Probability and magnitude evaluation in schizophrenia

Alterations in reinforcement learning and decision making in schizophrenia have been linked with orbitofrontal cortex (OFC) dysfunction, a region critical for weighing reward magnitude in the calculation of expected value (EV). However, much of this work has used complex tasks that require combined learning and EV calculation. Here we used a simple “Roulette” task that examined the calculation of EV directly through a combination of text and/or pictorial representation of reward probability and magnitude. Forty-four people with schizophrenia and 30 controls were recruited. Patients were less sensitive to adjustments in a parameter combining probability and magnitude into one EV construct. Breaking down the construct into independent contributions of probability and magnitude, we found that negative symptoms were associated with magnitude sensitivity. This is consistent with the hypothesized role of OFC in actively representing magnitude and the notion that negative symptoms may involve a failure to appropriately estimate and use future reward magnitude to guide decision making

Molecular basis of interactions between CaMKII and α-actinin-2 that underlie dendritic spine enlargement

Ca2+/calmodulin-dependent protein kinase II (CaMKII) is essential for long-term potentiation (LTP) of excitatory synapses that is linked to learning and memory. In this study, we focused on understanding how interactions between CaMKIIα and the actin crosslinking protein α-actinin-2 underlie long-lasting changes in dendritic spine architecture. We found that association of the two proteins was unexpectedly elevated within two minutes of NMDA receptor stimulation that triggers structural LTP in primary hippocampal neurons. Furthermore, disruption of interactions between the two proteins prevented the accumulation of enlarged mushroom-type dendritic spines following NMDA receptor activation. α-actinin-2 binds to the regulatory segment of CaMKII. Calorimetry experiments, and a crystal structure of α-actinin-2 EF hands 3 and 4 in complex with the CaMKII regulatory segment, indicate that the regulatory segment of autoinhibited CaMKII is not fully accessible to α-actinin-2. Pull-down experiments show that occupation of the CaMKII substrate binding groove by GluN2B markedly increases α-actinin-2 access to the CaMKII regulatory segment. Furthermore, in situ labelling experiments are consistent with the notion that recruitment of CaMKII to NMDA receptors contributes to elevated interactions between the kinase and α-actinin-2 during structural LTP. Overall, our study provides new mechanistic insight into the molecular basis of structural LTP and reveals an added layer of sophistication to the function of CaMKII

Tapinarof Cream 1% Once Daily for the Treatment of Plaque Psoriasis: Case Photography of Clinical Outcomes from Three Phase 3 Trials

Tapinarof cream 1% (VTAMA(®); Dermavant Sciences, Inc.) is a non-steroidal, topical, aryl hydrocarbon receptor agonist approved by the US Food and Drug Administration (FDA) to treat plaque psoriasis in adults and under investigation for the treatment of psoriasis in children down to 2 years of age, and for atopic dermatitis in adults and children down to 2 years of age. The PSOARING phase 3 clinical trial program evaluated tapinarof cream 1% once daily (QD) in adults with mild to severe plaque psoriasis for up to 52 weeks (NCT03956355, NCT03983980, NCT04053387). Here we present case photography documenting outcomes in the PSOARING trials. Cases illustrate various outcomes across different body areas, including responses meeting the formal FDA-mandated regulatory endpoint of a Physician Global Assessment (PGA) score of 0 (clear) or 1 (almost clear) and a decrease of at least 2 points from baseline at week 12, meaningful clinical improvement not meeting this formal endpoint, patient-reported outcomes, and pre-specified adverse events of special interest (AESIs). Tapinarof cream 1% QD demonstrated rapid and highly statistically significant efficacy, with improvements in disease activity and quality of life. In addition, a high rate (40.9%; n = 312/763) of complete disease clearance (PGA = 0) was achieved, and improvements exceeding National Psoriasis Foundation treatment goals were demonstrated. After first achieving complete disease clearance (PGA = 0), patients treated with tapinarof experienced an approximately 4-month remittive effect off therapy. Incidence and severity of folliculitis and contact dermatitis AESIs were generally mild or moderate, localized to the site of application, and associated with low discontinuation rates. Medical images are of importance in trials of dermatologic therapies to inform clinical decision-making and enhance patient assessment. Tapinarof cream 1% QD is efficacious and well tolerated in patients with mild to severe plaque psoriasis, with clinically relevant improvements seen early in the course of treatment. Clinicaltrials.gov numbers: NCT03956355, NCT03983980, NCT04053387

Overview of the Role for Calreticulin in the Enhancement of Wound Healing through Multiple Biological Effects

Calreticulin (CRT), an intracellular chaperone protein crucial for the proper folding and transport of proteins through the endoplasmic reticulum, has more recent acclaim as a critical regulator of extracellular functions, particularly in mediating cellular migration and as a requirement for phagocytosis of apoptotic cells. Consistent with these functions, we show that the topical application of CRT has profound effects on the process of wound healing by causing a dose-dependent increase in epithelial migration and granulation tissue formation in both murine and porcine normal and impaired animal models of skin injury. These effects of CRT are substantiated, in vitro, as we show that CRT strongly induces cell migration/wound closure of human keratinocytes and fibroblasts, using a wound/scratch plate assay, and stimulates cellular proliferation of human keratinocytes, fibroblasts, and vascular endothelial cells, providing mechanistic insight into how CRT functions in repair. Similarly, in both animal models, the histology of the wounds show marked proliferation of basal keratinocytes and dermal fibroblasts, dense cellularity of the dermis with notably increased numbers of macrophages and well-organized collagen fibril deposition. Thus, CRT profoundly affects the wound healing process by recruiting cells essential for repair into the wound, stimulating cell growth, and increasing extracellular matrix production

Decisional Informatics for Psychosocial Rehabilitation: A Feasibility Pilot on Tailored and Fluid Treatment Algorithms for Serious Mental Illness

This study introduces a computerized clinical decision-support tool, the Fluid Outpatient Rehabilitation Treatment (FORT), that incorporates individual and ever-evolving patient needs to guide clinicians in developing and updating treatment decisions in real-time. In this proof-of-concept feasibility pilot, FORT was compared against traditional treatment planning using similar behavioral therapies in 52 adults with severe mental illness attending community-based day treatment. At posttreatment and follow-up, group differences and moderate-to-large effect sizes favoring FORT were detected in social function, work readiness, self-esteem, working memory, processing speed, and mental flexibility. Of participants who identified obtaining a General Education Diploma as their goal, 73% in FORT passed the examination compared with 18% in traditional treatment planning. FORT was also associated with higher agency cost-effectiveness and a better average benefit-cost ratio, even when considering diagnosis, baseline symptoms, and education. Although the comparison groups were not completely equivalent, the findings suggest computerized decision support systems that collaborate with human decision-makers to personalize psychiatric rehabilitation and address critical decisions may have a role in improving treatment effectiveness and efficiency

Effects of human TRIM5α polymorphisms on antiretroviral function and susceptibility to human immunodeficiency virus infection

AbstractTRIM5α acts on several retroviruses, including human immunodeficiency virus (HIV-1), to restrict cross-species transmission. Using natural history cohorts and tissue culture systems, we examined the effect of polymorphism in human TRIM5α on HIV-1 infection. In African Americans, the frequencies of two non-coding SNP variant alleles in exon 1 and intron 1 of TRIM5 were elevated in HIV-1-infected persons compared with uninfected subjects. By contrast, the frequency of the variant allele encoding TRIM5α 136Q was relatively elevated in uninfected individuals, suggesting a possible protective effect. TRIM5α 136Q protein exhibited slightly better anti-HIV-1 activity in tissue culture than the TRIM5α R136 protein. The 43Y variant of TRIM5α was less efficient than the H43 variant at restricting HIV-1 and murine leukemia virus infections in cultured cells. The ancestral TRIM5 haplotype specifying no observed variant alleles appeared to be protective against infection, and the corresponding wild-type protein partially restricted HIV-1 replication in vitro. A single logistic regression model with a permutation test indicated the global corrected P value of <0.05 for both SNPs and haplotypes. Thus, polymorphism in human TRIM5 may influence susceptibility to HIV-1 infection, a possibility that merits additional evaluation in independent cohorts

Loss of vascular CD34 results in increased sensitivity to lung injury

Survival during lung injury requires a coordinated program of damage limitation and rapid repair. CD34 is a cell surface sialomucin expressed by epithelial, vascular and stromal cells that promotes cell adhesion, coordinates inflammatory cell recruitment, and drives angiogenesis. To test whether CD34 also orchestrates pulmonary damage and repair, we induced acute lung injury in wild type (WT) and Cd34-/- mice by bleomycin (BLM) administration. We found that Cd34-/- mice displayed severe weight loss and early mortality compared to WT controls. Despite equivalent early airway inflammation to WT mice, CD34-deficient animals developed interstitial edema and endothelial delamination, suggesting impaired endothelial function. Chimeric Cd34-/- mice reconstituted with WT hematopoietic cells exhibited early mortality compared to WT mice reconstituted with Cd34-/- cells, supporting an endothelial defect. CD34-deficient mice were also more sensitive to lung damage caused by influenza infection, showing greater weight loss and more extensive pulmonary remodeling. Together our data suggest that CD34 plays an essential role in maintaining vascular integrity in the lung in response to chemical- and infection-induced, tissue damage