Dubs

Heterotrimeric G proteins are signal-transducing switches conserved across eukaryotes. In humans, they work as critical mediators of intercellular communication in the context of virtually any physiological process. While G protein regulation by G protein-coupled receptors (GPCRs) is well-established and has received much attention, it has become recently evident that heterotrimeric G proteins can also be activated by cytoplasmic proteins. However, this alternative mechanism of G protein regulation remains far less studied than GPCR-mediated signaling...

This study was undertaken to investigate the dynamics of protein ubiquitination in pig gametes and their micro-environments, as well as to explore the action of deubiquitinases (DUBs) in sperm-oocyte binding. Protein ubiquitination states were evaluated by in the ejaculated sperm, seminal plasma, epididymal sperm, oocytes, zona pellucida (ZP) and follicular fluid (FF) by western blotting. Different concentrations of PR-619, a non-selective inhibitor of DUBs, were used to treat oocytes during in vitro maturation (IVM), the maturation rate, amount of ubiquitinated ZP proteins, and ZP solubility were assessed...

Ultracold molecules represent a fascinating research frontier in physics and chemistry, but it has proven challenging to prepare dense samples at low velocities. Here we present a solution to this goal by a non-conventional approach dubbed cryofuge. It employs centrifugal force to bring cryogenically cooled molecules to kinetic energies below 1 K × kB in the laboratory frame, with corresponding fluxes exceeding 10(10)/s at velocities below 20 m/s. By attaining densities higher than 10(9)/cm(3) and interaction times longer than 25 ms in samples of fluoromethane as well as deuterated ammonia, we observe cold dipolar collisions between molecules and determine their collision cross sections...

Hybrid halide perovskites combine ease of preparation and relatively abundant constituent elements with fascinating photophysical properties. Descriptions of the chemical and structural drivers of the remarkable properties have often focused on the potential role of the dynamic order/disorder of the molecular A-site cations. We reveal here a key aspect of the inorganic framework that potentially impacts the electronic, thermal, and dielectric properties. The temperature evolution of the X-ray pair distribution functions of hybrid perovskites ABX3 [A(+) = CH3NH3 (MA) or CH(NH2)2 (FA); B(2+) = Sn or Pb; X(-) = Br, or I] in their cubic phases above 300 K reveals temperature-activated displacement (off-centering) of the divalent group 14 cations from their nominal, centered sites...

PURPOSE: QUantitative Imaging of eXtraction of Oxygen and TIssue Consumption (QUIXOTIC) is a recent technique that measures voxel-wise oxygen extraction fraction (OEF) but suffers from long scan times, limiting its application. We implemented multiecho QUIXOTIC dubbed turbo QUIXOTIC (tQUIXOTIC) that reduces scan time eightfold and then applied it in functional MRI. METHODS: tQUIXOTIC utilizes a novel turbo gradient spin echo readout enabling measurement of venular blood transverse relaxation rate in a single tag-control acquisition...

We have developed a model system for membrane fusion that utilizes lipidated derivatives of a hetero-dimeric coiled-coil pair dubbed E3 (EIAALEK)3 and K3 (KIAALKE)3. In this system peptides are conjugated to a lipid anchor via a polyethyleneglycol (PEG) spacer, and this contribution studies the influence of the PEG-spacer length, coupled with the type of lipid anchor, on liposome-liposome fusion. The effects of these modifications on peptide secondary structure, their interactions with liposomes, and their ability to mediate fusion were studied using a variety of different content mixing experiments and CD spectroscopy...

Histone modifying enzymes, such as histone deacetylases (HDACs) and polycomb repressive complex (PRC) components, have been implicated in regulating tumor growth, epithelial-mesenchymal transition, tumor stem cell maintenance, or repression of tumor suppressor genes - and may be promising targets for combination therapies of melanoma and other cancers. According to recent findings, the histone H2A deubiquitinase 2A-DUB/Mysm1 interacts with the p53-axis in hematopoiesis and tissue differentiation in mice, in part by modulating DNA-damage responses in stem cell and progenitor compartments...

Genomes acquire lesions that can block the replication fork and some lesions must be bypassed to allow survival. The nuclear genome of flowering plants encodes two family-A DNA polymerases (DNAPs), the result of a duplication event, that are the sole DNAPs in plant organelles. These DNAPs, dubbed Plant Organellar Polymerases (POPs), resemble the Klenow fragment of bacterial DNAP I and are not related to metazoan and fungal mitochondrial DNAPs. Herein we report that replicative POPs from the plant model Arabidopsis thaliana (AtPolI) efficiently bypass one the most insidious DNA lesions, an apurinic/apyrimidinic (AP) site...

DNA primases recognize single-stranded DNA (ssDNA) sequences to synthesize RNA primers during lagging-strand replication. Arabidopsis thaliana encodes an ortholog of the DNA primase-helicase from bacteriophage T7, dubbed AtTwinkle, that localizes in chloroplasts and mitochondria. Herein, we report that AtTwinkle synthesizes RNA primers from a 5'-(G/C)GGA-3' template sequence. Within this sequence, the underlined nucleotides are cryptic, meaning that they are essential for template recognition but are not instructional during RNA synthesis...

We are witnessing the birth of a new variety of pharmacokinetics where non-integer-order differential equations are employed to study the time course of drugs in the body: this is dubbed "fractional pharmacokinetics". The presence of fractional kinetics has important clinical implications such as the lack of a half-life, observed, for example with the drug amiodarone and the associated irregular accumulation patterns following constant and multiple-dose administration. Building models that accurately reflect this behaviour is essential for the design of less toxic and more effective drug administration protocols and devices...

Prostate cancer (PCa) remains a leading cause of cancer-related death in men. Especially, a subset of patients will eventually progress to the metastatic castrate-resistant prostate cancer (CRPC) which is currently incurable. Deubiquitinases (DUBs) associated with the 19S proteasome regulatory particle are increasingly emerging as significant therapeutic targets in numerous cancers. Recently, a novel small molecule b-AP15 is identified as an inhibitor of the USP14/UCHL5 (DUBs) of the 19S proteasome, resulting in cell growth inhibition and apoptosis in several human cancer cell lines...

Oncogenic forms of the kinase FLT3 are important therapeutic targets in acute myeloid leukemia (AML); however, clinical responses to small-molecule kinase inhibitors are short-lived as a result of the rapid emergence of resistance due to point mutations or compensatory increases in FLT3 expression. We sought to develop a complementary pharmacological approach whereby proteasome-mediated FLT3 degradation could be promoted by inhibitors of the deubiquitinating enzymes (DUBs) responsible for cleaving ubiquitin from FLT3...

Post-stroke cognitive impairment (PSCI) warrants early detection and management. We sought to develop a risk score for screening patients at bedside for risk of delayed PSCI. Ischemic stroke survivors with PSCI and no cognitive impairments (NCI) 3-6 months post-stroke were studied to identify candidate variables predictive of PSCI. These variables were used to develop a risk score using regression models. The score, and the best identified clinical cutoff point, underwent development, stability testing, and internal and external validation in three independent cohorts from Singapore and Hong Kong...

More than a decade after a Nobel Prize was awarded for the discovery of the ubiquitin-proteasome system and clinical approval of proteasome and ubiquitin E3 ligase inhibitors, first-generation deubiquitylating enzyme (DUB) inhibitors are now approaching clinical trials. However, although our knowledge of the physiological and pathophysiological roles of DUBs has evolved tremendously, the clinical development of selective DUB inhibitors has been challenging. In this Review, we discuss these issues and highlight recent advances in our understanding of DUB enzymology and biology as well as technological improvements that have contributed to the current interest in DUBs as therapeutic targets in diseases ranging from oncology to neurodegeneration...

The authors proposed a new method to automatically mesh computed tomography (CT)-based three-dimensional human airway geometry for computational fluid dynamics (CFD)-based simulations of pulmonary gas-flow and aerosol delivery. Traditional methods to construct and mesh realistic geometry were time-consuming, because they were done manually using image-processing and mesh-generating programs. Furthermore, most of CT thoracic image data sets do not include the upper airway structures. To overcome these issues, the proposed method consists of CFD grid-size distribution, an automatic meshing algorithm, and the addition of a laryngeal model along with turbulent velocity inflow boundary condition attached to the proximal end of the trachea...

BACKGROUND: Childhood overweight and obesity is a public health epidemic with far-reaching medical, economic, and quality of life consequences. Brief, web-based interventions have received increased attention for their potential to combat childhood obesity. The purpose of our study was to evaluate a web-based, maternal-facilitated childhood obesity prevention intervention dubbed Enabling Mothers to Prevent Pediatric Obesity Through Web-Based Education and Reciprocal Determinism (EMPOWER), for its capacity to elicit sustained effects at the 2-year postintervention follow-up mark...

Uptake and release calcium from the sarcoplasmic reticulum (SR) (dubbed "calcium clock"), in the form of spontaneous, rhythmic, local diastolic calcium releases (LCRs), together with voltage-sensitive ion channels (membrane clock) form a coupled system that regulates the action potential (AP) firing rate. LCRs activate Sodium/Calcium exchanger (NCX) that accelerates diastolic depolarization and thus participating in regulation of the time at which the next AP will occur. Previous studies in rabbit SA node cells (SANC) demonstrated that the basal AP cycle length (APCL) is tightly coupled to the basal LCR period (time from the prior AP-induced Ca2+ transient to the diastolic LCR occurrence), and that this coupling is further modulated by autonomic receptor stimulation...

The deubiquitinase USP5 stabilizes c-Maf, a key transcription factor in multiple myeloma (MM), but the mechanisms and significance are unclear. In the present study, USP5 was found to interact with c-Maf and prevented it from degradation by decreasing its polyubiquitination level. Specifically, the 308th and 347th lysine residues in c-Maf were critical for USP5-mediated deubiquitination and stability. There are five key domains in the USP5 protein and subsequent studies revealed that the cryptic ZnF domain and the C-box domain interacted with c-Maf but the UBA1/UBA2 domain partly increased its stability...

We propose a minimal model for the spontaneous and persistent generation of polarity in a spherical cell based on dynamic microtubules and a single mobile molecular component. This component, dubbed the polarity factor, binds to microtubules nucleated from a centrosome located in the center of the cell, is subsequently delivered to the cell membrane, where it diffuses until it unbinds. The only feedback mechanism we impose is that the residence time of the microtubules at the membrane increases with the local density of the polarity factor...

Centchroman (INN: Ormeloxifene), a reversible post-coital/weekly oral contraceptive (half-life of about 168 hours), designed and developed at CDRI, Lucknow is the only non-steroidal oral contraceptive in clinical use in the world today. Synthesized in 1967 and completing pre-clinical and clinical studies in 1989, this drug was approved for marketing in 1991, social marketing in 1995 and NFPW in April 2016. It acts by preventing implantation of blastocyst in endometrium. It is the only contraceptive which neither suppresses ovulation nor interferes with the hypothalamic-pituitary-ovarian axis...