Modified Fluoroquinolones as Antimicrobial Compounds Targeting Chlamydia trachomatis

Chlamydia trachomatis causes the most common sexually transmitted bacterial infection and trachoma, an eye infection. Untreated infections can lead to sequelae, such as infertility and ectopic pregnancy in women and blindness. We previously enhanced the antichlamydial activity of the fluoroquinolone ciprofloxacin by grafting a metal chelating moiety onto it. In the present study, we pursued this pharmacomodulation and obtained nanomolar active molecules (EC₅₀) against this pathogen. This gain in activity prompted us to evaluate the antibacterial activity of this family of molecules against other pathogenic bacteria, such as Neisseria gonorrhoeae and bacteria from the ESKAPE group. The results show that the novel molecules have selectively improved activity against C. trachomatis and demonstrate how the antichlamydial effect of fluoroquinolones can be enhanced.     

New Standards Release Sets Stage for 5G Future

Over the past year or so,wireless companies have begun to roll out fifth-generation (5G),the latest generation wireless network[1].For today's consumers,moving ...     

Marriage as a risk factor for internalizing disorders: Clarifying scope and specificity.

Objective: Marital discord has been linked to both depression and anxiety; however, our understanding of how marriage contributes to the development of internalizing symptoms is limited in scope and lacking specificity. First, it is unclear whether the marital relationship contributes to the broad dimension of internalizing symptoms as opposed to specific diagnoses. Second, it is unclear how the marital relationship contributes to internalizing symptoms: through global marital dissatisfaction or through specific relationship processes (and which processes). The purpose of the present study was to address these 2 issues and, more generally, to develop a comprehensive and refined framework within which to understand the role of marriage in the developmental course of internalizing symptoms. Method: Questionnaire and interview data were collected from 102 husbands and wives 5 times over the first 7 years of marriage. Results: Results indicated that marital discord during the transition into marriage was associated with the broad dimension of internalizing symptoms for husbands but not for wives. Further, both global marital dissatisfaction and an imbalance of power and control put husbands at significant risk for symptoms over the first 7 years of marriage, whereas low levels of emotional intimacy put wives at significant risk. Conclusions: Results exemplify the need to routinely consider intimate relationship processes in etiological models of depression and anxiety and to identify specific clinical targets that can be prioritized in interventions aimed at preventing internalizing disorders. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Measurement invariance of the Gifted Rating Scales—School Form across five cultural groups.

This study examined measurement invariance of the Gifted Rating Scales—School Form (GRS–S) across the United States, Puerto Rico, China, South Korea, and Turkey, using multigroup confirmatory factor analysis. A total of 1,817 students were rated by 287 teachers using either translated versions of GRS–S or the original English GRS–S. Results indicate a similar factor structure for the GRS–S across the five locations; six factors with each of the 72 items equivalently loaded to the same latent variable across groups. The metric invariance test and the factor variance and covariance invariance tests reveal that the patterns of factor loadings and the factor variances and covariances are invariant across the five groups. Moreover, the scalar invariance test indicates that item means are equivalent across the groups. These results suggest that the GRS–S has intercultural utility and can be similarly interpreted. Implications and limitations of the present research for gifted identification are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Benchmarking advanced architecture computers

Recently, a number of advanced architecture machines have become commercially available. These new machines promise better cost performance than traditional computers, and some of them have the potential of competing with current supercomputers, such as the CRAY X-MP, in terms of maximum performance. This paper describes the methodology and results of a pilot study of the performance of a broad range of advanced architecture computers using a number of complete scientific application programs. The computers evaluated include:

• 1 shared-memory bus architecture machines such as the Alliant FX/8, the Encore Multimax, and the Sequent Balance and Symmetry
• 2 shared-memory network-connected machines such as the Butterfly
• 3 distributed-memory machines such as the NCUBE, Intel and Jet Propulsion Laboratory (JPL)/Caltech hypercubes
• 4 very long instruction word machines such as the Cydrome Cydra-5
• 5 SIMD machines such as the Connection Machine
• 6 ‘traditional’ supercomputers such as the CRAY X-MP, CRAY-2 and SCS-40.

Seven application codes from a number of scientific disciplines have been used in the study, although not all the codes were run on every machine. The methodology and guidelines for establishing a standard set of benchmark programs for advanced architecture computers are discussed. The CRAYs offer the best performance on the benchmark suite; the shared memory multiprocessor machines generally permitted some parallelism, and when coupled with substantial floating point capabilities (as in the Alliant FX/8 and Sequent Symmetry), provided an order of magnitude less speed than the CRAYs. Likewise, the early generation hypercubes studied here generally ran slower than the CRAYs, but permitted substantial parallelism from each of the application codes.     

Immunotherapy for Biliary Tract Cancer in the Era of Precision Medicine: Current Knowledge and Future Perspectives

Biliary tract cancers (BTC) represent a heterogeneous and aggressive group of tumors with dismal prognosis. For a long time, BTC has been considered an orphan disease with very limited therapeutic options. In recent years a better understanding of the complex molecular landscape of biology is rapidly changing the therapeutic armamentarium. However, while 40–50% of patients there are molecular drivers susceptible to target therapy, for the remaining population new therapeutic options represent an unsatisfied clinical need. The role of immunotherapy in the continuum of treatment of patients with BTC is still debated. Despite initial signs of antitumor-activity, single-agent immune checkpoint inhibitors (ICIs) demonstrated limited efficacy in an unselected population. Therefore, identifying the best partner to combine ICIs and predictive biomarkers represents a key challenge to optimize the efficacy of immunotherapy. This review provides a critical analysis of completed trials, with an eye on future perspectives and possible biomarkers of response.     

Skeletal Muscle Microvascular Dysfunction in Obesity-Related Insulin Resistance: Pathophysiological Mechanisms and Therapeutic Perspectives

Obesity is a worrisomely escalating public health problem globally and one of the leading causes of morbidity and mortality from noncommunicable disease. The epidemiological link between obesity and a broad spectrum of cardiometabolic disorders has been well documented; however, the underlying pathophysiological mechanisms are only partially understood, and effective treatment options remain scarce. Given its critical role in glucose metabolism, skeletal muscle has increasingly become a focus of attention in understanding the mechanisms of impaired insulin function in obesity and the associated metabolic sequelae. We examined the current evidence on the relationship between microvascular dysfunction and insulin resistance in obesity. A growing body of evidence suggest an intimate and reciprocal relationship between skeletal muscle microvascular and glucometabolic physiology. The obesity phenotype is characterized by structural and functional changes in the skeletal muscle microcirculation which contribute to insulin dysfunction and disturbed glucose homeostasis. Several interconnected etiologic molecular mechanisms have been suggested, including endothelial dysfunction by several factors, extracellular matrix remodelling, and induction of oxidative stress and the immunoinflammatory phenotype. We further correlated currently available pharmacological agents that have deductive therapeutic relevance to the explored pathophysiological mechanisms, highlighting a potential clinical perspective in obesity treatment.     

Expanding the Spectrum of Antibiotics Capable of Killing Multidrug-Resistant Staphylococcus aureus and Pseudomonas aeruginosa

Infections from antibiotic-resistant Staphylococcus aureus and Pseudomonas aeruginosa are a serious threat because reduced antibiotic efficacy complicates treatment decisions and prolongs the disease state in many patients. To expand the arsenal of treatments against antimicrobial-resistant (AMR) pathogens, 600-Da branched polyethylenimine (BPEI) can overcome antibiotic resistance mechanisms and potentiate β-lactam antibiotics against Gram-positive bacteria. BPEI binds cell-wall teichoic acids and disables resistance factors from penicillin binding proteins PBP2a and PBP4. This study describes a new mechanism of action for BPEI potentiation of antibiotics generally regarded as agents effective against Gram-positive pathogens but not Gram-negative bacteria. 600-Da BPEI is able to reduce the barriers to drug influx and facilitate the uptake of a non-β-lactam co-drug, erythromycin, which targets the intracellular machinery. Also, BPEI can suppress production of the cytokine interleukin IL-8 by human epithelial keratinocytes. This enables BPEI to function as a broad-spectrum antibiotic potentiator, and expands the opportunities to improve drug design, antibiotic development, and therapeutic approaches against pathogenic bacteria, especially for wound care.