Diffuse bipolar cells provide input to OFF parasol ganglion cells in the macaque retina

Parasol retinal ganglion cells are more sensitive to luminance contrast and respond more transiently at all levels of adaptation than midget ganglion cells. This may be due, in part, to differences between bipolar cells that provide their input, and the goal of these experiments was to study these differences. Midget bipolar cells are known to be presynaptic to midget ganglion cells. To identify the bipolar cells presynaptic to parasol cells, these ganglion cells were intracellularly injected with Neurobiotin, cone bipolar cells were immunolabeled, and the double-labeled material was analyzed. In the electron microscope, we found that DB3 diffuse bipolar cells labeled by using antiserum to calbindin D-28k were presynaptic to OFF parasol cells. In the confocal microscope, DB3 bipolars costratified with OFF parasol cell dendrites and made significantly more appositions with them than expected due to chance. Flat midget bipolar cells were labeled with antiserum to recoverin. Although they made a few appositions with parasol cells, the number was no greater than would be expected when two sets of processes have overlapping distributions in the inner plexiform layer. DB2 diffuse bipolar cells were labeled with antibodies to excitatory amino acid transporter 2, and they also made appositions with OFF parasol cells. These results suggest that DB2 bipolar cells are also presynaptic to OFF parasol ganglion cells, but midget bipolar cells are not. We estimate that midperipheral OFF parasol cells receive approximately 500 synapses from 50 DB3 bipolar cells that, in turn, receive input from 250 cones.     

Functional Alternatives to Alcohol

The consumption of alcohol is associated with well-known health harms and many governments worldwide are actively engaged in devising approaches to reduce them. To this end, a common proposed strategy aims at reducing alcohol consumption. This approach has led to the development of non-alcoholic drinks, which have been especially welcome by younger, wealthier, health-conscious consumers, who have been turning away from alcohol to look toward alternatives. However, a drawback of non-alcoholic drinks is that they do not facilitate social interaction in the way alcohol does, which is the main reason behind social drinking. Therefore, an alternative approach is to develop functional drinks that do not use alcohol yet mimic the positive, pro-social effects of alcohol without the associated harms. This article will discuss (1) current knowledge of how alcohol mediates its effects in the brain, both the desirable, e.g., antistress to facilitate social interactions, and the harmful ones, with a specific focus on the pivotal role played by the gamma-aminobutyric acid (GABA) neurotransmitter system and (2) how this knowledge can be exploited to develop functional safe alternatives to alcohol using either molecules already existing in nature or synthetic ones. This discussion will be complemented by an analysis of the regulatory challenges associated with the novel endeavour of bringing safe, functional alternatives to alcohol from the bench to bars.     

Mutational Analysis of Quinolone Resistance Protein QnrB1

Alanine substitutions and selected deletions have been used to localize amino acids in QnrB essential for its protective activity. Essential amino acids are found at positions i and i⁻² in the pentapeptide repeat module and in the larger of two loops, where deletion of only a single amino acid compromises activity. Deletion of 10 amino acids at the N terminus is tolerated, but removal of 3 amino acids in the C-terminal dimerization unit destroys activity.     

Self-Punishment as a Maladaptive Thought Control Strategy Mediates the Relationship Between Beliefs About Thoughts and Repugnant Obsessions

Cognitive-behavioral models of obsessive–compulsive disorder (OCD) propose that erroneous beliefs about the importance and need to control thoughts lead individuals with OCD to overuse maladaptive thought control strategies such as worry and self-punishment. These strategies are thought to backfire, leading to obsessional symptoms. Whereas previous studies have examined predictors of the use of thought control strategies, none have investigated these strategies as mediators in the prediction of OCD symptom severity. An additional gap in the literature is the lack of attention to OCD symptom dimensions. The present study, therefore, extended existing work by examining thought control strategies as mediators of the relationship between obsessive beliefs and OCD symptom dimensions in a treatment-seeking sample of 102 adults with OCD. In line with our hypotheses, the use of punishment (but not worry) as a thought control tactic mediated the relationship between dysfunctional beliefs about the importance/control of thoughts and unacceptable obsessions. These findings are discussed in terms of the conceptualization and treatment of OCD. Future research should investigate the extent to which these various thought control strategies may be helpful versus harmful using idiographic measures of thought control and employing experimental designs.     

A Clinical Guide to Combination Lipid-Lowering Therapy

Purpose of Review

We provide an overview of our current understanding of combination lipid-lowering therapies intended for dyslipidemia treatment and cardiovascular disease prevention. First, we analyze recent statin and non-statin combination therapy guidelines and clinical studies since the publication of 2013 American College of Cardiology Cholesterol Guidelines. Second, we examine the clinical utility of non-statin agents alone and in combination in terms of LDL-C lowering and ASCVD risk reduction.

Recent Findings

Medical societies, including the American College of Cardiology (ACC), National Lipid Association (NLA), and American Association of Clinical Endocrinologists (AACE), have released guidelines to address the appropriate use of non-statin therapies. The guidelines incorporated new evidence, including the IMPROVE-IT and FOURIER clinical trials, which demonstrate that the combination of statin therapy with other non-statin agents such as ezetimibe and PCSK9 inhibitors has a significant clinical benefit. Increasing evidence that aggressive low-density lipoprotein cholesterol (LDL-C) lowering leads to lower cardiovascular disease risk supports the need for continued exploration of the role of combination lipid-lowering therapies.

Summary

A review of guidelines and clinical trials evaluating non-statin agents illuminates the growing base of evidence and expert opinion supporting the use of combination lipid-lowering therapies. While the majority of clinical trial data utilizes dyslipidemia monotherapy, especially statins, combination therapies represent an opportunity for individualized, patient-centered approach to LDL-C lowering and atherosclerotic cardiovascular disease (ASCVD) risk reduction. The overview provides a perspective on lipid management intended for clinicians who seek additional information and guidance on the use of combination therapies.

     

Interactions between QnrB,QnrB Mutants,and DNA Gyrase

Plasmid-encoded protein QnrB1 protects DNA gyrase from ciprofloxacin inhibition. Using a bacterial two-hybrid system, we evaluated the physical interactions between wild-type and mutant QnrB1, the GyrA and GyrB gyrase subunits, and a GyrBA fusion protein. The interaction of QnrB1 with GyrB and GyrBA was approximately 10-fold higher than that with GyrA, suggesting that domains of GyrB are important for stabilizing QnrB1 interaction with the holoenzyme. Sub-MICs of ciprofloxacin or nalidixic acid reduced the interactions between QnrB1 and GyrA or GyrBA but produced no reduction in the interaction with GyrB or a quinolone-resistant GyrA:S83L (GyrA with S83L substitution) mutant, suggesting that quinolones and QnrB1 compete for binding to gyrase. Of QnrB1 mutants that reduced quinolone resistance, deletions in the C or N terminus of QnrB1 resulted in a marked decrease in interactions with GyrA but limited or no effect on interactions with GyrB and an intermediate effect on interactions with GyrBA. While deletion of loop B and both loops moderately reduced the interaction signal with GyrA, deletion of loop A resulted in only a small reduction in the interaction with GyrB. The loop A deletion also caused a substantial reduction in interaction with GyrBA, with little effect of loop B and dual-loop deletions. Single-amino-acid loop mutations had little effect on physical interactions except for a Δ105I mutant. Therefore, loops A and B may play key roles in the proper positioning of QnrB1 rather than as determinants of the physical interaction of QnrB1 with gyrase.