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Background: Locally advanced cervical cancer is treated with chemoradiotherapy (standard of care), but many patients still relapse and die from metastatic disease. We investigated chemoradiotherapy with or without induction chemotherapy to determine whether induction chemotherapy improves both progression-free survival and overall survival., Methods: The INTERLACE trial was a multicentre, randomised phase 3 trial done at 32 medical centres in Brazil, India, Italy, Mexico, and the UK. Adults (aged ≥18 years) with locally advanced cervical cancer (FIGO 2008 stage IB1 disease with nodal involvement, or stage IB2, IIA, IIB, IIIB, or IVA disease) were randomly assigned (1:1), by minimisation, using a central electronic system, to standard cisplatin-based chemoradiotherapy (once-a-week intravenous cisplatin 40 mg/m 2 for 5 weeks with 45·0-50·4 Gy external beam radiotherapy delivered in 20-28 fractions plus brachytherapy to achieve a minimum total 2 Gy equivalent dose of 78-86 Gy) alone or induction chemotherapy (once-a-week intravenous carboplatin area under the receiver operator curve 2 and paclitaxel 80 mg/m 2 for 6 weeks) followed by standard cisplatin-based chemoradiotherapy. Stratification factors were recruiting site, stage, nodal status, three-dimensional conformal radiotherapy or intensity modulated radiotherapy, age, tumour size, and histology (squamous vs non-squamous). Primary endpoints were progression-free survival and overall survival within the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT01566240, and EUDRACT, 2011-001300-35., Findings: Between Nov 8, 2012, and Nov 17, 2022, 500 eligible patients were enrolled and randomly assigned to the chemoradiotherapy alone group (n=250) or the induction chemotherapy with chemoradiotherapy group. Of 500 patients, 354 (70%) had stage IIB disease and 56 (11%) stage IIIB disease. Pelvic lymph nodes were positive in 215 (43%) patients. 230 (92%) patients who received induction chemotherapy had at least five cycles. Median interval between induction chemotherapy and chemoradiotherapy was 7 days. Four or more cycles of cisplatin were given to 212 (85%) participants in the induction chemotherapy with chemoradiotherapy group and to 224 (90%) of participants in the chemoradiotherapy alone group. 462 (92%) participants received external beam radiotherapy and brachytherapy with a median overall treatment time of 45 days. After a median follow-up of 67 months, 5-year progression-free survival rates were 72% in the induction chemotherapy with chemoradiotherapy group and 64% in the chemoradiotherapy alone group with a hazard ratio (HR) of 0·65 (95% CI 0·46-0·91, p=0·013). 5-year overall survival rates were 80% in the induction chemotherapy with chemoradiotherapy group and 72% in the chemoradiotherapy alone group, with an HR of 0·60 (95% CI 0·40-0·91, p=0·015). Grade 3 or greater adverse events were reported in 147 (59%) of 250 individuals in the induction chemotherapy with chemoradiotherapy group versus 120 (48%) of 250 individuals in the chemoradiotherapy alone group., Interpretation: Short-course induction chemotherapy followed by chemoradiotherapy significantly improves survival of patients with locally advanced cervical cancer., Funding: Cancer Research UK and University College London-University College London Hospitals Biomedical Research Centre., Competing Interests: Declaration of interests GE reports consulting fees from MSD and Eisai; payment or honoraria from Eisai and GSK; support for attending meeting from MSD; and participation on Data Safety Monitoring Board or Advisory Board for GSK, MSD, and Eisai, outside the submitted work. JAL reports grants from AstraZeneca and Merck/MSD; consulting fees from AstraZeneca, Clovis Oncology, GSK, Artios Pharma, Merck/MSD, VBL Therapeutics, Bristol Myers Squibb, Nuvation, Immagene, Incyte, Immunogen/AbbVie, and Novocure; payment or honoraria from AstraZeneca, MSD/Merck, Clovis Oncology, and GSK; participation on Data Safety Monitoring Board or Advisory Board for Mersana and SutroBio; and leadership role on the European Society for Medical Oncology's Clinical Practice Guidelines—Gynaecological Cancer—until December, 2023, past Vice President role for the European Society of Gynaecological Oncology, until 2021, and Chair for National Ovarian Cancer Audit Committee, outside the submitted work. MM reports payment or honoraria from MSD, Eisai, GSK, Roche, and Medscape; support for attending meetings or travel from Daiichi Sanko; and past role as a Chair of Cervical Cancer Research Network (until September 2021), outside the submitted work. AM reports participation on data safety monitoring board or advisory board for Cannariabio (on an ovarian cancer trial, since 2023) and executive committee member role with the Gynecologic Cancer Intergroup (since 2024), outside the submitted work. AH reports honoraria for educational activities from AbbVie, Almirall, Boehringer Ingelheim, Clovis Oncology, Ipsen, Takeda, AstraZeneca, Daiichi Sankyo, Merck Serono, MSD, UCB, Kyowa Kirin, Servier, Sobi, Pfizer, and Roche, outside the submitted work. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Artificial intelligence (AI) has the potential to transform healthcare practices, but the successful adoption of AI depends on the perception and acceptance of healthcare professionals. This study aimed to assess the understanding of AI concepts, recognize the attitude toward AI integration, and identify the barriers to AI adoption among healthcare professionals in a tertiary care hospital., Methods: A cross-sectional study was conducted among 200 healthcare professionals, including doctors, nurses, and paramedics, in a tertiary care teaching hospital in Chengalpattu district, India. A semi-structured questionnaire was used to collect data on sociodemographic characteristics, knowledge, attitude, and perceived barriers to AI adoption. The chi-square test was used to analyze the associations between variables., Results: The majority of the participants, i.e., 54% (n = 108), had moderate knowledge about AI adoption, while 48% (n = 96) had a low attitude toward it. Barriers to the adoption of AI in healthcare practices among healthcare professionals were low among the majority, i.e., 49% (n = 98), of the participants. A statistically significant association was found between knowledge and attitude (X² = 18.052, df = 4, p = 0.001), i.e., healthcare professionals with moderate knowledge levels had low attitudes toward the adoption of AI. A statistically significant association was also found between knowledge and perceived barriers (X² = 31.235, df = 4, p = 0.00), i.e., healthcare professionals with higher knowledge levels perceived lower barriers to the adoption of AI., Conclusion: The study highlights the need for education and training to improve knowledge, foster positive attitudes, and address the perceived barriers to AI adoption among healthcare professionals. Future research should focus on developing targeted interventions to enhance the understanding and acceptance of AI in healthcare practices., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Institutional Ethics Committee - Students SRM Medical College Hospital issued approval SRMIEC-ST0224-911. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, N et al.)

Cylindrospermopsin, a potent hepatotoxin produced by harmful cyanobacterial blooms, poses environmental and human health concerns. We used a 3D human liver in vitro model based on spheroids of HepG2 cells, in combination with molecular and biochemical assays, automated imaging, targeted LC-MS-based proteomics, and lipidomics, to explore cylindrospermopsin effects on lipid metabolism and the processes implicated in hepatic steatosis. Cylindrospermopsin (1 μM, 48 h) did not significantly affect cell viability but partially reduced albumin secretion. However, it increased neutral lipid accumulation in HepG2 spheroids while decreasing phospholipid levels. Simultaneously, cylindrospermopsin upregulated genes for lipogenesis regulation (SREBF1) and triacylglycerol synthesis (DGAT1/2) and downregulated genes for fatty acid synthesis (ACLY, ACCA, FASN, SCD1). Fatty acid uptake, oxidation, and lipid efflux genes were not significantly affected. Targeted proteomics revealed increased levels of perilipin 2 (adipophilin), a major hepatocyte lipid droplet-associated protein. Lipid profiling quantified 246 lipid species in the spheroids, with 28 significantly enriched and 15 downregulated by cylindrospermopsin. Upregulated species included neutral lipids, sphingolipids (e.g., ceramides and dihexosylceramides), and some glycerophospholipids (phosphatidylethanolamines, phosphatidylserines), while phosphatidylcholines and phosphatidylinositols were mostly reduced. It suggests that cylindrospermopsin exposures might contribute to developing and progressing towards hepatic steatosis or metabolic dysfunction-associated steatotic liver disease (MASLD)., Competing Interests: Declaration of competing 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 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The pandemic of SARS-CoV-2 was a novel situation, there was no conclusive knowledge, particularly concerning its effect on pregnant women and infants. Eminent obstetric organizations have introduced an array of guidelines to assist clinicians in countering this prior unknown outbreak. The primary objective of this study was to summarize the clinical characteristics, complications, and maternal and neonatal outcomes of COVID-19 during pregnancy and puerperium., Methods: This was a cross-sectional observational study conducted in the Outpatient/Emergency/Inpatient or COVID ward in the Department of Obstetrics and Gynaecology, of a tertiary hospital in Nadia district, West Bengal, India, from 1.7.2020 to 30.6.2021 including 104 pregnant or puerperal mothers with laboratory-confirmed, i.e., RT-PCR or Rapid Antigen Test positive reports after informed consent. The obstetric outcome, modes of delivery, and neonatal status including any complications or SNCU admission within six weeks postpartum were recorded., Results: The majority were in the ≥ 20-24 years age group, primigravida, residents of Nadia with no significant travel or contact history. 73.08% were affected in the third trimester and the comorbidities detected were chiefly anemia (15.38%), hypertensive or chronic liver diseases, and hypothyroidism. 45.19% of the mothers were asymptomatic while the other complaints were fever (18.27%), cough (11.55%), anosmia and/or ageusia (10.58%), sore throat (9.61%), respiratory distress, loose stools, and chest pain. The medical complications were predominantly low SpO2, convulsions, pneumonitis, and two maternal deaths. The obstetric complications were preterm birth (26.9%), pre-eclampsia/eclampsia (17.3%), antepartum (3.9%) and postpartum hemorrhage (4.4%), and sepsis (5.8%). Fourteen mothers had first-trimester termination, 63 had vaginal deliveries, and the rest had cesarean section. Out of 90 neonates, most were in the range of ≥ 2-2.5 kg birth weight and normal 1-min APGAR score. None tested positive for COVID-19 RTPCR and no detectable congenital anomaly or neonatal death was recorded., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Journal of Family Medicine and Primary Care.)

Microcystin-LR (MC-LR) is a potent hepatotoxin produced by harmful cyanobacterial blooms (CyanoHABs). MC-LR targets highly differentiated hepatocytes expressing organic anion transporting polypeptides OATP1B1 and OATP1B3 that are responsible for hepatocellular uptake of the toxin. The present study utilized an advanced 3D in vitro human liver model Hepoid-HepaRG based on the cultivation of collagen-matrix embedded multicellular spheroids composed of highly differentiated and polarized hepatocyte-like cells. 14-d-old Hepoid-HepaRG cultures showed increased expression of OATP1B1/1B3 and sensitivity to MC-LR cytotoxicity at concentrations >10 nM (48 h exposure, EC 20  = 26 nM). MC-LR induced neither caspase 3/7 activity nor expression of the endoplasmic reticulum stress marker gene BiP/GRP78, but increased release of pro-inflammatory cytokine IL-8, indicating a necrotic type of cell death. Subcytotoxic (10 nM) and cytotoxic (≥100 nM) MC-LR concentrations disrupted hepatocyte functions, such as xenobiotic metabolism phase-I enzyme activities (cytochrome P450 1A/1B) and albumin secretion, along with reduced expression of CYP1A2 and ALB genes. MC-LR also decreased expression of HNF4A gene, a critical regulator of hepatocyte differentiation and function. Genes encoding hepatobiliary membrane transporters (OATP1B1, BSEP, NTCP), hepatocyte gap junctional gene connexin 32 and the epithelial cell marker E-cadherin were also downregulated. Simultaneous upregulation of connexin 43 gene, primarily expressed by liver progenitor and non-parenchymal cells, indicated a disruption of tissue homeostasis. This was associated with a shift in the expression ratio of E-cadherin to N-cadherin towards the mesenchymal cell marker, a process linked to epithelial-mesenchymal transition (EMT) and hepatocarcinogenesis. The effects observed in the human liver cell in vitro model revealed mechanisms that can potentially contribute to the MC-LR-induced promotion and progression of hepatocellular carcinoma (HCC). Hepoid-HepaRG cultures provide a robust, accessible and versatile in vitro model, capable of sensitively detecting hepatotoxic effects at toxicologically relevant concentrations, allowing for assessing hepatotoxicity mechanisms, human health hazards and impacts of environmental hepatotoxins, such as MC-LR., Competing Interests: Declaration of competing 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 © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

γδ T cells are essential for immune defense and modulating physiological processes. While they have the potential to recognize large numbers of antigens through somatic gene rearrangement, the antigens which trigger most γδ T cell response remain unidentified, and the role of antigen recognition in γδ T cell function is contentious. Here, we show that some γδ T cell receptors (TCRs) exhibit polyspecificity, recognizing multiple ligands of diverse molecular nature. These ligands include haptens, metabolites, neurotransmitters, posttranslational modifications, as well as peptides and proteins of microbial and host origin. Polyspecific γδ T cells are enriched among activated cells in naive mice and the responding population in infection. They express diverse TCR sequences, have different functional potentials, and include the innate-like γδ T cells, such as the major IL-17 responders in various pathological/physiological conditions. We demonstrate that encountering their antigenic microbiome metabolite maintains their homeostasis and functional response, indicating that their ability to recognize multiple ligands is essential for their function. Human γδ T cells with similar polyspecificity also respond to various immune challenges. This study demonstrates that polyspecificity is a prevalent feature of γδ T cell antigen recognition, which enables rapid and robust T cell responses to a wide range of challenges, highlighting a unique function of γδ T cells., Competing Interests: Competing interests statement:The authors declare no competing interest.

N-terminal pro-B-type natriuretic peptide (NT-proBNP) has been used as a tool for diagnosis, severity assessment and prognostication of congestive heart failure (CHF) in adults, with specific cut off values for diagnosis and denoting points of intervention. However, there is scarcity of paediatric literature regarding role of NT-proBNP as a marker of heart failure severity and prognostication. So, this study was done to assess the utility of NT-proBNP as a marker of severity of heart failure in children with congenital heart diseases. Single centre, prospective observational study. Children (1 month to 5 years), with congenital heart disease, admitted in the paediatric wards with varying severity of CHF were enrolled. Heart failure severity grading was done according to Laer modification of Ross Classification at the time of presentation to hospital and children were classified as having no/grade I CHF (score: 0-2); mild/grade II CHF (score 3-6); moderate/grade III CHF (score 7-9) or severe/grade IV CHF (score 10-12). NT-proBNP levels were measured within 24 h of admission. Eighty children with congenital heart disease were enrolled in this study. As per modified Ross Classification, 11 had grade I/No heart failure (13.7%), 32 children had grade II/mild heart failure (40%), 36 had grade III/moderate heart failure (45%) and only 1 had grade IV/severe heart failure (1.25%). The median NT-proBNP levels (IQR) in the above mentioned grades of heart failure were found to be 321.11 (211.1-411.78 pg/ml), 750.62 (474.62-995.2 pg/ml), 4159.61 (1440.59-11,857 pg/ml) and 11,320.34 pg/ml, respectively. Seven children (8.75%) expired. Median NT-proBNP value in seven children who died was significantly higher than those who survived [median (IQR): 11,681.01 pg/ml (10,092.72-14,754 pg/ml) vs 839.4 pg/ml (456.67-3288.09 pg/ml), p value < 0.001]. NT-proBNP level of 520.2 pg/ml predicted grade II (mild heart failure) or more severe grades of heart failure with Sensitivity, Specificity, Negative Predictive Value and Positive Predictive Value of 83%, 91%, 57.1% and 98%, respectively. NT-proBNP levels increase progressively with increasing severity of CHF and can be used as a marker of severity of heart failure in children with congenital heart disease presenting with CHF., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Novel methodologies are now essential for identification of antibiotic resistant pathogens in order to resist them. Here, we are presenting a model, MACI (Machine learning-based Antibiotic resistance gene-specific drug Class Identification) that can take metagenomic fragments as input and predict the drug class of antibiotic resistant genes. In our study, we trained a model using the Comprehensive Antibiotic Resistance Database, containing 5138 representative sequences across 134 drug classes. Among these classes, 23 dominated, contributing 85% of the sequence data. The model achieved an average precision of 0.8389 ± 0.0747 and recall of 0.8197 ± 0.0782 for these 23 drug classes. Additionally, it exhibited higher performance (precision and recall: 0.8817 ± 0.0540 and 0.8620 ± 0.0493) for predicting multidrug resistant classes compared to single drug resistant categories (0.7923 ± 0.0669 and 0.7737 ± 0.0794). The model also showed promising results when tested on an independent data. We then analysed these 23 drug classes to identify class-specific overlapping nucleotide patterns. Five significant drug classes, viz. "Carbapenem; cephalosporin; penam", "cephalosporin", "cephamycin", "cephalosporin; monobactam; penam; penem", and "fluoroquinolone" were identified, and their patterns aligned with the functional domains of antibiotic resistance genes. These class-specific patterns play a pivotal role in rapidly identifying drug classes with antibiotic resistance genes. Further analysis revealed that bacterial species containing these five drug classes are associated with well-known multidrug resistance properties., Competing Interests: Declaration of competing interest The authors declare that they have no known conflict of interests that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

A brain-computer interface (BCI) is a computer-based system that allows for communication between the brain and the outer world, enabling users to interact with computers using neural activity. This brain signal is obtained from electroencephalogram (EEG) signals. A significant obstacle to the development of BCIs based on EEG is the classification of subject-independent motor imagery data since EEG data are very individualized. Deep learning techniques such as the convolutional neural network (CNN) have illustrated their influence on feature extraction to increase classification accuracy. In this paper, we present a multi-branch (five branches) 2D convolutional neural network that employs several hyperparameters for every branch. The proposed model achieved promising results for cross-subject classification and outperformed EEGNet, ShallowConvNet, DeepConvNet, MMCNN, and EEGNet&#95;Fusion on three public datasets. Our proposed model, EEGNet Fusion V2, achieves 89.6% and 87.8% accuracy for the actual and imagined motor activity of the eegmmidb dataset and scores of 74.3% and 84.1% for the BCI IV-2a and IV-2b datasets, respectively. However, the proposed model has a bit higher computational cost, i.e., it takes around 3.5 times more computational time per sample than EEGNet&#95;Fusion.

Background: Coronary artery disease is an incurable, life-threatening disease that was once considered primarily a disorder of lipid deposition. Coronary artery disease is now also characterized by chronic inflammation' notable for the buildup of atherosclerotic plaques containing immune cells in various states of activation and differentiation. Understanding how these immune cells contribute to disease progression may lead to the development of novel therapeutic strategies., Methods: We used single-cell technology and in vitro assays to interrogate the immune microenvironment of human coronary atherosclerotic plaque at different stages of maturity., Results: In addition to macrophages, we found a high proportion of αβ T cells in the coronary plaques. Most of these T cells lack high expression of CCR7 and L-selectin , indicating that they are primarily antigen-experienced memory cells. Notably, nearly one-third of these cells express the HLA-DRA surface marker, signifying activation through their TCRs (T-cell receptors). Consistent with this, TCR repertoire analysis confirmed the presence of activated αβ T cells (CD4

Human papillomavirus type-16 (HPV16) is classified into lineages, A, B, C and D and 10 sub-lineages portraying variable infectivity, persistence, and cytological outcomes, however, with geographical variations. Our objective was to delineate the distinctive features of lineages among cervical squamous cell carcinoma (SCC) in the eastern region of India. A total of 145 SCC cases and 24 non-malignant specimens, harboring episomal HPV16, were included. The presence of higher proportion of lineage A over D was observed among SCC cases (86.89% A1, 8.97% D1 and 4.14% D2), while only A1 sub-lineage viruses were found among control specimens. Among the A1 viruses, an association of variants in the E5 (Y44L, I65V), E6 (L83V) genes and LCR: C7577T with SCC, with combined Odd's ratio (95% CI) of 20.5(4.61-91.25) was observed. Network analyses revealed the presence of 10 clades of lineage A viruses comprising of 64 HPV16 genomes harboring the risk alleles. High episomal HPV16 DNA copy numbers (adjusted p-value= 0.0271) and E7 mRNA expression (p-value=0.000017) predominated in SCC with lineage A, over D. Our study highlights the distinctive modalities of oncogenicity among different HPV16 lineages., (Copyright © 2021. Published by Elsevier Inc.)

Two-dimensional (2D) van der Waals (vdW) magnetic materials have attracted a lot of attention owing to the stabilization of long range magnetic order down to atomic dimensions, and the prospect of novel spintronic devices with unique functionalities. The clarification of the magnetoresistive properties and its correlation to the underlying magnetic configurations is essential for 2D vdW-based spintronic devices. Here, the effect of Co-doping on the magnetic and magnetotransport properties of Fe 3 GeTe 2 have been investigated. Magnetotransport measurements reveal an unusual Hall effect behavior whose strength was considerably modified by Co-doping and attributed to arise from the underlying complicated spin textures. The present results provide a clue to tailoring of the underlying interactions necessary for the realization of a variety of unconventional spin textures for 2D vdW FM-based spintronics.

Background: At the initial management of overactive bladder (OAB) syndrome urge suppression technique along with other behavioural modification could be a good option., Methods: Prospective experimental study conducted between 2015 and 2019. Women complaining of OAB were enrolled. Three-day bladder diary and patient global impression of severity (PGI-S) scale were evaluated at baseline. Then, the women were asked to perform the urge suppression technique whenever urgency occurred. She stopped moving, sat down and started squeezing the pelvic floor muscle quickly and tightly about ten times without full relaxation in between squeezes. After that, she did something to distract her mind. Once urgency disappeared, she proceeded to the toilet. If urgency reappeared, she stopped moving and repeated the same thing. Only on relax mood she entered toilet. Modified fluid consumption was - total daily requirement divided into three parts and two-third of that was taken from morning to lunch. The remaining one-third was divided again in three parts and two-third of that was taken before evening. Rest few amount was taken from the evening till waking up the next morning. After 3 months, 3-day bladder diary and patient global impression of improvement (PGI-I) scale assessed the improvement., Results: Ninety-one women ultimately completed the study. Frequency and nocturia were reduced. Seventy-six women had improvement of their urgency sensation ( P < 0.001), whereas urgency urinary incontinence reduction was statistically not significant ( P > 0.05). PGI-I scale showed that 51.6% felt that either they were very much better or much better., Conclusion: Urge suppression and modified fluid consumption is good adjunct in female OAB management., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Urology Annals.)

Background: Quality of life and patient reported outcome measures (PROMs) are important secondary endpoints and incorporated in most contemporary clinical trials. There have been deficiencies in their assessment and reporting in ovarian cancer clinical trials, particularly in trials of maintenance treatment where they are of particular importance. The Gynecologic Cancer InterGroup (GCIG) symptom benefit committee (SBC) recently convened a brainstorming meeting with representation from all collaborative groups to address questions of how to best incorporate PROMs into trials of maintenance therapies to support the primary endpoint which is usually progression free survival (PFS). These recommendations should harmonize the collection, analysis and reporting of PROM's across future GCIG trials., Methods: Through literature review, trials analysis and input from international experts, the SBC identified four relevant topics to address with respect to promoting the role of PROMs to support the PFS endpoint in clinical trials of maintenance treatment for OC., Results: The GCIG SBC unanimously accepted the importance of integrating PROM's in future maintenance trials and developed four guiding principles to be considered early in trial design. These include 1) adherence to SPIRIT-PRO guidelines, 2) harmonization of selection, collection and reporting of PROM's; 3) combining Health Related Quality of Life (HRQL) measures with clinical endpoints and 4) common approaches to dealing with incomplete HRQL data., Conclusions: Close attention to incorporating HRQL and PROM's is critical to interpret the results of ovarian cancer clinical trials of maintenance therapies. There should be a consistent approach to assessing and reporting patient centered benefits across all GCIG trials to enable cross trial comparisons which can be used to inform practice., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a member of the family Coronaviridae, and the world is currently witnessing a global pandemic outbreak of this viral disease called COVID-19. With no specific treatment regime, this disease is now a serious threat to humanity and claiming several lives daily. In this work, we selected 24 phytochemicals for an in silico docking study as candidate drugs, targeting four essential proteins of SARS-CoV-2 namely Spike glycoprotein (PDB id 5WRG), Nsp9 RNA binding protein (PDB id 6W4B), Main Protease (PDB id 6Y84), and RNA dependent RNA Polymerase (PDB id 6M71). After statistical validation, the results indicated that a total of 11 phytochemicals divided into two clusters might be used as potential drug candidates against SARS-CoV-2., Supplementary Information: The online version contains supplementary material available at 10.1007/s13337-021-00654-x., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest., (© Indian Virological Society 2021.)

Local regulations on residential landscapes (yards and gardens) can facilitate or constrain ecosystem services and disservices in cities. To our knowledge, no studies have undertaken a comprehensive look at how municipalities regulate residential landscapes to achieve particular goals and to control management practices. Across six U.S. cities, we analyzed 156 municipal ordinances to examine regional patterns in local landscape regulations and their implications for sustainability. Specifically, we conducted content analysis to capture regulations aimed at: 1) goals pertaining to conservation and environmental management, aesthetics and nuisance avoidance, and health and wellbeing, and 2) management actions including vegetation maintenance, water and waste management, food production, and chemical inputs. Our results reveal significant variation in local and regional regulations. While regulatory goals stress stormwater management and nuisance avoidance, relatively few municipalities explicitly regulate residential yards to maintain property values, mitigate heat, or avoid allergens. Meanwhile, biological conservation and water quality protection are common goals, yet regulations on yard management practices (e.g., non-native plants or chemical inputs) sometimes contradict these purposes. In addition, regulations emphasizing aesthetics and the maintenance of vegetation, mowing of grass and weeds, as well as the removal of dead wood, may inhibit wildlife-friendly yards. As a whole, landscaping ordinances largely ignore tradeoffs between interacting goals and outcomes, thereby limiting their potential to support landscape sustainability. Recommendations therefore include coordinated, multiobjective planning through partnerships among planners, developers, researchers, and non-government entities at multiple scales., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Ebola and Dengue are the critical diseases caused by RNA viruses, especially in the tropical parts of the globe, including Asia and Africa, and no prominent therapeutic options are available so far. Here, an effort was made to evaluate the efficacy of black pepper ( Piper nigrum L.) alkaloid Piperine as a potential drug through computational docking simulation. Eight structurally essential proteins of Dengue and Ebola virus were selected as in silico docking targets for Piperine. Absorption, Distribution, Metabolism, and Excretion profile showed that Piperine was safe and possessed significant drug-like properties. Molecular dynamic simulation and binding free energy calculation showed that Piperine could inhibit Methyltransferase (PDB id 1L9K) of Dengue and VP35 Interferon Inhibitory Domain (PDB id 3FKE) of Ebola virus in comparison with the commercial antiviral Ribavirin. Furthermore, statistical analysis based on multivariate and clustering approaches revealed that Piperine had more affinity towards viral proteins than that of Ribavirin., Competing Interests: Conflict of interestThe authors declare no conflict of interest., (© Indian Virological Society 2020.)

The human impact on life on Earth has increased sharply since the 1970s, driven by the demands of a growing population with rising average per capita income. Nature is currently supplying more materials than ever before, but this has come at the high cost of unprecedented global declines in the extent and integrity of ecosystems, distinctness of local ecological communities, abundance and number of wild species, and the number of local domesticated varieties. Such changes reduce vital benefits that people receive from nature and threaten the quality of life of future generations. Both the benefits of an expanding economy and the costs of reducing nature's benefits are unequally distributed. The fabric of life on which we all depend-nature and its contributions to people-is unravelling rapidly. Despite the severity of the threats and lack of enough progress in tackling them to date, opportunities exist to change future trajectories through transformative action. Such action must begin immediately, however, and address the root economic, social, and technological causes of nature's deterioration., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Residential land is expanding in the United States, and lawn now covers more area than the country's leading irrigated crop by area. Given that lawns are widespread across diverse climatic regions and there is rising concern about the environmental impacts associated with their management, there is a clear need to understand the geographic variation, drivers, and outcomes of common yard care practices. We hypothesized that 1) income, age, and the number of neighbors known by name will be positively associated with the odds of having irrigated, fertilized, or applied pesticides in the last year, 2) irrigation, fertilization, and pesticide application will vary quadratically with population density, with the highest odds in suburban areas, and 3) the odds of irrigating will vary by climate, but fertilization and pesticide application will not. We used multi-level models to systematically address nested spatial scales within and across six U.S. metropolitan areas-Boston, Baltimore, Miami, Minneapolis-St. Paul, Phoenix, and Los Angeles. We found significant variation in yard care practices at the household (the relationship with income was positive), urban-exurban gradient (the relationship with population density was an inverted U), and regional scales (city-to-city variation). A multi-level modeling framework was useful for discerning these scale-dependent outcomes because this approach controls for autocorrelation at multiple spatial scales. Our findings may guide policies or programs seeking to mitigate the potentially deleterious outcomes associated with water use and chemical application, by identifying the subpopulations most likely to irrigate, fertilize, and/or apply pesticides., Competing Interests: The authors have declared that no competing interests exist.

The physical systems with ferromagnetism and 'bad' metallicity hosting unusual transport properties are playgrounds of novel quantum phenomena. Recently EuTi 1-x Nb x O 3 emerged as a ferromagnetic system where non-trivial temperature dependent transport properties are observed due to coexistence and competition of various magnetic and non-magnetic scattering processes. In the ferromagnetic state, the resistivity shows a T 2 temperature dependence possibly due to electron-magnon scattering and above the Curie temperature [Formula: see text], the dependence changes to T 3/2 behaviour indicating a correlation between transport and magnetic properties. In this paper, we show that the transport spin-polarization ([Formula: see text]) in EuTi 1-x Nb x O 3 , a low Curie temperature ferromagnet, is as high (∼40%) as that in some of the metallic ferromagnets with high Curie temperatures. In addition, owing to the low Curie temperature of EuTi 1-x Nb x O 3 , the temperature (T) dependence of [Formula: see text] could be measured systematically up to [Formula: see text] which revealed a proportionate relationship with magnetization [Formula: see text] versus T. This indicates that such proportionality is far more universally valid than the ferromagnets with ideal parabolic bands. Furthermore, our band structure calculations not only helped to understand the origin of such high spin polarization in EuTi 1-x Nb x O 3 but also provided a route to estimate the Hubbard U parameter in complex metallic ferromagnets in general using experimental inputs.

In natural grasslands, C 4 plant dominance increases with growing season temperatures and reflects distinct differences in plant growth rates and water use efficiencies of C 3 vs. C 4 photosynthetic pathways. However, in lawns, management decisions influence interactions between planted turfgrass and weed species, leading to some uncertainty about the degree of human vs. climatic controls on lawn species distributions. We measured herbaceous plant carbon isotope ratios (δ 13 C, index of C 3 /C 4 relative abundance) and C 4 cover in residential lawns across seven U.S. cities to determine how climate, lawn plant management, or interactions between climate and plant management influenced C 4 lawn cover. We also calculated theoretical C 4 carbon gain predicted by a plant physiological model as an index of expected C 4 cover due to growing season climatic conditions in each city. Contrary to theoretical predictions, plant δ 13 C and C 4 cover in urban lawns were more strongly related to mean annual temperature than to growing season temperature. Wintertime temperatures influenced the distribution of C 4 lawn turf plants, contrary to natural ecosystems where growing season temperatures primarily drive C 4 distributions. C 4 cover in lawns was greatest in the three warmest cities, due to an interaction between climate and homeowner plant management (e.g., planting C 4 turf species) in these cities. The proportion of C 4 lawn species was similar to the proportion of C 4 species in the regional grass flora. However, the majority of C 4 species were nonnative turf grasses, and not of regional origin. While temperature was a strong control on lawn species composition across the United States, cities differed as to whether these patterns were driven by cultivated lawn grasses vs. weedy species. In some cities, biotic interactions with weedy plants appeared to dominate, while in other cities, C 4 plants were predominantly imported and cultivated. Elevated CO 2 and temperature in cities can influence C 3 /C 4 competitive outcomes; however, this study provides evidence that climate and plant management dynamics influence biogeography and ecology of C 3 /C 4 plants in lawns. Their differing water and nutrient use efficiency may have substantial impacts on carbon, water, energy, and nutrient budgets across cities., (© 2019 by the Ecological Society of America.)

To permit the recognition of antigens, T cells generate a vast diversity of T cell receptor (TCR) sequences. Upon binding of the TCR to an antigen-MHC complex, T cells clonally expand to establish an immune response. To study antigen-specific T cell clonality, we have developed a method that allows selection of rare cells, based on RNA expression, before in-depth scRNA-seq (named SELECT-seq). We applied SELECT-seq to collect both TCR sequences and then transcriptomes from single cells of peripheral blood lymphocytes activated by a Mycobacterium tuberculosis ( Mtb ) lysate. TCR sequence analysis allowed us to preferentially select expanded conventional CD8 + T cells as well as invariant natural killer T (iNKT) cells and mucosal-associated invariant T (MAIT) cells. The iNKT and MAIT cells have a highly similar transcriptional pattern, indicating that they carry out similar immunological functions and differ considerably from conventional CD8 + T cells. While there is no relationship between expression profiles and clonal expansion in iNKT or MAIT cells, highly expanded conventional CD8 + T cells down-regulate the interleukin 2 (IL-2) receptor alpha (IL2RA, or CD25) protein and show signs of senescence. This suggests inherent limits to clonal expansion that act to diversify the T cell response repertoire., Competing Interests: The authors declare no conflict of interest., (Copyright © 2019 the Author(s). Published by PNAS.)

Heterogeneity in cervical cancers (CaCx) in terms of HPV16 physical status prompted us to investigate the mRNA and miRNA signatures among the different categories of CaCx samples. We performed microarray-based mRNA expression profiling and quantitative real-time PCR-based expression analysis of some prioritised miRNAs implicated in cancer-related pathways among various categories of cervical samples. Such samples included HPV16-positive CaCx cases that harboured either purely integrated HPV16 genomes (integrated) and those that harboured episomal viral genomes, either pure or concomitant with integrated viral genomes (episomal), which were compared with normal cervical samples that were either HPV negative or positive for HPV16. The mRNA expression profile differed characteristically between integrated and episomal CaCx cases for enriched biological pathways. miRNA expression profiles also differed among CaCx cases compared with controls (upregulation-miR-21, miR-16, miR-205, miR-323; downregulation-miR-143, miR-196b, miR-203, miR-34a; progressive upregulation-miR-21 and progressive downregulation-miR-143, miR-34a, miR-196b and miR-203) in the order of HPV-negative controls, HPV16-positive non-malignant samples and HPV16-positive CaCx cases. miR-200a was upregulated in HPV16-positive cervical tissues irrespective of histopathological status. Expression of majority of the predicted target genes was negatively correlated with their corresponding miRNAs, irrespective of the CaCx subtypes. E7 mRNA expression correlated positively with miR-323 expression among episomal cases and miR-203, among integrated cases. miR-181c expression was downregulated only among the episomal CaCx cases and negatively correlated with protein coding transcript of the proliferative target gene, CKS1B of the significantly enriched "G2/M DNA Damage Checkpoint Regulation" pathway among CaCx cases. Thus, the two CaCx subtypes are distinct entities at the molecular level, which could be differentially targeted for therapy. In fact, availability of a small molecule inhibitor of CKS1B , suggests that drugging CKS1B could be a potential avenue of treating the large majority of CaCx cases harbouring episomal HPV16., Competing Interests: The authors declare that they have no conflict of interest.

The type II Dirac semimetal PdTe[Formula: see text] is unique in the family of topological parent materials because it displays a superconducting ground state below 1.7 K. Despite wide speculation on the possibility of an unconventional topological superconducting phase, tunneling and heat capacity measurements revealed that the superconducting phase of PdTe[Formula: see text] follows predictions of the microscopic theory of Bardeen, Cooper and Schrieffer for conventional superconductors. The superconducting phase in PdTe[Formula: see text] is further interesting because it also displays properties that are characteristic of type-I superconductors and are generally unexpected for binary compounds. Here, from scanning tunneling spectroscopic measurements we show that the surface of PdTe[Formula: see text] displays intrinsic electronic inhomogeneities in the normal state which leads to a mixed type I and type II superconducting behaviour along with a spatial distribution of critical fields in the superconducting state. Understanding of the origin of such inhomogeneities may be important for understanding the topological properties of PdTe[Formula: see text] in the normal state.

Point mutations in genes encoding sarcomeric proteins are the leading cause of inherited primary cardiomyopathies. Among them are mutations in the TNNT2 gene that encodes cardiac troponin T (TnT). These mutations are clustered in the tropomyosin (Tm) binding region of TnT, TNT1 (residues 80-180). To understand the mechanistic changes caused by pathogenic mutations in the TNT1 region, six hypertrophic cardiomyopathy (HCM) and two dilated cardiomyopathy (DCM) mutants were studied by biochemical approaches. Binding assays in the absence and presence of actin revealed changes in the affinity of some, but not all, TnT mutants for Tm relative to WT TnT. HCM mutants were hypersensitive and DCM mutants were hyposensitive to Ca 2+ in regulated actomyosin ATPase activities. To gain better insight into the disease mechanism, we modeled the structure of TNT1 and its interactions with Tm. The stability predictions made by the model correlated well with the affinity changes observed in vitro of TnT mutants for Tm. The changes in Ca 2+ sensitivity showed a strong correlation with the changes in binding affinity. We suggest the primary reason by which these TNNT2 mutations between residues 92 and 144 cause cardiomyopathy is by changing the affinity of TnT for Tm within the TNT1 region., Competing Interests: Conflict of interest statement: J.A.S. is a founder of and owns shares in MyoKardia, Inc., a biotechnology company developing therapeutics to treat the underlying biomechanical defects leading to hypertrophic cardiomyopathy or dilated cardiomyopathy. J.A.S. is also a founder of Cytokinetics and MyoKardia and a member of their scientific advisory boards.

The Homeobox (HOX) genes encode important transcription factors showing deregulated expression in several cancers. However, their role in cervical cancer pathogenesis, remains largely unexplored. Herein, we studied their association with Human Papillomavirus type 16 (HPV16) mediated cervical cancers. Our previously published gene expression microarray data revealed a significant alteration of 12 out of 39 HOX cluster members among cervical cancer cases, in comparison to the histopathologically normal controls. Of these, we validated seven (HOXA10, HOXA13, HOXB13, HOXC8, HOXC9, HOXC11 and HOXD10) by quantitative real-time PCR. We identified decreased HOXA10 expression as opposed to the increased expression of the rest. Such decrease was independent of the integration status of HPV16 genome, but correlated negatively with E7 expression in clinical samples, that was confirmed in vitro. HOXA10 and HOXB13 revealed association with Epithelial-Mesenchymal Transition (EMT). While HOXA10 expression correlated positively with E-Cadherin and negatively with Vimentin expression, HOXB13 showed the reverse trend. Chromatin immunoprecipitation study in vitro revealed the ability of E7 to increase HOX gene expression by epigenetic regulation, affecting the H3K4me3 and H3K27me3 status of their promoters, resulting from a loss of PRC2-LSD1 complex activity. Thus, besides identifying the deregulated expression of HOX cluster members in HPV16 positive cervical cancer and their association with EMT, our study highlighted the mechanism of HPV16 E7-mediated epigenetic regulation of HOX genes in such cancers, potentially serving as bedrock for functional studies in the future.

Background: Germline knockout mice are invaluable in understanding the function of the targeted genes. Sometimes, however, unexpected phenotypes are encountered, due in part to the activation of compensatory mechanisms. Germline ablation of cardiac myosin light chain kinase (cMLCK) causes mild cardiac dysfunction with cardiomyocyte hypertrophy, whereas ablation in adult hearts results in acute heart failure with cardiomyocyte atrophy. We hypothesized that compensation after ablation of cMLCK is dependent on developmental staging and perinatal-onset of cMLCK ablation will result in more evident heart failure than germline ablation, but less profound when compared to adult-onset ablation. Methods and Results: The floxed-Mylk3 gene was ablated at the beginning of the perinatal stage using a single intra-peritoneal tamoxifen injection of 50 mg/kg into pregnant mice on the 19th day of gestation, this being the final day of gestation. The level of cMLCK protein level could no longer be detected 3 days after the injection, with these mice hereafter denoted as the perinatal Mylk3-KO . At postnatal day 19, shortly before weaning age, these mice showed reduced cardiac contractility with a fractional shortening 22.8 ± 1.0% ( n = 7) as opposed to 31.4 ± 1.0% ( n = 11) in controls. The ratio of the heart weight relative to body weight was significantly increased at 6.68 ± 0.28 mg/g ( n = 12) relative to the two control groups, 5.90 ± 0.16 (flox/flox, n = 11) and 5.81 ± 0.33 (wild/wild/Cre, n = 5), accompanied by reduced body weight. Furthermore, their cardiomyocytes were elongated without thickening, with a long-axis of 101.8 ± 2.4 μm ( n = 320) as opposed to 87.1 ± 1.6 μm ( n = 360) in the controls. Conclusion: Perinatal ablation of cMLCK produces an increase of heart weight/body weight ratio, a reduction of contractility, and an increase in the expression of fetal genes. The perinatal Mylk3-K O cardiomyocytes were elongated in the absence of thickening, differing from the compensatory hypertrophy shown in the germline knockout, and the cardomyocyte thinning shown in adult-inducible knockout.

Aims: Under pressure overload, initial adaptive hypertrophy of the heart is followed by cardiomyocyte elongation, reduced contractile force, and failure. The mechanisms governing the transition to failure are not fully understood. Pressure overload reduced cardiac myosin light chain kinase (cMLCK) by ∼80% within 1 week and persists. Knockdown of cMLCK in cardiomyocytes resulted in reduced cardiac contractility and sarcomere disorganization. Thus, we hypothesized that acute reduction of cMLCK may be causative for reduced contractility and cardiomyocyte remodelling during the transition from compensated to decompensated cardiac hypertrophy., Methods and Results: To mimic acute cMLCK reduction in adult hearts, the floxed-Mylk3 gene that encodes cMLCK was inducibly ablated in Mylk3(flox/flox)/merCremer mice (Mylk3-KO), and compared with two control mice (Mylk3(flox/flox) and Mylk3(+/+)/merCremer) following tamoxifen injection (50 mg/kg/day, 2 consecutive days). In Mylk3-KO mice, reduction of cMLCK protein was evident by 4 days, with a decline to below the level of detection by 6 days. By 7 days, these mice exhibited heart failure, with reduction of fractional shortening compared with those in two control groups (19.8 vs. 28.0% and 27.7%). Severely convoluted cardiomyocytes with sarcomeric disorganization, wavy fibres, and cell death were demonstrated in Mylk3-KO mice. The cardiomyocytes were also unable to thicken adaptively to pressure overload., Conclusion: Our results, using a new mouse model mimicking an acute reduction of cMLCK, suggest that cMLCK plays a pivotal role in the transition from compensated to decompensated hypertrophy via sarcomeric disorganization., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Adenine nucleotide translocases (ANTs) transport ADP and ATP through mitochondrial inner membrane, thus playing an essential role for energy metabolism of eukaryotic cells. Mice have three ANT paralogs, Ant1 (Slc25a4), Ant2 (Slc25a5) and Ant4 (Slc25a31), which are expressed in a tissue-dependent manner. While knockout mice have been characterized with Ant1 and Ant4 genes, which resulted in exercise intolerance and male infertility, respectively, the role of the ubiquitously expressed Ant2 gene in animal development has not been fully demonstrated. Here, we generated Ant2 hypomorphic mice by targeted disruption of the gene, in which Ant2 expression is largely depleted. The mice showed apparently normal embryonic development except pale phenotype along with a reduced birth rate. However, postnatal growth was severely retarded with macrocytic anemia, B lymphocytopenia, lactic acidosis and bloated stomach, and died within 4 weeks. Ant2 depletion caused anemia in a cell-autonomous manner by maturation arrest of erythroid precursors with increased reactive oxygen species and premature deaths. B-lymphocyte development was similarly affected by Ant2 depletion, and splenocytes showed a reduction in maximal respiration capacity and cellular ATP levels as well as an increase in cell death accompanying mitochondrial permeability transition pore opening. In contrast, myeloid, megakaryocyte and T-lymphocyte lineages remained apparently intact. Erythroid and B-cell development may be particularly vulnerable to Ant2 depletion-mediated mitochondrial dysfunction and oxidative stress.

Changes in land use, land cover, and land management present some of the greatest potential global environmental challenges of the 21st century. Urbanization, one of the principal drivers of these transformations, is commonly thought to be generating land changes that are increasingly similar. An implication of this multiscale homogenization hypothesis is that the ecosystem structure and function and human behaviors associated with urbanization should be more similar in certain kinds of urbanized locations across biogeophysical gradients than across urbanization gradients in places with similar biogeophysical characteristics. This paper introduces an analytical framework for testing this hypothesis, and applies the framework to the case of residential lawn care. This set of land management behaviors are often assumed--not demonstrated--to exhibit homogeneity. Multivariate analyses are conducted on telephone survey responses from a geographically stratified random sample of homeowners (n = 9,480), equally distributed across six US metropolitan areas. Two behaviors are examined: lawn fertilizing and irrigating. Limited support for strong homogenization is found at two scales (i.e., multi- and single-city; 2 of 36 cases), but significant support is found for homogenization at only one scale (22 cases) or at neither scale (12 cases). These results suggest that US lawn care behaviors are more differentiated in practice than in theory. Thus, even if the biophysical outcomes of urbanization are homogenizing, managing the associated sustainability implications may require a multiscale, differentiated approach because the underlying social practices appear relatively varied. The analytical approach introduced here should also be productive for other facets of urban-ecological homogenization.

Introduction: The development of vaccines is considered a key milestone in preventive medicine. There is no comparable cost-effective means for controlling or eradicating infectious diseases. Yet, a persistent societal problem is the concern about vaccine's safety and long-term effects, and this caters to detractors of vaccination. Pathogen-derived antigen(s) as well as adjuvants/immunostimulants are essential for vaccine efficacy. Currently, adjuvant selection is largely empirical, but the mechanism underlying adjuvanticity is beginning to unravel. This should help develop more defined or targeted adjuvants., Areas Covered: This review provides a brief account and analysis of the host immune parameters modulated by some commonly used as well as new adjuvants, including phytol-based diterpenoids. The major efforts are directed toward evaluating their relative safety and immunomodulatory efficiency, compared to known synthetic and natural adjuvants. Concerns for adverse pathological inflammation and autoimmunity are also addressed., Expert Opinion: The phytol-based adjuvants hold great promise for improving vaccine efficacy, as they cause little or no persistent inflammation, but are highly effective in stimulating a multifaceted immune response, characterized by proficient recruitment of immune cells, generation of antibody and immunological memory, and activation of both Th1 and Th2 responses. Future focus will be on developing cocktail adjuvants to activate the complement system, mobilize follicular T helper cells as well as NKT and γδ T cells and activate cross-presenting dendritic cells to stimulate CD8(+) effector T cells.

Grafting from polymerization was used to synthesize nano-titania/polyurethane (nTiO(2)/polyurethane) composite coatings, where nTiO(2) was chemically attached to the backbone of the polyurethane polymer matrix with a bifunctional monomer, 2,2-bis(hydroxymethyl) propionic acid (DMPA). This bifunctional monomer can coordinate to nTiO(2) through an available -COOH group, with two available hydroxyl groups that can react with diisocyanate terminated pre-polyurethane through step-growth polymerization. The coordination reaction was monitored by FTIR and TGA, with the coordination reaction found to follow first order kinetics. After step-growth polymerization, the polyurethane nanocomposites were found to be stable on standing with excellent distribution of Ti in the polymer matrix without any significant agglomeration compared to simple physical mixtures of nTiO(2) in the polyurethane coatings. The functionalized nTiO(2)-polyurethane composite coatings showed excellent antibacterial activity against gram-negative bacteria Escherichia coli; 99% of E. coli were killed within less than one hour under solar irradiation. Self-cleaning was also demonstrated using stearic acid as a model for 'dirt'.

Tremendous interest exists towards synthesizing nanoassemblies for dye-sensitized solar cells (DSSCs) using earth-abundant and -friendly materials with green synthetic approaches. In this work, high surface area TiO(2) nanowire arrays were grown on the surface of functionalized graphene sheets (FGSs) containing -COOH functionalities acting as a template by using a sol-gel method in the green solvent, supercritical carbon dioxide (scCO(2)). The effect of scCO(2) pressure (1500, 3000 and 5000 psi), temperature (40, 60 and 80 °C), acetic acid/titanium isopropoxide monomer ratios (HAc/TIP = 2, 4 and 6), functionalized graphene sheets (FGSs)/TIP weight ratios (1:20, 1:40 and 1:60 w/w) and solvents (EtOH, hexane) were investigated. Increasing the HAc/TIPweight ratio from 4 to 6 in scCO(2) resulted in increasing the TiO(2) nanowire diameter from 10 to 40 nm. Raman and high resolution XPS showed the interaction of TiO(2) with the -COOH groups on the surface of the graphene sheets, indicating that graphene acted as a template for polycondensation growth. UV-vis diffuse reflectance and photoluminescence spectroscopy showed a reduction in titania's bandgap and also a significant reduction in electron-hole recombination compared to bare TiO(2) nanowires. Photocurrent measurements showed that the TiO(2)nanowire/graphene composites prepared in scCO(2) gave a 5× enhancement in photoefficiency compared to bare TiO(2) nanowires.

This review describes the adjuvanticity of novel diterpenoids (synthetic phytol derivatives) compared to some commercially available adjuvants. The efficacy of the phytol-derived immunostimulants was evaluated in terms of their ability to activate innate immunity, amplify various antigen-specific immune responses, and engender immunological memory with no discernible adverse effects in both competent and immune-deficient mice. The profile that emerges out of these studies reveals that the phytol derivatives are excellent immunostimulants, superior to a number of commercial adjuvants in terms of long-term memory induction and activation of both innate and acquired immunity. Additionally, the phytol-derived compounds have no cumulative inflammatory or toxic effects even in immuno-compromised mice.

This study was undertaken to decipher the interdependent roles of (i) methylation within E2 binding site I and II (E2BS-I/II) and replication origin (nt 7862) in the long control region (LCR), (ii) expression of viral oncogene E7, (iii) expression of the transcript (E7-E1/E4) that encodes E2 repressor protein and (iv) viral load, in human papillomavirus 16 (HPV16) related cervical cancer (CaCx) pathogenesis. The results revealed over-representation (p<0.001) of methylation at nucleotide 58 of E2BS-I among E2-intact CaCx cases compared to E2-disrupted cases. Bisulphite sequencing of LCR revealed overrepresentation of methylation at nucleotide 58 or other CpGs in E2BS-I/II, among E2-intact cases than E2-disrupted cases and lack of methylation at replication origin in case of both. The viral transcript (E7-E1/E4) that produces the repressor E2 was analyzed by APOT (amplification of papillomavirus oncogenic transcript)-coupled-quantitative-RT-PCR (of E7 and E4 genes) to distinguish episomal (pure or concomitant with integrated) from purely integrated viral genomes based on the ratio, E7 C(T)/E4 C(T). Relative quantification based on comparative C(T) (threshold cycle) method revealed 75.087 folds higher E7 mRNA expression in episomal cases over purely integrated cases. Viral load and E2 gene copy numbers were negatively correlated with E7 C(T) (p = 0.007) and E2 C(T) (p<0.0001), respectively, each normalized with ACTB C(T), among episomal cases only. The k-means clustering analysis considering E7 C(T) from APOT-coupled-quantitative-RT-PCR assay, in conjunction with viral load, revealed immense heterogeneity among the HPV16 positive CaCx cases portraying integrated viral genomes. The findings provide novel insights into HPV16 related CaCx pathogenesis and highlight that CaCx cases that harbour episomal HPV16 genomes with intact E2 are likely to be distinct biologically, from the purely integrated viral genomes in terms of host genes and/or pathways involved in cervical carcinogenesis.

In a previous report, we observed that the phytol-derived immunostimulant, PHIS-01 (phytanol), is a nontoxic oil-in-water adjuvant which is superior to most commercial adjuvants. In contrast, the parent diterpene alcohol phytol, though highly effective as an adjuvant, is relatively toxic. To assess the importance of the polar functional group in PHIS-01, we prepared two new compounds PHIS-02 (phytanyl amine) and PHIS-03 (phytanyl mannose). All three phytol derivatives proved to be excellent adjuvants, but differed in solubility and mode of action. To delineate their molecular signatures in the local microenvironment, we performed inflammasome and cytokine microarray analyses with the peritoneal fluid of mice treated with alum or the phytol compounds above, in the presence or absence of soluble protein antigens. We report here that the phytol derivatives had a significant time-dependent impact on the host chemokine-cytokine microenvironment and subsequently on specific humoral responses. Moreover, the inclusion of protein immunogens induced further changes in host microenvironments, including rapid (<2h) expression of cytokines and chemotactic factors (IL-6, MCP-1, KC, MIP-1, and LIX), implying mobilization and activation of neutrophils, and monocytes. PHIS-01 proved to be the most effective in this regard. Inflammatory cytokine cascades were dominant even after 24h possibly to facilitate involvement of the acquired immune system with the release of B-lymphocyte chemo-attractant BLC, T-cell activation-3 chemokines TCA, IL-4, IL-12, and TIMP-1. We also noted enhanced expression of NLRP genes including NLRP3 with both alum and phytol derivatives (particularly PHIS-01)., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Oral cancer is a lifestyle-related cancer, with tobacco as a primary factor. Progression of oral cancer develops over several years from the stage of leukoplakia, erythroplakia, etc. A micronucleus test was applied to oral mucosal cells, considering them as the target site for carcinogens and cytogenetic damage. The test has been established as a reliable biomarker for differential prevalence of MN indices among oral cancers, pre-cancers, non-malignant oral pathologies, and healthy controls for the first time. Buccal scrapings were collected from 63 patients with cancer and pre-cancerous lesions, 42 with non-malignant oral problems, and 100 healthy controls. The analysis revealed that MN frequencies in cancer and pre-cancerous cases were 4-fold elevated (p < 0.001) and 3.87-fold (p < 0.002) elevated for other non-malignant pathologies. Significant associations between use of tobacco in various forms and development of oral pathologies are also established. The relative cancer risk for smoking healthy controls with a definite MN frequency was also found to be significant. The results indicate the validity of the MN test as a cytogenetic marker for the development of several oral pathologies.

Background: The hemochromatosis mutation, C282Y of the HFE gene, seems to have originated from a single event which once occurred in a person living in the north west of Europe carrying human leukocyte antigen (HLA)-A3-B7. In descendants of this ancestor also other haplotypes appear probably caused by local recombinations and founder effects. The background of these associations is unknown. Isolated river valley populations may be fruitful for the mapping of genetic disorders such as hemochromatosis. In this study, we try to test this hypothesis in a study from central Sweden where the haplotyope A1-B8 was common., Methods: HLA haplotypes and HFE mutations were studied in hemochromatosis patients with present or past parental origin in a sparsely populated (1/km(2)) rural district (n = 8366 in the year of 2005), in central Sweden. Pedigrees were constructed from the Swedish church book registry. Extended haplotypes were studied to evaluate origin of recombinations., Results: There were 87 original probands, 36 females and 51 males identified during 30 yr, of whom 86% carried C282Y/C282Y and 14% C282Y/H63D. Of 32 different HLA haplotypes A1-B8 was the most common (34%), followed by A3-B7 (16%), both in strong linkage disequilibrium with controls, (P < 0.001). Twenty-nine different families with A1-B8 had a common founder origin 15 generations ago in small bottleneck populations of the late 16th century. A second A1-B8 founder born 1655 was of Norwegian origin. Most of the A3 carriers (n = 26) had a common founder origin 16 generations ago in an even smaller nearby river valley. A fourth founder family carrying HLA-A2 seems to have originated from a recombination along the descendant lines from the A3 ancestor supported by extended haplotype studies. A1-haplotypes with alleles at the B locus different from B8 had a similar recombination origin as HLA-A2 alleles and a common founder origin 11 generations ago. The intergenerational time interval averaged 35.5 +/- 7.9 yr in men and 31.9 +/- 5.9 in females., Conclusions: River valley populations may contain HLA haplotypes reflecting their demographic history. This study has demonstrated that the resistance against recombinations between HLA-A and HFE make HLA haplotypes excellent markers for population movements. Founder effects and genetic drift from bottleneck populations (surviving the plague?) may explain the commonness of the mutation in central Scandinavia. The intergenerational time difference >30 yr was greater than expected and means that the age of the original mutation may be underestimated.

In this study we 1) describe the abundance of Anopheles and culicine immatures in different water body types in urban Malindi, Kenya, 2) compare Anopheles immature density in relation to culicine immature density, and 3) identify characteristics that influence the likelihood of water bodies being co-colonized by Anopheles and culicines. Entomological and environmental cross-sectional surveys conducted in 2001 and 2002 were used in the analysis. A total of 889 Anopheles and 7,217 culicine immatures were found in diverse water body types in 2001 and 2002. Car-track pools (n = 45) and unused swimming pools (n = 25) comprised 61% (70 of 115) of all water bodies found and served as the main habitats for Anopheles immatures. Of the 38 water bodies found containing Anopheles immature mosquitoes, 63% (24 of 38) were car-track pools and unused swimming pools. Culicine immatures utilized several water body types as habitats. We found that Anopheles and culicine immatures had higher density when occurring individually compared to when they occurred simultaneously. We determined that season, permanency, and water body area size influenced the likelihood of water bodies being simultaneously positive for Anopheles and culicines. Though Anopheles immatures were found in diverse water body types, their numbers were low compared to culicine immatures. The low density of Anopheles immatures suggests that Anopheles larval control is an achievable goal in Malindi.

Catalytic cross-coupling of aryl Grignard reagents with primary and secondary alkyl halides bearing beta-hydrogens is achieved using Fe(III) amine-bis(phenolate) halide complexes.

The increasing risk of mosquito-borne diseases in African urban environments has been partly attributed to failed planning and resource underdevelopment. Though engineered systems may reduce mosquito proliferation, there are few studies describing this relationship. This study investigates how engineered systems such as roads and piped water systems affect the odds of anopheline immatures (i.e., larvae and pupae) occurring in water bodies located in Malindi, Kenya. Anopheles gambiae s.s. (Giles), An. arabiensis (Patton), and An. merus (Dointz) were identified in urban Malindi, with Anopheles gambiae s.s. being the predominant species identified. The Breslow-Day test was used to explore interactions among independent variables. Logistic regression was used to test whether water bodies positive for anopheline immatures are associated with engineered systems, while controlling for potential confounding and interaction effects associated with urban water body characteristics. Water bodies more than 100 m from water pipes were 13 times more likely to have anopheline immatures present, compared to water bodies that were less than 100 m from water pipes (OR = 13.54, 95% CI: 3.15-58.23). Roads were not significantly associated with water bodies positive for anopheline immatures. Statistical interaction was detected between water body substrate type and distance to water pipes. This study provides insight into how water pipes influence the distribution of water bodies positive with immature anophelines in urban environments.

The major histocompatibility complex (MHC) is located on human Chromosome 6 and includes clusters of class I, class II, and class III genes. Centromeric to the class I region is a cluster of genes designated as MHC class IV encoding genes involved in immunity and inflammation, including the 1C7 gene. The human 1C7 gene has several alternatively spliced forms and potentially codes for proteins with at least three unique carboxy termini. 1C7 mRNA in human (h1C7) is present in spleen, tonsil, B and NK cell lines, and with a different splicing pattern in liver. The 1C7 RNA and protein are present at highest levels in the germinal center of the lymphoid follicles in tonsil. The protein is expressed in NKL cells, tonsil, and unexpectedly in brain. In contrast, the mouse 1C7 gene is transcribed in liver but is predicted to be a pseudogene. However, the 1C7 homologue expressed in rat is predicted to have long stretches of amino acids essentially identical to the human protein.

Malignant mixed mesodermal tumours of the ovary have been described together with a literature review. The characteristic histological pictures of the various representative tissue elements have been demonstrated and patients characteristics analysed in detail. This confirms the classical features of this group of advanced ovarian malignancy that highlight the aggressive nature of the tumour associated with poor survival. Although generally they are managed in the same line as epithelial ovarian carcinomas the appropriate treatment has yet to be established. Because of their rarity they also illustrate the potential problems of instituting prospective randomised controlled trials.