Comments on a class of orthogonality relations relevant to fluid-structure interaction

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Reconstructing historic Glacial Lake Outburst Floods through numerical modelling and geomorphological assessment:Extreme events in the Himalaya

Recession of high‐mountain glaciers in response to climatic change frequently results in the development of moraine‐dammed glacial lakes. Moraine dam failure is often accompanied by the release of large volumes of water and sediment, termed a Glacial Lake Outburst Flood (GLOF). Chukhung Glacier is a small (~3 km2) receding valley glacier in Mt. Everest (Sagarmatha) National Park, Nepal. Unlike many Himalayan glaciers, which possess a thick mantle of supraglacial debris, its surface is relatively clean. The glacier terminus has receded 1.3 km from its maximum Holocene position, and in doing so provided the space for an ice‐contact moraine‐dammed lake to develop. The lake had a maximum volume of 5.5 × 105 m3 and drained as a result of breaching of the terminal moraine. An estimated 1.3 × 105 m3 of material was removed from the terminal moraine during breach development. Numerical dam‐breach modelling, implemented within a Generalised Likelihood Uncertainty Estimation (GLUE) framework, was used to investigate a range of moraine‐dam failure scenarios. Reconstructed outflow peak discharges, including failure via overtopping and piping mechanisms, are in the range 146–2200 m3 s‐1. Results from two‐dimensional hydrodynamic GLOF modelling indicate that maximum local flow depths may have exceeded 9 m, with maximum flow velocities exceeding 20 m s‐1 within 700 m of the breach. The floodwaters mobilised a significant amount of material, sourced mostly from the expanding breach, forming a 300 m long and 100 m wide debris fan originating at the breach exit. moraine‐dam. These results also suggest that inundation of the entire floodplain may have been achieved within ten minutes of initial breach development, suggesting that debris fan development was rapid. We discuss the key glaciological and geomorphological factors that have determined the evolution of a hazardous moraine‐dammed lake complex and the subsequent generation of a GLOF and its geomorphological impact

Head and neck cancer predictive risk estimator to determine control and therapeutic outcomes of radiotherapy (HNC-PREDICTOR):development, international multi-institutional validation, and web implementation of clinic-ready model-based risk stratification for head and neck cancer

Background: Personalised radiotherapy can improve treatment outcomes of patients with head and neck cancer (HNC), where currently a ‘one-dose-fits-all’ approach is the standard. The aim was to establish individualised outcome prediction based on multi-institutional international ‘big-data’ to facilitate risk-based stratification of patients with HNC. Methods: The data of 4611 HNC radiotherapy patients from three academic cancer centres were split into four cohorts: a training (n = 2241), independent test (n = 786), and external validation cohorts 1 (n = 1087) and 2 (n = 497). Tumour- and patient-related clinical variables were considered in a machine learning pipeline to predict overall survival (primary end-point) and local and regional tumour control (secondary end-points); serially, imaging features were considered for optional model improvement. Finally, patients were stratified into high-, intermediate-, and low-risk groups. Results: Performance score, AJCC8th stage, pack-years, and Age were identified as predictors for overall survival, demonstrating good performance in both the training cohort (c-index = 0.72 [95% CI, 0.66–0.77]) and in all three validation cohorts (c-indices: 0.76 [0.69–0.83], 0.73 [0.68–0.77], and 0.75 [0.68–0.80]). Excellent stratification of patients with HNC into high, intermediate, and low mortality risk was achieved; with 5-year overall survival rates of 17–46% for the high-risk group compared to 92–98% for the low-risk group. The addition of morphological image feature further improved the performance (c-index = 0.73 [0.64–0.81]). These models are integrated in a clinic-ready interactive web interface: https://uic-evl.github.io/hnc-predictor/ Conclusions: Robust model-based prediction was able to stratify patients with HNC in distinct high, intermediate, and low mortality risk groups. This can effectively be capitalised for personalised radiotherapy, e.g., for tumour radiation dose escalation/de-escalation

Expression and analysis of the glycosylation properties of recombinant human erythropoietin expressed in Pichia pastoris

The Pichia pastoris expression system was used to produce recombinant human erythropoietin, a protein synthesized by the adult kidney and responsible for the regulation of red blood cell production. The entire recombinant human erythropoietin (rhEPO) gene was constructed using the Splicing by Overlap Extension by PCR (SOE-PCR) technique, cloned and expressed through the secretory pathway of the Pichia expression system. Recombinant erythropoietin was successfully expressed in P. pastoris. The estimated molecular mass of the expressed protein ranged from 32 kDa to 75 kDa, with the variation in size being attributed to the presence of rhEPO glycosylation analogs. A crude functional analysis of the soluble proteins showed that all of the forms were active in vivo

The Glu27 genotypes of the Beta2-adrenergic receptor are predictors for severe coronary artery disease

BACKGROUND: The role of the Beta2-adrenoceptor (beta2-AR) Gln27Glu polymorphism in the manifestation of cardiovascular diseases is still unclear. METHODS: In the present study, we evaluated the potential relevance of the c.79 C>G (p.Gln27Glu) polymorphism of this receptor gene for coronary artery disease (CAD) and its associated risk factors in Saudi Arabs. Genotyping was performed by PCR using the confronting two-pair primer (PCR-CTPP) method. RESULTS: In the general population group (BD) (n = 895), 68.5% were homozygous wild-type C/C, 28.3% were heterozygous C/G and 3.2% were homozygous mutant G/G. Among the CAD patients (n = 773), 50.6% were homozygous wild-type C/C, 43.6% were heterozygous C/G and 5.8% were homozygous mutant G/G, while in the angiographed control group (CON) (n = 528), 71.8% were C/C, 24.4% C/G and 3.8% G/G genotypes. These results indicate that both the C/G (p = < .001) and G/G (p = .005) genotypes are significantly associated with CAD, when compared to the CON group. In addition, C/G (p = < .001) and G/G (p = < .001) were significantly associated with CAD, when compared to the BD group. Furthermore, stepwise logistic regression showed that the genotype [C/G (p < .001) and G/G (p < .001)] increase the risk of CAD. CONCLUSION: These results shows that the Gln27Glu genotypes (homo- or heterozygous) of the beta2-AR may be independent predictors of severe CAD

The Rift Valley fever accessory proteins NSm and P78/NSm-GN are distinct determinants of virus propagation in vertebrate and invertebrate hosts.: Role of NSm-related proteins in RVFV infection

International audienceRift Valley fever virus (RVFV) is an enzootic virus circulating in Africa that is transmitted to its vertebrate host by a mosquito vector and causes severe clinical manifestations in humans and ruminants. RVFV has a tripartite genome of negative or ambisense polarity. The M segment contains five in-frame AUG codons that are alternatively used for the synthesis of two major structural glycoproteins, GN and GC, and at least two accessory proteins, NSm, a 14-kDa cytosolic protein, and P78/NSm-GN, a 78-kDa glycoprotein. To determine the relative contribution of P78 and NSm to RVFV infectivity, AUG codons were knocked out to generate mutant viruses expressing various sets of the M-encoded proteins. We found that, in the absence of the second AUG codon used to express NSm, a 13-kDa protein corresponding to an N-terminally truncated form of NSm, named NSm', was synthesized from AUG 3. None of the individual accessory proteins had any significant impact on RVFV virulence in mice. However, a mutant virus lacking both NSm and NSm' was strongly attenuated in mice and grew to reduced titers in murine macrophages, a major target cell type of RVFV. In contrast, P78 was not associated with reduced viral virulence in mice, yet it appeared as a major determinant of virus dissemination in mosquitoes. This study demonstrates how related accessory proteins differentially contribute to RVFV propagation in mammalian and arthropod hosts

Hypoxia Disruption of Vertebrate CNS Pathfinding through EphrinB2 Is Rescued by Magnesium

The mechanisms of hypoxic injury to the developing human brain are poorly understood, despite being a major cause of chronic neurodevelopmental impairments. Recent work in the invertebrate Caenorhabditis elegans has shown that hypoxia causes discrete axon pathfinding errors in certain interneurons and motorneurons. However, it is unknown whether developmental hypoxia would have similar effects in a vertebrate nervous system. We have found that developmental hypoxic injury disrupts pathfinding of forebrain neurons in zebrafish (Danio rerio), leading to errors in which commissural axons fail to cross the midline. The pathfinding defects result from activation of the hypoxia-inducible transcription factor (hif1) pathway and are mimicked by chemical inducers of the hif1 pathway or by expression of constitutively active hif1α. Further, we found that blocking transcriptional activation by hif1α helped prevent the guidance defects. We identified ephrinB2a as a target of hif1 pathway activation, showed that knock-down of ephrinB2a rescued the guidance errors, and showed that the receptor ephA4a is expressed in a pattern complementary to the misrouting axons. By targeting a constitutively active form of ephrinB2a to specific neurons, we found that ephrinB2a mediates the pathfinding errors via a reverse-signaling mechanism. Finally, magnesium sulfate, used to improve neurodevelopmental outcomes in preterm births, protects against pathfinding errors by preventing upregulation of ephrinB2a. These results demonstrate that evolutionarily conserved genetic pathways regulate connectivity changes in the CNS in response to hypoxia, and they support a potential neuroprotective role for magnesium