La autoantigen is required for the internal ribosome entry site-mediated translation of Coxsackievirus B3 RNA

Translation initiation in Coxsackievirus B3 (CVB3) occurs via ribosome binding to an internal ribosome entry site (IRES) located in the 5'-untranslated region (UTR) of the viral RNA. This unique mechanism of translation initiation requires various trans-acting factors from the host. We show that human La autoantigen (La) binds to the CVB3 5'-UTR and also demonstrate the dose-dependent effect of exogenously added La protein in stimulating CVB3 IRES-mediated translation. The requirement of La for CVB3 IRES mediated translation has been further demonstrated by inhibition of translation as a result of sequestering La and its restoration by exogenous addition of recombinant La protein. The abundance of La protein in various mouse tissue extracts has been probed using anti-La antibody. Pancreatic tissue, a target organ for CVB3 infection, was found to have a large abundance of La protein which was demonstrated to interact with the CVB3 5'-UTR. Furthermore, exogenous addition of pancreas extract to in vitro translation reactions resulted in a dose dependent stimulation of CVB3 IRES-mediated translation. These observations indicate the role of La in CVB3 IRES-mediated translation, and suggest its possible involvement in the efficient translation of the viral RNA in the pancreas

Synchronous multicentric giant cell tumor

Multicentric giant cell tumors represent less than 1% of all giant cell tumors of bones. We report a case of multicentric giant cell tumors around both the knee joints in a mentally and physically challenged adult male that resulted in rapidly progressive painful swelling, restricted mobility and, ultimately, fixed deformity. These tumors had typical radiological appearance and the diagnosis was confirmed on histopathology

Usage Pattern of Glimepiride/Metformin Fixed-dose Combination in Type 2 Diabetes Patients with CVD or at Risk of CVD: An Experience in Indian Setting

Background: Diabetes is associated with almost twofold increased risk of cardiovascular diseases (CVD). The present case-based questionnaire survey evaluated the treatment pattern and clinical experience of healthcare professionals in prescribing glimepiride/metformin fixed-dose combination (FDC) to type 2 diabetes mellitus (T2DM) patients with CVD or those patients who are at risk of CVD in the Indian settings. Material and methods: A retrospective, multicenter, observational, case-based questionnaire survey was conducted in Indian healthcare centers using medical records of patients having T2DM, with CVD or are at risk of CVD, who were prescribed any strength of glimepiride/metformin FDC. Data was collected from the patients’ medical records and was analyzed using statistical tests. Results: A total of 680 patients with T2DM with CVD or at risk of CVD were included in this study. Mean duration of diabetes in the patients was 5.7 ± 4.8 years. About 68.5% patients had hypertension, 47.9% had dyslipidemia, 25.4% had coronary artery disease (CAD), 3.6% had transient ischemic attack (TIA), 4.8% had peripheral arterial disease (PAD) and 2.9% had heart failure. Around 18.1% patients had CVD after diabetes was diagnosed, while 81.9% presented with cardiovascular (CV) issues at the time of diabetes diagnosis. All patients received glimepiride/metformin FDC as first-line therapy. About 68.2% patients on glimepiride/metformin FDC had blood pressure within optimal limits. A large proportion of patients had improvement in glycemic parameters. Weight change was noted in 18.4% of the patients overall. Of these, 59.2% had reduction in weight. There were no major adverse events and treatment efficacy and tolerability were reported as good to excellent for 94.6% and 92.9% patients, respectively. Conclusion: This case-based questionnaire survey demonstrates the usage pattern of various strengths of glimepiride/metformin FDC and the clinicians’ practice approach regarding early initiation of this combination in Indian patients with diabetes who have or are at risk of CVD

Asian Pacific Society of Cardiology Consensus Recommendations on Dyslipidaemia

The prevalence of dyslipidaemia has been increasing in the Asia-Pacific region and this is attributed to dietary changes and decreasing physical activity. While there has been substantial progress in dyslipidaemia therapy, its management in the region is hindered by limitations in awareness, adherence and healthcare costs. The Asian Pacific Society of Cardiology (APSC) developed these consensus recommendations to address the need for a unified approach to managing dyslipidaemia. These recommendations are intended to guide general cardiologists and internists in the assessment and treatment of dyslipidaemia and are hoped to pave the way for improving screening, early diagnosis and treatment. The APSC expert panel reviewed and appraised the evidence using the Grading of Recommendations Assessment, Development, and Evaluation system. Consensus recommendations were developed, which were then put to an online vote. The resulting consensus recommendations tackle contemporary issues in the management of dyslipidaemia, familial hypercholesterolaemia and lipoprotein(a) in the Asia-Pacific region

Inhibition of hepatitis C virus IRES-mediated translation by small RNAs analogous to stem–loop structures of the 5′-untranslated region

Translation of the hepatitis C virus (HCV) RNA is mediated by the interaction of ribosomes and cellular proteins with an internal ribosome entry site (IRES) located within the 5′-untranslated region (5′-UTR). We have investigated whether small RNA molecules corresponding to the different stem–loop (SL) domains of the HCV IRES, when introduced in trans, can bind to the cellular proteins and antagonize their binding to the viral IRES, thereby inhibiting HCV IRES-mediated translation. We have found that a RNA molecule corresponding to SL III could efficiently inhibit HCV IRES-mediated translation in a dose-dependent manner without affecting cap-dependent translation. The SL III RNA was found to bind to most of the cellular proteins which interacted with the HCV 5′-UTR. A smaller RNA corresponding to SL e+f of domain III also strongly and selectively inhibited HCV IRES-mediated translation. This RNA molecule interacted with the ribosomal S5 protein and prevented the recruitment of the 40S ribosomal subunit. This study reveals valuable insights into the role of the SL structures of the HCV IRES in mediating ribosome entry. Finally, these results provide a basis for developing anti-HCV therapy using small RNA molecules mimicking the SL structures of the 5′-UTR to specifically block viral RNA translation

Ribosome-RNA interaction: a potential target for developing antiviral against hepatitis C virus

Hepatitis C virus (HCV), a member of Flaviviridae, encoding a positive-sense single-stranded RNA translates by cap-independent mechanism using the internal ribosome entry site (IRES) present in the 5' UTR of the virus. The IRES has complex stem loop structures and is capable of recruiting the 40S ribosomal subunit in a factor-independent fashion. As the IRES sequence is highly conserved throughout the HCV genotypes and the translation is the first obligatory step of the HCV life cycle, the IRE'S-mediated translation, or more specifically, the ribosome HCV RNA interaction is an attractive target to design effective antivirals. This article will focus on the mechanism of the HCV IRES translation and the various ways in which the interaction of ribosome and IRES has been targeted

A petrogenetic model of basalts from the Northern Central Indian Ridge: 3-11° S

Mid-Ocean Ridge Basalts (MORB) from the Northern Central Indian Ridge (NCIR) were recovered between latitudes 3° and 11° S and are olivine tholeiite with higher abundances of K and Rb. They are of typical transitional MORB (T-MORB) variety and appear to have been generated from an enriched-mantle peridotite source. The primitive NCIR MORBs having #Mg > 0.68 are the product of partial melting at an estimated pressure of ~ 10 kbar. It is inferred that the magma was subsequently modified at a pressure > 10 kbar by crystal fractionation and spinel was the first mineral to crystallize followed by separation of relatively Fe-rich olivine with subsequent decrease in pressure. During progressive fractionation at lower pressure (between 10–5 GPa), the bulk composition of the magma became systematically depleted in MgO, and enriched in total FeOt, TiO2, P2O5 and Na2O. There was, however, limited gradual depletion in Al2O3 and CaO and concomitant enrichment in K2O. With the progressive fractionation these basalts became gradually enriched in V, Co, Y, Zr and to some extent in Sr, and depleted in Ni and Cr. In addition, the total REE of the magma also increased with fractionation, without any change in (La/Yb)N value

P b(P 1) resonance at 40 Hz: Effects of high stimulus rate on auditory middle latency responses (MLRs) explored using deconvolution

In this study, the effects of high stimulus rate on middle latency response (MLR) components P a and P b (P 1 or P50) were studied using high rate clicks in normal hearing awake subjects were investigated. Five jittered click sequences at different mean rates (24.4, 39.1, 58.6, 78.1, 97.7 Hz) were presented to 10 subjects. Overlapping MLRs were deconvolved using the frequency domain continuous loop averaging deconvolution (CLAD) [Özdamar Ö., Bohórquez, J., Signal to noise ratio and frequency analysis of continuous loop averaging deconvolution (CLAD) of overlapping evoked potentials. J. Acoust. Soc. Am., 119:429–438, 2006]. In addition conventional auditory transient MLRs at 4.88 Hz were obtained using conventional averaging. P a amplitude, latency and waveshape remained fairly constant up to 78.1 Hz. P b component, however, showed a variable waveshape with latencies covering a wide range (50–70 ms) and N b–P b amplitudes increasing at 39.1 and 58.6 Hz and decreasing at other rates. Recordings show that both P a and P b MLR components can be consistently recorded at all rates up to 100 Hz. P b amplitude shows an increase at around 40 Hz showing a resonance at that frequency. The dramatic increase of the P b component at around 40 Hz may account for the high amplitude of the 40 Hz ASSR

Two internal ribosome entry sites mediate the translation of p53 isoforms

The p53 tumour suppressor protein has a crucial role in cell-cycle arrest and apoptosis. Previous reports show that the p53 messenger RNA is translated to produce an amino-terminal-deleted isoform (ΔN-p53) from an internal initiation codon, which acts as a dominant-negative inhibitor of full-length p53. Here, we show that two internal ribosome entry sites (IRESs) mediate the translation of both full-length and ΔN-p53 isoforms. The IRES directing the translation of full-length p53 is in the 5′-untranslated region of the mRNA, whereas the IRES mediating the translation of ΔN-p53 extends into the protein-coding region. The two IRESs show distinct cell-cycle phase-dependent activity, with the IRES for full-length p53 being active at the G2–M transition and the IRES for ΔN-p53 showing highest activity at the G1–S transition. These results indicate a novel translational control of p53 gene expression and activity

Human la protein interaction with GCAC near the initiator AUG enhances hepatitis C virus RNA replication by promoting linkage between 5 ` and 3 ` untranslated regions

Human La protein has been implicated in facilitating the internal initiation of translation as well as replication of hepatitis C virus (HCV) RNA. Previously, we demonstrated that La interacts with the HCV internal ribosome entry site (IRES) around the GCAC motif near the initiator AUG within stem-loop IV by its RNA recognition motif (RRM) (residues 112 to 184) and influences HCV translation. In this study, we have deciphered the role of this interaction in HCV replication in a hepatocellular carcinoma cell culture system. We incorporated mutation of the GCAC motif in an HCV monocistronic subgenomic replicon and a pJFH1 construct which altered the binding of La and checked HCV RNA replication by reverse transcriptase PCR (RT-PCR). The mutation drastically affected HCV replication. Furthermore, to address whether the decrease in replication is a consequence of translation inhibition or not, we incorporated the same mutation into a bicistronic replicon and observed a substantial decrease in HCV RNA levels. Interestingly, La overexpression rescued this inhibition of replication. More importantly, we observed that the mutation reduced the association between La and NS5B. The effect of the GCAC mutation on the translation-to-replication switch, which is regulated by the interplay between NS3 and La, was further investigated. Additionally, our analyses of point mutations in the GCAC motif revealed distinct roles of each nucleotide in HCV replication and translation. Finally, we showed that a specific interaction of the GCAC motif with human La protein is crucial for linking 5' and 3' ends of the HCV genome. Taken together, our results demonstrate the mechanism of regulation of HCV replication by interaction of the cis-acting element GCAC within the HCV IRES with human La protein