Citations

Abstract This is a single Institute, prospective cohort study. We collected twenty- two postmenopausal women with pelvic organ prolapse planning to undergo vaginal hysterectomy with transvaginal pelvic reconstructive surgery, with or without a concomitant anti-incontinence procedure. Vaginal swabs and urine samples were longitudinally collected at five time points: preoperative consult visit (T1), day of surgery prior to surgical scrub (T2), immediately postoperative (T3), day of hospital discharge (T4), and at the postoperative exam visit (T5). Women experiencing urinary tract infection symptoms provided a sample set prior to antibiotic administration (T6). Microbiome analysis on vaginal and urinary specimens at each time point. Region V3-V5 of the 16S ribosomal RNA gene was amplified and sequenced. Sample DNA was analyzed with visit T1, T2, T5 and T6. Six (27.3%) participants developed postoperative urinary tract infection whose vaginal sample at first clinical visit (T1) revealed beta-diversity analysis with significant differences in microbiome structure and composition. Women diagnosed with a postoperative urinary tract infection had a vaginal microbiome characterized by low abundance of Lactobacillus and high prevalence of Prevotella and Gardnerella species. In our cohort, preoperative vaginal swabs can predict who will develop a urinary tract infection following transvaginal surgery for pelvic organ prolapse.

Background: Cellular senescence has been associated with neurodegenerative disease and clearance of senescent cells using genetic or pharmaceutical strategies (senolytics) has demonstrated beneficial effects in mouse models investigating individual disease etiologies of Alzheimer’s disease (AD). However, it has remained unclear if senescent cell clearance in a mouse model exhibiting both plaque and tau pathologies modifies the disease state (3xTg). Objective: To investigate the effects of senescent cell clearance in the 3xTg mouse model. Methods: 3xTg mice were treated with senolytics (ABT263 (navitoclax; NAVI), a combination of dasatinib and quercetin (D+Q)), or subjected to transgene-mediated removal of p16-expressing cells (via INK-ATTAC). Results: Senolytic treatments consistently reduced microgliosis and ameliorated both amyloid and tau pathology in 3xTg mice. Using RNA sequencing, we found evidence that synaptic dysfunction and neuroinflammation were attenuated with treatment. These beneficial effects were not observed with short-term senolytic treatment in mice with more advanced disease. Conclusions: Overall, our results further corroborate the beneficial effects senescent cell clearance could have on AD and highlight the importance of early intervention for the treatment of this debilitating disease.

Background: The existence and contribution of microglia with senescent-like alterations in the pathogenesis of age-related neurodegenerative diseases like Alzheimer’s disease (AD) have been suggested in recent years. However, the identification of this distinct microglial population in vivo has proven challenging, largely due to overlaps in the inflammatory phenotype of activated and senescent microglia. Furthermore, attempts at recapitulating senescence in microglia in vitro are limited. Objective: To identify and characterize senescent microglia that occur in vivo in an animal model of neurodegeneration driven by pathologic tau. Methods: We analyzed the RNA expression patterns of individual microglia from normal mice and the pathogenic tau P301 S PS19 mouse model. We have previously demonstrated that p16-expressing senescent microglia occur in these mice when neurodegeneration has occurred. Results: Here we identify a subset of disease-associated microglia with senescent features, notably characterized by the expression of Ccl4 . This signature overlaps with established markers of senescence from other cell types. Conclusion: Our characterization of senescent microglia can be used to better understand the role of senescent microglia in various age-related contexts, including whether clearance of senescent microglia represents a viable therapeutic option.

Microglial homeostasis has emerged as a critical mediator of health and disease in the central nervous system. In their neuroprotective role as the predominant immune cells of the brain, microglia surveil the microenvironment for debris and pathogens, while also promoting neurogenesis and performing maintenance on synapses. Chronological ageing, disease onset, or traumatic injury promotes irreparable damage or deregulated signaling to reinforce neurotoxic phenotypes in microglia. These insults may include cellular senescence, a stable growth arrest often accompanied by the production of a distinctive pro‐inflammatory secretory phenotype, which may contribute to age‐ or disease‐driven decline in neuronal health and cognition and is a potential novel therapeutic target. Despite this increased scrutiny, unanswered questions remain about what distinguishes senescent microglia and non‐senescent microglia reacting to insults occurring in ageing, disease, and injury, and how central the development of senescence is in their pivot from guardian to assailant. To intelligently design future studies to untangle senescent microglia from other primed and reactionary states, specific criteria must be developed that define this population and allow for comparisons between different model systems. Comparing microglial activity seen in homeostasis, ageing, disease, and injury allows for a more coherent understanding of when and how senescent and other harmful microglial subpopulations should be targeted.

Summary A low‐diversity microbial community, dominated by the γ ‐proteobacterium H alomonas sulfidaeris , was detected in samples of warm saline formation porewater collected from the C ambrian Mt. S imon S andstone in the I llinois B asin of the N orth A merican M idcontinent (1.8 km/5872 ft burial depth, 50° C , pH 8, 181 bars pressure). These highly porous and permeable quartz arenite sandstones are directly analogous to reservoirs around the world targeted for large‐scale hydrocarbon extraction, as well as subsurface gas and carbon storage. A new downhole low‐contamination subsurface sampling probe was used to collect in situ formation water samples for microbial environmental metagenomic analyses. Multiple lines of evidence suggest that this H . sulfidaeris ‐dominated subsurface microbial community is indigenous and not derived from drilling mud microbial contamination. Data to support this includes V 1‐ V 3 pyrosequencing of formation water and drilling mud, as well as comparison with previously published microbial analyses of drilling muds in other sites. Metabolic pathway reconstruction, constrained by the geology, geochemistry and present‐day environmental conditions of the Mt . S imon S andstone, implies that H . sulfidaeris ‐dominated subsurface microbial community may utilize iron and nitrogen metabolisms and extensively recycle indigenous nutrients and substrates. The presence of aromatic compound metabolic pathways suggests this microbial community can readily adapt to and survive subsurface hydrocarbon migration.