Performance analysis and modelling of circular jets aeration in an open channel using soft computing techniques.

Dissolved oxygen (DO) is an important parameter in assessing water quality. The reduction in DO concentration is the result of eutrophication, which degrades the quality of water. Aeration is the best way to enhance the DO concentration. In the current study, the aeration efficiency (E20) of various numbers of circular jets in an open channel was experimentally investigated for different channel angle of inclination (θ), discharge (Q), number of jets (Jn), Froude number (Fr), and hydraulic radius of each jet (HRJn). The statistical results show that jets from 8 to 64 significantly provide aeration in the open channel. The aeration efficiency and input parameters are modelled into a linear relationship. Additionally, utilizing WEKA software, three soft computing models for predicting aeration efficiency were created with Artificial Neural Network (ANN), M5P, and Random Forest (RF). Performance evaluation results and box plot have shown that ANN is the outperforming model with correlation coefficient (CC) = 0.9823, mean absolute error (MAE) = 0.0098, and root mean square error (RMSE) = 0.0123 during the testing stage. In order to assess the influence of different input factors on the E20 of jets, a sensitivity analysis was conducted using the most effective model, i.e., ANN. The sensitivity analysis results indicate that the angle of inclination is the most influential input variable in predicting E20, followed by discharge and the number of jets.

A review: Aeration efficiency of hydraulic structures in diffusing DO in water.

This paper contemplates the review of aeration efficiency with commonly used different aeration systems such as Venturi flumes, Weirs, Conduits, Stepped channels, In Venturi Aeration, the SAE value grows fast with the number of air holes. In Weir Aeration, it was found that among all the different labyrinth weir structure, triangular notch weirs are known for the optimum results for air entrainment. The ANN model was developed with parameters discharge (Q) and tail water depth (Tw) which showed that Q is more influential parameter than Tw. In conduits structure, it was found that circular high head gated conduits have better aeration performance than other conduits. Aeration efficiency in Stepped channels cascades may range from 30% to 70%. The sensitivity analysis with ANN model showed that discharge (Q) followed by number of steps (N) was the most influential parameter in E20. Bubble size was the important parameter to undertake when using bubble diffuser. The oxygen transfer efficiency (OTE) in jet diffusers was predicted developing an ANN model. It was found in sensitivity analysis that the input of 'velocity' is highly sensitive to OTE. According to literature, jets can provide OTE in the range of 1.91- 21.53kgO2/kW-hr.

An attempt to valorize the only black meat chicken breed of India by delineating superior functional attributes of its meat.

Kadaknath, the only black chicken indigenous to India, faces the threat of extinction due to declining numbers. Its meat is used in tribal medicine for invigorating and health-promoting properties. Expectations of immune-boosting and therapeutic properties in its meat are creating a buzz these days. Thus, Kadaknath meat was explored and further compared with the commercial Cobb 400 broiler (Cobb) for the functional traits that might be contributing towards proclaimed pharmacological benefits. Birds (n = 20/ group) were raised under similar management conditions and the two primal chicken meat cuts (breast and thigh) were collected at the marketing age. Kadaknath meat was found to be an enriched source of functional biomolecules (carnosine, anserine, creatine). Its breast meat carnosine content was more than double of the Cobb broiler, 6.10 ± 0.13 and 2.73 ± 0.1 mg/ g of wet tissue, respectively. Similarly, the thigh meat of Kadaknath was a significantly (P < 0.05) richer source of carnosine. The genetic background was a key determinant for muscle carnosine content as a significant abundance of CARNS1 and SLC36A1 expression was identified in the Kadaknath breast. The superior functional property of Kadaknath meat was established by the antioxidant capacity established by the Oxygen radical absorbance capacity assay and a stronger ability to inhibit the formation of advanced glycation end products (AGEs). The identification of fairly unknown nutritional and functional advantages of Kadaknath meat could potentially change the paradigm with its meat consumption. It will help in developing a brand name for Kadaknath products that will propel an increase in its market share and ultimately conservation of this unique but endangered poultry germplasm.

DNA aptamer selection and detection of marine biotoxin 20 Methyl Spirolide G.

This study reports the selection of DNA aptamer for the detection of 20 Methyl Spirolide G (SPXG). After 10 rounds of selection, theenriched pool of aptamers specific to SPXGwas cloned, sequenced and clustered into seven families based onsimilarity. Three sequences SPX1, SPX2 and SPX7, each belonging to different clades were further evaluated for their binding affinity. Surface plasmonresonancestudies determined the highest affinity KDof 0.0345x10-8 M for aptamer SPX7. A label-free microscale thermophoresis-based aptasensing using SPX7 with highest affinity, indicated a linear detection range from 1.9 to 125000 pg/mL (LOD = 0.39 pg/mL; LOQ = 1.17 pg/mL). Spiking studies in simulated contaminated samples of mussel and scallop indicated recoveries in the range of 86 to 108%. Results of this study indicate the successful development of an aptamer for detection of SPXG at picogram levels. It also opens up avenues to develop other sensing platforms for detection of SPXG using the reported aptamer.

ATLAS trial of adjuvant axitinib in patients with renal cell carcinoma: subgroup analyses with focus on axitinib dosing and racial groups.

BACKGROUND: The ATLAS trial, investigating adjuvant axitinib versus placebo in renal cell carcinoma (RCC), was stopped for futility at a preplanned interim analysis. We report subgroup outcome analyses by ethnicity, time on treatment, dose modification and toxicity. PATIENTS AND METHODS: Patient demographics, baseline characteristics, treatment duration and exposure and safety were analysed for Asian versus non-Asian patients treated with axitinib versus placebo. Disease-free survival (DFS) was analysed by ethnicity, treatment duration (≥1 versus <1 year), dose modification and adverse event (AE) grade. RESULTS: No DFS benefit was observed for Asian {hazard ratio (HR) 0.883 [95% confidence interval (CI) 0.638-1.220]} or non-Asian [HR 0.828 (95% CI 0.490-1.400)] patients treated with axitinib or placebo. Fewer Asian versus non-Asian patients were in the highest-risk group in axitinib (51.9% versus 72.3%) or placebo (51.5% versus 66.0%) arm. Highest-risk patients in both subgroups had no DFS benefit with either treatment. More axitinib-treated Asian versus non-Asian patients had dose reductions due to AEs (58.8% versus 46.0%; P = 0.028). Asian patients experienced more nasopharyngitis but less fatigue or asthenia than non-Asians. Among Asian patients, proteinuria, hypothyroidism, nasopharyngitis, and hypertension were more common in Japanese patients than Korean patients and more common in Korean patients than Chinese patients. Patients receiving axitinib >1 year versus ≤1 year did not have different DFS: HR 0.572 (95% CI 0.247-1.327); P = 0.1874. Compared with patients on stable axitinib dose, DFS was longer in patients with dose reduction [HR 0.458 (95% CI 0.305-0.687); P = 0.0001], whereas DFS was not different in those with dose escalation [HR 1.936 (95% CI 0.937-3.997); P = 0.0685]. DFS was not different in patients experiencing grade ≥2 versus <2 AEs within 6 months of initiating axitinib: HR 0.885 (95% CI 0.419-1.869); P = 0.7488. CONCLUSIONS: Asian versus non-Asian subgroup analysis revealed differences in AE experience and drug exposure. There were no DFS differences based on ethnicity or treatment duration, but axitinib dose reduction led to longer DFS.

Investigating BB0405 as a novel Borrelia afzelii vaccination candidate in Lyme borreliosis.

BB0405 is a surface exposed Borrelia burgdorferi protein and its vaccination protected mice against B. burgdorferi infection. As BB0405 is highly conserved across different B. burgdorferi sensu lato species, we investigated whether vaccination with recombinant BB0405 or through intradermal bb0405 DNA tattoo vaccination could provide protection against different Borrelia species, specifically against Borrelia afzelii, the predominant B. burgdorferi sensu lato genospecies causing Lyme borreliosis across Eurasia. We immunized C3H/HeN mice with recombinant BB0405 or with a codon-optimized bb0405 DNA vaccine using the pVAC plasmid and immunized corresponding control groups mice with only adjuvant or empty vectors. We subsequently subjected these immunized mice to a tick challenge with B. afzelii CB43-infected Ixodes ricinus nymphs. Upon vaccination, recombinant BB0405 induced a high total IgG response, but bb0405 DNA vaccination did not elicit antibody responses. Both vaccine formulations did not provide protection against Borrelia afzelii strain CB43 after tick challenge. In an attempt to understand the lack of protection of the recombinant vaccine, we determined expression of BB0405 and showed that B. afzelii CB43 spirochetes significantly and drastically downregulate the expression of BB0405 protein at 37 °C compared to 33 °C, where as in B. burgdorferi B31 spirochetes expression levels remain unaltered. Vaccination with recombinant BB0405 was previously shown to protect against B. burgdorferi sensu stricto. Here we show that vaccination with either recombinant BB0405 (or non-immunogenic bb0405 DNA), despite being highly conserved among B. burgdorferi sl genospecies, does not provide cross-protection against B. afzelii, mostly likely due to downregulation of this protein in B. afzelii in the mammalian host.

Role of nutraceuticals in cognition during aging and related disorders.

Cognitive abilities are compromised with advancing age posing a great risk for the development of dementia and other related brain disorders. Genetic susceptibility as well as environmental exposures determine the fate of cognitive aging and its transition to pathological states. Emerging epidemiological and observational studies have revealed the importance of lifestyle factors including dietary patterns and nutritional intake in the maintenance of cognitive health and reducing the risk of neurodegenerative disorders. In this context, nutraceutical interventions have gained considerable attention in preventing age-related cognitive deficits and counteracting pathological processes. Nutraceuticals include dietary plants and derivatives, food supplements and processed foods with nutritional and pharmaceutical values. The present review highlights the importance of nutraceuticals in attenuating cognitive aging and its progression to dementia, with specific emphasis on chemical constituents, neurocognitive properties and mechanism of action.

How long do people stick to a diet resolution? A digital epidemiological estimation of weight loss diet persistence.

OBJECTIVE: To use Internet search data to compare duration of compliance for various diets. DESIGN: Using a passive surveillance digital epidemiological approach, we estimated the average duration of diet compliance by examining monthly Internet searches for recipes related to popular diets. We fit a mathematical model to these data to estimate the time spent on a diet by new January dieters (NJD) and to estimate the percentage of dieters dropping out during the American winter holiday season between Thanksgiving and the end of December. SETTING: Internet searches in the USA for recipes related to popular diets over a 15-year period from 2004 to 2019. PARTICIPANTS: Individuals in the USA performing Internet searches for recipes related to popular diets. RESULTS: All diets exhibited significant seasonality in recipe-related Internet searches, with sharp spikes every January followed by a decline in the number of searches and a further decline in the winter holiday season. The Paleo diet had the longest average compliance times among NJD (5.32 ± 0.68 weeks) and the lowest dropout during the winter holiday season (only 14 ± 3 % dropping out in December). The South Beach diet had the shortest compliance time among NJD (3.12 ± 0.64 weeks) and the highest dropout during the holiday season (33 ± 7 % dropping out in December). CONCLUSIONS: The current study is the first of its kind to use passive surveillance data to compare the duration of adherence with different diets and underscores the potential usefulness of digital epidemiological approaches to understanding health behaviours.

Quantitative metabolic biomarker analysis of mild cognitive impairment in eastern U.P. and Bihar population.

Mild cognitive impairment (MCI) is a transition phase between healthy individuals and Alzheimer's disease (AD). Therefore, diagnosis of MCI at early stage will help to delay or prevent its progression to disease. In the present study, we aim to identify the metabolic biomarkers, which can help in the diagnosis of MCI. We have screened 2000 elderly individuals from north India, out of which 200 were identified as MCI. We continued our study on 10 MCI individuals who regularly participated in the follow-up. The age and gender matched 10 healthy individuals were taken as control. These control and MCI individuals were subjected to neuropsychological examination such as Hindi mental state examination (HMSE) and Montreal cognitive assessment (MOCA) followed by 1H Nuclear Magnetic Resonance (NMR) analysis. Remarkable changes were noted between control and MCI individuals at metabolic level. In silico study showed the involvement of eight metabolites in MCI. We found higher level of lactate, N-acetyl aspartate, histidine and lower level of formate, choline, alanine, creatinine and glucose in blood plasma of MCI individuals compared to control. Further, In silico study showed that choline might be directly associated with MCI or AD. Such In silico study with quantitative metabolite analysis of plasma could be used as diagnostic biomarkers for the identification of MCI.

Correction to: Age-related expression of Neurexin1 and Neuroligin3 is correlated with presynaptic density in the cerebral cortex and hippocampus of male mice.

The corresponding author noticed in his published paper that the images (30 weeks, CC, 10, 30 and 50 weeks DG) of fig. 3b are inadvertently duplicated with the images of fig. 3a. Now, these images have been replaced in the corrected panel (Fig. 3b) below.

Phase Ib study of atezolizumab combined with cobimetinib in patients with solid tumors.

BACKGROUND: Preclinical evidence suggests that MEK inhibition promotes accumulation and survival of intratumoral tumor-specific T cells and can synergize with immune checkpoint inhibition. We investigated the safety and clinical activity of combining a MEK inhibitor, cobimetinib, and a programmed cell death 1 ligand 1 (PD-L1) inhibitor, atezolizumab, in patients with solid tumors. PATIENTS AND METHODS: This phase I/Ib study treated PD-L1/PD-1-naive patients with solid tumors in a dose-escalation stage and then in multiple, indication-specific dose-expansion cohorts. In most patients, cobimetinib was dosed once daily orally for 21 days on, 7 days off. Atezolizumab was dosed at 800 mg intravenously every 2 weeks. The primary objectives were safety and tolerability. Secondary end points included objective response rate, progression-free survival, and overall survival. RESULTS: Between 27 December 2013 and 9 May 2016, 152 patients were enrolled. As of 4 September 2017, 150 patients received ≥1 dose of atezolizumab, including 14 in the dose-escalation cohorts and 136 in the dose-expansion cohorts. Patients had metastatic colorectal cancer (mCRC; n = 84), melanoma (n = 22), non-small-cell lung cancer (NSCLC; n = 28), and other solid tumors (n = 16). The most common all-grade treatment-related adverse events (AEs) were diarrhea (67%), rash (48%), and fatigue (40%), similar to those with single-agent cobimetinib and atezolizumab. One (<1%) treatment-related grade 5 AE occurred (sepsis). Forty-five (30%) and 23 patients (15%) had AEs that led to discontinuation of cobimetinib and atezolizumab, respectively. Confirmed responses were observed in 7 of 84 patients (8%) with mCRC (6 responders were microsatellite low/stable, 1 was microsatellite instable), 9 of 22 patients (41%) with melanoma, and 5 of 28 patients (18%) with NSCLC. Clinical activity was independent of KRAS/BRAF status across diseases. CONCLUSIONS: Atezolizumab plus cobimetinib had manageable safety and clinical activity irrespective of KRAS/BRAF status. Although potential synergistic activity was seen in mCRC, this was not confirmed in a subsequent phase III study. CLINICALTRIALS.GOV IDENTIFIER: NCT01988896 (the investigators in the NCT01988896 study are listed in the supplementary Appendix, available at Annals of Oncology online).

The Continuing Evolution of Molecular Functional Imaging in Clinical Oncology: The Road to Precision Medicine and Radiogenomics (Part II).

The present era of precision medicine sees "cancer" as a consequence of molecular derangements occurring at the commencement of the disease process, with morphological changes happening much later in the process of tumourigenesis. Conventional imaging techniques, such as computed tomography (CT), ultrasound (US) and magnetic resonance imaging (MRI) play an integral role in the detection of disease at the macroscopic level. However, molecular functional imaging (MFI) techniques entail the visualisation and quantification of biochemical and physiological processes occurring during tumourigenesis. MFI has the potential to play a key role in heralding the transition from the concept of "one-size-fits-all" treatment to "precision medicine". Integration of MFI with other fields of tumour biology such as genomics has spawned a novel concept called "radiogenomics", which could serve as an indispensable tool in translational cancer research. With recent advances in medical image processing, such as texture analysis, deep learning and artificial intelligence, the future seems promising; however, their clinical utility remains unproven at present. Despite the emergence of novel imaging biomarkers, the majority of these require validation before clinical translation is possible. In this two part review, we discuss the systematic collaboration across structural, anatomical and molecular imaging techniques that constitute MFI. Part I reviews positron emission tomography, radiogenomics, AI, and optical imaging, while part II reviews MRI, CT and ultrasound, their current status, and recent advances in the field of precision oncology.

Correction to: The Continuing Evolution of Molecular Functional Imaging in Clinical Oncology: The Road to Precision Medicine and Radiogenomics (Part II).

An Online First version of this article was made available online at http://link.springer.com/journal/40291/onlineFirst/page/1 on 01 Nov 2018. An error was subsequently identified in the article, and the following correction should be noted.

Xanthine scaffold: scope and potential in drug development.

Medicinal plants have been the basis for discovery of various important marketed drugs. Xanthine is one such lead molecule. Xanthines in various forms (caffeine, theophylline, theobromine, etc) are abode in tea, coffee, cocoa, chocolate etc. giving them popular recognition. These compounds are best known for their diverse pharmaceutical applications as cyclic nucleotide phosphodiesterase inhibition, antagonization of adenosine receptor, anti-inflammatory, anti-microbial, anti-oxidant and anti-tumor activities. These properties incentivize to use xanthine as scaffold to develop new derivatives. Chemical synthesis contributes greater diversity in xanthine based derivatisation. With highlighting the existing challenges in chemical synthesis, the present review focuses the probable solution to fill existing lacuna. The review summarizes the available knowledge of xanthine based drugs development along with exploring new xanthine led chemical synthesis path for bringing diversification in xanthine based research. The main objective of this review is to explore the immense potential of xanthine as scaffold in drug development.

Histone Deacetylase 2 Inhibition Attenuates Downregulation of Hippocampal Plasticity Gene Expression during Aging.

The brain undergoes several anatomical, biochemical, and molecular changes during aging, which subsequently result in downregulation of synaptic plasticity genes and decline of memory. However, the regulation of these genes during aging is not clearly understood. Previously, we reported that the expression of histone deacetylase (HDAC)2 was upregulated in the hippocampus of old mice and negatively correlated with the decline in recognition memory. As HDAC2 regulates key synaptic plasticity neuronal immediate early genes (IEGs), we have examined their expression and epigenetic regulation. We noted that the expression of neuronal IEGs decreased both at mRNA and protein level in the hippocampus of old mice. To explore the underlying regulation, we analyzed the binding of HDAC2 and level of histone acetylation at the promoter of neuronal IEGs. While the binding of HDAC2 was higher, H3K9 and H3K14 acetylation level was lower at the promoter of these genes in old as compared to young and adult mice. Further, we inhibited HDAC2 non-specifically by sodium butyrate and specifically by antisense oligonucleotide to recover epigenetic modification, expression of neuronal IEGs, and memory in old mice. Inhibition of HDAC2 increased histone H3K9 and H3K14 acetylation level at the promoter of neuronal IEGs, their expression, and recognition memory in old mice as compared to control. Thus, inhibition of HDAC2 can be used as a therapeutic target to recover decline in memory due to aging and associated neurological disorders.

Epigenetic Regulation of Memory-Therapeutic Potential for Disorders.

BACKGROUND: Memory is a vital function which declines in different physiological and pathological conditions such as aging and neurodegenerative diseases. Research in the past has reported that memory formation and consolidation require the precise expression of synaptic plasticity genes. However, little is known about the regulation of these genes. Epigenetic modification is now a well established mechanism that regulates synaptic plasticity genes and neuronal functions including memory. Therefore, we have reviewed the epigenetic regulation of memory and its therapeutic potential for memory dysfunction during aging and neurological disorders. METHOD: Research reports and online contents relevant to epigenetic regulation of memory during physiological and pathological conditions have been compiled and discussed. RESULTS: Epigenetic modifications include mainly DNA methylation and hydroxymethylation, histone acetylation and methylation which involve chromatin modifying enzymes. These epigenetic marks change during memory formation and impairment due to dementia, aging and neurodegeneration. As the epigenetic modifications are reversible, they can be modulated by enzyme inhibitors leading to the recovery of memory. CONCLUSION: Epigenetic modifications could be exploited as a potential therapeutic target to recover memory disorders during aging and pathological conditions.

Anxiety like behavior due to perinatal exposure to Bisphenol-A is associated with decrease in excitatory to inhibitory synaptic density of male mouse brain.

Bisphenol-A (BPA) is a synthetic endocrine disruptor which causes anxiety like behavior in rodents, though the underlying mechanism is not clearly understood. As excitatory-inhibitory synaptic proteins are the key regulators of anxiety, we have examined the effect of perinatal exposure to BPA on this behavior and the expression of excitatory (PSD95), inhibitory (gephyrin) and presynaptic density marker (synaptophysin) proteins in cerebral cortex and hippocampus of 3 and 8 weeks postnatal male mice. In open field (OF) test, BPA exposure reduced the time spent, number of entries and distance travelled in the central zone as compared to control in 8 weeks mice. On the other hand, elevated plus maze (EPM) results showed decrease in time spent and number of entries to the open arms. Immunoblotting and immunofluorescence analysis showed significant downregulation of PSD95 and synaptophysin, but upregulation of gephyrin, leading to reduction in excitatory to inhibitory protein ratio and synaptic density in postnatal 3 and 8 weeks mice. Thus, our findings show that the anxiety like behavior due to perinatal exposure to BPA is associated with decrease in excitatory to inhibitory synaptic density in postnatal male mice.

Binding of transcription factors to Presenilin 1 and 2 promoter cis-acting elements varies during the development of mouse cerebral cortex.

Previously, we reported differential expression of Presenilin (PS)1 and 2 and epigenetic modifications of their gene promoter in the cerebral cortex of mice during development. We identified the crucial role of DNA methylation and H3K9/14 acetylation in stage specific PS expression during brain development. Interestingly, we noted differential DNA methylation in putative binding sites of transcription factors considered pivotal for brain development. This prompted us to study the binding of transcription factors to cis-acting elements of PS1 and PS2 promoter in the cerebral cortex of mice during development. In-silico analysis revealed various cis-acting elements of PS1 and PS2 promoter and their putative transcription factors. We selected those cis-acting elements that were proven by wet lab experiments to interact with the transcription factors crucial for brain development. Electrophoretic mobility shift assay revealed that the binding of nuclear proteins to PS1 promoter cis-acting elements like HSF-1, Cdx1, Ets-1 and Sp1 significantly increased at embryonic day (E) 12.5, postnatal day (P) 45 and 20 weeks (w) as compared to P0. The binding pattern of these factors correlated well with the PS1 expression profile, indicating their cumulative influence on PS1 gene transcription. For PS2 promoter, the binding of Nkx2.2 and HFH-2 was high at prenatal stages (E12.5 and E18.5) while that of Cdx1 and NF-κB was maximum at postnatal stages (P45 and 20w). Taken together, our study shows that the binding of HSF-1, Cdx1, Ets-1 and Sp1 to PS1 promoter and that of Nkx2.2, HFH-2, Cdx1 and NF-κB to PS2 promoter regulate their differential expression during brain development.