m^6A RNA methylation promotes XIST-mediated transcriptional repression

The long non-coding RNA X-inactive specific transcript (XIST) mediates the transcriptional silencing of genes on the X chromosome. Here we show that, in human cells, XIST is highly methylated with at least 78 N^6-methyladenosine (m^6A) residues—a reversible base modification of unknown function in long non-coding RNAs. We show that m^6A formation in XIST, as well as in cellular mRNAs, is mediated by RNA-binding motif protein 15 (RBM15) and its paralogue RBM15B, which bind the m^6A-methylation complex and recruit it to specific sites in RNA. This results in the methylation of adenosine nucleotides in adjacent m^6A consensus motifs. Furthermore, we show that knockdown of RBM15 and RBM15B, or knockdown of methyltransferase like 3 (METTL3), an m^6A methyltransferase, impairs XIST-mediated gene silencing. A systematic comparison of m^6A-binding proteins shows that YTH domain containing 1 (YTHDC1) preferentially recognizes m^6A residues on XIST and is required for XIST function. Additionally, artificial tethering of YTHDC1 to XIST rescues XIST-mediated silencing upon loss of m^6A. These data reveal a pathway of m^6A formation and recognition required for XIST-mediated transcriptional repression

NLRP3 Inflammasome: Key Mediator of Neuroinflammation in Murine Japanese Encephalitis

Background: Japanese Encephalitis virus (JEV) is a common cause of acute and epidemic viral encephalitis. JEV infection is associated with microglial activation resulting in the production of pro-inflammatory cytokines including Interleukin-1 b (IL-1b) and Interleukin-18 (IL-18). The Pattern Recognition Receptors (PRRs) and the underlying mechanism by which microglia identify the viral particle leading to the production of these cytokines is unknown. Methodology/Principal Findings: For our studies, we have used murine model of JEV infection as well as BV-2 mouse microglia cell line. In this study, we have identified a signalling pathway which leads to the activation of caspase-1 as the key enzyme responsible for the maturation of both IL-1b and IL-18 in NACHT, LRR and PYD domains-containing protein-3 (NLRP3) dependent manner. Depletion of NLRP3 results in the reduction of caspase-1 activity and subsequent production of these cytokines. Conclusion/Significance: Our results identify a mechanism mediated by Reactive Oxygen Species (ROS) production and potassium efflux as the two danger signals that link JEV infection to caspase-1 activation resulting in subsequent IL-1b an

Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to 300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m 2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Omics-based molecular techniques in oral pathology centred cancer: Prospect and challenges in Africa

: The completion of the human genome project and the accomplished milestones in the human proteome project; as well as the progress made so far in computational bioinformatics and “big data” processing have contributed immensely to individualized/personalized medicine in the developed world.At the dawn of precision medicine, various omics-based therapies and bioengineering can now be applied accurately for the diagnosis, prognosis, treatment, and risk stratifcation of cancer in a manner that was hitherto not thought possible. The widespread introduction of genomics and other omics-based approaches into the postgraduate training curriculum of diverse medical and dental specialties, including pathology has improved the profciency of practitioners in the use of novel molecular signatures in patient management. In addition, intricate details about disease disparity among diferent human populations are beginning to emerge. This would facilitate the use of tailor-made novel theranostic methods based on emerging molecular evidences

Variation in neurosurgical management of traumatic brain injury: A survey in 68 centers participating in the CENTER-TBI study

Background Neurosurgical management of traumatic brain injury (TBI) is challenging, with only low-quality evidence. We aimed to explore differences in neurosurgical strategies for TBI across Europe. Methods A survey was sent to 68 centers participating in the Collaborative European Neurotrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. The questionnaire contained 21 questions, including the decision when to operate (or not) on traumatic acute subdural hematoma (ASDH) and intracerebral hematoma (ICH), and when to perform a decompressive craniectomy (DC) in raised intracranial pressure (ICP). Results The survey was completed by 68 centers (100%). On average, 10 neurosurgeons work in each trauma center. In all centers, a neurosurgeon was available within 30 min. Forty percent of responders reported a thickness or volume threshold for evacuation of an ASDH. Most responders (78%) decide on a primary DC in evacuating an ASDH during the operation, when swelling is present. For ICH, 3% would perform an evacuation directly to prevent secondary deterioration and 66% only in case of clinical deterioration. Most respondents (91%) reported to consider a DC for refractory high ICP. The reported cut-off ICP for DC in refractory high ICP, however, differed: 60% uses 25 mmHg, 18% 30 mmHg, and 17% 20 mmHg. Treatment strategies varied substantially between regions, specifically for the threshold for ASDH surgery and DC for refractory raised ICP. Also within center variation was present: 31% reported variation within the hospital for inserting an ICP monitor and 43% for evacuating mass lesions. Conclusion Despite a homogeneous organization, considerable practice variation exists of neurosurgical strategies for TBI in Europe. These results provide an incentive for comparative effectiveness research to determine elements of effective neurosurgical care

Improved synthesis of carbon nanotubes with junctions and of single-walled carbon nanotubes

Pyrolysis of thiophene over nickel nanoparticles dispersed on silica is shown to yield Y-junction carbon nanotubes with smaller diameters than those obtained by the pyrolysis of organometallic-thiophene mixtures. In the presence of water vapour, the pyrolysis of organometallic-hydrocarbon mixtures yields single-walled nanotubes, as well as relatively narrow-diameter carbon nanotubes with Y-junctions. Pyrolysis-of organometallic-hydrocarbon mixtures, in the absence of water vapour, only gives nanotubes with T- and Y-junctions

Nanorotors using asymmetric inorganic nanorods in an optical trap

We demonstrate how light force, irrespective of the polarization of the light, can be used to run a simple nanorotor. While the gradient force of a single beam optical trap is used to hold an asymmetric nanorod, we utilize the scattering force to generate a torque on the nanorod, making it rotate about the optic axis. The inherent textural irregularities or morphological asymmetries of the nanorods give rise to the torque under the radiation pressure. Even a small surface irregularity with non-zero chirality is sufficient to produce enough torque for moderate rotational speed. Different sized rotors can be used to set the speed of rotation over a wide range with fine tuning possible through the variation of the laser power. We present a simple dimensional analysis to qualitatively explain the observed trend of the rotational motion of the nanorods

Boron nitride nanotubes and nanowires

Simple methods of preparing boron nitride nanotubes and nanowires have been investigated. The methods involve heating boric acid with activated carbon, multi-walled carbon nanotubes, catalytic iron particles or a mixture of activated carbon and iron particles, in the presence of NH3. While with activated carbon, boron nitride nanowires constitute the primary product, high yields of clean boron nitride nanotubes are obtained with multi-walled carbon nanotubes. Aligned boron nitride nanotubes are produced when aligned multi-walled carbon nanotubes are employed as the starting material suggesting the templating role of the nanotubes. Boron nitride nanotubes with different structures have been obtained by reacting boric acid with NH3 in the presence of a mixture of activated carbon and Fe particles. (C) 2002 Elsevier Science B.V. All rights reserved