The first genome sequences of human bocaviruses from Vietnam.

As part of an ongoing effort to generate complete genome sequences of hand, foot and mouth disease-causing enteroviruses directly from clinical specimens, two complete coding sequences and two partial genomic sequences of human bocavirus 1 (n=3) and 2 (n=1) were co-amplified and sequenced, representing the first genome sequences of human bocaviruses from Vietnam. The sequences may aid future study aiming at understanding the evolution of the pathogen

Intrathecal Immunoglobulin for treatment of adult patients with tetanus: A randomized controlled 2x2 factorial trial

Despite long-standing availability of an effective vaccine, tetanus remains a significant problem in many countries. Outcome depends on access to mechanical ventilation and intensive care facilities and in settings where these are limited, mortality remains high. Administration of tetanus antitoxin by the intramuscular route is recommended treatment for tetanus, but as the tetanus toxin acts within the central nervous system, it has been suggested that intrathecal administration of antitoxin may be beneficial. Previous studies have indicated benefit, but with the exception of one small trial no blinded studies have been performed. The objective of this study is to establish whether the addition of intrathecal tetanus antitoxin reduces the need for mechanical ventilation in patients with tetanus. Secondary objectives: to determine whether the addition of intrathecal tetanus antitoxin reduces autonomic nervous system dysfunction and length of hospital/ intensive care unit stay; whether the addition of intrathecal tetanus antitoxin in the treatment of tetanus is safe and cost-effective; to provide data to inform recommendation of human rather than equine antitoxin. This study will enroll adult patients (≥16 years old) with tetanus admitted to the Hospital for Tropical Diseases, Ho Chi Minh City. The study is a 2x2 factorial blinded randomized controlled trial. Eligible patients will be randomized in a 1:1:1:1 manner to the four treatment arms (intrathecal treatment and human intramuscular treatment, intrathecal treatment and equine intramuscular treatment, sham procedure and human intramuscular treatment, sham procedure and equine intramuscular treatment). Primary outcome measure will be requirement for mechanical ventilation. Secondary outcome measures: duration of hospital/ intensive care unit stay, duration of mechanical ventilation, in-hospital and 240-day mortality and disability, new antibiotic prescription, incidence of ventilator associated pneumonia and autonomic nervous system dysfunction, total dose of benzodiazepines and pipecuronium, and incidence of adverse events. Trial registration: ClinicalTrials.gov NCT02999815 Registration date: 21 December 2016

A Model for the Prediction of Fiber Elasticity

A model is presented that enables the elastic properties of wood fibers to be estimated from the properties of its polymeric constituents, cellulose, hemicellulose, and lignin. The influence of the value of the axial stiffness of the cellulose crystal is demonstrated, its proper value being discussed in comparison with experimental data on fibers. The effects on fiber stiffness of the S2 fibril angle, the fibril angles of other layers, the crystallinity, and layer thicknesses are analyzed. The manner in which the effect of a variation in yield can be simulated by a change in shape factor of the reinforcing cellulose crystals is demonstrated, the cell wall thus being considered to be a discontinuous reinforced composite

Profiling of lung microbiota discloses differences in adenocarcinoma and squamous cell carcinoma

The lung is a complex ecosystem of host cells and microbes often disrupted in pathological conditions. Although bacteria have been hypothesized as agents of carcinogenesis, little is known about microbiota profile of the most prevalent cancer subtypes: adenocarcinoma (ADC) and squamous cell carcinoma (SCC). To characterize lung cancer (LC) microbiota a first a screening was performed through a pooled sequencing approach of 16S ribosomal RNA gene (V3-V6) using a total of 103 bronchoalveaolar lavage fluid samples. Then, identified taxa were used to inspect 1009 cases from The Cancer Genome Atlas and to annotate tumor unmapped RNAseq reads. Microbial diversity was analyzed per cancer subtype, history of cigarette smoking and airflow obstruction, among other clinical data. We show that LC microbiota is enriched in Proteobacteria and more diverse in SCC than ADC, particularly in males and heavier smokers. High frequencies of Proteobacteria were found to discriminate a major cluster, further subdivided into well-defined communities’ associated with either ADC or SCC. Here, a SCC subcluster differing from other cases by a worse survival was correlated with several Enterobacteriaceae. Overall, this study provides first evidence for a correlation between lung microbiota and cancer subtype and for its influence on patient life expectancy.We would like to thank all patients for donating their samples and for collaborating in this study. IPATIMUP integrates the i3S Research Unit, which is partially supported by the Portuguese Foundation for Science and Technology (FCT). This work was supported by the Portuguese Foundation for Science and Technology (FCT), financed by the European Social Funds (COMPETE-FEDER) and National Funds through the FCT (projects PEstC/SAU/LA0003/2013 and POCI-01-0145-FEDER-007274, fellowships SFRH/BPD/77646/2011 and SFRH/BPD/120777/2016 to S.G. and P.I.M., respectively, grant PTDC/BEXGMG/0242/2012 to S.S. and by Programa Operacional Regional do Norte (ON.2 – O Novo Norte and Norte 2020), through FEDER funds under the Quadro de Referência Estratégico Nacional (QREN; projects NORTE-07-0162-FEDER-00018 and NORTE-070162-FEDER-000067, and NORTE-01-0145-FEDER-000029)

A hysteretic multiscale formulation for nonlinear dynamic analysis of composite materials

This article has been made available through the Brunel Open Access Publishing Fund.A new multiscale finite element formulation is presented for nonlinear dynamic analysis of heterogeneous structures. The proposed multiscale approach utilizes the hysteretic finite element method to model the microstructure. Using the proposed computational scheme, the micro-basis functions, that are used to map the microdisplacement components to the coarse mesh, are only evaluated once and remain constant throughout the analysis procedure. This is accomplished by treating inelasticity at the micro-elemental level through properly defined hysteretic evolution equations. Two types of imposed boundary conditions are considered for the derivation of the multiscale basis functions, namely the linear and periodic boundary conditions. The validity of the proposed formulation as well as its computational efficiency are verified through illustrative numerical experiments

Hedgehog pathway mutations drive oncogenic transformation in high-risk T-cell acute lymphoblastic leukemia.

The role of Hedgehog signaling in normal and malignant T-cell development is controversial. Recently, Hedgehog pathway mutations have been described in T-ALL, but whether mutational activation of Hedgehog signaling drives T-cell transformation is unknown, hindering the rationale for therapeutic intervention. Here, we show that Hedgehog pathway mutations predict chemotherapy resistance in human T-ALL, and drive oncogenic transformation in a zebrafish model of the disease. We found Hedgehog pathway mutations in 16% of 109 childhood T-ALL cases, most commonly affecting its negative regulator PTCH1. Hedgehog mutations were associated with resistance to induction chemotherapy (P = 0.009). Transduction of wild-type PTCH1 into PTCH1-mutant T-ALL cells induced apoptosis (P = 0.005), a phenotype that was reversed by downstream Hedgehog pathway activation (P = 0.007). Transduction of most mutant PTCH1, SUFU, and GLI alleles into mammalian cells induced aberrant regulation of Hedgehog signaling, indicating that these mutations are pathogenic. Using a CRISPR/Cas9 system for lineage-restricted gene disruption in transgenic zebrafish, we found that ptch1 mutations accelerated the onset of notch1-induced T-ALL (P = 0.0001), and pharmacologic Hedgehog pathway inhibition had therapeutic activity. Thus, Hedgehog-activating mutations are driver oncogenic alterations in high-risk T-ALL, providing a molecular rationale for targeted therapy in this disease

Is the proteome of bronchoalveolar lavage extracellular vesicles a marker of advanced lung cancer?

Acellular bronchoalveolar lavage (BAL) proteomics can partially separate lung cancer from non-lung cancer patients based on principal component analysis and multivariate analysis. Furthermore, the variance in the proteomics data sets is correlated mainly with lung cancer status and, to a lesser extent, smoking status and gender. Despite these advances BAL small and large extracellular vehicles (EVs) proteomes reveal aberrant protein expression in paracrine signaling mechanisms in cancer initiation and progression. We consequently present a case-control study of 24 bronchoalveolar lavage extracellular vesicle samples which were analyzed by state-of-the-art liquid chromatography-mass spectrometry (LC-MS). We obtained evidence that BAL EVs proteome complexity correlated with lung cancer stage 4 and mortality within two years´ follow-up (p value = 0.006). The potential therapeutic target DNMT3B complex is significantly up-regulated in tumor tissue and BAL EVs. The computational analysis of the immune and fibroblast cell markers in EVs suggests that patients who deceased within the follow-up period display higher marker expression indicative of innate immune and fibroblast cells (four out of five cases). This study provides insights into the proteome content of BAL EVs and their correlation to clinical outcomes.R.M. is supported by Fundação para a Ciência e a Tecnologia (CEEC position, 2019–2025 investigator). This article is a result of the projects (iNOVA4Health—UID/Multi/04462/2013), supported by Lisboa Portugal Regional Operational Programme (Lisboa2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). This work is also funded by FEDER funds through the COMPETE 2020 Programme and National Funds through FCT—Portuguese Foundation for Science and Technology under the projects number PTDC/BTM-TEC/30087/2017 and PTDC/BTM-TEC/30088/2017. This work was supported by the Wellcome Trust/DBT India Alliance Margdarshi Fellowship (grant number IA/M/15/1/502023) awarded to A.P. B.C.-S., M.C.S.C. and C.B. are supported by the Champalimaud Foundation and the EMBO Installation Grant 3921

Overexpression of human kynurenine-3-monooxygenase protects against 3-hydroxykynurenine-mediated apoptosis through bidirectional non-linear feedback

Kynurenine 3-monooxygenase (KMO) is a critical regulator of inflammation. The preferred KMO substrate, kynurenine, is converted to 3-hydroxykynurenine (3HK), and this product exhibits cytotoxicity through mechanisms that culminate in apoptosis. Here, we report that overexpression of human KMO with orthotopic localisation to mitochondria creates a metabolic environment during which the cell exhibits increased tolerance for exogenous 3HK-mediated cellular injury. Using the selective KMO inhibitor Ro61-8048, we show that KMO enzyme function is essential for cellular protection. Pan-caspase inhibition with Z-VAD-FMK confirmed apoptosis as the mode of cell death. By defining expression of pathway components upstream and downstream of KMO, we observed alterations in other key kynurenine pathway components, particularly tryptophan-2,3-dioxygenase upregulation, through bidirectional nonlinear feedback. KMO overexpression also increased expression of inducible nitric oxide synthase (iNOS). These changes in gene expression are functionally relevant, because siRNA knockdown of the pathway components kynureninase and quinolinate phosphoribosyl transferase caused cells to revert to a state of susceptibility to 3HK-mediated apoptosis. In summary, KMO overexpression, and importantly KMO activity, have metabolic repercussions that fundamentally affect resistance to cell stress