OLIGODENDROCYTE 2PHATAL REVEALS DYNAMICS OF MYELIN DEGENERATION AND REPAIR

Oligodendrocytes are responsible for producing myelin in the central nervous system. This lipid-rich coating along axons helps to increase action potential velocity, provide metabolic support to axons, and facilitate fine-tuning of neuronal circuitry. Demyelination and/or myelin dysfunction is widespread in neurodegenerative diseases and aging. Despite this, we know very little about how individual oligodendrocytes, or the myelin sheaths they produce, degenerate. Myelin repair, carried out by resident oligodendrocyte precursor cells (OPCs), is known to occur following myelin damage in certain contexts. We sought to investigate the cellular dynamics of oligodendrocyte degeneration and repair by developing a non-inflammatory demyelination model, combining intravital imaging with a single-cell ablation technique called 2Phatal. Oligodendrocyte 2Phatal activated a stereotyped degeneration cascade which triggered remyelination by local OPCs. Remyelination efficiency was dependent on initial myelin patterns and dynamic imaging revealed rapid repair with near-seamless transitions between myelin loss and remyelination, a process we call synchronous remyelination. A subset of highly branched OPCs executed this remyelination, pointing towards demyelination-associated morphological signatures of fate. Age-related demyelination mirrored the degenerative cascade observed with 2Phatal; however, remyelination in aging was defective due to failed oligodendrogenesis. Thus, oligodendrocyte 2Phatal uncovered novel forms of rapid remyelination that restore myelin patterns in the adult but are absent in aging. We go on to demonstrate that the maturation state of oligodendrocytes determines the dynamics and mechanism of cell death. Premyelinating and newly formed oligodendrocytes degenerate more rapidly than mature oligodendrocytes, but faster than OPCs, following 2Phatal. Furthermore, they appear to utilize a caspase-dependent form of cell death, while mature oligodendrocytes do not. This new insight suggests that different cell death mechanisms are used by these two populations, necessitating distinct strategies to protect preestablished and new oligodendrocytes in human aging and/or disease

Competing risks of death in women treated with adjuvant aromatase inhibitors for early breast cancer on NCIC CTG MA.27

Baseline patient and tumor characteristics differentially affected type of death in the MA.17 placebo-controlled letrozole trial where cardiovascular death was not separately identified. The MA.27 trial allowed competing risks analysis of breast cancer (BC), cardiovascular, and other type (OT) of death. MA.27 was a phase III adjuvant breast cancer trial of exemestane versus anastrozole. Effects of baseline patient and tumor characteristics were tested for whether factors were associated with (1) all cause mortality and (2) cause-specific mortality. We also fit step-wise forward cause-specific-adjusted models. 7576 women (median age 64 years; 5417 (72 %) < 70 years and 2159 (28 %) ≥ 70 years) were enrolled and followed for median 4.1 years. The 432 deaths comprised 187 (43 %) BC, 66 (15 %) cardiovascular, and 179 (41 %) OT. Five baseline factors were differentially associated with type of death. Older patients had greater BC (p = 0.03), cardiovascular (p < 0.001), and other types (p < 0.001) of mortality. Patients with pre-existing cardiovascular history had worse cardiovascular mortality (p < 0.001); those with worse ECOG performance status had worse OT mortality (p < 0.001). Patients with T1 tumors (p < 0.001) and progesterone receptor positive had less BC mortality (p < 0.001). Fewer BC deaths occurred with node-negative disease (p < 0.001), estrogen receptor-positive tumors (p = 0.001), and without adjuvant chemotherapy (p = 0.005); worse cardiovascular mortality (p = 0.01), with trastuzumab; worse OT mortality, for non-whites (p = 0.03) and without adjuvant radiotherapy (p = 0.003). Overall, 57 % of deaths in MA.27 AI-treated patients were non-breast cancer related. Baseline patient and tumor characteristics differentially affected type of death with women 70 or older experiencing more non-breast cancer death

The Spitzer c2d Survey of Large, Nearby, Interstellar Clouds. VII. Ophiuchus Observed with MIPS

We present maps of 14.4 deg^2 of the Ophiuchus dark clouds observed by the Spitzer Space Telescope Multiband Imaging Photometer for Spitzer (MIPS). These high-quality maps depict both numerous point sources and extended dust emission within the star-forming and non–star-forming portions of these clouds. Using PSF-fitting photometry, we detect 5779 sources at 24 μm and 81 sources at 70 μm at the 10 σ level of significance. Three hundred twenty-three candidate young stellar objects (YSOs) were identified according to their positions on the MIPS/2MASS K versus color-magnitude diagrams, as compared to 24 μm detections in the SWIRE extragalactic survey. We find that more than half of the YSO candidates, and almost all those with protostellar Class I spectral energy distributions, are confined to the known cluster and aggregates

Unexposed populations and potential COVID-19 hospitalisations and deaths in European countries as per data up to 21 November 2021.

We estimate the potential remaining COVID-19 hospitalisation and death burdens in 19 European countries by estimating the proportion of each country's population that has acquired immunity to severe disease through infection or vaccination. Our results suggest many European countries could still face high burdens of hospitalisations and deaths, particularly those with lower vaccination coverage, less historical transmission and/or older populations. Continued non-pharmaceutical interventions and efforts to achieve high vaccination coverage are required in these countries to limit severe COVID-19 outcomes

PheMaDB: A solution for storage, retrieval, and analysis of high throughput phenotype data

<p>Abstract</p> <p>Background</p> <p>OmniLog™ phenotype microarrays (PMs) have the capability to measure and compare the growth responses of biological samples upon exposure to hundreds of growth conditions such as different metabolites and antibiotics over a time course of hours to days. In order to manage the large amount of data produced from the OmniLog™ instrument, PheMaDB (Phenotype Microarray DataBase), a web-based relational database, was designed. PheMaDB enables efficient storage, retrieval and rapid analysis of the OmniLog™ PM data.</p> <p>Description</p> <p>PheMaDB allows the user to quickly identify records of interest for data analysis by filtering with a hierarchical ordering of Project, Strain, Phenotype, Replicate, and Temperature. PheMaDB then provides various statistical analysis options to identify specific growth pattern characteristics of the experimental strains, such as: outlier analysis, negative controls analysis (signal/background calibration), bar plots, pearson's correlation matrix, growth curve profile search, <it>k</it>-means clustering, and a heat map plot. This web-based database management system allows for both easy data sharing among multiple users and robust tools to phenotype organisms of interest.</p> <p>Conclusions</p> <p>PheMaDB is an open source system standardized for OmniLog™ PM data. PheMaDB could facilitate the banking and sharing of phenotype data. The source code is available for download at <url>http://phemadb.sourceforge.net</url>.</p

A gut bacterial amyloid promotes α-synuclein aggregation and motor impairment in mice

Amyloids are a class of protein with unique self-aggregation properties, and their aberrant accumulation can lead to cellular dysfunctions associated with neurodegenerative diseases. While genetic and environmental factors can influence amyloid formation, molecular triggers and/or facilitators are not well defined. Growing evidence suggests that non-identical amyloid proteins may accelerate reciprocal amyloid aggregation in a prion-like fashion. While humans encode ~30 amyloidogenic proteins, the gut microbiome also produces functional amyloids. For example, curli are cell surface amyloid proteins abundantly expressed by certain gut bacteria. In mice overexpressing the human amyloid α-synuclein (αSyn), we reveal that colonization with curli-producing Escherichia coli promotes αSyn pathology in the gut and the brain. Curli expression is required for E. coli to exacerbate αSyn-induced behavioral deficits, including intestinal and motor impairments. Purified curli subunits accelerate αSyn aggregation in biochemical assays, while oral treatment of mice with a gut-restricted amyloid inhibitor prevents curli-mediated acceleration of pathology and behavioral abnormalities. We propose that exposure to microbial amyloids in the gastrointestinal tract can accelerate αSyn aggregation and disease in the gut and the brain

The antiangiogenic activity of naturally occurring and synthetic homoisoflavonoids from the Hyacinthaceae (sensu APGII)

Excessive blood vessel formation in the eye is implicated in wet age-related macular degeneration, proliferative diabetic retinopathy, neovascular glaucoma, and retinopathy of prematurity, which are major causes of blindness. Small molecule antiangiogenic drugs are strongly needed to supplement existing biologics. Homoisoflavonoids have been previously shown to have potent antiproliferative activities in endothelial cells over other cell types. Moreover, they demonstrated a strong antiangiogenic potential in vitro and in vivo in animal models of ocular neovascularization. Here, we tested the antiangiogenic activity of a group of naturally occurring homoisoflavonoids isolated from the family Hyacinthaceae and related synthetic compounds, chosen for synthesis based on structure–activity relationship observations. Several compounds showed interesting antiproliferative and antiangiogenic activities in vitro on retinal microvascular endothelial cells, a disease-relevant cell type, with the synthetic chromane, 46, showing the best activity (GI50 of 2.3 × 10–4 μM)

The Spitzer c2d Survey of Large, Nearby, Interstellar Clouds. IV. Lupus Observed with MIPS

We present maps of 7.78 square degrees of the Lupus molecular cloud complex at 24, 70, and $160\:\mu$m. They were made with the Spitzer Space Telescope's Multiband Imaging Photometer for Spitzer (MIPS) instrument as part of the Spitzer Legacy Program, ``From Molecular Cores to Planet-Forming Disks'' (c2d). The maps cover three separate regions in Lupus, denoted I, III, and IV. We discuss the c2d pipeline and how our data processing differs from it. We compare source counts in the three regions with two other data sets and predicted star counts from the Wainscoat model. This comparison shows the contribution from background galaxies in Lupus I. We also create two color magnitude diagrams using the 2MASS and MIPS data. From these results, we can identify background galaxies and distinguish them from probable young stellar objects. The sources in our catalogs are classified based on their spectral energy distribution (SED) from 2MASS and Spitzer wavelengths to create a sample of young stellar object candidates. From 2MASS data, we create extinction maps for each region and note a strong corresponence between the extinction and the $160\:\mu$m emission. The masses we derived in each Lupus cloud from our extinction maps are compared to masses estimated from $^{13}$CO and C$^{18}$O and found to be similar to our extinction masses in some regions, but significantly different in others. Finally, based on our color-magnitude diagrams, we selected 12 of our reddest candidate young stellar objects for individual discussion. Five of the 12 appear to be newly-discovered YSOs.Comment: 15 pages, 17 figures, uses emulateapj.cls. Accepted for publication in ApJ. A version with high-quality figures can be found at http://peggysue.as.utexas.edu/SIRTF

Limited effects of long-term daily cranberry consumption on the gut microbiome in a placebo-controlled study of women with recurrent urinary tract infections

Background: Urinary tract infections (UTIs) affect 15 million women each year in the United States, with > 20% experiencing frequent recurrent UTIs. A recent placebo-controlled clinical trial found a 39% reduction in UTI symptoms among recurrent UTI sufferers who consumed a daily cranberry beverage for 24 weeks. Using metagenomic sequencing of stool from a subset of these trial participants, we assessed the impact of cranberry consumption on the gut microbiota, a reservoir for UTI-causing pathogens such as Escherichia coli, which causes > 80% of UTIs. Results: The overall taxonomic composition, community diversity, carriage of functional pathways and gene families, and relative abundances of the vast majority of observed bacterial taxa, including E. coli, were not changed significantly by cranberry consumption. However, one unnamed Flavonifractor species (OTU41), which represented ≤1% of the overall metagenome, was significantly less abundant in cranberry consumers compared to placebo at trial completion. Given Flavonifractor’s association with negative human health effects, we sought to determine OTU41 characteristic genes that may explain its differential abundance and/or relationship to key host functions. Using comparative genomic and metagenomic techniques, we identified genes in OTU41 related to transport and metabolism of various compounds, including tryptophan and cobalamin, which have been shown to play roles in host-microbe interactions. Conclusion: While our results indicated that cranberry juice consumption had little impact on global measures of the microbiome, we found one unnamed Flavonifractor species differed significantly between study arms. This suggests further studies are needed to assess the role of cranberry consumption and Flavonifractor in health and wellbeing in the context of recurrent UTI. Trial registration: Clinical trial registration number: ClinicalTrials.govNCT01776021