Liver fat and SHBG affect insulin resistance in midlife women: The Study of Women's Health Across the Nation (SWAN)

Objective:

The liver is an insulin‐responsive organ that contributes significantly to both whole body insulin sensitivity and availability of sex steroids through the production of sex hormone binding globulin (SHBG). Our objective was to explore whether lower SHBG was associated with ectopic liver fat and mediated its effect on insulin resistance in The Study of Women's Health Across the Nation (SWAN).

Design and Methods:

A subset of midlife African American and Caucasian women from SWAN (n = 208; 50.9 ± 0.18 yrs; 71% Caucasian) had computed tomography scans to quantify visceral, subcutaneous and liver fat. Blood samples were collected and assayed for hormonal and metabolic markers.

Results:

The cohort, while overweight, was generally healthy, and both liver fat and SHBG were unaffected by menopausal stage or race. Both higher liver fat and lower SHBG levels were significantly associated with higher insulin concentrations after adjustment for adiposity (r = ?0.25, P < 0.001 and r = ?0.18, P = 0.01). SHBG and liver fat had additive effects on insulin concentrations such that women with the lowest SHBG and the highest fat levels had the highest values (interaction P = 0.09). The association between SHBG and insulin was more apparent among women with fattier livers. SHBG and liver fat appear to have independent effects on insulin levels as adjustment for each other did not diminish the strength of either association (P = 0.023 and 0.001 respectively).

Conclusion:

These results confirmed the strong independent associations between increased liver fat and decreased SHBG with increased metabolic risk in midlife women. Further these data underscore the need for additional research into the role of liver fat in modifying SHBG's influence on insulin levels.

     

Cannabinoid receptor 1 (CNR1) gene variant moderates neural index of cognitive disruption during nicotine withdrawal

Nicotine withdrawal‐related disruption of cognitive control may contribute to the reinforcement of tobacco use. Identification of gene variants that predict this withdrawal phenotype may lead to tailored pharmacotherapy for smoking cessation. Variation on the cannabinoid receptor 1 gene (CNR1) has been related to nicotine dependence, and CNR1 antagonists may increase attention and memory functioning. We targeted CNR1 variants as moderators of a validated neural marker of nicotine withdrawal‐related cognitive disruption. CNR1 polymorphisms comprising the ‘TAG’ haplotype (rs806379, rs1535255 and rs2023239) were tested independently, as no participants in this sample possessed this haplotype. Nicotine withdrawal‐related cognitive disruption was indexed as increased resting electroencephalogram (EEG) alpha‐1 power density across 17 electrodes. Seventy‐three Caucasian Non‐Hispanic smokers (≥15 cigarettes per day) visited the laboratory on two occasions following overnight smoking/nicotine deprivation. Either two nicotine or two placebo cigarettes were smoked prior to collecting EEG data at each session. Analyses showed that rs806379 moderated the effects of nicotine deprivation increasing slow wave EEG (P = 0.004). Smokers homozygous for the major allele exhibited greater nicotine withdrawal‐related cognitive disruption. The current findings suggest potential efficacy of cannabinoid receptor antagonism as a pharmacotherapy approach for smoking cessation among individuals who exhibit greater nicotine withdrawal‐related cognitive disruption.     

Marine biology of the pacific lamprey Entosphenus tridentatus

Reviews in Fish Biology and Fisheries - Pacific lamprey Entosphenus tridentatus has an anadromous life cycle that begins with larvae that filter-feed in freshwater, followed by transformation into...     

Length polymorphisms at two candidate genes explain variation of migratory behaviors in blackpoll warblers (Setophaga striata)

Migratory behaviors such as the timing and duration of migration are genetically inherited and can be under strong natural selection, yet we still know very little about the specific genes or molecular pathways that control these behaviors. Studies in candidate genes Clock and Adcyap1 have revealed that both of these loci can be significantly correlated with migratory behaviors in birds, though observed relationships appear to vary across species. We investigated geographic genetic structure of Clock and Adcyap1 in four populations of blackpoll warblers (Setophaga striata), a Neotropical–Nearctic migrant that exhibits geographic variation in migratory timing and duration across its boreal breeding distribution. Further, we used data on migratory timing and duration, obtained from light‐level geolocator trackers to investigate candidate genotype–phenotype relationships at the individual level. While we found no geographic structure in either candidate gene, we did find evidence that candidate gene lengths are correlated with five of the six migratory traits. Maximum Clock allele length was significantly and negatively associated with spring arrival date. Minimum Adcyap1 allele length was significantly and negatively associated with spring departure date and positively associated with fall arrival date at the wintering grounds. Additionally, we found a significant interaction between Clock and Adcyap1 allele lengths on both spring and fall migratory duration. Adcyap1 heterozygotes also had significantly shorter migration duration in both spring and fall compared to homozygotes. Our results support the growing body of evidence that Clock and Adcyap1 allele lengths are correlated with migratory behaviors in birds.     

Patient-level interventions to reduce alcohol-related harms in low- and middle-income countries: A systematic review and meta-summary

BackgroundDisease and disability from alcohol use disproportionately impact people in low- and middle-income countries (LMICs). While varied interventions have been shown to reduce alcohol use in high-income countries, their efficacy in LMICs has not been assessed. This systematic review describes current published literature on patient-level alcohol interventions in LMICs and specifically describes clinical trials evaluating interventions to reduce alcohol use in LMICs.Methods and findingsIn accordance with PRISMA, we performed a systematic review using an electronic search strategy from January 1, 1995 to December 1, 2020. Title, abstract, as well as full-text screening and extraction were performed in duplicate. A meta-summary was performed on randomized controlled trials (RCTs) that evaluated alcohol-related outcomes. We searched the following electronic databases: PubMed, EMBASE, Scopus, Web of Science, Cochrane, WHO Global Health Library, and PsycINFO. Articles that evaluated patient-level interventions targeting alcohol use and alcohol-related harm in LMICs were eligible for inclusion. No studies were excluded based on language.After screening 5,036 articles, 117 articles fit our inclusion criteria, 75 of which were RCTs. Of these RCTs, 93% were performed in 13 middle-income countries, while 7% were from 2 low-income countries. These RCTs evaluated brief interventions (24, defined as any intervention ranging from advice to counseling, lasting less than 1 hour per session up to 4 sessions), psychotherapy or counseling (15, defined as an interaction with a counselor longer than a brief intervention or that included a psychotherapeutic component), health promotion and education (20, defined as an intervention encouraged individuals’ agency of taking care of their health), or biologic treatments (19, defined as interventions where the biological function of alcohol use disorder (AUD) as the main nexus of intervention) with 3 mixing categories of intervention types. Due to high heterogeneity of intervention types, outcome measures, and follow-up times, we did not conduct meta-analysis to compare and contrast studies, but created a meta-summary of all 75 RCT studies. The most commonly evaluated intervention with the most consistent positive effect was a brief intervention; similarly, motivational interviewing (MI) techniques were most commonly utilized among the diverse array of interventions evaluated.ConclusionsOur review demonstrated numerous patient-level interventions that have the potential to be effective in LMICs, but further research to standardize interventions, populations, and outcome measures is necessary to accurately assess their effectiveness. Brief interventions and MI techniques were the most commonly evaluated and had the most consistent positive effect on alcohol-related outcomes.Trial registrationProtocol Registry: PROSPERO CRD42017055549

Catherine Staton and co-workers report on evidence about interventions against harmful alcohol use in low- and middle-income countries.     

Cytosolic delivery of granzyme B by bacterial toxins: evidence that endosomal disruption, in addition to transmembrane pore formation, is an important function of perforin

Granule-mediated cell killing by cytotoxic lymphocytes requires the combined actions of a membranolytic protein, perforin, and granule-associated granzymes, but the mechanism by which they jointly kill cells is poorly understood. We have tested a series of membrane-disruptive agents including bacterial pore-forming toxins and hemolytic complement for their ability to replace perforin in facilitating granzyme B-mediated cell death. As with perforin, low concentrations of streptolysin O and pneumolysin (causing <10% (51)Cr release) permitted granzyme B-dependent apoptosis of Jurkat and Yac-1 cells, but staphylococcal alpha-toxin and complement were ineffective, regardless of concentration. The ensuing nuclear apoptotic damage was caspase dependent and included cleavage of poly(ADP-ribose) polymerase, suggesting a mode of action similar to that of perforin. The plasma membrane lesions formed at low dose by perforin, pneumolysin, and streptolysin did not permit diffusion of fluorescein-labeled proteins as small as 8 kDa into the cell, indicating that large membrane defects are not necessary for granzymes (32 to 65 kDa) to enter the cytosol and induce apoptosis. The endosomolytic toxin, listeriolysin O, also effected granzyme B-mediated cell death at concentrations which produced no appreciable cell membrane damage. Cells pretreated with inhibitors of endosomal trafficking such as brefeldin A took up granzyme B normally but demonstrated seriously impaired nuclear targeting of granzyme B when perforin was also added, indicating that an important role of perforin is to disrupt vesicular protein trafficking. Surprisingly, cells exposed to granzyme B with perforin concentrations that produced nearly maximal (51)Cr release (1,600 U/ml) also underwent apoptosis despite excluding a 8-kDa fluorescein-labeled protein marker. Only at concentrations of >4,000 U/ml were perforin pores demonstrably large enough to account for transmembrane diffusion of granzyme B. We conclude that pore formation may allow granzyme B direct cytosolic access only when perforin is delivered at very high concentrations, while perforin's ability to disrupt endosomal trafficking may be crucial when it is present at lower concentrations or in killing cells that efficiently repair perforin pores.     

Neural control exploits changing mechanical advantage and context dependence to generate different feeding responses in <Emphasis Type="Italic">Aplysia</Emphasis>

How does neural control reflect changes in mechanical advantage and muscle function? In the Aplysia feeding system a protractor muscle's mechanical advantage decreases as it moves the structure that grasps food (the radula/odontophore) in an anterior direction. In contrast, as the radula/odontophore is moved forward, the jaw musculature's mechanical advantage shifts so that it may act to assist forward movement of the radula/odontophore instead of pushing it posteriorly. To test whether the jaw musculature's context-dependent function can compensate for the falling mechanical advantage of the protractor muscle, we created a kinetic model of Aplysia's feeding apparatus. During biting, the model predicts that the reduction of the force in the protractor muscle I2 will prevent it from overcoming passive forces that resist the large anterior radula/odontophore displacements observed during biting. To produce protractions of the magnitude observed during biting behaviors, the nervous system could increase I2's contractile strength by neuromodulating I2, or it could recruit the I1/I3 jaw muscle complex. Driving the kinetic model with in vivo EMG and ENG predicts that, during biting, early activation of the context-dependent jaw muscle I1/I3 may assist in moving the radula/odontophore anteriorly during the final phase of protraction. In contrast, during swallowing, later activation of I1/I3 causes it to act purely as a retractor. Shifting the timing of onset of I1/I3 activation allows the nervous system to use a mechanical equilibrium point that allows I1/I3 to act as a protractor rather than an equilibrium point that allows I1/I3 to act as a retractor. This use of equilibrium points may be similar to that proposed for vertebrate control of movement.     

Passive hinge forces in the feeding apparatus of<Emphasis Type="Italic"> Aplysia</Emphasis> aid retraction during biting but not during swallowing

Swallowing and biting responses in the marine mollusk Aplysia are both mediated by a cyclical alternation of protraction and retraction movements of the grasping structure, the radula and underlying odontophore, within the feeding apparatus of the animal, the buccal mass. In vivo observations demonstrate that Aplysia biting is associated with strong protractions and rapid initial retractions, whereas Aplysia swallowing is associated with weaker protractions and slower initial retractions. During biting, the musculature joining the radula/odontophore to the buccal mass (termed the hinge) is stretched more than in swallowing. To test the hypothesis that stretch of the hinge might contribute to rapid retractions observed in biting, we analyzed the hinges passive properties. During biting, the hinge is stretched sufficiently to assist retraction. In contrast, during swallowing, the hinge is not stretched sufficiently for its passive forces to assist retraction, because the odontophores anterior movement is smaller than during biting. A quantitative model demonstrated that steady-state passive forces were sufficient to generate the retraction movements observed during biting. Experimental measures of the relative magnitude of the hinges active and passive forces at the protraction displacements of biting suggest that passive forces are at least a third of the total force.Abbreviations I1/I3 intrinsic buccal muscles 1 and 3 - I2 intrinsic buccal muscle 2 (nomenclature from Howells 1942)