Perfil sócio-econômico e tecnológico das propriedades viticolas dos municípios de Bento Gonçalves e Flores da Cunha - RS.

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SC83288 is a clinical development candidate for the treatment of severe malaria

Severe malaria is a life-threatening complication of an infection with the protozoan parasite Plasmodium falciparum, which requires immediate treatment. Safety and efficacy concerns with currently used drugs accentuate the need for new chemotherapeutic options against severe malaria. Here we describe a medicinal chemistry program starting from amicarbalide that led to two compounds with optimized pharmacological and antiparasitic properties. SC81458 and the clinical development candidate, SC83288, are fast-acting compounds that can cure a P. falciparum infection in a humanized NOD/SCID mouse model system. Detailed preclinical pharmacokinetic and toxicological studies reveal no observable drawbacks. Ultra-deep sequencing of resistant parasites identifies the sarco/endoplasmic reticulum Ca(2+) transporting PfATP6 as a putative determinant of resistance to SC81458 and SC83288. Features, such as fast parasite killing, good safety margin, a potentially novel mode of action and a distinct chemotype support the clinical development of SC83288, as an intravenous application for the treatment of severe malaria

Packing of elastic wires in spherical cavities

We investigate the morphologies and maximum packing density of thin wires packed into spherical cavities. Using simulations and experiments, we find that ordered as well as disordered structures emerge, depending on the amount of internal torsion. We find that the highest packing densities are achieved in low torsion packings for large systems, but in high torsion packings for small systems. An analysis of both situations is given in terms of energetics and comparison is made to analytical models of DNA packing in viral capsids.Comment: 4 page

Structure of the merozoite surface protein 1 from Plasmodium falciparum

The merozoite surface protein 1 (MSP-1) is the most abundant protein on the surface of the erythrocyte-invading Plasmodium merozoite, the causative agent of malaria. MSP-1 is essential for merozoite formation, entry into and escape from erythrocytes, and is a promising vaccine candidate. Here, we present monomeric and dimeric structures of full-length MSP-1. MSP-1 adopts an unusual fold with a large central cavity. Its fold includes several coiled-coils and shows structural homology to proteins associated with membrane and cytoskeleton interactions. MSP-1 formed dimers through these domains in a concentration-dependent manner. Dimerization is affected by the presence of the erythrocyte cytoskeleton protein spectrin, which may compete for the dimerization interface. Our work provides structural insights into the possible mode of interaction of MSP-1 with erythrocytes and establishes a framework for future investigations into the role of MSP-1 in Plasmodium infection and immunity

KAHRP dynamically relocalizes to remodeled actin junctions and associates with knob spirals in Plasmodium falciparum-infected erythrocytes

The knob-associated histidine-rich protein (KAHRP) plays a pivotal role in the pathophysiology of Plasmodium falciparum malaria by forming membrane protrusions in infected erythrocytes, which anchor parasite-encoded adhesins to the membrane skeleton. The resulting sequestration of parasitized erythrocytes in the microvasculature leads to severe disease. Despite KAHRP being an important virulence factor, its physical location within the membrane skeleton is still debated, as is its function in knob formation. Here, we show by super-resolution microscopy that KAHRP initially associates with various skeletal components, including ankyrin bridges, but eventually colocalizes with remnant actin junctions. We further present a 35 Å map of the spiral scaffold underlying knobs and show that a KAHRP-targeting nanoprobe binds close to the spiral scaffold. Single-molecule localization microscopy detected ~60 KAHRP molecules/knob. We propose a dynamic model of KAHRP organization and a function of KAHRP in attaching other factors to the spiral scaffold

Acoustic cardiac triggering: a practical solution for synchronization and gating of cardiovascular magnetic resonance at 7 Tesla

<p>Abstract</p> <p>Background</p> <p>To demonstrate the applicability of acoustic cardiac triggering (ACT) for imaging of the heart at ultrahigh magnetic fields (7.0 T) by comparing phonocardiogram, conventional vector electrocardiogram (ECG) and traditional pulse oximetry (POX) triggered 2D CINE acquisitions together with (i) a qualitative image quality analysis, (ii) an assessment of the left ventricular function parameter and (iii) an examination of trigger reliability and trigger detection variance derived from the signal waveforms.</p> <p>Results</p> <p>ECG was susceptible to severe distortions at 7.0 T. POX and ACT provided waveforms free of interferences from electromagnetic fields or from magneto-hydrodynamic effects. Frequent R-wave mis-registration occurred in ECG-triggered acquisitions with a failure rate of up to 30% resulting in cardiac motion induced artifacts. ACT and POX triggering produced images free of cardiac motion artefacts. ECG showed a severe jitter in the R-wave detection. POX also showed a trigger jitter of approximately Δt = 72 ms which is equivalent to two cardiac phases. ACT showed a jitter of approximately Δt = 5 ms only. ECG waveforms revealed a standard deviation for the cardiac trigger offset larger than that observed for ACT or POX waveforms.</p> <p>Image quality assessment showed that ACT substantially improved image quality as compared to ECG (image quality score at end-diastole: ECG = 1.7 ± 0.5, ACT = 2.4 ± 0.5, p = 0.04) while the comparison between ECG vs. POX gated acquisitions showed no significant differences in image quality (image quality score: ECG = 1.7 ± 0.5, POX = 2.0 ± 0.5, p = 0.34).</p> <p>Conclusions</p> <p>The applicability of acoustic triggering for cardiac CINE imaging at 7.0 T was demonstrated. ACT's trigger reliability and fidelity are superior to that of ECG and POX. ACT promises to be beneficial for cardiovascular magnetic resonance at ultra-high field strengths including 7.0 T.</p

Erratum: SC83288 is a clinical development candidate for the treatment of severe malaria

No abstract available

Uncovering cis Regulatory Codes Using Synthetic Promoter Shuffling

Revealing the spectrum of combinatorial regulation of transcription at individual promoters is essential for understanding the complex structure of biological networks. However, the computations represented by the integration of various molecular signals at complex promoters are difficult to decipher in the absence of simple cis regulatory codes. Here we synthetically shuffle the regulatory architecture — operator sequences binding activators and repressors — of a canonical bacterial promoter. The resulting library of complex promoters allows for rapid exploration of promoter encoded logic regulation. Among all possible logic functions, NOR and ANDN promoter encoded logics predominate. A simple transcriptional cis regulatory code determines both logics, establishing a straightforward map between promoter structure and logic phenotype. The regulatory code is determined solely by the type of transcriptional regulation combinations: two repressors generate a NOR: NOT (a OR b) whereas a repressor and an activator generate an ANDN: a AND NOT b. Three-input versions of both logics, having an additional repressor as an input, are also present in the library. The resulting complex promoters cover a wide dynamic range of transcriptional strengths. Synthetic promoter shuffling represents a fast and efficient method for exploring the spectrum of complex regulatory functions that can be encoded by complex promoters. From an engineering point of view, synthetic promoter shuffling enables the experimental testing of the functional properties of complex promoters that cannot necessarily be inferred ab initio from the known properties of the individual genetic components. Synthetic promoter shuffling may provide a useful experimental tool for studying naturally occurring promoter shuffling