Correction: Inhibition of p38 MAPK Signaling Augments Skin Tumorigenesis via NOX2 Driven ROS Generation.

[This corrects the article DOI: 10.1371/journal.pone.

First protein drug target's appraisal of lead-likeness descriptors to unfold the intervening chemical space.

Despite the advances in combinatorial chemistry, high throughput and virtual screening experiments, plethora of clinical studies disquiet due to lead and drug-likeness attritions. For mitigation, the knowledge of physicochemical properties are really useful for guiding and selection of compounds from libraries dictated by certain rule of thumbs. However, robust bio-technological and instrumental innovations have created exponential increase in novel compounds and databases which compelled rethinking of the evaluation procedures.

Pyrazolobenzothiazine-based carbothioamides as new structural leads for the inhibition of monoamine oxidases: design, synthesis, bioevaluation and molecular docking studies.

Two new series of pyrazolobenzothiazine-based carbothioamides ( and ) were synthesized using saccharin as the starting material. The synthesized derivatives were investigated for their ability to inhibit monoamine oxidases (MAO). Compound was found to be a very potent MAO-A inhibitor with an IC value of 0.

IL-23 Inhibits Melanoma Development by Augmenting DNA Repair and Modulating T Cell Subpopulations.

In animal models, IL-12 and IL-23 participate in the development of malignant neoplasms of keratinocytes. However, the role of these cytokines in pigmented lesion development and their progression to melanoma has received little attention. IL-12p35, IL-23p19, and IL-12/IL-23p40 knockout mice on a C3H/HeN background, subjected to a melanomagenesis protocol, demonstrated profound differences in susceptibility to nevus initiation, transformation, tumorigenicity, and metastatic potential.

Compound heterozygous LDLR variant in severely affected familial hypercholesterolemia patient.

Familial hypercholesterolemia (FH) is most commonly caused by mutations in the LDL receptor (LDLR), which is responsible for hepatic clearance of LDL from the blood circulation. We described a severely affected FH proband and their first-degree blood relatives; the proband was resistant to statin therapy and was managed on an LDL apheresis program. In order to find the causative genetic variant in this family, direct exon sequencing of the LDLR, APOB and PCSK9 genes was performed.

Functional alterations due to amino acid changes and evolutionary comparative analysis of ARPKD and ADPKD genes.

A targeted customized sequencing of genes implicated in autosomal recessive polycystic kidney disease (ARPKD) phenotype was performed to identify candidate variants using the Ion torrent PGM next-generation sequencing. The results identified four potential pathogenic variants in gene [c.4870C > T, p.

A case of severe perioperative hypoxia in uncorrected tetralogy of fallot: Anesthetic management.

Tetralogy of fallot (TOF) is one of the most common congenital heart disease (CHD) in children. With the development of pediatric surgery and intensive care units, increasing number of grown-up CHD patients are presenting for non-cardiac surgeries. Non-operated TOF patients suffer from chronic hypoxia and decreased pulmonary blood flow resulting in considerable alteration in the physiology.

Defining cutaneous molecular pathobiology of arsenicals using phenylarsine oxide as a prototype.

Arsenicals are painful, inflammatory and blistering causing agents developed as chemical weapons in World War I/II. However, their large stockpiles still exist posing threat to public health. Phenylarsine oxide (PAO), a strong oxidant and a prototype arsenical is tested for its suitability to defining molecular mechanisms underlying arsenicals-mediated tissue injury.

ATF4 regulates arsenic trioxide-mediated NADPH oxidase, ER-mitochondrial crosstalk and apoptosis.

Arsenic is a mitochondrial toxin, and its derivatives, such as arsenic trioxide (ATO), can trigger endoplasmic reticulum (ER) and the associated unfolded protein response (UPR). Here, we show that arsenic induction of the UPR triggers ATF4, which is involved in regulating this ER-mitochondrial crosstalk that is important for the molecular pathogenesis of arsenic toxicity. Employing ATF4 and ATF4 MEFs, we show that ATO induces UPR and impairs mitochondrial integrity in ATF4 MEF cells which is largely ablated upon loss of ATF4.

Biological and environmental hazards associated with exposure to chemical warfare agents: arsenicals.

Arsenicals are highly reactive inorganic and organic derivatives of arsenic. These chemicals are very toxic and produce both acute and chronic tissue damage. On the basis of these observations, and considering the low cost and simple methods of their bulk syntheses, these agents were thought to be appropriate for chemical warfare.

Extracellular Signal-Regulated Kinase 2 and CHOP Restrict the Expression of the Growth Arrest-Specific p20K Lipocalin Gene to G0.

The activation of the growth arrest-specific (gas) p20K gene depends on the interaction of C/EBPβ with two elements of a 48-bp promoter region termed the quiescence-responsive unit (QRU). Here we identify extracellular signal-related kinase 2 (ERK2) as a transcriptional repressor of the p20K QRU in cycling chicken embryo fibroblasts (CEF). ERK2 binds to repeated GAAAG sequences overlapping the C/EBPβ sites of the QRU.

Communication of laboratory data and diagnostic test results to hospitalized patients: a study of preferences and recall.

Objective: To assess patients' preferences with respect to different methods of receiving test results while they were hospitalized and to determine whether the different modes of communication of the test results were associated with better recall.

Methods: Five discrete test results were shared with adult inpatients on general medicine service (blood pressure, white blood cell count, hematocrit, creatinine, and chest X-ray). The information was delivered by a physician in one of three ways: 1) verbally, 2) explained with a print out of the results, or 3) described while showing results on a computer monitor (electronic).

Detection of Anti-Hepatitis B Virus Drug Resistance Mutations Based on Multicolor Melting Curve Analysis.

Detection of anti-hepatitis B virus (HBV) drug resistance mutations is critical for therapeutic decisions for chronic hepatitis B virus infection. We describe a real-time PCR-based assay using multicolor melting curve analysis (MMCA) that could accurately detect 24 HBV nucleotide mutations at 10 amino acid positions in the reverse transcriptase region of the HBV polymerase gene. The two-reaction assay had a limit of detection of 5 copies per reaction and could detect a minor mutant population (5% of the total population) with the reverse transcriptase M204V amino acid mutation in the presence of the major wild-type population when the overall concentration was 10 copies/μl.

Molecular Mechanism Underlying Pathogenesis of Lewisite-Induced Cutaneous Blistering and Inflammation: Chemical Chaperones as Potential Novel Antidotes.

Lewisite is a potent arsenic-based chemical warfare agent known to induce painful cutaneous inflammation and blistering. Only a few modestly effective antidotes have so far been described in the literature. However, the discovery of effective antidotes for lewisite was hampered by the paucity of the exact molecular mechanism underlying its cutaneous pathogenesis.

Breast Cancer in Pakistan a Critical Appraisal of the Situation Regarding Female Health and Where the Nation Stands?

Breast cancer (BC) is the most common malignancy of women worldwide. In the past it was considered as disease of older middle aged women, but the incidence of BC in young females is growing in recent years concordant with studies in Pakistan. In this paper, we reviewed the mutant functions of tumor suppressor genes (BRCA1, BRCA2, p53, ATM and PTEN), epigenetic transformation and involvement of estrogen receptors in development of breast cancer.

Prosthetic Aortic Valve Endocarditis with Left Main Coronary Artery Embolism: A Case Report and Review of the Literature.

Context: Coronary embolization is potentially a fatal sequela of endocarditis. Although the primary cause of acute coronary syndrome is atherosclerotic disease, it is imperative to consider septic embolism as an etiological factor.

Case Report: Herein, we report a case of ventricular fibrillation and ST-segment depression myocardial infarction occurring in a patient who initially presented with fever and increased urinary frequency.

Use of Moringa oleifera Flower Pod Extract as Natural Preservative and Development of SCAR Marker for Its DNA Based Identification.

The use of Moringa oleifera as natural food preservative has been evaluated in the present study. In addition, for quality assurance, the study has also been focused on the shelf life of product to authenticate the identification of plant by development of DNA based marker. Among the different extracts prepared from flower pods of Moringa oleifera, methanol and aqueous extract exhibited high antibacterial and antioxidant activity, respectively.

Activating transcription factor 4 underlies the pathogenesis of arsenic trioxide-mediated impairment of macrophage innate immune functions.

Chronic arsenic exposure to humans is considered immunosuppressive with augmented susceptibility to several infectious diseases. The exact molecular mechanisms, however, remain unknown. Earlier, we showed the involvement of unfolded protein response (UPR) signaling in arsenic-mediated impairment of macrophage functions.

Abstracts from the 3rd International Genomic Medicine Conference (3rd IGMC 2015) : Jeddah, Kingdom of Saudi Arabia. 30 November - 3 December 2015.

O1 Regulation of genes by telomere length over long distances Jerry W. Shay O2 The microtubule destabilizer KIF2A regulates the postnatal establishment of neuronal circuits in addition to prenatal cell survival, cell migration, and axon elongation, and its loss leading to malformation of cortical development and severe epilepsy Noriko Homma, Ruyun Zhou, Muhammad Imran Naseer, Adeel G. Chaudhary, Mohammed Al-Qahtani, Nobutaka Hirokawa O3 Integration of metagenomics and metabolomics in gut microbiome research Maryam Goudarzi, Albert J.

Next-generation sequencing for molecular diagnosis of autosomal recessive polycystic kidney disease.

Autosomal recessive polycystic kidney disease (ARPKD) a rare genetic disorder, described by formation of cysts in the kidney. A targeted customized sequencing of genes implicated in ARPKD phenotype was performed to identify candidate variants using the Ion torrent PGM next-generation sequencing. The results identified likely pathogenic disease causing variants during the validation process.

AKT1 Activation is Obligatory for Spontaneous BCC Tumor Growth in a Murine Model that Mimics Some Features of Basal Cell Nevus Syndrome.

Patients with basal cell nevus syndrome (BCNS), also known as Gorlin syndrome, develop numerous basal cell carcinomas (BCC) due to germline mutations in the tumor suppressor PTCH1 and aberrant activation of Hedgehog (Hh) signaling. Therapies targeted at components of the Hh pathway, including the smoothened (SMO) inhibitor vismodegib, can ablate these tumors clinically, but tumors recur upon drug discontinuation. Using SKH1-Ptch1 as a model that closely mimics the spontaneous and accelerated growth pattern of BCCs in patients with BCNS, we show that AKT1, a serine/threonine protein kinase, is intrinsically activated in keratinocytes derived from the skin of newborn Ptch1 mice in the absence of carcinogenic stimuli.

Human genome meeting 2016 : Houston, TX, USA. 28 February - 2 March 2016.

O1 The metabolomics approach to autism: identification of biomarkers for early detection of autism spectrum disorder A. K. Srivastava, Y.

Limited ATF4 Expression in Degenerating Retinas with Ongoing ER Stress Promotes Photoreceptor Survival in a Mouse Model of Autosomal Dominant Retinitis Pigmentosa.

T17M rhodopsin expression in rod photoreceptors leads to severe retinal degeneration and is associated with the activation of ER stress related Unfolded Protein Response (UPR) signaling. Here, we show a novel role of a UPR transcription factor, ATF4, in photoreceptor cellular pathology. We demonstrated a pro-death role for ATF4 overexpression during autosomal dominant retinitis pigmentosa (ADRP).