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Background : Venous thromboembolism (VTE) is a common complication in acute COVID-19 and those with hematologic malignancy (HM) may be at an even higher risk. We performed a retrospective analysis of patients with history of HM and acute COVID-19 to evaluate thrombotic and clinical outcomes. Methods : Patients with COVID-19 were identified by positive SARS-CoV-2 PCR test. Our primary endpoints were rate of VTE and CVA in patients with HM compared to the general population (GP). Secondary outcomes included composite thrombotic events (CVA + VTE), COVID-19 fatality, respiratory support, ICU admission rates, and length of ICU stay Results : 833 patients were evaluated, 709 in the GP cohort, 124 patients in the HM cohort. CVA was more prevalent in the HM cohort (5.4% vs. 1.6%, p = 0.011). Rates of VTE were numerically higher for the HM cohort (8.0% vs. 3.6%, p = 0.069). The composite thrombotic rate was increased in the HM cohort (13.4% vs 5.2%, p = 0.005). Patients with HM had a higher inpatient fatality rate (35.5% vs 11.3%, p < 0.001), required more respiratory support (74.6% vs 46.5%, p < 0.001) and had a higher rate of ICU admission (31.9% vs 12.1%, p = 0.001). Conclusion : Our data demonstrated an increased rate of composite thrombotic (CVA + VTE) outcomes, indicating HM patients with acute COVID-19 are at increased risk of thrombosis. Irrespective of disease status, HM patients also have significantly increased need for intensive care, respiratory support, and have higher fatality rates., MicroAbstract: Background: We performed a retrospective analysis of patients with history of HM and acute COVID-19 to evaluate thrombotic and clinical outcomes., Methods: We evaluated various clinical parameters in patients with HM (n=124) compared to the general population (GP; n=709)., Results: The composite thrombotic rate (VTE + CVA) was increased in the HM cohort (13.4% vs 5.2%, p = 0.005)., Conclusion: HM patients with acute COVID-19 are at increased risk of thrombosis and have significantly increased need for intensive care, respiratory support, and have higher fatality rates.

Background: Genetic factors play an important role in prostate cancer (PCa) susceptibility.Objective: To discover common genetic variants contributing to the risk of PCa in men of African ancestry.Design, setting, and participants: We conducted a meta-analysis of ten genome-wide association studies consisting of 19378 cases and 61620 controls of African ancestry.Outcome measurements and statistical analysis: Common genotyped and imputed variants were tested for their association with PCa risk. Novel susceptibility loci were identified and incorporated into a multiancestry polygenic risk score (PRS). The PRS was evaluated for associations with PCa risk and disease aggressiveness.Results and limitations: Nine novel susceptibility loci for PCa were identified, of which seven were only found or substantially more common in men of African ancestry, including an African-specific stop-gain variant in the prostate-specific gene anoctamin 7 (ANO7). A multiancestry PRS of 278 risk variants conferred strong associations with PCa risk in African ancestry studies (odds ratios [ORs] >3 and >5 for men in the top PRS decile and percentile, respectively). More importantly, compared with men in the 40-60% PRS category, men in the top PRS decile had a significantly higher risk of aggressive PCa (OR = 1.23, 95% confidence interval = 1.10-1.38, p = 4.4 × 10-4).Conclusions: This study demonstrates the importance of large-scale genetic studies in men of African ancestry for a better understanding of PCa susceptibility in this high-risk population and suggests a potential clinical utility of PRS in differentiating between the risks of developing aggressive and nonaggressive disease in men of African ancestry.Patient summary: In this large genetic study in men of African ancestry, we discovered nine novel prostate cancer (PCa) risk variants. We also showed that a multiancestry polygenic risk score was effective in stratifying PCa risk, and was able to differentiate risk of aggressive and nonaggressive disease.

In the United States, the incidence of esophageal adenocarcinoma increased markedly since the 1970s with a recent stabilization. Despite evolving screening and surveillance strategies to diagnose, risk triage, and intervene in Barrett's esophagus patients to prevent esophageal adenocarcinoma, most cases present with advanced disease and poor resultant survival. Epidemiologic studies have identified the main risk factors for these conditions, including increasing age, male sex, white race, gastroesophageal reflux disease, abdominal obesity, cigarette smoking, and lack of infection with Helicobacter pylori. This review summarizes the current epidemiologic evidence with implications for screening and surveillance in Barrett's esophagus and esophageal adenocarcinoma.

Background: Advanced prostate cancer etiology is poorly understood. Few studies have examined associations of anthropometric factors (e.g. early adulthood obesity) with advanced prostate cancer risk.Patients and methods: We carried out pooled analyses to examine associations between body fatness, height, and prostate cancer risk. Among 830 772 men, 51 734 incident prostate cancer cases were identified, including 4762 advanced (T4/N1/M1 or prostate cancer deaths) cases, 2915 advanced restricted (same as advanced, but excluding localized cancers that resulted in death) cases, 9489 high-grade cases, and 3027 prostate cancer deaths. Cox proportional hazards models were used to calculate study-specific hazard ratios (HR) and 95% confidence intervals (CI); results were pooled using random effects models.Results: No statistically significant associations were observed for body mass index (BMI) in early adulthood for advanced, advanced restricted, and high-grade prostate cancer, and prostate cancer mortality. Positive associations were shown for BMI at baseline with advanced prostate cancer (HR = 1.30, 95% CI = 0.95-1.78) and prostate cancer mortality (HR = 1.52, 95% CI = 1.12-2.07) comparing BMI >= 35.0 kg/m(2) with 21-22.9 kg/m(2). When considering early adulthood and baseline BMI together, a 27% higher prostate cancer mortality risk (95% CI = 9% to 49%) was observed for men with BMI = 30.0 kg/m(2) at baseline compared with BMI = 110 cm with = 1.00 with = 1.90 m withConclusion: Our findings suggest that height and total and central adiposity in mid-to-later adulthood, but not early adulthood adiposity, are associated with risk of advanced forms of prostate cancer. Thus, maintenance of healthy weight may help prevent advanced prostate cancer.

A five-year record of surface current observations from HF radar in the region around Monterey Bay are used to describe the dominant circulation patterns under upwelling- and downwelling-favorable wind forcing. Conditional averages based on local wind observations reveal more structure and intensity in the circulation patterns than do traditional temporal averages. The predominant upwelling circulation pattern in the region is found to reach full strength after about three days of persistent upwelling-favorable wind forcing. In the opposite phase under downwelling-favorable winds, the circulation patterns differ between summer and winter with evidence for strong connectivity between the offshore waters and the coastline around Monterey Bay in summer that is not present in winter.

Graft copolymers with brush-type architectures are explored containing poly(ethylene glycol) methacrylates copolymerized with “thermoresponsive” monomers which impart lower critical solution temperatures to the polymer. Initially, the chemical structure of the thermoresponsive polymer is explored, synthesizing materials containing N-isopropyl acrylamide, N,N-diethyl acrylamide and diethylene glycol methyl ether methacrylate. Thermoresponsive graft-copolymers containing di(ethylene glycol) methyl ether methacrylate (DEGMA) exhibited phase transition temperature close to physiological conditions (ca 30 °C). The effect of polymer composition was explored, including molecular weight, PEG-methacrylate (PEGMA) terminal functionality and PEGMA/DEGMA ratios. Molecular weight exhibited complex relationships with phase behavior, where lower molecular weight systems appeared more stable above lower critical solution temperatures (LCST), but a lower limit was identified. PEGMA/DEGMA feed was able to control transition temperature, with higher PEGMA ratios elevating thermal transition. It was found that PEGMA terminated with methoxy functionality formed stable colloidal structures above LCST, whereas those the hydroxy termini generally formed two-phase sedimented systems when heated. Two thermoresponsive DEGMA-based graft polymers, poly(PEGMA7-ran-DEGMA170) and poly(PEGMA1-ran-DEGMA38), gave interesting temperature-dependent rheology, transitioning to a viscous state upon heating. These materials may find application in forming thermothickening systems which modify rheology upon exposure to the body’s heat.

Background Metastatic prostate cancer (PCA) remains a highly lethal malignancy in the USA. As prostate-specific antigen testing declines nationally, detailed assessment of current age- and race-specific incidence trends and quantitative forecasts are needed. Objective To evaluate the current trends of metastatic PCA by age and race, and forecast the number of new cases (annual burden) and future trends. Design, setting, and participants We derived incidence data for men aged ≥45 yr who were diagnosed with metastatic PCA from the population-based Surveillance, Epidemiology, and End Results registries. Outcome measurements and statistical analysis We examined the current trends of metastatic PCA from 2004 to 2014, and forecast the annual burden and incidence rates by age and race for 2015–2025, using age–period–cohort models and population projections. We also examined alternative forecasts (2012–2025) using trends prior to the revised screening guidelines issued in 2012. Results and limitations Metastatic PCA, steadily declining from 2004 to 2007 by 1.45%/yr, began to increase by 0.58%/yr after 2008, which accelerated to 2.74%/yr following the 2012 United States Preventive Services Task Force recommendations—a pattern that was magnified among men aged ≤69 yr and white men. Forecasts project the incidence to increase by 1.03%/yr through 2025, with men aged 45–54 yr (2.29%/yr) and 55–69 yr (1.53%/yr) increasing more rapidly. Meanwhile, the annual burden is expected to increase 42% by 2025. Our forecasts estimated an additional 15 891 metastatic cases from 2015 to 2025 compared with alternative forecasts using trends prior to 2012. Conclusions The recent uptick in metastatic PCA rates has resulted in forecasts that project increasing rates through 2025, particularly among men aged ≤69 yr. Moreover, racial disparities are expected to persist and the annual burden will increase considerably. The impact of the prior and current PCA screening recommendations on metastatic PCA rates requires continued examination. Patient summary In this report, we assessed how the incidence of metastatic prostate cancer has changed over recent years, and forecast future incidence trends and the number of new cases expected each year. We found that the incidence of metastatic prostate cancer has been increasing more rapidly since 2012, resulting in a rise in both future incidence and the number of new cases by 2025. Future incidence rates and the number of new cases were reduced in alternative forecasts using data prior to the 2012 United States Preventive Services Task Force (USPSTF) recommendations against prostate-specific antigen (PSA) testing for prostate cancer. There is a need for additional research that examines whether national declines in PSA testing contributed to increases in rates of metastatic disease. The incidence of metastatic disease in black men is still expected to occur at considerably higher rates compared with that in white men.

Intravaginal drug delivery can elicit a local effect, or deliver drugs systemically without hepatic first pass metabolism. There are a number of emerging areas in intravaginal drug delivery, but the vagina is a challenging route of administration, due to the clearance mechanisms present which result in poor retention of dosage forms, and the potential for irritation and other adverse reactions. Gel formulations are desirable due to the ease of application, spreading and that they cause little to no discomfort to the patient. However, these dosage forms, in particular, are poorly retained and traditional gels typically have little control over drug release rates. This has led to a large number of studies on improving the retention of vaginal gels and modulating the controlled release of drugs from the gel matrix. This review outlines the anatomy and physiology of the vagina, focussing on areas relevant to drug delivery. Medical applications of vaginally administered medicines is then discussed, followed by an overview of polymeric gels in intravaginal drug delivery. The sensorial properties of intravaginal gels, and how these relate to user compliance are also summarised. Finally, some important barriers to marketing approval are described.

Mucosa-mimetic materials are synthetic substrates which aim to replace animal tissue in mucoadhesion experiments. One potential mucosa-mimetic material is a hydrogel comprised of N-acryloyl-d-glucosamine and 2-hydroxyethylmethacrylate, which has been investigated as a surrogate for animal mucosae in the mucoadhesion testing of tablets and solution formulations. This study aims to investigate the efficacy of this mucosa-mimetic material in the testing of thermogelling semi-solid formulations, which transition from solution to gel upon warming. Two methods for assessing mucoadhesion have been used; tensile testing and a flow-through system, which allow for investigation under dramatically different conditions. It was found that the mucosa-mimetic material was a good surrogate for buccal mucosa using both testing methods. This material may be used to replace animal tissue in these experiments, potentially reducing the number of laboratory animals used in studies of this type.

Systems composed of bioadhesive and thermoresponsive polymers can combine in situ gelation with bio/mucoadhesion, enhancing retention of topically applied drugs. The effect of bioadhesive sodium carboxymethylcellulose (NaCMC) and hydroxypropyl methylcellulose cellulose (HPMC) on the properties of thermoresponsive Pluronic® F127 (F127) was explored, including micellization and the mucoadhesion. A computational analysis between these polymers and their molecular interactions were also studied, rationalising the design of improved binary polymeric systems for pharmaceutical and biomedical applications. The morphological characterization of polymeric systems was conducted by SEM. DSC analysis was used to investigate the crystallization and micellization enthalpy of F127 and the mixed systems. Micelle size measurements and TEM micrographs allowed for investigation into the interference of cellulose derivatives on F127 micellization. Both cellulose derivatives reduced the critical micellar concentration and enthalpy of micellization of F127, altering hydrodynamic diameters of the aggregates. Mucoadhesion performance was useful to select the best systems for mucosal application. The systems composed of 17.5% (w/w) F127 and 3% (w/w) HPMC or 1% (w/w) NaCMC are promising as topical drug delivery systems, mainly on mucosal surfaces. They were biocompatible when tested against Artemia salina, and also able to release a model of hydrophilic drug in a controlled manner.

Gastroesophageal reflux disease (GERD) causes local chronic inflammation that increases risks of Barrett’s esophagus (BE) and esophageal adenocarcinoma (EA), yet symptomatic GERD is absent in approximately half of all such patients. Obesity exacerbates GERD and is also a component of metabolic syndrome (MetS). We evaluated the hypothesis that MetS is a GERD-independent mechanism by which obesity is associated with increased risks of BE and EA using data from the UK Clinical Practice Research Datalink. BE cases (n=10,215) and EA cases (n=592) were each individually matched to five population controls based on age, sex, and general practice. MetS was defined as occurrence of at least three of the following: obesity, type 2 diabetes, hypertension, and high cholesterol. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression. MetS was marginally associated with BE (OR=1.12, 95%CI 1.00–1.25). Similar effects were found for the individual component factors of obesity, hypertension, and high cholesterol. History of GERD modified the association (p-effect modification < 1E 5), with the MetS-BE association confined to patients without a history of GERD (OR=1.33, 95%CI 1.12–1.58). No association between MetS and risk of EA was detected in the main or stratified analyses. In this large population-based case-control study, individuals with MetS had a marginally increased risk of BE in the absence of GERD. The systemic inflammatory state (MetS) may represent a reflux-independent inflammatory pathway that increases the risk of BE. MetS did not increase risk of EA in this study population.

When considering the impact and value of gunshot residues (GSR) as forensic trace evidence, the likelihood of a suspect producing a positive GSR analysis result without having direct exposure to a firearm is a major consideration. Therefore, the random prevalence of GSR and 'GSR-like' residues in the wider population is a highly pertinent question when considering the probative value of such evidence. The random prevalence of GSR in two Australian jurisdictions - Victoria and South Australia - was assessed through the collection and analysis of GSR samples obtained from randomly selected members of the public. Volunteers were asked to declare any firearms use, hobbies or potential firearms exposure before allowing their hands to be sampled using aluminium GSR sample stubs coated in adhesive tape. A total of 289 samples, 120 from Victoria and 169 from South Australia were collected and analysed using scanning electron microscopy coupled with energy dispersive X-ray microanalysis (SEM-EDS). Across all samples, three 'characteristic' three-component Pb/Ba/Sb particles were detected from a single subject in South Australia, corresponding to an overall prevalence of 0.3%. Two-component 'consistent' particles were more prevalent, with Pb/Sb particles being the most frequently occurring, in 8% of samples, and in South Australia only. A number of samples, approximately 7%, showed populations of single element particles of Pb, Ba and Sb, which has the potential to generate a false positive for GSR if using a bulk analysis technique such as NAA or AAS. The prevalence of GSR or 'GSR like' particles in this study matches closely with similar surveys conducted in other jurisdictions. Such surveys are a useful foundation for the creation of a probabilistic method for the assessment of GSR evidence.

This work investigated the permeability of lidocaine across human eyelid skin and compared this with published data for abdominal skin to understand the characteristics of this type of skin and whether topical anaesthesia for eyelid surgery may be feasible. Eyelid skin is thought to have a relatively high permeability to drugs, however how this compares to other body sites has not been previously quantified. Lidocaine solutions at pH 7.0 and 5.5 were applied to human eyelid skin mounted in Franz diffusion cells. Anatomical features of eyelid skin that may be linked to its increased permeability, superficial corneocyte area and stratum corneum (SC) thickness were measured using light microscopy. Steady-state fluxes of lidocaine at pH 7.0 and pH 5.5 were 283.9 and 41.0 μg/cm2/hr, 2.4 and 3.2 times greater respectively than literature values for abdominal skin. Superficial eyelid corneocyte area (800.5 μm2) was 35% smaller and the eyelid SC thickness (14.9 μm) was 31% thinner than reported abdominal skin values. These suggest that a shorter diffusional pathlength across the eyelid SC contributes to increased lidocaine permeability. The relatively high permeability of eyelid skin to lidocaine indicates considerable potential for achieving strong topical anaesthetic effects at this site.

Mucoadhesion describes an attractive interaction between dosage form and mucosal membrane. The evaluation of mucoadhesive excipients often requires the use of ex vivo mucosal tissues taken from laboratory animals. These can be difficult to source, highly heterogeneous, and require the use of animal products. Thus, from both a user-convenience and ethical point-of-view, it is desirable to produce a synthetic alternative to these tissues-a mucosa-mimetic material. In this mini-review, the use of alternative materials to test the performance of mucoadhesives is reviewed and discussed. There is a surprising prevalence of the use of mucosa-mimics in the literature, which hitherto has not been compiled and compared.

Background & Aims Esophageal adenocarcinoma is believed to result from the progression of gastroesophageal reflux disease to erosive esophagitis and re-epithelialization of the esophagus with a columnar cell population termed Barrett's esophagus (BE). Men develop BE and esophageal adenocarcinoma more frequently than women, yet little is known about the mechanisms of this difference. We assessed whether sex steroid hormones were associated with BE in a male population. Methods We analyzed data from the Barrett's Esophagus Early Detection Case Control Study, based at the Walter Reed National Military Medical Center. Blood samples were collected from 174 men with BE and 213 men without BE (controls, based on endoscopic analysis); 13 sex steroid hormones were measured by mass spectrometry and sex hormone binding globulin was measured by enzyme-linked immunosorbent assay. We also calculated free estradiol, free testosterone, and free dihydrotestosterone (DHT). We used multivariable logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) adjusted for age, race, smoking status, alcohol consumption, body mass index, heartburn, regurgitation, and gastroesophageal symptom score (excluding heartburn and regurgitation). Results Levels of free testosterone and free DHT were associated positively with BE risk; patients in the highest quartile for these hormones were most likely to have BE (free testosterone: OR, 5.36; 95% CI, 2.21–13.03; P = .0002; free DHT: OR, 4.25; 95% CI, 1.87–9.66; P = .001). Level of estrone sulfate was associated inversely with BE risk ( P for trend = .02). No other hormone was associated with BE risk. Relationships were not modified by age or BMI. Conclusions In an analysis of men, levels of free testosterone and free DHT were significantly associated with BE.

The more electric aircraft (MEA) concept aims to reduce emissions, fuel costs, and enable incorporation of electric weapon systems and advanced sensor platforms. These systems will further burden the electrical system due to the pulse like loading and require advanced control strategies and distributed energy storage systems to ensure stability. Furthermore, multi-physical coupling of thermal electrical systems are often compartmentalize and analyzed separately, forgoing congruency that could occur if analyzed together. Here, we study how exergy, the amount of useful energy throughout a system, can guide control design and system operation. A multi-physics networked microgrid model was developed of an aircraft with two generation sources, interconnecting power converters, a lumped thermal mass model and pulsed loading. The Hamiltonian Surface Shaping Power Flow Control (HSSPFC) strategy is applied to the electrical grid via idealized and distributed storage elements. The HSSPFC was first developed to solve a general, scalable, form a networked microgrid architecture and then applied to the specific aircraft model. Implementation of the HSSPFC requires an outer loop to balance installed generation and to manage storage. This was accomplished through an exergy optimal set point generation scheme that minimized exergy destruction in the power converters. Bus regulation of within 3% of the desired set point was achieved while servicing a 100 kW pulsed load. A tradeoff between optimization update rate and storage regulation was found to be limited by the algorithm execution speed. Increased optimization update rates were linked to reduced storage use and fewer transients in bus voltage. The thermal model was electrically coupled through pumping loads and by cooling the power electronics. Exergy optimal coolant pump operation was also studied. The minimal exergy and pump energy consumption were obtained by operating the coolant system near the upper temperature limit of the coolant, which minimized cooling electrical loads.

Energy storage requirements and its management are important considerations for dc microgrid designs that have a high penetration of stochastic distributed sources and loads. Modern control methods, such as Hamiltonian Surface Shaping and Power Flow Control (HSSPFC), often rely on a reduced order model of the microgrid for controller design. This paper explores (1) the reduced order boost converter model for use in development of advanced control schemes via a detailed, switching mode model implemented on a Typhoon HIL 602 with a controller-in-the-loop (CIL) and (2) a design methodology that may be used for determining converter distributed storage requirements for the closed loop controls.

New tetrabenzotriazaporphyrins are reported that are functionalised at the meso-position. The derivatives functionalised with meso-bromophenyl substituents are synthesised using an improved variation on the traditional reaction between phthalonitriles and Grignard reagents. For all other new derivatives, a modern protocol is employed that gives convenient access to these challenging materials by template co-macrocyclisation between phthalonitriles and aryl-aminoisoindoline derivatives like 15. The newly developed procedure allows design and synthesis of elaborate, functional composites and this is demonstrated by synthesis of meso-pyrenylTBTAP 24, a linked double chromophore in which the two complementary units lie perpendicular to each other and therefore have minimal ground state interaction.

Probiotic bacteria have gained popularity as a defence against disorders of the bowel. However, the acid sensitivity of these cells results in a loss of viability during gastric passage and, consequently, a loss of efficacy. Probiotic treatment can be supplemented using ‘prebiotics’, which are carbohydrates fermented specifically by probiotic cells in the body. This combination of probiotic and prebiotic is termed a ‘synbiotic’. Within this article a multiparticulate dosage form has been developed, consisting of poly(d,l-lactic-co-glycolic acid) (PLGA) microcapsules containing prebiotic Bimuno™ incorporated into an alginate–chitosan matrix containing probiotic Bifidobacterium breve. The aim of this multiparticulate was that, in vivo, the probiotic would be protected against gastric acid and the release of the prebiotic would occur in the distal colon. After microscopic investigation, this synbiotic multiparticulate was shown to control the release of the prebiotic during in vitro gastrointestinal transit, with the release of galacto-oligosaccharides (GOS) initially occurred over 6 h, but with a triphasic release pattern giving further release over 288 h. Encapsulation of B. breve in multiparticulates resulted in a survival of 8.0 ± 0.3 log CFU/mL cells in acid, an improvement over alginate–chitosan microencapsulation of 1.4 log CFU/mL. This was attributed to increased hydrophobicity by the incorporation of PLGA particles.

The aim of this work was to compare alginate and pectin beads for improving the survival of Lactobacillus plantarum and Bifidobacterium longum during storage in pomegranate and cranberry juice, and to evaluate the influence of various coating materials, including chitosan, gelatin and glucomannan on cell survival and on the size and hardness of the beads. In pomegranate juice, free cells of L. plantarum died within 4 weeks of storage and those of B. longum within 1 week; in cranberry juice both types of cells died within one week. Encapsulation within either alginate or pectin beads improved cell survival considerably, but coating of the beads with chitosan or gelatin improved it even further; coating with glucomannan did not have any positive effect. The double gelatin coated pectin beads gave the highest protection among all types of beads, as a final concentration of approximately 108 CFU/mL and 106 CFU/mL for both L. plantarum and B. longum was obtained after 6 weeks of storage in pomegranate and cranberry juice, respectively. The good protection could be attributed to the very strong interaction between the two polymers, as measured by turbidity experiments, leading to the formation of a polyelectrolyte complex. It was also shown that the coating was able to inhibit the penetration of gallic acid within the beads, which was used in this study as a model phenolic compound with antimicrobial activity; this is a likely mechanism through which the beads were able to protect the cells from the antimicrobial activity of phenolic compounds present in both types of juices. Despite their good protective effect, the pectin beads were considerably softer than the alginate beads, an issue that should be addressed in order to increase their mechanical stability.

DNA double-strand break (DSB) repair pathway choice is governed by the opposing activities of 53BP1 and BRCA1. 53BP1 stimulates nonhomologous end joining (NHEJ), whereas BRCA1 promotes end resection and homologous recombination (HR). Here we show that 53BP1 is an inhibitor of BRCA1 accumulation at DSB sites, specifically in the G1 phase of the cell cycle. ATM-dependent phosphorylation of 53BP1 physically recruits RIF1 to DSB sites, and we identify RIF1 as the critical effector of 53BP1 during DSB repair. Remarkably, RIF1 accumulation at DSB sites is strongly antagonized by BRCA1 and its interacting partner CtIP. Lastly, we show that depletion of RIF1 is able to restore end resection and RAD51 loading in BRCA1-depleted cells. This work therefore identifies a cell cycle-regulated circuit, underpinned by RIF1 and BRCA1, that governs DSB repair pathway choice to ensure that NHEJ dominates in G1 and HR is favored from S phase onward.

Hedging equity portfolios against the risk of large drawdowns is notoriously difficult and expensive. Holding, and continuously rolling, at-the-money put options on the S&P 500 is a very costly, if reliable, strategy to protect against market sell-offs. Holding ‘safe-haven’ US Treasury bonds, while providing a positive and predictable long-term yield, is generally an unreliable crisis-hedge strategy, since the post-2000 negative bond-equity correlation is a historical rarity. Long gold and long credit protection portfolios appear to sit between puts and bonds in terms of both cost and reliability. In contrast to these passive investments, we investigate two dynamic strategies that appear to have generated positive performance in both the long-run but also particularly during historical crises: futures time-series momentum and quality stock factors. Futures momentum has parallels with long option straddle strategies, allowing it to benefit during extended equity sell-offs. The quality stock strategy takes long positions in highest-quality and short positions in lowest-quality company stocks, benefitting from a ‘flight-to-quality’ effect during crises. These two dynamic strategies historically have uncorrelated return profiles, making them complementary crisis risk hedges. We examine both strategies and discuss how different variations may have performed in crises, as well as normal times, over the years 1985 to 2016.

This work studied the effect of multi-layer coating of alginate beads on the survival of encapsulated Lactobacillus plantarum in simulated gastric solution and during storage in pomegranate juice at 4 °C. Uncoated, single and double chitosan coated beads were examined. The survival of the cells in simulated gastric solution (pH 1.5) was improved in the case of the chitosan coated beads by 0.5–2 logs compared to the uncoated beads. The cell concentration in pomegranate juice after six weeks of storage was higher than 5.5 log CFU/mL for single and double coated beads, whereas for free cells and uncoated beads the cells died after 4 weeks of storage. In simulated gastric solution, the size of the beads decreased and their hardness increased with time; however, the opposite trend was observed for pomegranate juice, indicating that there is no correlation between cell survival and the hardness of the beads.

The biodiversity crisis, particularly dramatic in freshwaters, has prompted further setting of global and regional conservation priorities. Species rarity and endemism are among the most fundamental criteria for establishing these priorities. We studied the patterns of rarity and the role of rare species in community uniqueness using data on freshwater bivalve molluscs (family Unionidae) in Texas. Due to the large size and gradients in landscape and climate, Texas has diverse and distinct unionid communities, including numerous regional and state endemic species. Analysis of the state-wide distribution and abundance of Unionidae allowed us to develop a non-arbitrary method to classify species rarity based on their range size and relative density. Of the 46 Unionidae species currently present in Texas, 65% were classified as rare and very rare, including all state and regional endemics. We found that endemic species were a critical component in defining the uniqueness of unionid communities. Almost all endemics were found exclusively in streams and rivers, where diversity was almost double that of lentic waters. Man’s ongoing alteration of lotic with lentic waterbodies favors common species, and dramatically reduces habitat for endemics, contributing to homogenization of unionid fauna. We identified hotspots of endemism, prioritized species in need of protection, estimated their population size, and recommended changes to their current conservation status.

Enhanced electrochemical resolution of anodic processes is possible in the presence of [N(nBu)4][B(C6F5)4], 1, as supporting electrolyte over that obtained in the presence of [N(nBu)4][PF6]. By changing the anion of the supporting electrolyte to a salt having [B(C6F5)4]−, anions, electrochemical processes of especially cationic analytes can benefit. Thus, the redox chemistry of 0.5 mmol dm−3 solutions of [Ru2(μ-FcCOO)4·(CH3CH2OH)2][PF6], 2, Fc = ferrocenyl, in CH2Cl2/[N(nBu)4][B(C6F5)4] were found to involve four well-resolved ferrocenyl-based electrochemical reversible redox processes as well as reduction of RuIII–RuII. At 1.0 mmol dm−3 concentrations of 2, or in the presence of [N(nBu)4][PF6], the four ferrocenyl processes coalesced into only two waves as a result of (Fc+)⋯( PF 6 - ) ion paring. Seventeen of the possible 18 one-electron transfer processes of the biscadmium trisphthalocyaninato complex [Cd2{Pc(C6H13)8}3], 3, could be observed in THF/[N(nBu)4][B(C6F5)4], but the electrochemical window of CH2Cl2/[N(nBu)4][B(C6F5)4] only allowed detection of 15 of these processes. Although reduction processes were unaffected, THF solvation leading to species such as (3n+)(THF)x with 1 ⩽ n ⩽ 4 and x ⩾ 1 as well as ion pair formation of the type (3n+)⋯( PF 6 - ) prevented good resolution of oxidation processes. The CH2Cl2/[N(nBu)4][B(C6F5)4] system also allowed detection of reversible one-electron transfer ferrocenyl (Fc/Fc+) and ruthenocenyl-based (Rc/Rc+) processes for both enol and keto isomers of the β-diketone FcCOCH2CORc, 4, Rc = ruthenocenyl. In CH3CN/[N(nBu)4][PF6], the ruthenocenyl moiety was oxidised to a RuIV species.

Spun films of novel thermotropic liquid crystalline lutetium bisphthalocyanine sandwich complexes substituted with sixteen octyl chains are employed as active organic semiconducting layers in the fabrication of organic field-effect transistors (OFET). When the device is annealed under vacuum at 70 °C, an increase in the field effect mobility in the saturated regime by a factor of five is observed while the threshold voltage is reduced to half the value obtained for as-deposited films. The annealed devices exhibit an increase in on/off ratio by two orders of magnitude. An improvement in performance of OFETs annealed above the crystal to mesophase transition temperature is consistent with atomic force microscopic images indicating increases in grain sizes and decreases in mean surface roughness of the organic bisphthalocyanine films.

Mixed cyclisations have been performed to give phthalocyanine–naphthalocyanine hybrids bearing solubilising substituents. Reactivity differences between the two phthalonitrile precursors result in inefficient mixed-macrocyclisation under standard, non-templating conditions leading to predominant formation of symmetrical phthalocyanine. Templated mixed-macrocyclisation leads to the hybrids. However, the reaction proceeds with unexpected selectivity with only one of the possible 2:2 products observed.

Observations from disparate observational assets, including tide gauges, moorings, and high-frequency (HF) radars, were used to depict the tidal variability, and to evaluate model tidal simulations, for a region off central California, including the Monterey Bay. For this study, the hydrodynamic model was forced only with tides derived from a large-scale model for the northeast Pacific Ocean. Homogeneous density, and initially horizontally uniform density stratification, cases were considered. The model successfully reproduced tidal sea-surface height variations within the model domain, as determined by comparisons with sea level or bottom pressure measured at six locations. To achieve tidal currents with realistic amplitudes, as determined from HF radar and moored measurements, it was found that barotropic velocity, as well as sea level, from the large-scale regional tidal model must be included in specifying the open-boundary condition. However, even with such forcing, the model with homogeneous density field under-predicted the semidiurnal and diurnal barotropic currents as estimated from depth-averaged currents measured at 11 locations. In the diurnal frequency band, the observed surface and nearshore depth-averaged currents are likely influenced by meteorological forcing, which was not included in the model. The HF radar-measured surface tidal currents, both semidiurnal and diurnal, are consistent from year to year and between the winter season and the entire year. Semidiurnal surface tidal currents derived from year-long HF radar measurements do not resemble either the modeled or measured barotropic current fields. Rather, they exhibit amplitudes and small-scale spatial variability indicative of the presence of internal tides, thus indicating that model-derived barotropic tidal currents cannot be validated over large spatial extents using long time series of HF radar-derived surface currents. With initially horizontally uniform vertical density stratification, the model produced surface currents with spatial variability and amplitude range comparable to what was derived from HF radar surface current measurements, but the point by point comparisons are not impressive for this region of complex topography. Likewise, the subsurface current comparisons, performed at four deepwater locations, show considerable model-data differences. Possible reasons for these disparities include the effects of atmospheric forcing, spatially and temporally varying stratification, remotely generated coastally trapped waves, and remotely generated internal tides.

The phthalocyanine analogue containing non-peripheral, long alkyl-substituted benzenoid rings and pyridine rings, zinc bis(1,4-didecylbenzo)-bis(2,3-pyrido)porphyrazine was synthesized. The synthesized product is an interesting compound because quaternization of the pyridine nitrogen is expected to impart cationic amphiphilic character. Zinc bis(1,4-didecylbenzo)-bis(2,3-pyrido)porphyrazine was reacted with dimethyl sulfate and monochloroacetic acid to produce the quaternized products and with diethyl sulfate to produce the sulfo-substituted product; all such compounds displayed amphiphilic character. Identical peaks in cyclic voltammograms were obtained for the products before and after quaternization. Zinc bis(1,4-didecylbenzo)-bis(2,3-pyrido)porphyrazine had no changes in its reduction or oxidation properties compared to phthalocyanine analogues.

In a previous study, 18 repeated exposures of anaesthetized swine to an electro-muscular incapacitating device (TASER International's ADVANCED TASER X26 electronic control device) resulted in acidosis and increases in blood electrolytes. In the current study, experiments were performed to investigate effects of a more typical scenario of repeated exposures of the device on muscle contraction and changes in blood factors. Ten swine were exposed for 5s, followed by a 5-s period of no exposure, three times. Selected blood factors were monitored for 3h following exposure. Transient increases in blood glucose, lactate, sodium, potassium, calcium, and pCO(2) were consistent with previous reports in the literature dealing with studies of muscle stimulation or exercise. Blood pH was decreased immediately following exposure, but subsequently returned toward a normal level. Oxygen saturation (measured by pulse oximetry) was not changed significantly. In conclusion, three repeated TASER device exposures had only transient effects on blood factors, which all returned to pre-exposure levels, with the exception of hematocrit (which remained elevated after 3h). Since the increase in this factor was less than that which may occur after short periods of exercise, it is unlikely that this would be an indicator of any serious harm.

This paper describes for the first time the electrochemical properties of redox-active selfassembled films of single-walled carbon nanotubes (SWCNTs) coordinated to cobalt(II)tetra-aminophthalocyanine (CoTAPc) by sequential self-assembly onto a preformed aminoethanethiol (AET) self-assembled monolayer (SAM) on a gold electrode. Both redox-active SAMs (Au-AET-SWCNT and Au-AET-SWCNT-CoTAPc) exhibited reversible electrochemistry in aqueous (phosphate buffer) solution. X-ray photoelectron spectroscopy (XPS) confirmed the appearance on the gold surface of the various elements found on the SAMs. Atomic force microscopy (AFM) images prove, corroborating the estimated electrochemical surface concentrations, that these SAMs lie normal to the gold surface. Electrochemical impedance spectroscopy (EIS) analyses in the presence of [Fe(CN)6] 3−/4− as a redox probe revealed that the Au-AET-SWCNTCoTAPc showed much lower ( 10 times) electron-transfer resistance (Ret) and much higher ( 10 times) apparent electron-transfer rate constant (kapp) compared to the AuAET-SWCNT SAM. Interestingly, a preliminary electrocatalytic investigation showed that both SAMs exhibit comparable electrocatalytic responses towards the detection of

Repeated exposure to electro-muscular incapacitating devices could result in repetitive, sustained muscle contraction, with little or no muscle recovery period. Therefore, rhabdomyolysis and other physiological responses, including acidosis, hyperkalaemia, and altered levels of muscle enzymes in the blood, would be likely to occur. Experiments were performed to investigate effects of repeated exposures of TASER International's Advanced TASER X26 on muscle contraction and resultant changes in blood factors in an anaesthetized swine model. A total of 10 animals were used. Six swine were exposed for 5 s, followed by a 5-s period of no exposure, repeatedly for 3 min. (In five of the animals, after a 1-h delay, a second 3-min exposure period was added.) The remaining four animals were used for an additional pilot study. All four limbs of each animal exhibited contraction even though the electrodes were positioned in areas at some distances from the limbs. The degree of muscle contraction generated during the second exposure period was significantly lower than that in the first exposure series. This finding was consistent with previous studies showing that prolonged activity in skeletal muscle will eventually result in a decline of force production. There were some similarities in blood sample changes in the current experiments with previous studies of muscular exercise. Thus problems concerning biological effects of repeated TASER exposures may be related, not directly to the "electric output" per se, but rather to the resulting contraction of muscles (and related interruption of respiration) and subsequent sequelae. Transient increases in hematocrit, potassium, and sodium were consistent with previous reports in the literature dealing with studies of muscle stimulation or exercise. It is doubtful that these short-term elevations would have any serious health consequences in a healthy individual. Blood pH was significantly decreased for 1h following exposure, but subsequently returned toward a normal level. Leg muscle contractions and decreases in respiration each appeared to contribute to the acidosis. Lactate was highly elevated, with a slow return (time course greater than 1 h) to baseline. Other investigators have reported profound metabolic acidosis during restraint-associated cardiac arrest. Since restraint often occurs immediately after TASER exposure, this issue should be considered in further development of deployment concepts. On the basis of the results of the current studies, the repeated use of electro-muscular incapacitating devices in a short period of time is, at least, feasible, with the caveat that some medical monitoring of subjects may be required (to observe factors such as lactate and acidosis).

We have studied the molecular orientation of different metal (Mg, Zn) phthalocyanines (Pcs) grown as ultra-thin films on a polycrystalline gold substrate. For 10–20 nm thick films of Pcs with small substituents, a high degree of molecular orientation was observed. Similar to unsubstituted PcCu, the orientation of the molecules is perpendicular to the sample surface. Importantly, however, the molecular orientation is different for low coverages, the molecules lie on the substrate surface. The growth mode is discussed in terms of different molecule–molecule and molecule–substrate interactions.

Phthalocyanine derivatives have attracted attention in the photodynamic therapy of cancer. The preparation of cationic amphiphilic zinc phthalocyanine derivatives is described. Novel amphiphilic non-peripheral substituted zinc phthalocyanine derivative is performed by quaternation. Amphiphilic zinc bis(1,4-didecylbenzo)-bis(3,4-pyrido)porphyrazine will be a useful photosensitizer for photodynamic therapy of cancer.

The effect of the putative mitochondrial K(ATP) channel opener diazoxide (100 microM) was studied in terms of its ability to modulate the hypertrophic effect of 24 h treatment with the alpha(1) adrenoceptor agonist phenylephrine (PE; 10 microM) in cultured neonatal rat ventricular myocytes. PE on its own significantly increased cell size by 40%, (3)H leucine incorporation by 37% and produced more than a threefold elevation in both atrial natriuretic peptide and myosin light chain-2 expression. These effects were nearly completely prevented by diazoxide although the inhibitory effect of this agent was generally mitigated by the mitochondrial K(ATP) channel antagonists 5-hydroxydecanoic acid (100 microM) and glibenclamide (50 microM). Although PE produced an early threefold elevation in MAP kinase activation this was generally unaffected by diazoxide. PE also produced a greater than threefold increase in Na-H exchanger isoform 1 (NHE-1) expression which, was prevented by diazoxide treatment. Our study therefore, demonstrates a potential antihypertrophic influence of mitochondrial K(ATP) channel activation which, is related to diminished NHE-1 expression. Mitochondrial K(ATP) channel activation could represent an effective approach to minimize the myocardial hypertrophic process.

S1 domains occur in four of the major enzymes of mRNA decay in Escherichia coli: RNase E, PNPase, RNase II, and RNase G. Here, we report the structure of the S1 domain of RNase E, determined by both X-ray crystallography and NMR spectroscopy. The RNase E S1 domain adopts an OB-fold, very similar to that found with PNPase and the major cold shock proteins, in which flexible loops are appended to a well-ordered five-stranded beta-barrel core. Within the crystal lattice, the protein forms a dimer stabilized primarily by intermolecular hydrophobic packing. Consistent with this observation, light-scattering, chemical crosslinking, and NMR spectroscopic measurements confirm that the isolated RNase E S1 domain undergoes a specific monomer-dimer equilibrium in solution with a K(D) value in the millimolar range. The substitution of glycine 66 with serine dramatically destabilizes the folded structure of this domain, thereby providing an explanation for the temperature-sensitive phenotype associated with this mutation in full-length RNase E. Based on amide chemical shift perturbation mapping, the binding surface for a single-stranded DNA dodecamer (K(D)=160(+/-40)microM) was identified as a groove of positive electrostatic potential containing several exposed aromatic side-chains. This surface, which corresponds to the conserved ligand-binding cleft found in numerous OB-fold proteins, lies distal to the dimerization interface, such that two independent oligonucleotide-binding sites can exist in the dimeric form of the RNase E S1 domain. Based on these data, we propose that the S1 domain serves a dual role of dimerization to aid in the formation of the tetrameric quaternary structure of RNase E as described by Callaghan et al. in 2003 and of substrate binding to facilitate RNA hydrolysis by the adjacent catalytic domains within this multimeric enzyme.

We report a convenient method for the one-step synthesis of a fluorescein derivative under acidic conditions. Mechanistic studies indicate that the acid-promoted condensation of o-tolualdehyde and 4-chlororesorcinol to form the fluorescein derivative proceeds through a cyclization-oxidation pathway while an alternative oxidation–cyclization pathway remains possible.

The triplet state of zinc non-peripheral substituted alkylbenzopyridoporphyrazines and position isomers were measured, using laser-flash photolysis in poly(methyl methacrylate) film. The triplet lifetime increased with an increasing pyridine number in the molecule. The lowest symmetric isomer having two pyridine rings in the molecule showed the longest triplet state lifetime. The compound was suitable for the use the photosensitizer as a photodynamic therapy of cancer.

Examples of the novel tribenzo[b,g,l]thiopheno[3,4-q]porphyrazine and tribenzo[b,g,l]thiopheno[2,3-q]porphyrazine ring systems have been obtained by cross cyclotetramerisation reactions of 3,6-dialkylphthalonitriles with 3,4-dicyanothiophenes and 2,3-dicyanothiophene respectively. Dibenzodithiopheno[2,3]porphyrazines and benzotrithiopheno[2,3]porphyrazines have also been recovered. Octaoctyl tribenzo[b,g,l]thiopheno[3,4-q]porphyrazine, in particular, shows a strongly split Q-band absorption in the far red region of the spectrum, one component of which is highly bathochromically shifted relative to the corresponding band in octaoctyl phthalocyanine. The compounds, most of which exhibit columnar liquid crystal behaviour, form even, transparent spin-coated films which exhibit a broad band absorption envelope, in some instances extending from 600 nm to beyond 800 nm. Reaction of 2,3-dicyanothiophene with a 2,5-dialkyl-3,4-dicyanothiophene, the latter in excess, gives a product mixture rich in macrocycles derived predominantly from involvement of the former.