Experimental and Computational Analysis of a Large Protein Network That Controls Fat Storage Reveals the Design Principles of a Signaling Network

An approach combining genetic, proteomic, computational, and physiological analysis was used to define a protein network that regulates fat storage in budding yeast (Saccharomyces cerevisiae). A computational analysis of this network shows that it is not scale-free, and is best approximated by the Watts-Strogatz model, which generates “small-world” networks with high clustering and short path lengths. The network is also modular, containing energy level sensing proteins that connect to four output processes: autophagy, fatty acid synthesis, mRNA processing, and MAP kinase signaling. The importance of each protein to network function is dependent on its Katz centrality score, which is related both to the protein’s position within a module and to the module’s relationship to the network as a whole. The network is also divisible into subnetworks that span modular boundaries and regulate different aspects of fat metabolism. We used a combination of genetics and pharmacology to simultaneously block output from multiple network nodes. The phenotypic results of this blockage define patterns of communication among distant network nodes, and these patterns are consistent with the Watts-Strogatz model

Modeling and Analysis of Modular Structure in Diverse Biological Networks

Biological networks, like most engineered networks, are not the product of a singular design but rather are the result of a long process of refinement and optimization. Many large real-world networks are comprised of well-defined and meaningful smaller modules. While engineered networks are designed and refined by humans with particular goals in mind, biological networks are created by the selective pressures of evolution. In this paper, we seek to define aspects of network architecture that are shared among different types of evolved biological networks. First, we developed a new mathematical model, the Stochastic Block Model with Path Selection (SBM-PS) that simulates biological network formation based on the selection of edges that increase clustering. SBM-PS can produce modular networks whose properties resemble those of real networks. Second, we analyzed three real networks of very different types, and showed that all three can be fit well by the SBM-PS model. Third, we showed that modular elements within the three networks correspond to meaningful biological structures. The networks chosen for analysis were a proteomic network composed of all proteins required for mitochondrial function in budding yeast, a mesoscale anatomical network composed of axonal connections among regions of the mouse brain, and the connectome of individual neurons in the nematode C. elegans. We find that the three networks have common architectural features, and each can be divided into subnetworks with characteristic topologies that control specific phenotypic outputs

A new computational model captures fundamental architectural features of diverse biological networks

Complex biological systems are often represented by network graphs. However, their structural features are not adequately captured by existing computational graph models, perhaps because the datasets used to assemble them are incomplete and contain elements that lack shared functions. Here, we analyze three large, near-complete networks that produce specific cellular or behavioral outputs: a molecular yeast mitochondrial regulatory protein network, and two anatomical networks of very different scale, the mouse brain mesoscale connectivity network, and the C. elegans neuronal network. Surprisingly, these networks share similar characteristics. All consist of large communities composed of modules with general functions, and topologically distinct subnetworks spanning modular boundaries responsible for their more specific phenotypical outputs. We created a new model, SBM-PS, which generates networks by combining communities, followed by adjustment of connections by a path selection mechanism. This model captures fundamental architectural features that are common to the three networks

Broadly neutralizing antibodies abrogate established hepatitis C virus infection

In most exposed individuals, hepatitis C virus (HCV) establishes a chronic infection; this long-term infection in turn contributes to the development of liver diseases such as cirrhosis and hepatocellular carcinoma. The role of antibodies directed against HCV in disease progression is poorly understood. Neutralizing antibodies (nAbs) can prevent HCV infection in vitro and in animal models. However, the effects of nAbs on an established HCV infection are unclear. We demonstrate that three broadly nAbs—AR3A, AR3B, and AR4A—delivered with adeno-associated viral vectors can confer protection against viral challenge in humanized mice. Furthermore, we provide evidence that nAbs can abrogate an ongoing HCV infection in primary hepatocyte cultures and in a human liver chimeric mouse model. These results showcase a therapeutic approach to interfere with HCV infection by exploiting a previously unappreciated need for HCV to continuously infect new hepatocytes to sustain a chronic infection

Ionic mechanisms limiting cardiac repolarization-reserve in humans compared to dogs.

The species-specific determinants of repolarization are poorly understood. This study compared the contribution of various currents to cardiac repolarization in canine and human ventricle. Conventional microelectrode, whole-cell patch-clamp, molecular biological and mathematical modelling techniques were used. Selective IKr block (50–100 nmol l−1 dofetilide) lengthened AP duration at 90% of repolarization (APD90) >3-fold more in human than dog, suggesting smaller repolarization reserve in humans. Selective IK1 block (10 μmol l−1 BaCl2) and IKs block (1 μmol l−1 HMR-1556) increased APD90 more in canine than human right ventricular papillary muscle. Ion current measurements in isolated cardiomyocytes showed that IK1 and IKs densities were 3- and 4.5-fold larger in dogs than humans, respectively. IKr density and kinetics were similar in human versus dog. ICa and Ito were respectively ∼30% larger and ∼29% smaller in human, and Na+–Ca2+ exchange current was comparable. Cardiac mRNA levels for the main IK1 ion channel subunit Kir2.1 and the IKs accessory subunit minK were significantly lower, but mRNA expression of ERG and KvLQT1 (IKr and IKsα-subunits) were not significantly different, in human versus dog. Immunostaining suggested lower Kir2.1 and minK, and higher KvLQT1 protein expression in human versus canine cardiomyocytes. IK1 and IKs inhibition increased the APD-prolonging effect of IKr block more in dog (by 56% and 49%, respectively) than human (34 and 16%), indicating that both currents contribute to increased repolarization reserve in the dog. A mathematical model incorporating observed human–canine ion current differences confirmed the role of IK1 and IKs in repolarization reserve differences. Thus, humans show greater repolarization-delaying effects of IKr block than dogs, because of lower repolarization reserve contributions from IK1 and IKs, emphasizing species-specific determinants of repolarization and the limitations of animal models for human disease

Coma hipopotasémico: a propósito de un caso

Introduction: coma is the extreme degradation of consciousness. A syndrome characterized by a loss of vegetative functions, as an expression of acute and severe brain dysfunction.Presentation of the case: a 65-year-old male patient who two years ago commenced showing signs of loss of consciousness for two days In inter-crisis periods the studies did not confirm positive results. He was brought to the emergency room in a state of hyporeflexic coma. All parameters were normal except for a very discrete metabolic alkalosis and severe hypokalemia with 1,3 millimoles of potassium. General measures and complementary examinations were performed. Potassium values were replenished. As the potassium values standardized, a process of consciousness recovery was initiated. It was interpreted as a hypokalemic coma.Conclusions: hypopotassemia is a common imbalance, with repercussions in the different systems; this imbalance can result in alterations of the cardiovascular dynamics, progressive muscle weakness and coma. Therefore, in case of symptoms similar to hypokalemia, it is required to work on its diagnosis and treatment.Introducción: El coma es la máxima degradación del estado de conciencia. Síndrome caracterizado por una pérdida de las funciones de la vida de relación y conservación de las de la vida vegetativa, como expresión de una disfunción cerebral aguda y grave.Presentación del caso: paciente masculino de 65 años de edad que hace dos años comenzó con cuadros de pérdida de conciencia por espacio de dos días. En períodos intercrisis los estudios no arrojaron resultados positivos. Es traído a servicio de urgencia en estado de coma hiporrefléctico. Se tomaron medidas generales y se realizaron complementarios. Todo en parámetros de normalidad excepto por una muy discreta alcalosis metabólica y una hipocaliemia severa con 1,3 mili moles de potasio. Se reponen valores de potasio. En la medida que los valores de potasio se recuperaban se iniciaba un proceso de recuperación de la conciencia. Se interpreta como un coma hipopotasémico.Conclusiones: la hipopotasemia es un desbalance común, con repercusiones en los diferentes sistemas, que puede causar desde alteraciones de la dinámica cardiovascular, debilidad muscular progresiva y coma.  De ahí que ante sintomatologías similares a una hipopotasemia se deba trabajar en su diagnóstico y tratamiento.

A comparative study between ultrasound-guided interscalene and ultrasound-guided suprascapular nerve blocks in postoperative pain and hand motor power affection in shoulder scope surgeries

Abstract Background Interscalene approach for brachial plexus block is recognized as the gold standard technique for postoperative pain control after shoulder scope surgeries. However, it is associated with major adverse effects and patient discomfort due to paralysis of the hand muscles. The suprascapular nerve block is considered to be a safe and effective alternative to interscalene nerve block for shoulder surgery without affecting the motor function of the hand muscles and other serious complications of interscalene nerve block, especially in ambulatory surgery. The aim of this study is to compare interscalene and suprascapular nerve block in terms of postoperative pain, opioid consumption, and hand grip strength in shoulderscopic surgeries. This prospective, randomized trial was done in Ain Shams University Hospitals. A sample of 50 patients was divided into two groups; 25 patients in each group, namely Group ISB (interscalene approach of brachial plexus block) and Group SSNB (suprascapular nerve block). Visual analogue scale (VAS) was used to assess shoulder pain at rest and upon flexion in the first 24 h. The degree of hand motor power affection, the total amount of opioids used as rescue analgesia, and the incidence of complications were also recorded. Results The findings revealed no statistically significant difference between groups (P-value > 0.05) in pain control all over the 24 h by VAS score at rest and at arm flexion. SSNB received a larger total narcotic dose (60 ± 26.02) mg of pethidine than ISB (52 ± 22.73). However, there was no statistical difference between them throughout the 24 h regarding total narcotic consumption and 1st time for pethidine administration. The ISB group showed a statistically significant reduction in the hand power grip strength postoperatively (83.68 ± 4.75%). Conclusions The results of the present study favor SSNB as the first choice of pain control after shoulderscopic surgeries for a patient scheduled for early home discharge because of the complete recovery of the hand muscles’ motor power. Trial registration This study was registered on PACTR ( www.pactr.org ) database; identification number for the registry is PACTR202201840526231

Internode communication patterns deduced from drug-mutant interactions.

<p>(A) Representations of signaling relationships between drug targets and mutant genes. In the diagrams, gene A encodes protein A, while gene B encodes protein B, which is the target of the drug. (B) TLC assays of wild-type (wt) yeast (three replicates each) showing the impact of different drug treatments on triglyceride bands (arrows). All mutants were subjected to the same treatments and analyzed in the same manner, as exemplified by the three replicas of <i>mkk2∆</i> for each drug (note that U0126, which targets MAPKKs, does not increase fat levesl in <i>mkk2∆</i> cells relative to untreated mutant cells). (C-D) Networks of interactions between mutants and U0126 (C) and Rap (D). Protein names are given in the corresponding larger diagram in (E). Note that the majority of proteins have signaling interactions with the drugs that range from “same pathway” (no enhancement of drug effect by mutation; dark brown), to different degrees of synergism (enhancement of drug effect by mutation, indicated by different shades of light brown), and there are fewer cases of parallel pathway (independent) relationships, in which the drug and mutant effects are additive (light grey). These parallel pathway relationships are like the synthetic negative interactions seen in double mutant studies. Corresponding data for ChQ., Conc. A, and Cer. are in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004264#pcbi.1004264.s004" target="_blank">S4 Fig</a>. At the right side of panels (C) and (D) are indicated the global clustering coefficient (upper) and path length (lower) for a subnetwork of all proteins having a “same pathway” relationship to that drug (red font), presented over the mean of values from 10,000 simulated random networks with the same degree distribution and vertex count (green font). (E) Diagram of same pathway signaling relationships between drugs and network proteins. The circle color represents the number of drugs with which a protein has a same pathway relationship.</p

Genes for which mutations affect conversion of glucose or aspartic acid to fat affect connected proteins.

<p>(A) Proteins encoded by genes for which mutation produces more than a 20% increase in the rate of conversion of ¹⁴C labeled D-glucose to fat relative to wild-type tend to be proteomically connected to one another. (B) Proteins encoded by genes for which mutation produces more than a 20% increase in the rate of conversion of ¹⁴C labeled L-aspartic acid to fat relative to wild-type tend to be proteomically connected to one another. At the right side of each panel is the global clustering coefficient (upper) and path length (lower) for each subnetwork (red font), presented over the mean of values from 10,000 simulated random networks with the same degree distribution and vertex count as the subnetwork in that panel (green font). Key for diagrams as in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004264#pcbi.1004264.g001" target="_blank">Fig 1</a>.</p