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Novel functions can emerge in an enzyme family while conserving catalytic mechanism, motif or fold. Pyridoxal 5'-phosphate-dependent enzymes have evolved into seven fold-types and catalyze diverse reactions using the same mechanism for the formation of external aldimine. Nucleotide sugar aminotransferases (which will be henceforth referred to as aminotransferases) belong to fold type I and mediate the biosynthesis of several monosaccharides. They use diverse substrates but are highly selective to the C3 or C4 carbon to which amine group is transferred. Profile hidden Markov models (HMMs) were able to identify aminotransferases but could not capture reaction specificity. A search for discriminating features led to the discovery of sequence motifs that are located near the pyranose binding site suggesting their role in imparting reaction specificity. Using a position weight matrix for this motif, we were able to assign reaction specificity to a large number of aminotransferases. Inferences from this analysis set way for future experiments that can shed light on mechanisms of functional diversification in nucleotide sugar aminotransferases of fold type I.

The kinetic and mechanistic study of homogeneously Pd(II)-catalyzed oxidation of ampicillin by Cu(Bipy)2 2+ in alkaline medium have been conducted at 35 ± 0.1 ºC. Spectrophotometric titrations show that the stoichiometry of the reaction is 1:4 ([ampicillin]:[Cu(Bipy)2 2+] = 1:4). The first order kinetics is observed regarding [Cu(Bipy)2 2+] and [Pd(II)] however, less than unity order exhibited by [OH–]. On varying [ampicillin] and [bipyridyl], velocity of reaction remains unchanged. Reaction rate unaffected by changing ionic strength of the medium while with dielectric constant, it shows inverse relation. Various thermodynamic properties of reaction were calculated such as activation energy, activation entropy, etc. Oxophenyl acetic acid and 2-formyl-5,5-dimethylthiazolidine-4-carboxylic acid were identified as reaction product. With the help of kinetic observation, spectrophotometric data an appropriate reaction mechanism and rate law derived for aforesaid reaction.

Phishing Website Data set from UCI ML Repository Size (11055,31), 11055 samples and 30 features with 1 class label. Reference [10] in the paper. [10] R. M. Mohammad, F. Thabtah, and L. McCluskey, “Phishing Websites Features,” School of Computing and Engineering, University of Huddersfield, 2015. [Online]. Available: Index of /ml/machine?learning-databases/00327 (uci.edu)

This paper describes a robust autonomous disinfection tunnel to disinfect external surfaces of COVID-19 virus such as clothes and open body sections in public places such as airports, office complexes, schools, and malls. To make the tunnel effective and highly efficient, it has been provided with two chambers with three disinfection processes. Due to the multiple processes, the possibility of neutralizing the virus is quite high and higher than other solutions available at this point for this purpose. Chamber 1 sprays the solution of a disinfectant on the person. This solution can be either a dilute solution of approved chemical or any Ayurvedic/herbal disinfectant. Once the person enters chamber 2, he/she is exposed to hot air at 70 °C along with far-ultraviolet C rays (207–222 nm). Both chambers function autonomously by detecting a person in a chamber using ultrasonic sensors. The proposed tunnel is developed under industry–academia collaboration jointly by Technopark@iitk and ALIMCO under the ambit of the Ministry of Human Resources Development and the Ministry of Social Justice and Empowerment, respectively. The tunnel is referred to as the ‘Techno Advanced Disinfection Tunnel’ (TADT).

Neuregulin-1 (encoded by NRG1) serves as a ligand for ERBB3 and can lead to dysregulated cellular proliferation in cases of NRG1 fusions. The reported incidence of NRG1 fusions in solid tumors is ~0.1-0.3% with enrichment in invasive mucinous adenocarcinoma of the lung and KRAS wildtype pancreatic adenocarcinoma. However, the real-world incidence of NRG1 fusions across diverse tumor types continues to evolve with the clinical implementation of comprehensive next-generation sequencing (NGS) methods including RNA based NGS. The true diversity and prognostic significance of specific NRG1 fusion partners has yet to be elucidated. We report on NRG1 fusions from a large clinico-genomic database of patients (pts) in community-based oncology settings where NGS is ordered as standard clinical practice. We conducted a retrospective, records-based analysis of pts across Sarah Cannon’s network of over 299 partner community-based oncology clinics to identify pts with NRG1 fusions detected by commercial NGS testing ordered as a part of standard of care from 1/1/2017 - 7/7/2022. NRG1 fusions were reported in 0.05% (19 of 40,857) of pts with commercial NGS test results across a range of tumor types including lung (59%; n=11/19), pancreas (11%; n=2), breast (5%; n=1), colorectal (5%), esophageal (5%), endometrial (5%), soft tissue liposarcoma (5%), and carcinoma of unknown primary (5%). NGS identifying an NRG1 fusion was performed in 5 (26%) pts with early stage disease while 11 (58%) pts had NGS testing after initial diagnosis of or progression to advanced/metastatic disease. A majority of pts harboring NRG1 fusions were female (68%; n=13). NRG1 fusions were detected by DNA (58%; n=11) and RNA based (42%; n=8) NGS from liquid (5%; n=1) and tissue biopsies (95%; n=18). A total of 11 different fusion partners were reported. CD74 was the most prevalent fusion partner and was primarily detected by DNA NGS including in one pt from liquid biopsy. Five novel, as yet to be described, fusion partners (CDK13, IL1RL2, FUT10, PPP2R2A, PIM3) were detected - 3 by RNA sequencing and 2 by DNA sequencing of NRG1 (versus sequencing of the fusion partner). TP53 (42%; n=8), CDKN2A (32%; n=6), and MTAP (16%; n=3) were the most frequently co-altered genes. Other notable co-altered genes included mutations in PIK3CA (11%; n=2), BRAF (5%; n=1), EGFR (5%), ALK (5%), and NRAS (5%). Immune biomarkers were largely negative, with 16% (n=3) PD-L1 positive, 0% MSI-high, and 5% (n=1) TMB-high cases. These data highlight the importance of comprehensive molecular profiling for pts with solid tumors, as NRG1 fusions occur across tumor types and stage of disease. Appropriate test selection is paramount as novel NRG1 fusions are more robustly detected by RNA over DNA NGS and are more routinely detected in tissue over liquid biopsies. Clinical trials investigating therapies to target NRG1 fusions are ongoing [CRESTONE (NCT04383210); eNRGy (NCT02912949)]. Citation Format: Emma G. Sturgill, Jaya Srivastava, Jessica Correia, Cooper Schumacher, Daniel Luckett, Cesar A. Perez, Judy S. Wang, Stephen G. Divers, Babar Bashir, Jennifer Johnson, Valerie M. Jansen, Andrew J. McKenzie, David R. Spigel. Identification of NRG1 fusions in patients with solid tumors: analysis from a real-world community oncology network [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 921.

Novel functions can emerge in an enzyme family while conserving catalytic mechanism, motif or fold. PLP-dependent enzymes have evolved into seven fold types and catalyse diverse reactions using the same mechanism for the formation of external aldimine. Nucleotide sugar aminotransferases (NSATs) and dehydratases (NSDs) belong to fold type I and mediate the biosynthesis of several monosaccharides. NSATs use diverse substrates but are highly selective to the C3 or C4 carbon to which amine group is transferred. Factors responsible for reaction specificity in NSDs are known but remain unexplored in NSATs. Profile HMMs were able to identify NSATs but could not capture reaction specificity. A search for discriminating features led to the discovery of a sequence motif that is located near the pyranose binding site suggesting their role in imparting reaction specificity. Using a position weight matrix for this motif, we were able to assign reaction specificity to a large number of NSATs. Residues which upon mutation could convert NSD to NSAT have been reported in literature and we deduced that these are not conserved. This suggested the occurrence of non-generic family specific mutations underlying the evolution of dehydratases. Inferences from this analysis set way for future experiments that can shed light on mechanisms of functional diversification in enzymes of fold type I.

MotivationUniProt and BFD databases together have 2.5 billion protein sequences. A large majority of these proteins have been electronically annotated. Automated annotation pipelines, vis-à-vis manual curation, have the advantage of scale and speed but are fraught with relatively higher error rates. This is because sequence homology does not necessarily translate to functional homology, molecular function specification is hierarchic and not all functional families have the same amount of experimental data that one can exploit for annotation. Consequently, customization of annotation workflow is inevitable to minimize annotation errors.ResultsWe discuss possible ways of customizing the search of sequence databases for functional homologs using profile HMMs. Choosing an optimal bit score threshold is a critical step in the application of HMMs, which is illustrated using four Case Studies; the single domain nucleotide sugar 6-dehydrogenase and lysozyme-C families, and SH3 and GT-A domains which are typically found as a part of multi-domain proteins. We also discuss the limitations of using profile HMMs for functional annotation and suggests some possible ways to partially overcome such limitations.Supplementary informationSupplementary_material containing Figures S1-S7 and Tables S1 and S2Supplementary_dataset.xlsx

Context.— Measurable (minimal) residual disease (MRD) is an independent prognostic factor for survival outcomes in patients with lymphoid and plasma cell malignancies and has been incorporated into consensus criteria regarding treatment response, strategy, and clinical trial endpoints. clonoSEQ (a next-generation sequencing [NGS]-MRD assay) uses multiplex polymerase chain reaction and NGS to identify clonotypic rearrangements at the immunoglobulin (Ig) H, IgK, IgL, T-cell receptor (TCR)-β, and TCR-γ loci, as well as translocated B-cell lymphoma 1/IgH and 2/IgH sequences for MRD assessment. Additionally, it can be used to confirm diagnoses of cutaneous T-cell lymphoma (CTCL). Objective.— To review the technical aspects of our experience using the clonoSEQ Assay in routine clinical practice. Design.— In this single-center experience, 390 patients with lymphoid and plasma cell malignancies were assessed with the NGS-MRD Assay at a central laboratory. Results.— Median time from arrival of the shipment to initiation of the assay (defined as captured in Adaptive's secure tracking system) was 2.1 hours. Overall, 317 patients had 1 or more samples submitted for sequence identification. Of these, 290 (91.5%) had trackable sequences identified. The median calibration rate of samples by malignancy (where n ≥ 10 samples, excluding CTCL samples) was 88.1%, across a variety of fresh and archived sample sources (177 of 201 samples). TCR-β and/or TCR-γ clonotypes were identified in 40 of 95 samples (42.1%) from 66 patients with suspected CTCL. Conclusions.— This NGS-MRD Assay is a valuable and sensitive tool for monitoring MRD in patients with plasma cell and lymphoid malignancies and assisting in the diagnosis of CTCL.

This case report describes the nonsurgical endodontic management of a distolingual floor perforation in a mandibular first molar using an internal matrix and mineral trioxide aggregate (MTA) cement. The pulp chamber was properly cleaned, and after placement of a synthetic collagen material that served as a barrier at the level of furcation, MTA was used to repair the perforation defect. Root canal treatment was completed and the tooth was restored with a composite restoration followed by a porcelain-fused-to-metal crown.

A distinctive feature of glycans vis-à-vis proteins and nucleic acids is its structural complexity, which arises from the huge repertoire of monosaccharides, isomeric linkages and branching. A very large number of monosaccharides have so far been discovered in natural glycans. Experimentally, pathways for the biosynthesis have been characterized completely for 55 monosaccharides and partially for a few more. However, there is no single platform, which provides information about monosaccharide biosynthesis pathways and associated enzymes We have gathered 572 experimentally characterized enzymes of 66 biosynthesis pathways from literature and set up a first of its kind database called the Monosaccharide Biosynthesis Pathways Database http://www.bio.iitb.ac.in/mbpd/). Annotations such as the reaction catalyzed, substrate specificity, biosynthesis pathway and PubMed IDs are provided for all the enzymes in the database. Sequence homologs of the experimentally characterized enzymes found in nearly 13,000 completely sequenced genomes from Bacteria and Archaea have also been included in the database. This platform will help in the deduction of evolutionary relationships among enzymes such as aminotransferases, nucleotidyltransferases, acetyltransferases and SDR family enzymes. It can also facilitate experimental studies such as direct enzyme assays to validate putative annotations, establish structure–function relationship, expression profiling to determine the function, determine the phenotypic consequences of gene knock-out/knock-in and complementation studies.

A distinctive feature of glycans vis-à-vis proteins and nucleic acids is its structural complexity which arises from the huge repertoire of monosaccharides, isomeric linkages and branching. Around 70 monosaccharides have so far been discovered in natural glycans and the pathway for the biosynthesis of 57 of these have been experimentally characterized. However, there is no common platform with a comprehensive information of monosaccharide pathways and enzymes. We have gathered 542 experimentally characterized enzymes of these pathways from literature and set up a first of its kind database called GlycoPathDB (http://www.bio.iitb.ac.in/glycopathdb/). Annotations such as the reaction catalysed, substrate specificity, biosynthesis pathway and PubMed IDs are provided for all the enzymes in the database. Sequence homologs of the experimentally characterized enzymes found in nearly 13,000 completely sequenced genomes from Bacteria and Archaea have also been included in the database. This platform will help in deduction of evolutionary relationships among enzymes such as aminotransferases, nucleotidyltransferases, acetyltransferases and SDR family enzymes. It can also facilitate experimental studies such as direct enzyme assays to validate putative annotations, establish structure-function relationship, expression profiling to determine the function, determine the phenotypic consequences of gene knock-out/knock-in and complementation studies.

This paper investigates fixed point implementations of five thermistor linearization techniques, namely, Hoge 1, Hoge 2, Hoge 3, Hoge 4 and Hoge 5 on field programmable gate array (FPGA) in LabVIEW environment. The relative performance assessment, on the basis of residual nonlinearity and hardware utilization, has been carried out and presented so as to enable the user to choose a particular linearization technique for his/her application depending on the available FPGA hardware resources. The presented experimental investigations validated the residual nonlinearities in ascending order for Hoge 2, Hoge 3, Hoge 4, Hoge 1 and Hoge 5 techniques as 4.53812E-08, 1.80728E-06, 6.14227E-05, 5.86377E-04 and 2.87804E-02, respectively for an industrial grade thermistor (Model No.: TJ36-44004-1/4-12, M/S Omega Engineering). Further, hardware utilizations have been recorded using the number of flip-flops, 4 input LUTs, slices occupied and multiplexers for Hoge 3, Hoge 2, Hoge 4, Hoge 1 and Hoge 5 in descending order. The reported results, in this work, are expected to be of industrial importance as thermistor is a common sensor which finds lots of applications.

Several monosaccharides constitute naturally occurring glycans but it is uncertain if they constitute a universal set like the alphabets of proteins and DNA. Based on the available experimental observations, it is hypothesized herein that the glycan alphabet is not universal. Data on the presence / absence of pathways for the biosynthesis of 55 monosaccharides in 12939 completely sequenced archaeal and bacterial genomes are presented in support of this hypothesis. Pathways were identified by searching for homologs of biosynthesis pathway enzymes. Substantial variations are observed in the set of monosaccharides used by organisms belonging to the same phylum, genera and even species. Monosaccharides are grouped as Common, Less Common and Rare based on their prevalence in Archaea and Bacteria. It is observed that fewer enzymes suffice to biosynthesize the Common group. It appears that the Common group originated before the formation of three domains of life. In contrast, the Rare group are confined to a few species in a few phyla, suggesting that they evolved much later. Fold conservation, as observed in aminotransferases and SDR superfamily members involved in monosaccharide biosynthesis, suggests neo- and sub-functionalization of genes leading to the formation of Rare group monosaccharides. Non-universality of the glycan alphabet begets questions about the role of different monosaccharides in determining an organism’s fitness.Impact statementCarbohydrates, nucleic acids and proteins are important classes of biological macromolecules. The universality of DNA, RNA and protein alphabets has been established beyond doubt. However, the universality of glycan alphabet is unknown primarily because of the challenges associated with the elucidation of glycan structures. This has precluded a comprehensive investigation of glycan alphabet. To address this challenge, we have identified the prevalence of 55 monosaccharide biosynthesis pathways in 12939 completely sequenced archaeal and bacterial genomes by searching for homologs of biosynthesis pathway enzymes using HMM profiles, and in a few cases, BLASTp. This revealed that the glycan alphabet is highly variable; in fact, significant differences are found even among different strains of a species. Possible implications of this variability may be significant in understanding the evolution of Archaea and Bacteria in diverse and competitive environments. Factors that drive the choice of monosaccharides used by an organism need to be investigated, and will be of interest in understanding host-pathogen interactions. Additionally, the knowledge of glycan alphabet can be employed for structural characterization / validation of glycans inferred using mass spectrometry. Knowledge of unique monosaccharides and biosynthetic enzymes can also be used as novel drug targets against human pathogens.Data summaryThe curated set of proteins used in this study, with domain assignment, is listed in supplementary_data.xlsx. Corresponding 396 references with evidence of experimental characterization are included in supplementary material. Results of genome scan which include predictions of monosaccharides as well as the biosynthesis pathway enzymes is available at http://www.bio.iitb.ac.in/glycopathdb/ including the aforementioned information. Python script used to scan genomes to search for monosaccharide biosynthesis pathways are available on request.

BACKGROUND: The rate of institutional deliveries in India is 78.5%. Kerala and Tamil Nadu (99.8%) had the highest numbers of institutional deliveries in 2010–13, but still it is less than 60% in about 170 districts in the country. Balrampur (Uttar Pradesh) has recorded the least institutional deliveries in the country. OBJECTIVES: To assess the factors associated with low utilization of healthcare institutions for delivery in rural Balrampur district, Uttar Pradesh. METHODS: A community-based cross-sectional survey was conducted among mothers between the ages of 15–49 who gave birth 12 months before the study in Balrampur district, Uttar Pradesh. Both qualitative and quantitative methods were used for the study. Multistage random sampling was used to select the participants for the quantitative study. Qualitative data collection was done using in-depth interview among 10 women. RESULTS: Mothers who were not desirous of having more children had a 2.7 times greater chance of delivering at home compared to mothers who were desirous of having more children (OR 2.705, CI 95% 1.189–6.155). Women who married before 18 years of age had a greater chance of home delivery than women who married later (OR 2.381, CI 95% 1.034–5.482). Respondents living far away from home (more than 30 min–1 h travel) were more likely to deliver at home compared to those living close by (OR 2.385, CI 95% 2.357–8.028). Women who were unaware of complications of pregnancy were more like to deliver at home compared to their counterparts who were well aware (OR 2.355, CI 95% 1.677–3.309). Qualitative data showed that cultural beliefs, financial problems, lack of decision making power by the pregnant women were significant determinants of non-utilization of institutional deliveries. CONCLUSION: Despite the cash incentive program, strong cultural and social factors prevent women from accessing institutional deliveries in Balrampur district of UP.

Morphologically normal and fertile transgenic chickpea plants have been regenerated through a standardized transformation protocols. This protocol is based on the infection of apical meristem explants (AME) with Agrobacterium strain EHA105. The stain, carrying pCAMBIA2301 vector contained β-glucuronidase (uidA) gene and neomycin phosphotransferase (nptII) genes. Different explants of chickpea and Agrobacterium specific conditions were standardized with the help of transient β-glucuronidase (uidA) gene expression to further optimize the transformation protocol. Pre-conditiong of the explants, vacuum infiltration and presence of acetosyringone significantly enhanced the frequency of gus expression. Positive transformants with nptII and gus genes were confirmed by PCR and histochemical gus analysis. An overall successful chickpea transformation frequency of 1.2 was achieved. This high efficiency and easy to use method may provide opportunities for the development of transgenic lines with different useful genes in chickpea in near future.

Patients with chronic lymphocytic leukemia (CLL) who achieve blood or bone marrow (BM) undetectable minimal residual disease (U-MRD) status after first-line fludarabine, cyclophosphamide, and rituximab (FCR) have prolonged progression-free survival (PFS), when assessed by an assay with sensitivity 10-4 (MRD4). Despite reaching U-MRD4, many patients, especially those with unmutated IGHV, subsequently relapse, suggesting residual disease

The proline-rich Akt (v-akt murine thymoma viral oncogene homolog 1) substrate of 40 kDa (PRAS40), an inhibitory component of the mTORC1 complex, was identified as an Akt substrate through phosphorylation at Thr246. Phosphorylation at this site releases PRAS40 from the mammalian/mechanistic target of rapamycin complex 1 (mTORC1) complex allowing increased activity. Targeted expression of a mutant form of PRAS40 (PRAS40 T246A ) in basal keratinocytes of mouse epidermis (BK5.PRAS40 T246A mice) has allowed further examination of mTORC1-specific signaling in epithelial carcinogenesis. BK5.PRAS40 T246A mice were resistant to 12- O -tetradecanoylphorbol-13-acetate (TPA)-induced epidermal hyperproliferation and skin tumor development. In transgenic mice, PRAS40 T246A remained bound to raptor in keratinocytes even after treatment with TPA, consistent with reduced mTORC1 signaling and altered levels of cell cycle proteins. BK5.PRAS40 T246A mice also displayed attenuated skin inflammation in response to TPA. Inhibition of mTORC1 in keratinocytes significantly inhibited their migration in vitro and, in addition, inhibited 12- O -tetradecanoylphorbol-13-acetate-induced proliferation and migration of bulge-region stem cells in vivo. Furthermore, targeted inhibition of mTORC1 in BK5.PRAS40 T246A mice resulted in delayed wound healing. Decreased keratinocyte migration and impaired wound healing correlated with altered expression of epithelial-mesenchymal transition (EMT) markers and reduced smad signaling. Collectively, the current data using this unique mouse model provide further evidence that mTORC1 signaling in keratinocytes regulates key events in keratinocyte function and epithelial cancer development.

Through this article, we have tried to identify the factors that lead to organizational identification of postgraduate students with the institutes in which they are studying. The idea was to find out what contributes to strong identification with the institute and how this identification with the organization leads to mutual benefit. For the current study, a sample of 275 postgraduate students studying in various management colleges in the National Capital Region (NCR) was administered a questionnaire. The analysis of the data indicates that identification with the institute is heavily influenced by clarity regarding recruiters expectations; this was followed by information sharing, participation in decision making and lastly by performance feedback. The findings of this study are useful for academic administrators in policy making and institution building. They can get a better insight into the minds of students and assess what factors are perceived as most important for them, while identifying with the institute in which they are studying.

Myeloid/lymphoid neoplasms with eosinophilia and gene rearrangement are a unique category in the WHO classification, and include cases with rearrangement of PDGFRA, PDGFRB, FGFR1, and PCM1-JAK2. We report three patients presented with eosinophilia and FLT3 rearrangement: the first case with chronic eosinophilic leukemia, not otherwise specified and T-lymphoblastic leukemia/lymphoma; the second case with myeloid sarcoma; and the last case with high-grade myelodysplastic syndrome. The first case showed t(13;14)(q12;q32), which encoded FLT3-TRIP11. The patient was treated with intense chemotherapy and subsequently sorafenib with clinical improvement. Unfortunately, the patient showed persistent residual disease and passed away 9 months after the diagnosis from pneumonia. The other two cases both showed ETV6-FLT3. The second patient was treated with local radiation and systemic chemotherapy including sorafenib and was alive. The third patient was treated with chemotherapy but showed transformation to acute myeloid leukemia and died 15 months after diagnosis. These cases are among a growing number of cases with FLT3 rearrangement that all showed similar clinicopathologic features characterized by myeloproliferative neoplasm with eosinophilia and frequent T lymphoblastic leukemia/lymphoma. Therefore, we propose that the myeloid/lymphoid neoplasms with eosinophilia and FLT3 rearrangement be included in the WHO category of myeloid/lymphoid neoplasms with eosinophilia and gene rearrangement.

Stat3 is a member of the signal transducers and activators of transcription family and is a known regulator of essential biologic processes including angiogenesis, apoptosis, cell cycle progression, and cell migration. Canonical Stat3-mediated signaling involves tyrosine phosphorylation on specific residues that leads to homodimerization and translocation to the nucleus. For many years it was presumed that most, if not all, of the functions of Stat3, both normal and aberrant, were due to the canonical cytokine and growth factor signaling mechanisms. Recent studies suggest that Stat3 functions through alternate non-canonical pathways to bring about some of these biological functions both in normal cells as well as during cancer development and progression. A number of studies have now shown that Stat3 has a function in mitochondria and that unphosphorylated Stat3 (uStat3) can also function as a transcription factor broadening the potential mechanisms involved in Stat3 action. In this review article, we discuss these two main non-canonical functions of Stat3 and their potential roles in oncogenesis. Given the many facets of Stat3 signaling, additional comprehensive investigations are required to fully understand the role of non-canonical Stat3 signaling in cancer and whether these pathways can be targeted for cancer prevention and treatment. © 2015 Wiley Periodicals, Inc.

In the present study, we evaluated the effect of deleting Twist1 on keratinocyte proliferation and on skin tumor development using the two-stage chemical carcinogenesis model. BK5.Cre × Twist1(flox/flox) mice, which have a keratinocyte-specific Twist1 knockout (Twist1 KO), developed significantly reduced numbers of papilloma (70% reduction) and squamous cell carcinoma (75% reduction) as well as delayed tumor latency compared to wild-type (WT) mice. Interestingly, knockdown of Twist1 in primary keratinocytes impeded cell cycle progression at the G1/S transition that coincided with reduced levels of the cell cycle proteins c-Myc, Cyclin E1, and E2F1 and increased levels of p53 and p21. Furthermore, ChIP analyses revealed that Twist1 bound to the promoter regions of Cyclin E1, E2F1, and c-Myc at the canonical E-box binding motif suggesting a direct transcriptional regulation. Further analyses of Twist1 KO mice revealed a significant reduction in the number of label-retaining cells as well as the number of α6-integrin(+) /CD34(+) cells in the hair follicles of untreated mice compared to WT mice. These mice also exhibited significantly reduced epidermal proliferation in response to TPA treatment that again correlated with reduced levels of cell cycle regulators and increased levels of p53 and p21. Finally, Twist1 deficiency in keratinocytes led to an upregulation of p53 via its stabilization and nuclear localization, which is responsible for the increased expression of p21 in these cells. Collectively, these findings indicate that Twist1 has a novel role in epithelial carcinogenesis by regulating proliferation of keratinocytes, including keratinocyte stem cells during tumor promotion.

The development of drugs to counter diseases related to cell migration has resulted in a multi-billion dollar endeavor. Unfortunately, few drugs have emerged from this effort highlighting the need for new methods to enhance assays to study, analyze and control cell migration. In response to this complex process, computational models have emerged as potent tools to describe migration providing a high throughput and low cost method. However, most models are unable to predict migration response to drug with direct application to in vitro experiments. In addition to this, no model to date has attempted to describe migration in response to drugs while incorporating simultaneously protein signaling, proteolytic activity, and 3D culture. In this paper, we describe an integrated computational approach, in conjunction with in vitro observations, to serve as a platform to accurately predict migration in 3D matrices incorporating the function of matrix metalloproteinases (MMPs) and their interaction with the Extracellular signal-related kinase (ERK) signaling pathway. Our results provide biological insight into how matrix density, MMP activity, integrin adhesions, and p-ERK expression all affect speed and persistence in 3D. Predictions from the model provide insight toward improving drug combinations to more effectively reduce both speed and persistence during migration and the role of integrin adhesions in motility. In this way our integrated platform provides future potential to streamline and improve throughput toward the testing and development of migration targeting drugs with tangible application to current in vitro assays.

Background: Measuring residual disease during the continuum of care is fundamental to oncology practice. In particular, minimal residual disease (MRD) assessments and trends over time can help inform clinical management, including change in treatment regimen or treatment discontinuation. In patients (pts) with plasma cell and lymphoid malignancies, next-generation sequencing (NGS)-MRD is a valuable tool for assessing MRD and depth of response to treatment. MRD status is strongly prognostic of time to relapse and overall survival in multiple myeloma (MM), acute lymphoblastic leukemia (ALL), mantle cell lymphoma (MCL), and chronic lymphocytic leukemia (CLL). In this report, we summarize our 2-year experience with clinical implementation of NGS-MRD (clonoSEQ®) testing across a spectrum of plasma cell and lymphoid disease. Methods: This retrospective analysis summarizes our experience using the NGS-MRD Assay (Adaptive Biotechnologies, Seattle, WA) in plasma cell and lymphoid malignancies. The assay uses multiplex polymerase chain reaction (PCR) and NGS to identify, characterize, and monitor unique disease-associated sequence rearrangements or clonotypes of immunoglobulin (Ig) IgH (V-J), IgH (D-J), IgK, and IgL receptor gene sequences, and translocated BCL1/IgH (J) and BCL2/IgH (J) sequences in DNA extracted from high disease burden diagnostic (ID) and post-treatment (MRD) samples. PCR amplification bias control ensures a quantitative read-out of the full B-cell receptor repertoire present in the ID sample and provides direct measure of tumor burden. Our study included pts with plasma cell and lymphoid malignancies, including MM, ALL, CLL, and MCL treated at the Moffitt Cancer Center between March 2017 and March 2019 who had provided at least an ID sample for NGS-MRD testing. Results: A total of 423 ID tests using DNA from bone marrow (BM; n=407) or peripheral blood (PB; n=16) and 384 MRD tracking tests (BM, n=321; PB, n=63) were performed in 297 pts (Table). The median turnaround time from shipment arrival to assay initiation was 2.1 hours and from activation to report date was 7.1 days. For MM, ALL, MCL, and CLL, the numbers of tests ordered, calibration rates (defined as proportion of ID samples with trackable sequence[s]), and mean number of trackable sequences are shown in the Table. More ID tests were ordered than number of pts (range: 108-178%) due to multiple tests performed for each patient. Sequences analyzed for MRD tests included IgH, IgK/IgL, and T-cell receptors β and γ. The proportion of pts with detectable MRD is shown by indication in the Table. In MM, autologous stem cell transplant (autoSCT)-eligible pts or those who achieved excellent initial responses but were transplant-ineligible, were primarily considered for NGS-MRD testing as part of standard of care. NGS-MRD testing was performed prior to autoSCT and post-SCT before initiation of maintenance therapy for prognostication. More than 90% of MM cases with successful NGS-MRD results had trackable clones. Negative NGS-MRD assured excellent disease control and supported the decision to discontinue therapy in some pts with significant toxicities. In pts with ALL, treatment response after induction and/or consolidation guided decision-making for allogeneic (allo) SCT at first remission. MRD burden prior to alloSCT could potentially guide the decisions and timing on performing SCT or conditioning regimen intensity. In pts with MCL, treatment response evaluated by NGS-MRD following 6 cycles of therapy was a decision point in a randomized trial of auto-transplant + rituximab vs rituximab alone (ClinicalTrials.gov: NCT03267433). MRD is also being used to guide the duration of rituximab maintenance therapy. Updated data analysis for all indications, including CLL, is underway and will be presented at the meeting. Conclusions: The NGS-MRD Assay is a highly sensitive diagnostic tool for the observation of deeper disease response to therapy in multiple specimen types and in various lymphoid and plasma cell malignancies. NGS-MRD may assist in therapeutic decision-making or prognostication. NGS-MRD is a sensitive and powerful prognostic tool available for the majority of pts, which will help our understanding of the role of MRD in clinical management of plasma cell and lymphoid malignancies. Table Disclosures Srivastava: Adaptive Biotechnologies: Employment, Equity Ownership. Lee:Adaptive Biotechnologies: Employment, Equity Ownership. Nishihori:Novartis: Research Funding; Karyopharm: Research Funding. Shah:AstraZeneca: Honoraria; Pharmacyclics: Honoraria; Adaptive Biotechnologies: Honoraria; Spectrum/Astrotech: Honoraria; Novartis: Honoraria; Celgene/Juno: Honoraria; Kite/Gilead: Honoraria; Incyte: Research Funding; Jazz Pharmaceuticals: Research Funding. Alsina:Janssen: Speakers Bureau; Amgen: Speakers Bureau; Bristol-Myers Squibb: Research Funding. Baz:Merck: Research Funding; Sanofi: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Research Funding. Pinilla Ibarz:Abbvie: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Sanofi: Speakers Bureau; Bayer: Speakers Bureau; TG Therapeutics: Consultancy; Teva: Consultancy; Janssen: Consultancy, Speakers Bureau. Shain:Adaptive Biotechnologies: Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Sanofi Genzyme: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees.

Although very few studies have addressed the molecular and cellular mechanisms underlying the development of biliary tract cancer (BTC), several lines of evidence suggest a role for the erbB receptor family. Overexpression and activation of erbB2 has been reported in a significant percentage of human BTC. Further, we previously reported that overexpression of erbB2 basal epithelial cells of the biliary tract (BK5.erbB2 mouse) led to the development of BTC. However, the mechanisms by which erbB2 overexpression led to the spontaneous development of tumors specifically in the biliary tract are not completely understood. The goals of the current study were to (1) determine whether a cooperative relationship between bile acid exposure and erbB2 activation exists during biliary tract carcinogenesis and (2) to characterize the mechanism(s) underlying bile acid-mediated biliary tract carcinogenesis in cells with activated erbB2. In this study, we demonstrated that the secondary conjugated bile acid, taurochenodeoxycholic acid (TCDC), increased proliferation of primary cultured gallbladder epithelial cells from BK5.erbB2 mice and human BTC cells. TCDC treatment activated EGFR/erbB2 and downstream signaling molecules in both primary cultured cells and human BTC cells. TCDC also increased the expression of epidermal growth factor receptor (EGFR) ligands and TACE activity in human BTC cells. Inhibition of src activation led to attenuation of bile-induced upregulation of TACE activity as well as signaling through the EGFR/erbB2, suggesting that during the development of BTC erbB2 overexpression/activation accelerates the bile acid-induced signaling cascade: bile acid src TACE EGFR/erbB2 downstream signaling. We also provide direct evidence that bile acids possess tumor promoting capacity in epithelial cells overexpressing erbB2 using the two-stage skin carcinogenesis model. Collectively these findings suggest cooperative roles for bile acid and erbB2 activation in epithelial cell proliferation; bile acid appears to accelerate erbB2-induced pro-tumorigenic activities in the biliary tract and skin. © 2013 Wiley Periodicals, Inc.

The efficacy of seashells as a new adsorbent for removal of phenol from aqueous solutions was studied by performing batch equilibrium tests under different operating parameters such as solution pH, adsorbent dose, initial phenol concentration, and temperature. The phenol removal efficiency remained unaffected when the initial pH of the phenol solution was in the range of 3–8. The amount of phenol adsorbed increased with increasing initial phenol concentration while it decreased with increasing temperature. The adsorption equilibrium data showed excellent fit to the Langmuir isotherm model with maximum monolayer adsorption capacity of 175.27 mg g−1 at pH 4.0, initial phenol concentration = 50 mg L−1, adsorbent dose = 2 g and temperature = 293 K. Analysis of kinetic data showed that the adsorption process followed pseudo-second-order kinetics. Activation energy of the adsorption process, calculated using the Arrhenius equation, was found to be 51.38 kJ mol−1, suggesting that adsorption of phenol onto seashells involved chemical ion-exchange. The numerical value of the thermodynamic parameters (ΔG0, ΔH0 and ΔS0) indicated that adsorption of phenol onto seashells was feasible, spontaneous and endothermic under the examined conditions. The study shows that seashells can be used as an economic adsorbent for removal of phenol from aqueous solution.

Chickpea (Cicer arietinum L.) is a major food legume crops for the tropics and sub-tropical regions and is the main dietary protein source for vegetarians in developing countries. Besides several abiotic factors, its production is constrained by insect pests, as well as many fungal diseases. The success of any attempt to produce resistant varieties through genetic engineering to a large extent depends on the availability of efficient and reproducible regeneration and transformation procedures. Further, the transformation techniques can be more successfully applied if the ontogeny of shoot development is well understood. Ontogeny of shoot development from axillary meristem explants (AME) in chickpea has been studied with the optimization of conditions for high-frequency multiple shoot induction. Preculture of seeds in TDZ significantly enhances the frequency of multiple shoot induction from the explants. Ontogeny and early events of multiple shoot induction revealed direct adventitious origin of the shoots. The understanding of the regeneration process could be further utilized in the designing of efficient transformation methods.

Kinetics of the oxidation of lactose by Cu(II) complexed with bipyridyl have been investigated at 40 °C for the first time spectrophotometrically using Rh(III) chloride as homogeneous catalyst in aqueous alkaline medium in its nano-concentration range. The order of reaction was found to be fractional positive-order, when the concentration of Rh(III) chloride was varied from 0.30×10(-9) M to 6.00×10(-9) M. The reaction shows fractional positive-order kinetics with respect to [lactose] and [OH(-)] and zeroth-order kinetics with respect to [Cu(II)]. The reaction also shows slight increase in the rate by decreasing dielectric constant of the medium and remains unaffected by the change in ionic strength of the medium. The reaction was carried out at four different temperatures and observed values of rate constants were utilized to calculate various activation parameters specially the entropy of activation (ΔS(#)). The species, [RhCl(3)(H(2)O)(2)OH](-), was postulated as the main reactive species of Rh(III) chloride for the oxidation of lactose by Cu(II) in alkaline medium. On the basis of kinetic and equivalence studies together with spectrophotometric information for the formation of a complex, [formula see text] the most appropriate mechanism for the aforesaid reaction has been proposed. Support to the proposed mechanism was also given by the observed activation parameters and multiple regression analysis. Sodium salts of formic acid, arabinonic acid and lyxonic acid were identified as the main oxidation products of the reaction under investigation.

The present paper deals with the kinetics and mechanism of Pd(II)-catalyzed oxidation of tetracycline hydrate by Cu(Bip)22+ in alkaline medium. First-order kinetics with respect to [tetracycline hydrate] and fractional positive order kinetics in [Cu(II)] and [Pd(II)] was observed. Nil effect of [OH–] and [bipyridyl] on the rate of oxidation was observed. Almost no effect of ionic strength as well as dielectric constant of the medium on the rate of oxidation was observed. The reaction was studied at four different temperatures and observed values of rate constants were utilized to calculate various activation parameters specially the entropy of activation (ΔS#). With the help of the observed kinetic orders with respect to the reactants involved in the reaction, spectrophotometric evidence collected for the formation of reactive complexes and the positive entropy of activation, a most probable reaction mechanism for Pd(II)-catalyzed oxidation of tetracycline hydrate by Cu(Bip)22+ in alkaline medium has been...

Renewable energy represents an area of tremendous opportunity for India. Energy is considered a prime agent in the generation of wealth and a significant factor in economic development. Energy is also essential for improving the quality of life. Development of conventional forms of energy for meeting the growing energy needs of society at a reasonable cost is the responsibility of the Government. Limited fossil resources and associated environmental problems have emphasized the need for new sustainable energy supply options. India depends heavily on coal and oil for meeting its energy demand which contributes to smog, acid rain and greenhouse gases’ emission. Last 25 years has been a period of intense activities related to research, development, production and distribution of energy in India. Though major energy sources for electrical power are coal and natural gas, development and promotion of non-conventional sources of energy such as solar, wind and bio-energy, are also getting sustained attention. The use of electricity has grown since it can be used in variety of applications as well as it can be easily transmitted, the uses of renewable energy like wind and solar is rising. Wind energy is a clean, eco-friendly, renewable resource and is nonpolluting. The gross wind power potential is estimated at around 48,561 MW in the country; a capacity of 14,989.89 MW up to 31st August 2011 has so far been added through wind, which places India in the fifth position globally. This paper discusses the ways in which India has already supported the growth of renewable energy technologies i.e. wind energy and its potential to expand their contribution to world growth in a way that is consistent with world's developmental and environmental goals. The paper presents current status, major achievements and future aspects of wind energy in India.

The kinetic and mechanistic studies of homogeneously Rh(III)-catalysed oxidation of D-xylose and L-sorbose by Nbromoacetamide (NBA) in perchloric acid medium were carried out at 40 °C. The reactions were first-order with respect to each of [NBA], [Rh(III)] and [H+] and zero-order in [sugar]. Variation of [Cl−] showed positive effect while variation of [Hg(OAc)2] showed negative effect on the rate of the reactions. Addition of acetamide (NHA) had a negative effect on the rate of the reaction. The rate of the reaction was unaffected by the change in ionic strength (μ) of the medium. Various activation parameters were calculated with the help of pseudo-first-order rate constant, k1, obtained at four different temperatures. The mechanisms involving RhCl4(H2O)2−, as reactive species of rhodium(III), and H2OBr+, as reactive species of NBA, are proposed which find support from the spectrophotometric evidence and activation parameters, especially the entropy of activation.

Introduction Patients (pts) with CLL who achieve blood or bone marrow (BM) undetectable minimal residual disease (U-MRD), assessed with a sensitivity of at least 10-4 (MRD4), have long PFS after 1st-line treatment with FCR. A proportion of pts with mutated immunoglobulin heavy chain variable gene (M-IGHV) may be cured of CLL, given the reported PFS beyond 10 yrs. In contrast, most pts with unmutated (UM)-IGHV relapse, despite achieving BM U-MRD4. The likelihood of relapse and relapse kinetics relate to CLL biology, including depth of remission and proliferation rate. MRD testing using next generation sequencing (NGS) can achieve sensitivity up to 10-6 (MRD6) and can also be used to test for circulating tumor DNA in plasma, which may reflect residual tumor in the tissue (eg. lymph nodes), not detectable in the cellular fraction of blood or BM. To better assess the depth of remission following first-line FCR treatment for CLL, we performed NGS MRD6 testing in BM, peripheral blood mononuclear cells (PBMC) and plasma of pts enrolled in a single center, prospective, phase II study. All pts had BM U-MRD4 by 4-color flow cytometry (FLC) at the end of treatment (EOT). Methods The following EOT samples from 62 pts were analyzed for MRD6: 57 BM, 29 PBMC and 32 plasma. Adaptive Biotechnologies' NGS MRD assay uses multiplex PCR and NGS to amplify rearrangements within the B cell receptor CDR3 and identify disease associated clonotypes. Specifically, the assay utilizes multiplexed primers complementing V-J rearrangements (IGH, IGK/L) and D-J (IGH) rearrangements. Pre-treatment samples were sequenced to determine the malignant clonotype, which was then quantitated in the EOT samples, within the polyclonal background. Results Regardless of assay sensitivity, U-MRD rates by HTS according to sample type were: 14/57 (25%) in BM; 16/29 (55%) in PBMC; 24/32 (75.0%) in plasma. All pts with MRD+ in plasma simultaneously had detectable disease in either BM or PBMC. Of 16 pts who had U-MRD in PBMC, 7/12 with simultaneous BM samples were MRD+ in BM. In all patients, there was a trend toward increased likelihood of U-MRD in pts with M-IGHV [12/30 (40%) vs 4/24 (17%), OR 3.3 (0.9-12.2), p = 0.06]. Assay sensitivity varies according to amount of DNA in the sample and with malignant clonotype. Sensitivity of at least 10-6 was achieved in 74% and 62% of samples in BM and PBMC, respectively. Among patients with U-MRD by NGS: 4/14 BM (1.06-3.2 x 10-6, median 1.96 x 10-6) and 8/16 PBMC (1.001 x 10-6 to 3.56 x 10-6, median 1.54 x 10-6) samples did not have sensitivity of 10-6. Notably, 3 pts also had detectable disease at a level Median follow-up was 82 months (mo) (range: 28-112.4). Fifty-six of 62 (90.3%) pts are alive; 28 are progression-free. Median PFS for the whole cohort was 89 mo. When PFS was analyzed according to whether MRD was detected or not (regardless of sensitivity), pts with U-MRD at the EOT had superior PFS vs pts with MRD+, whether the sample type used was BM (p=0.02, median NR vs 67 mo) or PBMC (p=0.02, median NR vs 74 mo), Figure A, B. When analyzed according to whether MRD was /=10-6 (MRD6), 40/53 (75%) in BM and 13/21 (62%) in PBMC were MRD6+. For this analysis, pts were excluded if they had U-MRD but assay sensitivity did not reach at least 10-6. Despite smaller n, there were trends toward shorter PFS for pts with MRD6+ vs U-MRD6 (Figure C, D). Discussion The majority of pts with BM U-MRD4 after first-line FCR were MRD6+ and these patients had shorter PFS; MRD analysis with a more sensitive assay may therefore more accurately assign prognosis. Not accounting for sensitivity, a higher proportion of BM than PBMC samples were MRD+. Plasma analysis was uninformative as all pts MRD+ in plasma were MRD+ in simultaneous BM or PBMC samples. Defining prognostically-relevant thresholds for MRD using more sensitive methodology is important, particularly if U-MRD is used a surrogate for PFS in clinical trials or as an endpoint for treatment cessation. MRD6 may become increasingly relevant if venetoclax-based regimens and the addition of novel agents to chemoimmunotherapy achieve U-MRD6 in more patients than FCR. In this retrospective study, a number of samples did not achieve 10-6 sensitivity; optimization of sample collection is important to achieve 10-6 sensitivity in most pts. Finally, additional studies will be required to determine the risk for and kinetics of relapse in patients with low-level MRD6+. Disclosures Thompson: AbbVie: Honoraria, Research Funding; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees. Srivastava:Adaptive Biotechnologies: Employment. Hether:Adaptive Biotechnologies: Employment. O'Brien:Acerta: Research Funding; Sunesis: Consultancy, Research Funding; Regeneron: Research Funding; GlaxoSmithKline: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Pharmacyclics: Consultancy, Research Funding; Vaniam Group LLC: Consultancy; Abbvie: Consultancy; Aptose Biosciences Inc.: Consultancy; Pfizer: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Janssen: Consultancy; Astellas: Consultancy; Alexion: Consultancy; Kite Pharma: Research Funding; Gilead: Consultancy, Research Funding. Jain:ADC Therapeutics: Research Funding; Celgene: Research Funding; Abbvie: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Incyte: Research Funding; Genentech: Research Funding; Infinity: Research Funding; Astra Zeneca: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Servier: Research Funding; ADC Therapeutics: Research Funding; Verastem: Research Funding; Seattle Genetics: Research Funding; Cellectis: Research Funding; Incyte: Research Funding; Celgene: Research Funding; Adaptive Biotechnologioes: Research Funding; Astra Zeneca: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; Verastem: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wierda:Genentech: Research Funding; AbbVie, Inc: Research Funding.

The kinetic and mechanistic study of homogeneously Pd(II)-catalysed and Hg(II)- co-catalysed oxidation of d (+)melibiose (mel) by N -bromoacetamide (NBA) in perchloric acid medium have been made at temperature 40 °C ± 0.1 °C. Kinetic results show first-order kinetics with respect to NBA at its low concentrations, tending to zero-order at its high concentrations. The oxidation rate is directly proportional to [Pd(II)] and [sugar], indicating first-order kinetics with respect to Pd(II) and sugar. Zero effect of Cl − and H + ions throughout their variation have been noted. First-order kinetics with respect to Hg(II) at its low concentration tends to zero-order at its higher concentration. Addition of acetamide (NHA) decreases the first-order rate constant ( k 1 ) while the rate of reaction is not influenced by the change in ionic strength (μ) of the medium. The first-order rate constant decreases with an increase in dielectric constant of the medium. Arabinonic acid, lyxonic acid and formic acid were identified as oxidation products of the reaction. Various activation parameters including the entropy of activation were also calculated. A plausible mechanism conforming to kinetic data, spectrophotometric observations, reaction stoichiometry and product analysis has been proposed.

The kinetics of oxidation of the sugars d(+)Melibiose (mel) and Cellobiose (cel) by N-bromoacetamide (NBA) in the presence of Rh(III) chloride as homogeneous catalyst in acidic medium at 45 °C have been investigated. The reactions are first-order with respect to [NBA], [Rh(III)] and [substrate]. The rate is proportional to [H+]. No effects of [Hg(II)], [NHA] or [Cl−] on the rates were observed. Ionic strength and dielectric constant also have little effect. The observed kinetic data, available literature and spectroscopic evidence lead us to conclude that NBAH+ and [RhCl5(H2O)]2− are the reactive species of NBA and Rh(III) chloride, respectively. The rate-determining step of the proposed reaction path common for both sugars gives an activated complex by the interaction of a charged complex species and neutral sugar molecule, which in the subsequent steps disproportionates into the reaction products with the regeneration of catalyst. The reactions have been studied at four different temperatures and with the help of first-order rate constant values, various activation parameters have been calculated. The main oxidation products of the reactions were identified as arabinonic acid, formic acid and lyxonic acid in the case of mel and arabinonic acid and formic acid in the case of cel.

Kinetics of oxidation of maltose (mal) and d -galactose (gal) by protonated N-bromosuccinimide (N + BSH) using chloro-complex of Rh(III) in its nano-concentration range as homogeneous catalyst have been investigated at 40 °C for the first time. Almost constant values of pseudo-first-order rate constant ( k 1 ) throughout the variation of N-bromosuccinimide (NBS) in the oxidation of both the reducing sugars clearly demonstrate that order of reaction with respect to [NBS] is unity. First-order kinetics with respect to each [Rh(III)], [Sugar] and [H + ] is evident from the observed values of k 1 which increase in the same proportion in which the concentration of each reactant is increased. Negligible effects of variations of [Hg(II)], [Cl − ] and [succinimide] on the rate of oxidation of each reducing sugar have been observed. Variations in ionic strength ( μ ) and dielectric constant ( D ) of the medium have not influenced the oxidation rates. Protonated N-bromosuccinimide, N + BSH, and chloro-complex of Rh(III), [RhCl 5 (H 2 O)] 2− , have been postulated as the reactive species of NBS and Rh(III) chloride in acidic medium, respectively. Various activation parameters have been calculated using pseudo-first-order rate constant ( k 1 ) values observed at four different temperatures. The proposed mechanism, involving most reactive activated complex formed as a result of interaction between the complex species [RhCl 5 ·NHBr] − and a sugar molecule is supported by kinetic orders, spectrophotometric evidence, positive entropy of activation and observed zero effect of dielectric constant and ionic strength of the medium. Almost constant values of composite rate constant ( k ′) observed for the variations of [sugar], [NBS], [Rh(III)] and [H + ] in the oxidation of each reducing sugar provide further support to the proposed reaction path. The main oxidation products of the reactions were identified as arabinonic acid and formic acid in case of maltose and lyxonic acid and formic acid in case of d -galactose.

Mitochondrial toxicity results from pyrimidine nucleoside reverse transcriptase inhibitors (NRTIs) for HIV/AIDS. In the heart, this can deplete mitochondrial (mt) DNA and cause cardiac dysfunction (eg, left ventricle hypertrophy, LVH). Four unique transgenic, cardiac-targeted overexpressors (TGs) were generated to determine their individual impact on native mitochondrial biogenesis and effects of NRTI administration on development of mitochondrial toxicity. TGs included cardiac-specific overexpression of native thymidine kinase 2 (TK2), two pathogenic TK2 mutants (H121N and I212N), and a mutant of mtDNA polymerase, pol-gamma (Y955C). Each was treated with antiretrovirals (AZT-HAART, 3 or 10 weeks, zidovudine (AZT) + lamivudine (3TC) + indinavir, or vehicle control). Parameters included left ventricle (LV) performance (echocardiography), LV mtDNA abundance (real-time PCR), and mitochondrial fine structure (electron microscopy, EM) as a function of duration of treatment and presence of TG. mtDNA abundance significantly decreased in Y955C TG, increased in TK2 native and I212N TGs, and was unchanged in H121N TGs at 10 weeks regardless of treatment. Y955C and I212N TGs exhibited LVH during growth irrespective of treatment. Y955C TGs exhibited cardiomyopathy (CM) at 3 and 10 weeks irrespective of treatment, whereas H121N and I212N TGs exhibited CM only after 10 weeks AZT-HAART. EM features were consistent with cardiac dysfunction. mtDNA abundance and cardiac functional changes were related to TG expression of mitochondrially related genes, mutations thereof, and NRTIs.

PurposeThe purpose of this paper is to attempt to highlight the importance of Gandhi's philosophy for creating socially responsible systems for holistic development.Design/methodology/approachIt is a qualitative analysis of Gandhi's writings and interpretation of his ideas for the creation of socially responsible systems which will result in holistic development.FindingsThe analysis of Gandhian philosophy brings about a realization that focusing on unidimensional development is detrimental to society. There is a need to integrate various elements of human civilization for the overall happiness of mankind. Gandhi identified the inter‐linkages between various aspects of human life and insisted on creating harmony between them. The authors find that he was against compartmentalization of self and society. Hence, the paper talks about holistic management and the role that organization, social systems and individuals can play in its achievement. His philosophy provides a backdrop against which socially responsible systems can be created.Originality/valueThough Gandhi's contribution in politics has been widely acknowledged, there is very little work on integration of his philosophy to all walks of life. The paper is original in the sense that instead of dividing his philosophy into narrow segments, it tries to establish the inter‐linkage between the various dimensions of human life.

The kinetics of Ru(III)-catalyzed and Hg(II)-co-catalyzed oxidation of D-glucose (Glc) and cellobiose (Cel) by N-bromoacetamide (NBA) in the presence of perchloric acid at 40 °C have been investigated. The reactions exhibit the first order kinetics with respect to NBA, but tend towards the zeroth order to higher NBA. The reactions are the first order with respect to Ru(III) and are fractional positive order with respect to [reducing sugar]. Positive effect of Cl− and Hg(OAc)2 on the rate of reaction is also evident in the oxidation of both reducing sugars. A negative effect of variation of H+ and acetamide was observed whereas the ionic strength (µ) of the medium had no influence on the oxidation rate. The rate of reaction decreased with the increase in dielectric constant and this enabled the computation of dAB, the size of the activated complex. Various activation parameters have been evaluated and suitable explanation for the formation of the most reactive activated complex has been given. The main products of the oxidation are the corresponding arabinonic acid and formic acid. HOBr and [RuCl3(H2O)2OH]− were postulated as the reactive species of oxidant and catalyst respectively. A common mechanism, consistent with the kinetic data and supported by the observed effect of ionic strength, dielectric constant and multiple regression analysis, has been proposed. Formation of complex species such as [RuCl3·S·(H2O)OH]− and RuCl3·S·OHgBr·OH during the course of reaction was fully supported by kinetic and spectral evidences.

Mitochondrial (mt) DNA biogenesis is critical to cardiac contractility. DNA polymerase gamma (Pol gamma) replicates mtDNA, whereas thymidine kinase 2 (TK2) monophosphorylates pyrimidines intramitochondrially. Point mutations in POLG and TK2 result in clinical diseases associated with mtDNA depletion and organ dysfunction. Pyrimidine analogs (NRTIs) inhibit Pol gamma and mtDNA replication. Cardiac "dominant negative" murine transgenes (TGs; Pol gamma Y955C, and TK2 H121N or I212N) defined the role of each in the heart. mtDNA abundance, histopathological features, histochemistry, mitochondrial protein abundance, morphometry, and echocardiography were determined for TGs in "2 x 2" studies with or without pyrimidine analogs. Cardiac mtDNA abundance decreased in Y955C TGs ( approximately 50%) but increased in H121N and I212N TGs (20-70%). Succinate dehydrogenase (SDH) increased in hearts of all mutants. Ultrastructural changes occurred in Y955C and H121N TGs. Histopathology demonstrated hypertrophy in H121N, LV dilation in I212N, and both hypertrophy and dilation in Y955C TGs. Antiretrovirals increased LV mass ( approximately 50%) for all three TGs which combined with dilation indicates cardiomyopathy. Taken together, these studies demonstrate three manifestations of cardiac dysfunction that depend on the nature of the specific mutation and antiretroviral treatment. Mutations in genes for mtDNA biogenesis increase risk for defective mtDNA replication, leading to LV hypertrophy.

Kinetics of oxidation of d -glucose (glc) and d -fructose (fru) by potassium iodate has been studied for the first time in alkaline medium using Ru(III) as homogeneous catalyst. The linear dependence of the reaction rate at lower [IO 3 − ] and [OH − ] tends towards zero-order at their higher concentrations. Experimental results also show that the order with respect to [Ru(III)] is unity and the order with respect to [reducing sugar] is zero in the oxidation of both glc and fru. Variation in [Cl − ] and ionic strength ( μ ) of the medium does not affect the oxidation rate. The species, [RuCl 2 (H 2 O) 2 (OH) 2 ] − and IO 3 − , were found to be the reactive species of Ru(III) chloride and potassium iodate in alkaline medium, respectively. The reactions have also been studied at four different temperatures and with the help of observed values of pseudo-first-order rate constant ( k 1 ), the entropy of activation and other activation parameters have been calculated. A common mechanism, where the rate determining step involves the interaction between reactive species of Ru(III) chloride and reactive species of potassium iodate resulting in the formation of an activated complex, Download full-size image has been proposed. The formation of activated complex is very well supported by the spectrophotometric evidence, observed kinetic data and also by the negative entropy of activation observed for the oxidation of both glc and fru. Arabinonic acid and formic acid were identified as the main oxidation products of the reactions.

Kinetic studies in homogeneously Rh(III)-catalyzed oxidation of reducing sugars, i.e. maltose and lactose, by N -bromoacetamide (NBA) in the presence of perchloric acid have been made at 40 °C using mercuric acetate as Br − ion scavenger. The results obtained for the oxidation of both reducing sugars show first-order dependence of the reactions on NBA at its low concentrations, which shifts towards zero-order at its higher concentrations. First-order kinetics in [Rh(III)] and zero-order kinetics in [reducing sugar] were observed. Positive effect of [Cl − ] was observed in the oxidation of both maltose and lactose. Order of reaction was found to be one and half (1.5) throughout the variation of [H + ] in the oxidation of both maltose and lactose. An increase in the rate of reaction with the decrease in [Hg(OAc) 2 ] and [NHA] was observed for both the redox systems. The rate of oxidation is unaffected by the change in ionic strength ( μ ) of the medium. The main oxidation products of the reactions were identified as formic acid and arabinonic acid in the case of maltose and formic acid, arabinonic acid and lyxonic acid in the case of lactose. A common mechanism for the oxidation of both maltose and lactose, showing the formation of most reactive activated complex, [RhCl 4 (H 3 O)H 2 OBr] + , and an unreactive complex, [RhCl 4 (H 2 O)(H 2 OBrHg)] 2+ , has been proposed. Various activation parameters have also been calculated and on the basis of these parameters, a suitable explanation for the reaction mechanism has been given.

Five salts of dichloroanilinium bromide (DCABr) were prepared and characterized by elemental and spectral studies. The thermal decomposition of DCABr was studied by using TG-DTG-DTA techniques and the results are discussed here. Kinetic parameters with the help of model fitting and isoconversional methods have been evaluated critically. A mechanism of decomposition has also been suggested.

The present paper deals with the kinetics and mechanism of Ru(III)-catalyzed and Hg(II)- co -catalyzed oxidation of d -arabinose(ara) and d -mannose(man) by acidic solution of N -bromoacetamide(NBA). First-order dependence of the reaction on both NBA and sugar at low concentrations shifts to zero-order at their higher concentrations. First-order kinetics with respect to [Ru(III)] throughout its variation was observed in the oxidation of both arabinose and mannose. A positive effect on the oxidation rate is observed for [Hg(II)] and [Cl − ] whereas a negative effect is observed for [H + ] and [acetamide]. Ionic strength does not influence the oxidation rate. The decrease in the rate of reaction with the increase in dielectric constant ( D ) of the medium was observed in the oxidation of both reducing sugars and the kinetic data thus obtained were utilized to calculate d AB , the size of activated complex. Various activation parameters have also been calculated. Formic acid and erythronic acid for arabinose and formic acid and arabinonic acid for mannose were identified as main oxidation products of the reactions. Kinetic and equivalence studies together with spectral information, observed effect of dielectric constant on the rate of reaction, activation parameters and multiple regression analysis were made a basis for the formation of a common reaction mechanism for the catalyzed oxidation of both, arabinose and mannose.