Temporal acceleration of a turbulent channel flow

We report new laboratory experiments of a flow accelerating from an initially turbulent state following the opening of a valve, together with large eddy simulations of the experiments and extended Stokes first problem solutions for the early stages of the flow. The results show that the transient flow closely resembles an accelerating laminar flow superimposed on the original steady turbulent flow. The primary consequence of the acceleration is the temporal growth of a boundary layer from the wall, gradually leading to a strong instability causing transition. This extends the findings of previous direct numerical simulations of transient flow following a near-step increase in flow rate. In this interpretation, the initial turbulence is not the primary characteristic of the resulting transient flow, but can be regarded as noise, the evolution of which is strongly influenced by the development of the boundary layer. We observe the spontaneous appearance of turbulent spots and discontinuities in the velocity signals in time and space, revealing rich detail of the transition process, including a striking contrast between streamwise and wall-normal fluctuating velocities

Assessing the Impact of Financial Characteristics on the Performance of Ghana Club 100 Companies.

After a decade of reforming policy, building and developing the multi-national market in Ghana, the Ghana Investment Promotion Centre (GIPC) introduced Ghana Club 100 to recognize the top 100 performing companies in terms of their competitiveness and contribution to economic growth. We adopted a quantitative research methodology involving correlational and casual research design to assess the impact of financial characteristics on the performance of 80 listed Ghana Club 100 firms. Financial characteristics represent the independent variables measured using liquidity, financial leverage and business activity, whiles company performance represents measured using return on asset. SPSS Pearson's correlation coefficient and multiple regression were used to analyze the data gathered from the 80 listed companies. The data analysis reveals four key findings: 1/ a statistically significant positive relationship exists between leverage and performance; 2/ no statistically significant relationship exists between liquidity and performance; 3/ a statistically significant positive relationship exists between business activity and performance; and 4/ leverage, liquidity and business activity had statistically significant positive impact on firm performance. These findings contribute to knowledge by critically explaining the casual relationship between financial characteristics and firm performance with specific reference to Ghana Club 100 companies. The findings have strategic implications for the Ghanaian businesses and economy in terms of enhancing firm’s financial performance. Due to limited access to scarce resources, the scope of the study focused on Club 100 firms which represent all the companies in Ghana. Future research can be conducted on the effect of financial characteristics on the performance of non-listed companies in Ghana

Adolescent transport and unintentional injuries:a systematic analysis using the Global Burden of Disease Study 2019

Background Globally, transport and unintentional injuries persist as leading preventable causes of mortality and morbidity for adolescents. We sought to report comprehensive trends in injury-related mortality and morbidity for adolescents aged 10–24 years during the past three decades. Methods Using the Global Burden of Disease, Injuries, and Risk Factors 2019 Study, we analysed mortality and disability-adjusted life-years (DALYs) attributed to transport and unintentional injuries for adolescents in 204 countries. Burden is reported in absolute numbers and age-standardised rates per 100 000 population by sex, age group (10–14, 15–19, and 20–24 years), and sociodemographic index (SDI) with 95% uncertainty intervals (UIs). We report percentage changes in deaths and DALYs between 1990 and 2019. Findings In 2019, 369 061 deaths (of which 214 337 [58%] were transport related) and 31·1 million DALYs (of which 16·2 million [52%] were transport related) among adolescents aged 10–24 years were caused by transport and unintentional injuries combined. If compared with other causes, transport and unintentional injuries combined accounted for 25% of deaths and 14% of DALYs in 2019, and showed little improvement from 1990 when such injuries accounted for 26% of adolescent deaths and 17% of adolescent DALYs. Throughout adolescence, transport and unintentional injury fatality rates increased by age group. The unintentional injury burden was higher among males than females for all injury types, except for injuries related to fire, heat, and hot substances, or to adverse effects of medical treatment. From 1990 to 2019, global mortality rates declined by 34·4% (from 17·5 to 11·5 per 100 000) for transport injuries, and by 47·7% (from 15·9 to 8·3 per 100 000) for unintentional injuries. However, in low-SDI nations the absolute number of deaths increased (by 80·5% to 42 774 for transport injuries and by 39·4% to 31 961 for unintentional injuries). In the high-SDI quintile in 2010–19, the rate per 100 000 of transport injury DALYs was reduced by 16·7%, from 838 in 2010 to 699 in 2019. This was a substantially slower pace of reduction compared with the 48·5% reduction between 1990 and 2010, from 1626 per 100 000 in 1990 to 838 per 100 000 in 2010. Between 2010 and 2019, the rate of unintentional injury DALYs per 100 000 also remained largely unchanged in high-SDI countries (555 in 2010 vs 554 in 2019; 0·2% reduction). The number and rate of adolescent deaths and DALYs owing to environmental heat and cold exposure increased for the high-SDI quintile during 2010–19. Interpretation As other causes of mortality are addressed, inadequate progress in reducing transport and unintentional injury mortality as a proportion of adolescent deaths becomes apparent. The relative shift in the burden of injury from high-SDI countries to low and low–middle-SDI countries necessitates focused action, including global donor, government, and industry investment in injury prevention. The persisting burden of DALYs related to transport and unintentional injuries indicates a need to prioritise innovative measures for the primary prevention of adolescent injury

Pharmacokinetics of intramuscular maropitant in pigs (Sus scrofa domesticus)

Pigs are at risk of vomiting from medical conditions as well as the emetic side effects of drugs administered for peri-operative manipulations, but there is a lack of pharmacokinetic data for potential anti-emetic therapies, such as maropitant, in this species. The main objective of this study was to estimate plasma pharmacokinetic parameters for maropitant in pigs after a single intramuscular (IM) administration dosed at 1.0 mg/ kg. A secondary objective was to estimate pilot pharmacokinetic parameters in pigs after oral (PO) administration at 2.0 mg/kg. Maropitant was administered to six commercial pigs at a dose of 1.0 mg/kg IM. Plasma samples were collected over 72 h. After a 7-day washout period, two pigs were administered maropitant at a dose of 2.0 mg/ kg PO. Maropitant concentrations were measured via liquid chromatography/mass spectrometry (LC–MS/ MS). A non-compartmental analysis was used to derive pharmacokinetics parameters. No adverse events were noted in any of the study pigs after administration. Following single IM administration, maximum plasma concentration was estimated at 412.7 ± 132.0 ng/mL and time to maximum concentration ranged from 0.083 to 1.0 h. Elimination half-life was estimated at 6.7 ± 1.28 h, and mean residence time was 6.1 ± 1.2 h. Volume of distribution after IM administration was 15.9 L/ kg. Area under the curve was 1336 ± 132.0 h*ng/mL. The relative bioavailability of PO administration was noted to be 15.5% and 27.2% in the two pilot pigs. The maximum systemic concentration observed in the study pigs after IM administration was higher than what was observed after subcutaneous administration in dogs, cats, or rabbits. The achieved maximum concentration exceeded the concentrations for anti-emetic purposes in dogs and cats; however, a specific anti-emetic concentration is currently not known for pigs. Further research is needed into the pharmacodynam

Increasing cardiovascular medication adherence:A Medical Research Council complex mHealth intervention mixed-methods feasibility study to inform global practice

AimsTo evaluate a mHealth intervention to increase medication adherence among Iranian coronary heart disease patients.DesignQuantitative-dominant mixed-methods study.Data SourceIranian coronary heart disease patients’ responses and most recent clinical documents as well as responses from Iranian cardiac nurses who participated in this study.MethodsThe study was conducted between September 2015–April 2016 drawing on the Medical Research Council's Framework. Phase one comprised of a patients’ survey and focus groups with cardiac nurses. The automated short message service reminder was piloted in phase two. We recruited 78 patients and randomized to receive either 12-week daily reminders or usual care. The primary outcome was the effect on medication adherence; secondary outcomes were self-efficacy, ejection fraction, functional capacity, readmission rate and quality of life.ResultsFeasibility was evidenced by high ownership of mobile phones and high interest in receiving reminders. Participants in the intervention group showed significantly higher medication adherence compared with the control group.ConclusionThe mHealth intervention was well accepted and feasible with early evidence of effectiveness that needs to be confirmed in a fully powered future randomized clinical trial

Turbulence in a transient channel flow with a wall of pyramid roughness

A direct numerical simulation investigation of a transient flow in a channel with a smooth top wall and a roughened bottom wall made of close-packed pyramids is presented. An initially stationary turbulent flow is accelerated rapidly to a new flow rate and the transient flow behaviour after the acceleration is studied. The equivalent roughness heights of the initial and final flows are $k_{s}^{+}=14.5$k+s=14.5 and 41.5, respectively. Immediately after the acceleration ends, the induced change behaves in a ‘plug-flow’ manner. Above the roughness crests, the additional velocity due to the perturbation flow is uniform; below the crest, it reduces approximately linearly to zero at the bottom of the roughness elements. The interaction of the perturbation flow with the rough wall is characterised by a series of events that resemble those observed in roughness-induced laminar–turbulent transitions. The process has two broad stages. In the first of these, large-scale vortices, comparable in extent to the roughness wavelength, develop around each roughness element and high-speed streaks form along the ridge lines of the elements. After a short time, each vortex splits into two, namely (i) a standing vortex in front of the element and (ii) a counter-rotating hairpin vortex behind it. The former is largely inactive, but the latter advects downstream with increasing strength, and later lifts away from the wall. These hairpin vortices wrap around strong low-speed streaks. The second stage of the overall process is the breakdown of the hairpin vortices into many smaller multi-scale vortices distributed randomly in space, leading eventually to a state of conventional turbulence. Shortly after the beginning of the first stage, the three components of the r.m.s of the velocity fluctuation all increase significantly in the near-wall region as a result of the vortical structures, and their spectra bear strong signatures of the surface topology. During the second stage, the overall turbulence energy in this region varies only slightly, but the spectrum evolves significantly, eventually approaching that of conventional turbulence. The direct effect of roughness on the flow is confined to a region up to approximately three element heights above the roughness crests. Turbulence in the core region does not begin to increase until after the transition near the wall is largely complete. The processes of transition over the smooth and rough walls of the channel are practically independent of each other. The flow over the smooth wall follows a laminar–turbulent transition and, as known from previous work, resembles a free-stream turbulence-induced boundary layer bypass transition

Variant biomarker discovery using mass spectrometry-based proteogenomics

Genomic diversity plays critical roles in risk of disease pathogenesis and diagnosis. While genomic variants—including single nucleotide variants, frameshift variants, and mis-splicing isoforms—are commonly detected at the DNA or RNA level, their translated variant protein or polypeptide products are ultimately the functional units of the associated disease. These products are often released in biofluids and could be leveraged for clinical diagnosis and patient stratification. Recent emergence of integrated analysis of genomics with mass spectrometry-based proteomics for biomarker discovery, also known as proteogenomics, have significantly advanced the understanding disease risk variants, precise medicine, and biomarker discovery. In this review, we discuss variant proteins in the context of cancers and neurodegenerative diseases, outline current and emerging proteogenomic approaches for biomarker discovery, and provide a comprehensive proteogenomic strategy for detection of putative biomarker candidates in human biospecimens. This strategy can be implemented for proteogenomic studies in any field of enquiry. Our review timely addresses the need of biomarkers for aging related diseases

Frontotemporal lobar degeneration targets brain regions linked to expression of recently evolved genes

In frontotemporal lobar degeneration (FTLD), pathological protein aggregation in specific brain regions is associated with declines in human-specialized social-emotional and language functions. In most patients, disease protein aggregates contain either TDP-43 (FTLD-TDP) or tau (FTLD-tau). Here, we explored whether FTLD-associated regional degeneration patterns relate to regional gene expression of human accelerated regions (HARs), conserved sequences that have undergone positive selection during recent human evolution. To this end, we used structural neuroimaging from patients with FTLD and human brain regional transcriptomic data from controls to identify genes expressed in FTLD-targeted brain regions. We then integrated primate comparative genomic data to test our hypothesis that FTLD targets brain regions linked to expression levels of recently evolved genes. In addition, we asked whether genes whose expression correlates with FTLD atrophy are enriched for genes that undergo cryptic splicing when TDP-43 function is impaired. We found that FTLD-TDP and FTLD-tau subtypes target brain regions with overlapping and distinct gene expression correlates, highlighting many genes linked to neuromodulatory functions. FTLD atrophy-correlated genes were strongly enriched for HARs. Atrophy-correlated genes in FTLD-TDP showed greater overlap with TDP-43 cryptic splicing genes and genes with more numerous TDP-43 binding sites compared with atrophy-correlated genes in FTLD-tau. Cryptic splicing genes were enriched for HAR genes, and vice versa, but this effect was due to the confounding influence of gene length. Analyses performed at the individual-patient level revealed that the expression of HAR genes and cryptically spliced genes within putative regions of disease onset differed across FTLD-TDP subtypes. Overall, our findings suggest that FTLD targets brain regions that have undergone recent evolutionary specialization and provide intriguing potential leads regarding the transcriptomic basis for selective vulnerability in distinct FTLD molecular-anatomical subtypes

Mis-spliced transcripts generate de novo proteins in TDP-43–related ALS/FTD

Functional loss of TDP-43, an RNA binding protein genetically and pathologically linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), leads to the inclusion of cryptic exons in hundreds of transcripts during disease. Cryptic exons can promote the degradation of affected transcripts, deleteriously altering cellular function through loss-of-function mechanisms. Here, we show that mRNA transcripts harboring cryptic exons generated de novo proteins in TDP-43–depleted human iPSC–derived neurons in vitro, and de novo peptides were found in cerebrospinal fluid (CSF) samples from patients with ALS or FTD. Using coordinated transcriptomic and proteomic studies of TDP-43–depleted human iPSC–derived neurons, we identified 65 peptides that mapped to 12 cryptic exons. Cryptic exons identified in TDP-43–depleted human iPSC–derived neurons were predictive of cryptic exons expressed in postmortem brain tissue from patients with TDP-43 proteinopathy. These cryptic exons produced transcript variants that generated de novo proteins. We found that the inclusion of cryptic peptide sequences in proteins altered their interactions with other proteins, thereby likely altering their function. Last, we showed that 18 de novo peptides across 13 genes were present in CSF samples from patients with ALS/FTD spectrum disorders. The demonstration of cryptic exon translation suggests new mechanisms for ALS/FTD pathophysiology downstream of TDP-43 dysfunction and may provide a potential strategy to assay TDP-43 function in patient CSF

TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A

Variants of UNC13A, a critical gene for synapse function, increase the risk of amyotrophic lateral sclerosis and frontotemporal dementia1-3, two related neurodegenerative diseases defined by mislocalization of the RNA-binding protein TDP-434,5. Here we show that TDP-43 depletion induces robust inclusion of a cryptic exon in UNC13A, resulting in nonsense-mediated decay and loss of UNC13A protein. Two common intronic UNC13A polymorphisms strongly associated with amyotrophic lateral sclerosis and frontotemporal dementia risk overlap with TDP-43 binding sites. These polymorphisms potentiate cryptic exon inclusion, both in cultured cells and in brains and spinal cords from patients with these conditions. Our findings, which demonstrate a genetic link between loss of nuclear TDP-43 function and disease, reveal the mechanism by which UNC13A variants exacerbate the effects of decreased TDP-43 function. They further provide a promising therapeutic target for TDP-43 proteinopathies