8-Mop/uva Inhibits Maturation Of Extracorporeal Photochemotherapy (ecp) Generated Dendritic Cells

Extracorporeal photochemotherapy (ECP), a cellular therapy involving a light activated drug, is FDA approved for the treatment of Cutaneous T-cell lymphoma (CTCL) and used for reversal of Graft-versus-Host Disease (GHVD) and solid organ transplant rejection. The mechanism by which ECP functions as an immunomodulating treatment is unknown, although work by our lab and others suggests ECP generates functional Dendritic cells (DC) that may be involved in tolerization. Both radiation and chemotherapy have been shown to be involved in generation of tolerizing DC, and so we hypothesized that UVA activated chemotherapy 8-Methoxypsoralen (8MOP) exposure induces a tolerizing phenotype in ECP generated DC. In this study, normal donor peripheral blood mononuclear cells (PBMC) were treated in an in vitro model of the ECP apparatus, and collected (no8MOP/UVA sample) or treated with 8MOP (100ng/ml), UVA (2J/cm2) (8MOP/UVA sample). We measured phenotype and functionality of generated cells by two-color flow cytometry and functional assays. In all populations, we noted a statistically significant increase in percentage of cells staining double positive for DC markers (HLA-DR+/CD83+) 18 hours post treatment. 8MOP/UVA treatment reduced expression of mature DC markers (membrane HLA-DR/CD83) and co- stimulatory molecules (CD80/CD86) when compared to no8MOP/UVA and positive control DC, and failed to stimulate CD4+Tcells in antigen presenting assay. These data suggest 8MOP/UVA exposure during ECP inhibits DC maturation and induces a tolerizing phenotype. These tolerizing DC may play a role in the immunosuppressive effects of ECP in the treatment of GVHD and solid organ transplant rejection

Eye-Gaze Direction Modulates Race-Related Amygdala Activity

Although previous research has found greater activity in the human amygdala in response to Black male compared with White male targets, the basis of this effect remains unclear. For example, is it race alone that triggers amygdala activity, or do other stimulus cues, in conjunction with racial group membership, also play a critical role in this regard? To address this issue, we used functional magnetic resonance imaging to measure amygdala activity in response to Black and White male targets displaying different eye-gaze directions (i.e. direct or averted gaze), as gaze cues have been shown to influence the socio-emotional aspects of person construal. The results revealed that eye-gaze direction significantly moderates race-related amygdala activity. Specifically, Black targets only generated greater amygdala activity than White targets when the faces bore direct gaze. This finding is noteworthy as it demonstrates the importance of compound stimulus cues in the appraisal of social targets

Affinity enrichment of extracellular vesicles from plasma reveals mRNA changes associated with acute ischemic stroke

Currently there is no in vitro diagnostic test for acute ischemic stroke (AIS), yet rapid diagnosis is crucial for effective thrombolytic treatment. We previously demonstrated the utility of CD8(+) T-cells’ mRNA expression for AIS detection; however extracellular vesicles (EVs) were not evaluated as a source of mRNA for AIS testing. We now report a microfluidic device for the rapid and efficient affinity-enrichment of CD8(+) EVs and subsequent EV’s mRNA analysis using droplet digital PCR (ddPCR). The microfluidic device contains a dense array of micropillars modified with anti-CD8α monoclonal antibodies that enriched 158 ± 10 nm sized EVs at 4.3 ± 2.1 × 109 particles/100 µL of plasma. Analysis of mRNA from CD8(+) EVs and their parental T-cells revealed correlation in the expression for AIS-specific genes in both cell lines and healthy donors. In a blinded study, 80% test positivity for AIS patients and controls was revealed with a total analysis time of 3.7 h

Airships: A New Horizon for Science

The "Airships: A New Horizon for Science" study at the Keck Institute for Space Studies investigated the potential of a variety of airships currently operable or under development to serve as observatories and science instrumentation platforms for a range of space, atmospheric, and Earth science. The participants represent a diverse cross-section of the aerospace sector, NASA, and academia. Over the last two decades, there has been wide interest in developing a high altitude, stratospheric lighter-than-air (LTA) airship that could maneuver and remain in a desired geographic position (i.e., "station-keeping") for weeks, months or even years. Our study found considerable scientific value in both low altitude (< 40 kft) and high altitude (> 60 kft) airships across a wide spectrum of space, atmospheric, and Earth science programs. Over the course of the study period, we identified stratospheric tethered aerostats as a viable alternative to airships where station-keeping was valued over maneuverability. By opening up the sky and Earth's stratospheric horizon in affordable ways with long-term flexibility, airships allow us to push technology and science forward in a project-rich environment that complements existing space observatories as well as aircraft and high-altitude balloon missions.Comment: This low resolution version of the report is 8.6 MB. For the high resolution version see: http://kiss.caltech.edu/study/airship

A case of autism with an interstitial deletion on 4q leading to hemizygosity for genes encoding for glutamine and glycine neurotransmitter receptor sub-units (AMPA 2, GLRA3, GLRB) and neuropeptide receptors NPY1R, NPY5R

BACKGROUND: Autism is a pervasive developmental disorder characterized by a triad of deficits: qualitative impairments in social interactions, communication deficits, and repetitive and stereotyped patterns of behavior. Although autism is etiologically heterogeneous, family and twin studies have established a definite genetic basis. The inheritance of idiopathic autism is presumed to be complex, with many genes involved; environmental factors are also possibly contributory. The analysis of chromosome abnormalities associated with autism contributes greatly to the identification of autism candidate genes. CASE PRESENTATION: We describe a child with autistic disorder and an interstitial deletion on chromosome 4q. This child first presented at 12 months of age with developmental delay and minor dysmorphic features. At 4 years of age a diagnosis of Pervasive Developmental Disorder was made. At 11 years of age he met diagnostic criteria for autism. Cytogenetic studies revealed a chromosome 4q deletion. The karyotype was 46, XY del 4 (q31.3-q33). Here we report the clinical phenotype of the child and the molecular characterization of the deletion using molecular cytogenetic techniques and analysis of polymorphic markers. These studies revealed a 19 megabase deletion spanning 4q32 to 4q34. Analysis of existing polymorphic markers and new markers developed in this study revealed that the deletion arose on a paternally derived chromosome. To date 33 genes of known or inferred function are deleted as a consequence of the deletion. Among these are the AMPA 2 gene that encodes the glutamate receptor GluR2 sub-unit, GLRA3 and GLRB genes that encode glycine receptor subunits and neuropeptide Y receptor genes NPY1R and NPY5R. CONCLUSIONS: The deletion in this autistic subject serves to highlight specific autism candidate genes. He is hemizygous for AMPA 2, GLRA3, GLRB, NPY1R and NPY5R. GluR2 is the major determinant of AMPA receptor structure. Glutamate receptors maintain structural and functional plasticity of synapses. Neuropeptide Y and its receptors NPY1R and NPY5R play a role in hippocampal learning and memory. Glycine receptors are expressed in very early cortical development. Molecular cytogenetic studies and DNA sequence analysis in other patients with autism will be necessary to confirm that these genes are involved in autism

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

Female Aggression: Evolution’s Not So Secret Weapon

In the present article, we examine the relatively recent and substantial increase in physical aggression among adolescent females. We review what is known about the prevalence and specific characteristics of aggression among adolescent females, and then propose a novel way of understanding this behavior. Existing evidence from multiple academic disciplines is reviewed and integrated to propose a new framework for considering the underpinnings of physical aggression in females. Most examinations of physical aggression in females have focused on non-human animal models of maternal aggression. In spite of this, the growing prevalence of physical aggression among adolescent females continues to be poorly understood. We endeavor to integrate multiple viewpoints on female aggression and posit a conceptualization of female aggression among adolescents that reflects an immature, socially inexperienced, precursor to functional maternal aggression