Spacetime Singularities in String and its Low Dimensional Effective Theory

Spacetime singularities are studied in both the $D+d$-dimensional string theory and its $D$-dimensional effective theory, obtained by the Kaluza-Klein compactification. It is found that spacetime singularities in the low dimensional effective theory may or may not remain after lifted to the $D+d$-dimensional string theory, depending on particular solutions. It is also found that there exist cases in which spacetime singularities appearing in high/low dimensional spacetimes do not necessarily happen on the same surfaces.Comment: revtex4, 15 pages, 10 figures. Typos are corrected. Version to appear in Inter. J. Mod. Phys.

Impact of HuR inhibition by the small molecule MS-444 on colorectal cancer cell tumorigenesis.

Colorectal cancer (CRC) is the third most common cancer and a leading cause of cancer-related mortality. Observed during CRC tumorigenesis is loss of post-transcriptional regulation of tumor-promoting genes such as COX-2, TNFα and VEGF. Overexpression of the RNA-binding protein HuR (ELAVL1) occurs during colon tumorigenesis and is abnormally present within the cytoplasm, where it post-transcriptionally regulates genes through its interaction with 3\u27UTR AU-rich elements (AREs). Here, we examine the therapeutic potential of targeting HuR using MS-444, a small molecule HuR inhibitor. Treatment of CRC cells with MS-444 resulted in growth inhibition and increased apoptotic gene expression, while similar treatment doses in non-transformed intestinal cells had no appreciable effects. Mechanistically, MS-444 disrupted HuR cytoplasmic trafficking and released ARE-mRNAs for localization to P-bodies, but did not affect total HuR expression levels. This resulted in MS-444-mediated inhibition of COX-2 and other ARE-mRNA expression levels. Importantly, MS-444 was well tolerated and inhibited xenograft CRC tumor growth through enhanced apoptosis and decreased angiogenesis upon intraperitoneal administration. In vivo treatment of MS-444 inhibited HuR cytoplasmic localization and decreased COX-2 expression in tumors. These findings provide evidence that therapeutic strategies to target HuR in CRC warrant further investigation in an effort to move this approach to the clinic

Birth prevalence of neural tube defects and orofacial clefts in India: a systematic review and meta-analysis.

BACKGROUND: In the last two decades, India has witnessed a substantial decrease in infant mortality attributed to infectious disease and malnutrition. However, the mortality attributed to birth defects remains constant. Studies on the prevalence of birth defects such as neural tube defects and orofacial clefts in India have reported inconsistent results. Therefore, we conducted a systematic review of observational studies to document the birth prevalence of neural tube defects and orofacial clefts. METHODS: A comprehensive literature search for observational studies was conducted in MEDLINE and EMBASE databases using key MeSH terms (neural tube defects OR cleft lip OR cleft palate AND Prevalence AND India). Two reviewers independently reviewed the retrieved studies, and studies satisfying the eligibility were included. The quality of included studies was assessed using selected criteria from STROBE statement. RESULTS: The overall pooled birth prevalence (random effect) of neural tube defects in India is 4.5 per 1000 total births (95% CI 4.2 to 4.9). The overall pooled birth prevalence (random effect) of orofacial clefts is 1.3 per 1000 total births (95% CI 1.1 to 1.5). Subgroup analyses were performed by region, time period, consanguinity, and gender of newborn. CONCLUSION: The overall prevalence of neural tube defects from India is high compared to other regions of the world, while that of orofacial clefts is similar to other countries. The majority of studies included in the review were hospital based. The quality of these studies ranged from low to moderate. Further well-designed, high quality community-based observational studies are needed to accurately estimate the burden of neural tube defects and orofacial clefts in India

Regulation of HuR structure and function by dihydrotanshinone-I

The Human antigen R protein (HuR) is an RNA-binding protein that recognizes U/AU-rich elements in diverse RNAs through two RNA-recognition motifs, RRM1 and RRM2, and post-transcriptionally regulates the fate of target RNAs. The natural product dihydrotanshinone-I (DHTS) prevents the association of HuR and target RNAs in vitro and in cultured cells by interfering with the binding of HuR to RNA. Here, we report the structural determinants of the interaction between DHTS and HuR and the impact of DHTS on HuR binding to target mRNAs transcriptome-wide. NMR titration and Molecular Dynamics simulation identified the residues within RRM1 and RRM2 responsible for the interaction between DHTS and HuR. RNA Electromobility Shifts and Alpha Screen Assays showed that DHTS interacts with HuR through the same binding regions as target RNAs, stabilizing HuR in a locked conformation that hampers RNA binding competitively. HuR ribonucleoprotein immunoprecipitation followed by microarray (RIP-chip) analysis showed that DHTS treatment of HeLa cells paradoxically enriched HuR binding to mRNAs with longer 3'UTR and with higher density of U/AU-rich elements, suggesting that DHTS inhibits the association of HuR to weaker target mRNAs. In vivo, DHTS potently inhibited xenograft tumor growth in a HuR-dependent model without systemic toxicity

A study on fetomaternal outcome of hypertensive disorders of pregnancy

Background: Hypertensive disorders of pregnancy are one of the most common medical disorders seen during pregnancy. Early diagnosis of hypertensive disorders in pregnancy by regular antenatal checkup can help in proper management, thus decreasing the maternal and fetal complications related it. Ensuring timely and effective care requires appropriate use of evidence-based clinical and nonclinical interventions, strengthened health infrastructure, and motivated and competent health care providers. The objective of this study was to study the feto-maternal outcome of hypertensive disorders of pregnancy and complications related to them. Methods: A study was conducted in the department of obstetrics and gynecology at JJ Group of hospitals, Mumbai, India for a duration of 18 months from January 2020 to June 2021. This study had a sample size of 500 antenatal patients. Necessary information such as their detailed clinical, and obstetric history, clinical examination, investigations was noted. Results: In our study, the incidence of hypertensive disorders of pregnancy was 10.2%, being most common in age group of 21-25 years (45.1%) and Primigravida patients (47.1%). The most common type of hypertensive disorder in our study was non severe preeclampsia with incidence of 74.50%. The most common complication was oligohydramnios (11.76%), followed by preterm delivery (9.80%) and IUGR (9.80%). The most common drug used in the management of hypertensive disorder was lobetalol. Most common neonatal complication in PIH group was low birth weight, followed by fetal distress (19.6%), prematurity (9.8%) and IUGR (9.8%). Conclusions: Hypertensive disorders of pregnancy are one of the medical conditions affecting pregnancy. Hypertensive disorders of pregnancy are more prevalent in younger and nulliparous mothers. Early diagnosis and appropriate timely management of hypertensive disorders in pregnant women can prevent the maternal and fetal complications and improve the outcome of pregnancy. These women should be monitored carefully to prevent maternal morbidity and mortality

A study on lactate dehydrogenase levels in hypertensive disorders of pregnancy and its correlation with feto-maternal outcome

Background: Hypertensive disorders of pregnancy are one of the most common medical disorders seen during pregnancy. Lactate dehydrogenase (LDH) is an intracellular enzyme. The objective of this study was to compare lactate dehydrogenase levels in women with hypertensive disorders of pregnancy and normal pregnant women, to correlate lactate dehydrogenase levels with complications of hypertensive disorders of pregnancy and role of lactate dehydrogenase as an early predictor of hypertensive disorders of pregnancy. Methods: A study was conducted in the department of obstetrics and gynecology at JJ group of hospitals, Mumbai, India for a duration of 18 months from January 2020 to June 2021. This study has a sample size of 500 antenatal patients. Necessary information such as their detailed clinical, and obstetric history, clinical examination, investigations was noted. LDH were measured at 12-16 weeks of pregnancy and at the time of delivery. Results: In our study, the incidence of hypertensive disorders of pregnancy was 10.2% There was no association between LDH levels at 12-16 weeks of gestation and development of hypertensive disorders of pregnancy. There was association between levels of lactate dehydrogenase levels at time of delivery and severity of hypertensive disorders in our study. Higher serum LDH levels were associated with increased incidence of maternal and fetal complications like abruption placenta, HELLP syndrome, IUGR, IUFD, prematurity and oligohydramnios in our study. Conclusions: Hypertensive disorders of pregnancy are one of the medical conditions affecting pregnancy. Lactate dehydrogenase levels at 12-16 weeks of gestation is not early predictor of hypertensive disorders of pregnancy. Serum lactate dehydrogenase levels at time of delivery helps in prediction of severity of disease, adverse outcomes and complications of hypertensive disorders of pregnancy. Hence lactate dehydrogenase acts as prognostic factor in hypertensive disorders of pregnancy

Quantifying dissipation in stochastic complex oscillations

Fluctuations-driven complex oscillations are experimentally observed in cellular systems such as hepatocytes, cardiac cells, neuronal cells, etc. These systems are generally operating in regimes far from thermodynamic equilibrium. To study nonequilibrium thermodynamic properties such as energy dissipation in stochastic complex oscillations, we consider stochastic modeling of two nonlinear biological oscillators, namely, the intracellular calcium (Ca$^{2+}$) oscillation model and the Hindmarsh-Rose model for neuronal dynamics. These models exhibit various types of complex oscillations like bursting and quasi-periodic oscillations for various system parameter values. In this work, we formulate open chemical reaction schemes for the two model systems driving the systems far from thermodynamic equilibrium. We then analyze the steady-state total entropy production rate (EPR) in the various types of stochastic complex oscillations. Our results show higher values of steady-state total EPR in stochastic complex oscillations than simple periodic oscillations. Moreover, in the Hindmarsh-Rose neuronal model, we observe an order-to-disorder transition from periodic (organized) bursts of spikes to chaotic (unorganized) oscillations with distinct behaviors of steady-state total EPR. Our results reveal that stochastic complex oscillations are produced at the cost of higher energy consumption and that it requires a higher thermodynamic cost to maintain the periodic bursts than chaotic oscillations. Our findings indicate that complex cellular regulatory or signaling processes by Ca$^{2+}$ that help perform complex tasks of the nervous system or rich information coding by neurons involve a higher thermodynamic cost. The results deepen our understanding of energy dissipation in nonlinear, nonequilibrium biological systems with stochastic complex oscillatory dynamics

ZikaPLAN: addressing the knowledge gaps and working towards a research preparedness network in the Americas.

Zika Preparedness Latin American Network (ZikaPLAN) is a research consortium funded by the European Commission to address the research gaps in combating Zika and to establish a sustainable network with research capacity building in the Americas. Here we present a report on ZikaPLAN`s mid-term achievements since its initiation in October 2016 to June 2019, illustrating the research objectives of the 15 work packages ranging from virology, diagnostics, entomology and vector control, modelling to clinical cohort studies in pregnant women and neonates, as well as studies on the neurological complications of Zika infections in adolescents and adults. For example, the Neuroviruses Emerging in the Americas Study (NEAS) has set up more than 10 clinical sites in Colombia. Through the Butantan Phase 3 dengue vaccine trial, we have access to samples of 17,000 subjects in 14 different geographic locations in Brazil. To address the lack of access to clinical samples for diagnostic evaluation, ZikaPLAN set up a network of quality sites with access to well-characterized clinical specimens and capacity for independent evaluations. The International Committee for Congenital Anomaly Surveillance Tools was formed with global representation from regional networks conducting birth defects surveillance. We have collated a comprehensive inventory of resources and tools for birth defects surveillance, and developed an App for low resource regions facilitating the coding and description of all major externally visible congenital anomalies including congenital Zika syndrome. Research Capacity Network (REDe) is a shared and open resource centre where researchers and health workers can access tools, resources and support, enabling better and more research in the region. Addressing the gap in research capacity in LMICs is pivotal in ensuring broad-based systems to be prepared for the next outbreak. Our shared and open research space through REDe will be used to maximize the transfer of research into practice by summarizing the research output and by hosting the tools, resources, guidance and recommendations generated by these studies. Leveraging on the research from this consortium, we are working towards a research preparedness network

An experimental study on wistar rats to see the effect of Gymnema sylvestre on blood pressure

Background: Hypertension is a leading cause of morbidity and mortality globally. It is a well-known risk factor for an array of adverse cardiovascular outcomes. Obesity is considered as one of the major contributing factors to essential hypertension in humans. Obesity in itself is a risk factor for conditions like insulin resistance, hypertension, stroke, ischemic heart diseases, CHF etc. Undoubtedly in recent times we have achieved great advances in terms of management of hypertension but still we have miles to cover to have dominance over it. Gymnema sylvestre is a valuable indigenous herb. A number of animal and human studies have shown the potential role of Gymnema sylvestre (GS) as an anti-diabetic and anti-obesity agent.Methods: Adult Female Wistar rats, weighing between 150-200 gm, were included in the study. They were randomly divided into five groups with six rats in each group. High Fat Diet (HFD) was given for 4 weeks to induce hypertension in all the groups except group I which was fed with normal chow. Drugs along with respective diets were given to the rats for next 4 weeks by oral feeding cannula. Systolic blood pressure was measured by NIBP controller machine.Results: On feeding rats with HFD for 4 weeks the mean systolic blood pressure increased significantly. After giving drugs GS (100mg/kg), GS (200mg/kg) and Amlodipine (10mg/kg) to groups III, IV, V respectively for next 4 weeks, mean systolic blood pressure fell significantly (p <0.05) as compared to group II (HFD control group). At final evaluation at week 8 (as compared to Group 2) SBP got maximally reduced in Group 5 (35.1%) followed by Group 4 (26.4%), Group 3 (20.1%). On comparing Amlodipine standard (group 5) with other groups, a significant difference was found. This showed that Gymnema sylvestre reduced the elevated systolic blood pressure significantly but this anti-hypertensive effect was inferior to Amlodipine.Conclusions: The present study concludes that Gymnema sylvestre has a potent dose- dependent antihypertensive action but the effect is inferior to Amlodipine. Hence it can be used as an add-on to standard drugs for hypertension