Meeting PM/WRA’s New Director Col. (Ret.) Stanley L. Brown

Continuing the funding for conventional weapons destruction programs remains a primary objective for Stan Brown, the new director of the Office of Weapons Removal and Abatement in the U.S. Department of State’s Bureau of Political-Military Affairs (PM/WRA). This interview introduces the director, provides a snapshot of his past experience and shares his hopes for the future of humanitarian demining

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

A first update on mapping the human genetic architecture of COVID-19

peer reviewe

Photobiomodulation Mitigates Diabetes-Induced Retinopathy by Direct and Indirect Mechanisms: Evidence from Intervention Studies in Pigmented Mice.

Daily application of far-red light from the onset of diabetes mitigated diabetes-induced abnormalities in retinas of albino rats. Here, we test the hypothesis that photobiomodulation (PBM) is effective in diabetic, pigmented mice, even when delayed until weeks after onset of diabetes. Direct and indirect effects of PBM on the retina also were studied.Diabetes was induced in C57Bl/6J mice using streptozotocin. Some diabetics were exposed to PBM therapy (4 min/day; 670 nm) daily. In one study, mice were diabetic for 4 weeks before initiation of PBM for an additional 10 weeks. Retinal oxidative stress, inflammation, and retinal function were measured. In some mice, heads were covered with a lead shield during PBM to prevent direct illumination of the eye, or animals were treated with an inhibitor of heme oxygenase-1. In a second study, PBM was initiated immediately after onset of diabetes, and administered daily for 2 months. These mice were examined using manganese-enhanced MRI to assess effects of PBM on transretinal calcium channel function in vivo.PBM intervention improved diabetes-induced changes in superoxide generation, leukostasis, expression of ICAM-1, and visual performance. PBM acted in part remotely from the retina because the beneficial effects were achieved even with the head shielded from the light therapy, and because leukocyte-mediated cytotoxicity of retinal endothelial cells was less in diabetics treated with PBM. SnPP+PBM significantly reduced iNOS expression compared to PBM alone, but significantly exacerbated leukostasis. In study 2, PBM largely mitigated diabetes-induced retinal calcium channel dysfunction in all retinal layers.PBM induces retinal protection against abnormalities induced by diabetes in pigmented animals, and even as an intervention. Beneficial effects on the retina likely are mediated by both direct and indirect mechanisms. PBM is a novel non-pharmacologic treatment strategy to inhibit early changes of diabetic retinopathy

Significant Systemic Insulin Resistance is Associated With Unique Glioblastoma Multiforme Phenotype

Background: Some glioblastoma multiforme (GBM) are characterized by the presence of gemistocytes (GCs), a unique phenotype of reactive astrocytes. Certain GCs can be identified as neoplastic cells but these cells were also found to be associated with diabetes in non-neoplastic lesions of the central nervous system. Our aim was to find a correlation between insulin - resistance metabolic features and the presence of GCs in patients with newly diagnosed GBM. Methods: Medical records from histologically confirmed GBM patients were retrospectively extracted for different systemic metabolic variables. A statistic-based comparison was made between GBM, diabetic patients with and without GC. Patients with poorly controlled diabetes (ie, hemoglobin A1C ⩾ 8.0) were also compared between the 2 groups. Results: A total of 220 newly diagnosed GBM patients were included in our study. 58 (26.3%) patients had a history of diabetes mellitus type 2 (DM2) at the time of admission. The rate of poorly-controlled DM2 was nearly as twice in the GC-GBM group than in the non-GC GBM group (18.75% vs 9.5%; P  = .130). In the DM2 cohort, the subgroup of GC-GBM was significantly associated with demographic and metabolic features related to insulin resistance such as male gender predominance (89% vs 50%, P  = .073) and morbid obesity (weight ⩾85 kg: OR 6.16; P  = .0019 and mean BMI: 34.1 ± 11.42 vs 28.7 ± 5.44; P  = .034 for group with and without GCs, respectively). In the poorly-controlled DM2 group, none of the GC-GBM patients were using insulin prior to diagnosis, compared to 61.1% in the non-GC GBM patients (OR = 0.04, P  = .045). Conclusion: Systemic metabolic factors related to marked insulin resistance (DM2, morbid obesity, male gender) are associated with a unique histologic phenotype of GBM, characterized by the presence of GCs. This feature is prominent in poorly-controlled DM2 GBM patients who are not using synthetic insulin. This novel finding may add to the growing data on the relevance of glucose metabolism in astrocytes and in astrocytes associated with high-grade gliomas. In GBM patients, a correlation between patients’ metabolic status, tumor’s histologic phenotype, tumor’s molecular changes, use of anti-diabetic drugs and the respective impact of these factor on survival warrants further investigation

Preventive PBM treatment corrects diabetes-induced calcium channel dysfunction across the retina.

<p>Central (± 0.4–1 mm from the optic nerve head) retinal manganese uptake (as evaluated via 1/T1) profiles of A) dark adapted WT mice (closed black circles, n = 9), untreated diabetic mice (closed green circle, n = 5), and PBM treated diabetic mice (closed magenta circle, n = 5). Data are shown as a function of distance from the retina / non-retina borders, where 0% is the vitreous/retina border and 100% is the retina/choroid border. Regions near borders are not shown because these regions likely include some signal from outside the retina (i.e., partial volume averaging with vitreous or choroid/sclera). Lines above profiles indicate retinal regions with statistically significant differences between indicated groups. A simplified schematic of retina is provided to provide best estimates of MEMRI localization in the retina. The high resolution of our MEMRI images (21.9 μm axial resolution [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0139003#pone.0139003.ref040" target="_blank">40</a>]) and the well-defined laminar structure of retina allows us to reasonably label uptake at 24–50% depth as the inner nuclear layer (INL), at 50–68% depth as the outer nuclear layer (ONL), at 68–88% depth as the rod inner segment region (IS), and > 88% as the rod outer segment region (OS).</p

Effect of PBM intervention on retinal (a) ICAM-1, (b) iNOS and (c) HO-1 in diabetic mice.

<p>Intervention with PBM significantly reversed the diabetes-induced induction of retinal ICAM-1, whereas effects on iNOS and HO-1 expression were less marked or absent. Use of the head shield (PBM + HS) or inhibiting HO-1 with SnPP (PBM + SnPP) did not affect the effect of PBM on expression of ICAM-1 significantly, but SnPP did tend to normalize iNOS expression, and both the head shield and SNPP increased HO-1 expression. Representative immunoblots are shown in (c). Total duration of diabetes was 14 weeks, but PBM was applied only for the last 10 weeks of that duration. N, non-diabetic; D, diabetic; D+PBM, mice getting PBM. Horizontal lines above the figure indicate significant differences. n = 4–6 per group.</p

Intervention with PBM mitigates leukocyte-mediated cytotoxicity of endothelial cells caused by leukocytes from diabetic animals.

<p>Co-culture of transformed mouse retinal endothelial cells (mREC) with leukocytes from diabetic mice resulted in significantly more dead endothelial cells than when leukocytes were isolated from nondiabetic animals. In contrast, diabetes-induced killing of endothelial cells in the co-culture assay was significantly inhibited when using leukocytes isolated from diabetic animals who had been treated daily with PBM as an intervention therapy. N, non-diabetic; D, diabetic; D+PBM, mice getting PBM as an intervention for the last 10 weeks of diabetes. Horizontal lines above the figure indicate significant differences. n = 3 per group.</p

Animal Data.

<p>* PBM initiated 4 weeks after induction of diabetes, and continued for an additional 10 weeks (total, 14 weeks)</p><p>** p<0.001 compared to N; there are no significant differences among diabetic groups</p><p>Average body weight, non-fasting blood glucose, and HbA1c of nondiabetics (N), diabetics (D), diabetics receiving PBM therapy (D+ PBM), diabetics receiving PBM therapy with head shield (D+ PBM + HS), and diabetics receiving PBM therapy and SnPP treatment (S+ PBM+ SnPP).</p