Characterization of Metabolic, Diffusion, and Perfusion Properties in GBM: Contrast-Enhancing versus Non-Enhancing Tumor.

BackgroundAlthough the contrast-enhancing (CE) lesion on T1-weighted MR images is widely used as a surrogate for glioblastoma (GBM), there are also non-enhancing regions of infiltrative tumor within the T2-weighted lesion, which elude radiologic detection. Because non-enhancing GBM (Enh-) challenges clinical patient management as latent disease, this study sought to characterize ex vivo metabolic profiles from Enh- and CE GBM (Enh+) samples, alongside histological and in vivo MR parameters, to assist in defining criteria for estimating total tumor burden.MethodsFifty-six patients with newly diagnosed GBM received a multi-parametric pre-surgical MR examination. Targets for obtaining image-guided tissue samples were defined based on in vivo parameters that were suspicious for tumor. The actual location from where tissue samples were obtained was recorded, and half of each sample was analyzed for histopathology while the other half was scanned using HR-MAS spectroscopy.ResultsThe Enh+ and Enh- tumor samples demonstrated comparable mitotic activity, but also significant heterogeneity in microvascular morphology. Ex vivo spectroscopic parameters indicated similar levels of total choline and N-acetylaspartate between these contrast-based radiographic subtypes of GBM, and characteristic differences in the levels of myo-inositol, creatine/phosphocreatine, and phosphoethanolamine. Analysis of in vivo parameters at the sample locations were consistent with histological and ex vivo metabolic data.ConclusionsThe similarity between ex vivo levels of choline and NAA, and between in vivo levels of choline, NAA and nADC in Enh+ and Enh- tumor, indicate that these parameters can be used in defining non-invasive metrics of total tumor burden for patients with GBM

Liquid droplet formation by HP1α suggests a role for phase separation in heterochromatin.

Gene silencing by heterochromatin is proposed to occur in part as a result of the ability of heterochromatin protein 1 (HP1) proteins to spread across large regions of the genome, compact the underlying chromatin and recruit diverse ligands. Here we identify a new property of the human HP1α protein: the ability to form phase-separated droplets. While unmodified HP1α is soluble, either phosphorylation of its N-terminal extension or DNA binding promotes the formation of phase-separated droplets. Phosphorylation-driven phase separation can be promoted or reversed by specific HP1α ligands. Known components of heterochromatin such as nucleosomes and DNA preferentially partition into the HP1α droplets, but molecules such as the transcription factor TFIIB show no preference. Using a single-molecule DNA curtain assay, we find that both unmodified and phosphorylated HP1α induce rapid compaction of DNA strands into puncta, although with different characteristics. We show by direct protein delivery into mammalian cells that an HP1α mutant incapable of phase separation in vitro forms smaller and fewer nuclear puncta than phosphorylated HP1α. These findings suggest that heterochromatin-mediated gene silencing may occur in part through sequestration of compacted chromatin in phase-separated HP1 droplets, which are dissolved or formed by specific ligands on the basis of nuclear context

Polymicrobial periodontal disease triggers a wide radius of effect and unique virome.

Periodontal disease is a microbially-mediated inflammatory disease of tooth-supporting tissues that leads to bone and tissue loss around teeth. Although bacterially-mediated mechanisms of alveolar bone destruction have been widely studied, the effects of a polymicrobial infection on the periodontal ligament and microbiome/virome have not been well explored. Therefore, the current investigation introduced a new mouse model of periodontal disease to examine the effects of a polymicrobial infection on periodontal ligament (PDL) properties, changes in bone loss, the host immune response, and the microbiome/virome using shotgun sequencing. Periodontal pathogens, namely Porphyromonas gingivalis, Treponema denticola, Tannerella forsythia, and Fusobacterium nucleatum were used as the polymicrobial oral inoculum in BALB/cByJ mice. The polymicrobial infection triggered significant alveolar bone loss, a heightened antibody response, an elevated cytokine immune response, a significant shift in viral diversity and virome composition, and a widening of the PDL space; the latter two findings have not been previously reported in periodontal disease models. Changes in the PDL space were present at sites far away from the site of insult, indicating that the polymicrobial radius of effect extends beyond the bone loss areas and site of initial infection and wider than previously appreciated. Associations were found between bone loss, specific viral and bacterial species, immune genes, and PDL space changes. These findings may have significant implications for the pathogenesis of periodontal disease and biomechanical properties of the periodontium. This new polymicrobial mouse model of periodontal disease in a common mouse strain is useful for evaluating the features of periodontal disease

Age constraints in the double pulsar system J0737-3039

We investigate the age constraints that can be placed on the double pulsar system using models for the spin-down of the first-born 22.7-ms pulsar A and the 2.77-s pulsar B with characteristic ages of 210 and 50 Myr respectively. Standard models assuming dipolar spin-down of both pulsars suggest that the time since the formation of B is ~50 Myr, i.e. close to B's characteristic age. However, adopting models which account for the impact of A's relativistic wind on B's spin-down we find that the formation of B took place either 80 or 180 Myr ago, depending the interaction mechanism. Formation 80 Myr ago, closer to B's characteristic age, would result in the contribution from J0737-3039 to the inferred coalescence rates for double neutron star binaries increasing by 40%. The 180 Myr age is closer to A's characteristic age and would be consistent with the most recent estimates of the coalescence rate. The new age constraints do not significantly impact recent estimates of the kick velocity, tilt angle between pre and post-supernova orbital planes or pre-supernova mass of B's progenitor.Comment: 5 pages, 2 figures, 1 table, accepted for publication by MNRA

Evaluating metabolites in patients with major depressive disorder who received mindfulness-based cognitive therapy and healthy controls using short echo MRSI at 7 Tesla.

ObjectivesOur aim was to evaluate differences in metabolite levels between unmedicated patients with major depressive disorder (MDD) and healthy controls, to assess changes in metabolites in patients after they completed an 8-week course of mindfulness-based cognitive therapy (MBCT), and to exam the correlation between metabolites and depression severity.Materials and methodsSixteen patients with MDD and ten age- and gender-matched healthy controls were studied using 3D short echo-time (20 ms) magnetic resonance spectroscopic imaging (MRSI) at 7 Tesla. Relative metabolite ratios were estimated in five regions of interest corresponding to insula, anterior cingulate cortex (ACC), caudate, putamen, and thalamus.ResultsIn all cases, MBCT reduced severity of depression. The ratio of total choline-containing compounds/total creatine (tCr) in the right caudate was significantly increased compared to that in healthy controls, while ratios of N-acetyl aspartate (NAA)/tCr in the left ACC, myo-inositol/tCr in the right insula, and glutathione/tCr in the left putamen were significantly decreased. At baseline, the severity of depression was negatively correlated with my-inositol/tCr in the left insula and putamen. The improvement in depression severity was significantly associated with changes in NAA/tCr in the left ACC.ConclusionsThis study has successfully evaluated regional differences in metabolites for patients with MDD who received MBCT treatment and in controls using 7 Tesla MRSI

Human stem cell-derived astrocytes replicate human prions in a PRNP genotype-dependent manner.

Prions are infectious agents that cause neurodegenerative diseases such as Creutzfeldt-Jakob disease (CJD). The absence of a human cell culture model that replicates human prions has hampered prion disease research for decades. In this paper, we show that astrocytes derived from human induced pluripotent stem cells (iPSCs) support the replication of prions from brain samples of CJD patients. For experimental exposure of astrocytes to variant CJD (vCJD), the kinetics of prion replication occur in a prion protein codon 129 genotype-dependent manner, reflecting the genotype-dependent susceptibility to clinical vCJD found in patients. Furthermore, iPSC-derived astrocytes can replicate prions associated with the major sporadic CJD strains found in human patients. Lastly, we demonstrate the subpassage of prions from infected to naive astrocyte cultures, indicating the generation of prion infectivity in vitro. Our study addresses a long-standing gap in the repertoire of human prion disease research, providing a new in vitro system for accelerated mechanistic studies and drug discovery

The Association Between Pelvic Discomfort and Erectile Dysfunction in Adult Male Bicyclists.

BackgroundBicycle riding's impact on erectile function remains a topic of great interest given cycling's popularity as a mode of transportation and exercise.AimWe evaluated risk factors for sexual dysfunction in male cyclists with the primary intention of determining if genital/pelvic pain and numbness are associated with erectile dysfunction (ED).MethodsWe surveyed male cyclists using an online anonymous questionnaire. Cyclists were queried on their demographics, cycling experience, and sexual function using the Sexual Health Inventory for Men (SHIM). ED was diagnosed when a completed SHIM score was <22. Regression analysis was used to evaluate the risk of ED in men with genital/pelvic pain or numbness after riding. The survey was designed in the United States.OutcomesQuantitative characterization of cycling habits, onset and timing of genital pain and numbness, and SHIM score.ResultsA total of 1635 participants completed the survey. A majority of men were over the age of 50 (58%, 934/1,607), Caucasian (88%, 1,437/1,635), had been active cyclists for over 10 years (63%, 1,025/1,635) and used road bikes (97%, 1,578/1,635). Overall, 22%, 30%, and 57% of men reported ED, genital pain, and genital numbness, respectively. While controlling for cohort demographics, body mass index, cycling intensity and equipment, and medical comorbidities, no saddle characteristics were associated with the risk of developing genital numbness. However, men reporting penile numbness were at higher risk of reporting ED (odds ratio [OR] = 1.453, P = .048). In addition, quicker onset of numbness and resolution of numbness within a day was associated with impaired erectile function. For example, numbness occurring less than 1 hour after cycling had greater odds of leading to ED than numbness after 5 hours (OR = 2.002, P = .032). Similarly, genital pain occurring less than 1 hour (OR = 2.466, P = .031) after cycling was associated with higher ED risk.Strengths & limitationsStrengths include a large sample size of high-intensity cyclists and validated questionnaire use. Limitations include reliance on anonymous self-reported survey data and minimal inquiry into the riding preferences and terrain traversed by cyclists.ConclusionsPelvic pain and numbness are common complaints among male riders in the United States. Men with such complaints are more likely to also report ED especially if it occurs earlier in the ride. Although direction of causality and temporality are uncertain, alleviation of factors resulting in pelvic discomfort may reduce cycling's impact on sexual function. Such interventions are critical given that cycling for both active travel and aerobic exercise confers numerous health benefits. Balasubramanian A, Yu J, Breyer BN, et al. The Association Between Pelvic Discomfort and Erectile Dysfunction in Adult Male Bicyclists. J Sex Med 2020;17:919-929