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High level activation of p53-dependent transcription occurs following cellular exposure to genotoxic damaging agents such as UV-C, while ionizing radiation damage does not induce a similarly potent induction of p53-dependent gene expression. Reasoning that one of the major differences between UV-C and ionizing radiation damage is that the latter does not inhibit general transcription, we attempted to reconstitute p53-dependent gene expression in ionizing irradiated cells by co-treatment with selected transcription inhibitors that alone do not activate p53. p53-dependent transcription can be dramatically enhanced by the treatment of ionizing irradiated cells with low doses of DRB, which on its own does not induce p53 activity. The mechanism of ionizing radiation-dependent activation of p53-dependent transcription using DRB is more likely due to inhibition of gene transcription rather than prolonged DNA damage, as the non-genotoxic and general transcription inhibitor Roscovitine also synergistically activates p53 function in ionizing irradiated cells. These results identify two distinct signal transduction pathways that cooperate to fully activate p53-dependent gene expression: one responding to lesions induced by ionizing radiation and the second being a kinase pathway that regulates general RNA Polymerase II activity.

The [George Bush] administration remains divided over just how much to work with the United Nations. [Tony Blair]'s views have coincided nearly perfectly with those of Secretary of State Colin L. Powell, who believes it would be better for all concerned to get U.N. backing for attacking Iraq. Last summer, at a time when Powell was in the minority inside the administration, Blair's support helped Powell's views hold sway. That was the message Blair delivered to British diplomats in the January speech, warning of \"chaos\" should the world split \"into rival poles of power: the U.S. in one corner; anti-U.S. forces in another.\" And it leaves Blair with, as he has put it privately to American officials, \"no choice\" but to get inside Washington's tent. Both sides have already been helped by Blair's diplomatic groundwork over the last week. Thursday's release of a letter signed by Blair and seven other European leaders urging solidarity with the U.S. lanced some of the pressure on Bush. But it also gave Blair ammunition against those in Britain who accused him of taking his country out of sync with wider European opinion.

In April 2020, during the peak of the coronavirus disease 2019 (COVID-19) pandemic in Europe, a cluster of children with hyperinflammatory shock with features similar to Kawasaki disease and toxic shock syndrome was reported in England* (1). The patients' signs and symptoms were temporally associated with COVID-19 but presumed to have developed 2-4 weeks after acute COVID-19; all children had serologic evidence of infection with SARS-CoV-2, the virus that causes COVID-19 (1). The clinical signs and symptoms present in this first cluster included fever, rash, conjunctivitis, peripheral edema, gastrointestinal symptoms, shock, and elevated markers of inflammation and cardiac damage (1). On May 14, 2020, CDC published an online Health Advisory that summarized the manifestations of reported multisystem inflammatory syndrome in children (MIS-C), outlined a case definition, and asked clinicians to report suspected U.S. cases to local and state health departments. As of July 29, a total of 570 U.S. MIS-C patients who met the case definition had been reported to CDC. A total of 203 (35.6%) of the patients had a clinical course consistent with previously published MIS-C reports, characterized predominantly by shock, cardiac dysfunction, abdominal pain, and markedly elevated inflammatory markers, and almost all had positive SARS-CoV-2 test results. The remaining 367 (64.4%) of MIS-C patients had manifestations that appeared to overlap with acute COVID-19 (2-4), had a less severe clinical course, or had features of Kawasaki disease. Median duration of hospitalization was 6 days; 364 patients (63.9%) required care in an intensive care unit (ICU), and 10 patients (1.8%) died. As the COVID-19 pandemic continues to expand in many jurisdictions, clinicians should be aware of the signs and symptoms of MIS-C and report suspected cases to their state or local health departments; analysis of reported cases can enhance understanding of MIS-C and improve characterization of the illness for early detection and treatment.

Previous research on gender-based economic inequality has emphasized occupational segregation as the leading explanatory factor for the gender wage gap. Yet the globalization of the U.S. economy has affected gender inequality in fundamental ways and potentially diminished the influence of occupational gender segregation. We examine whether occupational gender segregation continues to be the main determinant of gender earnings inequality and to what extent globalization processes have emerged as important determinants of inequality between women's and men's earnings. We study factors contributing to the gender earnings ratio as well as the median earnings of men and women for 271 U.S. metropolitan areas. The results indicate that occupational segregation is still the leading determinant of gender earnings inequality, that its effects are only slightly diminished by the presence of globalization, and that various aspects of the global economy independently influence the gender earnings gap.

ObjectivesThe imbalance between effector and regulatory T (Treg) cells is crucial in the pathogenesis of autoimmune arthritis. Immune responses are often investigated in the blood because of its accessibility, but circulating lymphocytes are not representative of those found in inflamed tissues. This disconnect hinders our understanding of the mechanisms underlying disease. Our goal was to identify Treg cells implicated in autoimmunity at the inflamed joints, and also readily detectable in the blood upon recirculation.MethodsWe compared Treg cells of patients with juvenile idiopathic arthritis responding or not to therapy by using: (i) T cell receptor (TCR) sequencing, to identify clonotypes shared between blood and synovial fluid; (ii) FOXP3 Treg cell-specific demethylated region DNA methylation assays, to investigate their stability and (iii) flow cytometry and suppression assays to probe their tolerogenic functions.ResultsWe found a subset of synovial Treg cells that recirculated into the bloodstream of patients with juvenile idiopathic and adult rheumatoid arthritis. These inflammation-associated (ia)Treg cells, but not other blood Treg cells, expanded during active disease and proliferated in response to their cognate antigens. Despite the typical inflammatory-skewed balance of immune mechanisms in arthritis, iaTreg cells were stably committed to the regulatory lineage and fully suppressive. A fraction of iaTreg clonotypes were in common with pathogenic effector T cells.ConclusionsUsing an innovative antigen-agnostic approach, we uncovered a population of bona fide synovial Treg cells readily accessible from the blood and selectively expanding during active disease, paving the way to non-invasive diagnostics and better understanding of the pathogenesis of autoimmunity.

Real-time monitoring of hydration biomarkers in tandem with biophysical markers can offer valuable physiological insights about heat stress and related thermoregulatory response. These metrics have been challenging to achieve with wearable sensors. Here we present a closed-loop electrochemical/biophysical wearable sensing device and algorithms that directly measure whole-body sweat loss, sweating rate, sodium concentration, and sodium loss with electrode arrays embedded in a microfluidic channel. The device contains two temperature sensors for skin temperature and thermal flux recordings, and an accelerometer for real-time monitoring of activity level. An onboard haptic module enables vibratory feedback cues to the wearer once critical sweat loss thresholds are reached. Data is stored onboard in memory and autonomously transmitted via Bluetooth to a smartphone and cloud portal. Field studies conducted in physically demanding activities demonstrate the key capabilities of this platform to inform hydration interventions in highly challenging real-world settings.

ObjectivesSystemic immunological processes are profoundly shaped by the micro-environments where antigen recognition occurs. Identifying molecular signatures distinctive of such processes is pivotal to understand pathogenic immune responses and manipulate them for therapeutic purposes. Unfortunately, direct investigation of peripheral tissues, enriched in pathogenic T cells, is often impossible or imposingly invasive in humans. Conversely, blood is easily accessible, but pathogenic signatures are diluted systemically as a result of the strict compartmentalisation of immune responses. In this work, we aimed at defining immune mediators shared between the bloodstream and the synovial micro-environment, and relevant for disease activity in autoimmune arthritis.MethodsCD4+ T cells from blood and synovium of patients with juvenile idiopathic arthritis (JIA) were immunophenotyped by flow cytometry. The TCR repertoire of a circulating subset showing similarity with the synovium was analysed through next-generation sequencing of TCR β-chain CDR3 to confirm enrichment in synovial clonotypes. Finally, clinical relevance was established by monitoring the size of this subset in the blood of patients with JIA and rheumatoid arthritis (RA).ResultsWe identified a small subset of circulating CD4+ T cells replicating the phenotypical signature of lymphocytes infiltrating the inflamed synovium. These circulating pathogenic-like lymphocytes (CPLs) were enriched in synovial clonotypes and they exhibited strong production of pro-inflammatory cytokines. Importantly, CPLs were expanded in patients with JIA, who did not respond to therapy, and also correlated with disease activity in patients with RA.ConclusionsCPLs provide an accessible reservoir of pathogenic cells recirculating into the bloodstream and correlating with disease activity, to be exploited for diagnostic and research purposes.

Despite the negative impacts of increased ultraviolet radiation intensity on plants, these organisms continue to grow and produce under the increased environmental UV levels. We hypothesized that ambient UV intensity can generate acclimations in plant growth, leaf morphology, and photochemical functioning in modern genotypes of Coffea arabica and C. canephora. Coffee plants were cultivated for ca. six months in a mini greenhouse under either near ambient (UVam) or reduced (UVre) ultraviolet regimes. At the plant scale, C. canephora was substantially more impacted by UVam when compared to C. arabica, investing more carbon in all juvenile plant components than under UVre. When subjected to UVam, both species showed anatomic adjustments at the leaf scale, such as increases in stomatal density in C. canephora, at the abaxial and adaxial cuticles in both species, and abaxial epidermal thickening in C. arabica, although without apparent impact on the thickness of palisade and spongy parenchyma. Surprisingly, C. arabica showed more efficient energy dissipation mechanism under UVam than C. canephora. UVam promoted elevated protective carotenoid content and a greater use of energy through photochemistry in both species, as reflected in the photochemical quenching increases. This was associated with an altered chlorophyll a/b ratio (significantly only in C. arabica) that likely promoted a greater capability to light energy capture. Therefore, UV levels promoted different modifications between the two Coffea sp. regarding plant biomass production and leaf morphology, including a few photochemical differences between species, suggesting that modifications at plant and leaf scale acted as an acclimation response to actual UV intensity.

Specific support requested by trainees to facilitate research involvement included supervisory and methodological support.Table 1 Results from thematic analysis of responses to motivators and barriers around research Motivators/benefits to research Example quotes Clinical care ‘I feel it can benefit so many more children than I am able to see clinically on an individual basis. The TRN recognises the positive impact of signposting all trainees to relevant support systems when developing research or quality improvement studies.3 Without appropriate exposure to high-quality research while in training, we risk compromising evidence-based care. Contributors Survey review, analysis of data, drafting and review of article—TR, HM, FM, LP, ELW, CWC, CJ and the RCPCH Trainee Research Network Working Group.

Monkeypox (mpox) cases in the 2022 outbreak have primarily occurred among adult gay, bisexual, and other men who have sex with men (MSM); however, other populations have also been affected (1). To date, data on mpox in cisgender women and pregnant persons have been limited. Understanding transmission in these populations is critical for mpox prevention. In addition, among pregnant persons, Monkeypox virus can be transmitted to the fetus during pregnancy or to the neonate through close contact during or after birth (2-5). Adverse pregnancy outcomes, including spontaneous abortion and stillbirth, have been reported in previous mpox outbreaks (3). During May 11-November 7, 2022, CDC and U.S. jurisdictional health departments identified mpox in 769 cisgender women aged ≥15 years, representing 2.7% of all reported mpox cases. Among cases with available data, 44% occurred in cisgender women who were non-Hispanic Black or African American (Black), 25% who were non-Hispanic White (White), and 23% who were Hispanic or Latino (Hispanic). Among cisgender women with available data, 73% reported sexual activity or close intimate contact as the likely route of exposure, with mpox lesions most frequently reported on the legs, arms, and genitals. Twenty-three mpox cases were reported in persons who were pregnant or recently pregnant ; all identified as cisgender women based on the mpox case report form. Four pregnant persons required hospitalization for mpox. Eleven pregnant persons received tecovirimat, and no adverse reactions were reported. Continued studies on mpox transmission risks in populations less commonly affected during the outbreak, including cisgender women and pregnant persons, are important to assess and understand the impact of mpox on sexual, reproductive, and overall health.