Square-to-sine wave filter

Square-to-sine wave filter network tested for regulation and stability under fixed load

An empirical investigation of the conditional risk-return trade-off in South Africa.

One of the fundamental tenets of finance is the relationship between risk and return. This research report contributes to the debate by testing the conditional risk-return relationship of shares on the Johannesburg Stock Exchange (JSE) for the period 2001 to 2011. More specifically, the extent to which beta, standard deviation, semi-deviation and value-at-risk (VaR) are individually able to explain total share return, taking into account the conditional framework of up and down markets and sub-periods, is investigated. Portfolios based on these risk measures have been tracked and regressed. The robustness of the relationships are tested by using value and equal weighted portfolios. The study indicates that standard deviation was able to explain the risk-return relationship across all scenarios (overall, up/down markets and sub-periods), while beta proved to be an ineffective measure of risk under all scenarios. The testing of downside risk measures revealed that semi-deviation produced weak results under all scenarios, while value-at-risk proved to be an effective measure of risk both during poor market conditions and on an overall basis

Maeotian Gray Clay Cups of the 4th – 3rd Centuries BC

The article is devoted to the typology and chronology of gray clay cups from the Maeotian burial grounds on the right bank of the Kuban river. Type 1 refers to biconical cups with a high, narrow neck widening upwards (30 items). A little over half of the studied vessels come from assemblages with a wide chronological range dating back to the 4th and early 3rd centuries BC, where they are accompanied by swords of the Sindian-Maeotian type or sets of pottery characteristic of this period. The remaining burials with cups can be dated more precisely by the finds of container amphorae from different centers (Heraclea, Thasos, Ikos, Mende, Sinope, etc.). The wide chronological framework of the existence of type 1 cups among the Maeotians can be determined within the first half of the 4th century BC, but their narrow chronology is limited to the second quarter of this century. Two versions of the origin of cups of this shape are put forward: the first one is from imported red clay vessels; the second one is from hand-made cups of the 6th–5th centuries BC. Type 2 is truncated conical cups widening upwards (13 items). There are not enough strong chronological references for a narrow dating of this type of cups. Furthermore, apart from the cups, imported vessels were found in the three assemblages including amphorae of Rhodes, a black glazed plate and a fish plate. As the analysis of the assemblages shows, type 2 cups existed among the Maeotians for a rather limited period from the late 3rd century BC up until the beginning of the next century

A VSV-G Pseudotyped Last Generation Lentiviral Vector Mediates High Level and Persistent Gene Transfer in Models of Airway Epithelium In Vitro and In Vivo

The aim of this work was to evaluate the efficiency and duration of gene expression mediated by a VSV-G pseudotyped last generation lentiviral (LV) vector. We studied LV efficiency in ex-vivo models of respiratory epithelial cells, obtained from bronchial biopsies and nasal polyps, by GFP epifluorescence and cytofluorimetry. In vivo efficiency and persistence of gene expression was investigated by GFP immunohistochemistry and luciferase activity in lung cryosections and homogenates, respectively, upon intranasal and intratracheal administration protocols in C57Bl/6 mice. Both primary bronchial and nasal epithelial cells were transduced up to 70–80% 72 hr after the LV infection. In vivo nasal luciferase expression was increased by lysophosphatidylcholine pre-treatment of the nose. Conversely, the bronchial epithelium was transduced in the absence of any pre-conditioning treatment and luciferase expression lasted for at least 6 months without any decline. We conclude that a last generation LV vector is a promising gene transfer agent in the target organ of genetic and acquired lung diseases, as in the case of cystic fibrosis

Australian government media strategies

This paper argues that the liberal media in terms of government intervention is increasingly rhetorical in today’s global climate.Liberal governments such as in Australia are increasingly moved by image management concerns and employ vigorous counter offensives at news media to support their national interests and this use of propaganda or “targeted public affairs material” is often little understood or recognized. Although liberal media system normally prohibits government’s intervention, in Australia the government always intervenes, influences and manages their media to suit government agendas.Thus, Jurgen Habermas’ theory of the public sphere can be used to explain the role of the media and media system in Australia. This paper argues that the Australian government manipulates the public sphere of the media for the purpose of managing public opinion

rAAV9 airway delivery results in effective knockdown of mutant alpha 1-antitrypsin in the liver while upregulating wildtype alpha 1-antitrypsin in the lung

Alpha 1-Antitrypsin (AAT) deficiency is a human genetic disease resulting in the production of mutant AAT, a hepatocyte produced serine protease inhibitor that functions to prevent alveolar epithelial damage by inhibiting neutrophil elastase. Patients with AAT deficiency have increased lung disease, due to decreased proteolytic protection, as well as sporadic severe liver disease secondary to accumulation of mutant AAT, especially a common mutant form termed PiZ, within hepatocytes. We previously showed, in a PiZ mutant mouse model, simultaneous knock-down of mutant PiZ-AAT and augmentation of wild-type AAT production through intravenous delivery of a recombinant adeno-associated viral (rAAV) vector encoding both a miRNA targeting PiZ-AAT and a miRNA-resistant wild-type AAT gene. In this study we tested the hypothesis that rAAV2/9 vector administered intra-nasally or intra-tracheally can deliver a gene of interest to both the airways and liver. Initially C57Bl/6 mice were administered intra-nasally 1011 genome copies (GC) of rAAV2/9 vector expressing a firefly luciferase, which resulted in increased luminescence in the nasal passages, liver, and lung 21 days post delivery. Next, 1012 GC of rAAV2/9 vector expressing GFP and miRNAs targeting PiZ-AAT were delivered via oro-tracheal intubation to PiZ mice. This resulted in decreased serum AAT levels in the PiZ mice and GFP expression in both the liver and lungs. Finally, 1012 GC of rAAV2/9 vector encoding miRNA resistant wild-type AAT and miRNAs targeting PiZ-AAT were delivered via oro-tracheal intubation. This resulted in both systemic and local (liver and lung) elevations in wild-type AAT as well as decreased PiZ-AAT levels. In conclusion, tracheal delivery of rAAV2/9 resulted in expression of AAT in the liver and lung of treated animals, with sufficient targeting of the liver to mediate knock-down of mutant AAT to a similar degree as intravenous delivery, representing a potential non-invasive delivery route for gene therapy in AAT deficient patients

HCO3− Secretion by Murine Nasal Submucosal Gland Serous Acinar Cells during Ca2+-stimulated Fluid Secretion

Airway submucosal glands contribute to airway surface liquid (ASL) composition and volume, both important for lung mucociliary clearance. Serous acini generate most of the fluid secreted by glands, but the molecular mechanisms remain poorly characterized. We previously described cholinergic-regulated fluid secretion driven by Ca2+-activated Cl− secretion in primary murine serous acinar cells revealed by simultaneous differential interference contrast (DIC) and fluorescence microscopy. Here, we evaluated whether Ca2+-activated Cl− secretion was accompanied by secretion of HCO3−, possibly a critical ASL component, by simultaneous measurements of intracellular pH (pHi) and cell volume. Resting pHi was 7.17 ± 0.01 in physiological medium (5% CO2–25 mM HCO3−). During carbachol (CCh) stimulation, pHi fell transiently by 0.08 ± 0.01 U concomitantly with a fall in Cl− content revealed by cell shrinkage, reflecting Cl− secretion. A subsequent alkalinization elevated pHi to above resting levels until agonist removal, whereupon it returned to prestimulation values. In nominally CO2–HCO3−-free media, the CCh-induced acidification was reduced, whereas the alkalinization remained intact. Elimination of driving forces for conductive HCO3− efflux by ion substitution or exposure to the Cl− channel inhibitor niflumic acid (100 μM) strongly inhibited agonist-induced acidification by >80% and >70%, respectively. The Na+/H+ exchanger (NHE) inhibitor dimethylamiloride (DMA) increased the magnitude (greater than twofold) and duration of the CCh-induced acidification. Gene expression profiling suggested that serous cells express NHE isoforms 1–4 and 6–9, but pharmacological sensitivities demonstrated that alkalinization observed during both CCh stimulation and pHi recovery from agonist-induced acidification was primarily due to NHE1, localized to the basolateral membrane. These results suggest that serous acinar cells secrete HCO3− during Ca2+-evoked fluid secretion by a mechanism that involves the apical membrane secretory Cl− channel, with HCO3− secretion sustained by activation of NHE1 in the basolateral membrane. In addition, other Na+-dependent pHi regulatory mechanisms exist, as evidenced by stronger inhibition of alkalinization in Na+-free media

A regimen containing bedaquiline and delamanid compared to bedaquiline in patients with drug-resistant tuberculosis.

There are limited data on combining delamanid and bedaquiline in drug-resistant tuberculosis (DR-TB) regimens. Prospective long-term outcome data, including in HIV-infected persons, are unavailable.We prospectively followed up 122 South African patients (52.5% HIV-infected) with DR-TB and poor prognostic features between 2014 and 2018. We examined outcomes and safety in those who received a bedaquiline-based regimen (n=82) compared to those who received a bedaquiline-delamanid combination regimen (n=40).There was no significant difference in 6-month culture conversion (92.5% versus 81.8%; p=0.26) and 18-month favourable outcome rate (63.4% versus 67.5%; p=0.66) in the bedaquiline versus the bedaquiline-delamanid combination group, despite the latter having more advanced drug resistance (3.7% versus 22.5% resistant to at least five drugs; p=0.001) and higher pre-treatment failure rates (12.2% versus 52.5% with pre-treatment multidrug-resistant TB therapy failure; p60 ms from baseline (p=0.001) or >450 ms during treatment (p=0.001)), there were no symptomatic cases or drug withdrawals in either group. Results were similar in HIV-infected patients.A bedaquiline-delamanid combination regimen showed comparable long-term safety compared to a bedaquiline-based regimen in patients with DR-TB, irrespective of HIV status. These data inform regimen selection in patients with DR-TB from TB-endemic settings

Linezolid interruption in patients with fluoroquinolone-resistant tuberculosis receiving a bedaquiline-based treatment regimen.

BACKGROUND: Treatment outcomes of patients with extensively drug-resistant tuberculosis (XDR-TB) are suboptimal and treatment options remain limited. Linezolid is associated with improved outcomes but also substantial toxicity, and details about the relationship between these are lacking from resource-poor HIV-endemic settings. METHODS: This was a prospective follow-up study of 63 South African XDR-TB patients (58.7% HIV-infected; median CD4 131 cells/μl) between 2014 and 2018. The frequency and severity of linezolid-associated adverse events and the impact on treatment outcomes were compared between linezolid interrupters and non-interrupters. RESULTS: Twenty-two patients (34.9%) discontinued or underwent dose reduction due to presumed linezolid-associated toxicity. Anaemia (77.3% vs. 7.3%; p< 0.001), peripheral neuropathy (63.6% vs. 14.6%; p= 0.003), and optic neuritis (18.2% vs. 9.8%; p= 0.34) occurred more frequently in linezolid interrupters than in non-interrupters. Anaemia, peripheral neuropathy, and optic neuritis occurred at a median of 5, 18, and 23 weeks, respectively, after treatment initiation. Linezolid interruption was not associated with unfavourable outcomes but was strongly associated with HIV co-infection (adjusted hazard ratio 4.831, 95% confidence interval 1.526-15.297; p= 0.007) and bacterial load (culture days to positivity; adjusted hazard ratio 0.824, 95% confidence interval 0.732- 0.927; p= 0.001). CONCLUSIONS: Linezolid-related treatment interruption is common, is strongly associated with HIV co-infection, and system-specific toxicity occurs within predictable time frames. These data inform the clinical management of patients with drug-resistant TB