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New archival evidence reveals how UK governments, since the 1970s, have been concerned primarily with domestic courts encroaching on executive powers rather than those of the legislature. Alongside the Human Rights Act 1998, a mechanism of judicial ‘deference’ to Parliament evolved to justify courts deferring to an act of Parliament, or to decisions of the legislature, or executive. As this article argues, failure to clarify which of these three is at play has served as a helpful vehicle for Governments to convey the powerful narrative of courts using human rights frameworks to usurp the democratic powers of Parliament as legislature at times of conflict between the courts and the executive. In the prisoner voting debate, actors thus successfully invoked ‘parliamentary sovereignty’ to generate an emotive narrative that the European Court of Human Rights was usurping the powers of ‘Parliament’ when instead the Court, supported by the UK legal community, was challenging the dangerous precedent set by the UK Divisional Court’s deference, in 2001, to the executive. Interview data demonstrate how the 2011 backbench parliamentary debate to flout Strasbourg’s judgments was largely manufactured to curtail the ECHR mechanism which empowers domestic courts to effectively hold the government to account.

When the skin is damaged, a variety of cell types must migrate, proliferate, and differentiate to reform a functional barrier to the external environment. Recent studies have shown that progenitor cells residing in hair follicles (HFs) are able to contribute to this re-epithelialization of wounds in vivo. However, the influence of the hair cycle on wound healing has not previously been addressed. Here, we have exploited spontaneous postnatal hair-cycle synchronicity in mice to systematically examine the influence of the different hair-cycle stages on murine skin wound healing. We report significant acceleration of healing during the anagen phase of HF cycling in vivo, associated with alterations in epithelial, endothelial, and inflammatory cell types. Intriguingly, gene profiling data reveal a clear correlation between the transcription of genes beneficial for wound healing and those upregulated during the anagen phase of the hair cycle in unwounded skin. These findings, which demonstrate a previously unappreciated association between HF cycling and wound healing, reveal numerous molecular correlates for further investigation.JID JOURNAL CLUB ARTICLE: For questions, answers, and open discussion about this article, please go to https://www.sciencedirect.com/journal/journal-of-investigative-dermatology/journalclub

Nuocytes are innate cells with critical roles during infection with parasitic worms. McKenzie and colleagues show that nuocytes differentiate from common lymphoid progenitors and require IL-7, IL-33, Notch and RORα for development. Nuocytes are essential in innate type 2 immunity and contribute to the exacerbation of asthma responses. Here we found that nuocytes arose in the bone marrow and differentiated from common lymphoid progenitors, which indicates they are distinct, previously unknown members of the lymphoid lineage. Nuocytes required interleukin 7 (IL-7), IL-33 and Notch signaling for development in vitro . Pro-T cell progenitors at double-negative stage 1 (DN1) and DN2 maintained nuocyte potential in vitro , although the thymus was not essential for nuocyte development. Notably, the transcription factor RORα was critical for the development of nuocytes and their role in the expulsion of parasitic worms.

Research studies have repeatedly demonstrated that chronic lung infection in cystic fibrosis is polymicrobial and consequently does not adhere to the single microbe-based Koch’s postulates. Despite the plethora of evidence, the role of the constituent taxa present is largely unknown. Here we demonstrate how an ecological modeling perspective on lung infection microbiota can tease out potential interactions that alter progression of disease. Using techniques akin to genome-wide association studies, we show and validate 22 taxa, present in the chronic respiratory disease associated with cystic fibrosis, which have significant interactions that are negatively associated with patient lung function, the majority of which are “non-pathogenic” organisms. This work highlights the need to understand the interactive landscapes of the microbiomes to fully appreciate the complexity and treat chronic lung infections. Furthermore, this presents testable hypotheses for manipulative experiments in model systems to elucidate key mechanisms to driving disease progression.

Efficient local monocyte/macrophage recruitment is critical for tissue repair. Recruited macrophages are polarized toward classical (proinflammatory) or alternative (prohealing) activation in response to cytokines, with tight temporal regulation crucial for efficient wound repair. Estrogen acts as a potent anti-inflammatory regulator of cutaneous healing. However, an understanding of estrogen/estrogen receptor (ER) contribution to macrophage polarization and subsequent local effects on wound healing is lacking. Here we identify, to our knowledge previously unreported, a role whereby estrogen receptor α (ERα) signaling preferentially polarizes macrophages from a range of sources to an alternative phenotype. Cell-specific ER ablation studies confirm an in vivo role for inflammatory cell ERα, but not ERβ, in poor healing associated with an altered cytokine profile and fewer alternatively activated macrophages. Furthermore, we reveal intrinsic changes in ERα-deficient macrophages, which are unable to respond to alternative activation signals in vitro. Collectively, our data reveal that inflammatory cell-expressed ERα promotes alternative macrophage polarization, which is beneficial for timely healing. Given the diverse physiological roles of ERs, these findings will likely be of relevance to many pathologies involving excessive inflammation.

Ductal carcinoma in situ (DCIS) is the most common form of preinvasive breast cancer and, despite treatment, a small fraction (5–10%) of DCIS patients develop subsequent invasive disease. A fundamental biologic question is whether the invasive disease arises from tumor cells in the initial DCIS or represents new unrelated disease. To address this question, we performed genomic analyses on the initial DCIS lesion and paired invasive recurrent tumors in 95 patients together with single-cell DNA sequencing in a subset of cases. Our data show that in 75% of cases the invasive recurrence was clonally related to the initial DCIS, suggesting that tumor cells were not eliminated during the initial treatment. Surprisingly, however, 18% were clonally unrelated to the DCIS, representing new independent lineages and 7% of cases were ambiguous. This knowledge is essential for accurate risk evaluation of DCIS, treatment de-escalation strategies and the identification of predictive biomarkers. A genomic analysis of ductal carcinoma in situ (DCIS) samples with matched ipsilateral invasive breast cancer recurring later shows that around 18% of tumors were unrelated to the DCIS, and had distinct clonal origins.

Wound infection is a major clinical problem, yet understanding of bacterial host interactions in the skin remains limited. Microbe-derived molecules, known as pathogen-associated molecular patterns, are recognised in barrier tissues by pattern-recognition receptors. In particular, the pathogen-associated molecular pattern, lipopolysaccharide (LPS), a component of microbial cell walls and a specific ligand for Toll-like receptor 4, has been widely used to mimic systemic and local infection across a range of tissues. Here we administered LPS derived from Klebsiella pneumoniae, a species of bacteria that is emerging as a wound-associated pathogen, to full-thickness cutaneous wounds in C57/BL6 mice. Early in healing, LPS-treated wounds displayed increased local apoptosis and reduced proliferation. Subsequent healing progression was delayed with reduced re-epithelialisation, increased proliferation, a heightened inflammatory response and perturbed wound matrix deposition. Our group and others have previously demonstrated the beneficial effects of 17β-estradiol treatment across a range of preclinical wound models. Here we asked whether oestrogen would effectively promote healing in our LPS bacterial infection model. Intriguingly, co-treatment with 17β-estradiol was able to promote re-epithelialisation, dampen inflammation and induce collagen deposition in our LPS-delayed healing model. Collectively, these studies validate K. pneumoniae-derived LPS treatment as a simple yet effective model of bacterial wound infection, while providing the first indication that oestrogen could promote cutaneous healing in the presence of infection, further strengthening the case for its therapeutic use.

Background Acute pulmonary exacerbations (PEx) are associated with increased morbidity and earlier mortality for people living with cystic fibrosis (pwCF). The most common causes of PEx in CF are by bacterial infection and concomitant inflammation leading to progressive airway damage. To draw attention to the seriousness of PEx they have been labelled as ‘lung attacks’, much like a ‘heart attack’ for acute myocardial infarction. Treatment typically starts when a pwCF presents with worsening respiratory symptoms. Hence, there is a pressing need to identify indicative biomarkers of PEx onset to allow more timely intervention. Set within an ecological framework, we investigated temporal microbiota dynamics to connect changes in the lung microbiota of pwCF to changes in disease states across a PEx event. Results Species-time relationships (STR) describe how the richness of a community changes with time, here STRs were used to assess temporal turnover ( w ) within the lung microbiota of each pwCF ( n  = 12, mean sample duration 315.9 ± 42.7 days). STRs were characterised by high interpatient variability, indicating that turnover and hence temporal organization are a personalized feature of the CF lung microbiota. Greater turnover was found to be significantly associated with greater change in lung function with time. When microbiota turnover was examined at a finer scale across each pwCF time series, w -values could clearly be observed to increase in the exacerbation period, then peaking within the treatment period, demonstrating that increases in turnover were not solely a result of perturbations caused by PEx antibiotic interventions. STR w -values have been found to have a remarkable degree of similarity for different organisms, in a variety of habitats and ecosystems, and time lengths (typically not exceeding w  = 0.5). Here, we found w -values soon increased beyond that. It was therefore possible to use the departure from that expected norm up to start of treatment to approximate onset of PEx in days (21.2 ± 8.9 days across the study participants). Conclusions Here, we illustrate that changes in turnover of the lung microbiota of pwCF can be indicative of PEx onset in considerable advance of when treatment would normally be initiated. This offers translational potential to enable early detection of PEx and consequent timely intervention. -UBwaq9ieFjbu4sxH5Vhzn Video Abstract