Domestic credit growth and international capital flows

Europe experienced substantial cross-country variation in domestic credit growth and cross border capital flows during the pre-crisis period. We investigate the inter-relations between domestic credit growth and international capital flows over 1993-2008, with a special focus on the 2003-2008 boom period. We establish that domestic credit growth in European countries is strongly related to net debt inflows but not to net equity inflows. This pattern also holds for an extended sample of 54 advanced and emerging economies

On-orbit assembly using superquadric potential fields

The autonomous on-orbit assembly of a large space structure is presented using a method based on superquadric artificial potential fields. The final configuration of the elements which form the structure is represented as the minimum of some attractive potential field. Each element of the structure is then considered as presenting an obstacle to the others using a superquadric potential field attached to the body axes of the element. A controller is developed which ensures that the global potential field decreases monotonically during the assembly process. An error quaternion representation is used to define both the attractive and superquadric obstacle potentials allowing the final configuration of the elements to be defined through both relative position and orientation. Through the use of superquadric potentials, a wide range of geometric objects can be represented using a common formalism, while collision avoidance can make use of both translational and rotation maneuvers to reduce total maneuver cost for the assembly process

Seminaphthofluorescein-Based Fluorescent Probes for Imaging Nitric Oxide in Live Cells

Fluorescent turn-on probes for nitric oxide based on seminaphthofluorescein scaffolds were prepared and spectroscopically characterized. The Cu(II) complexes of these fluorescent probes react with NO under anaerobic conditions to yield a 20–45-fold increase in integrated emission. The seminaphthofluorescein-based probes emit at longer wavelengths than the parent FL1 and FL2 fluorescein-based generations of NO probes, maintaining emission maxima between 550 and 625 nm. The emission profiles depend on the excitation wavelength; maximum fluorescence turn-on is achieved at excitations between 535 and 575 nm. The probes are highly selective for NO over other biologically relevant reactive nitrogen and oxygen species including NO3–, NO2–, HNO, ONOO–, NO2, OCl–, and H2O2. The seminaphthofluorescein-based probes can be used to visualize endogenously produced NO in live cells, as demonstrated using Raw 264.7 macrophages.National Science Foundation (U.S.) (CHE-0611944)National Institutes of Health (U.S.) (K99GM092970

Triad3a induces the degradation of early necrosome to limit RipK1-dependent cytokine production and necroptosis.

Understanding the molecular signaling in programmed cell death is vital to a practical understanding of inflammation and immune cell function. Here we identify a previously unrecognized mechanism that functions to downregulate the necrosome, a central signaling complex involved in inflammation and necroptosis. We show that RipK1 associates with RipK3 in an early necrosome, independent of RipK3 phosphorylation and MLKL-induced necroptotic death. We find that formation of the early necrosome activates K48-ubiquitin-dependent proteasomal degradation of RipK1, Caspase-8, and other necrosomal proteins. Our results reveal that the E3-ubiquitin ligase Triad3a promotes this negative feedback loop independently of typical RipK1 ubiquitin editing enzymes, cIAPs, A20, or CYLD. Finally, we show that Triad3a-dependent necrosomal degradation limits necroptosis and production of inflammatory cytokines. These results reveal a new mechanism of shutting off necrosome signaling and may pave the way to new strategies for therapeutic manipulation of inflammatory responses

Lipidomics Reveals Early Metabolic Changes in Subjects with Schizophrenia: Effects of Atypical Antipsychotics

There is a critical need for mapping early metabolic changes in schizophrenia to capture failures in regulation of biochemical pathways and networks. This information could provide valuable insights about disease mechanisms, trajectory of disease progression, and diagnostic biomarkers. We used a lipidomics platform to measure individual lipid species in 20 drug-naïve patients with a first episode of schizophrenia (FE group), 20 patients with chronic schizophrenia that had not adhered to prescribed medications (RE group), and 29 race-matched control subjects without schizophrenia. Lipid metabolic profiles were evaluated and compared between study groups and within groups before and after treatment with atypical antipsychotics, risperidone and aripiprazole. Finally, we mapped lipid profiles to n3 and n6 fatty acid synthesis pathways to elucidate which enzymes might be affected by disease and treatment. Compared to controls, the FE group showed significant down-regulation of several n3 polyunsaturated fatty acids (PUFAs), including 20:5n3, 22:5n3, and 22:6n3 within the phosphatidylcholine and phosphatidylethanolamine lipid classes. Differences between FE and controls were only observed in the n3 class PUFAs; no differences where noted in n6 class PUFAs. The RE group was not significantly different from controls, although some compositional differences within PUFAs were noted. Drug treatment was able to correct the aberrant PUFA levels noted in FE patients, but changes in re patients were not corrective. Treatment caused increases in both n3 and n6 class lipids. These results supported the hypothesis that phospholipid n3 fatty acid deficits are present early in the course of schizophrenia and tend not to persist throughout its course. These changes in lipid metabolism could indicate a metabolic vulnerability in patients with schizophrenia that occurs early in development of the disease. © 2013 McEvoy et al

Hospitalization rates in patients switched from oral anti-psychotics to aripiprazole once-monthly: final efficacy analysis

Abstract Objective: To compare hospitalization rates in patients with schizophrenia treated prospectively with aripiprazole once-monthly 400 mg (AOM 400; an extended-release injectable suspension) vs the same patients\u27 retrospective rates with their prior oral anti-psychotic therapy. Research design and methods: Multi-center, open-label, mirror-image, naturalistic study in a community setting in North America. Patients who required a change in treatment and/or would benefit from long-acting injectable anti-psychotic therapy were treated prospectively for 6 months with AOM 400. Retrospective data on hospitalization rates were obtained. Clinical trial registration: ClinicalTrials.gov: NCT01432444. Main outcome measures: The proportion of patients with \u3e/=1 psychiatric inpatient hospitalization with oral anti-psychotic therapy examined retrospectively (months -4 to -1 before oral conversion) and after switching to AOM 400 (months 4-6 after initiating AOM 400). Results: Psychiatric hospitalization rates were significantly lower when patients were treated with AOM 400 compared with oral anti-psychotic therapy both in the 3-month primary efficacy sample (2.7% [n = 9/336] vs 27.1% [n = 91/336], respectively; p \u3c 0.0001) and in the total sample (6-month prospective rate: 8.8% [n = 38/433] vs 6-month retrospective rate: 38.1% [n = 165/433]; p \u3c 0.0001). Discontinuations due to adverse events (AEs) during cross-titration were lower in patients cross-titrated on oral aripiprazole for \u3e1 and(2.9% [n = 7/239]) compared with patients cross-titrated fo

Process design and optimisation for the continuous manufacturing of Nevirapine, an Active Pharmaceutical Ingredient (API) for H.I.V. treatment

Development of efficient and cost-effective manufacturing routes towards HIV active pharmaceutical ingredients (APIs) is essential to ensure their global, affordable access. Continuous pharmaceutical manufacturing (CPM) is a new production paradigm for the pharmaceutical industry, whose potential for enhanced efficiency and economic viability over currently implemented batch protocols offers promise for improving HIV API production. Nevirapine is a widely-prescribed HIV API, whose continuous flow synthesis was recently demonstrated. This paper presents technoeconomic optimisation of nevirapine CPM, including the continuous flow synthesis and a conceptual continuous crystallisation. Arrhenius law parameter estimation from published reaction kinetic data allows explicit modelling of the temperature-dependence of reaction performance and an experimentally validated aqueous API solubility computation method is used to model crystallisation processes. A nonlinear optimisation problem for cost minimisation is formulated for comparative evaluation of different plant designs. Higher reactor temperatures are favoured for CPM total cost minimisation, while lower pH (less neutralising agent) is required to attain the desired plant capacities for cost optimal configurations compared to batch crystallisation designs. Suitable E-factors for pharmaceutical manufacturing are attained when higher solvent recoveries are assumed. Implementing CPM designs significantly lowers the nevirapine cost of goods towards reducing the price of societally- mportant HIV medicines

Prevalence of Plasmodium species in asymptomatic individuals in North-Eastern South Africa: 2018 - 2019

Background. Asymptomatic Plasmodium infections in endemic areas pose a challenge to malaria prevention and control strategies. The Ha-Lambani area in Vhembe district, Limpopo Province, South Africa, experiences periodic malaria outbreaks, possibly influenced by asymptomatic Plasmodium infections. In addition, the identification and monitoring of the Plasmodium falciparum Kelch 13 (Pfk13) gene associated with artemisinin resistance are crucial for understanding the emergence and spread of drug-resistant malaria in endemic areas. Objective. To determine the prevalence of asymptomatic Plasmodium infection and Pfk13 gene polymorphisms in the Ha-Lambani area in the absence of a malaria outbreak. Methods. Finger-prick dried blood spots from 985 asymptomatic individuals were collected from November 2018 to May 2019. A P. falciparum-specific rapid diagnostic test (RDT) was used to test for Plasmodium infection. High-resolution melt (HRM) analysis was used to test for P. falciparum, P. ovale, P. vivax and P. malariae. The prevalence of Plasmodium infection was determined by the proportion of positive cases detected by at least one of the tests. The Pfk13 gene was amplified from P. falciparum-positive samples, sequenced by Sanger and Illumina next-generation sequencing (NGS) and analysed for genetic diversity and resistance mutations to artemisinin. Results. A prevalence of 7.1% (70/985; 95% confidence interval (CI): 0.054 - 0.087) of Plasmodium infection was observed. The dominant species was P. ovale (57.14%; n=40), followed by P. falciparum (37.1%; n=26), P. malariae (1.43%) and P. vivax (1.43%). Mixed infections were P. falciparum/P. ovale (2.9%). Plasmodium infections differed significantly by village (p<0.01). The Pfk13 gene was amplified from 5/30 (95% CI: 0.03 - 0.29). Analysis of NGS reads revealed 57 single nucleotide polymorphisms (SNPs) across the Pfk13 gene (≥20% minority level). Up to 70.1% (39/57; 95% CI: 0.59 - 0.83) of the SNPs were non-synonymous and none was previously associated with artemisinin resistance. However, novel SNPs (H719Q, P701T, M472I, I526R and P443S) were detected in the propeller domain. Conclusion. A relatively high asymptomatic Plasmodium infection prevalence was observed in the study area, with P. ovale being the most prevalent species. Therefore, P. ovale infections may be missed with the Plasmodium RDT. R21 and RTS,S vaccines may not offer protection against P. ovale in the study area. Further research is needed to link asymptomatic infections in the study area and the periodic malaria outbreaks, and to determine the significance of the novel SNP in the Pfk13 gene