The recently identified plant photoreceptor UVR8 triggers regulatory changes in gene expression in response to ultraviolet-B (UV-B) light via an unknown mechanism. Here, crystallographic and solution structures of the UVR8 homodimer, together with mutagenesis and far-UV circular dichroism spectroscopy, reveal its mechanisms for UV-B perception and signal transduction. β-propeller subunits form a remarkable, tryptophan-dominated, dimer interface stitched together by a complex salt-bridge network. Salt-bridging arginines flank the excitonically coupled cross-dimer tryptophan “pyramid” responsible for UV-B sensing. Photoreception reversibly disrupts salt bridges, triggering dimer dissociation and signal initiation. Mutation of a single tryptophan to phenylalanine re-tunes the photoreceptor to detect UV-C wavelengths. Our analyses establish how UVR8 functions as a photoreceptor without a prosthetic chromophore to promote plant development and survival in sunlight.

UV-B light initiates photomorphogenic responses in plants. Arabidopsis UV RESISTANCE LOCUS8 (UVR8) specifically mediates these responses by functioning as a UV-B photoreceptor. UV-B exposure converts UVR8 from a dimer to a monomer, stimulates the rapid accumulation of UVR8 in the nucleus, where it binds to chromatin, and induces interaction of UVR8 with CONSTITUTIVELY PHOTO-MORPHOGENIC1 (COP1), which functions with UVR8 to control photomorphogenic UV-B responses. Although the crystal structure of UVR8 reveals the basis of photoreception, it does not show how UVR8 initiates signaling through interaction with COP1. Here we report that a region of 27 amino acids from the C terminus of UVR8 (C27) mediates the interaction with COP1. The C27 region is necessary for UVR8 function in the regulation of gene expression and hypocotyl growth suppression in Arabidopsis. However, UVR8 lacking C27 still undergoes UV-B-induced monomerization in both yeast and plant protein extracts, accumulates in the nucleus in response to UV-B, and interacts with chromatin at the UVR8-regulated ELONGATED HYPOCOTYL5 (HY5) gene. The UV-B-dependent interaction of UVR8 and COP1 is reproduced in yeast cells and we show that C27 is both necessary and sufficient for the interaction of UVR8 with the WD40 domain of COP1. Furthermore, we show that C27 interacts in yeast with the REPRESSOR OF UV-B PHOTOMORPHO-GENESIS proteins, RUP1 and RUP2, which are negative regulators of UVR8 function. Hence the C27 region has a key role in UVR8 function.U V-B wavelengths (280-315 nm) are a minor component of sunlight but have a major impact on living organisms. The damaging effects of UV-B are well documented, but plants rarely show signs of UV-damage despite constant exposure to sunlight. This is because plants have evolved effective means of protection against UV-B, including the deposition of UV-absorbing phenolic compounds in the outer tissues and the production of efficient antioxidant and DNA repair systems (1-4). These UV-protective mechanisms are stimulated by low doses of UV-B through differential gene expression. Moreover, low levels of UV-B regulate other responses in plants, including the suppression of hypocotyl extension (5). Thus, in plants, UV-B acts as a key regulatory signal that initiates photomorphogenic responses and promotes survival.The low dose, photomorphogenic responses to UV-B are mediated by the photoreceptor UVR8 (3-7). UVR8 acts specifically in UV-B to regulate over 100 genes, many of which are involved in UV protection (5, 6). Arabidopsis uvr8 mutant plants are highly sensitive to UV-B because they fail to express UVprotective genes (6,8). Among the genes regulated by UVR8 is that encoding the ELONGATED HYPOCOTYL 5 (HY5) transcription factor, which mediates most, if not all, gene expression responses initiated by UVR8 (6, 7). UVR8 interacts with chromatin via histones, in particular H2B (9) at the HY5 gene (6, 9) and a number of other UVR8-regulated genes (9), which raises the possibility that UVR8 promotes recruitment or activation of...

Background Surgery is the main modality of cure for solid cancers and was prioritised to continue during COVID-19 outbreaks. This study aimed to identify immediate areas for system strengthening by comparing the delivery of elective cancer surgery during the COVID-19 pandemic in periods of lockdown versus light restriction. Methods This international, prospective, cohort study enrolled 20 006 adult (≥18 years) patients from 466 hospitals in 61 countries with 15 cancer types, who had a decision for curative surgery during the COVID-19 pandemic and were followed up until the point of surgery or cessation of follow-up (Aug 31, 2020). Average national Oxford COVID-19 Stringency Index scores were calculated to define the government response to COVID-19 for each patient for the period they awaited surgery, and classified into light restrictions (index <20), moderate lockdowns (20–60), and full lockdowns (>60). The primary outcome was the non-operation rate (defined as the proportion of patients who did not undergo planned surgery). Cox proportional-hazards regression models were used to explore the associations between lockdowns and non-operation. Intervals from diagnosis to surgery were compared across COVID-19 government response index groups. This study was registered at ClinicalTrials.gov , NCT04384926 . Findings Of eligible patients awaiting surgery, 2003 (10·0%) of 20 006 did not receive surgery after a median follow-up of 23 weeks (IQR 16–30), all of whom had a COVID-19-related reason given for non-operation. Light restrictions were associated with a 0·6% non-operation rate (26 of 4521), moderate lockdowns with a 5·5% rate (201 of 3646; adjusted hazard ratio [HR] 0·81, 95% CI 0·77–0·84; p<0·0001), and full lockdowns with a 15·0% rate (1775 of 11 827; HR 0·51, 0·50–0·53; p<0·0001). In sensitivity analyses, including adjustment for SARS-CoV-2 case notification rates, moderate lockdowns (HR 0·84, 95% CI 0·80–0·88; p<0·001), and full lockdowns (0·57, 0·54–0·60; p<0·001), remained independently associated with non-operation. Surgery beyond 12 weeks from diagnosis in patients without neoadjuvant therapy increased during lockdowns (374 [9·1%] of 4521 in light restrictions, 317 [10·4%] of 3646 in moderate lockdowns, 2001 [23·8%] of 11 827 in full lockdowns), although there were no differences in resectability rates observed with longer delays. Interpretation Cancer surgery systems worldwide were fragile to lockdowns, with one in seven patients who were in regions with full lockdowns not undergoing planned surgery and experiencing longer preoperative delays. Although short-term oncological outcomes were not compromised in those selected for surgery, delays and non-operations might lead to long-term reductions in survival. During current and future periods of societal restriction, the resilience of elective surgery systems requires strengthening, which might include...

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Among insured children 18 years or younger, increased health care utilization was associated with lower rates of perforated appendicitis. Primary health care relationships may facilitate timely presentation or serve as a marker for health-related self-efficacy, thereby contributing to outcomes for acute surgical conditions.

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Background Differentiating large lipomas from atypical lipomatous tumors (ALT) is challenging and preoperative management guidelines are not well-defined. The diagnostic ambiguity leads many surgeons to refer all patients with large lipomatous masses to an oncologic specialist, perhaps unneccessarily. Study Design In this retrospective cohort study of patients with nonretroperitoneal lipomatous tumors, preoperative characteristics discernible without invasive diagnostic procedures were evaluated for diagnostic predictive value. Results 319 patients (256 with lipomas, 63 with ALTs) treated between 1994 and 2012 were identified. Patients with ALTs were older (60.5 vs. 53.5 years, p<0.0001), had larger tumors (16.0 vs 8.3 cm, p<0.0001), had tumors more often located on an extremity (88.9% vs. 60.5% torso, p<0.0001), and more frequently had a history of prior operations at the same site, exclusive of excision leading to diagnosis and referral (20.6% vs. 5.9%, p=0.001). Local recurrence was observed in 2 patients with lipomas (0.8%) vs. 14 with ALTs (22.6%, p<0.0001). No patients with ALTs developed distant metastases or disease-specific mortality with a median follow-up of 27.4 months (range 0–164.6 months). On multivariate analysis age ≥55 years, tumor size ≥10 cm, extremity location, and history of prior operations were predictors for diagnosis of ALT (p<0.05). Conclusions Characteristics of lipomatous masses that are associated with a diagnosis of ALT include patient age ≥55 years, tumor size ≥10 cm, previous resection, and extremity location (vs torso). These easily identifiable traits may guide surgical management or referral to a specialist.

BACKGROUND:The first methodologic step needed to compare pediatric health outcomes at children's hospitals (CHs) and non-children's hospitals (NCHs) is to classify hospitals into CH and NCH categories. However, there are currently no standardized or validated methods for classifying hospitals. The purpose of this study was to describe a novel and reproducible hospital classification methodology.METHODS: By using data from the 2015 American Hospital Association survey, 4464 hospitals were classified into 4 categories (tiers A-D) on the basis of self-reported presence of pediatric services. Tier A included hospitals that only provided care to children. Tier B included hospitals that had key pediatric services, including pediatric emergency departments, PICUs, and NICUs. Tier C included hospitals that provided limited pediatric services. Tier D hospitals provided no key pediatric services. Classifications were then validated by using publicly available data on hospital membership in various pediatric programs as well as Health Care Cost Institute claims data.RESULTS: Fifty-one hospitals were classified as tier A, 228 as tier B, 1721 as tier C, and 1728 as tier D. The majority of tier A hospitals were members of the Children's Hospital Association, Children's Oncology Group, and National Surgical Quality Improvement Program-Pediatric. By using claims data, the percentage of admissions that were pediatric was highest in tier A (88.9%), followed by tiers B (10.9%), C (3.9%), and D (3.9%). CONCLUSIONS:Using American Hospital Association survey data is a feasible and valid method for classifying hospitals into CH and NCH categories by using a reproducible multitiered system.