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JPhys energy 5(2), 021501 (2023). doi:10.1088/2515-7655/acaa57, Published by IOP Publishing, Bristol

Language and culture play a critical role in international commercial relations. Since the 19th century, the English language has undeniably held the prominent position as the global lingua franca to facilitate communication between nations. However, China’s contemporary re-emergence as an economic superpower has expanded its global influence. Consequently, awareness of Chinese culture and language is becoming important not only globally, but also in the Caribbean, where China’s economic footprint has expanded considerably in recent years. This article conceptually explores the important role of language and culture within the growing Sino-Caribbean commercial relationship. Specifically, it discusses the potential impact of language on the trade and tourism sectors, which are two key industries that drive the economies of English-speaking Caribbean small island developing states. It does this by charting the development of the English and Chinese languages as dominant languages. It then briefly looks at the current level of Chinese engagement with the region in trade and, more contemporarily, the potential of greater Chinese tourism in the Caribbean. It discusses the value of deeper cultural and linguistic understanding in nurturing and expanding these relationships. Finally, the article concludes by providing meaningful recommendations on ways to mitigate cultural and linguistic barriers in order to promote deeper Sino-Caribbean trade and tourism.

Guanylate cyclase 2C (GC‐C), encoded by the GUCY2C gene, is implicated in hereditary early onset chronic diarrhea. Several families with chronic diarrhea symptoms have been identified with autosomal dominant, gain‐of‐function mutations in GUCY2C. We have identified a Mennonite patient with a novel GUCY2C variant (c.2381A > T; p.Asp794Val) with chronic diarrhea and an extensive maternal family history of chronic diarrhea and bowel dilatation. Functional studies including co‐segregation analysis showed that all family members who were heterozygous for this variant had GI‐related symptoms. HEK‐293 T cells expressing the Asp794Val GC‐C variant showed increased cGMP production when stimulated with Escherichia coli heat‐stable enterotoxin STp (HST), which was reversed when 5‐(3‐Bromophenyl)‐5,11‐dihydro‐1,3‐dimethyl‐1H‐indeno[2′,1′:5,6]pyrido[2,3‐d]pyrimidine‐2,4,6(3H)‐trione (BPIPP; a GC‐C inhibitor) was used. In addition, cystic fibrosis transmembrane conductance regulator (CFTR) activity measured with SPQ fluorescence assay was increased in these cells after treatment with HST, indicating a crucial role for CFTR activity in the pathogenesis of this disorder. These results support pathogenicity of the GC‐C Asp794Val variant as a cause of chronic diarrhea in this family. Furthermore, this work identifies potential candidate drug, GC‐C inhibitor BPIPP, to treat diarrhea caused by this syndrome.

The authors report the occurrence of pulsus alternans, a condition characterised by the alternance of pulses of higher and lower amplitude, in two dogs and one cat under general anaesthesia. The presence of an underlying cardiac disease was confirmed in the cat but not in either dog, which - based on history and clinical findings - had presumably normal cardiovascular function before the anaesthetic. Possible mechanisms, including negative inotropy and haemodynamic and Frank-Starling effects, as well as the role of general anaesthesia as the potential triggering factor, are discussed in this report. Ephedrine resulted in the successful treatment of pulsus alternans, as demonstrated by the return of normal pulse and synchronisation of heart and pulse rates in the cat and in one dog. In the other dog, pulse pattern and frequency returned to normal once the guidewire for central line placement was withdrawn.

Prader-Willi (PWS) and Angelman (AS) syndromes are two clinically distinct imprinted disorders characterized by genetic abnormalities at 15q11-q13. Early diagnosis of both syndromes provides improved treatment and accurate genetic counseling. Whole blood (WB) is the most common DNA source of many methodologies to detect PWS and AS, however, the need of WB makes a massive screening difficult in newborns due to economic and technical limitations. The aim of this study was to adapt a Methylation-sensitive High-Resolution Melting (MS-HRM) approach from dried blood spot (DBS) samples, assessing the different DNA isolation techniques and diagnostic performance. Over a 1-year period, we collected 125 DBS cards, of which 45 had already been diagnosed by MS-HRM (20 PWS, 1 AS, and 24 healthy individuals). We tested three different DBS-DNA extraction techniques assessing the DNA concentration and quality, followed by MS-HRM and statistical comparison. Each DBS-DNA extraction method was capable of accuracy in detecting all PWS and AS individuals. However, the efficiency to detect healthy individuals varied according to methodology. In our experience, DNA extracted from DBS analyzed by the MS-HRM methodology provides an accurate approach for genetic screening of imprinting related disorders in newborns, offering several benefits compared to traditional whole blood methods.

Scanning Transmission Electron Microscopy (STEM) offers high-resolution images that are used to quantify the nanoscale atomic structure and composition of materials and biological specimens. In many cases, however, the resolution is limited by the electron beam damage, since in traditional STEM, a focused electron beam scans every location of the sample in a raster fashion. In this paper, we propose a scanning method based on the theory of Compressive Sensing (CS) and subsampling the electron probe locations using a line hop sampling scheme that significantly reduces the electron beam damage. We experimentally validate the feasibility of the proposed method by acquiring real CS-STEM data, and recovering images using a Bayesian dictionary learning approach. We support the proposed method by applying a series of masks to fully-sampled STEM data to simulate the expectation of real CS-STEM. Finally, we perform the real data experimental series using a constrained-dose budget to limit the impact of electron dose upon the results, by ensuring that the total electron count remains constant for each image., Comment: submitted to ICASSP 2022

Prader-Willi syndrome (PWS) is a multisystem disorder with neurobehavioral, metabolic, and hormonal phenotypes, caused by loss of expression of a paternally-expressed imprinted gene cluster. Prior evidence from a PWS mouse model identified abnormal pancreatic islet development with retention of aged insulin and deficient insulin secretion. To determine the collective roles of PWS genes in β-cell biology, we used genome-editing to generate isogenic, clonal INS-1 insulinoma lines having 3.16 Mb deletions of the silent, maternal (control) or active, paternal PWS-alleles. PWS β-cells demonstrated a significant cell-autonomous reduction in basal and glucose-stimulated insulin secretion. Further, proteomic analyses revealed reduced levels of cellular and secreted hormones, including all insulin peptides and amylin, concomitant with reduction of at least ten endoplasmic reticulum (ER) chaperones, including GRP78 and GRP94. Critically, transcriptomic studies demonstrated that the broad reduction of ER chaperones originated from transcriptional downregulation without corresponding changes for Ins1 and Ins2. In contrast to the dosage compensation previously seen for ER chaperones in Grp78 or Grp94 gene knockouts or knockdown, compensation is precluded by the stress-independent deficiency of ER chaperones in PWS β-cells. Consistent with reduced ER chaperones levels, PWS INS-1 β-cells are more sensitive to ER stress, leading to earlier activation of all three arms of the unfolded protein response. These findings suggest that a chronic shortage of ER chaperones in PWS β-cells leads to a deficiency of protein folding and/or delay in ER transit of insulin and other cargo. In summary, our results illuminate the pathophysiological basis of pancreatic β-cell hormone deficits in PWS, with evolutionary implications for the multigenic PWS-domain, and indicate that PWS-imprinted genes coordinate concerted regulation of ER chaperone biosynthesis and β-cell secretory pathway function.

Background It is crucial to promote mental and physical health during adolescence to protect against lifetime risks of mental health problems and obesity. Internalized weight bias (self-directed stigmatizing attitudes about perceived weight status) and bullying are implicated as potential mechanisms in the relationship between mental health and obesity in adolescence. We examined internalized weight bias and bullying as potential mediators of the relationship between mental health and weight status across adolescence in the United Kingdom (UK). Methods We analysed data on 8,688 adolescents from the UK Millennium Cohort Study. Weight status was defined using sex and age specific International Obesity Taskforce cut points for body-mass index (not overweight/obese; overweight; obese) at 11 and 17 years. Mental health was defined using parental reported emotional (anxiety and depression), and externalizing (aggression and impulsivity) symptoms at 11 and 17 years (low; moderate; high). Self-reported measures of internalized weight bias captured via body-dissatisfaction and self-esteem and bullying at 14 years were tested as mediators. We used Generalized Structural Equation Models to examine longitudinal pathways between weight status and mental health across 11 and 17 years, whilst accounting for concurrent associations and potential confounders. Results Adolescents with high emotional (relative risk (RR) 1.98, 95% CI 1.28 to 3.07) or externalizing symptoms (RR 2.07, 95% CI 1.23 to 3.48) at 11 years were twice as likely to be obese at 17 years compared with those who had low symptoms. The impact of emotional and externalizing symptoms on weight status was found to be partially attributable to internalized weight bias, but not bullying, with significant mediation for body-dissatisfaction and low self-esteem. Conclusions Internalized weight bias partially explains the relationship between mental health and weight status across adolescence. Key messages There is a need for a holistic, early prevention strategy to focus on reducing weight stigma to encourage healthy mental and physical development of children. The relationship between mental health and weight status across adolescence is partly attributable to internalized weight bias.

This study examined the impact of management and team member support on employee attitudes through the mediating effect of safety climate. Five hundred fifty-six physicians and nurses from a large ...

Phenylalanine hydroxylase–deficient (PAH-deficient) phenylketonuria (PKU) results in systemic hyperphenylalaninemia, leading to neurotoxicity with severe developmental disabilities. Dietary phenylalanine (Phe) restriction prevents the most deleterious effects of hyperphenylalaninemia, but adherence to diet is poor in adult and adolescent patients, resulting in characteristic neurobehavioral phenotypes. Thus, an urgent need exists for new treatments. Additionally, rodent models of PKU do not adequately reflect neurocognitive phenotypes, and thus there is a need for improved animal models. To this end, we have developed PAH-null pigs. After selection of optimal CRISPR/Cas9 genome-editing reagents by using an in vitro cell model, zygote injection of 2 sgRNAs and Cas9 mRNA demonstrated deletions in preimplantation embryos, with embryo transfer to a surrogate leading to 2 founder animals. One pig was heterozygous for a PAH exon 6 deletion allele, while the other was compound heterozygous for deletions of exon 6 and of exons 6–7. The affected pig exhibited hyperphenylalaninemia (2000–5000 μM) that was treatable by dietary Phe restriction, consistent with classical PKU, along with juvenile growth retardation, hypopigmentation, ventriculomegaly, and decreased brain gray matter volume. In conclusion, we have established a large-animal preclinical model of PKU to investigate pathophysiology and to assess new therapeutic interventions., A phenylalanine hydroxylase–deficient pig model of phenylketonuria is established and characterized.

Although often thought of as a contemporary practice, audience development and pedagogies for listener education can be traced throughout the history of the public concert where their origins were forged. This paper unpacks how western listening and audience practices have developed over time, the changes in listening and behaviour norms, the emergence of early practitioners who developed ideas and pedagogies for listener education within the concert hall in Europe, and exposes the current paucity of research on the educational dimension of audience development and pedagogies of listening in the contemporary orchestral concert hall. It is argued that by understanding the past we can better understand the current concert hall and the ways we ourselves actively participate and create our own histories in the ongoing evolution of classical music performance. The paper concludes that this cultural inheritance has implications for arts organisations, educators, audiences, and listeners alike.

In the spring of 1621, James I sent the Great Seal of England to his newly appointed Lord Keeper, John Williams, the Dean of Westminster. Naming an ecclesiastic to this position shocked contemporary legal and political commentators, and subsequent historians have generally shared this negative appraisal. Even more positive analyses have held that Williams’ primary attraction for the king lay in his intellect and learning, and an expectation that he would do James’ bidding on the Court of Chancery. Williams actually possessed both stronger legal qualifications than have traditionally been recognized, and a politico-legal philosophy that had helped to modify James’ own views of the role of his prerogative courts and powers. An examination of Williams’ career prior to 1621 reveals the development of a candidate uniquely placed to fill this particular role at that specific moment in James’ reign.

The risks and consequences of the Covid-19 pandemic are too well known to need any elaboration. For a small and open economy like Barbados, which is currently implementing an International Monetary...

To conduct qualitative social research requires not only a declarative knowledge of the research methods and methodology, but also a set of honed practical, applied skills. For beginning researchers, particularly those undertaking phenomenological research, the skills of bracketing, the phenomenological reductions and having an awareness of one’s positionality or relationship to their chosen research methods, participants and contexts is of significant importance. More generally, these skills are also required in other qualitative research disciplines under the guise of reflexivity or critical reflective practice. Regardless, these are notoriously slippery and require more than prior reading to translate from theory and philosophy into practice. There is literature which also identifies and highlights the disparity between theory, skill development and practice; however, these practicalities of how one can bracket or bridle and undertake reductions require further elaboration and guidance for how researchers can develop these applied skills of research. In this article, I propose and demonstrate that the therapeutic tradition of mindfulness as specifically practised in dialectical behaviour therapy can be used to de-mystify the practices of reflexivity and work specifically within the tradition of phenomenological reduction and bracketing. I also assert that this innovation can provide a practical tool to craft qualitative and phenomenological research and make achievable the original philosophical ideas which underpin phenomenological research. I begin by focusing on the theory of bracketing and reduction from the philosophic tradition of phenomenology as a framework for research methodology and methods, and then introduce the practical skill of mindfulness as prescribed in dialectical behaviour therapy as an innovation which can assist the researcher in developing these skills. I finish by illustrating the usefulness of mindfulness in undertaking phenomenological research drawing on examples from a current research project.

International audience; We identified individuals with variations in ACTL6B, a component of the chromatin remodeling machinery including the BAF complex. Ten individuals harbored bi-allelic mutations and presented with global developmental delay, epileptic encephalopathy, and spasticity, and ten individuals with de novo heterozygous mutations displayed intellectual disability, ambulation deficits, severe language impairment, hypotonia, Rett-like stereotypies, and minor facial dysmorphisms (wide mouth, diastema, bulbous nose). Nine of these ten unrelated individuals had the identical de novo c.1027G>A (p.Gly343Arg) mutation. Human-derived neurons were generated that recaptured ACTL6B expression patterns in development from progenitor cell to post-mitotic neuron, validating the use of this model. Engineered knock-out of ACTL6B in wild-type human neurons resulted in profound deficits in dendrite development, a result recapitulated in two individuals with different bi-allelic mutations, and reversed on clonal genetic repair or exogenous expression of ACTL6B. Whole-transcriptome analyses and whole-genomic profiling of the BAF complex in wild-type and bi-allelic mutant ACTL6B neural progenitor cells and neurons revealed increased genomic binding of the BAF complex in ACTL6B mutants, with corresponding transcriptional changes in several genes including TPPP and FSCN1, suggesting that altered regulation of some cytoskeletal genes contribute to altered dendrite development. Assessment of bi-alleic and heterozygous ACTL6B mutations on an ACTL6B knock-out human background demonstrated that bi-allelic mutations mimic engineered deletion deficits while heterozygous mutations do not, suggesting that the former are loss of function and the latter are gain of function. These results reveal a role for ACTL6B in neurodevelopment and implicate another component of chromatin remodeling machinery in brain disease.

Small heat-shock proteins (sHsps; HspBs) are molecular chaperones involved in the cellular stress response and a range of basal functions. Despite a multitude of targets, sHsp interactions are not well understood due their heterogeneous structures and weak binding affinities. The most widely expressed human sHsp, HspB1, is prevalent in striated muscle, where the actin cross-linker filamin C (FLNC, γ-filamin, ABP-L) is a putative binding partner. Musculoskeletal HspB1 is phosphorylated in response to a variety of cues, including mechanical stress, which promotes oligomer disassembly and association with myoarchitectural elements. Here, we report the up-regulation and interaction of both proteins in the hearts of a mouse model of heart failure, with HspB1 being phosphorylated and FLNC increasingly associated with the sarcomeric Z-disc. We used a combination of structural approaches to reveal that phosphorylation of HspB1 results in increased availability of the residues surrounding the phosphosite, facilitating their interaction with folded FLNC domains equivalent to a force-sensing region in the paralog filamin A. By employing native mass spectrometry, we show that domains 18 to 21 of FLNC are extensible under conditions mimicking force, with phosphorylated HspB1 stabilising an intermediate from further unfolding. These findings report on conformations accessible during the cycles of mechanical extension central to filamin function, and are consistent with an interaction between the chaperone and a native target that is strengthened upon the application of force. This may represent a new mode of molecular chaperone activity, allowing HspB1 to protect FLNC from over-extension during mechanical stress.

This article compares both new and commonly used boundary conditions for generating pressure-driven water flows through carbon nanotubes in molecular dynamics simulations. Three systems are considered: (1) a finite carbon nanotube membrane with streamwise periodicity and ‘gravity’-type Gaussian forcing, (2) a non-periodic finite carbon nanotube membrane with reservoir pressure control, and (3) an infinite carbon nanotube with periodicity and ‘gravity’-type uniform forcing. Comparison between these focuses on the flow behaviour, in particular the mass flow rate and pressure gradient along the carbon nanotube, as well as the radial distribution of water density inside the carbon nanotube. Similar flow behaviour is observed in both membrane systems, with the level of user input required for such simulations found to be largely dependent on the state controllers selected for use in the reservoirs. While System 1 is simple to implement in common molecular dynamics codes, System 2 is more complicated, and the selection of control parameters is less straightforward. A large pressure difference is required between the water reservoirs in these systems to compensate for large pressure losses sustained at the entrance and exit of the nanotube. Despite a simple set-up and a dramatic increase in computational efficiency, the infinite length carbon nanotube in System 3 does not account for these significant inlet and outlet effects, meaning that a much smaller pressure gradient is required to achieve a specified mass flow rate. The infinite tube set-up also restricts natural flow development along the carbon nanotube due to the explicit control of the fluid. Observation of radial density profiles suggests that this results in over-constraint of the water molecules in the tube.

Context: Recombinant human GH (rhGH) therapy in Prader-Willi syndrome (PWS) has been used by the medical community and advocated by parental support groups since its approval in the United States in 2000 and in Europe in 2001. Its use in PWS represents a unique therapeutic challenge that includes treating individuals with cognitive disability, varied therapeutic goals that are not focused exclusively on increased height, and concerns about potential life-threatening adverse events. Objective: The aim of the study was to formulate recommendations for the use of rhGH in children and adult patients with PWS. Evidence: We performed a systematic review of the clinical evidence in the pediatric population, including randomized controlled trials, comparative observational studies, and long-term studies (>3.5 y). Adult studies included randomized controlled trials of rhGH treatment for ≥6 months and uncontrolled trials. Safety data were obtained from case reports, clinical trials, and pharmaceutical registries. Methodology: Forty-three international experts and stakeholders followed clinical practice guideline development recommendations outlined by the AGREE Collaboration (www.agreetrust.org). Evidence was synthesized and graded using a comprehensive multicriteria methodology (EVIDEM) (http://bit.ly.PWGHIN). Conclusions: Following a multidisciplinary evaluation, preferably by experts, rhGH treatment should be considered for patients with genetically confirmed PWS in conjunction with dietary, environmental, and lifestyle interventions. Cognitive impairment should not be a barrier to treatment, and informed consent/assent should include benefit/risk information. Exclusion criteria should include severe obesity, uncontrolled diabetes mellitus, untreated severe obstructive sleep apnea, active cancer, or psychosis. Clinical outcome priorities should vary depending upon age and the presence of physical, mental, and social disability, and treatment should be continued for as long as demonstrated benefits outweigh the risks. Copyright

This paper presents a numerical study involving the deformation of contact faces in the metal-to-metal seal in a typical pressure relief valve. The valve geometry is simplified to an axisymmetric problem, which comprises a simple geometry consisting of only 3 components. A cylindrical nozzle, which has a valve seat on top, contacts with a disk, which is preloaded by a compressed linear spring. All the components are made of AISI type 316N(L) steel defined using the multilinear kinematic hardening model based on monotonic and cyclic tests at 20° C. In-service observations show that there is a limited fluid leakage through the valve seat at operational pressures about 90% of the set pressure, which is caused by the fluid penetrating into surface asperities at the microscale. Nonlinear FEA in ANSYS using the fluid pressure penetration (FPP) technique revealed that there is a limited amount of fluid penetrating into gap, which is caused by the plastic deformation of the valve seat at the macroscale. Prediction of the fluid pressure distribution over the valve seat just before the valve lift is addressed in this study considering the FPP interaction on multiscale. This is the principal scope, since it allows adjustment of the valve spring force in order to improve the leak tightness.

Although alpha thalassaemia is rare in north Europeans, it has been identified in British people with no known foreign ancestry. Twelve such patients were studied, of whom eight shared a distinctive molecular defect, which was clearly different from defects seen in subjects of Mediterranean or South East Asian origin. A rare but specific form of alpha thalassaemia is therefore present in the British population. In addition, two patients from families of mixed racial origin were encountered who had a moderately severe form of thalassaemia (HbH disease) due to the inheritance of one form of alpha thalassaemia from the British parent and another type from the foreign parent. This shows the importance of careful genetic counselling of British patients with haematological findings of thalassaemia.

This study evaluated the impact of five, single- or double- moment bulk microphysics schemes (BMPS) on Weather Research and Forecasting (WRF) model (version 3.6.1) winter storm simulations. Model simulations were integrated for 180 hours, starting 72 hours prior to the first measurable precipitation in the highly populated Mid-Atlantic U.S. Simulated precipitation fields were well-matched to precipitation products. However, total accumulations tended to be over biased (1.10–2.10) and exhibited low-to-moderate threat scores (0.27–0.59). Non-frozen hydrometeor species from single-moment BMPS produced similar mixing ratio profiles and maximum saturation levels due to a common parameterization heritage. Greater variability occurred with frozen microphysical species due to varying assumptions among BMPSs regarding ice supersaturation amounts, the dry collection of snow by graupel, various ice collection efficiencies, snow and graupel density and size mappings/intercept parameters, and hydrometeor terminal velocities. The addition of double-moment rain and cloud water resulted in minimal change to species spatial extent or maximum saturation level, however rain mixing ratios tended higher. Although hydrometeor differences varied by up to an order of magnitude among the BMPSs, similarly large variability was not upscaled to mesoscale and synoptic scales.

The use of real-time plant simulators running in parallel with a nuclear plant to predict the control system behaviour and highlighting unexpected plant behaviour is presented. The study is performed on a 910 MW Generation II Framatome Pressurised Water Reactor model and simulator. By simulating the plant behaviour in real-time whilst comparing it with the real-time transient the plant is following, a complete second set of expected control operations and simulated plant measurements is generated. This enables the calculation of the unknown set of variables introduced into the plant as a fault condition. The benefit of such a system is that plant faults that are too small to detect (especially during transients when the plant operating point is moving around) can be identified as unexpected or faulty plant behaviour. The behaviour of the control system is also continually predicted so the effect of the control system compensating for fault symptoms (which in most cases hides the fault condition) is used to characterise the fault as a control variable acting on the plant. The approach is illustrated by simulating a specific fault, small enough to go undetected for an extended period of time, during a typical transient. This is continually compared with a plant simulation, simulating the same transient without the fault. Using the described methodology, the fault is detected and characterised long before the plant safety is jeopardised or the fault is detected by the conventional protection system.

Prader-Willi syndrome (PWS) is a multisystem disorder caused by genetic loss of function of a cluster of imprinted, paternally expressed genes. Neonatal failure to thrive in PWS is followed by childhood-onset hyperphagia and obesity among other endocrine and behavioral abnormalities. PWS is typically assumed to be caused by an unknown hypothalamic-pituitary dysfunction, but the underlying pathogenesis remains unknown. A transgenic deletion mouse model (TgPWS) has severe failure to thrive, with very low levels of plasma insulin and glucagon in fetal and neonatal life prior to and following onset of progressive hypoglycemia. In this study, we tested the hypothesis that primary deficits in pancreatic islet development or function may play a fundamental role in the TgPWS neonatal phenotype. Major pancreatic islet hormones (insulin, glucagon) were decreased in TgPWS mice, consistent with plasma levels. Immunohistochemical analysis of the pancreas demonstrated disrupted morphology of TgPWS islets, with reduced α- and β-cell mass arising from an increase in apoptosis. Furthermore, in vivo and in vitro studies show that the rate of insulin secretion is significantly impaired in TgPWS β-cells. In TgPWS pancreas, mRNA levels for genes encoding all pancreatic hormones, other secretory factors, and the ISL1 transcription factor are upregulated by either a compensatory response to plasma hormone deficiencies or a primary effect of a deleted gene. Our findings identify a cluster of imprinted genes required for the development, survival, coordinate regulation of genes encoding hormones, and secretory function of pancreatic endocrine cells, which may underlie the neonatal phenotype of the TgPWS mouse model.

The local- and regional-scale environments associated with intense convective systems in West Africa during 2003 were diagnosed from soundings, operational analysis, and space-based datasets. Convective system cases were identified from the Tropical Rainfall Measuring Mission (TRMM) microwave imagery and classified by the system minimum 85-GHz brightness temperature and the estimated elapsed time of propagation from terrain greater than 500 m. The speed of the midlevel jet, the magnitude of the low-level shear, and the surface equivalent potential temperature θe were greater for the intense cases compared to the nonintense cases, although the differences between the means tended to be small: less than 3 K for surface θe and less than 2 × 10−3 s−1 for low-level wind shear. Hypothesis testing of a series of commonly used intensity prediction metrics resulted in significant results only for low-level metrics such as convective available potential energy and not for any of the mid- or upper-level metrics such as the 700-hPa θe. None of the environmental variables or intensity metrics by themselves or in combination appeared to be reliable direct predictors of intensity. In the regional-scale analysis, the majority of intense convective systems occurred in the surface baroclinic zone where surface θe exceeded 344 K and the 700-hPa zonal wind speeds were less than −6 m s−1. Fewer intense cases compared to nonintense cases were associated with African easterly wave troughs. Fewer than 25% of these cases occurred in environments with detectable Saharan dust loads, and the results for intense and nonintense cases were similar. Although the discrimination between the intense and nonintense environments was narrow, the results were robust and consistent with the seasonal movement of the West African monsoon, regional differences in topography, and African easterly wave energetics.

The Monte Alban state emerged in the Valley of Oaxaca, Mexico, between 300 and 100 BC. Archaeological evidence indicates that this case of state formation was linked to the territorial expansion of the Monte Alban polity. We argue that rulers at Monte Alban adopted an expansionist strategy in order to acquire resources they could use to fund campaigns against rival polities and to bolster their position in a competitive sociopolitical environment. Logistical challenges associated with expansion favored experimentation with new (state) forms of administrative control, while importation of exotic goods contributed to the development of social stratification. Multiple lines of evidence—including excavation data from Tilcajete and Yaasuchi, survey data from the Sola Valley, and a GIS model of potential transportation routes—indicate that the Pacific coast of Oaxaca likely was a target of Monte Alban’s expansion. Our model explains the variable nature of that expansion and its impact on the developmental histories of neighboring regions, as well as the synergistic increase in complexity among interacting societies in Late Formative Oaxaca. Cross-cultural comparison demonstrates that key factors in the formation of the Monte Alban state (e.g., status rivalry, inter-polity conflict, territoriality, militarism, trade) are evident elsewhere in the world.

Hardwood panels made from edge-glued material are a versatile product that could be within the reach of many smaller wood products firms. However, products would need to be accepted throughout the supply chain for this opportunity to be achieved. This study evaluated preferences of consumers and manufacturers towards edge-glued panels from Alaskan red alder and paper birch. A total of 11 panels were constructed, including different levels of character-mark features such as knots and natural stain. We found strong preferences for the birch panel having high levels of natural stain. This panel was also the highest rated panel on three attributes (character marks, grain consistency and overall colour). Both residential consumers and wood products producers preferred birch panels featuring natural stain to birch panels featuring knots. Both groups also preferred red alder panels that were either clear or with high levels of character (but not intermediate levels of character). Residential consumers favoured birch panels (versus red alder panels) to a greater extent than did wood product producers and generally were less familiar with red alder than were producers.

In addition to normal alternative splicing events (those that take place in untreated cells), there are also those that are inducible in response to environmental stimuli. We previously reported that the alternative splicing of p53-inducible gene 3 (PIG3) exon 4 is modulated in response to UV radiation. Here, we investigate the mechanisms mediating the alternative splicing of this exon. Through the use of various minigene constructs our results reveal that numerous factors influence the normal alternative splicing of PIG3 exon 4, and that these ultimately affect its UV-inducible alternative splicing. Included among these are sequence elements located within exon 4 itself as well as adjacent sequences required for intron definition (the pyrimidine tract, 3'- and 5'-splice sites). Within exon 4, we identified a novel hnRNP A1-dependent exonic splicing silencer (ESS) whose mutation inhibited the alternative splicing of a PIG3 minigene. Although previously implicated in the UV-inducible alternative splicing of other transcripts, RNAi-mediated silencing of hnRNP A1/A2 or hSlu7 did not prevent the UV-enhancement of exon 4 skipping. Overall, our results suggest that numerous factors contribute to the normal alternative splicing of PIG3 exon 4 and that UV-inducible increases in this process require that the splicing of this exon be maintained in a sufficiently weakened state under normal conditions.

To characterize a novel splice variant of the alpha subunit of the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor (GMRalpha), which we discovered in human neutrophils.We used reverse transcriptase polymerase chain reaction to identify, characterize, and examine the expression of a novel splice variant of the GMRalpha transcript. At the protein level, surface plasmon resonance was used to measure the affinity of a recombinant soluble form of the novel GMRalpha protein for GM-CSF ligand. The full-length novel GMRalpha protein was expressed in a recombinant cell culture system, and its expression and localization were examined using Western blotting, I(125) GM-CSF binding assays, flow cytometry, and a soluble GMRalpha enzyme-linked immunosorbent assay.The novel GMRalpha transcript identified herein contains a previously undescribed exon of the GMRalpha gene; this exon derives from an Alu DNA repeat element, and is alternatively spliced in the novel GMRalpha transcript. Inclusion of this 102 nucleotide exon results in translation of a protein product, which we have named Alu-GMRalpha. Alu-GMRalpha is identical to cell surface GMRalpha, but additionally contains a 34 amino-acid insert in the juxtamembrane region of the extracellular domain of GMRalpha. Functionally, the Alu-GMRalpha-specific epitope does not modify the ability of the protein to bind GM-CSF, but rather appears to be preferentially targeted by ectodomain proteases to mediate the release of a third soluble GM-CSF receptor into the extracellular space.This study provides the first example of a cytokine receptor system in which soluble receptors are produced by three distinct mechanisms. Our results highlight the importance of soluble GMRalpha proteins in regulation of GM-CSF signaling.

We report a high-quality draft of the genome sequence of the grey, short-tailed opossum (Monodelphis domestica). As the first metatherian ('marsupial') species to be sequenced, the opossum provides a unique perspective on the organization and evolution of mammalian genomes. Distinctive features of the opossum chromosomes provide support for recent theories about genome evolution and function, including a strong influence of biased gene conversion on nucleotide sequence composition, and a relationship between chromosomal characteristics and X chromosome inactivation. Comparison of opossum and eutherian genomes also reveals a sharp difference in evolutionary innovation between protein-coding and non-coding functional elements. True innovation in protein-coding genes seems to be relatively rare, with lineage-specific differences being largely due to diversification and rapid turnover in gene families involved in environmental interactions. In contrast, about 20% of eutherian conserved non-coding elements (CNEs) are recent inventions that postdate the divergence of Eutheria and Metatheria. A substantial proportion of these eutherian-specific CNEs arose from sequence inserted by transposable elements, pointing to transposons as a major creative force in the evolution of mammalian gene regulation.

An observational analysis of the structure and synoptic setting of tropical dendritic cumulus formations was undertaken using 30 months of global data from the Moderate Resolution Imaging Spectroradiometer aboard the National Aeronautics and Space Administration Terra satellite, the Quick Scatterometer aboard the SeaWinds satellite, and the National Centers for Environmental Prediction global reanalysis. This analysis yielded 1216 cases of tropical dendritic cumulus formations of which 61 were randomly selected for quantitative study. From these sample cases, it was found that dendritic patterns in shallow cumulus occurred over warm tropical oceans in response to cold air advection. They typically dissipate downstream in regions of cooler water, neutral to warm advection, or deep convection. Moreover, shallow cumulus formations take on a dendritic pattern only in areas where the background wind velocity is between 1.5 and 13 m s−1 in the surface to the 850-mb layer and a shallow layer of conditional instability is present. Individual cumulus clouds in these dendritic formations are arranged in a compound, hierarchical branching pattern in which each element of the pattern takes the form of a Y-shaped cloud line. Analysis of the cloud pattern observations in conjunction with the scatterometer-derived surface winds and the lower-tropospheric wind profiles from reanalysis data reveals that the individual Y elements are aligned closely with the surface wind direction, as linear cloud streets would be. These Y elements are oriented so that their forked end aligns as closely as possible with the surface-to-850-mb shear vector, even when this conflicts with the surface wind direction. A formation mechanism is hypothesized by which the secondary circulation of a towering cumulus line modifies the shear and stability profiles in the adjacent areas to favor shallower cumulus lines oriented at an angle to itself, thus forming a hierarchical branching structure. This hypothesis is supported by stability profiles from the reanalysis data.

The initial aim of this study was to compare OpenFoam and Ansys Fluent in order to verify OpenFoam’s Lagrangian Library and erosion capabilities. However, it was found that previous versions of Fluent have been providing wrong results for the discrete phase and the differences with the latest version (Ansys Fluent 15) are shown. A Submerged Jet Impingement Test is an effective method for studying erosion created by solid particles entrained in a liquid. When considering low particle concentrations a Lagrangian modeling of the particulate phase is a reasonable approach. Proper linkage between OpenFOAM’s Lagrangian library and the solver pimpleFoam for incompressible transient flows allows two-phase simulations to be undertaken for comparison with Ansys Fluent with the aim of verifying OpenFoam’s accuracy. Steady state convergence for the fluid flow is first accomplished and the results are compared, confirming a good agreement between the two packages. A transient simulation was then set up and spherical particles incorporated into the fluid flow. An assessment of the two codes’ discrete phase models was carried out, focusing on the differences between impact angles and velocities yielded at the impingement plate’s surface employing a similar strategy to that outlined first by Hattori et al. (2008) and later by Gnanavelu et al. (2009, 2011). In the comparison of OpenFoam with the latest version of Fluent, the main differences between the injection models are highlighted and the coupling possibilities between phases are taken into consideration. Agreement between trends for both impact angles and velocities is satisfactory when the last version of the commercial package is considered and the average discrepancy between numerical values is very low, verifying OpenFoam’s Lagrangian library. Two different Jet Impingement Test configurations are also compared and the differences highlighted.

The psychological and social outcomes of bariatric surgery in adolescents, together with psychological and social predictors of success, were systematically reviewed. PubMed, EMBASE, ISI Web of Science and PsychInfo were searched on July 2014. Existing data were sparse; 15 were suitable for qualitative review and six for meta-analysis (four quality of life [QOL], two depression). One study was a randomized controlled trial. A total of 139 subjects underwent Roux-en-Y gastric bypass, 202 underwent adjustable gastric band and 64 underwent sleeve gastrectomy. Overall QOL improved after bariatric surgery, regardless of surgical type with peak improvement at 6-12 months. Meta-analysis of four studies showed changed in overall QOL at latest follow-up of 2.80 standard deviation (SD) (95% confidence interval [CI] 1.23-4.37). Depression improved across all studies, regardless of procedure (effect size -0.47 SD [95% CI -0.76, -0.18] at 4-6 months). Two cohorts reported changes in both overall QOL and depression following a quadratic trajectory, with overall improvement over 2 years and deterioration in the second post-operative year. There were limited data on other psychological and social outcomes. There were insufficient data on psychosocial predictors of outcome to form evidence-based recommendations for patient selection for bariatric surgery at this time.

This study investigates the behaviour of the contact faces in the metal-to-metal seal of a typical pressure relief valve. The valve geometry is simplified to an axisymmetric problem. A cylindrical nozzle, which has a valve seat on top, contacts with a disk, which is preloaded by a compressed linear spring. All the components are made of the steel AISI type 316N(L) defined using the multilinear kinematic hardening material model based on monotonic and cyclic tests at 20◦C. Analysis considerations include the effects of the Fluid Pressure Penetration (FPP) across the valve seat which exists at two different scales. There is certain limited fluid leakage through the valve seat at operational pressures, which is caused by the fluid penetrating into surface asperities at the microscale. At the macroscale, non-linear FE analysis using the FPP technique available in ANSYS revealed that there is also a limited amount of fluid penetrating into gap. Accurate prediction of the fluid pressure profile over the valve seat is addressed in this study by considering the FPP interaction on both scales. The shape of this pressure profile introduces an additional component of the spring force, which needs to be considered to provide a reliable sealing. The analysis showed that the evolution of the profile, which is caused by the isotropic softening of the material, is significant during the cyclic operation of the valve.

Purpose Oxaliplatin, a platinum-type alkylator, is not classified as a vesicant but can cause local reactions when infused by peripheral vein. Providence Cancer Center, like other institutions, deferred the venous administration method to clinical judgment incorporating patient preference. Patient experience was evaluated for oxaliplatin-related local reactions by peripheral or central venous administration. Methods A retrospective review of the electronic medical record was performed of the period of January 2011 to March 2013 to identify patients who received oxaliplatin. Included were 59 patients who were given the option of either peripheral or central venous drug administration. The two patient groups (peripheral vein vs. central vein administration) were compared in terms of frequency and type of local reactions (redness/discoloration, swelling, numbness/cold, or pain/discomfort). Results Nineteen (63.3%) of the patients in the peripheral vein group experienced some type of local reaction compared to none in the central vein group ( p Conclusion This is the first published report to characterize and quantify a single institution's experience with oxaliplatin-related local reactions. A significantly greater number of local reactions, particularly pain, occurred with the administration of oxaliplatin peripherally vs. centrally. This analysis impacted our institution's best practice for oxaliplatin infusions.

Prader-Willi syndrome (PWS) has a biphasic clinical phenotype with failure to thrive in the neonatal period followed by hyperphagia and severe obesity commencing in childhood among other endocrinological and neurobehavioral abnormalities. The syndrome results from loss of function of several clustered, paternally expressed genes in chromosome 15q11-q13. PWS is assumed to result from a hypothalamic defect, but the pathophysiological basis of the disorder is unknown. We hypothesize that a fetal developmental abnormality in PWS leads to the neonatal phenotype, whereas the adult phenotype results from a failure in compensatory mechanisms. To address this hypothesis and better characterize the neonatal failure to thrive phenotype during postnatal life, we studied a transgenic deletion PWS (TgPWS) mouse model that shares similarities with the first stage of the human syndrome. TgPWS mice have fetal and neonatal growth retardation associated with profoundly reduced insulin and glucagon levels. Consistent with growth retardation, TgPWS mice have deregulated liver expression of IGF system components, as revealed by quantitative gene expression studies. Lethality in TgPWS mice appears to result from severe hypoglycemia after postnatal d 2 after depletion of liver glycogen stores. Consistent with hypoglycemia, TgPWS mice appear to have increased fat oxidation. Ghrelin levels increase in TgPWS reciprocally with the falling glucose levels, suggesting that the rise in ghrelin reported in PWS patients may be secondary to a perceived energy deficiency. Together, the data reveal defects in endocrine pancreatic function as well as glucose and hepatic energy metabolism that may underlie the neonatal phenotype of PWS.

Prader–Willi syndrome (PWS) is a neurobehavioral disorder caused by the lack of paternal expression of imprinted genes in the human chromosome region 15q11–13. Recent studies of rare human translocation patients narrowed the PWS critical genes to a 121-kb region containing PWCR1/HBII-85 and HBII-438 snoRNA genes. The existing mouse models of PWS that lack the expression of multiple genes, including Snrpn, Ube3a, and many intronic snoRNA genes, are characterized by 80%–100% neonatal lethality. To define the candidate region for PWS-like phenotypes in mice, we analyzed the expression of several genetic elements in mice carrying the large radiation-induced p 30PUb deletion that includes the p locus. Mice having inherited this deletion from either parent develop normally into adulthood. By Northern blot and RT-PCR assays of brain tissue, we found that Pwcr1/MBII-85 snoRNAs are expressed normally, while MBII-52 snoRNAs are not expressed when the deletion is paternally inherited. Mapping of the distal deletion breakpoint indicated that the p 30PUb deletion includes the entire MBII-52 snoRNA gene cluster and three previously unmapped EST sequences. The lack of expression of these elements in mice with a paternal p 30PUb deletion indicates that they are not critical for the neonatal lethality observed in PWS mouse models. In addition, we identified MBII-436, the mouse homolog of the HBII-436 snoRNA, confirmed its imprinting status, and mapped it outside of the p 30PUb deletion. Taking together all available data, we conclude that the lack of Pwcr1/MBII-85 snoRNA expression is the most likely cause for the neonatal lethality in PWS model mice.

Prader-Willi syndrome (PWS) is a complex neurobehavioral disorder that results from loss of function of 10 clustered, paternally expressed genes in a 1.5-Mb region of chromosome 15q11-q13. Many of the primary PWS region genes appear to have nuclear RNA regulatory functions, suggesting that multiple genetic pathways could be secondarily affected in PWS. Using a transgenic mouse model of PWS (TgPWS) with an approximately 4-Mb chromosome 7C deletion of paternal origin that models the neonatal phenotype of the human syndrome we compared by oligonucleotide microarrays expression levels of approximately 12,000 genes and ESTs in TgPWS and wild-type brain. Hybridization data were processed with two distinct statistical algorithms and revealed a dramatically reduced expression of 4 imprinted genes within the deletion region in TgPWS mice, with 2 nonimprinted, codeleted genes reduced twofold. However, only 3 genes outside the deletion were significantly altered in TgPWS mouse brain, with approximately 1.5-fold up-regulation of mRNA levels. Remarkably, these genes map to a single chromosome domain (18B3), and by quantitative RT-PCR we show that 8 genes in this domain are up-regulated in TgPWS brain. These 18B3 genes were up-regulated in an equivalent manner in Angelman syndrome mouse (TgAS) brain, which has the same deletion but of maternal origin. Therefore, the trans-regulation of the chromosome 18B3 domain is due to decreased expression of a nonimprinted gene within the TgPWS/AS mouse deletion in mouse chromosome 7C. Most surprisingly, since 48-60% of the genome was screened, it appears that the imprinted mouse PWS loci do not widely regulate mRNA levels of other genes and may regulate RNA structure.

The p53-inducible gene 3 (PIG3) is a transcriptional target of the tumor suppressor protein p53 and is thought to play a role in apoptosis. In this report, we identify a novel alternatively spliced product from the PIG3 gene that we call PIG3AS (PIG3 alternative splice). PIG3AS results from alternative pre-mRNA splicing that skips exon 4 of the five exons included in the PIG3 transcript. The resulting protein product shares its first 206 amino acids with PIG3 but has a unique 42-amino acid C terminus. In unstressed cells and after most DNA damage conditions that induce transcription from the PIG3 gene, production of the PIG3 transcript dominates. However, in response to UV light, pre-mRNA splicing shifts dramatically in favor of PIG3AS. Unlike the PIG3 protein, the PIG3AS protein is rapidly degraded with a short half-life and is stabilized by proteasome inhibition. Our results illustrate the first example of an endogenous, UV-inducible, alternative splicing event and that control of the splicing machinery is involved in the cellular DNA damage response. They also suggest that rapid proteolytic degradation represents a cellular mechanism for uncoupling p53 activity from PIG3 gene activation that is independent of promoter selectivity.