In vitro methylation of the U7 snRNP subunits Lsm11 and SmE by the PRMT5/MEP50/pICln methylosome.

U7 snRNP is a multisubunit endonuclease required for 3' end processing of metazoan replication-dependent histone pre-mRNAs. In contrast to the spliceosomal snRNPs, U7 snRNP lacks the Sm subunits D1 and D2 and instead contains two related proteins, Lsm10 and Lsm11. The remaining five subunits of the U7 heptameric Sm ring, SmE, F, G, B, and D3, are shared with the spliceosomal snRNPs. The pathway that assembles the unique ring of U7 snRNP is unknown. Here, we show that a heterodimer of Lsm10 and Lsm11 tightly interacts with the methylosome, a complex of the arginine methyltransferase PRMT5, MEP50, and pICln known to methylate arginines in the carboxy-terminal regions of the Sm proteins B, D1, and D3 during the spliceosomal Sm ring assembly. Both biochemical and cryo-EM structural studies demonstrate that the interaction is mediated by PRMT5, which binds and methylates two arginine residues in the amino-terminal region of Lsm11. Surprisingly, PRMT5 also methylates an amino-terminal arginine in SmE, a subunit that does not undergo this type of modification during the biogenesis of the spliceosomal snRNPs. An intriguing possibility is that the unique methylation pattern of Lsm11 and SmE plays a vital role in the assembly of the U7 snRNP.

A general method for rapid synthesis of refractory carbides by low-pressure carbothermal shock reduction.

Refractory carbides are attractive candidates for support materials in heterogeneous catalysis because of their high thermal, chemical, and mechanical stability. However, the industrial applications of refractory carbides, especially silicon carbide (SiC), are greatly hampered by their low surface area and harsh synthetic conditions, typically have a very limited surface area (<200 m2 g-1), and are prepared in a high-temperature environment (>1,400 °C) that lasts for several or even tens of hours. Based on Le Chatelier's principle, we theoretically proposed and experimentally verified that a low-pressure carbothermal reduction (CR) strategy was capable of synthesizing high-surface area SiC (569.9 m2 g-1) at a lower temperature and a faster rate (∼1,300 °C, 50 Pa, 30 s). Such high-surface area SiC possesses excellent thermal stability and antioxidant capacity since it maintained stability under a water-saturated airflow at 650 °C for 100 h. Furthermore, we demonstrated the feasibility of our strategy for scale-up production of high-surface area SiC (460.6 m2 g-1), with a yield larger than 12 g in one experiment, by virtue of an industrial viable vacuum sintering furnace. Importantly, our strategy is  also applicable to the rapid synthesis of refractory metal carbides (NbC, Mo2C, TaC, WC) and even their emerging high-entropy carbides (VNbMoTaWC5, TiVNbTaWC5). Therefore, our low-pressure CR method provides an alternative strategy, not merely limited to temperature and time items, to regulate the synthesis and facilitate the upcoming industrial applications of carbide-based advanced functional materials.

Dexamethasone in Hospitalized Patients with Covid-19.

BACKGROUND: Coronavirus disease 2019 (Covid-19) is associated with diffuse lung damage. Glucocorticoids may modulate inflammation-mediated lung injury and thereby reduce progression to respiratory failure and death. METHODS: In this controlled, open-label trial comparing a range of possible treatments in patients who were hospitalized with Covid-19, we randomly assigned patients to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone. The primary outcome was 28-day mortality. Here, we report the final results of this assessment. RESULTS: A total of 2104 patients were assigned to receive dexamethasone and 4321 to receive usual care. Overall, 482 patients (22.9%) in the dexamethasone group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization (age-adjusted rate ratio, 0.83; 95% confidence interval [CI], 0.75 to 0.93; P<0.001). The proportional and absolute between-group differences in mortality varied considerably according to the level of respiratory support that the patients were receiving at the time of randomization. In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%; rate ratio, 0.64; 95% CI, 0.51 to 0.81) and among those receiving oxygen without invasive mechanical ventilation (23.3% vs. 26.2%; rate ratio, 0.82; 95% CI, 0.72 to 0.94) but not among those who were receiving no respiratory support at randomization (17.8% vs. 14.0%; rate ratio, 1.19; 95% CI, 0.92 to 1.55). CONCLUSIONS: In patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support. (Funded by the Medical Research Council and National Institute for Health Research and others; RECOVERY ClinicalTrials.gov number, NCT04381936; ISRCTN number, 50189673.).

Impact of age >70 years on oncological outcomes in patients with non-muscle-invasive bladder cancer treated with Bacillus Calmette-Guérin.

OBJECTIVE: To evaluate the impact of age on oncological outcomes in a large contemporary cohort of patients with non-muscle-invasive bladder cancer (NMIBC) treated with adequate Bacillus Calmette-Guérin (BCG). PATIENTS AND METHODS: We performed an Institutional Review Board-approved retrospective study analysing patients with NMIBC treated with adequate BCG at our institution from 2000 to 2020. Adequate BCG was defined as per United States Food and Drug Administration (FDA) guidelines as being receipt of at least five of six induction BCG instillations with a minimum of two additional doses (of planned maintenance or of re-induction) of BCG instillations within a span of 6 months. The study's primary outcome was to determine if age >70 years was associated with progression to MIBC cancer or distant metastasis. The cumulative incidence method and the competing-risk regression analyses were used to investigate the association of advanced age (>70 years) with progression, high-grade (HG) recurrence and cancer-specific mortality (CSM). RESULTS: Overall, data from 632 patients were analysed: 355 patients (56.2%) were aged ≤70 years and 277 (43.8%) were >70 years. Age >70 years did not adversely affect either cumulative incidence of progression or HG recurrence (P = 0.067 and P = 0.644, respectively). On competing-risk regression analyses, age >70 years did not emerge as an independent predictor of progression or HG recurrence (sub-standardised hazard ratio [SHR] 1.57, 95% confidence interval [CI] 0.87-2.81, P = 0.134; and SHR 1.05, 95% CI 0.77-1.44, P = 0.749). Not unexpectedly, patients in the older group did have higher overall mortality (P < 0.001) but not CSM (P = 0.057). CONCLUSION: Age >70 years was not associated with adverse oncological outcomes in a large contemporary cohort of patients receiving adequate intravesical BCG for NMIBC. BCG should not be withheld from older patients seeking for bladder sparing options.

Influence of lamina propria invasion extension on T1 high-grade non-muscle-invasive bladder cancer in patients undergoing BCG or radical cystectomy.

OBJECTIVE: To evaluate the prognostic value of T1 substaging in patients treated with bacillus Calmette-Guérin (BCG) or immediate radical cystectomy (iRC). MATERIALS AND METHODS: We performed an institutional review board-approved retrospective study analysing non-muscle-invasive bladder cancer (NMIBC) patients with pT1 disease treated with either BCG or iRC between 2000 and 2020. Lamina propria (LP) invasion characteristics were extracted from the pathology report. The Kaplan-Meier method was used to calculate overall survival (OS), cancer-specific survival (CSS) and metastasis-free survival (MFS). Multivariable Cox models were used to determine the association between progression-free survival (PFS) and characteristics in the BCG cohort. A logistic regression model explored the relationship between T1 substaging and upstaging to >pT2 at iRC. RESULTS: A total of 411 T1 high-grade patients were identified. LP invasion characteristics were as follows: not specified: 115 (28%); focal/superficial (F/S): 147 (35.8%); and extensive/multifocal (E/M): 149 (36.2%). Overall, 303 patients (73.7%) received BCG, and 108 patients (26.3%) underwent iRC. The median (interquartile range) follow-up was 53 (32-96) months. Patients with E/M LP invasion were significantly more likely to undergo iRC (34% vs. 19%; P = 0.003). Patients with E/M LP invasion showed poorer MFS and CSS compared to those with F/S LP invasion when treated with BCG but not when treated with iRC. Among BCG-treated patients, progression occurred in 41 patients and E/M LP invasion was independently associated with progression after BCG (hazard ratio 5.3, 95% confidence interval [CI] 2.2-13.1; P < 0.001). T1 substaging was not associated with upstaging at RC (odds ratio 3.15, 95% CI 0.82-12.12; P = 0.095). CONCLUSIONS: Extensive/multifocal LP invasion was associated with poor PFS, MFS and CSS in patients treated with BCG. T1 substaging provides valuable prognostic information and should be reported in pathology reports.

Evaluating the diagnostic performance of a large language model-powered chatbot for providing immunohistochemistry recommendations in dermatopathology.

BACKGROUND: Large language model (LLM)-powered chatbots such as ChatGPT have numerous applications. However, their effectiveness in dermatopathology has not been formally evaluated. Dermatopathological cases often require immunohistochemical workup. Here, we evaluate the performance of a chatbot in providing diagnostically useful information on immunohistochemistry relating to dermatological diseases. METHODS: We queried a commonly used chatbot for the immunophenotypes of 51 cutaneous diseases, including a diverse variety of epidermal, adnexal, hematolymphoid, and soft tissue entities. We requested it to provide references for each diagnosis. All tests were repeated, compiled, quantified, and then compared with established literature standards. RESULTS: Clustering analysis demonstrated that recommendations correlated with tumor type, suggesting chatbots can supply appropriate panels. However, a significant portion of recommendations were factually incorrect (13.9%). Citations were rarely clinically useful (24.5%). Many were confabulated (27.2%). Prompt responses for cutaneous adnexal lesions tended to be less accurate while literature references were less useful. Reference retrieval performance was associated with the number of PubMed entries per entity. CONCLUSIONS: This foundational study suggests that LLM-powered chatbots may be useful for generating immunohistochemical panels for dermatologic diagnoses. However, specific performance capabilities and biases must be considered. In addition, extreme caution is advised regarding the tendencies to fabricate material. Future models intentionally fine-tuned to augment diagnostic medicine may prove to be valuable.

Mechanisms of substrate recognition and N6-methyladenosine demethylation revealed by crystal structures of ALKBH5-RNA complexes.

AlkB homologue 5 (ALKBH5) is a ferrous iron and 2-oxoglutarate dependent oxygenase that demethylates RNA N6-methyladenosine (m6A), a post-transcriptional RNA modification with an emerging set of regulatory roles. Along with the fat mass and obesity-associated protein (FTO), ALKBH5 is one of only two identified human m6A RNA oxidizing enzymes and is a potential target for cancer treatment. Unlike FTO, ALKBH5 efficiently catalyzes fragmentation of its proposed nascent hemiaminal intermediate to give formaldehyde and a demethylated nucleoside. A detailed analysis of the molecular mechanisms used by ALKBH5 for substrate recognition and m6A demethylation is lacking. We report three crystal structures of ALKBH5 in complex with an m6A-ssRNA 8-mer substrate and supporting biochemical analyses. Strikingly, the single-stranded RNA substrate binds to the active site of ALKBH5 in a 5'-3' orientation that is opposite to single-stranded or double-stranded DNA substrates observed for other AlkB subfamily members, including single-stranded DNA bound to FTO. The combined structural and biochemical results provide insight into the preference of ALKBH5 for substrates containing a (A/G)m6AC consensus sequence motif. The results support a mechanism involving formation of an m6A hemiaminal intermediate, followed by efficient ALKBH5 catalyzed demethylation, enabled by a proton shuttle network involving Lys132 and Tyr139.

Effect of Hydroxychloroquine in Hospitalized Patients with Covid-19.

BACKGROUND: Hydroxychloroquine and chloroquine have been proposed as treatments for coronavirus disease 2019 (Covid-19) on the basis of in vitro activity and data from uncontrolled studies and small, randomized trials. METHODS: In this randomized, controlled, open-label platform trial comparing a range of possible treatments with usual care in patients hospitalized with Covid-19, we randomly assigned 1561 patients to receive hydroxychloroquine and 3155 to receive usual care. The primary outcome was 28-day mortality. RESULTS: The enrollment of patients in the hydroxychloroquine group was closed on June 5, 2020, after an interim analysis determined that there was a lack of efficacy. Death within 28 days occurred in 421 patients (27.0%) in the hydroxychloroquine group and in 790 (25.0%) in the usual-care group (rate ratio, 1.09; 95% confidence interval [CI], 0.97 to 1.23; P = 0.15). Consistent results were seen in all prespecified subgroups of patients. The results suggest that patients in the hydroxychloroquine group were less likely to be discharged from the hospital alive within 28 days than those in the usual-care group (59.6% vs. 62.9%; rate ratio, 0.90; 95% CI, 0.83 to 0.98). Among the patients who were not undergoing mechanical ventilation at baseline, those in the hydroxychloroquine group had a higher frequency of invasive mechanical ventilation or death (30.7% vs. 26.9%; risk ratio, 1.14; 95% CI, 1.03 to 1.27). There was a small numerical excess of cardiac deaths (0.4 percentage points) but no difference in the incidence of new major cardiac arrhythmia among the patients who received hydroxychloroquine. CONCLUSIONS: Among patients hospitalized with Covid-19, those who received hydroxychloroquine did not have a lower incidence of death at 28 days than those who received usual care. (Funded by UK Research and Innovation and National Institute for Health Research and others; RECOVERY ISRCTN number, ISRCTN50189673; ClinicalTrials.gov number, NCT04381936.).

Readmission following hospital admission for community-acquired pneumonia in England.

INTRODUCTION: Readmission rates following hospital admission with community-acquired pneumonia (CAP) have increased in the UK over the past decade. The aim of this work was to describe the cohort of patients with emergency 30-day readmission following hospitalisation for CAP in England and explore the reasons for this. METHODS: A retrospective analysis of cases from the British Thoracic Society national adult CAP audit admitted to hospitals in England with CAP between 1 December 2018 and 31 January 2019 was performed. Cases were linked with corresponding patient level data from Hospital Episode statistics, providing data on the primary diagnosis treated during readmission and mortality. Analyses were performed describing the cohort of patients readmitted within 30 days, reasons for readmission and comparing those readmitted and primarily treated for pneumonia with other diagnoses. RESULTS: Of 8136 cases who survived an index admission with CAP, 1304 (15.7%) were readmitted as an emergency within 30 days of discharge. The main problems treated on readmission were pneumonia in 516 (39.6%) patients and other respiratory disorders in 284 (21.8%). Readmission with pneumonia compared with all other diagnoses was associated with significant inpatient mortality (15.9% vs 6.5%; aOR 2.76, 95% CI 1.86 to 4.09, p<0.001). A diagnosis of hospital-acquired infection was more frequent in readmissions treated for pneumonia than other diagnoses (22.1% vs 3.9%, p<0.001). CONCLUSION: Pneumonia is the most common condition treated on readmission following hospitalisation with CAP and carries a higher mortality than both the index admission or readmission due to other diagnoses. Strategies to reduce readmissions due to pneumonia are required.

Evolving systemic management of urothelial cancers.

PURPOSE OF REVIEW: Bladder cancer is the 12th most common cancer worldwide. Historically, the systemic management of urothelial carcinoma has been confined to platinum-based chemotherapy. In this review, we discuss the evolving landscape of systemic treatment for urothelial carcinoma. RECENT FINDINGS: Since 2016, when the Food and Drug Administration approved the first immune checkpoint inhibitor (CPI), programmed cell death 1 and programmed cell death ligand 1 inhibitors have been evaluated in the nonmuscle invasive bladder cancer, localized muscle invasive bladder cancer as well as advanced/metastatic bladder cancer settings. Newer approved treatments such as fibroblast growth factor receptor (FGFR) inhibitors and antibody-drug conjugates (ADCs) represent second-line and third-line options. These novel treatments are now being assessed in combination as well as with older traditional platinum-based chemotherapy. SUMMARY: Novel therapies continue to improve bladder cancer outcomes. Personalized approach with well validated biomarkers are important to predict response to therapy.

Low-intensity pulsed ultrasound ameliorates glia-mediated inflammation and neuronal damage in experimental intracerebral hemorrhage conditions.

BACKGROUND: Intracerebral hemorrhage (ICH) is a condition associated with high morbidity and mortality, and glia-mediated inflammation is a major contributor to neurological deficits. However, there is currently no proven effective treatment for clinical ICH. Recently, low-intensity pulsed ultrasound (LIPUS), a non-invasive method, has shown potential for neuroprotection in neurodegenerative diseases. This study aimed to investigate the neuroprotective effects and potential mechanisms of LIPUS on glia-mediated inflammation in ICH. METHODS: This study used 289 mice to investigate the effects of LIPUS on ICH. ICH was induced by injecting bacterial collagenase (type VII-S; 0.0375 U) into the striatum of the mice. LIPUS was applied noninvasively for 3 days, including a 2-h-delayed intervention to mimic clinical usage. The study evaluated neurological function, histology, brain water content, hemoglobin content, MRI, and protein expression of neurotrophic factors, inflammatory molecules, and apoptosis. In vitro studies investigated glia-mediated inflammation by adding thrombin (10 U/mL) or conditioned media to primary and cell line cultures. The PI3K inhibitor LY294002 was used to confirm the effects of PI3K/Akt signaling after LIPUS treatment. RESULTS: LIPUS treatment improved neurological deficits and reduced tissue loss, edema, and neurodegeneration after ICH. The protective effects of LIPUS resulted from decreased glia-mediated inflammation by inhibiting PI3K/Akt-NF-κB signaling, which reduced cytokine expression and attenuated microglial activation-induced neuronal damage in vitro. CONCLUSIONS: LIPUS treatment improved neurological outcomes and reduced glia-mediated inflammation by inhibiting PI3K/Akt-NF-κB signaling after ICH. LIPUS may provide a non-invasive potential management strategy for ICH.

International Bladder Cancer Group Intermediate-risk Nonmuscle-invasive Bladder Cancer Scoring System Predicts Outcomes of Patients on Active Surveillance.

PURPOSE: We sought to determine if the International Bladder Cancer Group IR-NMIBC (Intermediate-risk Nonmuscle-invasive Bladder Cancer) scoring system can predict the requirement of delayed transurethral resection of bladder tumor in low-grade nonmuscle-invasive bladder cancer managed by active surveillance. MATERIALS AND METHODS: We prospectively studied recurrent low-grade Ta/T1 nonmuscle-invasive bladder cancer patients managed with active surveillance with the following characteristics: low-grade papillary nonmuscle-invasive bladder cancer, ≤5 apparent low-grade nonmuscle-invasive bladder tumors, tumor diameter ≤1 cm, absence of gross hematuria, and negative urinary cytology. Subsequent transurethral resection of bladder tumor was offered to patients who no longer met the inclusion criteria or patient choice. The ability of the International Bladder Cancer Group IR-NMIBC scoring system to predict receipt of subsequent transurethral resection of bladder tumor was determined. Multivariable Cox proportional hazards analysis was used to determine factors associated with subsequent transurethral resection of bladder tumor. RESULTS: A total of 163 patients with low-grade Ta/T1 nonmuscle-invasive bladder cancer were included for analysis. After a median follow-up of 33 months (IQR: 21-46), transurethral resection of bladder tumor was performed on 109 patients. At landmark time point of 24 months, patients with 0 risk factors were over 2-fold more likely to continue active surveillance compared to patients with ≥3 risk factors (59% vs 24%). Multivariable Cox regression suggested that the International Bladder Cancer Group IR-NMIBC scoring system was associated with subsequent transurethral resection of bladder tumor (1-2 risk factors [HR: 1.66, 95% CI: 0.96-2.90, P = .072], ≥3 risk factors [HR: 3.21, 95% CI: 1.70-6.09, P < .001]) after adjusting for age, T stage, and sex. CONCLUSIONS: The International Bladder Cancer Group IR-NMIBC scoring system can predict the risk of subsequent transurethral resection of bladder tumor in patients with low-grade nonmuscle-invasive bladder cancer on active surveillance.

Heterozygous NOTCH1 Variants Cause CNS Immune Activation and Microangiopathy.

NOTCH1 belongs to the NOTCH family of proteins that regulate cell fate and inflammatory responses. Somatic and germline NOTCH1 variants have been implicated in cancer, Adams-Oliver syndrome, and cardiovascular defects. We describe 7 unrelated patients grouped by the presence of leukoencephalopathy with calcifications and heterozygous de novo gain-of-function variants in NOTCH1. Immunologic profiling showed upregulated CSF IP-10, a cytokine secreted downstream of NOTCH1 signaling. Autopsy revealed extensive leukoencephalopathy and microangiopathy with vascular calcifications. This evidence implicates that heterozygous gain-of-function variants in NOTCH1 lead to a chronic central nervous system (CNS) inflammatory response resulting in a calcifying microangiopathy with leukoencephalopathy. ANN NEUROL 2022;92:895-901.

Bi-Layer nanoimprinting lithography for metal-assisted chemical etching with application on silicon mold replication.

This paper reports a new type of nanoimprinting method called Bi-layer nanoimprinting lithography (BL-NIL), which can work along with metal-assisted chemical etching (MaCE) for fabricating nanostructures on silicon. In contrast to conventional nanoimprinting techniques, BL-NIL adds an interposing layer between the imprinting resist layer and silicon substrate. After the standard imprinting process, dry etching was used to etch away the residual imprinting layer and part of the interposing layer. Finally, the remaining interposing layer was wet-etched using its remover. This innovative approach can ensure cleanliness at the metal/silicon interface after metal lift-off processes, and therefore guarantees the success of MaCE. By combining BL-NIL and MaCE, expensive silicon molds with sub-micrometer/nanometer-scale feature sizes can be easily replicated and preserved. This is important for the application of nanoimprinting technologies in industrial manufacturing.

Asymmetric homotypic interactions of the atypical cadherin flamingo mediate intercellular polarity signaling.

Acquisition of planar cell polarity (PCP) in epithelia involves intercellular communication, during which cells align their polarity with that of their neighbors. The transmembrane proteins Frizzled (Fz) and Van Gogh (Vang) are essential components of the intercellular communication mechanism, as loss of either strongly perturbs the polarity of neighboring cells. How Fz and Vang communicate polarity information between neighboring cells is poorly understood. The atypical cadherin, Flamingo (Fmi), is implicated in this process, yet whether Fmi acts permissively as a scaffold or instructively as a signal is unclear. Here, we provide evidence that Fmi functions instructively to mediate Fz-Vang intercellular signal relay, recruiting Fz and Vang to opposite sides of cell boundaries. We propose that two functional forms of Fmi, one of which is induced by and physically interacts with Fz, bind each other to create cadherin homodimers that signal bidirectionally and asymmetrically, instructing unequal responses in adjacent cell membranes to establish molecular asymmetry.

Reflectance confocal microscopic visualization of melanocytic bodies in the stratum corneum overlying acral lentiginous melanoma.

BACKGROUND: We present a case of RCM evaluation of ALM surgical margins demonstrating intracorneal melanocytic bodies overlying subsequently confirmed melanoma in situ by histopathology. CASE PRESENTATION: A 73-year-old male with a history of acral lentiginous melanoma (ALM) of the right great toe presented to our clinic for evaluation of positive surgical margins. The positive margin was localized for examination and subsequent biopsy with reflectance confocal microscopy (RCM) which allowed targeted re-resection of the area of concern. Three punch biopsies were obtained in the area of concern, which confirmed residual melanoma in situ. Immunostains confirmed the cellular remnants in the stratum corneum were melanocytic. To correlate the intra stratum corneum findings seen with confocal to the histopathology, a 3D rendering of a stack of images was used to demonstrate the location. DISCUSSION: Typically, acral surfaces are challenging to examine with RCM due to the limited ability of light to penetrate thickened stratum corneum; however, we observed unique cellular features with confocal. Scattered hyper-reflective pleomorphic cells consistent with melanocytes were observed in the stratum corneum, although the visualized underlying epidermis appeared normal. Confocal microscopy may aid in diagnosis and management of ALM, especially in the context of positive surgical margins.

High-standard farmland destruction monitoring by high-resolution remote sensing methods: a 2017-2018 case study of Hebei and Guangdong, China.

Remote sensing has emerged as a new technique for collecting farmland data due to its rapid advancement, rising popularity, and application in social production practice. In order to understand and manage farmland resources in China, it is essential to account for and monitor high-standard farmland and its usage. Therefore, this work used satellite remote sensing empowered with various abilities for monitoring high-standard farmland by employing GF-2 high-resolution satellite images to identify targets and objects in Hebei and Guangdong provinces. Farmland occupation and utilization were analyzed by detecting destructions, underutilization, and overutilization, and converting farmland for other economic activities registered on a special field sheet for quantification. A statistical summary was compiled for the two provinces, and the results reveal that high-standard farmland irregularities were detected in both Hebei and Guangdong provinces. However, in Hebei province, this was due to domestic purposes, such as building home shelters and domestic factories. On a contract, the result shows that in Guangdong province, farmland was being converted for economic purposes on an industrial scale, such as high residential apartment blocks and new industrial zones, and environmental destruction. Furthermore, the results reveal that there is still a steady and continuous decline in arable land due to accelerated industrialization and population pressure, especially in the Guangdong provinces, which is a threat to national food security. The high interpretation accuracy demonstrates that high-resolution remote sensing is an effective farmland monitoring tool that can be used to advance policy formulation.

Effects of tobacco smoking on recurrent hospitalisation with pneumonia: a population-based cohort study.

The incidence of and risk factors for recurrent hospitalisation for pneumonia were investigated using data from Hospital Episode Statistics, linked to a UK primary care database. Within 90 days and 1 year of follow-up, 1733 (3.1%) and 5064 (9.0%), developed recurrent pneumonia respectively. Smoking status at the time of hospitalisation with index pneumonia was associated with the risk of readmission with recurrent pneumonia within a year of discharge: current versus never smokers: adjusted subhazard ratio (sHR) 1.42, 95% CI 1.32 to 1.53, p<0.001, and ex smokers versus never smokers: adjusted sHR 1.24, 95% CI 1.15 to 1.34, p<0.001. Other independent risk factors associated with recurrent pneumonia were age, gender, deprivation and underlying comorbidities.

Studies with recombinant U7 snRNP demonstrate that CPSF73 is both an endonuclease and a 5'-3' exonuclease.

Metazoan replication-dependent histone pre-mRNAs are cleaved at the 3' end by U7 snRNP, an RNA-guided endonuclease that contains U7 snRNA, seven proteins of the Sm ring, FLASH, and four polyadenylation factors: symplekin, CPSF73, CPSF100, and CstF64. A fully recombinant U7 snRNP was recently reconstituted from all 13 components for functional and structural studies and shown to accurately cleave histone pre-mRNAs. Here, we analyzed the activity of recombinant U7 snRNP in more detail. We demonstrate that in addition to cleaving histone pre-mRNAs endonucleolytically, reconstituted U7 snRNP acts as a 5'-3' exonuclease that degrades the downstream product generated from histone pre-mRNAs as a result of the endonucleolytic cleavage. Surprisingly, recombinant U7 snRNP also acts as an endonuclease on single-stranded DNA substrates. All these activities depend on the ability of U7 snRNA to base-pair with the substrate and on the presence of the amino-terminal domain (NTD) of symplekin in either cis or trans, and are abolished by mutations within the catalytic center of CPSF73, or by binding of the NTD to the SSU72 phosphatase of RNA polymerase II. Altogether, our results demonstrate that recombinant U7 snRNP functionally mimics its endogenous counterpart and provide evidence that CPSF73 is both an endonuclease and a 5'-3' exonuclease, consistent with the activity of other members of the ß-CASP family. Our results also raise the intriguing possibility that CPSF73 may be involved in some aspects of DNA metabolism in vivo.

Recovery of health-related quality of life in patients undergoing robot-assisted radical cystectomy with intracorporeal diversion.

OBJECTIVE: To report the health-related quality of life (HRQoL) after robot-assisted radical cystectomy and intracorporeal urinary diversion (iRARC), and to identify factors impacting on return to baseline. PATIENTS AND METHODS: Consecutive patients undergoing iRARC between January 2016 and December 2017 completed the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire 30-item core (EORTC-QLQ-C30) and EORTC-QLQ-Muscle-Invasive Bladder Cancer Module (EORTC-QLQ-BLM30) questionnaires before surgery and had a minimum of 12 months follow-up postoperatively. RESULTS: A total of 76 patients met the inclusion criteria at 12 months. Neobladder (NB) cases (n = 24) were younger (57.0 vs 71.0 years, P < 0.001) and fitter than ileal conduit (IC) cases (n = 52), and had higher physical (100.0 vs 93.3, P = 0.039) and sexual functioning (66.7 vs 50.0, P = 0.013) scores at baseline. Longitudinal analysis of the EORTC-QLQ-C30 showed that physical (NB: 93.3 vs 100.0, P = 0.020; IC: 80.0 vs 93.3, P < 0.001) and role functioning scores (NB: 83.3 vs 100.0, P = 0.010; IC: 83.3 vs 100.0, P = 0.017) decreased and fatigue score (NB: 22.2 vs 11.1, P = 0.026; IC: 33.3 vs 22.2, P = 0.008) increased at 3 months in both diversion groups. Scores returned to baseline at 6 months except physical functioning score in IC patients that remained below baseline until 12 months (86.7 vs 93.3, P = 0.012). The global HRQoL score did not show significant change postoperatively in both groups. A major 90-day Clavien-Dindo complication was a significant predictor (odds ratio [OR] 0.11, 95% confidence interval [CI] 0.02-0.62; P = 0.012) of deteriorated global HRQoL score at 3 months, while occurrence of a late complication (OR 0.14, 95% CI 0.03-0.65; P = 0.013) was a predictor of deteriorated global HRQoL score at 12 months. Longitudinal analysis of the EORTC-QLQ-BLM30 showed that urinary problems (NB: 14.3 vs 38.3, P < 0.001; IC: 5.6 vs 19.1, P < 0.001) and future perspective (NB: 33.3 vs 44.4, P = 0.004; IC: 22.2 vs 44.4, P < 0.001) scores were better than baseline at 3 months. Sexual function deteriorated significantly at 3 months (NB: 8.3 vs 66.7, P < 0.001; IC: 4.2 vs 50.0, P < 0.001) and then showed improvement at 12 months but was still below baseline (NB: 33.3 vs 66.7, P = 0.001; IC: 25.0 vs 50.0, P < 0.001). Involvement in penile rehabilitation was shown to be a significant predictor (ß 18.62, 95% CI 6.06-30.45; P = 0.005) of higher sexual function score at 12 months. CONCLUSION: While most functional domains and symptoms scales recover to or exceed baseline within 6 months of iRARC, physical function remains below baseline in IC patients up to 12 months. Global HRQoL is preserved for both types of urinary diversion; however, postoperative complications seem to be the main driving factor for global HRQoL. Sexual function is adversely affected after iRARC suggesting that structured rehabilitation of sexual function should be an integral part of the RC pathway.