Identification of critical paralog groups with indispensable roles in the regulation of signaling flow

Extensive cross-talk between signaling pathways is required to integrate the myriad of extracellular signal combinations at the cellular level. Gene duplication events may lead to the emergence of novel functions, leaving groups of similar genes - termed paralogs - in the genome. To distinguish critical paralog groups (CPGs) from other paralogs in human signaling networks, we developed a signaling network-based method using cross-talk annotation and tissue-specific signaling flow analysis. 75 CPGs were found with higher degree, betweenness centrality, closeness, and ‘bowtieness’ when compared to other paralogs or other proteins in the signaling network. CPGs had higher diversity in all these measures, with more varied biological functions and more specific post-transcriptional regulation than non-critical paralog groups (non-CPG). Using TGF-beta, Notch and MAPK pathways as examples, SMAD2/3, NOTCH1/2/3 and MEK3/6-p38 CPGs were found to regulate the signaling flow of their respective pathways. Additionally, CPGs showed a higher mutation rate in both inherited diseases and cancer, and were enriched in drug targets. In conclusion, the results revealed two distinct types of paralog groups in the signaling network: CPGs and non-CPGs. Thus highlighting the importance of CPGs as compared to non-CPGs in drug discovery and disease pathogenesis

Hypothermia for moderate or severe neonatal encephalopathy in low-income and middle-income countries (HELIX): a randomised controlled trial in India, Sri Lanka, and Bangladesh

Background: Although therapeutic hypothermia reduces death or disability after neonatal encephalopathy in high-income countries, its safety and efficacy in low-income and middle-income countries is unclear. We aimed to examine whether therapeutic hypothermia alongside optimal supportive intensive care reduces death or moderate or severe disability after neonatal encephalopathy in south Asia. Methods: We did a multicountry open-label, randomised controlled trial in seven tertiary neonatal intensive care units in India, Sri Lanka, and Bangladesh. We enrolled infants born at or after 36 weeks of gestation with moderate or severe neonatal encephalopathy and a need for continued resuscitation at 5 min of age or an Apgar score of less than 6 at 5 min of age (for babies born in a hospital), or both, or an absence of crying by 5 min of age (for babies born at home). Using a web-based randomisation system, we allocated infants into a group receiving whole body hypothermia (33·5°C) for 72 h using a servo-controlled cooling device, or to usual care (control group), within 6 h of birth. All recruiting sites had facilities for invasive ventilation, cardiovascular support, and access to 3 Tesla MRI scanners and spectroscopy. Masking of the intervention was not possible, but those involved in the magnetic resonance biomarker analysis and neurodevelopmental outcome assessments were masked to the allocation. The primary outcome was a combined endpoint of death or moderate or severe disability at 18–22 months, assessed by the Bayley Scales of Infant and Toddler Development (third edition) and a detailed neurological examination. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, NCT02387385. Findings: We screened 2296 infants between Aug 15, 2015, and Feb 15, 2019, of whom 576 infants were eligible for inclusion. After exclusions, we recruited 408 eligible infants and we assigned 202 to the hypothermia group and 206 to the control group. Primary outcome data were available for 195 (97%) of the 202 infants in the hypothermia group and 199 (97%) of the 206 control group infants. 98 (50%) infants in the hypothermia group and 94 (47%) infants in the control group died or had a moderate or severe disability (risk ratio 1·06; 95% CI 0·87–1·30; p=0·55). 84 infants (42%) in the hypothermia group and 63 (31%; p=0·022) infants in the control group died, of whom 72 (36%) and 49 (24%; p=0·0087) died during neonatal hospitalisation. Five serious adverse events were reported: three in the hypothermia group (one hospital readmission relating to pneumonia, one septic arthritis, and one suspected venous thrombosis), and two in the control group (one related to desaturations during MRI and other because of endotracheal tube displacement during transport for MRI). No adverse events were considered causally related to the study intervention. Interpretation: Therapeutic hypothermia did not reduce the combined outcome of death or disability at 18 months after neonatal encephalopathy in low-income and middle-income countries, but significantly increased death alone. Therapeutic hypothermia should not be offered as treatment for neonatal encephalopathy in low-income and middle-income countries, even when tertiary neonatal intensive care facilities are available. Funding: National Institute for Health Research, Garfield Weston Foundation, and Bill & Melinda Gates Foundation. Translations: For the Hindi, Malayalam, Telugu, Kannada, Singhalese, Tamil, Marathi and Bangla translations of the abstract see Supplementary Materials section

Synthesis and Biological Evaluation of some Important Heterocycles as possible Drug Candidates

This thesis describes about the synthesis of some heterocyclic compounds, such as isobenzofuran-1-one, benzophenone, tetrahydroisoqunoline, furan and hydroxychavicol derivatives in very good yields. This thesis also depicts the results of these heterocyclic compounds against various biological activities such as inhibition of soybean lipoxygenase (SB-LOX), and also antiparkinson‟s, anti-cancer activities, anti-microbial and anti-leishmanial activities. The mild and efficient iodine catalyzed one pot synthesis of isobenzofuran-1-one and benzophenone derivatives were achieved with good yields. Among the synthesized isobenzofuran-1-one derivatives,five of them showed anti-leshmanial activit with IC50 14.25 μM and 16.72 μM respectively for 4-chloro phenyl substituted isobenzofuran-1-one and 4-methyl phenyl substituted benzophenone. Further screening of all the compounds in-vitro and in-vivo for anti-leishmanial activity may lead potent anti-leishmanial drugs. The inhibitory activity against soybean lipoxygenase (SB-LOX) of furan derivatives were investigated by in-vitro experiment 5-(4-Bromo-phenyl)-4-[2-(4-bromo-phenyl)-2-oxo-ethyl]-2-methyl-furan-3-carboxylic acid ethyl esters was found to be the most active compound among various derivatives of furan. This observation was validated by carrying out docking studies using AutoDock 4.0. The entire synthesized compounds were found to be selective inhibitors of the gram-positive bacteria such as S. aureus and B. subtilis with the MIC of 1.1- 2.9 M except. Further pharmacological studies of 2-Methyl-4- (2-oxo-2-phenyl-ethyl)-5-phenyl-furan-3-carboxylic acid ethyl ester derivatives may lead to develop novel anti-inflammatory as well as anti-bacterial agents. The tetrahydroisoquinoline derivatives were synthesized with good yields, and synthesized derivatives were screened for anti-Parkinson‟s disease by in–vivo animal model. Thus tetrahydroisoquinolines possesses significant antiparkinsonian properties and has got ability to target diverse molecular and cellular events implicated in the pathophysiology of PD together makes that these synthetic tetrahydroisoquinoline derivatives could be extremely desirable molecules for further investigation as new drug entity for the treatment of this neurological disorder. The hydroxychavicol analogues have been synthesized efficiently, and all the compounds were screened for broad-spectrum anti-cancer activity. They showed good anticancer activity by both in-vitro and in-vivo models. Further studies on these compounds may lead to develop potent anticancer drug. Overall, the preliminary results obtained in this research work once again suggest that the heterocyclic compounds posses enormous biological activities .Further detailed Pharmacological studies may lead to develop potential drug candidates against studied diseases. Part of these results have already been published in journals and filed International patents.Biologically active heterocyclic compounds: A Review Introduction Heterocycles form, by far, the largest of the classical divisions of organic chemistry. Moreover, they are of immense importance not only biologically and industrially but also for the functioning of any developed human society as well. Their participation in a wide range of areas cannot be under estimated. The majority of pharmaceutical products that mimic natural products with biological activity are heterocycles. Therefore, researchers are on a continuous pursuit to design and produce better pharmaceuticals, pesticides, insecticides, rodenticides, and weed killers by following natural models. Heterocycles play a major part in biochemical processes and are also side groups of the most typical and essential constituents of living cells. Other important practical applications of these compounds can also be cited, for instance, their use as additives and modifiers in a wide variety of industries including cosmetics, reprography, information storage, plastics, solvents, antioxidants, and vulcanization accelerators. Finally, as an applied science, heterocyclic chemistry is an inexhaustible resource of novel compounds

Antibacterial Activity and Anticorrosive Efficiency of Aqueous Methanolic Extract of Artemisia pallens (Asteraceae) and its major Constituent

An aqueous-methanolic [methanol:water (1:1)1 extract of the whole plant of Artemisia pallens (Family: Asteraceae) has shown good antibacterial activity against Pseudomonas aeruginosa and Shigella flexneri at the concentration of 100 mg/mL. The activity-guided fractionation has led to isolation of compound 4-hydroxyphenyl-/3-D-glucopyranoside (which is known as arbutin), as a major constituent and exhibited the same antibacterial activity at a concen-tration of 17 mg/mL. Both the crude extract and arbutin also showed 94% anticorrosive efficiency against mild steel in 1M HC1 at concentration of 200 mg/L

Eco-Friendly Synthesis and Study of new Plant Growth Promoters: 3,30-Diindolylmethane and its Derivatives

—3,30-Diindolylmethane (DIM) derivatives 3a–k, prepared in one-pot from indoles 1a–k and hexamethylenetetramine (2) using ionic liquid [Bmim]BF4 as eco-friendly recyclable solvent as well as catalyst, showed good plant growth promoting activity on Oryza sativa. Among the DIM derivatives synthesized 3c shows potent auxin like growth promoting activity

Hydroxychavicol, a Piper betle leaf component, induces apoptosis of CML cells through mitochondrial reactive oxygen species-dependent JNK and endothelial nitric oxide synthase activation and overrides imatinib resistance

Alcoholic extract of Piper betle (Piper betle L.) leaves was recently found to induce apoptosis of CML cells expressing wild type and mutated Bcr-Abl with imatinib resistance phenotype. Hydroxy-chavicol (HCH), a constituent of the alcoholic extract of Piper betle leaves, was evaluated for anti-CML activity. Here, we report that HCH and its analogues induce killing of primary cells in CML patients and leukemic cell lines expressing wild type and mutated Bcr-Abl, including the T315I mutation, with minimal toxicity to normal human peripheral blood mononuclear cells. HCH causes early but transient increase of mitochondria-derived reactive oxygen species. Reactive oxygen species-dependent persistent activation of JNK leads to an increase in endothelial nitric oxide synthase-mediated nitric oxide generation. This causes loss of mitochondrial membrane potential, release of cytochrome c from mitochondria, cleavage of caspase 9, 3 and poly-adenosine diphosphate-ribose polymerase leading to apoptosis. One HCH analogue was also effective in vivo in SCID mice against grafts expressing the T315I mutation, although to a lesser extent than grafts expressing wild type Bcr-Abl, without showing significant bodyweight loss. Our data describe the role of JNK-dependent endothelial nitric oxide synthase-mediated nitric oxide for anti-CML activity of HCH and this molecule merits further testing in pre-clinical and clinical settings

Parental and professional perceptions of informed consent and participation in a time-critical neonatal trial: a mixed-methods study in India, Sri Lanka and Bangladesh

Introduction Time-critical neonatal trials in low-and-middle-income countries (LMICs) raise several ethical issues. Using a qualitative-dominant mixed-methods design, we explored informed consent process in Hypothermia for encephalopathy in low and middle-income countries (HELIX) trial conducted in India, Sri Lanka and Bangladesh.Methods Term infants with neonatal encephalopathy, aged less than 6 hours, were randomly allocated to cooling therapy or usual care, following informed parental consent. The consenting process was audio-video (A-V) recorded in all cases. We analysed A-V records of the consent process using a 5-point Likert scale on three parameters—empathy, information and autonomy. In addition, we used exploratory observation method to capture relevant aspects of consent process and discussions between parents and professionals. Finally, we conducted in-depth interviews with a subgroup of 20 parents and 15 healthcare professionals. A thematic analysis was performed on the observations of A-V records and on the interview transcripts.Results A total of 294 A-V records of the HELIX trial were analysed. Median (IQR) score for empathy, information and autonomy was 5 (0), 5 (1) and 5 (1), respectively. However, thematic analysis suggested that the consenting was a ceremonial process; and parental decision to participate was based on unreserved trust in the treating doctors, therapeutic misconception and access to an expensive treatment free of cost. Most parents did not understand the concept of a clinical trial nor the nature of the intervention. Professionals showed a strong bias towards cooling therapy and reported time constraints and explaining to multiple family members as key challenges.Conclusion Despite rigorous research governance and consent process, parental decisions were heavily influenced by situational incapacity and a trust in doctors to make the right decision on their behalf. Further research is required to identify culturally and context-appropriate strategies for informed trial participation