The State of the Circumstellar Medium Surrounding Gamma-Ray Burst Sources and its Effect on the Afterglow Appearance

We present a numerical investigation of the contribution of the presupernova ejecta of Wolf-Rayet stars to the environment surrounding gamma-ray bursts (GRBs), and describe how this external matter can affect the observable afterglow characteristics. An implicit hydrodynamic calculation for massive stellar evolution is used here to provide the inner boundary conditions for an explicit hydrodynamical code to model the circumstellar gas dynamics. The resulting properties of the circumstellar medium are then used to calculate the deceleration of a relativistic, gas-dynamic jet and the corresponding afterglow light curve produced as the shock wave propagates through the shocked-wind medium. We find that variations in the stellar wind drive instabilities that may produce radial filaments in the shocked-wind region. These comet-like tails of clumps could give rise to strong temporal variations in the early afterglow lightcurve. Afterglows may be expected to differ widely among themselves, depending on the angular anisotropy of the jet and the properties of the stellar progenitor; a wide diversity of behaviors may be the rule, rather than the exception.Comment: 17 pages, 7 figures, ApJ in pres

Ultrasound assisted one-pot synthesis of benzo-fused indole-4, 9-dinones from 1,4-naphthoquinone and α-aminoacetals

A one-pot synthesis of benzo[f]indole-4,9-diones from 1,4-naphthoquinone with α-aminoacetals has been developed. This method provides a straightforward synthesis of benzo[f]indole-4,9-diones via intramolecular nucleophilic attack of aminoquinones to aldehydes under mild reaction conditions. The detailed mechanism was also investigated

Considerations on equity in management of end-stage kidney disease in low- and middle-income countries

Achievement of equity in health requires development of a health system in which everyone has a fair opportunity to attain their full health potential. The current, large country-level variation in the reported incidence and prevalence of treated end-stage kidney disease indicates the existence of system-level inequities. Equitable implementation of kidney replacement therapy (KRT) programs must address issues of availability, affordability, and acceptability. The major structural factors that impact equity in KRT in different countries are the organization of health systems, overall health care spending, funding and delivery models, and nature of KRT prioritization (transplantation, hemodialysis or peritoneal dialysis, and conservative care). Implementation of KRT programs has the potential to exacerbate inequity unless equity is deliberately addressed. In this review, we summarize discussions on equitable provision of KRT in low- and middle-income countries and suggest areas for future research

Aberrant upregulation of the glycolytic enzyme PFKFB3 in CLN7 neuronal ceroid lipofuscinosis

CLN7 neuronal ceroid lipofuscinosis is an inherited lysosomal storage neurodegenerative disease highly prevalent in children. CLN7/MFSD8 gene encodes a lysosomal membrane glycoprotein, but the biochemical processes affected by CLN7-loss of function are unexplored thus preventing development of potential treatments. Here, we found, in the Cln7∆ex2 mouse model of CLN7 disease, that failure in autophagy causes accumulation of structurally and bioenergetically impaired neuronal mitochondria. In vivo genetic approach reveals elevated mitochondrial reactive oxygen species (mROS) in Cln7∆ex2 neurons that mediates glycolytic enzyme PFKFB3 activation and contributes to CLN7 pathogenesis. Mechanistically, mROS sustains a signaling cascade leading to protein stabilization of PFKFB3, normally unstable in healthy neurons. Administration of the highly selective PFKFB3 inhibitor AZ67 in Cln7∆ex2 mouse brain in vivo and in CLN7 patients-derived cells rectifies key disease hallmarks. Thus, aberrant upregulation of the glycolytic enzyme PFKFB3 in neurons may contribute to CLN7 pathogenesis and targeting PFKFB3 could alleviate this and other lysosomal storage diseases

Taxane-Platin-Resistant Lung Cancers Co-develop Hypersensitivity to JumonjiC Demethylase Inhibitors

Although non-small cell lung cancer (NSCLC) patients benefit from standard taxane-platin chemotherapy, many relapse, developing drug resistance. We established preclinical taxane-platin-chemoresistance models and identified a 35-gene resistance signature, which was associated with poor recurrence-free survival in neoadjuvant-treated NSCLC patients and included upregulation of the JumonjiC lysine demethylase KDM3B. In fact, multi-drug-resistant cells progressively increased the expression of many JumonjiC demethylases, had altered histone methylation, and, importantly, showed hypersensitivity to JumonjiC inhibitors in vitro and in vivo. Increasing taxane-platin resistance in progressive cell line series was accompanied by progressive sensitization to JIB-04 and GSK-J4. These JumonjiC inhibitors partly reversed deregulated transcriptional programs, prevented the emergence of drug-tolerant colonies from chemo-naive cells, and synergized with standard chemotherapy in vitro and in vivo. Our findings reveal JumonjiC inhibitors as promising therapies for targeting taxane-platin-chemoresistant NSCLCs.Fil: Dalvi, Maithili P.. University of Texas. Southwestern Medical Center; Estados UnidosFil: Wang, Lei. University of Texas. Southwestern Medical Center; Estados UnidosFil: Zhong, Rui. University of Texas. Southwestern Medical Center; Estados UnidosFil: Kollipara, Rahul K.. University of Texas. Southwestern Medical Center; Estados UnidosFil: Park, Hyunsil. University of Texas. Southwestern Medical Center; Estados UnidosFil: Bayo Fina, Juan Miguel. University of Texas. Southwestern Medical Center; Estados Unidos. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; ArgentinaFil: Yenerall, Paul. University of Texas. Southwestern Medical Center; Estados UnidosFil: Zhou, Yunyun. University of Texas. Southwestern Medical Center; Estados UnidosFil: Timmons, Brenda C.. University of Texas. Southwestern Medical Center; Estados UnidosFil: Rodriguez Canales, Jaime. University of Texas; Estados UnidosFil: Behrens, Carmen. Md Anderson Cancer Center; Estados UnidosFil: Mino, Barbara. University of Texas; Estados UnidosFil: Villalobos, Pamela. University of Texas; Estados UnidosFil: Parra, Edwin R.. University of Texas; Estados UnidosFil: Suraokar, Milind. University of Texas; Estados UnidosFil: Pataer, Apar. University of Texas; Estados UnidosFil: Swisher, Stephen G.. University of Texas; Estados UnidosFil: Kalhor, Neda. University of Texas; Estados UnidosFil: Bhanu, Natarajan V.. University of Pennsylvania; Estados UnidosFil: Garcia, Benjamin A.. University of Pennsylvania; Estados UnidosFil: Heymach, John V.. University of Texas; Estados UnidosFil: Coombes, Kevin. University of Texas; Estados UnidosFil: Xie, Yang. University of Texas. Southwestern Medical Center; Estados UnidosFil: Girard, Luc. University of Texas. Southwestern Medical Center; Estados UnidosFil: Gazdar, Adi F.. University of Texas. Southwestern Medical Center; Estados UnidosFil: Kittler, Ralf. University of Texas. Southwestern Medical Center; Estados UnidosFil: Wistuba, Ignacio I.. University of Texas; Estados UnidosFil: Minna, John D.. University of Texas. Southwestern Medical Center; Estados UnidosFil: Martinez, Elisabeth D.. University of Texas. Southwestern Medical Center; Estados Unido

Genetically inferred birthweight, height, and puberty timing and risk of osteosarcoma

INTRODUCTION: Several studies have linked increased risk of osteosarcoma with tall stature, high birthweight, and early puberty, although evidence is inconsistent. We used genetic risk scores (GRS) based on established genetic loci for these traits and evaluated associations between genetically inferred birthweight, height, and puberty timing with osteosarcoma. METHODS: Using genotype data from two genome-wide association studies, totaling 1039 cases and 2923 controls of European ancestry, association analyses were conducted using logistic regression for each study and meta-analyzed to estimate pooled odds ratios (ORs) and 95% confidence intervals (CIs). Subgroup analyses were conducted by case diagnosis age, metastasis status, tumor location, tumor histology, and presence of a known pathogenic variant in a cancer susceptibility gene. RESULTS: Genetically inferred higher birthweight was associated with an increased risk of osteosarcoma (OR =1.59, 95% CI 1.07-2.38, P = 0.02). This association was strongest in cases without metastatic disease (OR =2.46, 95% CI 1.44-4.19, P = 9.5 ×10-04). Although there was no overall association between osteosarcoma and genetically inferred taller stature (OR=1.06, 95% CI 0.96-1.17, P = 0.28), the GRS for taller stature was associated with an increased risk of osteosarcoma in 154 cases with a known pathogenic cancer susceptibility gene variant (OR=1.29, 95% CI 1.03-1.63, P = 0.03). There were no significant associations between the GRS for puberty timing and osteosarcoma. CONCLUSION: A genetic propensity to higher birthweight was associated with increased osteosarcoma risk, suggesting that shared genetic factors or biological pathways that affect birthweight may contribute to osteosarcoma pathogenesis

A Statistical Model for Estimating Maternal-Zygotic Interactions and Parent-of-Origin Effects of QTLs for Seed Development

Proper development of a seed requires coordinated exchanges of signals among the three components that develop side by side in the seed. One of these is the maternal integument that encloses the other two zygotic components, i.e., the diploid embryo and its nurturing annex, the triploid endosperm. Although the formation of the embryo and endosperm contains the contributions of both maternal and paternal parents, maternally and paternally derived alleles may be expressed differently, leading to a so-called parent-of-origin or imprinting effect. Currently, the nature of how genes from the maternal and zygotic genomes interact to affect seed development remains largely unknown. Here, we present a novel statistical model for estimating the main and interaction effects of quantitative trait loci (QTLs) that are derived from different genomes and further testing the imprinting effects of these QTLs on seed development. The experimental design used is based on reciprocal backcrosses toward both parents, so that the inheritance of parent-specific alleles could be traced. The computing model and algorithm were implemented with the maximum likelihood approach. The new strategy presented was applied to study the mode of inheritance for QTLs that control endoreduplication traits in maize endosperm. Monte Carlo simulation studies were performed to investigate the statistical properties of the new model with the data simulated under different imprinting degrees. The false positive rate of imprinting QTL discovery by the model was examined by analyzing the simulated data that contain no imprinting QTL. The reciprocal design and a series of analytical and testing strategies proposed provide a standard procedure for genomic mapping of QTLs involved in the genetic control of complex seed development traits in flowering plants

Smoking and alcohol by HPV status in head and neck cancer : A Mendelian Randomization Study

Peer reviewe

Early acquisition and high nasopharyngeal co-colonisation by Streptococcus pneumoniae and three respiratory pathogens amongst Gambian new-borns and infants

BACKGROUND: Although Haemophilus influenzae type b (Hib), Staphylococcus aureus and Moraxella catarrhalis are important causes of invasive and mucosal bacterial disease among children, co-carriage with Streptococcus pneumoniae during infancy has not been determined in West Africa. METHODS: Species specific PCR was applied to detect each microbe using purified genomic DNA from 498 nasopharyngeal (NP) swabs collected from 30 Gambian neonates every two weeks from 0 to 6 months and bi-monthly up to 12 months. RESULTS: All infants carried S. pneumoniae, H. influenzae and M. catarrhalis at several time points during infancy. S.pneumoniae co-colonized the infant nasopharynx with at least one other pathogen nine out of ten times. There was early colonization of the newborns and neonates, the average times to first detection were 5, 7, 3 and 14 weeks for S. pneumoniae, H. influenzae, M. catarrhalis and S. aureus respectively. The prevalence of S. pneumoniae, H. influenzae and M. catarrhalis increased among the neonates and exceeded 80% by 13, 15 and 23 weeks respectively. In contrast, the prevalence of S. aureus decreased from 50% among the newborns to 20% amongst nine-week old neonates. S. pneumoniae appeared to have a strong positive association with H. influenzae (OR 5.03; 95% CI 3.02, 8.39; p<0.01) and M. catarrhalis (OR 2.20; 95% CI 1.29; p<0.01) but it was negatively associated with S. aureus (OR 0.53; 95% CI 0.30, 0.94; p=0.03). CONCLUSION: This study shows early acquisition and high co-carriage of three important respiratory pathogens with S. pneumoniae in the nasopharyngeal mucosa among Gambian neonates and infants. This has important potential implications for the aetiology of respiratory polymicrobial infections, biofilm formation and vaccine strategies