Explore the vast range of titles available.

Based on an international literature review and selected case studies, this article discusses the potential of the Caring City policies for an urban public culture of care. In recent years, “the caring city” has entered feminist and urbanist debates and local politics as a concept to overcome the multiple crises of care. The concept draws on a longstanding tradition of feminist research and critique, but is a comparatively new attempt to transform care arrangements at the local level. It addresses the urban as a system of mutual care and a place of daily and (inter)generational care for oneself, others, and the planet. In terms of the importance of local infrastructure in enabling or hindering care, the concept also includes a debate on planning as caring practice. It is enhanced and put into practice by local governments, such as in Barcelona and Madrid (Spain) and Bogotá (Colombia). Here, Caring City policies range from integrated care strategies to neighbourhood care systems, including care centres, mutual support networks, and awareness‐raising. The article provides an overview of Caring City policies, their genesis, objectives, and essential elements. We argue that the concept resonates well with the current quest to develop more sustainable and equitable cities by establishing public urban cultures of care. The Caring City policies’ long‐term effects, however, require monitoring, as the case studies demonstrate how little established Caring City policies still are and how much effort it takes to anchor them in local politics in the long term.

Autosomal dominant polycystic kidney disease (ADPKD) affects more than 12 million people worldwide. Mutations in PKD1 and PKD2 cause cyst formation through unknown mechanisms. To unravel the pathogenic mechanisms in ADPKD, multiple studies have investigated transcriptional mis-regulation in cystic kidneys from patients and mouse models, and numerous dysregulated genes and pathways have been described. Yet, the concordance between studies has been rather limited. Furthermore, the cellular and genetic diversity in cystic kidneys has hampered the identification of mis-expressed genes in kidney epithelial cells with homozygous PKD mutations, which are critical to identify polycystin-dependent pathways. Here we performed transcriptomic analyses of Pkd1- and Pkd2-deficient mIMCD3 kidney epithelial cells followed by a meta-analysis to integrate all published ADPKD transcriptomic data sets. Based on the hypothesis that Pkd1 and Pkd2 operate in a common pathway, we first determined transcripts that are differentially regulated by both genes. RNA sequencing of genome-edited ADPKD kidney epithelial cells identified 178 genes that are concordantly regulated by Pkd1 and Pkd2. Subsequent integration of existing transcriptomic studies confirmed 31 previously described genes and identified 61 novel genes regulated by Pkd1 and Pkd2. Cluster analyses then linked Pkd1 and Pkd2 to mRNA splicing, specific factors of epithelial mesenchymal transition, post-translational protein modification and epithelial cell differentiation, including CD34, CDH2, CSF2RA, DLX5, HOXC9, PIK3R1, PLCB1 and TLR6. Taken together, this model-based integrative analysis of transcriptomic alterations in ADPKD annotated a conserved core transcriptomic profile and identified novel candidate genes for further experimental studies.

In countries with intensive pig husbandry in stables, the prevalence of livestock-associated (LA) methicillin-resistant Staphylococcus aureus (MRSA) on such farms has remained high in the last few years or has also further increased. Simple measures to reduce the LA-MRSA among pigs have not yet been successfully implemented. Earlier publications showed a decontamination of LA-MRSA was only possible with great effort. The aim of this study is to determine the suitability of routine cleaning and disinfection (C&D) for adequate LA-MRSA decontamination. For this purpose, at least 115 locations in a piglet-rearing compartment were examined before and after cleaning and disinfection. The sample locations were stratified according to accessibility for pigs and the difficulty of cleaning. The cleaning work was carried out routinely by farm employees, who were not informed about the sampling (single blinded). While before cleaning and disinfection, 85% of the samples from the surfaces were LA-MRSA positive, while only 2% were positive thereafter. All LA-MRSA-positive samples after cleaning and disinfection were outside the animal area. Air samples also showed no LA-MRSA after cleaning and disinfection. Conclusion: In well-managed livestock farms, decontamination of the LA-MRSA barn is quite possible; after C&D no LA-MRSA was detectable at animal height.

BackgroundQuantitative serological assays detecting response to SARS-CoV-2 are needed to quantify immunity. This study analyzed the performance and correlation of two quantitative anti-S1 assays in oligo-/asymptomatic individuals from a population-based cohort.MethodsIn total, 362 plasma samples (108 with reverse transcription-polymerase chain reaction [RT-PCR]-positive pharyngeal swabs, 111 negative controls, and 143 with positive serology without confirmation by RT-PCR) were tested with quantitative assays (Euroimmun Anti-SARS-CoV-2 QuantiVac enzyme-linked immunosorbent assay [EI-S1-IgG-quant]) and Roche Elecsys® Anti-SARS-CoV-2 S [Ro-RBD-Ig-quant]), which were compared with each other and confirmatory tests, including wild-type virus micro-neutralization (NT) and GenScript®cPass™. Square roots R of coefficients of determination were calculated for continuous variables and non-parametric tests were used for paired comparisons.ResultsQuantitative anti-S1 serology correlated well with each other (true positives, 96%; true negatives, 97%). Antibody titers decreased over time (< 30 to > 240 days after initial positive RT-PCR). Agreement with GenScript-cPass was 96%/99% for true positives and true negatives, respectively, for Ro-RBD-Ig-quant and 93%/97% for EI-S1-IgG-quant. Ro-RBD-Ig-quant allowed distinct separation between positives and negatives, and less non-specific reactivity versus EI-S1-IgG-quant. Raw values (95% CI) ≥ 28.7 U/mL (22.6–36.4) for Ro-RBD-Ig-quant and ≥ 49.8 U/mL (43.4–57.1) for EI-S1-IgG-quant predicted NT > 1:5 in 95% of cases.ConclusionsOur findings suggest both quantitative anti-S1 assays (EI-S1-IgG-quant and Ro-RBD-Ig-quant) may replace direct neutralization assays in quantitative measurement of immune protection against SARS-CoV-2 in certain circumstances. However, although the mean antibody titers for both assays tended to decrease over time, a higher proportion of Ro-RBD-Ig-quant values remained positive after 240 days.

Regulation of centrosome structure, duplication and segregation is integrated into cellular pathways that control cell cycle progression and growth. As part of these pathways, numerous proteins with well‐established non‐centrosomal localization and function associate with the centrosome to fulfill regulatory functions. In turn, classical centrosomal components take up functional and structural roles as part of other cellular organelles and compartments. Thus, although a comprehensive inventory of centrosome components is missing, emerging evidence indicates that its molecular composition reflects the complexity of its functions. We analysed the Drosophila embryonic centrosomal proteome using immunoisolation in combination with mass spectrometry. The 251 identified components were functionally characterized by RNA interference. Among those, a core group of 11 proteins was critical for centrosome structure maintenance. Depletion of any of these proteins in Drosophila SL2 cells resulted in centrosome disintegration, revealing a molecular dependency of centrosome structure on components of the protein translation machinery, actin‐ and RNA‐binding proteins. In total, we assigned novel centrosome‐related functions to 24 proteins and confirmed 13 of these in human cells. Combining mass spectrometric analyses, localization studies and RNAi loss‐of‐function screening, this study provides a comprehensive characterization of centrosomes from fly embryos, including identification of new proteins essential for centrosome maintenance and validation of their conserved function in human cells.

Antibiotic‐resistant enterococci represent a significant global health challenge. Unfortunately, most β‐lactam antibiotics are not applicable for enterococcal infections due to intrinsic resistance. To extend their antimicrobial spectrum, polycationic peptides are conjugated to examples from each of the four classes of β‐lactam antibiotics. Remarkably, the β‐lactam–peptide conjugates gained an up to 1000‐fold increase in antimicrobial activity against vancomycin‐susceptible and vancomycin‐resistant enterococci. Even against β‐lactam‐resistant Gram‐negative strains, the conjugates are found to be effective despite their size exceeding the exclusion volume of porins. The extraordinary gain of activity can be explained by an altered mode of killing. Of note, the conjugates showed a concentration‐dependent activity in contrast to the parent β‐lactam antibiotics that exhibited a time‐dependent mode of action. In comparison to the parent β‐lactams, the conjugates showed altered affinities to the penicillin‐binding proteins. Furthermore, it is found that peptide conjugation also resulted in a different elimination route of the compounds when administered to rodents. In mice systemically infected with vancomycin‐resistant enterococci, treatment with a β‐lactam–peptide conjugate reduced bacterial burden in the liver compared to its originator. Therefore, peptide modification of β–lactam antibiotics represents a promising platform strategy to broaden their efficacy spectrum, particularly against enterococci. Novel potent compounds are urgently required for the treatment of antibiotic‐resistant bacteria. Conjugation of polycationic peptides to β‐lactam antibiotics extends their efficacy spectrum against enterococci. The β‐lactam–peptide conjugates show significant differences in mechanism and biodistribution compared to their originators. Due to their high potency, the β‐lactam–peptide conjugates can serve as an alternative treatment option for severe enterococcal infections.

The spindle assembly checkpoint guards the fidelity of chromosome segregation. It requires the close cooperation of cell cycle regulatory proteins and cytoskeletal elements to sense spindle integrity. The role of the centrosome, the organizing center of the microtubule cytoskeleton, in the spindle checkpoint is unclear. We found that the molecular requirements for a functional spindle checkpoint included components of the large γ-tubulin ring complex (γ-TuRC). However, their localization at the centrosome and centrosome integrity were not essential for this function. Thus, the spindle checkpoint can be activated at the level of microtubule nucleation.

With longitudinal untargeted assessment of circulating tumor DNA in metastatic HR+ breast cancer patients during CDK4/6 treatment and joint model analyses, we demonstrated that tumor fraction trajectories rather than single time point measurements provide important dynamic information on developing disease progression. The joint model can also use the trajectories for providing dynamic predictions for the individual patient. Despite improved clinical outcomes, intrinsic or acquired resistance to CDK4/6 inhibitor treatment has limited the success of this treatment in HR+HER2− metastatic breast cancer patients. Biomarkers are urgently needed, and longitudinal biomarker measurements may harbor more dynamic predictive and prognostic information compared to single time point measurements. The aim of this study was to explore the longitudinal evolution of circulating tumor fractions within cell‐free DNA assessed by an untargeted sequencing approach during CDK4/6 therapy and to quantify the potential association between longitudinal z‐score measurements and clinical outcome by using joint models. Forty‐nine HR+HER2− metastatic breast cancer patients were enrolled, and z‐score levels were measured at baseline and during 132 follow‐up visits (median number of measurements per patient = 3, 25th–75th percentile: 3–5, range: 1–8). We observed higher baseline z‐score levels (estimated difference 0.57, 95% CI: 0.147–0.983, P‐value = 0.008) and a constant increase of z‐score levels over follow‐up time (overall P‐value for difference in log z‐score over time = 0.024) in patients who developed progressive disease. Importantly, the joint model revealed that elevated z‐score trajectories were significantly associated with higher progression risk (HR of log z‐score at any time of follow‐up = 3.3, 95% CI, 1.44–7.55, P = 0.005). In contrast, single z‐score measurement at CDK4/6 inhibitor treatment start did not predict risk of progression. In this prospective study, we demonstrate proof‐of‐concept that longitudinal z‐score trajectories rather than single time point measurements may harbor important dynamic information on the development of disease progression in HR+HER2− breast cancer patients undergoing CDK4/6 inhibitor treatment.

Although anti-Catholicism and anti-Jacobinism primed many Britons to fear what one observer called “the hordes of vagabond French” who reached their shores in the fall of 1792, others launched widespread relief efforts. Among the more remarkable was the Wilmot Committee. This subscription charity convened in September 1792, channeling donations from the public to destitute French priests at a time when the British government remained hesitant to directly aid refugees from revolutionary France. This article situates the committee's particular structures in both their eighteenth-century philanthropic contexts and Britain's history of aid to foreign refugees. It then traces interconnections between charitable giving and wartime exigencies, arguing that the Wilmot Committee, which managed relief efforts first to clergy and then also to laity throughout the subsequent war years in an evolving partnership with government, played a crucial role in shaping and shifting attitudes toward foreigners during an era of ideological revolution. Ultimately, the committee worked alongside legislation like the Aliens and Emigrant Corps Acts to underline that foreigners of different religious persuasions—provided their loyalties were confirmed, their principles appropriate, and their backgrounds appealing—might be mobilized to strengthen national interests. By the 1790s, shared opposition to revolutionary republican ideology came to supersede shared Protestantism in predicting foreigners’ utility to Britain.

Background Assessing the residual cancer burden (RCB) predictive performance, the potential subgroup effects, and time-dependent impact on breast cancer patients who underwent neoadjuvant therapy in a developer’s independent cohort is essential for its usage in clinical routine. Methods Between 2011 and 2016, the RCB scores of 184 female breast cancer patients were prospectively collected, and subsequent clinicopathological and follow-up data were obtained retrospectively. Recurrence-free survival (RFS), overall survival (OS), as well as subgroup analysis, and time-dependent variables were calculated with multivariate, complex, or linear statistical models. Results A total of 184 patients (HER2 33%, TNBC 27%), with a mean follow-up time of 4 years, treated with neoadjuvant systemic therapy (92% anthracycline-taxane based) were analyzed revealing 43 events (38 recurrences, 28 deaths). High RCB scores were associated with recurrence (median index: 2.34 vs. 1.39 points, rank-sum p  < 0.0001), decreased RFS (hazard ratio [HR] = 1.80, 95% confidence interval [CI] 1.44–2.24, p  < 0.0001) and reduced OS (HR 1.96, 95% CI 1.49–2.59, p  < 0.0001). The RCB score showed proportionality of hazards (interaction HR with linear follow-up time = 1.00, p  = 0.896) and good discriminating power (Harrell’s c index 0.7). Conclusions Our results confirm the RCB score as externally valid prognostic marker and being independent of molecular subtype for RFS and OS in a clinical setting.