Learning, Mood, and Music: Depression, anxiety, and stress reflect processing biases in positive and negative chord sequences

Cognitive biases in information processing of valenced stimuli are a major contributor to the phenomenology of mood disorders. However, current screening tools for mood disorders rely on self-report questionnaires, which include uncomfortably invasive questions and are confounded by socially desirable responding. Taken together, assessing information processing biases may be a promising proxy to screen non-invasively for mood disorders. Here, we report data of 60 participants that performed a continuous statistical learning task in which respondents were asked to predict the next event in a sequence of musical chords. An underlying transitional probability matrix governed the chord sequences. Each participant performed both a positive- and negative-valence block of this task, where blocks differed in the precise musical chords used. A pilot experiment established that the sequences from both blocks evoked their intended perceived valence. Furthermore, cognitive assessment (Raven’s advanced matrices) as well as mood scores (DASS-21) were collected. Bayesian mixed effects models revealed that participants were able to extract the underlying transitional probabilities and that higher cognitive ability predicted higher performance. Furthermore, there was strong evidence that the depression, anxiety, and stress subscales all predicted learning trajectories, and interacted with stimulus valence. Thus, the present results show that information processing differences in a musical context are consistent with the phenomenology of mood disorders. The present study is one step towards a non-invasive musical tool to screen for mood disorders

The CXCL12/CXCR4 signaling axis retains neutrophils at inflammatory sites in zebrafish

The inappropriate retention of neutrophils at inflammatory sites is a major driver of the excessive tissue damage characteristic of respiratory inflammatory diseases including COPD, ARDS, and cystic fibrosis. The molecular programmes which orchestrate neutrophil recruitment to inflammatory sites through chemotactic guidance have been well-studied. However, how neutrophil sensitivity to these cues is modulated during inflammation resolution is not understood. The identification of neutrophil reverse migration as a mechanism of inflammation resolution and the ability to modulate this therapeutically has identified a new target to treat inflammatory disease. Here we investigate the role of the CXCL12/CXCR4 signaling axis in modulating neutrophil retention at inflammatory sites. We used an in vivo tissue injury model to study neutrophilic inflammation using transgenic zebrafish larvae. Expression of cxcl12a and cxcr4b during the tissue damage response was assessed using in situ hybridization and analysis of RNA sequencing data. CRISPR/Cas9 was used to knockdown cxcl12a and cxcr4b in zebrafish larvae. The CXCR4 antagonist AMD3100 was used to block the Cxcl12/Cxcr4 signaling axis pharmacologically. We identified that cxcr4b and cxcl12a are expressed at the wound site in zebrafish larvae during the inflammatory response. Following tail-fin transection, removal of neutrophils from inflammatory sites is significantly increased in cxcr4b and cxcl12a CRISPR knockdown larvae. Pharmacological inhibition of the Cxcl12/Cxcr4 signaling axis accelerated resolution of the neutrophil component of inflammation, an effect caused by an increase in neutrophil reverse migration. The findings of this study suggest that CXCR4/CXCL12 signaling may play an important role in neutrophil retention at inflammatory sites, identifying a potential new target for the therapeutic removal of neutrophils from the lung in chronic inflammatory disease

Population Modeling Highlights Drug Disposition Differences Between Tenofovir Alafenamide and Tenofovir Disoproxil Fumarate in the Blood and Semen

Understanding antiretroviral disposition in the male genital tract, a distinct viral compartment, can provide insight for the eradication of HIV. Population pharmacokinetic modeling was conducted to investigate the disposition of tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF), and emtricitabine and their metabolites in blood and semen. Blood plasma and seminal plasma (SP) concentrations of tenofovir and emtricitabine were measured, as were tenofovir-diphosphate and emtricitabine-triphosphate concentrations in peripheral blood mononuclear cells (PBMCs) and seminal mononuclear cells. Sequential compartmental modeling described drug disposition in blood and semen. Our modeling suggests slower elimination of apparent tenofovir-diphosphate PBMC and faster elimination of tenofovir SP after administration of TAF compared with TDF, likely reflecting flip-flop kinetics. Additionally, TAF metabolism to tenofovir appeared slower in semen compared with blood; however, SP elimination of TAF-derived tenofovir appeared faster than its blood plasma elimination. These findings provide valuable insight for further mechanistic study of cellular entry and drug metabolism in the male genital tract

The Effects of Prophylactic Cyclosporin A on Experimental Allergic Neuritis (EAN) in the Lewis Rat: Induction of Relapsing EAN Using Low Dose Cyclosporin A

Experimental allergic neuritis (EAN) was induced in Lewis rats by inoculation with bovine intradural root myelin plus adjuvants. Animals treated with high dose (30 mg/kg) cyclosporin A (CsA) 3 times per week did not develop clinical EAN during the period of CsA treatment, but had an episode of EAN after cessation of CsA treatment. Animals treated with low dose (4 mg/kg) CsA 3 times per week developed EAN during the period of treatment, and after cessation of CsA treatment all of these animals developed relapsing EAN with disease continuing for up to four episodes. In contrast, 30-40% of untreated animals had a mild second episode of EAN but no further attacks. Histological studies performed in treated and untreated animals at the time of clinical episodes revealed inflammation and demyelination in the spinal roots and dorsal root ganglia. When animals were challenged with a second inoculation at age 7 months, one of 15 untreated control animals but none of the CsA treated animals developed an episode of EAN

A Zebrafish Compound Screen Reveals Modulation of Neutrophil Reverse Migration as an Anti-Inflammatory Mechanism

Diseases of failed inflammation resolution are common and largely incurable. Therapeutic induction of inflammation resolution is an attractive strategy to bring about healing without increasing susceptibility to infection. However, therapeutic targeting of inflammation resolution has been hampered by a lack of understanding of the underlying molecular controls. To address this drug development challenge, we developed an in vivo screen for proresolution therapeutics in a transgenic zebrafish model. Inflammation induced by sterile tissue injury was assessed for accelerated resolution in the presence of a library of known compounds. Of the molecules with proresolution activity, tanshinone IIA, derived from a Chinese medicinal herb, potently induced inflammation resolution in vivo both by induction of neutrophil apoptosis and by promoting reverse migration of neutrophils. Tanshinone IIA blocked proinflammatory signals in vivo, and its effects are conserved in human neutrophils, supporting a potential role in treating human inflammation and providing compelling evidence of the translational potential of this screening strategy

Born into adversity: psychological distress in two birth cohorts of second-generation Irish children growing up in Britain

This work was supported by the Medical Research Council (MRC), in the form of a fellowship awarded to J.D.-M. (grant no. G0701595/1).

Differential Extracellular, but Similar Intracellular, Disposition of two Tenofovir Formulations in the Male Genital Tract

Background: The male genital tract (MGT) is a viral sanctuary and likely HIV reservoir; understanding MGT pharmacokinet-ics (PK) of antiretrovirals (ARVs) used for curative strategies is critical to eradication and cure. Tenofovir alafenamide (TAF) is a tenofovir (TFV) formulation designed to maximize efficacy/minimize toxicity with unknown MGT PK. Methods: HIV-positive and HIV-negative men receiving TFV-based regimens provided six paired blood plasma (BP) and semen samples. Extracellular (TFV, TAF, emtricitabine [FTC]) drug concentrations in BP and seminal plasma (SP), and intracellular metabolite (IM) and endogenous nucleotide (EN) concentrations were measured in peripheral blood mononuclear cells (PBMCs) and seminal mononuclear cells (SMCs). Exposure ratios for SP:BP, SMC:PBMC and IM:EN were calculated from PK parameters generated by noncompartmental analysis. HIV viral load was measured in BP and SP. Results: Sixteen HIV-positive (n=8, TDF/FTC; n=8, TAF/FTC) and eight HIV-negative (TDF/FTC) men provided samples. Median TFV SP:BP ratios differed between TDF and TAF (1.5 versus 7.4), due to lower TFV BP concentrations with TAF coupled with TFV SP concentrations similar to TDF. FTC SP:BP ratios were approximately 3. SMC concentrations of IMs and ENs were a fraction of PBMC concentrations (1–22%), though IM:EN ratios exceed a suggested protective threshold. Conclusions: TAF SP PK was unexpected. IM SMC concentrations were low relative to PBMC, as were EN concentrations, suggesting differences in cell phenotype and lineage in the MGT; these differences in phenotype and pharmacology may have an impact on selecting and dosing ARVs used in cure strategies

Assembly of the LongSHOT cohort: Public record linkage on a grand scale

Background: Virtually all existing evidence linking access to firearms to elevated risks of mortality and morbidity comes from ecological and case-control studies. To improve understanding of the health risks and benefits of firearm ownership, we launched a cohort study: the Longitudinal Study of Handgun Ownership and Transfer (LongSHOT). Methods: Using probabilistic matching techniques we linked three sources of individual-level, state-wide data in California: official voter registration records, an archive of lawful handgun transactions and all-cause mortality data. There were nearly 28.8 million unique voter registrants, 5.5 million handgun transfers and 3.1 million deaths during the study period (18 October 2004 to 31 December 2016). The linkage relied on several identifying variables (first, middle and last names; date of birth; sex; residential address) that were available in all three data sets, deploying them in a series of bespoke algorithms. Results: Assembly of the LongSHOT cohort commenced in January 2016 and was completed in March 2019. Approximately three-quarters of matches identified were exact matches on all link variables. The cohort consists of 28.8 million adult residents of California followed for up to 12.2 years. A total of 1.2 million cohort members purchased at least one handgun during the study period, and 1.6 million died. Conclusions: Three steps taken early may be particularly useful in enhancing the efficiency of large-scale data linkage: thorough data cleaning; assessment of the suitability of off-the-shelf data linkage packages relative to bespoke coding; and careful consideration of the minimum sample size and matching precision needed to support rigorous investigation of the study questions