Cathelicidin Antimicrobial Peptides Block Dendritic Cell TLR4 Activation and Allergic Contact Sensitization

Abstract Cathelicidins are antimicrobial peptides of the innate immune system that establish an antimicrobial barrier at epithelial interfaces and have been proposed to have a proinflammatory function. We studied the role of cathelicidin in allergic contact dermatitis, a model requiring dendritic cells of the innate immune response and T cells of the adaptive immune response. Deletion of the murine cathelicidin gene Cnlp enhanced an allergic contact response, whereas local administration of cathelicidin before sensitization inhibited the allergic response. Cathelicidins inhibited TLR4 but not TLR2 mediated induction of dendritic cell maturation and cytokine release, and this inhibition was associated with an alteration of cell membrane function and structure. Further analysis in vivo connected these observations because inhibition of sensitization by exogenous cathelicidin was dependent on the presence of functional TLR4. These observations provide evidence that cathelicidin antimicrobial peptides mediate an anti-inflammatory response in part by their activity at the membrane

Impact of acute stress, sex, and childhood maltreatment on fear learning and fear generalization in a fear-potentiated startle paradigm

Many researchers approach the etiology of trauma-, stressor-, and anxiety-related mental disorders from the perspective of classical conditioning processes gone awry. According to this view, abnormal associative relationships between conditioned and unconditioned stimuli may underlie pathological anxiety and result in unusually intense fear memories or fear memories that cannot be properly extinguished. Recent work has expanded on this view by showing that many psychological disorders involving pathological anxiety are associated with an exaggerated form of stimulus generalization, leading individuals with such disorders to respond with fear and anxiety to a variety of contexts and cues that should not be threatening. It is well-known that stress, biological sex, childhood maltreatment, and certain dispositional factors can increase one’s susceptibility for pathological anxiety and significantly impact fear learning; thus, it is possible that these factors, alone or in combination, contribute to clinical anxiety by influencing fear generalization processes. In the present study, 478 healthy undergraduate students were exposed to the socially-evaluated cold pressor test immediately or 30 min prior to learning to associate one geometrical shape, but not another, with an aversive stimulus in a fear-potentiated startle paradigm. The next day, participants were tested for fear generalization by measuring their fear responses to a variety of stimuli that were similar to, but different from, the shapes observed on Day 1. Objective and subjective measures of stress were collected on Day 1, and childhood maltreatment was quantified with the Childhood Trauma Questionnaire. The results revealed that, across both stress time points, greater heart rate and greater cortisol levels in response to stress were associated with weaker fear acquisition and a flatter generalization gradient. These effects were influenced by participant sex and trait anxiety. We also found evidence to suggest that greater childhood maltreatment was associated with impaired fear acquisition in males but enhanced fear acquisition in females. These findings reveal a complex interaction between acute stress, biological sex, childhood maltreatment, dispositional anxiety, and fear learning that may lend insight into the etiology of certain stress-related psychological disorders

Observational Constraints on the Molecular Gas Content in Nearby Starburst Dwarf Galaxies

Using star formation histories derived from optically resolved stellar populations in nineteen nearby starburst dwarf galaxies observed with the Hubble Space Telescope, we measure the stellar mass surface densities of stars newly formed in the bursts. By assuming a star formation efficiency (SFE), we then calculate the inferred gas surface densities present at the onset of the starbursts. Assuming a SFE of 1%, as is often assumed in normal star-forming galaxies, and assuming that the gas was purely atomic, translates to very high HI surface densities (~10^2-10^3 Msun pc^-2), which are much higher than have been observed in dwarf galaxies. This implies either higher values of SFE in these dwarf starburst galaxies or the presence of significant amounts of H_2 in dwarfs (or both). Raising the assumed SFEs to 10% or greater (in line with observations of more massive starbursts associated with merging galaxies), still results in HI surface densities higher than observed in 10 galaxies. Thus, these observations appear to require that a significant fraction of the gas in these dwarf starbursts galaxies was in the molecular form at the onset of the bursts. Our results imply molecular gas column densities in the range 10^19-10^21 cm^-2 for the sample. In those galaxies where CO observations have been made, these densities correspond to values of the CO-H_2 conversion factor (X_CO) in the range >3-80x10^20 cm^-2 (K km s^-1)^-1, or up to 40x greater than Galactic X_CO values.Comment: 8 pages, 4 figures, 2 table

Enhanced micronutrient supplementation in low marine diets reduced vertebral malformation in diploid and triploid Atlantic salmon (Salmo salar) parr, and increased vertebral expression of bone biomarker genes in diploids

Highlights The use of plant ingredients affects the level of micronutrients in salmon feeds. Increased micronutrient supplementation reduced the prevalence of spinal deformity. Triploid salmon showed higher prevalence of malformation. In diploids, the expression of bone genes was affected by micronutrient levels. Micronutrients should be supplemented when feeding salmon low marine diets. Previously we showed that, for optimum growth, micronutrient levels should be supplemented above current National Research Council (2011) recommendations for Atlantic salmon when they are fed diets formulated with low levels of marine ingredients. In the present study, the impact of graded levels (100, 200, 400%) of a micronutrient package (NP) on vertebral deformities and bone gene expression were determined in diploid and triploid salmon parr fed low marine diets. The prevalence of radiologically detectable spinal deformities decreased with increasing micronutrient supplementation in both ploidy. On average, triploids had a higher incidence of spinal deformity than diploids within a given diet. Micronutrient supplementation particularly reduced prevalence of fusion deformities in diploids and compression and reduced spacing deformities in triploids. Prevalence of affected vertebrae within each spinal region (cranial, caudal, tail and tail fin) varied significantly between diet and ploidy, and there was interaction. Prevalence of deformities was greatest in the caudal region of triploids and the impact of graded micronutrient supplementation in reducing deformities also greatest in triploids. Diet affected vertebral morphology with length:height (L:H) ratio generally increasing with level of micronutrient supplementation in both ploidy with no difference between ploidy. Increased dietary micronutrients level in diploid salmon increased the vertebral expression of several bone biomarker genes including bone morphogenetic protein 2 (bmp2), osteocalcin (ostcn), alkaline phosphatase (alp), matrix metallopeptidase 13 (mmp13), osteopontin (opn) and insulin-like growth factor 1 receptor (igf1r). In contrast, although some genes showed similar trends in triploids, vertebral gene expression was not significantly affected by dietary micronutrients level. The study confirmed earlier indications that dietary micronutrient levels should be increased in salmon fed diets with low marine ingredients and that there are differences in nutritional requirements between ploidies

Tunnel vision, false memories, and intrusive memories following exposure to the Trier Social Stress Test

Most research examining the impact of stress on learning and memory has exposed participants to a stressor and measured how it affects learning and memory for unrelated material (e.g., list of words). Such work has been helpful, but it has not been the most translational to the human condition. When considering phenomena such as intrusive memories in post-traumatic stress disorder (PTSD) or an eyewitness\u27s memory for a crime, it is most useful to know what an individual remembers about the stress experience itself, not unrelated information. In prior work, investigators used a modified version of the Trier Social Stress Test (TSST) to quantify participant memory for the stressor. We aimed to replicate this work by examining participant memory for the TSST and extend on it by quantifying false and intrusive memories that result from TSST exposure. Forty-six undergraduate students from Ohio Northern University were exposed to the TSST or the friendly-TSST (f-TSST). The TSST required participants to deliver a ten-minute speech in front of two lab panel members as part of a mock job interview; the f-TSST required participants to casually converse with the panel members about their interests and hobbies. In both conditions, the panel members interacted with (central) or did not interact with (peripheral) several objects sitting on a desk in front of them. Participants’ anxiety levels were assessed before and after the TSST or f-TSST, and saliva samples were collected to assay for cortisol. The next day, participants’ memory for the objects that were present on Day 1 was assessed with recall and recognition tests. We also quantified participants’ intrusive memories for each task by having them complete an intrusive memory questionnaire on Days 2, 4, 6, and 8. Participants exposed to the TSST exhibited greater recall of central objects than participants exposed to the f-TSST. There were no differences observed for the recall of peripheral objects or for recognition memory. Interestingly, TSST exposure increased false recall in males, but reduced it in females. Females exposed to the TSST also showed greater evidence of intrusive memories than males exposed to the TSST. Consistent with prior work, these findings show that stress enhances memory for the central details of a stressful experience. They also extend on prior work by showing that stressful experiences sex-dependently impact the manifestation of false and intrusive memories. This is the first study of which we are aware to quantify intrusive memory formation with the TSST; the modified TSST paradigm may be useful in understanding differential susceptibility to intrusive memory formation and the development of PTSD

Prognostic Prediction of Genotype vs Phenotype in Genetic Cardiomyopathies

Background: Diverse genetic backgrounds often lead to phenotypic heterogeneity in cardiomyopathies (CMPs). Previous genotype-phenotype studies have primarily focused on the analysis of a single phenotype, and the diagnostic and prognostic features of the CMP genotype across different phenotypic expressions remain poorly understood. Objectives: We sought to define differences in outcome prediction when stratifying patients based on phenotype at presentation compared with genotype in a large cohort of patients with CMPs and positive genetic testing. Methods: Dilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy, left-dominant arrhythmogenic cardiomyopathy, and biventricular arrhythmogenic cardiomyopathy were examined in this study. A total of 281 patients (80% DCM) with pathogenic or likely pathogenic variants were included. The primary and secondary outcomes were: 1) all-cause mortality (D)/heart transplant (HT); 2) sudden cardiac death/major ventricular arrhythmias (SCD/MVA); and 3) heart failure-related death (DHF)/HT/left ventricular assist device implantation (LVAD). Results: Survival analysis revealed that SCD/MVA events occurred more frequently in patients without a DCM phenotype and in carriers of DSP, PKP2, LMNA, and FLNC variants. However, after adjustment for age and sex, genotype-based classification, but not phenotype-based classification, was predictive of SCD/MVA. LMNA showed the worst trends in terms of D/HT and DHF/HT/LVAD. Conclusions: Genotypes were associated with significant phenotypic heterogeneity in genetic cardiomyopathies. Nevertheless, in our study, genotypic-based classification showed higher precision in predicting the outcome of patients with CMP than phenotype-based classification. These findings add to our current understanding of inherited CMPs and contribute to the risk stratification of patients with positive genetic testing

WALLABY Pre-Pilot and Pilot Survey: the Tully Fisher Relation in Eridanus, Hydra, Norma and NGC4636 fields

The WALLABY pilot survey has been conducted using the Australian SKA Pathfinder (ASKAP). The integrated 21-cm HI line spectra are formed in a very different manner compared to usual single-dish spectra Tully-Fisher measurements. It is thus extremely important to ensure that slight differences (e.g. biases due to missing flux) are quantified and understood in order to maximise the use of the large amount of data becoming available soon. This article is based on four fields for which the data are scientifically interesting by themselves. The pilot data discussed here consist of 614 galaxy spectra at a rest wavelength of 21cm. Of these spectra, 472 are of high enough quality to be used to potentially derive distances using the Tully-Fisher relation. We further restrict the sample to the 251 galaxies whose inclination is sufficiently close to edge-on. For these, we derive Tully-Fisher distances using the deprojected WALLABY velocity widths combined with infrared (WISE W1) magnitudes. The resulting Tully-Fisher distances for the Eridanus, Hydra, Norma and NGC 4636 clusters are 21.5, 53.5, 69.4 and 23.0 Mpc respectively, with uncertainties of 5–10%, which are better or equivalent to the ones obtained in studies using data obtained with giant single dish telescopes. The pilot survey data show the benefits of WALLABY over previous giant single-dish telescope surveys. WALLABY is expected to detect around half a million galaxies with a mean redshift of 푧 = 0.05(200푀 푝푐). This study suggests that about 200,000 Tully-Fisher distances might result from the survey