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•Time-resolved serial femtosecond crystallography (tr-SFX) probes structure and function in each sample.•X-ray free electron lasers (XFELS) provide atomic and electronic structures ...with femtosecond temporal resolution.•Correlated multidisciplinary datasets provide deep mechanistic insights.•Synergy between X-ray free electron lasers (XFELs) and synchrotrons enable routine time-resolved studies.
Time-resolved serial femtosecond crystallography (tr-SFX) methods exploit slurries of crystalline samples that range in size from hundreds of nanometers to a few tens of micrometers, at near-physiological temperature and pressure, to generate atomic resolution models and probe authentic function with the same experiment. ‘Dynamic structural biology’ is often used to encompass the research philosophy and techniques. Reaction cycles for tr-SFX studies are initiated by photons or ligand addition/mixing strategies, wherein the latter are potentially generalizable across enzymology. Thus, dynamic structural biology often creates stop-motion molecular movies of macromolecular function. In metal-dependent systems, complementary spectroscopic information can also be collected from the same samples and X-ray pulses, which provides even more detailed mechanistic insights. These types of experimental data also complement quantum mechanical and classical dynamics numerical calculations. Correlated structural-functional results will yield more detailed mechanistic insights and will likely translate into better drugs and treatments impacting human health, and better catalysis for clean energy and agriculture.
Earthquake early warning (EEW) is the delivery of ground shaking alerts or warnings. It is distinguished from earthquake prediction in that the earthquake has nucleated to provide detectable ground ...motion when an EEW is issued. Here we review progress in the field in the last 10 years. We begin with EEW users, synthesizing what we now know about who uses EEW and what information they need and can digest. We summarize the approaches to EEW and gather information about currently existing EEW systems implemented in various countries while providing the context and stimulus for their creation and development. We survey important advances in methods, instrumentation, and algorithms that improve the quality and timeliness of EEW alerts. We also discuss the development of new, potentially transformative ideas and methodologies that could change how we provide alerts in the future.
Earthquake early warning (EEW) is the rapid detection and characterization of earthquakes and delivery of an alert so that protective actions can be taken.
EEW systems now provide public alerts in Mexico, Japan, South Korea, and Taiwan and alerts to select user groups in India, Turkey, Romania, and the United States.
EEW methodologies fall into three categories, point source, finite fault, and ground motion models, and we review the advantages of each of these approaches.
The wealth of information about EEW uses and user needs must be employed to focus future developments and improvements in EEW systems.
This review targets emotional intelligence (EI) in sport and physical activity. We systematically review the available literature and offer a sound theoretical integration of differing EI ...perspectives (the tripartite model of EI) before considering applied practice in the form of EI training. Our review identified 36 studies assessing EI in an athletic or physical activity context. EI has most often been conceptualized as a trait. In the context of sport performance, we found that EI relates to emotions, physiological stress responses, successful psychological skill usage, and more successful athletic performance. In the context of physical activity, we found that trait EI relates to physical activity levels and positive attitudes toward physical activity. There was a shortage of research into the EI of coaches, officials, and spectators, non‐adult samples, and longitudinal and experimental methods. The tripartite model proposes that EI operates on three levels – knowledge, ability, and trait – and predicts an interplay between the different levels of EI. We present this framework as a promising alternative to trait and ability EI conceptualizations that can guide applied research and professional practice. Further research into EI training, measurement validation and cultural diversity is recommended.
Environmental impacts of utility-scale solar energy Hernandez, R.R.; Easter, S.B.; Murphy-Mariscal, M.L. ...
Renewable & sustainable energy reviews,
January 2014, 2014, 2014-1-00, 20140101, Letnik:
29
Journal Article
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Renewable energy is a promising alternative to fossil fuel-based energy, but its development can require a complex set of environmental tradeoffs. A recent increase in solar energy systems, ...especially large, centralized installations, underscores the urgency of understanding their environmental interactions. Synthesizing literature across numerous disciplines, we review direct and indirect environmental impacts – both beneficial and adverse – of utility-scale solar energy (USSE) development, including impacts on biodiversity, land-use and land-cover change, soils, water resources, and human health. Additionally, we review feedbacks between USSE infrastructure and land-atmosphere interactions and the potential for USSE systems to mitigate climate change. Several characteristics and development strategies of USSE systems have low environmental impacts relative to other energy systems, including other renewables. We show opportunities to increase USSE environmental co-benefits, the permitting and regulatory constraints and opportunities of USSE, and highlight future research directions to better understand the nexus between USSE and the environment. Increasing the environmental compatibility of USSE systems will maximize the efficacy of this key renewable energy source in mitigating climatic and global environmental change.
- Malignant mesothelioma (MM) is an uncommon tumor that can be difficult to diagnose.
- To provide updated, practical guidelines for the pathologic diagnosis of MM.
- Pathologists involved in the ...International Mesothelioma Interest Group and others with an interest and expertise in the field contributed to this update. Reference material included up-to-date, peer-reviewed publications and textbooks.
- There was discussion and consensus opinion regarding guidelines for (1) distinguishing benign from malignant mesothelial proliferations (both epithelioid and spindle cell lesions), (2) cytologic diagnosis of MM, (3) recognition of the key histologic features of pleural and peritoneal MM, (4) use of histochemical and immunohistochemical stains in the diagnosis and differential diagnosis of MM, (5) differentiating epithelioid MM from various carcinomas (lung, breast, ovarian, and colonic adenocarcinomas, and squamous cell and renal cell carcinomas), (6) diagnosis of sarcomatoid MM, (7) use of molecular markers in the diagnosis of MM, (8) electron microscopy in the diagnosis of MM, and (9) some caveats and pitfalls in the diagnosis of MM. Immunohistochemical panels are integral to the diagnosis of MM, but the exact makeup of panels employed is dependent on the differential diagnosis and on the antibodies available in a given laboratory. Depending on the morphology, immunohistochemical panels should contain both positive and negative markers for mesothelial differentiation and for lesions considered in the differential diagnosis. Immunohistochemical markers should have either sensitivity or specificity greater than 80% for the lesions in question. Interpretation of positivity generally should take into account the localization of the stain (eg, nuclear versus cytoplasmic) and the percentage of cells staining (>10% is suggested for cytoplasmic and membranous markers). Selected molecular markers are now being used to distinguish benign from malignant mesothelial proliferations. These guidelines are meant to be a practical diagnostic reference for the pathologist; however, some new pathologic predictors of prognosis and response to therapy are also included.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Summary Background Head and neck cancers positive for human papillomavirus (HPV) are exquisitely radiosensitive. We investigated whether chemoradiotherapy with reduced-dose radiation would maintain ...survival outcomes while improving tolerability for patients with HPV-positive oropharyngeal carcinoma. Methods We did a single-arm, phase 2 trial at two academic hospitals in the USA, enrolling patients with newly diagnosed, biopsy-proven stage III or IV squamous-cell carcinoma of the oropharynx, positive for HPV by p16 testing, and with Zubrod performance status scores of 0 or 1. Patients received two cycles of induction chemotherapy with 175 mg/m2 paclitaxel and carboplatin (target area under the curve of 6) given 21 days apart, followed by intensity-modulated radiotherapy with daily image guidance plus 30 mg/m2 paclitaxel per week concomitantly. Complete or partial responders to induction chemotherapy received 54 Gy in 27 fractions, and those with less than partial or no responses received 60 Gy in 30 fractions. The primary endpoint was progression-free survival at 2 years, assessed in all eligible patients who completed protocol treatment. This study is registered with ClinicalTrials.gov , numbers NCT02048020 and NCT01716195. Findings Between Oct 4, 2012, and March 3, 2015, 45 patients were enrolled with a median age of 60 years (IQR 54–67). One patient did not receive treatment and 44 were included in the analysis. 24 (55%) patients with complete or partial responses to induction chemotherapy received 54 Gy radiation, and 20 (45%) with less than partial responses received 60 Gy. Median follow-up was 30 months (IQR 26–37). Three (7%) patients had locoregional recurrence and one (2%) had distant metastasis; 2-year progression-free survival was 92% (95% CI 77–97). 26 (39%) of 44 patients had grade 3 adverse events, but no grade 4 events were reported. The most common grade 3 events during induction chemotherapy were leucopenia (17 39%) and neutropenia (five 11%), and during chemoradiotherapy were dysphagia (four 9%) and mucositis (four 9%). One (2%) of 44 patients was dependent on a gastrostomy tube at 3 months and none was dependent 6 months after treatment. Interpretation Chemoradiotherapy with radiation doses reduced by 15–20% was associated with high progression-free survival and an improved toxicity profile compared with historical regimens using standard doses. Radiotherapy de-escalation has the potential to improve the therapeutic ratio and long-term function for these patients. Funding University of California.
Despite impressive durable responses, immune checkpoint inhibitors do not provide a long-term benefit to the majority of patients with cancer. Understanding genomic correlates of response and ...resistance to checkpoint blockade may enhance benefits for patients with cancer by elucidating biomarkers for patient stratification and resistance mechanisms for therapeutic targeting. Here we review emerging genomic markers of checkpoint blockade response, including those related to neoantigens, antigen presentation, DNA repair, and oncogenic pathways. Compelling evidence also points to a role for T cell functionality, checkpoint regulators, chromatin modifiers, and copy-number alterations in mediating selective response to immune checkpoint blockade. Ultimately, efforts to contextualize genomic correlates of response into the larger understanding of tumor immune biology will build a foundation for the development of novel biomarkers and therapies to overcome resistance to checkpoint blockade.
Little is known about differences in rates of fibrosis progression between patients with nonalcoholic fatty liver (NAFL) vs nonalcoholic steatohepatitis (NASH). We conducted a systematic review and ...meta-analysis of all studies that assessed paired liver biopsy specimens to estimate the rates of fibrosis progression in patients with nonalcoholic fatty liver disease (NAFLD) including NAFL and NASH.
Through a systematic search of multiple databases and author contact, up to June 2013, we identified studies of adults with NAFLD that collected paired liver biopsy specimens at least 1 year apart. From these, we calculated a pooled-weighted annual fibrosis progression rate (number of stages changed between the 2 biopsy samples) with 95% confidence intervals (CIs), and identified clinical risk factors associated with progression.
We identified 11 cohort studies including 411 patients with biopsy-proven NAFLD (150 with NAFL and 261 with NASH). At baseline, the distribution of fibrosis for stages 0, 1, 2, 3, and 4 was 35.8%, 32.5%, 16.7%, 9.3%, and 5.7%, respectively. Over 2145.5 person-years of follow-up evaluation, 33.6% had fibrosis progression, 43.1% had stable fibrosis, and 22.3% had an improvement in fibrosis stage. The annual fibrosis progression rate in patients with NAFL who had stage 0 fibrosis at baseline was 0.07 stages (95% CI, 0.02-0.11 stages), compared with 0.14 stages in patients with NASH (95% CI, 0.07-0.21 stages). These findings correspond to 1 stage of progression over 14.3 years for patients with NAFL (95% CI, 9.1-50.0 y) and 7.1 years for patients with NASH (95% CI, 4.8-14.3 y).
Based on a meta-analysis of studies of paired liver biopsy studies, liver fibrosis progresses in patients with NAFL and NASH.
The emergence of treatment de-escalation as a feasible option for patients with newly diagnosed human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma has generated considerable ...excitement among both providers and patients alike. Since HPV-positive oropharyngeal carcinoma has been shown to be a unique entity with distinct clinical and molecular characteristics, the rationale for customizing treatment for patients with this disease is compelling. Indeed, evidence has accumulated demonstrating that patients with HPV-positive oropharyngeal cancer have a significantly improved prognosis as a result of their exquisite radiosensitivity compared to their HPV-negative counterparts and thus might possibly be targeted with de-escalated approaches. The fundamental goal of de-escalation is to maintain the high cure and survival rates associated with traditional approaches while reducing the intensity of treatment and thus the incidence of both short- and long-term toxicity. Given the rapidly increasing incidence of this disease, particularly among younger patients who are generally healthy, the focus on quality of life seems germane. Although the exact reason for the improved sensitivity of HPV-positive oropharyngeal carcinoma to treatment is uncertain, prospective studies have now been published demonstrating that de-escalated radiation can successfully maintain the high rates of cure and preserve quality of life for appropriately selected patients with this disease. However, these studies have been fairly heterogeneous in design, and it remains questionable how to apply their findings to real-world practice. The potential of integrating translational approaches into clinical paradigms is also just starting to become recognized. Consequently, multiple uncertainties continue to exist with respect to de-escalation for HPV-positive oropharyngeal cancer, and these questions comprise the crux of this review.
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