system of the North Eastern Himalayan Region (NEHR) of India, and apart from HYVs like VL Mandua 352, local landraces, viz., Nagaland-2 and Sikkim-1 , should also be promoted for ensuring food and nutritional security in this fragile 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 Layek, Rangappa, Das, Ansari, Choudhary, Rajbonshi, Patra, Kumar, Mishra, Ravisankar, Kumar, Hazarika, Dutta, Babu, Tahasildar and Shettigar.)

Seaweed extracts have shown profoundly positive effects on crop growth, quality and reproduction in diverse agricultural and horticultural crops. Seaweed extracts can be used to promote the rooting and growth of cuttings in perennial fruit species like kiwifruit ( Actinidia deliciosa ). In this study, the cuttings were treated with 1, 5, 10 and 50% solutions of G Sap ( Gracilaria edulis ), K Sap ( Kappaphycus alvarezii ), AN ( Ascophyllum nodosum ), EM ( Ecklonia maxima ), HA (Humic acid) and control (water) for 6 h as base dipping. Subsequently, the treatments of G Sap, K Sap, AN, EM, HA and control were repeated every 15 days for a period of six months as application of 50 ml solutions in the potted cuttings. All the treatments exhibited significant effects on the rooting percent in all the kiwifruit cultivars, namely 'Monty', 'Abott', 'Hayward', 'Allison' and 'Bruno' ( P  ≤ 0.01) as compared to the control. Shoot and root growth parameters including leaf number per cutting, number of roots per cutting, number of branches, plant height, shoot diameter, root length, root diameter and root weight were all positively increased with the application of seaweed extracts ( P  ≤ 0.05). Cuttings treated with seaweed extract exhibited significantly higher levels of pigments (chlorophyll a , chlorophyll b and total carotenoids), metabolites (total carbohydrates and soluble phenols) and less electrolyte leakage as compared to the control cuttings. Significant positive and negative correlations were observed between biochemical parameters combined with plant nutrient concentration. Principal component analysis (PCA) revealed that PC1 and PC2 (first two principal components) accounted for 75% of the entire variation. While, PC1 accounted for 63% of the total variation, PC2 accounted for 11% of the total variation. The leaves and the roots of kiwifruit cultivar 'Hayward' treated with G Sap at 10%, K Sap at 10%, AN at 10%, EM at 10%, HA at 10% exhibited higher expression of all four root promoting candidate genes ( GH3-3, LBD16, LBD29 and LRP1 ) compared to the control. Therefore, it can be concluded that, seaweed extract and humic acid can be used as a suitable alternative to synthetic hormones for promoting the rooting and growth of kiwifruit cuttings., Competing Interests: 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., (© 2023 The Authors.)

A new Hemidactylus belonging to the H. prashadi group is described herein, based on a series of four specimens from the Chota Nagpur Plateau in northern Odisha. Hemidactylus paucifasciatus sp. nov. can be diagnosed from regional congeners by its large body size (SVL up to 117.7 mm), the number of dorsal tubercle rows at mid-body, three or four bands on the dorsum, the number of enlarged tubercles in paravertebral rows, the number of femoral pores and poreless scales separating the left and right series on the femoral-precloacal row in males, and the number of ventral scales across the belly at mid-body. A mitochondrial phylogeny demonstrates that the new species is nested within the H. triedrus complex of the northern clade within the H. prashadi group, with 16.2-16.5 % pairwise divergence in ND2 sequence data from members of the H. triedrus complex and > 21 % from other members of the prashadi group. Hemidactylus paucifasciatus sp. nov. is the first endemic gecko to be described from the Chota Nagpur Plateau.

Background: The COVID-19 pandemic impacted healthcare delivery worldwide. Resource limitations prompted a multicenter quality initiative to enhance outpatient sleeve gastrectomy workflow and reduce the inpatient hospital burden., Objectives: This study aimed to determine the efficacy of this initiative, as well as the safety of outpatient sleeve gastrectomy and potential risk factors for inpatient admission., Setting: A retrospective analysis of sleeve gastrectomy patients was conducted from February 2020 to August 2021., Methods: Inclusion criteria were adult patients discharged on postoperative day 0, 1, or 2. Exclusion criteria were body mass index ≥60 kg/m 2 and age ≥65 years. Patients were divided into outpatient and inpatient cohorts. Demographic, operative, and postoperative variables were compared, as well as monthly trends in outpatient versus inpatient admission. Potential risk factors for inpatient admission were assessed, as well as early Clavien-Dindo complications., Results: Analysis included 638 sleeve gastrectomy surgeries (427 outpatient, 211 inpatient). Significant differences between cohorts were age, co-morbidities, surgery date, facility, operative duration, and 30-day emergency department (ED) readmission. Monthly frequency of outpatient sleeve gastrectomy rose as high as 71% regionally. An increased number of 30-day ED readmissions was found for the inpatient cohort (P = .022). Potential risk factors for inpatient admission included age, diabetes, hypertension, obstructive sleep apnea, pre-COVID-19 surgery date, and operative duration., Conclusion: Outpatient sleeve gastrectomy is safe and efficacious. Administrative support for extended postanesthesia care unit recovery was critical to successful protocol implementation for outpatient sleeve gastrectomy within this large multicenter healthcare system, demonstrating potential applicability nationwide., (Copyright © 2023 American Society for Metabolic and Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Background: As of 2019, the highest prevalence of human immunodeficiency virus (HIV) in India is seen in the Northeastern states. Endocrine and metabolic disturbances can occur in HIV infection. Thyroid dysfunction is one of the common endocrinopathies. In HIV infection, thyroid function abnormalities are seen in about 4-35% of adult patients. Thyroid function abnormalities range from overt hypothyroidism, subclinical hypothyroidism, and sick euthyroid syndrome to overt hyperthyroidism. Among them, subclinical hypothyroidism is the commonest abnormality. To our knowledge, there have been no studies from Northeastern India done in this regard., Aims and Objectives: To study the thyroid function in newly diagnosed cases of HIV infection attending anti-retroviral therapy (ART) center, Assam Medical College. To estimate the prevalence and types of thyroid dysfunction in newly diagnosed HIV-infected individuals. To study thyroid dysfunctions with respect to age, sex, and cluster of differentiation (CD) 4 count., Materials and Methods: Hospital-based observational study was done at a tertiary care centre of upper Assam on newly diagnosed HIV-positive patients who were not started on antiretroviral therapy and who attended the ART centre, Assam Medical College during the period of our study. History, examinations and laboratory investigations, including thyroid stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxine (FT4), and CD4 count, are done in all such patients, and only those who fulfilled the inclusion and exclusion criteria of our study are taken as study participants, and their findings tabulated., Results and Observations: A total of 95 newly diagnosed HIV-positive patients fulfilling the inclusion and exclusion criteria of our study were taken. In our study, a total of 36.84% of the patients had thyroid dysfunction. We got subclinical hypothyroidism, overt hypothyroidism, sick euthyroid syndrome, and overt hyperthyroidism as the types of thyroid dysfunction. Among all the types of thyroid dysfunction, subclinical hypothyroidism was the commonest abnormality in our study. Under sick euthyroid syndrome, we got only low FT3 as the biochemical abnormality. Thyroid dysfunctions were more common in females (42.3%) than males (35.8%) and were more common in the age group of 30-39 years. In the present study, among patients with thyroid dysfunction, it was seen that 51.43% of the patients had a CD4 cell count in the range 101-200 cells/mm3, whereas only 11.43% of patients had a CD4 cell count in the range <50 cells/mm3 and no patient had a CD4 cell count >500 cells/mm3 ., Conclusion: In our study, we found that thyroid dysfunctions were common in newly diagnosed HIV-positive patients, the prevalence of which was much higher in the general population. Thyroid dysfunction was present in all the stages of the HIV disease., (© Journal of the Association of Physicians of India 2011.)

The flavivirus genus contains several clinically important pathogens that account for tremendous global suffering. Primarily transmitted by mosquitos or ticks, these viruses can cause severe and potentially fatal diseases ranging from hemorrhagic fevers to encephalitis. The extensive global burden is predominantly caused by six flaviviruses: dengue, Zika, West Nile, yellow fever, Japanese encephalitis and tick-borne encephalitis. Several vaccines have been developed, and many more are currently being tested in clinical trials. However, flavivirus vaccine development is still confronted with many shortcomings and challenges. With the use of the existing literature, we have studied these hurdles as well as the signs of progress made in flavivirus vaccinology in the context of future development strategies. Moreover, all current licensed and phase-trial flavivirus vaccines have been gathered and discussed based on their vaccine type. Furthermore, potentially relevant vaccine types without any candidates in clinical testing are explored in this review as well. Over the past decades, several modern vaccine types have expanded the field of vaccinology, potentially providing alternative solutions for flavivirus vaccines. These vaccine types offer different development strategies as opposed to traditional vaccines. The included vaccine types were live-attenuated, inactivated, subunit, VLPs, viral vector-based, epitope-based, DNA and mRNA vaccines. Each vaccine type offers different advantages, some more suitable for flaviviruses than others. Additional studies are needed to overcome the barriers currently faced by flavivirus vaccine development, but many potential solutions are currently being explored.

In recent years, polymer-supported magnetic iron oxide nanoparticles (MIO-NPs) have gained a lot of attention in biomedical and healthcare applications due to their unique magnetic properties, low toxicity, cost-effectiveness, biocompatibility, and biodegradability. In this study, waste tissue papers (WTP) and sugarcane bagasse (SCB) were utilized to prepare magnetic iron oxide (MIO)-incorporated WTP/MIO and SCB/MIO nanocomposite particles (NCPs) based on in situ co-precipitation methods, and they were characterized using advanced spectroscopic techniques. In addition, their anti-oxidant and drug-delivery properties were investigated. Field emission scanning electron microscopy (FESEM) and X-ray diffraction (XRD) analyses revealed that the shapes of the MIO-NPs, SCB/MIO-NCPs, and WTP/MIO-NCPs were agglomerated and irregularly spherical with a crystallite size of 12.38 nm, 10.85 nm, and 11.47 nm, respectively. Vibrational sample magnetometry (VSM) analysis showed that both the NPs and the NCPs were paramagnetic. The free radical scavenging assay ascertained that the WTP/MIO-NCPs, SCB/MIO-NCPs, and MIO-NPs exhibited almost negligible antioxidant activity in comparison to ascorbic acid. The swelling capacities of the SCB/MIO-NCPs and WTP/MIO-NCPs were 155.0% and 159.5%, respectively, which were much higher than the swelling efficiencies of cellulose-SCB (58.3%) and cellulose-WTP (61.6%). The order of metronidazole drug loading after 3 days was: cellulose-SCB < cellulose-WTP < MIO-NPs < SCB/MIO-NCPs < WTP/MIO-NCPs, whereas the sequence of the drug-releasing rate after 240 min was: WTP/MIO-NCPs < SCB/MIO-NCPs < MIO-NPs < cellulose-WTP < cellulose-SCB. Overall, the results of this study showed that the incorporation of MIO-NPs in the cellulose matrix increased the swelling capacity, drug-loading capacity, and drug-releasing time. Therefore, cellulose/MIO-NCPs obtained from waste materials such as SCB and WTP can be used as a potential vehicle for medical applications, especially in a metronidazole drug delivery system.

Lead halide perovskite nanocrystal heterostructures have been extensively studied in the recent past for improving their photogenerated charge carriers mobility. However, most of such heterostructures are formed with random connections without having strong evidence of epitaxial relation. Perovskite-chalcohalides are the first in this category, where all-inorganic heterostructures are formed with epitaxial growth. Going beyond one facet, herein, different polyhedral nanocrystals of CsPbBr 3 are explored for facet-selective secondary epitaxial sulfobromide growths. Following a decoupled synthesis process, the heterojunctions are selectively established along {110} as well as {200} facets of 26-faceted rhombicuboctahedrons, the {110} facets of armed hexapods, and the {002} facets of 12-faceted dodecahedron nanocrystals of orthorhombic CsPbBr 3 . Lattice matching induced these epitaxial growths, and their heterojunctions have been extensively studied with electron microscopic imaging. Unfortunately, these heterostructures did not retain the intense host emission because of their indirect band structures, but such combinations are found to be ideal for promoting photocatalytic CO 2 reduction. The pseudo-Type-II combination helped here in the successful movement of charge carriers and also improved the rate of catalysis. These results suggest that facet-selective all-inorganic perovskite heterostructures can be epitaxially grown and this could help in improving their catalytic activities.

Objectives: Suprachoroidal injection of triamcinolone acetonide is the first Food and Drug Administration-approved treatment for macular edema associated with uveitis. A cost-effectiveness analysis was performed comparing this treatment with best supportive care (BSC) for the management of this indication from US Medicare and commercial payer perspectives., Methods: A patient-level simulation was developed per the patient characteristics and changes in best-corrected visual acuity letter scores observed in a phase III study of triamcinolone acetonide (PEACHTREE). The wholesale acquisition cost of triamcinolone acetonide was $1650/injection; suprachoroidal injection cost was assumed at $200/injection. Healthcare costs were informed by a US claims-based analysis. Mortality risk associated with severe vision loss and blindness was modeled by applying a hazard ratio to all-cause mortality rates of the US general population. Health-related quality of life weights, obtained from a regression model fitted to the Visual Function Questionnaire-25 data from PEACHTREE, were applied based on the best-corrected visual acuity scores of both eyes. Costs (2020 US dollar) and benefits were discounted at 3% annually. Incremental cost-effectiveness ratios were estimated over a 10-year horizon., Results: In the base-case, the incremental cost-effectiveness ratio comparing triamcinolone acetonide with BSC was $28 479 per quality-adjusted life-year gained. The wholesale acquisition cost for triamcinolone acetonide for suprachoroidal use was ∼68%, ∼56%, and ∼27% below the willingness-to-pay thresholds of $150 000, $100 000, and $50 000 per quality-adjusted life-year gained, respectively. Results were robust in sensitivity and scenario analyses., Conclusions: Triamcinolone acetonide for suprachoroidal use is cost-effective compared with BSC for patients with macular edema associated with uveitis., (Copyright © 2022. Published by Elsevier Inc.)

We have performed a combined quantum mechanical and microkinetic modeling study to understand the nascent decomposition pathways of methane pyrolysis, catalyzed by gas-phase ZnCl 2 , in a constant pressure batch reactor at 1273 K. We find that ZnCl 2 catalyzes methane pyrolysis with an apparent activation energy of 227 kJ/mol. We have also performed sensitivity analysis on a reaction network comprising initiation, termination, and primary propagation reactions. The results suggest that the whole reaction network can be simplified to four reactions, which contributes to the initial rate of methane decomposition. Based on these insights, we have also explored the catalyzing effects of gas-phase AlCl 3 , CoCl 2 , CuCl 2 , FeCl 2 , and NiCl 2 for methane decomposition. Our calculations suggest that gas-phase CuCl 2 and NiCl 2 are the most active catalysts among the metal halides studied in this work.

Halide content of the reaction medium not only enhances the brightness of CsPbCl 3 nanocrystals but also, control the shape modulations as well as doping Mn(II) in these host nanocrystals. Correlating both the shape effect and doping, herein, an in situ reaction of nucleophile-controlled halide release was explored for monitoring facets modulations and doping in CsPbCl 3 nanocrystals. This was performed using alkyl amine as nucleophile which reacted with α-halo ketone, phenacyl chloride, to release chloride ions. Increase in amine concentration which released more Cl ions, reduced the possibility of shape transformation from perfect to truncated cubes during annealing. Similarly, for Mn(II) doping, the dopant photoluminescence intensity remained directly proportional to the amount of introduced amine nucleophiles. Quality of both doped and undoped nanocrystals obtained in this procedure remained unparallel and the method provided a strong correlation of rate of halide release with both facet modulations and doping in these nanocrystals.

Chikungunya virus (CHIKV) infection and subsequent high patient morbidity is a global threat. The present study aimed to identify the potent antiviral agent against Chikungunya virus, with minimum in vitro cytotoxicity. CHIKV nsP4 3D structure was determined using the I-TASSER server followed by its refinement and pocket determination. Furthermore, high-throughput molecular docking was employed to identify candidate CHIKV nsP4 inhibitors in a library containing 214 compounds. The top ranked compound was evaluated further with various assays, including cytotoxicity, antiviral activity, time of drug addition, viral entry attachment, and microneutralization assays. High-throughput computational screening indicated silibinin to have the best interaction with CHIKV nsP4 protein, immature and mature glycoproteins with highest negative free binding energy, - 5.24 to - 5.86 kcal/mol, and the lowest inhibitory constant, 50.47 to 143.2 µM. Further in vitro analysis demonstrated silibinin could exhibit statistically significant (p < 0.05) dose-dependent anti-CHIKV activity within 12.5-100-µM concentrations with CC 50 as 50.90 µM. In total, 50 µM silibinin interfered with both CHIKV attachment (75%) and entry (82%) to Vero cells. Time of addition assay revealed silibinin interfered with late phase of the CHIKV replication cycle. Microneutralization assay revealed that silibinin could inhibit clearing of 50% Vero cell monolayer caused by CHIKV-induced CPE at a minimum dose of 25 µM. These data indicated silibinin to be a promising candidate drug against CHIKV infection., (© 2022. The Society for In Vitro Biology.)

Background and objective Coronavirus disease 2019 (COVID-19) was first reported in China two years ago as primarily a lung infection associated with cough and fever. It spread rapidly across the world and was declared a pandemic in early 2020, with 131 million people infected and 2.85 million deaths worldwide. To date, approximately 550,000 deaths have occurred due to COVID-19 in the United States and the numbers continue to rise. The extrapulmonary manifestations of this disease such as acute kidney injury (AKI), cardiovascular events, and gastrointestinal (GI) indications were not emphasized initially. However, subsequent studies from the United States and Canada have noted GI involvement in this disease in a large number of cases. Our group, taking care of these patients during the early phase of the pandemic in 2020, observed the frequent presentations of GI symptoms such as diarrhea and hepatic dysfunction and this study examines the same. Methods We undertook a retrospective study of 184 consecutive adult patients who were hospitalized at our center with confirmed COVID-19 infection, with a view to further elucidate the GI and hepatic involvement during the early breakout (March 17-May 17, 2020) of this illness. Results Major comorbidities associated with this illness in our cohort of patients included hypertension (HTN, 66%), diabetes mellitus (DM, 44%), obesity (41%), and chronic kidney disease (CKD, 17%). The most common GI manifestation was diarrhea (25%) and, interestingly, more than two-thirds of the patients had at least one liver function abnormality. The most common liver function abnormality was elevated serum aspartate aminotransferase (AST). Elevated AST was significantly correlated (p<0.05) with inflammatory markers such as D-dimer, lactate dehydrogenase (LDH), and ferritin, as well as AKI by bi-variate analysis. Salient observations from our study include higher mortality, frequent AKI, and cardiovascular events in male patients (p<0.05).  The liver injury in our cohort was suspected to be multifactorial, involving excessive cytokine release, viral infiltration of the hepatocytes, and cholangiocytes playing a role in transaminitis. The mean (±SD) duration of hospital stay was 13.5 ±15 days with 33% admissions to the ICU. The overall mortality was around 27%, with no significant difference between African Americans and Caucasians. However, patients admitted to the ICU had a very high mortality rate (54%) compared to those admitted to intermediate care (IMC)/acute care who had less severity of illness and associated pulmonary complications. Conclusions This study evaluates the presence of comorbidities such as DM, HTN, and obesity in patients hospitalized with COVID-19 at a community hospital in the Mid-Atlantic region of the United States. Statistical analysis of the data obtained for this cohort revealed a high frequency of GI symptoms, with diarrhea as the predominant common initial manifestation of the disease. Serum AST elevations were common and correlated with inflammatory markers and AKI. Male gender was also significantly associated with the development of AKI, higher frequency of cardiovascular events, and increased mortality. Overall mortality was noted to be 27%, with higher mortality in patients admitted to the ICU (54%) as compared to the IMC/floor (13%). These observations should spur future investigations into the role of these comorbidities, development of diarrhea, and hepatic dysfunction in COVID-19., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Hasel et al.)

In widespread species, the diverse ecological conditions in which the populations occur, and the presence of many potential geographical barriers through their range are expected to have created ample opportunities for the evolution of distinct, often cryptic lineages. In this work, we tested for species boundaries in one such widespread species, the king cobra, Ophiophagus hannah (Cantor, 1836), a largely tropical elapid snake distributed across the Oriental realm. Based on extensive geographical sampling across most of the range of the species, we initially tested for candidate species (CS) using Maximum-Likelihood analysis of mitochondrial genes. We then tested the resulting CS using both morphological data and sequences of three single-copy nuclear genes. We used snapclust to determine the optimal number of clusters in the nuclear dataset, and Bayesian Phylogenetics and Phylogeography (BPP) to test for likely species status. We used non-metric multidimensional scaling (nMDS) analysis for discerning morphological separation. We recovered four independently evolving, geographically separated lineages that we consider Confirmed Candidate Species: (1) Western Ghats lineage; (2) Indo-Chinese lineage (3) Indo-Malayan lineage; (4) Luzon Island lineage, in the Philippine Archipelago. We discuss patterns of lineage divergence, particularly in the context of low morphological divergence, and the conservation implications of recognizing several endemic king cobra lineages., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The increase of the stability of perovskite nanocrystals with respect to exposure to polar media, layers growth, or shelling with different materials is in demand. While these are widely studied for metal chalcogenide nanocrystals, it has yet to be explored for perovskite nanocrystals. Even growth of a single monolayer on any facet or on the entire surface of these nanocrystals could not be established yet. To address this, herein, a secondary growth approach leading to creation of a secondary lattice with subsequent expansion on preformed CsPbBr 3 perovskite nanocrystals is reported. As direct layer growth by adding precursors was not successful, Cs-lattice extension to preformed CsPbBr 3 nanocrystals was performed by coupling CsBr to these nanocrystals. Opening both {110}/{002} and {200} facets of parent CsPbBr 3 nanocrystals, CsBr was observed to be connected with lattice matching to the {200} facets. Further with Pb(II) incorporation, the Cs-sublattices of CsBr were expanded to CsPbBr 3 and led to cube-couple nanocrystals. However, as cubes in these nanostructures were differently oriented, these showed lattice mismatch at their junctions. This lattice mismatch though restricted complete shelling but successfully favored the secondary growth on specific facets of parent CsPbBr 3 nanocrystals. Details of this secondary growth via lattice extension and expansion are microscopically analyzed and reported. These results further suggest that lead halide perovskite nanocrystals can be epitaxially grown under proper reaction design and more complex as well as heterostructures of these materials can be fabricated to meet the current demands.

Vascular endothelial cell growth factor (VEGF) is a key regulator of vascular permeability. Herein we aim to understand how acute and chronic exposures of VEGF induce different levels of vascular permeability. We demonstrate that chronic VEGF exposure leads to decreased phosphorylation of VEGFR2 and c-Src as well as steady increases of nitric oxide (NO) as compared to that of acute exposure. Utilizing heat-inducible VEGF transgenic zebrafish ( Danio rerio ) and establishing an algorithm incorporating segmentation techniques for quantification, we monitored acute and chronic VEGF-induced vascular hyperpermeability in real time. Importantly, dimethylarginine dimethylaminohydrolase-1 (DDAH1), an enzyme essential for NO generation, was shown to play essential roles in both acute and chronic vascular permeability in cultured human cells, zebrafish model, and Miles assay. Taken together, our data reveal acute and chronic VEGF exposures induce divergent signaling pathways and identify DDAH1 as a critical player and potentially a therapeutic target of vascular hyperpermeability-mediated pathogenesis., Competing Interests: The authors declare no competing interests., (© 2021 The Authors.)

PLEXIND1 is upregulated in several cancers, including pancreatic ductal adenocarcinoma (PDAC). It is an established mediator of semaphorin signaling, and neuropilins are its known coreceptors. Herein, we report data to support the proposal that PLEXIND1 acts as a transforming growth factor beta (TGFβ) coreceptor, modulating cell growth through SMAD3 signaling. Our findings demonstrate that PLEXIND1 plays a pro-tumorigenic role in PDAC cells with oncogenic KRAS (KRAS mut ). We show in KRAS mut PDAC cell lines (PANC-1, AsPC-1,4535) PLEXIND1 downregulation results in decreased cell viability (in vitro) and reduced tumor growth (in vivo). Conversely, PLEXIND1 acts as a tumor suppressor in the PDAC cell line (BxPC-3) with wild-type KRAS (KRAS wt ), as its reduced expression results in higher cell viability (in-vitro) and tumor growth (in vivo). Additionally, we demonstrate that PLEXIND1-mediated interactions can be selectively disrupted using a peptide based on its C-terminal sequence (a PDZ domain-binding motif), an outcome that may possess significant therapeutic implications. To our knowledge, this is the first report showing that (1) PLEXIND1 acts as a TGFβ coreceptor and mediates SMAD3 signaling, and (2) differential roles of PLEXIND1 in PDAC cell lines correlate with KRAS mut and KRAS wt status.

Renal artery aneurysm (RAA) is a rare disease. With modern non-invasive imaging modalities, the disease is being increasingly diagnosed. It is a slow-growing aneurysm with high mortality in the event of rupture; especially in pregnant females for in which case patients were treated surgically. With advances in endovascular therapy, numerous techniques have been employed to manage complex RAA in artery bifurcation, branch and segmental arteries with excellent technical and clinical success. The various recent techniques include the use of flow diverter stents, remodelling with stent-assisted coil embolization (SACE), balloon-assisted coil embolization (BACE), selective embolization with coils-sac packing, inflow occlusion and coil trapping and selective embolization with liquid embolic agents-hystroacril and onyx. A combination of stent-graft with liquid embolization and liquid with microcoil embolization has been advocated with success. The most common complication encountered is renal infarction. This is mostly without impairment of renal function and secondary to embolization. Endovascular therapy has shorter operative time, less blood loss, shorter intensive care stay, done under conscious sedation and is associated with lesser postoperative morbidity compared to surgery. Reduction in hypertension, improvement of renal function and symptoms has been seen in most studies. Endovascular management of RAA has become the management of choice even with complex anatomy and technically challenging lesions.

Background: Recurrent Clostridioides diffícile infection (RCDI) is associated with major bacterial dysbiosis and colitis. Fecal microbiota transplantation (FMT) is a highly effective therapeutic modality for RCDI. While several studies have identified bacterial species associated with resolution of symptoms in patients, characterization of the fecal microbiome at the bacterial strain level in RCDI patients before and after FMT and healthy donors, has been lacking. The aim of this study was to examine the ability of bacterial strains from healthy donors to engraft in the gastrointestinal tract of patients with RCDI following FMT., Methods: Fecal samples were collected from 22 patients with RCDI before and after FMT and their corresponding healthy donors. Total DNA was extracted from each sample and analyzed by shotgun metagenomic sequencing. The Cosmos-ID analysis platform was used for taxonomic assignment of sequences and calculation of the relative abundance (RA) of bacterial species and strains. From these data, the total number of bacterial strains (BSI), Shannon diversity index, dysbiosis index (DI), and bacterial engraftment factor, were calculated for each strain., Findings: A marked reduction (p<0·0001) in the RA of total and specific bacterial strains, especially from phylum Firmicutes, was observed in RCDI patients prior to FMT. This change was associated with an increase in the DI (p<0·0001) and in pathobiont bacterial strains from phylum Proteobacteria, such as Escherichia coli O157:H7 and Klebsiella pneumoniae UCI 34. BSI was significantly lower in this group of patients as compared to healthy donors and correlated with the Shannon Index. (p<0·0001). Identification and engraftment of bacterial strains from healthy donors revealed a greater diversity and higher relative abundance of short-chain fatty acid (SCFA)-producing bacterial strains, including Lachnospiraceae bacterium 5&#95;1&#95;63FAA&#95;u&#95;t, Dorea formicigenerans ATCC 27755, Anaerostipes hadrusand others, in RCDI patients after FMT., Interpretation: These observations identify a group of SCFA-producing bacterial strains from healthy donors that engraft well in patients with RCDI following FMT and are associated with complete resolution of clinical symptoms and bacterial dysbiosis., Competing Interests: The authors have read the journal’s policy and have the following competing interests: PPN owns NonInvasive Technologies LLC. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare.

Lead halide perovskite nanocrystals, whether formed by their own nucleation and growth or by ion diffusion into the lattice of others, are still under investigation. Moreover, beyond isotropic nanocrystals, fabricating anisotropic perovskite nanocrystals by design has remained difficult. Exploring the lattice of orthorhombic-phase Cs 2 ZnBr 4 with the complete replacement of Zn tetrahedra by Pb octahedra, dimension-tunable anisotropic nanocrystals of CsPbBr 3 are reported. This B-site ion introduction led to CsPbBr 3 nanorods having [100] as major axis, in contrast with all reports on rods/wires where the lengths were along the [001] direction. This was possible by using derivatives of α-bromo ketones, which helped in tuning the shape of Cs 2 ZnBr 4 and also the facets of transformed CsPbBr 3 . While similar experiments are extended to orthorhombic Cs 2 HgBr 4 , standard nanorods with [001] as the major axis were observed. From these results, it is further concluded that anisotropic perovskite nanocrystals might not follow any specific rules for directional growth and instead might depend on the structure of the parent lattice.

Background: Thymoquinone (TQ) has potential anti-inflammatory, immunomodulatory and anticancer effects but its clinical use is limited by its low solubility, poor bioavailability and rapid clearance. Aim: To enhance systemic bioavailability and tumor-specific toxicity of TQ. Materials & methods: Cationic liposomal formulation of TQ (D1T) was prepared via ethanol injection method and their physicochemical properties, anticancer effects in orthotopic xenograft pancreatic tumor model and pharmacokinetic behavior of D1T relative to TQ were evaluated. Results: D1T showed prominent inhibition of pancreatic tumor progression, significantly greater in vivo absorption, approximately 1.5-fold higher plasma concentration, higher bioavailability, reduced volume of distribution and improved clearance relative to TQ. Conclusion: Encapsulation of TQ in cationic liposomal formulation enhanced its bioavailability and anticancer efficacy against xenograft pancreatic tumor.

Glioblastoma multiforme (GBM) is a highly proliferative and locally invasive cancer with poor prognosis and a high recurrence rate. Although anti-VEGF (vascular endothelial growth factor) therapy offers short-term benefit to GBM patients, this approach fails as the tumor develops into a more invasive and drug-resistant phenotype and ultimately recurs. Recently, both glioma stemlike cells (GSCs) and brain tumor-initiating cells (BTICs) have been implicated in GBM recurrence and its resistance to therapy. We observed that patient-derived GBM cells expressing shRNAs of VEGF or neuropilin-1 (NRP-1) attenuate cancer stem cell markers, inhibit the tumor-initiating cell's neurosphere-forming capacity, and migration. Furthermore, both VEGF and NRP-1 knockdown inhibit the growth of patient-derived GBM xenografts in both zebrafish and mouse models. Interestingly, NRP-1-depleted patient-derived GBM xenografts substantially prolonged survival in mice compared to that of VEGF depletion. Our results also demonstrate that NRP-1 ablation of patient-derived GBM cells improves the sensitivity of TMZ and enhances the overall survival of the respective tumor-bearing mice. This improved outcome may provide insight into the inhibition of GBM progression and effective treatment strategies by targeting NRP-1 in addition to chemotherapy and radiotherapy.

We describe a distinct new species of Hemiphyllodactylus from a sacred grove near Humma in Ganjam District of Odisha state, eastern India. Hemiphyllodactylus minimus sp. nov. is the smallest member of the genus and can be diagnosed from all peninsular Indian congeners by its small body size (SVL ≤32.2 mm, n=11), having 15-18 dorsal scales and eight or nine ventral scales at mid-body contained within one longitudinal eye diameter, nine or ten precloacal pores separated by 4-6 poreless scales from a series of six or seven femoral pores on each thigh in males, lamellar formula of manus 2222 and of pes 2332 2333, as well as subtle colour pattern differences. Additionally, the new species is 16.0-22.7 % divergent from all other peninsular Indian Hemiphyllodactylus in uncorrected ND2 sequence data. The new species is the first member of the genus described from Odisha state and also the first Hemiphyllodactylus known from < 100 m asl. The discovery of Hemiphyllodactylus minimus sp. nov. from a low elevation coastal locality in the Eastern Ghats open ups the possibilities that the genus could be more widespread than currently understood and potentially harbour many more distinct undescribed lineages. Therefore, dedicated fine-scale sampling efforts are needed to uncover the true diversity and distribution of Hemiphyllodactylus in the region.

Background: Urinary tract infections (UTI) account for millions of office visits and approximately 400 000 hospital admissions every year in the United States; as a result, the cost burden of UTI in the USA is estimated at approximately $2.8 billion. There is a great deal of interest in finding newer, faster, and more reliable methods for diagnosing UTI as compared to the standard urine culture., Methods: An automated fluorescent microbial cell counter was used to compare urine samples found to be positive for Escherichia coli UTI via cell culturing (n = 11) with UTI-negative samples (n = 10)., Results: Patients with a positive urine culture had significantly higher cell count results using the microbial cell counter (1.01 × 10 8 cells/mL) as compared to the negative samples (2.35 × 10 6 cells/mL; P = .0022)., Conclusions: These observations suggest that automated microbial cell counters may serve as a rapid, objective method for the detection of bacteriuria in urine samples submitted for evaluation of suspected UTI., (© 2020 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals Inc.)

Chikungunya virus (CHIKV) is an alphavirus that causes a febrile illness accompanied by myalgia and arthralgia. Despite having re-emerged as a significant public health threat, there are no approved therapeutics or prophylactics for CHIKV infection. In this study, we explored the anti-CHIKV effects of proteasome inhibitors and their potential mechanism of antiviral action. A panel of proteasome inhibitors with different functional groups reduced CHIKV infectious titers in a dose-dependent manner. Bortezomib, which has been FDA-approved for multiple myeloma and mantle cell lymphoma, was further investigated in downstream studies. The inhibitory activities of bortezomib were confirmed using different cellular models and CHIKV strains. Time-of-addition and time-of-removal studies suggested that bortezomib inhibited CHIKV at an early, post-entry stage of replication. In western blot analysis, bortezomib treatment resulted in a prominent decrease in structural protein levels as early as 6 hpi. Contrastingly, nsP4 levels showed strong elevations across all time-points. NsP2 and nsP3 levels showed a fluctuating trend, with some elevations between 12 to 20 hpi. Finally, qRT-PCR data revealed increased levels of both positive- and negative-sense CHIKV RNA at late stages of infection. It is likely that the reductions in structural protein levels is a major factor in the observed reductions in virus titer, with the alterations in non-structural protein ratios potentially being a contributing factor. Proteasome inhibitors like bortezomib likely disrupt CHIKV replication through a variety of complex mechanisms and may display a potential for use as therapeutics against CHIKV infection. They also represent valuable tools for studies of CHIKV molecular biology and virus-host interactions., Competing Interests: The authors have declared that no competing interests exist.

Despite recent advancements, effective treatment for pancreatic ductal adenocarcinoma (PDAC) has remained elusive. The overall survival rate in PDAC patients has been dismally low due to resistance to standard therapies. In fact, the failure of monotherapies to provide long-term survival benefits in patients led to ascension of several combination therapies for PDAC treatment. However, these combination therapies provided modest survival improvements while increasing treatment-related adverse side effects. Hence, recent developments in drug delivery methods hold the potential for enhancing therapeutic benefits by offering cocktail drug loading and minimizing chemotherapy-associated side effects. Nanoformulations-aided deliveries of anticancer agents have been a success in recent years. Yet, improving the tumor-targeted delivery of drugs to PDAC remains a major hurdle. In the present paper, we developed several new tumor-targeted dual intervention-oriented drug-encapsulated (DIODE) liposomes. We successfully formulated liposomes loaded with gemcitabine (G), paclitaxel (P), erlotinib (E), XL-184 (c-Met inhibitor, X), and their combinations (GP, GE, and GX) and evaluated their in vitro and in vivo efficacies. Our novel DIODE liposomal formulations improved median survival in comparison with gemcitabine-loaded liposomes or vehicle. Our findings are suggestive of the importance of the targeted delivery for combination therapies in improving pancreatic cancer treatment., Competing Interests: The authors declare the following competing financial interest(s): D.M., V.S.M, and KP have applied for protection of intellectual property related to the results in the manuscript. There are no other conflicts of interest to declare.

Light-emitting lead halide perovskite nanocrystals are typically obtained in a six-faceted cube shape. However, for applications such as catalysis, more active facets for the adsorption/desorption of reactants/products and the suppression of carrier recombination are essentially required. To meet these challenges, herein CsPbBr 3 perovskite nanocrystals in cube and faceted noncube shapes were explored for photocatalytic reductions of CO 2 . Importantly, halide-deficient dim multifaceted noncube emitters having less than 1% photoluminescence quantum yields showed superior catalytic activity compared to that of bright halide-rich cube nanocrystals. Beyond these, hexapod-shaped nanocrystals were also explored, and these remained in an intermediate state. With the support of density functional theory, the adsorption and desorption probabilities of reactants/products on different facets were also calculated and correlated with experimental findings. These results indicated that facets and defects of perovskite nanocrystals are equally important for carrying out catalytic reactions.

Analysis of the temporal, seasonal and demographic distribution of dengue virus (DENV) infections in Barbados was conducted using national surveillance data from a total of 3994 confirmed dengue cases. Diagnosis was confirmed either by DENV-specific real time reverse transcriptase polymerase chain reaction (rRT-PCR), or non-structural protein 1 (NS1) antigen or enzyme linked immunosorbent assay (ELISA) tests; a case fatality rate of 0.4% (10/3994) was observed. The prevalence rate of dengue fever (DF) varied from 27.5 to 453.9 cases per 100,000 population among febrile patients who sought medical attention annually. DF cases occurred throughout the year with low level of transmission observed during the dry season (December to June), then increased transmission during rainy season (July to November) peaking in October. Three major dengue epidemics occurred in Barbados during 2010, 2013 and possibly 2016 with an emerging three-year interval. DF prevalence rate among febrile patients who sought medical attention overall was highest among the 10-19 years old age group. The highest DF hospitalisation prevalence rate was observed in 2013. Multiple serotypes circulated during the study period and Dengue virus serotype 2 (DENV-2) was the most prevalent serotype during 2010, whilst DENV-1 was the most prevalent serotype in 2013. Two DENV-1 strains from the 2013 DENV epidemic were genetically more closely related to South East Asian strains, than Caribbean or South American strains, and represent the first ever sequencing of DENV strains in Barbados. However, the small sample size ( n = 2) limits any meaningful conclusions. DF prevalence rates were not significantly different between females and males. Public health planning should consider DENV inter-epidemic periodicity, the current COVID-19 pandemic and similar clinical symptomology between DF and COVID-19. The implementation of routine sequencing of DENV strains to obtain critical data can aid in battling DENV epidemics in Barbados.

Connecting nanocrystals with removal of interface ligand barriers is one of the key steps for efficient carrier transportation in optoelectronic device fabrication. Typically, ion migration for crystal deformation or connection with other nanocrystals needs a solvent as medium. However, on the contrary, this has been observed for CsPbBr 3 perovskite nanocrystals in film where nanocrystals were swollen to get wider and fused with adjacent nanocrystals in self-assembly on film during solvent evaporation. Depending on precursor composition and exposed facets, again these connections could be programmed for tuning their connecting directions leading to different shapes. Aging further on solid substrate, these were also turned to continuous film of nanostructures eliminating all interparticle gaps on the film. This transformation could be ceased at any point of time, simply by heating or adding sufficient ligands. Analysis suggested that these unique and controlled connections were only observed with polyhedron shaped nanostructures with certain compositions and not with traditionally cubes. Details of this solid-surface transformation during solvent evaporation were analyzed, and an interparticle material transfer type mechanism was proposed. As these observations were not seen in chalcogenide and oxide nanocrystals and exclusively observed in perovskite nanocrystals, this would add new fundamentals to the insights of crystal growths of nanocrystals and would also help in obtaining films of connecting nanocrystals.

The ankyrin (ANK) repeat protein family is largely distributed across plants and has been found to participate in multiple processes such as plant growth and development, hormone response, response to biotic and abiotic stresses. It is considered as one of the major markers of capsaicin content in pepper fruits. In this study, we performed a genome-wide identification and expression analysis of genes encoding ANK proteins in three Capsicum species: Capsicum baccatum, Capsicum annuum and Capsicum chinense. We identified a total of 87, 85 and 96 ANK genes in C. baccatum, C. annuum and C. chinense genomes, respectively. Next, we performed a comprehensive bioinformatics analysis of the Capsicum ANK gene family including gene chromosomal localization, Cis-elements, conserved motif identification, intron/exon structural patterns and gene ontology classification as well as profile expression. Phylogenetic and domain organization analysis grouped the Capsicum ANK gene family into ten subfamilies distributed across all 12 pepper chromosomes at different densities. Analysis of the expression of ANK genes in leaf and pepper fruits suggested that the ANKs have specific expression patterns at various developmental stages in placenta tissue. Our results provide valuable information for further studies of the evolution, classification and putative functions of ANK genes in pepper.

The ladybird beetle, Harmonia sedecimnotata (F.) was studied in biology, life table, consumption rates, molecular characterization, and field evaluation. The net reproductive rate (R 0 ), based on the age-stage and two-sex life table, was 43.2 eggs/individual. The female adults lived longer (68.1 d) than the male adults (62.9 d). The rate of consumption increased with progress in each stage of development. Compared to the other larval stages of the predator, the fourth stadium consumed most quantities of Aphis gossypii Glover nymphs (Hemiptera: Aphididae) (200.4). Both female (2214.6) and male (1792.4) consumed more prey (nymphs) than larvae. The net rate of consumption was 1458.92 nymphs of melon aphids. There was no variation in the sequences of the two nucleotides out of 583 bp, H sedecimnotata China (EU392410) and India (MG720024). Our investigations demonstrated that inoculative release of 30 or 40 or 50 adults per 100 m 2 attained high reduction of aphids (>90%). Thus, it may be recommended the release rate of 40 adults per 100 m 2 to suppress the eggplant aphid population. H. sedecimnotata is therefore one of the most promising biological control agents for cotton aphids that can be achieved for instant control through an inoculative release of adults.

Propylea dissecta (Mulsant) (Coleoptera: Coccinellidae) is one of the most promising ladybird beetle against many sucking pests. Predation rates, developmental biology, life table, and field assessment of this ladybird were examined against mustard aphid, Lipaphis erysimi (Kalt.) (Hemiptera: Aphididae), on broccoli. Data on the life history were collected at 23 ± 1°C and 70 ± 1% RH and were evaluated using the two-sex, age-stage life table. Results showed that the two-sex, age-stage life table-based net reproductive rate (R0) was 11.264 ± 6.197 offspring. The adult females lived longer (33.8 ± 2.356 d) than the adult males (32.2 ± 0.841 d). The fourth instar consumed most of L. erysimi (113.97 ± 5.76) compared to the other larval stages of the predator. Male (1,821) and female (2,673) consumed more aphids than larvae. The net consumption rate was 741.78 ± 89.91 aphids. Other aphidophagous predators such as Coccinella septempunctata L., Micraspis discolor (F.), Coccinella transversalis (F.), and syrphid (Diptera: Syrphidae) were also noted in broccoli. Our research showed that inoculative release of 150 or 200 adults per 1,000 m2 for two times on broccoli achieved a significant decrease in aphids L. erysimi and Brevicoryne brassicae L. (Hemiptera: Aphididae) (>95%). The release rate of 150 adults per 1,000 m2 for two times may, therefore, be recommended to manage the aphid population on broccoli., (© The Author(s) 2019. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Key Message: Transcriptome landscape reveals the molecular mechanisms involved in the improvement of fruit traits by the grafting of watermelon and bottle gourd. Grafting has been used as a sustainable alternative for watermelon breeding to control soil-borne pathogens and to increase tolerance to various abiotic stresses. However, some reports have shown that grafting can negatively affect the quality of fruits. Despite several field studies on the effects of grafting on fruit quality, the regulation of this process at the molecular level has not been revealed. The aim of this study was to elucidate various molecular mechanisms involved in different tissues of heterografted watermelon and bottle gourd plants. Grafting with bottle gourd rootstock increased the size and rind thickness of watermelon fruits, whereas that with watermelon rootstock produced bottle gourd fruits with higher total soluble solid content and thinner rinds. Correspondingly, genes related to ripening, softening, cell wall strengthening, stress response and disease resistance were differentially expressed in watermelon fruits. Moreover, genes associated mainly with sugar metabolism were differentially expressed in bottle gourd fruits. RNA-seq revealed more than 400 mobile transcripts across the heterografted sets. More than half of these were validated from PlaMoM, a database for plant mobile macromolecules. In addition, some of these mobile transcripts contained a transfer RNA-like structure. Other RNA motifs were also enriched in these transcripts, most with a biological role based on GO analysis. This transcriptome study provided a comprehensive understanding of various molecular mechanisms underlying grafted tissues in watermelon.

Quiescin sulfhydryl oxidase 1 (QSOX1) is an enzyme overexpressed by many different tumor types. QSOX1 catalyzes the formation of disulfide bonds in proteins. Because short hairpin knockdowns (KD) of QSOX1 have been shown to suppress tumor growth and invasion in vitro and in vivo , we hypothesized that chemical compounds inhibiting QSOX1 enzymatic activity would also suppress tumor growth, invasion, and metastasis. High throughput screening using a QSOX1-based enzymatic assay revealed multiple potential QSOX1 inhibitors. One of the inhibitors, known as "SBI-183," suppresses tumor cell growth in a Matrigel-based spheroid assay and inhibits invasion in a modified Boyden chamber, but does not affect viability of nonmalignant cells. Oral administration of SBI-183 inhibits tumor growth in 2 independent human xenograft mouse models of renal cell carcinoma. We conclude that SBI-183 warrants further exploration as a useful tool for understanding QSOX1 biology and as a potential novel anticancer agent in tumors that overexpress QSOX1., (©2019 American Association for Cancer Research.)

Lead halide perovskite nanocrystals have recently emerged as an efficient optical material for light harvesting. While these have been extensively studied for obtaining bright emissions, their use as catalysts for enhancing the rate of chemical reactions has been explored little. Considering their importance in catalysis, herein, Fe(II)-doped CsPbBr 3 perovskite nanocrystals have been explored for photocatalytic reduction of CO 2 . In comparison to undoped CsPbBr 3 , doped nanocrystals showed enhanced catalytic activity and also predominantly led to evolution of CH 4 instead of CO. The observation of a reverse trend of predominated CH 4 evolution in doped nanocrystals rather than CO observed for undoped nanocrystals was correlated to the adsorption/desorption energy of respective products established theoretically earlier. This selective evolution of major products on doping remained unique and also a step forward for understanding more regarding light to chemical energy conversions using perovskite nanocrystals.

Clear cell renal cell carcinoma (ccRCC) is known for its highly vascular phenotype which is associated with elevated expression of vascular endothelial growth factor A (VEGF), also known as vascular permeability factor (VPF). Accordingly, VEGF has been an attractive target for antiangiogenic therapies in ccRCC. Two major strategies have hitherto been utilized for VEGF-targeted antiangiogenic therapies: targeting VEGF by antibodies, ligand traps or aptamers, and targeting the VEGF receptor signaling via antibodies or small-molecule tyrosine-kinase inhibitors (TKIs). In the present article we utilized two entirely different approaches: targeting mammalian target of rapamycin (mTOR) pathway that is known to be involved in VEGF synthesis, and disruption of VEGF/Neuroplin-1 (NRP1) axis that is known to activate proangiogenic and pro-tumorigenic signaling in endothelial and tumor cells, respectively. Everolimus (E) and a small-molecule inhibitor EG00229 (G) were used for the inhibition of mTOR and the disruption of VEGF/NRP1 axis, respectively. We also exploited a liposomal formulation decorated with a proprietary tumor-targeting-peptide (TTP) to simultaneously deliver these two agents in a tumor-targeted manner. The TTP-liposomes encapsulating both Everolimus and EG00229 (EG-L) demonstrated higher in vitro and in vivo growth retardation than the single drug-loaded liposomes (E-L and G-L) in two different ccRCC models and led to a noticeable reduction in lung metastasis in vivo. In addition, EG-L displayed remarkable inhibition of tumor growth in a highly aggressive syngeneic immune-competent mouse model of ccRCC developed in Balb/c mice. Taken together, this study demonstrates an effective approach to achieve improved therapeutic outcome in ccRCC., Competing Interests: Competing interestsThe authors declare the following competing financial interest(s): K.P., V.S.M., and D.M. have applied for protection of intellectual property related to the results in the manuscript. There are no other conflicts of interest to declare., (© The Author(s) 2019.)

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease. Nanomedicine, however, offers new opportunities to facilitate drug delivery in PDAC. Our previous work has shown that poly(ethylene glycol)-functionalized nanodiamond (ND) mediated drug delivery offered a considerable improvement over free drug in PDAC. Inspired by this result and guided by molecular simulations, we opted for simultaneous loading of irinotecan and curcumin in ultra-small PEGylated NDs (ND-IRT + CUR). We observed that ND-IRT + CUR was more efficacious in killing AsPC-1 and PANC-1 cells than NDs with single drugs. Using NDs functionalized with a near-infrared (NIR) dye, we demonstrated the preferential localization of the NDs in tumors and metastatic lesions. We further demonstrate that ND-IRT + CUR is capable of producing pronounced anti-tumor effects in two different clinically relevant, immune-competent genetic models of PDAC. Cytokine profiling indicated that NDs with or without drugs downregulated the expression of IL-10, a key modulator of the tumor microenvironment. Thus, using a combination of in silico, in vitro, and in vivo approaches, we show for the first time the remarkable anti-tumor efficacy of PEGylated NDs carrying a dual payload of irinotecan plus curcumin. These results highlight the potential use of such nano-carriers in the treatment of patients with pancreatic cancer.

Insights of Mn(II) doping in CsPbCl 3 -armed hexapod nanostructures is reported. These complex structures were typically formed in halide concentration tuned modulated reactions. Cores were first formed under halide deficient condition and with enriching halides; these were transformed to armed structures. Doping of Mn(II) was observed facilitated during the arm growth in the second stage of the reaction. These observations were supported with decoupled reactions with minimized and maximized halide concentrations carried out in separate reactions. However, less interference for the exciton to dopant energy transfer was noticed for the defect states created in halide-deficient medium, and the intensity of the dopant emission remained proportional to the amount of dopant inserted in the nanocrystals. Being this is an in situ observation in the coupled reactions of both poor and rich halide reaction systems, the finding would strengthen the understanding of doping in perovskite host nanocrystals.

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a predominantly fatal common malignancy with inadequate treatment options. Glycogen synthase kinase 3β (GSK-3β) is an emerging target in human malignancies including PDAC. Experimental Design: Pancreatic cancer cell lines and patient-derived xenografts were treated with a novel GSK-3 inhibitor 9-ING-41 alone or in combination with chemotherapy. Activation of the DNA damage response pathway and S-phase arrest induced by gemcitabine were assessed in pancreatic tumor cells with pharmacologic inhibition or siRNA depletion of GSK-3 kinases by immunoblotting, flow cytometry, and immunofluorescence., Results: 9-ING-41 treatment significantly increased pancreatic tumor cell killing when combined with chemotherapy. Inhibition of GSK-3 by 9-ING-41 prevented gemcitabine-induced S-phase arrest suggesting an impact on the ATR-mediated DNA damage response. Both 9-ING-41 and siRNA depletion of GSK-3 kinases impaired the activation of ATR leading to the phosphorylation and activation of Chk1. Mechanistically, depletion or knockdown of GSK-3 kinases resulted in the degradation of the ATR-interacting protein TopBP1, thus limiting the activation of ATR in response to single-strand DNA damage., Conclusions: These data identify a previously unknown role for GSK-3 kinases in the regulation of the TopBP1/ATR/Chk1 DNA damage response pathway. The data also support the inclusion of patients with PDAC in clinical studies of 9-ING-41 alone and in combination with gemcitabine., (©2019 American Association for Cancer Research.)

Pancreatic ductal adenocarcinoma (PDAC) has one of the highest mortality rates among cancers. Chemotherapy is the standard first-line treatment, but only modest survival benefits are observed. With the advent of targeted therapies, epidermal growth factor receptor (EGFR) has been acknowledged as a prospective target in PDAC since it is overexpressed in up to 60% of cases. Similarly, the tyrosine-protein kinase Met (cMET) is also overexpressed in PDAC (27-60%) and is a prognostic marker for poor survival. Interestingly, EGFR and cMET share some common signaling pathways including PI3K/Akt and MAPK pathways. Small molecule inhibitors or bispecific antibodies that can target both EGFR and cMET are therefore emerging as novel options for cancer therapy. We previously developed a dual EGFR and cMET inhibitor (N19) that was able to inhibit tumor growth in nonsmall cell lung cancer models resistant to EGFR tyrosine kinase inhibitors (TKI). Here, we report the development of a novel liposomal formulation of N19 (LN19) and showed significant growth inhibition and increased sensitivity toward gemcitabine in the pancreatic adenocarcinoma orthotopic xenograft model. Taken together, our results suggest that LN19 can be valued as an effective combination therapy with conventional chemotherapy such as gemcitabine for PDAC patients.

We investigated the phylogenetic relationship of the Critically Endangered bush frog Philautus sanctisilvaticus Das and Chanda, 1997 and other species distributed across the fragmented forests of Deccan Peninsula and the northern Eastern Ghats. A short fragment of the mitochondrial 16S rRNA gene was employed to assess phylogenetic relationships across Philautus sanctisilvaticus Das and Chanda, 1997, Raorchestes terebrans (Das and Chanda, 1998) and Philautus similipalensis Dutta, 2003. All sequenced specimens, including material from near the type localities of P. sanctisilvaticus (Amarkantak) and P. similipalensis (Simlipal) were genetically extremely similar, with pairwise uncorrected distances 1% in the 16S gene, and were phylogenetically placed within the genus Raorchestes. The results based on morphology are ambiguous and do not go hand in hand with molecular data, which however do not provide support for a three species hypothesis either. our findings advocate the need for making nomenclatural amendments. Philautus sanctisilvaticus Das and Chanda, 1997, is the first available nomen for this taxon, and we propose to include this species in Raorchestes as Raorchestes sanctisilvaticus (Das and Chanda, 1997), and to consider the nomina Philautus terebrans Das and Chanda, 1998 syn. nov. and Philautus similipalensis Dutta, 2003 syn. nov. as junior subjective synonyms for this nomen following the Principle of Priority in article 23.1 of the ICZN. The findings are notable from the point of conservation of the species and present a novel case with remarkable genetic homogeneity across the fragmented forests of Deccan Peninsula and Eastern Ghats.

Highly emissive isotropic CsPbX 3 (X = Cl, Br, and I) perovskite nanocrystals are typically observed in a six-faceted cube shape. When a unique approach is adopted and the reaction medium is enriched with halides, arm growth on all six facets was carried out and reported. Analysis suggested that these armed nanostructures were obtained from intermediate polyhedron shaped structures having 26 facets, and these were formed under halide-deficient conditions. Surface energy calculations further supported the possible existence of all facets for both of these structures under different halide composition environments. The entire study was first explored for CsPbBr 3 and then extended to CsPbCl 3 ; however, for CsPbI 3 nanocrystals, Sr(II) dopant was used for obtaining stable emission. Arm lengths could also be tuned with a function of reaction temperature for CsPbBr 3 . Formation of stable facets in polyhedron shaped nanostructures and their transformation to respective hexapods under halide-deficient and halide-rich conditions add new fundamental concepts for these nanostructures and their shape evolutions.

Pancreatic ductal adenocarcinoma (PDAC) is a highly desmoplastic cancer with limited treatment options. There is an urgent need for tools that monitor therapeutic responses in real time. Drugs such as gemcitabine and irinotecan elicit their therapeutic effect in cancer cells by producing hydrogen peroxide (H 2 O 2 ). In this study, specific DNA-wrapped single-walled carbon nanotubes (SWCNT), which precisely monitor H 2 O 2 , were used to determine the therapeutic response of PDAC cells in vitro and tumors in vivo . Drug therapeutic efficacy was evaluated in vitro by monitoring H 2 O 2 differences in situ using reversible alteration of Raman G-bands from the nanotubes. Implantation of the DNA-SWCNT probe inside the PDAC tumor resulted in approximately 50% reduction of Raman G-band intensity when treated with gemcitabine versus the pretreated tumor; the Raman G-band intensity reversed to its pretreatment level upon treatment withdrawal. In summary, using highly specific and sensitive DNA-SWCNT nanosensors, which can determine dynamic alteration of hydrogen peroxide in tumor, can evaluate the effectiveness of chemotherapeutics. SIGNIFICANCE: A novel biosensor is used to detect intratumoral hydrogen peroxide, allowing real-time monitoring of responses to chemotherapeutic drugs., (©2019 American Association for Cancer Research.)

The role of the microbiome in health and human disease has emerged at the forefront of medicine in the 21st century. Over the last 2 decades evidence has emerged to suggest that inflammation-derived oxidative damage and cytokine induced toxicity may play a significant role in the neuronal damage associated with Parkinson's disease (PD). Presence of pro-inflammatory cytokines and T cell infiltration has been observed in the brain parenchyma of patients with PD. Furthermore, evidence for inflammatory changes has been reported in the enteric nervous system, the vagus nerve branches and glial cells. The presence of α-synuclein deposits in the post-mortem brain biopsy in patients with PD has further substantiated the role of inflammation in PD. It has been suggested that the α-synuclein misfolding might begin in the gut and spread "prion like" via the vagus nerve into lower brainstem and ultimately to the midbrain; this is known as the Braak hypothesis. It is noteworthy that the presence of gastrointestinal symptoms (constipation, dysphagia, and hypersalivation), altered gut microbiota and leaky gut have been observed in PD patients several years prior to the clinical onset of the disease. These clinical observations have been supported by in vitro studies in mice as well, demonstrating the role of genetic (α-synuclein overexpression) and environmental (gut dysbiosis) factors in the pathogenesis of PD. The restoration of the gut microbiome in patients with PD may alter the clinical progression of PD and this alteration can be accomplished by carefully designed studies using customized probiotics and fecal microbiota transplantation.

Objective: Significant data support the efficacy and safety of fecal microbiota transplant (FMT) in recurrent Clostridium difficile infection (CDI). The objective of our study was to determine the success rate of FMT in patients diagnosed with severe and complicated CDI with impending colectomy in the intensive care setting., Methods: This was a 2-center study of 9 patients who met the criteria for severe and complicated CDI and had an impending colectomy. All 9 patients had failed conventional antibiotic therapy and were deemed too unstable to undergo a colectomy. Hence, FMT was considered to be the next step in managing their condition., Results: Following FMT there was marked improvement in the patients' clinical status, with the resolution of diarrhea, reduced requirement for vasopressor, and the reduction in abdominal distention and pain. The primary cure rate of our study after a single round of FMT was 78% (7/9). Of the 9 patients 8 (88.88%) avoided a colectomy during the same hospital admission. the CDI-related death rate was 12.5% (1/9) and that of non-CDI was 12.5% (1/9)., Conclusion: Our success with FMT in fulminant CDI shows that this therapeutic modality is a promising alternative to a colectomy and could be a potential bowel-saving intervention., (© 2019 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)