Gene Networks of Fully Connected Triads with Complete Auto-Activation Enable Multistability and Stepwise Stochastic Transitions

Fully-connected triads (FCTs), such as the Oct4-Sox2-Nanog triad, have been implicated as recurring transcriptional motifs embedded within the regulatory networks that specify and maintain cellular states. To explore the possible connections between FCT topologies and cell fate determinations, we employed computational network screening to search all possible FCT topologies for multistability, a dynamic property that allows the rise of alternate regulatory states from the same transcriptional network. The search yielded a hierarchy of FCTs with various potentials for multistability, including several topologies capable of reaching eight distinct stable states. Our analyses suggested that complete auto-activation is an effective indicator for multistability, and, when gene expression noise was incorporated into the model, the networks were able to transit multiple states spontaneously. Different levels of stochasticity were found to either induce or disrupt random state transitioning with some transitions requiring layovers at one or more intermediate states. Using this framework we simulated a simplified model of induced pluripotency by including constitutive overexpression terms. The corresponding FCT showed random state transitioning from a terminal state to the pluripotent state, with the temporal distribution of this transition matching published experimental data. This work establishes a potential theoretical framework for understanding cell fate determinations by connecting conserved regulatory modules with network dynamics. Our results could also be employed experimentally, using established developmental transcription factors as seeds, to locate cell lineage specification networks by using auto-activation as a cipher

Analgesic use and potential hearing loss: a pharmacovigilance study

Background: Hearing loss is the most common sensory deficit in humans today. In India, as per WHO there are approximately 63 million people, who are suffering from significant auditory impairment and estimated prevalence at 6.3% in Indian population. The objective of the study was to determine the potential hearing loss in patients on analgesics.Methods: Prospective, observational study examined the association between analgesic use and potential hearing loss in 30 patients receiving NSAIDS. Data was collected using specialized designed case record form. The clinical signs like onset of tinnitus, appearance of another sound that didn't exist before, sinus infection or a respiratory illness, development of vertigo or spinning sensation were looked for. Audiometry test was advised for all the patients receiving analgesics.Results: Total of 30 patients were included in the study. Male predominance was noted Maximum patients were in the age group between 35-45 years (33.33%). The socioeconomic status was analyzed using revised kuppuswamy scale. 30% (n=09) of patients were in lower class. Majority of the patients were reported with road traffic accidents (n=19; 63.33%) and received analgesics for more than 2 weeks. Patients received different combination of NSAIDs among which aceclofenac was most commonly prescribed. 11 (36.66%) patients had hearing loss received either diclofenac or aceclofenac for more than 25 days.Conclusions: Regular usage of NSAIDS may increase the risk of hearing loss and the impact could be larger on younger individuals. Hence, extra precaution to be taken while prescribing NSAIDS

Testosterone levels in men with type 2 diabetes mellitus

Background: To study testosterone levels in men with type 2 diabetes mellitus in age group of 30-50 years.Methods: In this cross sectional study of 193 type 2 diabetes men aged between 30-50 years, total and free testosterone levels were calculated along with other relevant clinical variables like hypertension, BMI, dyslipidemia, peripheral neuropathy, retinopathy.Results: The study group had study out of 193 patients 34.7% have low total testosterone levels, 29.53% have low free testosterone levels and 23.3% have both low and free testosterone levels. Maximum number of patients with low total testosterone levels were in the age group between 46-50 years (41.0%) and with low free total testosterone levels were in the age group between 36-40 years (41.8%).Conclusions: Type 2 diabetes mellitus is associated with low levels of total and free testosterone. Obesity and dyslipidemia are also associated with low testosterone levels

Polyphenols, Flavonoids, Mineral Elements, and Biological Activities of Ginger and Cinnamon Essential Oil and Extracts as Regulated by Their Isolation Procedures

Our research compared the chemical make-up of wild Ginger and cinnamon, including their essential oils (EOs), total phenol, and total flavonoid, for their antioxidant and antibacterial effects in vitro. The mineral (nutritional and poisonous) components of the plant were also identified in this investigation. Hydro distillation (HD), steam distillation (SD), and microwave-assisted distillation (MAD) were used to extract the EOs, and gas chromatography with flame ionization detection (GC-FID) and mass spectrometry detection (GC-MS) were used to examine them. 2,2-diphenyl-1-picrylhydrazyl (DPPH) was used to evaluate the EOs' antioxidant properties. The essential oil was analyzed, and twenty-six components were found to make up 97.73% of the oil with a yield of 0.202%. The primary components were pulegone (74.81%), menthone (13.01%) and piperitone (3.82%). Neutron activation analysis (INAA) and inductively coupled plasma optical emission spectrometry (ICP-OES) were used to detect twenty-one elements, including macro- and micro-elements (Ba, Br, Ca, Cl, Co, Cr, Cs, Eu, Fe, K, Mg, Mn, Mo, Na, Rb, Sb, Sc, Sr, Th, U, and Zn), with the mineral element concentration being very close to the FAO recommendation

Scaling approach to tight-binding transport in realistic graphene devices:the case of transverse magnetic focusing

Ultraclean graphene sheets encapsulated between hexagonal boron nitride crystals host two-dimensional electron systems in which low-temperature transport is solely limited by the sample size. We revisit the theoretical problem of carrying out microscopic calculations of nonlocal ballistic transport in such micron-scale devices. By employing the Landauer-Büttiker scattering theory, we propose a scaling approach to tight-binding nonlocal transport in realistic graphene devices. We test our numerical method against experimental data on transverse magnetic focusing (TMF), a textbook example of nonlocal ballistic transport in the presence of a transverse magnetic field. This comparison enables a clear physical interpretation of all the observed features of the TMF signal, including its oscillating sign

Analyzing Land Cover Change Using Remote Sensing and GIS: A Case Study of Gilgit River Basin, North Pakistan

Mountainous areas of northern Pakistan are rich in biodiversity, glaciers and key watershed of Indus Riversystem which provide ecosystem services for their inhabitants. These regions have experienced extensive deforestationand are presently vulnerable by rapid land cover changes, therefore an effective assessment and monitoring is essentialto capture such changes. The aim of this study is to analyze the observed changes in land cover over a period of thirtynine years, divided into three stages (1976-1999, 1999-2008 and 2008-2015). Four images from Landsat 2Multispectral Scanner System (MSS), Landsat 5 Thematic Mapper (TM), Landsat 7 Enhanced Thematic Mapper andLandsat 8 Operation Land Imager data were obtained to detect land cover change. This study used supervisedclassification-maximum likelihood algorithm in ERDAS imagine to identify land cover changes perceived in GilgitRiver Basin, Pakistan. The result showed that the range land, glaciers, water bodies, built-up/agricultural cover are themajor categories that have been altered by the natural and anthropogenic actions. In 1976, built up/agriculture, rangeland, water bodies and glacier cover was 1.13%, 45.3%, 0.66% and 13.2%, respectively. Whereas in 2015, builtup/agriculture, range land, water bodies and glacier cover was 3.25%, 12.7%, 0.91% and 8.2%, respectively. Thesesland cover shifts posed acute threat to watershed resources. Therefore, a comprehensive watershed resourcemanagement is essential or otherwise, these resources will deplete rapidly and no longer be capable of playing their rolein socioeconomic and sustainable environmental development of the are

Transfer of knowledge from model organisms to evolutionarily distant non-model organisms: The coral Pocillopora damicornis membrane signaling receptome

With the ease of gene sequencing and the technology available to study and manipulate non-model organisms, the extension of the methodological toolbox required to translate our understanding of model organisms to non-model organisms has become an urgent problem. For example, mining of large coral and their symbiont sequence data is a challenge, but also provides an opportunity for understanding functionality and evolution of these and other non-model organisms. Much more information than for any other eukaryotic species is available for humans, especially related to signal transduction and diseases. However, the coral cnidarian host and human have diverged over 700 million years ago and homologies between proteins in the two species are therefore often in the gray zone, or at least often undetectable with traditional BLAST searches. We introduce a two-stage approach to identifying putative coral homologues of human proteins. First, through remote homology detection using Hidden Markov Models, we identify candidate human homologues in the cnidarian genome. However, for many proteins, the human genome alone contains multiple family members with similar or even more divergence in sequence. In the second stage, therefore, we filter the remote homology results based on the functional and structural plausibility of each coral candidate, shortlisting the coral proteins likely to have conserved some of the functions of the human proteins. We demonstrate our approach with a pipeline for mapping membrane receptors in humans to membrane receptors in corals, with specific focus on the stony coral, P. damicornis. More than 1000 human membrane receptors mapped to 335 coral receptors, including 151 G protein coupled receptors (GPCRs). To validate specific sub-families, we chose opsin proteins, representative GPCRs that confer light sensitivity, and Toll-like receptors, representative non-GPCRs, which function in the immune response, and their ability to communicate with microorganisms. Through detailed structure-function analysis of their ligand-binding pockets and downstream signaling cascades, we selected those candidate remote homologues likely to carry out related functions in the corals. This pipeline may prove generally useful for other non-model organisms, such as to support the growing field of synthetic biology

Mir-214-Dependent Regulation of the Polycomb Protein Ezh2 in Skeletal Muscle and Embryonic Stem Cells

Arthur Manuscript date: 2010 October 9Polycomb group (PcG) proteins exert essential functions in the most disparate biological processes. The contribution of PcG proteins to cell commitment and differentiation relates to their ability to repress transcription of developmental regulators in embryonic stem (ES) cells and in committed cell lineages, including skeletal muscle cells (SMC). PcG proteins are preferentially removed from transcribed regions, but the underlying mechanisms remain unclear. Here, PcG proteins are found to occupy and repress transcription from an intronic region containing the microRNA miR-214 in undifferentiated SMC. Differentiation coincides with PcG disengagement, recruitment of the developmental regulators MyoD and myogenin, and activation of miR-214 transcription. Once transcribed, miR-214 negatively feeds back on PcG by targeting the Ezh2 3′UTR, the catalytic subunit of the PRC2 complex. miR-214-mediated Ezh2 protein reduction accelerates SMC differentiation and promotes unscheduled transcription of developmental regulators in ES cells. Thus, miR-214 and Ezh2 establish a regulatory loop controlling PcG-dependent gene expression during differentiation.National Institute of Arthritis and Musculoskeletal and Skin Diseases (U.S.) (Intramural Research Program

Evidence That Gene Activation and Silencing during Stem Cell Differentiation Requires a Transcriptionally Paused Intermediate State

A surprising portion of both mammalian and Drosophila genomes are transcriptionally paused, undergoing initiation without elongation. We tested the hypothesis that transcriptional pausing is an obligate transition state between definitive activation and silencing as human embryonic stem cells (hESCs) change state from pluripotency to mesoderm. Chromatin immunoprecipitation for trimethyl lysine 4 on histone H3 (ChIP-Chip) was used to analyze transcriptional initiation, and 3′ transcript arrays were used to determine transcript elongation. Pluripotent and mesodermal cells had equivalent fractions of the genome in active and paused transcriptional states (∼48% each), with ∼4% definitively silenced (neither initiation nor elongation). Differentiation to mesoderm changed the transcriptional state of 12% of the genome, with roughly equal numbers of genes moving toward activation or silencing. Interestingly, almost all loci (98–99%) changing transcriptional state do so either by entering or exiting the paused state. A majority of these transitions involve either loss of initiation, as genes specifying alternate lineages are archived, or gain of initiation, in anticipation of future full-length expression. The addition of chromatin dynamics permitted much earlier predictions of final cell fate compared to sole use of conventional transcript arrays. These findings indicate that the paused state may be the major transition state for genes changing expression during differentiation, and implicate control of transcriptional elongation as a key checkpoint in lineage specification