The radicals in cigarette tar: their nature and suggested physiological implications.
The paramagnetism of cigarette tar is found to be associated with at least four different types of species. One of the types is responsible for over 80 percent of the total paramagnetism and has a signal intensity that is independent of temperature from 60 to 250 K. This non-Curie-Weiss temperature dependence indicates that the principal paramagnetic species in tar is not an organic monoradical (doublet) species but instead is a donor-acceptor excimer with a paramagnetic excited state and a diamagnetic ground state. Modeling experiments suggest that the excimer consists of quinone (Q) and hydroquinone (QH2) molecules held in a tar matrix. Since such Q-QH2 species are catalysts for the oxidation of hydrocarbons and are very active redox systems, this paramagnetic species may be implicated in the cocarcinogenic properties of tar. Alternatively, since semiquinone radicals are known to bind to DNA, the tar paramagnetic species may be directly involved in the carcinogenic properties of tar.


Continuity and change in self-esteem during emerging adulthood.
The present study examined the development of self-esteem in a sample of emerging adults (N = 295) followed longitudinally over 4 years of college. Six waves of self-esteem data were available. Participants also rated, at the end of their 4th year, the degree to which they thought their self-esteem had changed during college. Rank-order stability was high across all waves of data (Mdn disattenuated correlation = .87). On average, self-esteem levels dropped substantially during the 1st semester (d = -.68), rebounded by the end of the 1st year (d = .73), and then gradually increased over the next 3 years, producing a small (d = .16) but significant mean-level increase in self-esteem from the beginning to the end of college. Individuals who received good grades in college tended to show larger increases in self-esteem. In contrast, individuals who entered college with unrealistically high expectations about their academic achievement tended to show smaller increases in self-esteem, despite beginning college with relatively high self-esteem. With regard to perceived change, 67% reported that their self-esteem increased during college, whereas 12% reported that it declined; these perceptions tended to correspond with actual increases and decreases in their self-esteem scale scores (β = .56). Overall, the findings support the perspective that self-esteem, like other personality characteristics, can change in systematic ways while exhibiting continuity over time.


Genotype-phenotype correlations in Peutz-Jeghers syndrome.
Peutz-Jeghers syndrome (PJS) is a dominantly inherited disorder often caused by mutations in STK11. Time to onset of symptoms was characterised for a large collection of individuals with PJS who had been tested for STK11 mutations and genotype-phenotype correlations were evaluated. We characterised mutations in 42 independent probands and also used a historical cohort design to study 51 individuals with Peutz-Jeghers syndrome who had completed self-administered questionnaires. Mutations were detected in 22/32 (69%) probands with PJS and 0/10 probands referred to rule out PJS. Real-time PCR analysis to quantitate DNA failed to detect any large deletions in PJS participants without STK11 mutations. The median time to onset for gastrointestinal symptoms or polypectomy was 13 years of age but showed a wide variability. Gastric polyps were frequent in PJS participants, with a median age at onset of 16 years. Individuals with missense mutations had a significantly later time to onset of first polypectomy (p = 0.04) and of other symptoms compared with those participants either with truncating mutations or no detectable mutation. STK11 mutation analysis should be restricted to individuals who meet PJS criteria or their close relatives. Direct sequencing of STK11 yields a high rate of point mutations in individuals who meet phenotypic PJS criteria. Individuals with missense mutations of STK11 typically had a later time to onset for PJS symptoms. The common occurrence of gastric polyps may facilitate chemopreventive studies for this disorder.


The integration of 'omic' disciplines and systems biology in cattle breeding.
Enormous progress has been made in the selection of animals, including cattle, for specific traits using traditional quantitative genetics approaches. Nevertheless, considerable variation in phenotypes remains unexplained, and therefore represents potential additional gain for animal production. In addition, the paradigm shift in new disciplines now being applied to animal breeding represents a powerful opportunity to prise open the 'black box' underlying the response to selection and fully understand the genetic architecture controlling the traits of interest. A move away from traditional approaches of animal breeding toward systems approaches using integrative analysis of data from the 'omic' disciplines represents a multitude of exciting opportunities for animal breeding going forward as well as providing alternatives for overcoming some of the limitations of traditional approaches such as the expressed phenotype being an imperfect predictor of the individual's true genetic merit, or the phenotype being only expressed in one gender or late in the lifetime of an animal. This review aims to discuss these opportunities from the perspective of their potential application and contribution to cattle breeding. Harnessing the potential of this paradigm shift also poses some new challenges for animal scientists - and they will also be discussed.


Mechanisms linking adipose tissue inflammation to cardiac hypertrophy and fibrosis.
Adipose tissue is classically recognized as the primary site of lipid storage, but in recent years has garnered appreciation for its broad role as an endocrine organ comprising multiple cell types whose collective secretome, termed as adipokines, is highly interdependent on metabolic homeostasis and inflammatory state. Anatomical location (e.g. visceral, subcutaneous, epicardial etc) and cellular composition of adipose tissue (e.g. white, beige, and brown adipocytes, macrophages etc.) also plays a critical role in determining its response to metabolic state, the resulting secretome, and its potential impact on remote tissues. Compared with other tissues, the heart has an extremely high and constant demand for energy generation, of which most is derived from oxidation of fatty acids. Availability of this fatty acid fuel source is dependent on adipose tissue, but evidence is mounting that adipose tissue plays a much broader role in cardiovascular physiology. In this review, we discuss the impact of the brown, subcutaneous, and visceral white, perivascular (PVAT), and epicardial adipose tissue (EAT) secretome on the development and progression of cardiovascular disease (CVD), with a particular focus on cardiac hypertrophy and fibrosis.


Humoral and cellular immune responses to split-virion H5N1 influenza vaccine in young and elderly adults.
We evaluated the humoral and cellular immunogenicity of adjuvanted and non-adjuvanted H5N1 influenza vaccine in two groups of 300 adults: aged 18-60 and >60 years in a randomized, open-label, uncontrolled phase 2 trial. Participants received two injections (D0, D21) of 7.5 microg hemagglutinin without adjuvant or 30 microg with aluminum hydroxide adjuvant. Antibody responses and cytokine secretion were assessed before and after vaccination. Excluding the 6/300 non-elderly and 47/300 elderly participants with pre-existing antibodies, geometric mean titers (dil(-1)) on D42 were higher with 30 microg+Ad and were comparable between age groups. Participants with pre-existing antibodies responded strongly to the first vaccination (GMTs in the range 147-228 on D21). Vaccination increased both Th1 and Th2 T-cell responses. The predominantly Th1 profile observed before vaccination was unaffected by vaccination. H5N1 influenza vaccine is no less immunogenic in elderly adults than in younger adults and, due to a higher proportion non-naïve elderly, immunogenicity was higher in this latter group.


Evidence for niche adaptation in the genome of the bovine pathogen Streptococcus uberis.
Streptococcus uberis, a Gram positive bacterial pathogen responsible for a significant proportion of bovine mastitis in commercial dairy herds, colonises multiple body sites of the cow including the gut, genital tract and mammary gland. Comparative analysis of the complete genome sequence of S. uberis strain 0140J was undertaken to help elucidate the biology of this effective bovine pathogen. The genome revealed 1,825 predicted coding sequences (CDSs) of which 62 were identified as pseudogenes or gene fragments. Comparisons with related pyogenic streptococci identified a conserved core (40%) of orthologous CDSs. Intriguingly, S. uberis 0140J displayed a lower number of mobile genetic elements when compared with other pyogenic streptococci, however bacteriophage-derived islands and a putative genomic island were identified. Comparative genomics analysis revealed most similarity to the genomes of Streptococcus agalactiae and Streptococcus equi subsp. zooepidemicus. In contrast, streptococcal orthologs were not identified for 11% of the CDSs, indicating either unique retention of ancestral sequence, or acquisition of sequence from alternative sources. Functions including transport, catabolism, regulation and CDSs encoding cell envelope proteins were over-represented in this unique gene set; a limited array of putative virulence CDSs were identified. S. uberis utilises nutritional flexibility derived from a diversity of metabolic options to successfully occupy a discrete ecological niche. The features observed in S. uberis are strongly suggestive of an opportunistic pathogen adapted to challenging and changing environmental parameters.


α-Ketoglutaramate: an overlooked metabolite of glutamine and a biomarker for hepatic encephalopathy and inborn errors of the urea cycle.
Glutamine metabolism is generally regarded as proceeding via glutaminase-catalyzed hydrolysis to glutamate and ammonia, followed by conversion of glutamate to α-ketoglutarate catalyzed by glutamate dehydrogenase or by a glutamate-linked aminotransferase (transaminase). However, another pathway exists for the conversion of glutamine to α-ketoglutarate that is often overlooked, but is widely distributed in nature. This pathway, referred to as the glutaminase II pathway, consists of a glutamine transaminase coupled to ω-amidase. Transamination of glutamine results in formation of the corresponding α-keto acid, namely, α-ketoglutaramate (KGM). KGM is hydrolyzed by ω-amidase to α-ketoglutarate and ammonia. The net glutaminase II reaction is: L - Glutamine + α - keto acid + H2O → α - ketoglutarate + L - amino acid + ammonia. In this mini-review the biochemical importance of the glutaminase II pathway is summarized, with emphasis on the key component KGM. Forty years ago it was noted that the concentration of KGM is increased in the cerebrospinal fluid (CSF) of patients with hepatic encephalopathy (HE) and that the level of KGM in the CSF correlates well with the degree of encephalopathy. In more recent work, we have shown that KGM is markedly elevated in the urine of patients with inborn errors of the urea cycle. It is suggested that KGM may be a useful biomarker for many hyperammonemic diseases including hepatic encephalopathy, inborn errors of the urea cycle, citrin deficiency and lysinuric protein intolerance.


Proneural genes influence gliogenesis in Drosophila.
Fly glial cells in the wing peripheral nervous system of Drosophila melanogaster originate from underlying epithelial cells. Two findings indicate that gliogenesis is closely associated with neurogenesis. First, it only occurs in regions that also give rise to sensory organs. Second, in mutants that induce the development of ectopic sensory organs glial cells develop at new positions. These findings prompted a genetic analysis to establish whether glial and sensory organ differentiation depend on the same genes. Loss of function mutations of the achaete-scute complex lead to a significant reduction of sensory bristles and glial cells. Genes within the complex affect gliogenesis with different strength and display some functional redundancy. Thus, neurogenesis and gliogenesis share the same genetic pathway. Despite these similarities, however, the mechanism of action of the achaete-scute complex seems to be different in the two processes. Neural precursors express products of the complex, therefore the role of these genes on neurogenesis is direct. However, markers specific to glial cells do not colocalize with products of the achaete-scute complex, showing that the complex affects gliogenesis indirectly. These observations lead to the hypothesis that gliogenesis is induced by the presence of sensory organ cells, either the precursor or its progeny.


Firefly synchrony: a behavioral strategy to minimize visual clutter.
Most firefly species (Coleoptera: Lampyridae) use bioluminescent flashes for signaling. In some species, the flashing between males occurs rhythmically and repeatedly (synchronically) with millisecond precision. We studied synchrony's behavioral role in the North American firefly, Photinus carolinus. We placed a female in a virtual environment containing artificial males that flashed at varying degrees of synchrony. Females responded to an average of 82% of synchronous flashes compared with as few as 3% of asynchronous flashes. We conclude that one function of flash synchrony is to facilitate a female's ability to recognize her conspecific male's flashing by eliminating potential visual clutter from other flashing males.


Chemical countermeasures for the control of bacterial biofilms: effective compounds and promising targets.
The pathogenic nature of many infectious bacteria is enhanced by their ability to form surface-associated, protected communities known as "biofilms." Due to various factors, bacteria in biofilm communities display significantly greater resistance to traditional antimicrobial therapies than their planktonic brethren. This resistance complicates many common bacterial infections, resulting in recurrent ear infections, bacterial endocarditis, chronic lung infection in cystic fibrosis, infectious kidney stones, and surface infection of implanted medical devices. Owing to the serious nature of many biofilm-mediated infections and the near-complete dearth of effective strategies for treating them, efforts are underway to further understand the nature of bacterial infections involving biofilms and to discover and develop effective therapies to combat them. Particularly, several classes of chemical compounds have shown promise in combating biofilms when used in conjunction with traditional antimicrobials. The vast majority of these compounds exert their anti-biofilm properties through disruption of "quorum sensing," a common means of intercellular communication in bacterial communities that allows coordinated expression of virulence factors and facilitates formation of the oft-complex architecture of mature bacterial biofilms. Other new chemical entities are effective against biofilms without necessarily affecting quorum sensing. This review summarizes salient research in the development of effective chemical countermeasures for Gram-negative and Gram-positive bacterial infections involving biofilms.


Functional characterization of type-B response regulators in the Arabidopsis cytokinin response.
Cytokinins play critical roles in plant growth and development, with the transcriptional response to cytokinin being mediated by the type-B response regulators. In Arabidopsis (Arabidopsis thaliana), type-B response regulators (ARABIDOPSIS RESPONSE REGULATORS [ARRs]) form three subfamilies based on phylogenic analysis, with subfamily 1 having seven members and subfamilies 2 and 3 each having two members. Cytokinin responses are predominantly mediated by subfamily 1 members, with cytokinin-mediated effects on root growth and root meristem size correlating with type-B ARR expression levels. To determine which type-B ARRs can functionally substitute for the subfamily 1 members ARR1 or ARR12, we expressed different type-B ARRs from the ARR1 promoter and assayed their ability to rescue arr1 arr12 double mutant phenotypes. ARR1, as well as a subset of other subfamily 1 type-B ARRs, restore the cytokinin sensitivity to arr1 arr12. Expression of ARR10 from the ARR1 promoter results in cytokinin hypersensitivity and enhances shoot regeneration from callus tissue, correlating with enhanced stability of the ARR10 protein compared with the ARR1 protein. Examination of transfer DNA insertion mutants in subfamilies 2 and 3 revealed little effect on several well-characterized cytokinin responses. However, a member of subfamily 2, ARR21, restores cytokinin sensitivity to arr1 arr12 roots when expressed from the ARR1 promoter, indicating functional conservation of this divergent family member. Our results indicate that the type-B ARRs have diverged in function, such that some, but not all, can complement the arr1 arr12 mutant. In addition, our results indicate that type-B ARR expression profiles in the plant, along with posttranscriptional regulation, play significant roles in modulating their contribution to cytokinin signaling.


Adaptive system correction for robust Fourier ptychographic imaging.
Fourier ptychography (FP) is a recently developed imaging approach that bypasses the resolution limit defined by the lens' aperture. In current FP imaging platforms, systematic noise sources come from the intensity fluctuation of multiple LED elements and the pupil aberrations of the employed optics. These system uncertainties can significantly degrade the reconstruction quality and limit the achievable resolution, imposing a restriction on the effectiveness of the FP approach. In this paper, we report an optimization procedure that performs adaptive system correction for Fourier ptychographic imaging. Similar to the techniques used in phase retrieval, the reported procedure involves the evaluation of an image-quality metric at each iteration step, followed by the estimation of an improved system correction. This optimization process is repeated until the image-quality metric is maximized. As a demonstration, we used this process to correct for illumination intensity fluctuation, to compensate for pupil aberration of the optics, and to recover several unknown system parameters. The reported adaptive correction scheme may improve the robustness of Fourier ptychographic imaging by factoring out system imperfections and uncertainties.


Strengths, altered investment, risk management, and other elaborations on the behavioural constellation of deprivation.
We are grateful to have received so many insightful commentaries from interested colleagues regarding our proposed behavioural constellation of deprivation (BCD) and our thoughts on its causes and consequences. In this response article, we offer some clarifications regarding our perspective and tackle some common misperceptions, including, for example, assumptions that the BCD is adaptive and that it should include all behaviours that vary with socioeconomic status. We then welcome some excellent proposals for extensions and modifications of our ideas, such as the conceptualisation of the BCD as a risk-management strategy and the calls for a greater focus on strengths and differential investment rather than deficits and disinvestment. Finally, we highlight some insightful explorations of the implications of our ideas for ethics, policy, and practice.


Nucleotide exchange in dimeric MCAK induces longitudinal and lateral stress at microtubule ends to support depolymerization.
Members of the kinesin-13 subfamily use motor domains in an unconventional fashion to initiate microtubule (MT) depolymerization at MT ends, suggesting unique conformational transitions for lattice engagement, end adaptation, or both. Using hydrogen-deuterium exchange and electron microscopy, we explored conformational changes in free dimeric mitotic centromere-associated kinesin (MCAK) and when bound to a depolymerization intermediate. ATP hydrolysis relaxes the conformation of the dimer, notably in the neck and N-terminal domain. Exchanging ADP in dimeric MCAK with ATP at the MT plus end induces outward curvature in α/β-tubulin, accompanied by a restructuring of the MCAK neck and N terminus, as it returns to a closed state. Reestablishing a closed dimer induces lateral separation of paired tubulin dimers, which may assist in depolymerization. Thus, full-length ADP-MCAK transitions from an open diffusion-competent configuration to a closed state upon plus end-mediated nucleotide exchange, which is mediated by conformational changes in the N-terminal domains of the dimer.


Iron Pill Gastritis: An Under Diagnosed Condition With Potentially Serious Outcomes.
Given the ubiquitous use of oral iron therapy, their side effects are often encountered and well recognized in clinical practice. However, iron pill gastritis remains an often under-reported and elusive diagnosis. An astute clinician should be aware of this condition in order to promptly discontinue oral iron and institute timely treatment. Here in, we present a case of a 46-year-old woman who presented to the gastroenterology clinic with vague epigastric pain and microcytic anemia. Esophagogastroduodenoscopy revealed multiple gastric erosions and non-bleeding gastric antral ulcer with biopsies showing excessive iron deposition suggestive of iron pill gastritis. We reviewed the clinical features, pathology, and treatment of iron pill gastritis along with the review of the literature.


Comparison of the effects of a supervised exercise program and usual care in patients with colorectal cancer undergoing chemotherapy.
Although exercise has been addressed as a promising therapy for cancer adverse effects, few studies have evaluated the beneficial effects of exercise for colorectal cancer (CRC) patients during chemotherapy. The purpose of this study was to compare the effects of supervised-exercise intervention with those of usual care on cardiorespiratory fitness, muscle strength, fatigue, emotional distress, sleep quality, and quality of life (QoL) in patients with CRC undergoing chemotherapy. Patients with stage II or III CRC admitted for adjuvant chemotherapy were allocated to either a supervised-exercise group that received a combined aerobic and resistance exercise program or a "usual care" control group for 12 weeks. The outcomes, QoL, muscle strength, cardiorespiratory fitness, emotional distress, physical activity, fatigue, and sleep quality, were assessed at baseline and after intervention. Significant interactions between intervention and time were observed for the role functioning and pain subscales of QoL and physical activity level. The time main effects were significant for the secondary outcomes: hand-grip strength, cardiorespiratory fitness, physical activity level, and physical functioning, role functioning, social functioning, fatigue, and pain subscales of QoL. Compared with usual care, the supervised exercise demonstrated larger effects than usual care on physical activity level and role functioning and pain subscales of QoL. Supervised-exercise program is suggested to be incorporated as part of supportive care to promote the cardiorespiratory fitness, muscle strength, physical activity level, and QoL of patients with CRC undergoing chemotherapy.


Inappropriate expression of blood group antigens on biliary and colonic epithelia in primary sclerosing cholangitis.
The distribution of carbohydrate antigens of the ABO, Lewis, and Kell systems was examined in biliary and colonic epithelial of 11 patients with primary sclerosing cholangitis (PSC) using a panel of 11 monoclonal antibodies. Controls consisted of 27 liver biopsy specimens (11 normal, six alcoholic liver disease, five extrahepatic obstruction, and five primary biliary cirrhosis) and 24 colonic biopsy specimens (six normal, four Crohn's disease, and 14 ulcerative colitis). There was inappropriate staining with anti-A (four of six, 66%) and anti-B (nine of 11, 81%) in biliary epithelium of PSC patients compared with normal and disease controls. Expression of Lewis antigens was increased in patients with cholestatic liver disease. Ninety one per cent of PSC patients showed a similar pattern of inappropriate staining by anti-A and anti-B antibodies in colonic epithelium compared with 33% of normal and 42% of inflammatory bowel disease controls. There is inappropriate expression of A and B carbohydrate antigens in biliary and colonic epithelium in PSC. Whether these oncofetal antigens are implicated in the pathogenesis of this condition is discussed.


Reported quality of randomized controlled trials in neglect rehabilitation.
The aim of this study is to assess the reported quality of randomized controlled trials (RCTs) on the effectiveness of neglect rehabilitation using a standardized scale. A search of seven electronic databases was carried out. Selected articles were scored using the PEDro scale and classified as high or low quality study both with the original cut off of 6 and a modified cut off of 5. A linear regression analysis between year of publication and quality rate was used to test whether the quality of the studies improved with time. A total of 18 RCTs were selected. Six articles (33.3%) and 10 articles (55.56%) were classified as having high quality when the original cut off or the modified cut off of the PEDro scale were used, respectively. Analysis shows no time-related changes in PEDro scores. The results show that reported quality is moderate for RCTs in neglect rehabilitation.


Using event-triggered naturalistic data to examine the prevalence of teen driver distractions in rear-end crashes.
While teen driver distraction is cited as a leading cause of crashes, especially rear-end crashes, little information is available regarding its true prevalence. The majority of distraction studies rely on data derived from police reports, which provide limited information regarding driver distraction. This study examined over 400 teen driver rear-end crashes captured by in-vehicle event recorders. A secondary data analysis was conducted, paying specific attention to driver behaviors, eyes-off-road time, and response times to lead-vehicle braking. Among teens in moderate to severe rear-end crashes, over 75% of drivers were observed engaging in a potentially distracting behavior. The most frequently seen driver behaviors were cell phone use, attending to a location outside the vehicle, and attending to passengers. Drivers using a cell phone had a significantly longer response time than drivers not engaged in any behaviors, while those attending to passengers did not. Additionally, in about 50% of the rear-end crashes where the driver was operating/looking at a phone (e.g., texting), the driver showed no driver response (i.e., braking or steering input) before impact, compared to 10% of crashes where the driver was attending to a passenger. The high frequency of attending to passengers and use of a cell phone leading up to a crash, compounded with the associated risks, underlines the importance of continued investigation in these areas. Parents and teens must be educated regarding the frequency of and the potential effects of distractions. Additional enforcement may be necessary if Graduated Driver Licensing (GDL) programs are to be effective. Systems that alert distracted teens could also be especially helpful in reducing rear-end collisions.


Human cytosolic extracts stabilize the HIV-1 core.
The stability of the HIV-1 core in the cytoplasm is crucial for productive HIV-1 infection. Mutations that stabilize or destabilize the core showed defects on HIV-1 reverse transcription and infection. We developed a novel and simple assay to measure the stability of in vitro-assembled HIV-1 CA-NC complexes. The assay allowed us to demonstrate that cytosolic extracts strongly stabilize the HIV-1 core. Interestingly, stabilization of in vitro-assembled HIV-1 CA-NC complexes is not due solely to macromolecular crowding, suggesting the presence of specific cellular factors that stabilize the HIV-1 core. By using our novel assay, we measured the abilities of different drugs, such as PF74, CAP-1, IXN-053, cyclosporine, Bi2 (also known as BI-2), and the peptide CAI, to modulate the stability of in vitro-assembled HIV-1 CA-NC complexes. Interestingly, we found that PF74 and Bi2 strongly stabilized HIV-1 CA-NC complexes. On the other hand, the peptide CAI destabilized HIV-1 CA-NC complexes. We also found that purified cyclophilin A destabilizes in vitro-assembled HIV-1 CA-NC complexes in the presence of cellular extracts in a cyclosporine-sensitive manner. In agreement with previous observations using the fate-of-the-capsid assay, we also demonstrated the ability of recombinant CPSF6 to stabilize HIV-1 CA-NC complexes. Overall, our findings suggested that cellular extracts specifically stabilize the HIV-1 core. We believe that our assay can be a powerful tool to assess HIV-1 core stability in vitro.


Development and validation of a gas chromatography-mass spectrometry method for the simultaneous determination of buprenorphine, flunitrazepam and their metabolites in rat plasma: application to the pharmacokinetic study.
Buprenorphine (BUP), a synthetic opioid analgesic, is frequently abused alone, and in association with benzodiazepines. Fatalities involving buprenorphine alone seem very unusual while its association with benzodiazepines, such as flunitrazepam (FNZ), has been reported to result in severe respiratory depression and death. The quantitative relationship between these drugs remain, however, uncertain. Our objective was to develop an analytical method that could be used as a means to study and explore, in animals, the toxicity and pharmacological interaction mechanisms between buprenorphine, flunitrazepam and their active metabolites. A procedure based on gas chromatography-mass spectrometry (GC-MS) is described for the simultaneous analysis of buprenorphine, norbuprenorphine (NBUP), flunitrazepam, N-desmethylflunitrazepam (N-DMFNZ) and 7-aminoflunitrazepam (7-AFNZ) in rat plasma. The method was set up and adapted for the analysis of small plasma samples taken from rats. Plasma samples were extracted by liquid-liquid extraction using Toxi-tubes A. Extracted compounds were derivatized with N,O-bis-(trimethylsilyl)trifluoroacetamide (BSTFA), using trimethylchlorosilane (TMCS) as a catalyst. They were then separated by GC on a crosslinked 5% phenyl-methylpolysiloxane analytical column and determined by a quadrupole mass spectrometer detector operated under selected ion monitoring mode. Excellent linearity was found between 0.125 and 25 ng/microl plasma for BUP, 0.125 and 12.5 ng/microl for NBUP and N-DMFNZ, 0.125 and 5 ng/microl for FNZ, and between 0.025 and 50 ng/microl for 7-AFNZ. The limit of quantification was 0.025 ng/microl plasma for 7-AFNZ and 0.125 ng/microl for the four other compounds. A good reproducibility (intra-assay CV=0.32-11.69%; inter-assay CV=0.63-9.55%) and accuracy (intra-assay error=2.58-12.73%; inter-assay error=0.83-11.07%) were attained. Recoveries were 71, 67 and 81%, for BUP, FNZ and N-DMFNZ, respectively, and 51% for NBUP and 7-AFNZ, with CV ranging from 5.4 to 13.9%, and were concentration-independent. The GC-MS method was successfully applied to the pharmacokinetic study of BUP, NBUP, FNZ, DMFNZ and 7-AFNZ in rats, after administration of BUP and FNZ.


Waterpipes and electronic cigarettes: increasing prevalence and expanding science.
The prevalence of non-cigarette tobacco product use is on the rise across the globe, especially for waterpipes (also known as hookah, narghile, and shisha) and electronic cigarettes (e-cigarettes). The scientific literature reveals that waterpipe tobacco smoking is associated with exposure to a variety of toxicants that can cause short- and long-term adverse health events. In contrast, there is far less evidence of health harms related to e-cigarette use, although the variety of products in this category makes it difficult to generalize. We searched the PubMed database for all publications on waterpipes and e-cigarettes from January 2000 to March 2014. The number of publications on waterpipes rose in a slow, linear pattern during this time, while the number of publications on e-cigarettes showed exponential growth. The different trends suggest there may be more interest in studying a novel nicotine product (the e-cigarette) over a traditional tobacco product (the waterpipe). We posit that, although the specific research needs for these products are different, public health would be served best by a more equitable research approach. Scientists should continue to devote attention to understanding the unknown long-term health effects of e-cigarettes and their potential to serve as harm reduction or smoking cessation tools while simultaneously investigating how to reduce waterpipe smoking given that it exposes users to toxicants known to cause harm to health. Recent regulatory action in the United States, which proposes to include waterpipes and e-cigarettes under some of the same regulations as tobacco cigarettes, makes such research particularly timely.


"17" is odd and "seventeen" is even: Meaning and physical form in stimulus-parity synaesthesia.
For individuals with stimulus-parity synaesthesia, eliciting stimuli (e.g., shapes, numbers, letters, colours) trigger a compelling feeling of oddness or evenness. Given that (a) many inducers are conceptual and (b) parity is itself a conceptual property, one questions whether stimulus-parity synaesthesia will be a categorically higher subtype, such that the conceptual properties of stimuli will be crucial in determining parity. We explore this question as it applies to Synaesthete R, one of only two stimulus-parity synaesthetes known to the contemporary literature. In Experiments 1 and 2, we examine whether parity is tied to concepts or percepts, asking, for example, whether a rectangle is even regardless of whether it is presented as an image or a word. Our results indicate that the parity of shapes (words and images), numbers (words, digits, and Roman numerals), and letters (lowercase and uppercase) differs according to the stimulus format, supporting a perceptual explanation. In Experiment 3, we examine the parity of colour stimuli, showing a systematic relationship between the measurable physical properties of hue, saturation, and lightness and synaesthetic parity. Despite the conceptual nature of inducers and concurrents, for Synaesthete R, stimulus-parity synaesthesia is a lower subtype; perceptual properties of stimuli determine parity.


PRIMARY STROKE PREVENTION IN CHILDREN WITH SICKLE CELL ANEMIA LIVING IN AFRICA: THE FALSE CHOICE BETWEEN PATIENT-ORIENTED RESEARCH AND HUMANITARIAN SERVICE.
In the United States, primary stroke prevention in children with sickle cell anemia (SCA) is now the standard of care and includes annual transcranial Doppler ultrasound evaluation to detect elevated intracranial velocities; and for those at risk, monthly blood transfusion therapy for at least a year followed by the option of hydroxyurea therapy. This strategy has decreased stroke prevalence in children with SCA from approximately 11% to 1%. In Africa, where 80% of all children with SCA are born, no systematic approach exists for primary stroke prevention. The two main challenges for primary stroke prevention in children with SCA in Africa include: 1) identifying an alternative to blood transfusion therapy, because safe monthly blood transfusion therapy is not feasible; and 2) assembling a health care team to implement and expand this effort. We will emphasize early triumphs and challenges to decreasing the incidence of strokes in African children with SCA.


First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer.
Enhancing tumor-specific T-cell immunity by inhibiting programmed death ligand 1 (PD-L1)-programmed death 1 (PD-1) signaling has shown promise in the treatment of extensive-stage small-cell lung cancer. Combining checkpoint inhibition with cytotoxic chemotherapy may have a synergistic effect and improve efficacy. We conducted this double-blind, placebo-controlled, phase 3 trial to evaluate atezolizumab plus carboplatin and etoposide in patients with extensive-stage small-cell lung cancer who had not previously received treatment. Patients were randomly assigned in a 1:1 ratio to receive carboplatin and etoposide with either atezolizumab or placebo for four 21-day cycles (induction phase), followed by a maintenance phase during which they received either atezolizumab or placebo (according to the previous random assignment) until they had unacceptable toxic effects, disease progression according to Response Evaluation Criteria in Solid Tumors, version 1.1, or no additional clinical benefit. The two primary end points were investigator-assessed progression-free survival and overall survival in the intention-to-treat population. A total of 201 patients were randomly assigned to the atezolizumab group, and 202 patients to the placebo group. At a median follow-up of 13.9 months, the median overall survival was 12.3 months in the atezolizumab group and 10.3 months in the placebo group (hazard ratio for death, 0.70; 95% confidence interval [CI], 0.54 to 0.91; P=0.007). The median progression-free survival was 5.2 months and 4.3 months, respectively (hazard ratio for disease progression or death, 0.77; 95% CI, 0.62 to 0.96; P=0.02). The safety profile of atezolizumab plus carboplatin and etoposide was consistent with the previously reported safety profile of the individual agents, with no new findings observed. The addition of atezolizumab to chemotherapy in the first-line treatment of extensive-stage small-cell lung cancer resulted in significantly longer overall survival and progression-free survival than chemotherapy alone. (Funded by F. Hoffmann-La Roche/Genentech; IMpower133 ClinicalTrials.gov number, NCT02763579 .).


Consent for Use of Genetic Data among US Hispanics/Latinos: Results from the Hispanic Community Health Study/ Study of Latinos.
Inclusion of historically underrepresented populations in biomedical research is critical for large precision medicine research initiatives. Among 13,721 Hispanic Community Health Study/Study of Latinos (HCHS/SOL) enrollees, we used multivariable-adjusted prevalence ratios to describe characteristics associated with participants' willingness to consent to different levels of biospecimen and genetic data analysis and sharing. At baseline (2008-2011), HCHS/SOL participants almost universally consented to the use of biospecimens and genetic data by study investigators and their collaborators (97.6%; 95%CI: 97.1, 98.0). Fewer consented to biospecimen and genetic data sharing with investigators not affiliated with the HCHS/SOL research team (81%, 95%CI: 80, 82) or any data sharing with commercial/for-profit entities (75%, 95%CI: 74, 76). Those refusing to share their data beyond the study investigators group were more often females, Spanish language-speakers and non-US born individuals. As expected, participants who were retained and reconsented at the six-year follow up visit tended to embrace broader data sharing, although this varied by group. Over time, Puerto Ricans and Dominicans were more likely to convert to broader data sharing than individuals of a Mexican background. Our analysis suggests that acculturation and immigration status of specific Hispanic/Latino communities may influence decisions about participation in genomic research projects and biobanks.


Elevated cyclooxygenase-2 levels in Min mouse adenomas.
Mutations in the APC gene result in an increased propensity to develop intestinal neoplasia; however, a complete understanding of the mechanisms resulting in tumor formation has remained elusive. Min mice possess a mutation in the APC gene and display a neoplastic phenotype similar to that observed in familial adenomatous polyposis coli in humans. Cyclooxygenase (COX) inhibitors decrease tumor multiplicity in the Min mouse intestine. The present study was designed to determine if there was an increase in COX-2 in adenomas harvested from Min mouse intestine. COX-2 messenger RNA levels were determined by Northern blots and reverse-transcription polymerase chain reactions of B6Min x 129 mouse-derived tumors. Protein levels and localization were determined by Western blots and immunohistochemical staining. The Northern blots revealed an approximately threefold increase in the level of COX-2 messenger RNA in Min mouse adenoma compared with normal mucosa. COX-2 protein levels in adenomatous tissues were also approximately threefold higher compared with normal mucosa from the same mouse. Immunohistochemical staining with a monospecific COX-2 antibody confirmed that increases in COX-2 immunoreactivity were restricted to dysplastic and neoplastic foci within intestinal mucosa. These data show that COX-2 levels may be increased at an early stage in colorectal neoplasia during polyp formation and before invasion.


Responses by Dendroctonus frontalis and Dendroctonus mesoamericanus (Coleoptera: Curculionidae) to Semiochemical Lures in Chiapas, Mexico: Possible Roles of Pheromones During Joint Host Attacks.
In southern Mexico and Central America, the southern pine beetle Dendroctonus frontalis Zimmermann (Coleoptera: Curculionidae: Scolytinae) commonly colonizes host trees simultaneously with Dendroctonus mesoamericanus Armendáriz-Toledano and Sullivan, a recently described sibling species. We hypothesized that cross-species pheromone responses by host-seeking beetles might mediate joint mass attack, bole partitioning, and reproductive isolation between the species. Previous studies had indicated that D. frontalis females produce frontalin and that female D. mesoamericanus produce frontalin, endo-brevicomin, and ipsdienol (males of both species produce endo-brevicomin and possibly ipsdienol). In field trapping trials in the Mexican state of Chiapas, D. frontalis was attracted to the lure combination of turpentine and racemic frontalin; racemic endo-brevicomin enhanced this response. In a single test, D. mesoamericanus was attracted in low numbers to the combination of turpentine, racemic frontalin, and racemic endo-brevicomin after the addition of racemic ipsdienol; in contrast, racemic ipsdienol reduced responses of D. frontalis. Inhibition of D. frontalis was generated in both sexes by (+)- and racemic ipsdienol, but by (−)-ipsdienol only in females. Logs infested with D. mesoamericanus females (the pioneer sex in Dendroctonus) attracted both species in greater numbers than either D. frontalis female-infested or uninfested logs. Our data imply that D. frontalis may be more attracted to pioneer attacks of D. mesoamericanus females, and that this could be owing to the presence of endo-brevicomin in the latter. Possible intra- and inter-specific functions of semiochemicals investigated in our experiments are discussed.


Reexamination of the Rehm-Weller data set reveals electron transfer quenching that follows a Sandros-Boltzmann dependence on free energy.
In a landmark publication over 40 years ago, Rehm and Weller (RW) showed that the electron transfer quenching constants for excited-state molecules in acetonitrile could be correlated with the excited-state energies and the redox potentials of the electron donors and acceptors. The correlation was interpreted in terms of electron transfer between the molecules in the encounter pair (A*/D ⇌ A(•-)/D(•+) for acceptor A and donor D) and expressed by a semiempirical formula relating the quenching constant, k(q), to the free energy of reaction, ΔG. We have reinvestigated the mechanism for many Rehm and Weller reactions in the endergonic or weakly exergonic regions. We find they are not simple electron transfer processes. Rather, they involve exciplexes as the dominant, kinetically and spectroscopically observable intermediate. Thus, the Rehm-Weller formula rests on an incorrect mechanism. We have remeasured k(q) for many of these reactions and also reevaluated the ΔG values using accurately determined redox potentials and revised excitation energies. We found significant discrepancies in both ΔG and k(q), including A*/D pairs at high endergonicity that did not exhibit any quenching. The revised data were found to obey the Sandros-Boltzmann (SB) equation k(q) = k(lim)/[1 + exp[(ΔG + s)/RT]]. This behavior is attributed to rapid interconversion among the encounter pairs and the exciplex (A*/D ⇌ exciplex ⇌ A(•-)/D(•+)). The quantity k(lim) represents approximately the diffusion-limited rate constant, and s the free energy difference between the radical ion encounter pair and the free radical ions (A(•-)/D(•+) vs A(•-) + D(•+)). The shift relative to ΔG for the overall reaction is positive, s = 0.06 eV, rather than the negative value of -0.06 eV assumed by RW. The positive value of s involves the poorer solvation of A(•-)/D(•+) relative to the free A(•-) + D(•+), which opposes the Coulombic stabilization of A(•-)/D(•+). The SB equation does not involve the microscopic rate constants for interconversion among the encounter pairs and the exciplex. Data that fit this equation contain no information about such rate constants except that they are faster than dissociation of the encounter pairs to (re-)form the corresponding free species (A* + D or A(•-) + D(•+)). All of the present conclusions agree with our recent results for quenching of excited cyanoaromatic acceptors by aromatic donors, with the two data sets showing indistinguishable dependencies of k(q) on ΔG.


Frontiers proposal. National Institute on Aging "bench to bedside: estrogen as a case study".
On 28-29 September 2004, the National Institute on Aging (NIA) convened scientists for a workshop on the aging female brain focused on translating into clinical practice discoveries concerning estrogens and progestogens. Workshop objectives were to examine effects of estrogen and progestogen on brain and cognitive function in relation to aging, to examine consistencies and apparent discrepancies between Women's Health Initiative Memory Study findings and other research on cognitive function, to determine whether additional hormone interventions could be developed in this area, and to offer advice on design of clinical trials for other interventions that might ameliorate cognitive aging. Following the workshop, participants joined by other interested scientists organized into regional work groups to continue the dialogue begun in Bethesda and to propose recommendations for NIA. The resulting recommendations, referred to as the "Frontiers Proposal for Estrogen and Cognitive Aging", acknowledge the persistence of critical gaps in our understanding of how decline in ovarian steroid secretion during reproductive aging and use of ovarian steroid hormone therapy affect normal brain function and risk for late-life neurodegenerative disorders such as Alzheimer's disease. There is a pressing need for preclinical, human, and integrated studies on the relationship between the menopausal transition and midlife exposures to estrogens, progestogens and related compounds, and risks for age-associated cognitive disorders. Research is also needed on better predictors of adverse cognitive outcomes, valid biomarkers for risks associated with hormone therapy use, enhanced tools for monitoring brain function and disease progression, and novel forms of therapy for improving long-term cognitive outcomes.


Acute dietary protein intake restriction is associated with changes in myostatin expression after a single bout of resistance exercise in healthy young men.
Skeletal muscle satellite cells (SCs) play an important role in the myogenic adaptive response to exercise. It remains to be established whether nutrition plays a role in SC activation in response to exercise. In the present study, we assessed whether dietary protein alters the SC response to a single bout of resistance exercise. Twenty healthy young (aged 21 ± 2 y) males were randomly assigned to consume a 4-d controlled diet that provided either 1.2 g protein ⋅ kg body weight(-1) ⋅ d(-1) [normal protein diet (NPD)] or 0.1 g protein ⋅ kg body weight(-1) ⋅ d(-1) [low protein diet (LPD)]. On the second day of the controlled diet, participants performed a single bout of resistance exercise. Muscle biopsies from the vastus lateralis were collected before and after 12, 24, 48, and 72 h of post-exercise recovery. SC content and activation status were determined using immunohistochemistry. Protein and mRNA expression were determined using Western blotting and reverse transcription polymerase chain reaction. The number of myostatin + SCs decreased significantly at 12, 24, and 48 h (range, -14 to -49%; P < 0.05) after exercise cessation, with no differences between groups. Although the number of myostatin + SCs returned to baseline in the type II fibers on the NPD after 72 h of recovery, the number remained low on the LPD. At the 48 and 72 h time points, myostatin protein expression was elevated (86 ± 26% and 88 ± 29%, respectively) on the NPD (P < 0.05), whereas it was reduced at 72 h (-36 ± 12% compared with baseline) in the LPD group (P < 0.05). This study demonstrates that dietary protein intake does not modulate the post-exercise increase in SC content but modifies myostatin expression in skeletal muscle tissue. This trial was registered at clinicaltrials.gov as NCT01220037.


Early podocyte injury and elevated levels of urinary podocyte-derived extracellular vesicles in swine with metabolic syndrome: role of podocyte mitochondria.
Metabolic syndrome (MetS) is associated with nutrient surplus and kidney hyperfiltration, accelerating chronic renal failure. The potential involvement of podocyte damage in early MetS remains unclear. Mitochondrial dysfunction is an important determinant of renal damage, but whether it contributes to MetS-related podocyte injury remains unknown. Domestic pigs were studied after 16 wk of diet-induced MetS, MetS treated with the mitochondria-targeted peptide elamipretide (ELAM; 0.1 mg·kg-1·day-1 sc) for the last month of diet, and lean controls (n = 6 pigs/group). Glomerular filtration rate (GFR) and renal blood flow (RBF) were measured using multidetector computed tomography, and podocyte and mitochondrial injury were measured by light and electron microscopy. Urinary levels of podocyte-derived extracellular vesicles (pEVs; nephrin positive/podocalyxin positive) were characterized by flow cytometry. Body weight, blood pressure, RBF, and GFR were elevated in MetS. Glomerular size and glomerular injury score were also elevated in MetS and decreased after ELAM treatment. Evidence of podocyte injury, impaired podocyte mitochondria, and foot process width were all increased in MetS but restored with ELAM. The urinary concentration of pEVs was elevated in MetS pigs and directly correlated with renal dysfunction, glomerular injury, and fibrosis and inversely correlated with glomerular nephrin expression. Additionally, pEV numbers were elevated in the urine of obese compared with lean human patients. Early MetS induces podocyte injury and mitochondrial damage, which can be blunted by mitoprotection. Urinary pEVs reflecting podocyte injury might represent early markers of MetS-related kidney disease and a novel therapeutic target.


Association between the COVID-19 Vaccine and Preventive Behaviors: Panel Data Analysis from Japan.
The coronavirus (COVID-19) vaccine is key to reducing the probability of contracting COVID-19. The vaccine is generally known to prevent severe illness, death, and hospitalization as a result of the disease and for considerably reduce COVID-19 infection risk. Accordingly, this might significantly change an individual's perceived risk of altering everyday behaviors. For instance, the proliferation of vaccination is anticipated to reduce preventive behaviors such as staying at home, handwashing, and wearing a mask. We corresponded with the same individuals monthly for 18 months from March 2020 (early stage of COVID-19) to September 2021 in Japan to independently construct large sample panel data (N = 54,007), with a participation rate of 54.7%. We used a fixed effects model, controlling for key confounders, to determine whether vaccination was associated with a change in preventive behaviors. The major findings are as follows. Contrary to the prediction, (1) based on the whole sample, being vaccinated against COVID-19 led people to stay at home; however, it did not change the habit of handwashing and wearing a mask. Especially after the second shot, respondents were likelier to stay at home by 0.107 (95% CIs: 0.059-0.154) points on a 5-point scale compared to before the vaccination. Dividing the entire sample into young and old, (2) those aged ≤ 40 years were more likely to go out after being vaccinated, and (3) people over 40 years of age were more likely to stay at home (similar to the first result). Preventive behaviors impact all individuals during the current pandemic. Informal social norms motivate people to increase or maintain preventive behaviors even after being vaccinated in societies where these behaviors are not enforced.


Hiding opaque eyes in transparent organisms: a potential role for larval eyeshine in stomatopod crustaceans.
Opaque screening pigments are a fundamental requisite for preserving resolution in image-forming eyes. Possession of any type of image-forming eye in a transparent, pelagic animal will thus undermine the ability of that animal to be invisible in the water column. Transparent, pelagic animals must therefore deal with the trade-off between the ability to see and the ability of other animals to see them. Stomatopod larvae, like many transparent crustaceans, possess specialized optics in their compound eyes that minimize the volume of the opaque retina. Though the volumes of these retinas are reduced, their opacity remains conspicuous to an observer. The light reflected from structures overlying the retinas of stomatopod crustacean larval eyes, referred to here as eyeshine, is hypothesized to further reduce the visibility of opaque retinas. Blue or green wavelengths of light are most strongly reflected in stomatopod larval eyeshine, suggesting a putative spectral matching to the light environment against which the larval eyes are viewed. We tested the efficacy of stomatopod crustacean larval eyeshine as an ocular camouflaging mechanism by photographing larvae in their natural light environment and analysing the contrast of eyes with the background light. To test for spectral matching between stomatopod larval eyeshine and the background light environment, we characterized the spectrum of eyeshine and calculated its performance using radiometric measurements collected at the time of each photographic series. These results are the first to demonstrate an operative mirror camouflage matched in both spectrum and radiance to the pelagic background light environment.


Methylation of novel markers of fragile X alleles is inversely correlated with FMRP expression and FMR1 activation ratio.
The fragile X syndrome (FXS) is caused by silencing of the fragile X mental retardation gene (FMR1) and the absence of its product, fragile X mental retardation protein (FMRP), resulting from CpG island methylation associated with large CGG repeat expansions (more than 200) termed full mutation (FM). We have identified a number of novel epigenetic markers for FXS using matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS), naming the most informative fragile X-related epigenetic element 1 (FREE1) and 2 (FREE2). Methylation of both regions was correlated with that of the FMR1 CpG island detected using Southern blot (FREE1 R = 0.97; P < 0.00001, n = 23 and FREE2 R = 0.93; P < 0.00001, n = 23) and negatively correlated with lymphocyte expression of FMRP (FREE1 R = -0.62; P = 0.01, n = 15 and FREE2 R = -0.55; P = 0.03, n = 15) in blood of partially methylated 'high functioning' FM males. In blood of FM carrier females, methylation of both markers was inversely correlated with the FMR1 activation ratio (FREE1 R = -0.93; P < 0.0001, n = 12 and FREE2 R = -0.95; P < 0.0001, n = 9). In a sample set of 49 controls, 18 grey zone (GZ 40-54 repeats), 22 premutation (PM 55-170 repeats) and 22 (affected) FXS subjects, the FREE1 methylation pattern was consistent between blood and chorionic villi as a marker of methylated FM alleles and could be used to differentiate FXS males and females from controls, as well as from carriers of GZ/PM alleles, but not between GZ and PM alleles and controls. Considering its high-throughput and specificity for pathogenic FM alleles, low cost and minimal DNA requirements, FREE MALDI-TOF MS offers a unique tool in FXS diagnostics and newborn population screening.


Content and comprehensibility of juvenile and adult tender-of-plea forms: implications for knowing, intelligent, and voluntary guilty pleas.
The overwhelming majority of criminal convictions in the United States are obtained through guilty pleas. To be constitutionally valid, guilty pleas must be knowing, voluntary, and intelligent. The information the defendant relies on to make a knowing, voluntary, and intelligent plea decision may be conveyed to the defendant through several modes, including but not limited to communication with defense counsel. Here, we address a mode that to our knowledge has previously not been systematically examined-tender-of-plea (ToP) forms. ToP forms are written instruments that inquire into whether the defendant understands and appreciates the plea decision and is capable of entering it. Using content analysis and comprehensibility measures, we examined a national sample of 208 tender-of-plea forms for both juvenile and adult defendants to determine what information they contained and their level of comprehensibility. The ToP forms were coded for several items concerning knowledge and voluntariness including rights waived, direct and collateral consequences, and capacity. Our findings show that the forms (a) are highly variable in their content, (b) exceed the reading comprehension of most defendants, and (c) are available more often to adult than to juvenile defendants. The implications of these findings are the forms should not be used to stand in place of "full and vigorous" judicial plea colloquies or meaningful defender-defendant discussions about plea decision-making. (PsycINFO Database Record


Establishment of Arabidopsis thaliana ribosomal protein RPL23A-1 as a functional homologue of Saccharomyces cerevisiae ribosomal protein L25.
Arabidopsis thaliana ribosomal protein (r-protein) RPL23A-1 shows 54% amino acid sequence identity to the Saccharomyces cerevisiae equivalent r-protein, L25. AtRPL23A-1 also shows high amino acid sequence identity to members of the L23/L25 r-protein family in other species. R-protein L25 in S. cerevisiae has been identified as a primary rRNA-binding protein that directly binds to a specific site on yeast 26S rRNA. It is translocated to the nucleolus where it binds to 26S rRNA during early large ribosome subunit assembly; this binding is thought to play an important role in ribosome assembly. The S. cerevisiae mutant strain YCR61 expresses L25 when grown on galactose, but not glucose, medium. Transformation of YCR61 with a shuttle vector containing the AtRPL23A-1 cDNA allowed transformed colonies to grow in and on glucose selection medium. R-protein AtRPL23A-1 can complement the L25 mutation, demonstrating the functional equivalence of the two r-proteins and introducing AtRPL23A-1 as the first plant member of the L23/L25 r-protein family.


Resource-rational analysis: Understanding human cognition as the optimal use of limited computational resources.
Modeling human cognition is challenging because there are infinitely many mechanisms that can generate any given observation. Some researchers address this by constraining the hypothesis space through assumptions about what the human mind can and cannot do, while others constrain it through principles of rationality and adaptation. Recent work in economics, psychology, neuroscience, and linguistics has begun to integrate both approaches by augmenting rational models with cognitive constraints, incorporating rational principles into cognitive architectures, and applying optimality principles to understanding neural representations. We identify the rational use of limited resources as a unifying principle underlying these diverse approaches, expressing it in a new cognitive modeling paradigm called resource-rational analysis. The integration of rational principles with realistic cognitive constraints makes resource-rational analysis a promising framework for reverse-engineering cognitive mechanisms and representations. It has already shed new light on the debate about human rationality and can be leveraged to revisit classic questions of cognitive psychology within a principled computational framework. We demonstrate that resource-rational models can reconcile the mind's most impressive cognitive skills with people's ostensive irrationality. Resource-rational analysis also provides a new way to connect psychological theory more deeply with artificial intelligence, economics, neuroscience, and linguistics.


Consumption of sheep milk compared to cow milk can affect trabecular bone ultrastructure in a rat model.
Cow milk has a positive effect on bone health due to the effects of its protein, fat, lipid, vitamin, and mineral components. Sheep milk contains a unique composition of all of these components. However, to the best of our knowledge the benefits of sheep milk in relation to bone development have not been studied. The aim of the present study was to determine the effects of the consumption of sheep milk in comparison to cow milk on the structural and physical characteristics of growing bone in a rat model. Newly weaned male rats were fed either cow milk, sheep milk or sheep milk diluted to the same total solids content as cow milk for 28 days in addition to a basal chow. At the end of the feeding period animals were euthanized, the femora harvested and stored. The femora were analysed by μ-CT, mechanical bending tests, and ICP-MS. Rats consuming sheep milk in the trial were found to have significantly higher trabecular bone surface density and trabecular bone surface to volume ratio (p < 0.05) when compared to the rats consuming cow milk. No significant differences were observed in the mechanical properties and the mineral composition of the bones (p > 0.05). With the exception of Rb, which was found to be present in higher concentrations in rats consuming sheep milk (p < 0.05). Our results indicate that consumption of sheep milk may positively influence the structural integrity of bone, which may result in an enhancement of bone health.


CRISPR-Cas9-Mediated Gene Editing of MYB28 Genes Impair Glucoraphanin Accumulation of Brassica oleracea in the Field.
Discoveries in model plants grown under optimal conditions can provide important directions for crop improvement. However, it is important to verify whether results can be translated to crop plants grown in the field. In this study, we sought to study the role of MYB28 in the regulation of aliphatic glucosinolate (A-GSL) biosynthesis and associated sulfur metabolism in field-grown Brassica oleracea with the use of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9 gene-editing technology. We describe the first myb28 knockout mutant in B. oleracea, and the first CRISPR field trial in the United Kingdom approved and regulated by the UK Department for Environment, Food & Rural Affairs after the reclassification of gene-edited crops as genetically modified organisms by the European Court of Justice on July 25, 2018. We report that knocking out myb28 results in downregulation of A-GSL biosynthesis genes and reduction in accumulation of the methionine-derived glucosinolate, glucoraphanin, in leaves and florets of field-grown myb28 mutant broccoli plants, whereas accumulation of sulfate, S-methyl cysteine sulfoxide, and indole glucosinolate in leaf and floret tissues remained unchanged. These results demonstrate the potential of gene-editing approaches to translate discoveries in fundamental biological processes for improved crop performance.


Bacterial charity work leads to population-wide resistance.
Bacteria show remarkable adaptability in the face of antibiotic therapeutics. Resistance alleles in drug target-specific sites and general stress responses have been identified in individual end-point isolates. Less is known, however, about the population dynamics during the development of antibiotic-resistant strains. Here we follow a continuous culture of Escherichia coli facing increasing levels of antibiotic and show that the vast majority of isolates are less resistant than the population as a whole. We find that the few highly resistant mutants improve the survival of the population's less resistant constituents, in part by producing indole, a signalling molecule generated by actively growing, unstressed cells. We show, through transcriptional profiling, that indole serves to turn on drug efflux pumps and oxidative-stress protective mechanisms. The indole production comes at a fitness cost to the highly resistant isolates, and whole-genome sequencing reveals that this bacterial altruism is made possible by drug-resistance mutations unrelated to indole production. This work establishes a population-based resistance mechanism constituting a form of kin selection whereby a small number of resistant mutants can, at some cost to themselves, provide protection to other, more vulnerable, cells, enhancing the survival capacity of the overall population in stressful environments.


Analysis of the Cdc28 protein kinase complex by dosage suppression.
In the interest of identifying components of the Cdc28 protein kinase complex, dosage suppression analysis was performed on temperature-sensitive and dominant negative CDC28 mutations. Dosage suppression is based on a rationale in which elevated expression of wild-type genes can rescue mutations in a target gene as a result of interaction between the respective encoded proteins. Three sequences capable of rescuing a temperature sensitive cdc28 mutation were isolated from a library of wild-type genomic DNA segments in the high copy vector YEp13. Two of these, named CLN1 and CLN2 were found to encode closely related proteins with homology to cyclins. The third, CKS1, encodes an 18K (K = 10(3) Mr) protein that has been shown to be a component of the Cdc28 protein kinase complex and is a homolog of the suc1+ product of fission yeast. A number of dosage suppressors of the CDC28-dn1 dominant negative mutation have been isolated. The one analyzed to date encodes a truncated subunit of the mitochondrial enzyme succinyl-CoA synthetase. The basis for suppression in this case remains to be elucidated.


Solution structure of the aminofluorene [AF]-external conformer of the anti-[AF]-C8-dG adduct opposite dC in a DNA duplex.
The Escherichia coli genome contains a C-G1-G2-C-G3-C-C NarI hot spot sequence for -2 deletion mutations at G3 by aromatic amine carcinogens 2-acetylaminofluorene (AAF) and 2-aminofluorene (AF) that form covalent adducts at the C8-position of the guanine ring. Each of the three guanines are positioned in different sequence contexts (C-G1-G, G-G2-C, and C-G3-C) which provides an opportunity to investigate the potential sequence dependent interconversion between AF-intercalated and AF-external conformers of the [AF]dG adduct positioned opposite dC within the NarI sequence at the duplex level. We have prepared and purified DNA duplexes containing the [AF]dG adduct positioned in C-[AF]G-G, G-[AF]G-C, and C-[AF]G-C NarI sequence contexts and observe the ratio of AF-intercalated to AF-external conformers to be 30:70, 10:90, and 50:50, respectively. We have applied a combined NMR-molecular mechanics approach to define the structure of the AF-external conformer in the G-[AF]G-C NarI sequence context where it is the predominant conformation (90%) in solution. The modified guanine of the [AF]dG adduct aligns through Watson-Crick pairing with its partner cytosine and is stacked into the helix between flanking Watson-Crick dG.dC base pairs. The AF-external conformer with its anti-[AF]dG residue causes minimal perturbations in the DNA duplex at and adjacent to the lesion site with the covalently linked fluorenyl ring readily accommodated in the major groove and tilted toward the 5'-end of the modified strand of the helix. This paper on the structure of the AF-external conformer with an anti-[AF]dG adduct together with the preceding paper in this issue on the structure of the AF-intercalated conformer with a syn-[AF]dG adduct defines for the first time the capacity of the mutagenic [AF]dG lesion to adopt interconverting syn and antialignments with the equilibrium shifting between the conformers depending on nearest neighbor and next-nearest neighbor sequences. Perhaps, recognition of the [AF]dG lesion by the repair machinery would be able to discriminate between the AF-intercalated conformer with its base displacement-fluorenyl ring insertion perturbation of the helix and the AF-external conformer where the DNA helix is essentially unperturbed at the lesion site and the fluorenyl ring is positioned with directionality in the major groove.


Combined oral contraception and obesity are strong predictors of low-grade inflammation in healthy individuals: results from the Danish Blood Donor Study (DBDS).
C-reactive protein (CRP) is a well-established marker of inflammation. The level of CRP is affected by several lifestyle factors. A slightly increased CRP level, also known as low-grade inflammation (LGI), is associated with increased risk of several diseases, especially cardiovascular disease. The aim of this study was to identify predictors of increased CRP levels in healthy individuals. We therefore assessed CRP in a large cohort of blood donors. We measured plasma CRP levels in 15,684 participants from the Danish Blood Donor Study. CRP was measured by a commercial assay. Furthermore, all participants completed a standard questionnaire on smoking status, alcohol consumption, physical activity, diet, and various body measurements. Female participants also reported the use of contraception, childbirth, and menopausal status. The relationship between LGI (defined here as a plasma CRP level between 3 mg/L and 10 mg/L) and predictors was explored by multivariable logistic regression analysis. Results were presented as odds ratios (OR) with 95% confidence intervals (CI). We found LGI in a total of 1,561 (10.0%) participants. LGI was more frequent in women using combined oral contraception (OC) (29.9%) than in men (6.1%) and women not using OC (7.9%). Among premenopausal women, OC was the strongest predictor of LGI (odds ratio = 8.98, p<0.001). Additionally, body mass index (BMI) and waist circumference were positively associated with LGI. High BMI and abdominal obesity strongly predicted LGI among healthy individuals. However, the most striking finding was the high prevalence of LGI among premenopausal women who used combined oral contraception. Although the significance of CRP as a marker of inflammation is well known, the role of CRP in pathogenesis is still uncertain. The impact of oral contraception on CRP levels should nevertheless be considered when CRP is used in risk assessment.


Distinguishing the time course of lexical and discourse processes through context, coreference, and quantified expressions.
How does prior context influence lexical and discourse-level processing during real-time language comprehension? Experiment 1 examined whether the referential ambiguity introduced by a repeated, anaphoric expression had an immediate or delayed effect on lexical and discourse processing, using an eye-tracking-while-reading task. Eye movements indicated facilitated recognition of repeated expressions, suggesting that prior context can rapidly influence lexical processing. However, context effects at the discourse level affected later processing, appearing in longer regression-path durations 2 words after the anaphor and in greater rereading times of the antecedent expression. Experiments 2 and 3 explored the nature of this delay by examining the role of the preceding context in activating relevant representations. Offline and online interpretations confirmed that relevant referents were activated following the critical context. Nevertheless, their initial unavailability during comprehension suggests a robust temporal division between lexical and discourse-level processing.


Consistent and contrasting properties of lineage-specific genes in the apicomplexan parasites Plasmodium and Theileria.
Lineage-specific genes, the genes that are restricted to a limited subset of related organisms, may be important in adaptation. In parasitic organisms, lineage-specific gene products are possible targets for vaccine development or therapeutics when these genes are absent from the host genome. In this study, we utilized comparative approaches based on a phylogenetic framework to characterize lineage-specific genes in the parasitic protozoan phylum Apicomplexa. Genes from species in two major apicomplexan genera, Plasmodium and Theileria, were categorized into six levels of lineage specificity based on a nine-species phylogeny. In both genera, lineage-specific genes tend to have a higher level of sequence divergence among sister species. In addition, species-specific genes possess a strong codon usage bias compared to other genes in the genome. We found that a large number of genus- or species-specific genes are putative surface antigens that may be involved in host-parasite interactions. Interestingly, the two parasite lineages exhibit several notable differences. In Plasmodium, the (G + C) content at the third codon position increases with lineage specificity while Theileria shows the opposite trend. Surface antigens in Plasmodium are species-specific and mainly located in sub-telomeric regions. In contrast, surface antigens in Theileria are conserved at the genus level and distributed across the entire lengths of chromosomes. Our results provide further support for the model that gene duplication followed by rapid divergence is a major mechanism for generating lineage-specific genes. The result that many lineage-specific genes are putative surface antigens supports the hypothesis that lineage-specific genes could be important in parasite adaptation. The contrasting properties between the lineage-specific genes in two major apicomplexan genera indicate that the mechanisms of generating lineage-specific genes and the subsequent evolutionary fates can differ between related parasite lineages. Future studies that focus on improving functional annotation of parasite genomes and collection of genetic variation data at within- and between-species levels will be important in facilitating our understanding of parasite adaptation and natural selection.


Magnesium deficiency prevents high-fat-diet-induced obesity in mice.
Hypomagnesaemia (blood Mg2+ <0.7 mmol/l) is a common phenomenon in individuals with type 2 diabetes. However, it remains unknown how a low blood Mg2+ concentration affects lipid and energy metabolism. Therefore, the importance of Mg2+ in obesity and type 2 diabetes has been largely neglected to date. This study aims to determine the effects of hypomagnesaemia on energy homeostasis and lipid metabolism. Mice (n = 12/group) were fed either a low-fat diet (LFD) or a high-fat diet (HFD) (10% or 60% of total energy) in combination with a normal- or low-Mg2+ content (0.21% or 0.03% wt/wt) for 17 weeks. Metabolic cages were used to investigate food intake, energy expenditure and respiration. Blood and tissues were taken to study metabolic parameters and mRNA expression profiles, respectively. We show that low dietary Mg2+ intake ameliorates HFD-induced obesity in mice (47.00 ± 1.53 g vs 38.62 ± 1.51 g in mice given a normal Mg2+-HFD and low Mg2+-HFD, respectively, p < 0.05). Consequently, fasting serum glucose levels decreased and insulin sensitivity improved in low Mg2+-HFD-fed mice. Moreover, HFD-induced liver steatosis was absent in the low Mg2+ group. In hypomagnesaemic HFD-fed mice, mRNA expression of key lipolysis genes was increased in epididymal white adipose tissue (eWAT), corresponding to reduced lipid storage and high blood lipid levels. Low Mg2+-HFD-fed mice had increased brown adipose tissue (BAT) Ucp1 mRNA expression and a higher body temperature. No difference was observed in energy expenditure between the two HFD groups. Mg2+-deficiency abrogates HFD-induced obesity in mice through enhanced eWAT lipolysis and BAT activity.


IPD-Work consortium: pre-defined meta-analyses of individual-participant data strengthen evidence base for a link between psychosocial factors and health.
Established in 2008 and comprising over 60 researchers, the IPD-Work (individual-participant data meta-analysis in working populations) consortium is a collaborative research project that uses pre-defined meta-analyses of individual-participant data from multiple cohort studies representing a range of countries. The aim of the consortium is to estimate reliably the associations of work-related psychosocial factors with chronic diseases, disability, and mortality. Our findings are highly cited by the occupational health, epidemiology, and clinical medicine research community. However, some of the IPD-Work's findings have also generated disagreement as they challenge the importance of job strain as a major target for coronary heart disease (CHD) prevention, this is reflected in the critical discussion paper by Choi et al (1). In this invited reply to Choi et al, we aim to (i) describe how IPD-Work seeks to advance research on associations between work-related psychosocial risk factors and health; (ii) demonstrate as unfounded Choi et al's assertion that IPD-Work has underestimated associations between job strain and health endpoints; these include the dichotomous measurement of job strain, potential underestimation of the population attributable risk (PAR) of job strain for CHD, and policy implications arising from the findings of the IPD-Work consortium; and (iii) outline general principles for designing evidence-based policy and prevention from good-quality evidence, including future directions for research on psychosocial factors at work and health. In addition, we highlight some problems with Choi et al's approach.


Madumycin II inhibits peptide bond formation by forcing the peptidyl transferase center into an inactive state.
The emergence of multi-drug resistant bacteria is limiting the effectiveness of commonly used antibiotics, which spurs a renewed interest in revisiting older and poorly studied drugs. Streptogramins A is a class of protein synthesis inhibitors that target the peptidyl transferase center (PTC) on the large subunit of the ribosome. In this work, we have revealed the mode of action of the PTC inhibitor madumycin II, an alanine-containing streptogramin A antibiotic, in the context of a functional 70S ribosome containing tRNA substrates. Madumycin II inhibits the ribosome prior to the first cycle of peptide bond formation. It allows binding of the tRNAs to the ribosomal A and P sites, but prevents correct positioning of their CCA-ends into the PTC thus making peptide bond formation impossible. We also revealed a previously unseen drug-induced rearrangement of nucleotides U2506 and U2585 of the 23S rRNA resulting in the formation of the U2506•G2583 wobble pair that was attributed to a catalytically inactive state of the PTC. The structural and biochemical data reported here expand our knowledge on the fundamental mechanisms by which peptidyl transferase inhibitors modulate the catalytic activity of the ribosome.


Clinical utility of family history for cancer screening and referral in primary care: a report from the Family Healthware Impact Trial.
To assess the effectiveness of computerized familial risk assessment and tailored messages for identifying individuals for targeted cancer prevention strategies and motivating behavior change. We conducted a randomized clinical trial in primary care patients aged 35-65 years using Family Healthware, a self-administered, internet-based tool that collects family history for six common diseases including breast cancer, colon cancer, and ovarian cancer, stratifies risk into three tiers, and provides tailored prevention messages. Cancer screening adherence and consultation were measured at baseline and 6-month follow-up. Of 3283 participants, 34% were at strong or moderate risk of at least one of the cancers. Family Healthware identified additional participants for whom earlier screening (colon cancer, 4.4%; breast cancer, women ages: 35-39 years, 9%) or genetic assessment (colon cancer, 2.5%; breast cancer, 10%; and ovarian cancer, 4%) may be indicated. Fewer than half were already adherent with risk-based screening. Screening adherence improved for all risk categories with no difference between intervention and control groups. Consultation with specialists did not differ between groups. Family Healthware identified patients for intensified cancer prevention. Engagement of clinicians and patients, integration with clinical decision support, and inclusion of nonfamilial risk factors may be necessary to achieve the full potential of computerized risk assessment.


Use of Poultry Manure Combined with Soil Solarization as a Control Method for Meloidogyne incognita in Carnation.
The effectiveness of a combination of soil solarization and poultry manure (raw or pelletized) amendments for the control of root-knot nematode (Meloidogyne incognita) was tested in carnation (Dianthus caryophyllus) crops grown in in-ground beds under plastic-covered greenhouse conditions in southern Spain. Our trials demonstrated that soil solarization alone did not provide sufficient control of root-knot nematode, because the carnation growing season in this region only partly coincides with the most effective period for solarization, resulting in an insufficient duration of treatment during a key period for effectiveness. Chemical fumigation with 1,3-dichloropropene + chloropicrin prior to planting was effective in reducing nematode population densities in soil. Its effects spanned 9 months after planting, resulting in acceptable crop yields. In comparison, the combination of soil solarization and raw or pelletized poultry manure was slightly less effective than chemical fumigation for control of this pathogen but crop yields after 9 months were similar. However, the higher root gall indices observed after 9 months, in comparison with chemically fumigated plots, indicated the need for a reapplication of the organic manure treatment at the start of each successive growing season.


Diagnostic challenges and treatment options of a suspected pericardial metallic projectile foreign body in a dog.
To describe a case of a suspected pericardial metallic projectile foreign body in a dog with a history of trauma to the left shoulder and to review the literature regarding the management of cardiac and intracardiac foreign bodies. A 3-year-old male, neutered Brittany spaniel presented with a 10-day history of decreased activity and partial anorexia. Serial thoracic radiographs identified a migrating pericardial metallic projectile foreign body and an echocardiogram diagnosed pericardial effusion and abdominal ultrasound identified the presence of ascites. Concern for a possible effusive-constrictive pericarditis prompted a subphrenic pericardectomy performed via thoracoscopy. The foreign body was not recovered. Six months postsurgery, the dog remained asymptomatic. Considering the high rate of complications that develop in human patients where the foreign bodies are not removed, veterinarians should be aware of risks associated with long standing pericardial foreign bodies even when no clinical signs are present. Guidelines from the human literature may be considered for investigation of, and treatment options for, cardiac and intracardiac metallic projectile foreign bodies in dogs.


EFFECTS OF CHRONIC EXCESS SALT INGESTION. ROLE OF GENETIC FACTORS IN BOTH DOCA-SALT AND RENAL HYPERTENSION.
By selective inbreeding, two strains of rats were developed previously that differed markedly in their susceptibility to the development of experimental hypertension from excess salt ingestion (1, 2). The present report indicates that with animals derived from the same strains, similar differences in response were obtained in rats subjected to either combined desoxycorticosterone-NaCl (DOCA-salt) treatment or unilateral renal artery compression without extra dietary salt. Thus differences in genetic substrate appear to influence the development of experimental hypertension produced by these three techniques and possibly this may hold true for all "varieties" of experimental hypertension. If true, it might allow the development of a unifying hypothesis that could be relevant not only to experimental hypertension but perhaps to human hypertension as well. The DOCA-salt regimen was more toxic to the animals than unilateral renal artery compression. Tentatively, this was ascribed to either, or both, the younger age or the higher NaCl intake of the animals in the former.


Cisplatin enhances cell stiffness and decreases invasiveness rate in prostate cancer cells by actin accumulation.
We focused on the biomechanical and morphological characteristics of prostate cancer cells and their changes resulting from the effect of docetaxel, cisplatin, and long-term zinc supplementation. Cell population surviving the treatment was characterized as follows: cell stiffness was assessed by atomic force microscopy, cell motility and invasion capacity were determined by colony forming assay, wound healing assay, coherence-controlled holographic microscopy, and real-time cell analysis. Cells of metastatic origin exhibited lower height than cells derived from the primary tumour. Cell dry mass and CAV1 gene expression followed similar trends as cell stiffness. Docetaxel- and cisplatin-surviving cells had higher stiffness, and decreased motility and invasive potential as compared to non-treated cells. This effect was not observed in zinc(II)-treated cells. We presume that cell stiffness changes may represent an important overlooked effect of cisplatin-based anti-cancer drugs. Atomic force microscopy and confocal microscopy data images used in our study are available for download in the Zenodo repository ( https://zenodo.org/ , Digital Object Identifiers:10.5281/zenodo.1494935).


Two tests of approach-iron golf skill and their ability to predict tournament performance.
The aim of this study was to investigate the convergent and predictive validity of two skill tests that examine the ability of golfers to hit accurate approach-iron shots. Twenty-four high-level golfers (handicap = 2.6 ± 1.7) performed the Nine-Ball Skills Test (assesses the ability to shape/control ball trajectory with high accuracy) and the Approach-Iron Skill Test (assesses the ability to hit straight shots from varying distances with high accuracy). Participants then completed at least eight rounds of tournament golf over the following 90 days and reported an indicator of approach-iron accuracy (per cent error index). A moderate correlation (r = 0.50, P < 0.05) was noted between scores for both tests. Generalised estimating equations, using two covariates (lie of the ball and distance to hole), were used to determine model fit and the amount of variance explained for tournament per cent error index. Results showed that the Approach-Iron Skill Test was the slightly stronger predictor of on-course per cent error index. With both test scores considered together, a minimal amount of additional variance was explained. These findings suggest that either of the tests used individually or combined may be used to predict tournament approach iron performance in high-level golfers.


What is the optimal outcome after endoscopic sinus surgery in the treatment of chronic rhinosinusitis? A consultation of Canadian experts.
Many experts feel that in the absence of well-defined goals for success, they have an easier time identifying failure. As success ought to not be defined only by absence of failure, we aimed to define optimal outcomes for endoscopic sinus surgery (ESS) in chronic rhinosinusitis (CRS) by obtaining expert surgeon perspectives. A total of 12 surgeons participated in this targeted consultation. Face to face semi-structured interviews were performed with expert surgeons in the field of CRS and ESS. General impressions and personal definitions of acceptable operative success and optimal operative outcomes were compiled and summarized. According to an expert survey, patients' main objectives are an improvement in their chief complain, a general improvement in quality of life (QoL), and a better overall symptomatic control. The most important aspects of endoscopy for defining a successful intervention were an adequate mucus circulation, a healthy mucosa, minimal edema, and patency of all explored cavities or ostia. In the assessment of surgical outcomes, it was determined that both objective and patient reported data must be carefully examined, with more attention given to subjective outcomes. According to data gathered from a Canadian expert consultation, a definition of success must be based on both subjective data and nasal endoscopy. We propose to define an acceptable outcome as either a subjective improvement of at least the minimal clinically improvement difference of a validated patient reported outcome questionnaire, along with a satisfactory endoscopic result (1) or a complete subjective resolution with a sub-optimal endoscopy (2).


[Effects of cryotherapy on chemotherapy-induced peripheral neuropathy: self-controlled clinical trial].
Chemotherapy induced peripheral neuropathy (CIPN) is a numbness or tingling of the hands and feet that occur as a side effect of anticancer drugs including taxanes and platinum drugs. The effective treatments or preventive strategy are not established. Once it develops, symptoms persist for a long time and cause impairment in activity of daily living. Topical cooling is a preventive strategy for side effects of chemotherapy such as hair loss, oral microsites, and skin and nail disorder of the hands and feet. We conducted a clinical trial in breast cancer patients who received paclitaxel treatment to assess the effectiveness of cooling for CIPN prevention. In this study, the individual background factor was standardized using an intra-individual comparison design. In 40 subjects, frozen gloves and socks were applied on the dominant hand and foot from 15 minutes before the anti-cancer drug administration to 15 minutes after the end of administration (total 90 minutes) and compared with non-dominant hand and foot. As a result, clinically and statistically significant differences were observed for changes in tactile threshold evaluated by the monofilament test, subjective symptoms, and changes in dexterity evaluated by functional test. The current cooling system has not been well implemented in oncology field due to the lack of facility and human resources. To deliver this therapy broadly, it will be urgent to develop a medical cooling device that can provide safe and effective cryotherapy.


Experiences with insecticide-treated curtains: a qualitative study in Iquitos, Peru.
Dengue is an arthropod-borne viral disease responsible for approximately 400 million infections annually; the only available method of prevention is vector control. It has been previously demonstrated that insecticide treated curtains (ITCs) can lower dengue vector infestations in and around houses. As part of a larger trial examining whether ITCs could reduce dengue transmission in Iquitos, Peru, the objective of this study was to characterize the participants' experience with the ITCs using qualitative methods. Knowledge, attitudes, and practices (KAP) surveys (at baseline, and 9 and 27 months post-ITC distribution, with n = 593, 595 and 511, respectively), focus group discussions (at 6 and 12 months post-ITC distribution, with n = 18 and 33, respectively), and 11 one-on-one interviews (at 12 months post-distribution) were conducted with 605 participants who received ITCs as part of a cluster-randomized trial. Focus groups at 6 months post-ITC distribution revealed that individuals had observed their ITCs to function for approximately 3 months, after which they reported the ITCs were no longer working. Follow up revealed that the ITCs required re-treatment with insecticide at approximately 1 year post-distribution. Over half (55.3 %, n = 329) of participants at 9 months post-ITC distribution and over a third (34.8 %, n = 177) at 27 months post-ITC distribution reported perceiving a decrease in the number of mosquitoes in their home. The percentage of participants who would recommend ITCs to their family or friends in the future remained high throughout the study (94.3 %, n = 561 at 9 months and 94.6 %, n = 488 at 27 months post-distribution). When asked why, participants reported that ITCs were effective at reducing mosquitoes (81.6 and 37.8 %, at 9 and 27 months respectively), that they prevent dengue (5.7 and 51.2 %, at 9 and 27 months), that they are "beautiful" (5.9 and 3.1 %), as well as other reasons (6.9 and 2.5 %). ITCs have substantial potential for long term dengue vector control because they are liked by users, both for their perceived effectiveness and for aesthetic reasons, and because they require little proactive behavioral effort on the part of the users. Our results highlight the importance of gathering process (as opposed to outcome) data during vector control studies, without which researchers would not have become aware that the ITCs had lost effectiveness early in the trial.


Evaluating Polypoidal Choroidal Vasculopathy With Optical Coherence Tomography Angiography.
We observed and analyzed the morphologic characteristics of polypoidal lesions and abnormal branching vascular network (BVN) in patients with polypoidal choroidal vasculopathy (PCV) by optical coherence tomography angiography (OCTA). A retrospective observational case series was done of patients with PCV. All patients were scanned with a 70-kHz spectral-domain OCT system using the split-spectrum amplitude-decorrelation angiography (SSADA) algorithm to distinguish blood flow from static tissue. The OCTA images of these patients were compared to those from indocyanine green angiography (ICGA). Semiautomated segmentation was used to further analyze the polypoidal lesion and the BVN. We studied 13 eyes of 13 patients 51 to 69 years old. A total of 11 patients were treatment-naive. Two patients had multiple anti-VEGF injections and one underwent photodynamic therapy (PDT). Optical coherence tomography angiography was able to detect the BVN in all cases. Using cross-sectional OCTA, BVN locations were shown to be in the space between the RPE and Bruch's membrane. Using en face OCTA, the BVN vascular pattern could be shown more clearly than by ICGA. Polypoidal lesions showed high flow signals in different patterns in 12 cases in the outer retina slab. Using cross-sectional OCTA, the polyps were shown to be just below the top of the pigment epithelial detachment (PED). In one case, the polypoidal lesion was not detectable at the outer retina slab. Optical coherence tomography angiography is a noninvasive imaging tool for detecting vascular changes in PCV. Branching vascular networks showed more clearly on OCTA than on ICGA. Polypoidal lesions had variable patterns on OCTA and were not always detected. The OCTA patterns of the polypoidal lesions and the BVN are helpful in understanding the pathology of PCV.


Autocorrelation structure at rest predicts value correlates of single neurons during reward-guided choice.
Correlates of value are routinely observed in the prefrontal cortex (PFC) during reward-guided decision making. In previous work (Hunt et al., 2015), we argued that PFC correlates of chosen value are a consequence of varying rates of a dynamical evidence accumulation process. Yet within PFC, there is substantial variability in chosen value correlates across individual neurons. Here we show that this variability is explained by neurons having different temporal receptive fields of integration, indexed by examining neuronal spike rate autocorrelation structure whilst at rest. We find that neurons with protracted resting temporal receptive fields exhibit stronger chosen value correlates during choice. Within orbitofrontal cortex, these neurons also sustain coding of chosen value from choice through the delivery of reward, providing a potential neural mechanism for maintaining predictions and updating stored values during learning. These findings reveal that within PFC, variability in temporal specialisation across neurons predicts involvement in specific decision-making computations.