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Catheter-associated urinary tract infections (CAUTIs) are amongst the most common nosocomial infections worldwide and are difficult to treat partly due to development of multidrug-resistance from CAUTI-related pathogens. Importantly, CAUTI often leads to secondary bloodstream infections and death. A major challenge is to predict when patients will develop CAUTIs and which populations are at-risk for bloodstream infections. Catheter-induced inflammation promotes fibrinogen (Fg) and fibrin accumulation in the bladder which are exploited as a biofilm formation platform by CAUTI pathogens. Using our established mouse model of CAUTI, here we identified that host populations exhibiting either genetic or acquired fibrinolytic-deficiencies, inducing fibrin deposition in the catheterized bladder, are predisposed to severe CAUTI and septicemia by diverse uropathogens in mono- and poly-microbial infections. Furthermore, here we found that Enterococcus faecalis , a prevalent CAUTI pathogen, uses the secreted protease, SprE, to induce fibrin accumulation and create a niche ideal for growth, biofilm formation, and persistence during CAUTI. Catheter-associated urinary tract infections can often lead to secondary bloodstream infections, and catheter-induced bladder inflammation. In this work, authors utilise murine models to probe defective fibrinolysis drives extravascular fibrin formation, potentially predisposing hosts to severe CAUTI.

Urinary catheterization causes bladder damage, predisposing hosts to catheter-associated urinary tract infections (CAUTIs). CAUTI pathogenesis is mediated by bladder damage-induced inflammation, resulting in accumulation and deposition of the blood-clotting protein fibrinogen (Fg) and its matrix form fibrin, which are exploited by uropathogens as biofilm platforms to establish infection. Catheter-induced inflammation also results in robust immune cell recruitment, including macrophages (Mϕs). A fundamental knowledge gap is understanding the mechanisms by which the catheterized-bladder environment suppresses the Mϕ antimicrobial response, allowing uropathogen persistence. Here, we found that Fg and fibrin differentially modulate M1 and M2 Mϕ polarization, respectively. We unveiled that fibrin accumulation in catheterized mice induced an anti-inflammatory M2-like Mϕ phenotype, correlating with pathogen persistence. Even GM-CSF treatment of wildtype mice to promote M1 polarization was not sufficient to reduce bacterial burden and dissemination, indicating that the catheterized-bladder environment provides mixed signals, dysregulating Mϕ polarization, hindering its antimicrobial response against uropathogens.

Online public forum discussion in the Reddit science community is moderated to ensure a high standard of scientific content in discourse. This thesis project creates predictive models to distinguish between acceptable and unacceptable forum comments, and it seeks to interpret those models based on input from moderators. Information was collected from moderators (their demographics, moderation habits, moderation decisions and reasons for removing comments) to curate a deeper understanding of the online moderation community and predictive models for automated moderation support.

The development of metal-catalysed cross-coupling reactions between one electrophilic and one organometallic nucleophilic partner has revolutionized the practice of chemical synthesis, with coupling reactions between sp 2 centres now commonplace in both academic and industrial research. Methods to allow coupling of sp 3 centres are rapidly being developed, with many recent advances even enabling control of the absolute configuration of newly formed stereogenic centres. The related cross-electrophile couplings have not been developed as thoroughly owing to the challenge of obtaining cross-selectivity between two substrates with similar reactivity. However, the discovery of improved methods to address this challenge has led to significant recent progress. The development of enantioselective cross-electrophile coupling reactions is an emerging area of research. Both stereoconvergent and stereospecific variants have been reported for the synthesis of a range of products containing tertiary stereogenic centres. Many of these transformations build on lessons learnt from traditional (electrophile–nucleophile) cross-couplings of alkyl electrophiles. For example, all enantioselective transformations described to date use a nickel catalyst. Continued progression is likely to provide strategic disconnections for asymmetric synthesis of natural products and medicinal agents. The cross-electrophile coupling approach to stereocontrolled C–C bond formation provides a complementary alternative to traditional cross-coupling methods. This Perspective provides an overview of the recent development of nickel-catalysed asymmetric cross-electrophile coupling reactions. Both stereoconvergent and stereospecific examples are considered and mechanistic details are highlighted.

Macroautophagy is a key stress-response pathway that can suppress or promote tumorigenesis depending on the cellular context. Notably, Kirsten rat sarcoma (KRAS)-driven tumors have been reported to rely on macroautophagy for growth and survival, suggesting a potential therapeutic approach of using autophagy inhibitors based on genetic stratification. In this study, we evaluated whether KRAS mutation status can predict the efficacy to macroautophagy inhibition. By profiling 47 cell lines with pharmacological and genetic loss-of-function tools, we were unable to confirm that KRAS-driven tumor lines require macroautophagy for growth. Deletion of autophagy-related 7 (ATG7) by genome editing completely blocked macroautophagy in several tumor lines with oncogenic mutations in KRAS but did not inhibit cell proliferation in vitro or tumorigenesis in vivo. Furthermore, ATG7 knockout did not sensitize cells to irradiation or to several anticancer agents tested. Interestingly, ATG7-deficient and -proficient cells were equally sensitive to the antiproliferative effect of chloroquine, a lysosomotropic agent often used as a pharmacological tool to evaluate the response to macroautophagy inhibition. Moreover, both cell types manifested synergistic growth inhibition when treated with chloroquine plus the tyrosine kinase inhibitors erlotinib or sunitinib, suggesting that the antiproliferative effects of chloroquine are independent of its suppressive actions on autophagy.

Social isolation during the juvenile critical window is detrimental to proper functioning of the prefrontal cortex (PFC) and establishment of appropriate adult social behaviors. However, the specific circuits that undergo social experience-dependent maturation to regulate social behavior are poorly understood. We identify a specific activation pattern of parvalbumin-positive interneurons (PVIs) in dorsal-medial PFC (dmPFC) prior to an active bout, or a bout initiated by the focal mouse, but not during a passive bout when mice are explored by a stimulus mouse. Optogenetic and chemogenetic manipulation reveals that brief dmPFC-PVI activation triggers an active social approach to promote sociability. Juvenile social isolation decouples dmPFC-PVI activation from subsequent active social approach by freezing the functional maturation process of dmPFC-PVIs during the juvenile-to-adult transition. Chemogenetic activation of dmPFC-PVI activity in the adult animal mitigates juvenile isolation-induced social deficits. Therefore, social experience-dependent maturation of dmPFC-PVI is linked to long-term impacts on social behavior. Isolation during critical periods of development prevents development of normal social behaviours in mice, and this is thought to involve the prefrontal cortex. Here, the authors identify an activation pattern in parvalbumin-positive interneurons in the dorsal medial prefrontal cortex that when activated promotes sociability behaviours in mice.

Unvaccinated persons without previous Covid-19 had the highest risk of omicron infection; those who had been infected after emergence of the delta variant and had received three mRNA vaccine doses were the most protected.

Aging is the most prominent risk factor for osteoarthritis onset, but the etiology of aging-associated cartilage degeneration is not fully understood. Recent studies by Guilak and colleagues have highlighted the crucial roles of cell-matrix interactions in cartilage homeostasis and disease. This study thus quantified aging-associated changes in cartilage biomechanics and chondrocyte intracellular calcium signaling, [Ca2+]i, activities in wild-type mice at 3, 12 and 22 months of age. In aged mice, articular cartilage exhibits reduced staining of sulfated glycosaminoglycans (sGAGs), indicating decreased aggrecan content. On cartilage surface, collagen fibrils undergo significant thickening while retaining their transverse isotropic architecture, and exhibit signs of fibril crimping in the 22-month group. These compositional and structural changes contribute to a significant decrease in cartilage modulus at 22 months of age (0.55 ± 0.25 MPa, mean ± 95 % CI, n = 8) relative to those at 3 and 12 months (1.82 ± 0.48 MPa and 1.45 ± 0.46 MPa, respectively, n ≥ 8). Despite the decreases in sGAG content and tissue modulus, chondrocytes do not exhibit significantly demoted [Ca2+]i activities in situ, in both physiological (isotonic) and osmotically instigated (hypo- and hypertonic) conditions. At 12 months of age, there exists a sub-population of chondrocytes with hyper-active [Ca2+]i responses under hypotonic stimuli, possibly indicating a phenotypic shift of chondrocytes during aging. Together, these results yield new insights into aging-associated biomechanical and mechanobiological changes of murine cartilage, providing a benchmark for elucidating the molecular mechanisms of age-related changes in cell-matrix interactions.

To compare the effects of an exercise and dietary intervention with those of standard-of-care management upon change in lift and carry performance and mobility-related self-efficacy beliefs and explore associations in prostate cancer patients undergoing androgen deprivation therapy. 32 prostate cancer patients (M age = 66.2 years; SD = 7.8) undergoing androgen deprivation therapy were randomly assigned to a 3-month exercise and dietary lifestyle intervention (n = 16) or standard-of-care management (n = 16). Outcome assessments were obtained at baseline, 2- and 3-month follow-up. The lifestyle intervention resulted in significantly greater improvements in lift and carry performance (p = 0.01) at 2 Months (d = 1.01; p < 0.01) and 3 Months (d = 0.95; p < 0.01) and superior improvements in mobility-related self-efficacy at 2 Months (d = 0.38) and 3 Months (d = 0.58) relative to standard-of-care. Mobility-related self-efficacy (r = -.66; p = 0.006) and satisfaction with function (r = -.63; p = 0.01) were significantly correlated with lift and carry performance at 3 Months. The exercise and dietary lifestyle intervention yielded superior improvements in lift and carry performance and mobility-related self-efficacy relative to standard-of-care and key social cognitive outcomes were associated with more favorable mobility performance.

Objectives: Expression of strong nuclear STAT6 is thought to be a specific marker for solitary fibrous tumors (SFTs). Little is known about subtle expression patterns in other mesenchymal lesions. Methods: We performed immunohistochemical studies against the C-terminus of STAT6 in tissue microarrays and whole sections, comprising 2366 mesenchymal lesions. Results: Strong nuclear STAT6 was expressed in 285 of 2,021 tumors, including 206 of 240 SFTs, 49 of 408 well-differentiated/dedifferentiated liposarcomas, eight of 65 unclassified sarcomas, and 14 of 184 desmoid tumors, among others. Expression in SFTs was predominately limited to the nucleus. Other positive tumors typically expressed both nuclear and cytoplasmic STAT6. Complete absence of STAT6 was most common in pleomorphic liposarcoma and alveolar soft part sarcoma (60% and 72% cases negative, respectively). Conclusions: Strong nuclear STAT6 is largely specific for SFTs. Physiologic low-level cytoplasmic/nuclear expression is common in mesenchymal neoplasia and is of uncertain significance.