Action Spotting and Recognition Based on a Spatiotemporal Orientation Analysis.
This paper provides a unified framework for the interrelated topics of action spotting, the spatiotemporal detection and localization of human actions in video, and action recognition, the classification of a given video into one of several predefined categories. A novel compact local descriptor of video dynamics in the context of action spotting and recognition is introduced based on visual spacetime oriented energy measurements. This descriptor is efficiently computed directly from raw image intensity data and thereby forgoes the problems typically associated with flow-based features. Importantly, the descriptor allows for the comparison of the underlying dynamics of two spacetime video segments irrespective of spatial appearance, such as differences induced by clothing, and with robustness to clutter. An associated similarity measure is introduced that admits efficient exhaustive search for an action template, derived from a single exemplar video, across candidate video sequences. The general approach presented for action spotting and recognition is amenable to efficient implementation, which is deemed critical for many important applications. For action spotting, details of a real-time GPU-based instantiation of the proposed approach are provided. Empirical evaluation of both action spotting and action recognition on challenging datasets suggests the efficacy of the proposed approach, with state-of-the-art performance documented on standard datasets.


Navigating possible endometriosis in primary care: a qualitative study of GP perspectives.
Endometriosis affects approximately 6-10% of women, with well documented delays between initial presentation with symptoms and diagnosis. In England, women typically seek help first in primary care, making this setting pivotal in women's pathways to diagnosis and treatment. English GP perspectives on managing possible endometriosis have not been previously reported. To explore what GPs identify as important considerations when caring for women with symptoms that raise the possibility of endometriosis. Qualitative study in English primary care. Semi-structured scenario-based telephone interviews with 42 GPs from April 2019 to January 2020, based around a fictional scenario of a woman presenting to primary care with symptoms suggesting possible endometriosis. Interviews were thematically coded and analysed. Managing possible endometriosis in primary care brings challenges. While knowledge and awareness were prerequisites for considering endometriosis, other important considerations were raised. Symptoms suggestive of endometriosis are non-specific, making endometriosis one possible consideration of many. GPs move through a diagnostic hierarchy to exclude sinister causes and utilise trials of treatment as both therapeutic interventions and diagnostic tools; processes which take time. An endometriosis label or diagnosis has advantages and risks. GPs reported sharing decisions about investigation and referral while holding women's priorities as pivotal. These conversations were underpinned by their knowledge of uncertainties and unknowns, including the wide spectrum and unpredictability of endometriosis. GPs considerations are more complex than simply lacking awareness. The unknowns surrounding endometriosis matter to GPs. Further research and tailored resources for primary care, where women present with undifferentiated symptoms, are needed.


Meiotic instability of the R-r complex arising from displaced intragenic exchange and intrachromosomal rearrangement.
The R complex of Zea mays encodes a tissue-specific transcriptional activator of the anthocyanin pigment biosynthetic pathway. Certain R alleles comprise two genetically distinct components that confer the plant (P) and seed (S) aspects of the pigmentation pattern. These alleles are meiotically unstable, losing (P) or (S) function, often accompanied by exchange of flanking markers. We show that the (P) component consists of a single gene within the R-r complex, whereas the (S) component is part of a more complex arrangement of multiple R genes or gene subfragments. A third, cryptic region of the complex, termed (Q), consists of a truncated R sequence. The analysis of R-r crossover derivative alleles shows they arise from unequal exchange between the (P) gene and one of several distinct regions of the R-r complex. Restriction site polymorphisms were used to show that most of these unequal exchanges are intragenic. The frequency of displaced intragenic recombination is comparable to previous estimates for intragenic recombination in maize involving genes that are not duplicated. These exchange events have been used to determine the arrangement of components within the complex and their orientation in the chromosome. We also show that localized rearrangements in the (P) or (S) components are responsible for noncrossover derivative alleles. The organization of R-r has implications for these noncrossover derivatives and models for their origin are discussed.


A clinical perspective on mucoadhesive buccal drug delivery systems.
Mucoadhesion can be defined as a state in which two components, of which one is of biological origin, are held together for extended periods of time by the help of interfacial forces. Among the various transmucosal routes, buccal mucosa has excellent accessibility and relatively immobile mucosa, hence suitable for administration of retentive dosage form. The objective of this paper is to review the works done so far in the field of mucoadhesive buccal drug delivery systems (MBDDS), with a clinical perspective. Starting with a brief introduction of the mucoadhesive drug delivery systems, oral mucosa, and the theories of mucoadhesion, this article then proceeds to cover the works done so far in the field of MBDDS, categorizing them on the basis of ailments they are meant to cure. Additionally, we focus on the various patents, recent advancements, and challenges as well as the future prospects for mucoadhesive buccal drug delivery systems.


The effects of circulating testosterone and pubertal maturation on risk for disordered eating symptoms in adolescent males.
Testosterone may be a biological factor that protects males against eating disorders. Elevated prenatal testosterone exposure is linked to lower levels of disordered eating symptoms, but effects emerge only after mid-puberty. Whether circulating levels of testosterone account for decreased risk for disordered eating in boys after mid-puberty is currently unknown; however, animal data support this possibility. In rodents, prenatal testosterone's masculinizing effects on sex-differentiated behaviors emerge during puberty when circulating levels of testosterone increase and 'activate' the expression of masculinized phenotypes. This study investigated whether higher levels of circulating testosterone predict lower levels of disordered eating symptoms in adolescent boys, and in particular whether effects are associated with advancing pubertal maturation. Participants were 213 male twins from the Michigan State University Twin Registry. The Minnesota Eating Behavior Survey and Eating Disorder Examination Questionnaire assessed several disordered eating symptoms. The Pubertal Development Scale assessed pubertal status. Afternoon saliva samples were assayed for testosterone using enzyme immunoassays. Consistent with animal data, higher levels of circulating testosterone predicted lower levels of disordered eating symptoms in adolescent boys and effects emerged with advancing puberty. Results were not accounted for by several important covariates, including age, adiposity, or mood/anxiety symptoms. Findings suggest that elevated circulating testosterone may be protective and underlie decreased risk for eating pathology in males during/after puberty, whereas lower levels of testosterone may increase risk and explain why some, albeit relatively few, males develop eating disorders.


Cashew Tree Pollen: An Unknown Source of IgE-Reactive Molecules.
Pollinosis is sub-diagnosed and rarely studied in tropical countries. Cashew tree pollen has been reported as an allergen source although the knowledge of its immunoglobulin E (IgE)-reactive molecules is lacking. Therefore, this work aimed to identify IgE-reactive molecules and provide a proteomic profile of this pollen. From the 830 proteins identified by shotgun analysis, 163 were annotated to gene ontology, and a list of 39 proteins filtered for high confidence was submitted to the Allfam database where nine were assigned to allergenic families. Thus, 12 patients from the northeast of Brazil with persistent allergic rhinitis and aggravation of symptoms during cashew flowering season were selected. Using a 2D-based approach, we identified 20 IgE-reactive proteins, four already recognized as allergens, including a homolog of the birch isoflavone-reductase (Bet v 6). IgE-reactivity against the extract in native form was confirmed for five patients in ELISA, with three being positive for Bet v 6. Herein, we present a group of patients with rhinitis exposed to cashew tree pollen with the first description of IgE-binding proteins and a proteomic profile of the whole pollen. Cashew tree pollen is considered an important trigger of rhinitis symptoms in clinical practice in the northeast of Brazil, and the elucidation of its allergenic molecules can improve the diagnostics and treatment for allergic patients.


Persistence of magic cluster stability in ultra-thin semiconductor nanorods.
The progression from quasi zero-dimensional (Q0D) nanoclusters to quasi one-dimensional (Q1D) nanorods, and, with increasing length, to nanowires, represents the most conceptually fundamental transition from the nanoscale to bulk-like length scales. This dimensionality crossover is particularly interesting, both scientifically and technologically, for inorganic semiconducting (ISC) materials, where striking concomitant changes in optoelectronic properties occur.(1,2) Such effects are most pronounced for ultra-thin(3) ISC nanorods/nanowires, where the confining and defective nature of the atomic structure become key. Although experiments on ISC materials in this size regime have revealed especially stable (or "magic") non-bulk-like Q0D nanoclusters,(4,5) all ISC Q1D nanostructures have been reported as having structures corresponding to bulk crystalline phases. For two important ISC materials (CdS and CdSe) we track the Q0D-to-Q1D transition employing state-of-the-art electronic structure calculations demonstrating an unexpected persistence of magic cluster stability over the bulk-like structure in ultra-thin nanorods up to >10 nm in length. The transition between the magic-cluster-based and wurtzite nanorods is found to be accompanied by a large change in aspect ratio thus potentially providing a route to nano-mechanical transducer applications.


Epithelial Notch signaling regulates interstitial fibrosis development in the kidneys of mice and humans.
Chronic kidney disease is a leading cause of death in the United States. Tubulointerstitial fibrosis (TIF) is considered the final common pathway leading to end-stage renal disease (ESRD). Here, we used pharmacologic, genetic, in vivo, and in vitro experiments to show that activation of the Notch pathway in tubular epithelial cells (TECs) in patients and in mouse models of TIF plays a role in TIF development. Expression of Notch in renal TECs was found to be both necessary and sufficient for TIF development. Genetic deletion of the Notch pathway in TECs reduced renal fibrosis. Consistent with this, TEC-specific expression of active Notch1 caused rapid development of TIF. Pharmacologic inhibition of Notch activation using a γ-secretase inhibitor ameliorated TIF. In summary, our experiments establish that epithelial injury and Notch signaling play key roles in fibrosis development and indicate that Notch blockade may be a therapeutic strategy to reduce fibrosis and ESRD development.


Global patterns of prostate cancer incidence, aggressiveness, and mortality in men of african descent.
Prostate cancer (CaP) is the leading cancer among men of African descent in the USA, Caribbean, and Sub-Saharan Africa (SSA). The estimated number of CaP deaths in SSA during 2008 was more than five times that among African Americans and is expected to double in Africa by 2030. We summarize publicly available CaP data and collected data from the men of African descent and Carcinoma of the Prostate (MADCaP) Consortium and the African Caribbean Cancer Consortium (AC3) to evaluate CaP incidence and mortality in men of African descent worldwide. CaP incidence and mortality are highest in men of African descent in the USA and the Caribbean. Tumor stage and grade were highest in SSA. We report a higher proportion of T1 stage prostate tumors in countries with greater percent gross domestic product spent on health care and physicians per 100,000 persons. We also observed that regions with a higher proportion of advanced tumors reported lower mortality rates. This finding suggests that CaP is underdiagnosed and/or underreported in SSA men. Nonetheless, CaP incidence and mortality represent a significant public health problem in men of African descent around the world.


First Report of Volutella Blight on Pachysandra Caused by Volutella pachysandricola in China.
Pachysandra (Pachysandra terminalis, Buxaceae) and Japanese Pachysandra, also called Japanese Spurge, is a woody ornamental groundcover plant distributed mostly in Zhejiang, Guizhou, Henan, Hubei, Sichuan, Shanxi, and Gansu provinces in China. In April 2010, P. terminalis asymptomatic plants were shipped from Beijing Botanical Garden Institute of Botany Chinese Academy of Science to the garden nursery of Jilin Agricultural University (43°48'N, 125°23'E), Jilin Province. In June 2011, Volutella blight (sometimes called leaf blight and stem canker) of P. terminalis was observed on these plants. Infected leaves showed circular or irregular, tan-to-brown spots often with concentric rings and dark margins. The spots eventually grew and coalesced until the entire leaf died. Cankers appeared as greenish brown and water-soaked diseased areas, subsequently turning brown or black, and shriveled and often girdled the stems and stolons. During wet, humid weather in autumn, reddish orange, cushion-like fruiting structures of the fungus appeared on the stem cankers and undersides of leaf spots. Symptoms of the disease were consistent with previous descriptions (2-4). Five isolates were obtained from necrotic tissue of leaf spots and cankers of stems and stolons and cultured on potato dextrose agar. The colony surface was salmon colored and slimy. Conidia were hyaline, one celled, spindle shaped, and 12.57 to 22.23 × 3.33 to 4.15 μm with rounded ends. Morphological characteristics of the fungus were consistent with the description by Dodge (2), and the fungus was identified as Volutella pachysandricola (telemorph Pseudonectria pachysandricola). The internal transcribed spacer (ITS) regions of the nuclear rDNA were amplified using primers ITS4/ITS5 (1). The ITS sequences were 553 bp long and identical among these five isolates (GenBank Accession No. HE612114). They were 100% identical to Pseudonectria pachysandricola voucher KUS-F25663 (Accession No. JN797821) and 99% identical to P. pachysandricola culture-collection DAOM (Accession No. HQ897807). Pathogenicity was confirmed by spraying leaves of clonally propagated cuttings of P. terminalis with a conidial suspension (1 × 106 conidia/ml) of the isolated V. pachysandricola. Control leaves were sprayed with sterile water. Plants were covered with plastic bags and kept in a greenhouse at 20 to 25°C for 72 h. After 5 to 8 days, typical disease symptoms appeared on leaves, while the control plants remained healthy. V. pachysandricola was reisolated from the leaf spots of inoculated plants. Pachysandra leaf blight and stem canker also called Volutella blight, is the most destructive disease of P. terminalis and previously reported in the northern humid areas of the United States (Illinois, Connecticut, Ohio, Indiana, Iowa, Massachusetts, Missouri, Kentucky, and Wisconsin), northern Europe (Britain, Germany, and Poland), and the Czech Republic. To our knowledge, this is the first report of the disease caused by V. pachysandricola in China. The disease may become a more significant problem in P. terminalis cultivation areas if the disease spreads on P. terminalis in nursery beds. References: (1) D. E. L. Cooke et al. Mycol. Res. 101:667, 1997. (2) B. O. Dodge. Mycologia 36:532, 1944. (3) S. M. Douglas. Online publication. Volutella Blight of Pachysandra. The Connecticut Agricultural Experiment Station, 2008. (4) I. Safrankova. Plant Protect. Sci.43:10, 2007.


Structural insights into the prereaction state of pyruvate decarboxylase from Zymomonas mobilis .
Pyruvate decarboxylase (PDC) uses thiamine diphosphate as an essential cofactor to catalyze the formation of acetaldehyde on the pathway of ethanol synthesis. Here we report the crystallographic image of a prereaction intermediate of a bacterial pyruvate decarboxylase prepared by cocrystallizing the enzyme with pyruvate and a stable analogue of the cofactor's activated ylid form. A second crystal structure of PDC in complex with fluoride shows that the ion organizes a water molecule that occludes the pyruvate binding site, accounting for the inhibitory effect of the halide. Also reported is a structure of the cofactor-free apo form, which when compared to the structure of the holo form indicates how thiamine diphosphate organizes the active site pocket of pyruvate decarboxylase to support catalysis. Guided by the structural and enzymatic data, we propose roles for several key residues in the catalytic mechanism.


Assessment and treatment of physical health problems among people with schizophrenia: national cross-sectional study.
In the UK and other high-income countries, life expectancy in people with schizophrenia is 20% lower than in the general population. To examine the quality of assessment and treatment of physical health problems in people with schizophrenia. Method Retrospective audit of records of people with schizophrenia or schizoaffective disorder aged ⩾18. We collected data on nine key aspects of physical health for 5091 patients and combined these with a cross-sectional patient survey. Body mass index was recorded in 2599 (51.1%) patients during the previous 12 months and 1102 (21.6%) had evidence of assessment of all nine key measures. Among those with high blood sugar, there was recorded evidence of 53.5% receiving an appropriate intervention. Among those with dyslipidaemia, this was 19.9%. Despite this, most patients reported that they were satisfied with the physical healthcare they received. Assessment and treatment of common physical health problems in people with schizophrenia falls well below acceptable standards. Cooperation and communication between primary and secondary care services needs to improve if premature mortality in this group is to be reduced.


["Routine" Laboratory Test Requests in Family Medicine: A Cross-Sectional Study Based on Clinical Practice in Portugal].
In Portugal, patients still believe they should perform a periodic check-up. The present study was designed to study the prescription pattern of "routine" laboratory tests in the Family practice in Portugal. We performed a cross-sectional study in the Portuguese primary healthcare setting. We surveyed physicians on their "routine" laboratory test request pattern and the reasons for requesting or not requesting laboratory tests. The questions were based on the panel of the most prescribed tests in the of Central Lisbon health centre group. Most of the inquired doctors said they requested "routine" laboratory tests (51.4%). There is a significant difference in the request of "routine" laboratory tests performed by trainees or specialists (p = 0.013). The most requested laboratory tests in adults are total cholesterol (92.2%) and blood glucose while the most requested laboratory tests in children are blood glucose, total cholesterol and full blood count. Many doctors (79.4%) that request "routine" laboratory tests do so to perform screening and the doctors that do not request routine" laboratory tests do so mainly (80.8%) because there's lack of scientific evidence. We found differences in the prescription pattern of Family Physicians in Portugal, namely regarding the request of "routine" laboratory tests by doctors from different regions, degrees of specialization and age. We found that there is an association between prescribing "routine" laboratory tests and their request for screening. These physicians aparently want to track different types of pathology, even though patients have no symptoms or risks that could justify it. Most doctors, who do not prescribe "routine" laboratory tests, do not agree with screening for asymptomatic individuals, which is consistent with the evidence. Our results suggest that there is an excessive request of laboratory tests which can lead to overdiagnosis and overtreatment that requires global Social Marketing strategies to change the prevailing culture.


Reducing V3 Antigenicity and Immunogenicity on Soluble, Native-Like HIV-1 Env SOSIP Trimers.
Native-like trimers of the SOSIP design are being developed as immunogens in human immunodeficiency virus type 1 (HIV-1) vaccine development programs. These trimers display the epitopes for multiple broadly neutralizing antibodies (bNAbs) but can also expose binding sites for some types of nonneutralizing antibodies (non-NAbs). Among the latter are epitopes in the gp120 V3 region that are highly immunogenic when SOSIP trimers are evaluated in animal models. It is presently uncertain whether antibodies against V3 can interfere with the induction of NAbs, but there are good arguments in favor of suppressing such "off-target" immune responses. Accordingly, we have assessed how to minimize the exposure of V3 non-NAb epitopes and thereby reduce their immunogenicity by introducing N-glycans within the V3 region of BG505 SOSIP trimers. We found that inserting glycans at positions 306 and 314 (termed M1 and M7) markedly reduced V3 antigenicity while improving the presentation of trimer apex bNAb epitopes. Both added glycans were shown to be predominantly of the Man6GlcNAc2 form. The additional introduction of the E64K ground-state stabilizing substitution markedly reduced or ablated soluble CD4 (sCD4) induction of non-NAb epitopes in V3 and/or associated with the coreceptor binding site. When a V3 glycan- and E64K-modified trimer variant, BG505 SOSIP.664-E64K.M1M7, was tested in rabbits, V3 immunogenicity was eliminated while the autologous NAb response was unchanged.IMPORTANCE Trimeric proteins are being developed for future HIV-1 vaccine trials in humans, with the goal of eliciting broadly active neutralizing antibodies (NAbs) that are active against a wide variety of circulating strains. In animal models, the present generation of native-like trimer immunogens, exemplified by the BG505 SOSIP.664 construct, induces narrow-specificity antibodies against the neutralization-resistant (tier-2), sequence-matched virus and more broadly active antibodies against sequence-divergent atypically neutralization-sensitive (tier-1) viruses. A concern in the trimer immunogen design field has been whether the latter off-target antibodies might interfere with the induction of the more desired responses to tier-2 epitopes. Here, we have inserted two glycans into the dominant site for tier-1 NAbs, the gp120 V3 region, to block the induction of off-target antibodies. We characterized the new trimers, tested them as immunogens in rabbits, and found that the blocking glycans eliminated the induction of tier-1 NAbs to V3-epitopes.


Accuracy Bounds for Array-Based Positioning in Dense Multipath Channels.
The accuracy of radio-based positioning systems will be limited by multipath interference in realistic application scenarios. This paper derives closed-form expressions for the Cramér⁻Rao lower bound (CRLB) on the achievable time-of-arrival (ToA) and angle-of-arrival (AoA) estimation-error variances, considering the presence of multipath radio channels, and extends these results to position estimation. The derivations are based on channel models comprising deterministic, specular multipath components as well as stochastic, diffuse/dense multipath. The derived CRLBs thus allow an evaluation of the influence of channel parameters, the geometric configuration of the environment, and system parameters such as signal bandwidth and array geometry. Our results quantify how the ToA and AoA accuracies decrease when the signal bandwidth is reduced, because more multipath will then interfere with the useful LoS component. Antenna arrays can (partly) compensate this performance loss, exploiting diversity among the multipath interference. For example, the AoA accuracy with a 16-element linear array at 1 MHz bandwidth is similar to a two-element array at 1 GHz , in the magnitude order of one degree. The ToA accuracy, on the other hand, still scales by a factor of 100 from the cm-regime to the m-regime because of the dominating influence of the signal bandwidth. The position error bound shows the relationship between the range and angle information under realistic indoor channel conditions and their different scaling behaviors as a function of the anchor⁻agent placement. Specular multipath components have a maximum detrimental influence near the walls. It is shown for an L-shaped room that a fairly even distribution of the position error bound can be achieved throughout the environment, using two anchors equipped with 2 × 2 -array antennas. The accuracy limit due to multipath increases from the 1⁻10-cm-range at 1 GHz bandwidth to the 0.5⁻1-m-range at 100 MHz .


New spin filters for interferometric fringe patterns and grating patterns.
The basic spin filter for interferometric fringe patterns is improved and developed into several new versions for different applications. These spin filters can filter off random noise efficiently and have almost no blurring effect and phase distortion for the fringe patterns. First, they find the local fringe tangent direction, and then they apply a one-dimensional low-pass filter on this direction. In this way the spin filters can separate easily and clearly high-frequency noise from a real fringe signal with nearly zero frequency. The new spin filters are suitable not only for various fringe patterns but also for wrapped-phase, line-grating, and cross-grating patterns, which are impossible by common filters.


Cosmic rays: a review for astrobiologists.
Cosmic rays represent one of the most fascinating research themes in modern astronomy and physics. Significant progress is being made toward an understanding of the astrophysics of the sources of cosmic rays and the physics of interactions in the ultrahigh-energy range. This is possible because several new experiments in these areas have been initiated. Cosmic rays may hold answers to a great number of fundamental questions, but they also shape our natural habitat and influence the radiation environment of our planet Earth. The importance of the study of cosmic rays has been acknowledged in many fields, including space weather science and astrobiology. Here, we concentrate on the astrobiological aspects of cosmic rays with regard to the enormous amount of new data available, some of which may, in fact, improve our knowledge about the radiation of cosmic origin on Earth. We focus on fluxes arriving at Earth and doses received, and will guide the reader through the wealth of scientific literature on cosmic rays. We have prepared a concise and self-contained source of data and recipes useful for performing interdisciplinary research in cosmic rays and their effects on life on Earth.


Is Acropora palmata recovering? A case study in Los Roques National Park, Venezuela.
Eight years ago (2007), the distribution and status of Acropora palmata was quantified throughout Los Roques archipelago in Venezuela. The aim was to produce a baseline study for this species which combined population genetics with demographic data. The results highlighted that A. palmata had the potential to recover in at least 6 out of 10 sites surveyed. Recovery potential was assumed to be high at sites with a relatively high abundance of the coral, low disease prevalence, high genetic diversity, and high rates of sexual reproduction. However, as noted, Zubillaga et al. (2008) realized recovery was still strongly dependent on local and regional stressors. In 2014 (this study), the status of A. palmata was re-evaluated at Los Roques. We increased the number of sites from 10 in the original baseline study to 106. This allowed us to assess the population status throughout the entirety of the MPA. Furthermore, we also identified local threats that may have hindered population recovery. Here, we show that A. palmata now has a relatively restricted distribution throughout the park, only occurring in 15% of the sites surveyed. Large stands of old dead colonies were common throughout the archipelago; a result which demonstrates that this species has lost almost 50% of its original distribution over the past decades. The majority of corals recorded were large adults (∼2 m height), suggesting that these older colonies might be less susceptible or more resilient to local and global threats. However, 45% of these surviving colonies showed evidence of partial mortality and degradation of living tissues. Interestingly, the greatest increase in partial mortality occurred at sites with the lowest levels of protection ([Formula: see text]; df = 4, p < 0.05). This may suggest there is a positive role of small scale marine management in assisting reef recovery. We also recorded a significant reduction ([Formula: see text]; df = 8; p < 0.05) in the density of A. palmata in sites that had previously been categorized as having a high potential for recovery. One explanation for this continued decline may be due to the fact that over the past 10 years, two massive bleaching events have occurred throughout the Caribbean with records showing that Los Roques has experienced unprecedented declines in overall coral cover. We therefore conclude that although local protection could promote recovery, the impacts from global threats such as ocean warming may hamper the recovery of this threatened species.


The subsequence composition of polypeptides.
The quantitative underpinning of the information content of biosequences represents an elusive goal and yet also an obvious prerequisite to the quantitative modeling and study of biological function and evolution. Several past studies have addressed the question of what distinguishes biosequences from random strings, the latter being clearly unpalatable to the living cell. Such studies typically analyze the organization of biosequences in terms of their constituent characters or substrings and have, in particular, consistently exposed a tenacious lack of compressibility on behalf of biosequences. This article attempts, perhaps for the first time, an assessement of the structure and randomness of polypeptides in terms on newly introduced parameters that relate to the vocabulary of their (suitably constrained) subsequences rather than their substrings. It is shown that such parameters grasp structural/functional information, and are related to each other under a specific set of rules that span biochemically diverse polypeptides. Measures on subsequences separate few amino acid strings from their random permutations, but show that the random permutations of most polypeptides amass along specific linear loci.


A Review of CRISPR Tools for Treating Usher Syndrome: Applicability, Safety, Efficiency, and In Vivo Delivery.
This review considers research into the treatment of Usher syndrome, a deaf-blindness syndrome inherited in an autosomal recessive manner. Usher syndrome mutations are markedly heterogeneous, involving many different genes, and research grants are limited due to minimal patient populations. Furthermore, gene augmentation therapies are impossible in all but three Usher syndromes as the cDNA sequence exceeds the 4.7 kb AAV packaging limit. It is, therefore, vital to focus research efforts on alternative tools with the broadest applicability. The CRISPR field took off in recent years following the discovery of the DNA editing activity of Cas9 in 2012. New generations of CRISPR tools have succeeded the original CRISPR/Cas9 model to enable more sophisticated genomic amendments such as epigenetic modification and precise sequence alterations. This review will evaluate the most popular CRISPR tools to date: CRISPR/Cas9, base editing, and prime editing. It will consider these tools in terms of applicability (in relation to the ten most prevalent USH2A mutations), safety, efficiency, and in vivo delivery potential with the intention of guiding future research investment.


Lactobacillus rhamnosus strain JB-1 reverses restraint stress-induced gut dysmotility.
Environmental stress affects the gut with dysmotility being a common consequence. Although a variety of microbes or molecules may prevent the dysmotility, none reverse the dysmotility. We have used a 1 hour restraint stress mouse model to test for treatment effects of the neuroactive microbe, L. rhamnosus JB-1™ . Motility of fluid-filled ex vivo gut segments in a perfusion organ bath was recorded by video and migrating motor complexes measured using spatiotemporal maps of diameter changes. Stress reduced jejunal and increased colonic propagating contractile cluster velocities and frequencies, while increasing contraction amplitudes for both. Luminal application of 10E8 cfu/mL JB-1 restored motor complex variables to unstressed levels within minutes of application. L. salivarius or Na.acetate had no treatment effects, while Na.butyrate partially reversed stress effects on colonic frequency and amplitude. Na.propionate reversed the stress effects for jejunum and colon except on jejunal amplitude. Our findings demonstrate, for the first time, a potential for certain beneficial microbes as treatment of stress-induced intestinal dysmotility and that the mechanism for restoration of function occurs within the intestine via a rapid drug-like action on the enteric nervous system.


Inhibition of HER2/neu (erbB-2) and mitogen-activated protein kinases enhances tamoxifen action against HER2-overexpressing, tamoxifen-resistant breast cancer cells.
HER2/neu (erbB-2) overexpression has been causally associated with tamoxifen resistance in human breast cancer cells. Forced expression of HER2 in MCF-7 breast cancer cells resulted in mitogen-activated protein kinase (MAPK) hyperactivity and tamoxifen resistance. Inhibition of HER2 and MAPKs with AG1478 and U0126, respectively, as well as dominant-negative MEK-1/2 constructs restored the inhibitory effect of tamoxifen on estrogen receptor (ER)-mediated transcription and cell proliferation. Both AG1478 and U0126 also restored the tamoxifen-mediated association of ER with nuclear receptor corepressor (N-CoR) in the antiestrogen-resistant MCF-7 cells. Treatment with a combination of tamoxifen and a HER2 kinase inhibitor reduced tumor MAPK activity and markedly prevented growth of HER2-overexpressing MCF-7 xenografts in athymic mice. Thus, blockade of HER2 and MAPK signaling may enhance tamoxifen action and abrogate antiestrogen resistance in human breast cancer.


A rapid ATR-FTIR spectroscopic method for classification of gelatin gummy candies in relation to the gelatin source.
Gelatin is widely used in gummy candies because of its unique functional properties. Generally, porcine and bovine gelatins are used in the food industry. FTIR-ATR combined with chemometrics analysis such as hierarchical cluster analysis (HCA) (OPUS Version 7.2 software), principal component analysis (PCA) (OPUS Version 7.2 software) and partial least squares-discriminant analysis (PLS-DA) (Matlab R2017b) were used for classification and discrimination of gelatin gummy candies related to their gelatin source. The spectral region between 1734 and 1528 cm-1 was selected for chemometric analysis. The potential of FTIR spectroscopy for determination of bovine and porcine source in gummy candies was examined and validated by a real-time polymerase chain reaction (PCR) method. Twenty commercial samples were tested by developed ATR-FTIR methodology and RT-PCR technique, mutually confirming and supporting results were obtained. Gummy candies were classified and discriminated in relation to the bovine or porcine source of gelatin with 100% success without any sample preparation using FTIR-ATR technique.


Polycythemia vera and essential thrombocythemia: 2017 update on diagnosis, risk-stratification, and management.
Polycythemia Vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms respectively characterized by erythrocytosis and thrombocytosis; other disease features include leukocytosis, splenomegaly, thrombosis, bleeding, microcirculatory symptoms, pruritus, and risk of leukemic or fibrotic transformation. PV is defined by a JAK2 mutation, whose absence, combined with normal or increased serum erythropoietin level, makes the diagnosis unlikely. JAK2, CALR, and MPL mutations are the mutually exclusive "driver" mutations in ET with respective incidences of 55%, 25%, and 3%; approximately 17% are triple-negative. However, the same molecular markers might also be present in prefibrotic myelofibrosis, whose morphological distinction from ET is prognostically relevant. Median survivals are approximately 14 years for PV and 20 years for ET; the corresponding values for younger patients (age <60 years) are 24 and 33 years. Life-expectancy in ET is inferior to the control population. Driver mutational status has not been shown to affect survival in ET whereas the presence of JAK2/MPL mutations has been associated with higher risk of arterial thrombosis and that of MPL with higher risk of fibrotic progression. Risk factors for overall survival in both ET and PV include advanced age, leukocytosis and thrombosis. Leukemic transformation rates at 20 years are estimated at <10% for PV and 5% for ET; fibrotic transformation rates are slightly higher. Most recently, ASXL1, SRSF2, and IDH2 mutations have been associated with inferior overall, leukemia-free or fibrosis-free survival in PV; similarly adverse mutations in ET included SH2B3, SF3B1, U2AF1, TP53, IDH2, and EZH2. Current risk stratification in PV and ET is designed to estimate the likelihood of recurrent thrombosis. Accordingly, PV includes two risk categories: high-risk (age >60 years or thrombosis history) and low-risk (absence of both risk factors). In ET, risk stratification includes four categories: very low risk (age ≤60 years, no thrombosis history, JAK2/MPL un-mutated), low risk (age ≤60 years, no thrombosis history, JAK2/MPL mutated), intermediate risk (age >60 years, no thrombosis history, JAK2/MPL un-mutated), and high risk (thrombosis history or age >60 years with JAK2/MPL mutation). In addition, presence of extreme thrombocytosis (platelets >1000 × 10(9)/L) might be associated with acquired von Willebrand syndrome (AvWS) and, therefore, risk of bleeding. The main goal of therapy in PV and ET is to prevent thrombohemorrhagic complications. All patients with PV require phlebotomy to keep hematocrit below 45% and once-daily aspirin (81 mg). In addition, high-risk patients with PV require cytoreductive therapy. Very low risk ET patients might not require any form of therapy while low-risk patients require at least once-daily aspirin therapy. Cytoreductive therapy is also recommended for high-risk ET patients but it is not mandatory for intermediate-risk patients. First-line drug of choice for cytoreductive therapy, in both ET and PV, is hydroxyurea and second-line drugs of choice are interferon-α and busulfan. We currently do not recommend treatment with ruxolutinib or other JAK2 inhibitors in PV or ET, unless in the presence of severe and protracted pruritus or marked splenomegaly that is not responding to the aforementioned drugs. Screening for AvWS is recommended before administrating aspirin, in the presence of extreme thrombocytosis. Am. J. Hematol. 92:95-108, 2017. © 2016 Wiley Periodicals, Inc.


Perturbation of manganese metabolism disrupts cell division in Streptococcus pneumoniae.
Manganese (Mn) is an essential micronutrient and required cofactor in bacteria. Despite its importance, excess Mn can impair bacterial growth, the mechanism of which remains largely unexplored. Here, we show that proper Mn homeostasis is critical for cellular growth of the major human respiratory pathogen Streptococcus pneumoniae. Perturbations in Mn homeostasis genes, psaBCA, encoding the Mn importer, and mntE, encoding the Mn exporter, lead to Mn sensitivity during aerobiosis. Mn-stressed cells accumulate iron and copper, in addition to Mn. Impaired growth is a direct result of Mn toxicity and does not result from iron-mediated Fenton chemistry, since cells remain sensitive to Mn during anaerobiosis or when hydrogen peroxide biogenesis is significantly reduced. Mn-stressed cells are significantly elongated, whereas Mn-limitation imposed by zinc addition leads to cell shortening. We show that Mn accumulation promotes aberrant dephosphorylation of cell division proteins via hyperactivation of the Mn-dependent protein phosphatase PhpP, a key enzyme involved in the regulation of cell division. We discuss a mechanism by which cellular Mn:Zn ratios dictate PhpP specific activity thereby regulating pneumococcal cell division. We propose that Mn-metalloenzymes are particularly susceptible to hyperactivation or mismetallation, suggesting the need for exquisite cellular control of Mn-dependent metabolic processes.


Identification of a novel regulatory region critical for expression of the RANTES chemokine in activated T lymphocytes.
The RANTES chemokine is a T cell-expressed, proinflammatory cytokine recently implicated as a suppressive agent of HIV replication. We have identified tandem kappaB-like sequences within the promoter for RANTES that are critical for RANTES promoter-reporter gene activity in both the T cell tumor line Hut78 and in PHA-activated PBL. This region binds not only Rel family members (including p50-p65 heterodimers and p50-p50 homodimers) but also non-Rel factors up-regulated in PBL 3 to 5 days following activation. The expression of these "late" expressed nuclear factors correlates with an up-regulation of RANTES message found at this point in T cell activation. These factors are also constitutively expressed in functionally mature CD8+ T cells. We hypothesize that these apparently novel proteins are responsible in part for the temporal regulation of RANTES seen in peripheral blood T cells and represent a component of transcriptional regulatory machinery newly expressed at this "late" stage of peripheral T cell development.


Association of initial CT findings with quality-of-life outcomes for traumatic brain injury in children.
Traumatic brain injury (TBI) is a leading cause of acquired disability in children and adolescents. To demonstrate the association between specific findings on initial noncontrast head CT and long-term outcomes in children who have suffered TBI. This was an IRB-approved prospective study of children ages 2-17 years treated in emergency departments for TBI and who underwent a head CT as part of the initial work-up (n = 347). The change in quality of life at 12 months after injury was measured by the PedsQL scale. Children with TBI who had intracranial injuries identified on the initial head CT had a significantly lower quality-of-life scores compared to children with TBI whose initial head CTs were normal. In multivariate analysis, children whose initial head CT scans demonstrated intraventricular hemorrhage, parenchymal injury, midline shift ≥ 5 mm, hemorrhagic shear injury, abnormal cisterns or subdural hematomas ≥ 3 mm had lower quality of life scores 1 year after injury than children whose initial CTs did not have these same injuries. Associations exist between findings from the initial noncontrast head CT and quality of life score 12 months after injury in children with TBI.


Primate insular/opercular taste cortex: neuronal representations of the viscosity, fat texture, grittiness, temperature, and taste of foods.
It is shown that the primate primary taste cortex represents not only taste but also information about many nontaste properties of oral stimuli. Of 1,122 macaque anterior insular/frontal opercular neurons recorded, 62 (5.5%) responded to oral stimuli. Of the orally responsive neurons, some (53%) represented the viscosity, tested using carboxymethyl-cellulose in the range 1-10,000 cP. Other neurons (8%) responded to fat in the mouth by encoding its texture (as shown similar responses to nonfat oils), and 8% responded to gritty texture. Some neurons (35%) responded to the temperature of the liquid in the mouth. Some neurons responded to capsaicin, and others to fatty acids. Some neurons (56%) had taste responses. Some (50%) of these neurons were unimodal, responding to one of these types of stimulus, and the majority combined responsiveness to these types of stimulus, with 23% responding for example to both taste and temperature. Some neurons respond to taste, texture, and temperature unimodally, but others combine these inputs. None of these orally responsive neurons responded to odor or to the sight of food. These results provide fundamental evidence about the information channels used to represent the taste, texture, and temperature of food in the first cortical area involved in taste in the primate brain. The results are relevant to understanding the physiological and pathophysiological processes related to how the properties of oral stimuli are represented in the brain and thus to the control of food intake and food selection.


Structure and function of the PB1 domain, a protein interaction module conserved in animals, fungi, amoebas, and plants.
Proteins containing the PB1 domain, a protein interaction module conserved in animals, fungi, amoebas, and plants, participate in diverse biological processes. The PB1 domains adopt a ubiquitin-like beta-grasp fold, containing two alpha helices and a mixed five-stranded beta sheet, and are classified into groups harboring an acidic OPCA motif (type I), the invariant lysine residue on the first beta strand (type II), or both (type I/II). The OPCA motif of a type I PB1 domain forms salt bridges with basic residues, especially the conserved lysine, of a type II PB1 domain, thereby mediating a specific PB1-PB1 heterodimerization, whereas additional contacts contribute to high affinity and specificity of the modular interaction. The canonical PB1 dimerization is required for the formation of complexes between p40(phox) and p67(phox) (for activation of the NADPH oxidase crucial for mammalian host defense), between the scaffold Bem1 and the guanine nucleotide exchange factor Cdc24 (for polarity establishment in yeasts), and between the polarity protein Par6 and atypical protein kinase C (for cell polarization in animal cells), as well as for the interaction between the mitogen-activated protein kinase kinase kinases MEKK2 or MEKK3 and the downstream target mitogen-activated protein kinase kinase MEK5 (for early cardiovascular development in mammals). PB1 domains can also mediate interactions with other protein domains. For example, an intramolecular interaction between the PB1 and PX domains of p40(phox) regulates phagosomal targeting of the microbicidal NADPH oxidase; the PB1 domain of MEK5 is likely responsible for binding to the downstream kinase ERK5, which lacks a PB1 domain; and the scaffold protein Nbr1 associates through a PB1-containing region with titin, a sarcomere protein without a PB1 domain. This Review describes various aspects of PB1 domains at the molecular and cellular levels.


Estradiol Exposure Differentially Alters Monolayer versus Microtissue MCF-7 Human Breast Carcinoma Cultures.
The development of three-dimensional (3D) cultures is increasing, as they are able to provide the utility of in vitro models and the strength of testing in physiologically relevant systems. When cultured in a scaffold-free agarose hydrogel system, MCF-7 human breast carcinoma cells organize and develop into microtissues that contain a luminal space, in stark contrast to the flat morphology of MCF-7 two-dimensional (2D) monolayer cultures. Following exposure to 1nM E2, expression of typical estrogen-responsive genes, including progesterone receptor (PGR), PDZ containing domain 1 (PDZK1) and amphiregulin (AREG) is increased in both 2D and 3D cultures. When examining expression of other genes, particularly those involved in cell adhesion, there were large changes in 3D MCF-7 microtissues, with little to no change observed in the MCF-7 monolayer cultures. Together, these results indicate that while the initial estrogen-regulated transcriptional targets respond similarly in 2D and 3D cultures, there are large differences in activation of other pathways related to cell-cell interactions.


Who attains social status? Effects of personality and physical attractiveness in social groups.
One of the most important goals and outcomes of social life is to attain status in the groups to which we belong. Such face-to-face status is defined by the amount of respect, influence, and prominence each member enjoys in the eyes of the others. Three studies investigated personological determinants of status in social groups (fraternity, sorority, and dormitory), relating the Big Five personality traits and physical attractiveness to peer ratings of status. High Extraversion substantially predicted elevated status for both sexes. High Neuroticism, incompatible with male gender norms, predicted lower status in men. None of the other Big Five traits predicted status. These effects were independent of attractiveness, which predicted higher status only in men. Contrary to previous claims, women's status ordering was just as stable as men's but emerged later. Discussion focuses on personological pathways to attaining status and on potential mediators.


Some consequences of having too little.
Poor individuals often engage in behaviors, such as excessive borrowing, that reinforce the conditions of poverty. Some explanations for these behaviors focus on personality traits of the poor. Others emphasize environmental factors such as housing or financial access. We instead consider how certain behaviors stem simply from having less. We suggest that scarcity changes how people allocate attention: It leads them to engage more deeply in some problems while neglecting others. Across several experiments, we show that scarcity leads to attentional shifts that can help to explain behaviors such as overborrowing. We discuss how this mechanism might also explain other puzzles of poverty.


Race/skin color and mental health disorders in Brazil: a systematic review of the literature.
Mental health disorders contribute a significant burden to society. This systematic literature review aims to summarize the current state of the literature on race/skin color and mental health disorders in Brazil. PubMed and Lilacs were searched using descriptors for mental health disorders (depression, anxiety, Common Mental Disorders, psychiatric morbidity, etc.) and race to find studies conducted in Brazil. Studies of non-population groups, that did not analyze race/skin color, or for which the mental disorder was not the object of study were excluded. After evaluation of quality, 14 articles were selected for inclusion. There was an overall higher prevalence of mental health disorders in non-Whites. Of the six multivariate analyses that found statistically significant results, five indicated a greater prevalence or odds of mental health disorder in non-Whites compared to Whites (measure of association between 1.18-1.85). This review identified the trend in the literature regarding the association between race and mental health disorders. However, important difficulties complicate the comparability of the studies, principally in function of the differences in the mental health disorders studied, the method of categorizing race/skin color, and the screening tools used in the studies analyzed.


Endogenous Formaldehyde Is a Hematopoietic Stem Cell Genotoxin and Metabolic Carcinogen.
Endogenous formaldehyde is produced by numerous biochemical pathways fundamental to life, and it can crosslink both DNA and proteins. However, the consequences of its accumulation are unclear. Here we show that endogenous formaldehyde is removed by the enzyme alcohol dehydrogenase 5 (ADH5/GSNOR), and Adh5(-/-) mice therefore accumulate formaldehyde adducts in DNA. The repair of this damage is mediated by FANCD2, a DNA crosslink repair protein. Adh5(-/-)Fancd2(-/-) mice reveal an essential requirement for these protection mechanisms in hematopoietic stem cells (HSCs), leading to their depletion and precipitating bone marrow failure. More widespread formaldehyde-induced DNA damage also causes karyomegaly and dysfunction of hepatocytes and nephrons. Bone marrow transplantation not only rescued hematopoiesis but, surprisingly, also preserved nephron function. Nevertheless, all of these animals eventually developed fatal malignancies. Formaldehyde is therefore an important source of endogenous DNA damage that is counteracted in mammals by a conserved protection mechanism.


On sufficient statistics of least-squares superposition of vector sets.
The problem of superposition of two corresponding vector sets by minimizing their sum-of-squares error under orthogonal transformation is a fundamental task in many areas of science, notably structural molecular biology. This problem can be solved exactly using an algorithm whose time complexity grows linearly with the number of correspondences. This efficient solution has facilitated the widespread use of the superposition task, particularly in studies involving macromolecular structures. This article formally derives a set of sufficient statistics for the least-squares superposition problem. These statistics are additive. This permits a highly efficient (constant time) computation of superpositions (and sufficient statistics) of vector sets that are composed from its constituent vector sets under addition or deletion operation, where the sufficient statistics of the constituent sets are already known (that is, the constituent vector sets have been previously superposed). This results in a drastic improvement in the run time of the methods that commonly superpose vector sets under addition or deletion operations, where previously these operations were carried out ab initio (ignoring the sufficient statistics). We experimentally demonstrate the improvement our work offers in the context of protein structural alignment programs that assemble a reliable structural alignment from well-fitting (substructural) fragment pairs. A C++ library for this task is available online under an open-source license.


Awareness of alcohol marketing one year after initial implementation of Ireland's Public Health (Alcohol) Act and during the COVID-19 pandemic.
The Republic of Ireland is introducing new controls on alcohol marketing, starting in November 2019 with restrictions on some outdoor and cinema advertising, and a ban on public transport advertising. We examined changes in marketing awareness one year after initial implementation and during the COVID-19 pandemic. Repeat online cross-sectional surveys with adults in Ireland conducted October 2019 (n = 1,007) and October 2020 (n = 1,020). Participants self-reported past-month awareness of alcohol marketing and completed the Alcohol Use Disorders Identification Test-Concise (AUDIT-C). Current drinkers were categorised as those reporting heavy episodic drinking at least monthly and higher-risk drinkers (≥5 AUDIT-C). In both waves, most participants recalled some marketing awareness (94.1% vs. 93.8%). For 9/13 activities measured in both waves, there were decreases in the proportion reporting any awareness and frequency of awareness, including for the newly restricted activities. For example, any awareness of public transport advertising decreased between waves (ORAdj = 0.66, 95%CI: 0.53-0.81). In both waves, higher past-month awareness was associated with at least monthly heavy episodic drinking and higher-risk consumption. We recommend a precautionary interpretation. It is plausible that both Ireland's initial controls and COVID-19 restrictions contributed to decreases in awareness, but longer-term evaluation is required to determine relative contribution.


Family and neighbourhood socioeconomic inequalities in childhood trajectories of BMI and overweight: longitudinal study of Australian children.
Socioeconomic inequalities in longitudinal patterning of childhood overweight could cause marked differentials in total burden by adulthood. This study aims to determine timing and strength of the association between socioeconomic status (SES) and children's body mass index (BMI) in the pre- and primary school years, and to examine socioeconomic differences in overweight trajectories across childhood. Participants were 4949 children from the Longitudinal Study of Australian Children. BMI was measured at four biennial waves starting at age 4-5 years in 2004. Developmental trajectories of childhood overweight were identified with latent class analyses. Composite variables of family and neighbourhood SES were used. Socioeconomic differences in mean BMI z-scores already present at age 4-5 more than doubled by age 10-11 years, reflecting decreasing mean BMI among advantaged rather than increasing means among disadvantaged children. Latent class analysis identified children with 'stable normal weight' (68%), and with 'persistent' (15%), 'late-onset' (14%), and 'resolving' overweight (3%). Risks of persistent and late-onset childhood overweight were highest among low SES families (e.g. most disadvantaged quintile: OR(persistent) = 2.51, 95%CI: 1.83-3.43), and only partly explained by birth weight and parental overweight. Relationships with neighbourhood SES were weaker and attenuated fully on adjustment for family SES. No socioeconomic gradient was observed for resolving overweight. Childhood has become the critical period when socioeconomic inequalities in overweight emerge and strengthen. Although targeting disadvantaged children with early overweight must be a top priority, the presence of childhood overweight even among less-disadvantaged families suggests only whole-society approaches will eliminate overweight-associated morbidity.


Regulation of human histone gene expression: transcriptional and posttranscriptional control in the coupling of histone messenger RNA stability with DNA replication.
The extent to which transcriptional and posttranscriptional regulation contributes to the coupling of histone gene expression and DNA replication was examined during the cell cycle in synchronized HeLa S3 cells. Rates of transcription were determined in vitro in isolated nuclei. A 3-5-fold increase in cell cycle dependent histone gene transcription was observed in early S phase, prior to the peak of DNA synthesis. This result is consistent with a previous determination of histone mRNA synthesis in intact cells [Plumb, M., Stein, J., & Stein, G. (1983) Nucleic Acids Res. 11, 2391]. The transcription of these genes did not change appreciably after inhibition of DNA replication by hydroxyurea treatment, although Northern blot analysis indicated that cellular levels of histone mRNA decreased rapidly in the presence of the drug. Total cellular levels of histone mRNA closely parallel the rate of DNA synthesis as a function of cell cycle progression, reaching a maximal 20-fold increase as compared with non S phase levels. This DNA synthesis dependent accumulation of histone mRNA occurs predominantly in the cytoplasm and appears to be mediated primarily by control of histone mRNA stability. Changes in nuclear histone mRNA levels were less pronounced. These combined observations suggest that both transcriptional regulation and posttranscriptional regulation contribute toward control of the cell cycle dependent accumulation of histone mRNA during S phase, while the stability of histone mRNA throughout S phase and the selective turnover of histone mRNAs, either at the natural termination of S phase or following inhibition of DNA synthesis, are posttranscriptionally regulated.(ABSTRACT TRUNCATED AT 250 WORDS)


Case mix and content of trainee consultations: findings from the north of England study of standards and performance in general practice.
Previous studies have examined the differences in the work of trainees and trainers. However, they have not investigated how many of these differences are due to differences in the case mix seen by trainees. A study was undertaken to investigate the effect of case mix on the content of consultations with trainee general practitioners. Details of surgery consultations with 207 trainee general practitioners and 255 principals in 62 training practices in the north of England were prospectively recorded during one week in each of four consecutive years. Trainee general practitioners saw a higher proportion of younger patients and those categorized as suffering from an acute minor condition compared with principals. They saw a lower proportion of patients categorized as suffering from chronic intermediate, chronic major and female conditions. The reported content of trainee and principal consultations differed over all four years in that trainees examined more patients, issued more new prescriptions, issued fewer repeat prescriptions, arranged fewer return appointments and referred fewer patients. However, adjusting for case mix reduced the number of significant differences between trainees and principals to two: trainees issued fewer repeat prescriptions and had more consultations lasting longer than nine minutes. The case mix and content of consultations differ between trainees and principals and some of the differences in content are due to the differences in case mix; trainees generally behave more like principals than has been previously suggested. Thus, case mix is an important factor in understanding the content of trainee consultations.


Antioxidant and eicosanoid enzyme inhibition properties of pomegranate seed oil and fermented juice flavonoids.
The antioxidant and eicosanoid enzyme inhibition properties of pomegranate (Punica granatum) fermented juice and seed oil flavonoids were studied. The pomegranate fermented juice (pfj) and cold pressed seed oil (pcpso) showed strong antioxidant activity close to that of butylated hydroxyanisole (BHA) and green tea (Thea sinensis), and significantly greater than that of red wine (Vitis vitifera). Flavonoids extracted from pcpso showed 31-44% inhibition of sheep cyclooxygenase and 69-81% inhibition of soybean lipoxygenase. Flavonoids extracted from pfj showed 21-30% inhibition of soybean lipoxygenase though no significant inhibition of sheep cyclooxygenase. The pcpso was analyzed for its polyphenol content and fatty acid composition. Total polyphenols in pcpso showed a concentration by weight of approximately 0.015%. Pcpso fatty acid composition showed punicic acid (65.3%) along with palmitic acid (4.8%), stearic acid (2.3%), oleic acid (6.3%), linoleic acid (6.6%) and three unidentified peaks from which two (14.2%) are probably isomers of punicic acid (El-Shaarawy, M.I., Nahpetian, A., 1983). Studies on pomegranate seed oil. Fette Seifen Anstrichmittel 83(3), 123-126).


Enhanced malignant transformation is accompanied by increased survival recovery after ionizing radiation in Chinese hamster embryo fibroblasts.
Transformed Chinese hamster embryo fibroblasts (CHEF), which gradually increase in tumor-forming ability in nude mice, were isolated from normal diploid CHEF/18 cells. Transformed CHEF cells (i.e. T30-4 > 21-2M3 > 21-2 > normal CHEF/18) showed gradual increases in potentially lethal damage (PLD) survival recovery. beta-Lapachone and camptothecin, modulators of topoisomerase I (Topo I) activity, not only prevented survival recovery in normal as well as in tumor cells, but enhanced unscheduled DNA synthesis. These seemingly conflicting results are due to the fact that Topo I activity can be modulated by inhibitors to convert single-stranded DNA lesions into double-stranded breaks. Increases in unscheduled DNA synthesis may result from a continual supply of free ends, on which DNA repair processes may act. Altering Topo I activity with modulators appears to increase X-ray lethality via a DNA lesion modification suicide pathway. Cells down-regulate Topo I immediately after ionizing radiation to prevent Topo I-mediated lesion modification and to enhance survival recovery.


Histiocytic and dendritic cell neoplasms: what have we learnt by studying 67 cases.
Tumors derived from histiocytic and dendritic cells encompass a large and heterogeneous group of neoplastic and reactive conditions, and their diagnosis is challenging both for pathologists and clinicians. Diagnosis is based on morphological and phenotypical findings, but hybrid features are not uncommon. Furthermore, recent studies uncovered the molecular mechanisms driving some of these tumors, improving diagnostic adequacy, and providing the basis for effective therapeutic breakthroughs.Sixty-seven cases were submitted to the accessory cell and histiocytic neoplasms session at the European Association of Haematopathology/Society for Hematopathology workshop 2016 held in Basel, Switzerland. The cases included histiocytic sarcomas (HS), Langerhans cell tumors (LCT), Erdheim-Chester disease, interdigitating dendritic cell sarcomas (IDCS), indeterminate dendritic cell tumors (IND-DCT), follicular dendritic cell sarcomas, and blastic plasmacytoid dendritic cell neoplasms. Rosai-Dorfman disease and, more rare, conditions such as ALK-positive histiocytosis were also submitted. These cases illustrated classical and unexpected features at morphological, phenotypical, and molecular levels, providing a valuable compendium for pathologists confronting with these tumors.The paper summarizes the most notable features of every single group of diseases, with comments about the most challenging issues, in the attempt to provide practical indications for their recognition.


Altered expression and function of small-conductance (SK) Ca(2+)-activated K+ channels in pilocarpine-treated epileptic rats.
Small conductance calcium (Ca(2+)) activated SK channels are critical regulators of neuronal excitability in hippocampus. Accordingly, these channels are thought to play a key role in controlling neuronal activity in acute models of epilepsy. In this study, we investigate the expression and function of SK channels in the pilocarpine model of mesial temporal lobe epilepsy. For this purpose, protein expression was assessed using western blotting assays and gene expression was analyzed using TaqMan-based probes and the quantitative real-time polymerase chain reaction (qPCR) comparative method delta-delta cycle threshold ( big up tri, open big up tri, openCT) in samples extracted from control and epileptic rats. In addition, the effect of SK channel antagonist UCL1684 and agonist NS309 on CA1 evoked population spikes was studied in hippocampal slices. Western blotting analysis showed a significant reduction in the expression of SK1 and SK2 channels at 10days following status epilepticus (SE), but levels recovered at 1month and at more than 2months after SE. In contrast, a significant down-regulation of SK3 channels was detected after 10days of SE. Analysis of gene expression by qPCR revealed a significant reduction of transcripts for SK2 (Kcnn1) and SK3 (Kcnn3) channels as early as 10days following pilocarpine-induced SE and during the chronic phase of the pilocarpine model. Moreover, bath application of UCL1684 (100nM for 15min) induced a significant increase of the population spike amplitude and number of spikes in the hippocampal CA1 area of slices obtained control and chronic epileptic rats. This effect was obliterated by co-administration of UCL1684 with SK channel agonist NS309 (1microM). Application of NS309 failed to modify population spikes in the CA1 area of slices taken from control and epileptic rats. These data indicate an abnormal expression of SK channels and a possible dysfunction of these channels in experimental MTLE.


Tumour necrosis factor-alpha and endotoxin induce less prostaglandin E2 production from hypothalami of rats fed coconut oil than from hypothalami of rats fed maize oil.
1. The primary aim of the study was to determine whether the stimulatory effect of tumour necrosis factor-alpha and endotoxin on hypothalamic prostaglandin E2 production was influenced by dietary fats containing different amounts of linoleic acid. Rats received diets containing 20% (w/w) maize oil or 19% (w/w) coconut oil plus 1% (w/w) maize oil for 8 weeks. 2. A subsidiary part of the study examined the effect of tumour necrosis factor-alpha on the ability of the calcium ionophore A23187 to stimulate prostaglandin E2 and leukotriene C4 production by hypothalami from chow-fed rats. 3. While tumour necrosis factor-alpha enhanced prostaglandin E2 production in response to A23187, neither agent had an effect on leukotriene C4 production. 4. Hypothalami from rats fed maize oil exhibited increased prostaglandin E2 production in response to both pyrogens. This did not occur with hypothalami from rats fed coconut oil. 5. Coconut oil might exert its modulatory effect by bringing about a reduction in membrane phospholipid arachidonic acid content.


Microbial source tracking: a forensic technique for microbial source identification?
As the requirements of the Water Framework Directive (WFD) and the US Clean Water Act (USCWA) for the maintenance of microbiological water quality in 'protected areas' highlight, there is a growing recognition that integrated management of point and diffuse sources of microbial pollution is essential. New information on catchment microbial dynamics and, in particular, the sources of faecal indicator bacteria found in bathing and shellfish harvesting waters is a pre-requisite for the design of any 'programme of measures' at the drainage basin scale to secure and maintain compliance with existing and new health-based microbiological standards. This paper reports on a catchment-scale microbial source tracking (MST) study in the Leven Estuary drainage basin, northwest England, an area for which quantitative faecal indicator source apportionment empirical data and land use information were also collected. Since previous MST studies have been based on laboratory trials using 'manufactured' samples or analyses of spot environmental samples without the contextual microbial flux data (under high and low flow conditions) and source information, such background data are needed to evaluate the utility of MST in USCWA total maximum daily load (TMDL) assessments or WFD 'Programmes of Measures'. Thus, the operational utility of MST remains in some doubt. The results of this investigation, using genotyping of Bacteroidetes using polymerase chain reaction (PCR) and male-specific ribonucleic acid coliphage (F + RNA coliphage) using hybridisation, suggest some discrimination is possible between livestock- and human-derived faecal indicator concentrations but, in inter-grade areas, the degree to which the tracer picture reflected the land use pattern and probable faecal indicator loading were less distinct. Interestingly, the MST data was more reliable on high flow samples when much of the faecal indicator flux from catchment systems occurs. Whilst a useful supplementary tool, the MST information did not provide quantitative source apportionment for the study catchment. Thus, it could not replace detailed empirical measurement of microbial flux at key catchment outlets to underpin faecal indicator source apportionment. Therefore, the MST techniques reported herein currently may not meet the standards required to be a useful forensic tool, although continued development of the methods and further catchment scale studies could increase confidence in such methods for future application.


Cryptochrome and Period Proteins Are Regulated by the CLOCK/BMAL1 Gene: Crosstalk between the PPARs/RXRalpha-Regulated and CLOCK/BMAL1-Regulated Systems.
Feeding and the circadian system regulate lipid absorption and metabolism, and the expression of enzymes involved in lipid metabolism is believed to be directly controlled by the clock system. To investigate the interaction between the lipid metabolism system and the circadian system, we analyzed the effect of a CLOCK/BMAL1 heterodimer on the transcriptional regulation of PPAR-controlled genes through PPAR response elements (PPREs). Transcription of acyl-CoA oxidase, cellular retinol binding protein II (CRBPII), and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase was altered by CLOCK/BMAL1, and transcriptional activity via PPRE by PPARs/RXRalpha was enhanced by CLOCK/BMAL1 and/or by PPARs ligand/activators. We also found that CLOCK/BMAL1-mediated transcription of period (PER) and cryptochrome (CRY) was modulated by PPARalpha/RXRalpha. These results suggest that there may be crosstalk between the PPARs/RXRalpha-regulated system and the CLOCK/BMAL1-regulated system.


Validation of Turkish version of brief negative symptom scale.
Negative symptoms in schizophrenia have been assessed by many instruments. However, a current consensus on these symptoms has been built and new tools, such as the Brief Negative Symptom Scale (BNSS), are generated. This study aimed to evaluate reliability and validity of the Turkish version of BNSS. The scale was translated to Turkish and backtranslated to English. After the approval of the translation, 75 schizophrenia patients were interviewed with BNSS, Positive and Negative Syndrome Scale (PANSS), Calgary Depression Scale for Schizophrenia (CDSS) and Extrapyramidal Symptom Rating Scale (ESRS). Reliability and validity analyses were then calculated. In the reliability analysis, the Cronbach's alpha coefficient was 0.96 and item-total score correlation coefficients were between 0.655-0.884. The intraclass correlation coefficient was 0.665. The inter-rater reliability was 0.982 (p < 0.0001). In the validity analysis, the total score of BNSS-TR was correlated with PANSS Total Score, Positive Symptoms Subscale, Negative Symptoms Subscale, and General Psychopathology Subscale. CDSS and ESRS were not correlated with BNSS-TR. The factor structure of the scale was consisting the same items as in the original version. Our study confirms that the Turkish version of BNSS is an applicable tool for the evaluation of negative symptoms in schizophrenia.


Maternal multiple micronutrient supplements and child cognition: a randomized trial in Indonesia.
We investigated the relative benefit of maternal multiple micronutrient (MMN) supplementation during pregnancy and until 3 months postpartum compared with iron/folic acid supplementation on child development at preschool age (42 months). We assessed 487 children of mothers who participated in the Supplementation with Multiple Micronutrients Intervention Trial, a cluster-randomized trial in Indonesia, on tests adapted and validated in the local context measuring motor, language, visual attention/spatial, executive, and socioemotional abilities. Analysis was according to intention to treat. In children of undernourished mothers (mid-upper arm circumference <23.5 cm), a significant benefit of MMNs was observed on motor ability (B = 0.39 [95% confidence interval (CI): 0.08-0.70]; P = .015) and visual attention/spatial ability (B = 0.37 [95% CI: 0.11-0.62]; P = .004). In children of anemic mothers (hemoglobin concentration <110 g/L), a significant benefit of MMNs on visual attention/spatial ability (B = 0.24 [95% CI: 0.02-0.46]; P = .030) was also observed. No robust effects of maternal MMN supplementation were found in any developmental domain over all children. When pregnant women are undernourished or anemic, provision of MMN supplements can improve the motor and cognitive abilities of their children up to 3.5 years later, particularly for both motor function and visual attention/spatial ability. Maternal MMN but not iron/folic acid supplementation protected children from the detrimental effects of maternal undernutrition on child motor and cognitive development.


Pilot Feasibility Study of a Digital Storytelling Intervention for Immigrant and Refugee Adults With Diabetes.
Purpose The purpose of this pilot feasibility project was to examine the potential effectiveness of a digital storytelling intervention designed through a community-based participatory research (CBPR) approach for immigrants and refugees with type 2 diabetes mellitus (T2DM). Methods The intervention was a 12-minute culturally and linguistically tailored video consisting of an introduction, 4 stories, and a concluding educational message. A structured interview was used to assess the intervention for acceptability, interest level, and usefulness among 25 participants with T2DM (15 Latino, 10 Somali) across 5 primary care clinical sites. After watching the video, participants rated their confidence and motivation about managing T2DM as a result of the intervention. Baseline A1C and follow-up values (up to 6 months) were abstracted from medical records. Results All participants reported that the intervention got their attention, was interesting, and was useful; 96% reported that they were more confident about managing their T2DM than before they watched the video, and 92% reported that the video motivated them to change a specific behavior related to T2DM self-management. The mean baseline A1C level for the intervention participants was 9.3% (78 mmol/mol). The change from baseline to first follow-up A1C level was -0.8% (-10 mmol/mol) ( P < .05). Conclusions Implementation of a digital storytelling intervention for T2DM among immigrant populations in primary care settings is feasible and resulted in self-rated improvement in psychosocial constructs that are associated with healthy T2DM self-management behaviors, and there was some evidence of improvement in glycemic control. A large-scale efficacy trial of the intervention is warranted.


Motivational interviewing in long-term sickness absence: study protocol of a randomized controlled trial followed by qualitative and economic studies.
Motivational interviewing (MI), mainly used and shown effective in health care (substance abuse, smoking cessation, increasing exercise and other life style changes), is a collaborative conversation (style) about change that could be useful for individuals having problems related to return to work (RTW). The aim of this paper is to describe the design of a randomized controlled trial evaluating the effect of MI on RTW among sick listed persons compared to usual care, in a social security setting. The study is a randomized controlled trial with parallel group design. Individuals between 18 and 60 years who have been sick listed for more than 7 weeks, with a current sick leave status of 50-100%, are identified in the Norwegian National Social Security System and invited to participate in the study. Exclusion criteria are no employment and pregnancy. Included participants are randomly assigned to the MI intervention or one of two control groups. The MI intervention consists of two MI sessions offered by caseworkers at the Norwegian Labor and Welfare Service (NAV), while the comparative arms consist of a usual care group and a group that receives two extra sessions without MI content (to control for attentional bias). The primary outcome measure is the total number of sickness absence days during 12 months after inclusion, obtained from national registers. Secondary outcomes include time until full sustainable return to work, health-related quality of life and mental health status. In addition, a health economic evaluation, a feasibility/process evaluation and qualitative studies will be performed as part of the study. A previous study has suggested an effect of MI on RTW for sick listed workers with musculoskeletal complaints. The present study will evaluate the effect of MI for all sick listed workers, regardless of diagnosis. The knowledge from this study will potentially be important for policy makers, clinicians and other professionals` practical work. ClinicalTrials.gov: NCT03212118 (registered July 11, 2017).


Colonoscopic miss rates for right-sided colon cancer: a population-based analysis.
Colonoscopy contains an inherent miss rate for colorectal cancer. Although miss rates from academic centers or units known for their endoscopic expertise have been previously reported, the colorectal cancer miss rate of colonoscopy performed in usual clinical practice is unknown. We conducted a population-based study to estimate the proportion of right-sided colon cancers missed during colonoscopy in Ontario. All persons > or =20 years old with a new diagnosis of right-sided colon cancer admitted to the hospital for surgical resection in Ontario from April 1, 1997, to March 31, 2001, were identified. Patients who had a colonoscopy within 3 years of their diagnosis were divided into 2 groups: detected cancers (those who had a colonoscopy up to 6 months before the diagnosis) and missed cancers (those who had a colonoscopy between 6 and 36 months before the diagnosis). Data were obtained from the Canadian Institute for Health Information Discharge Abstract Database, the Ontario Health Insurance Plan database, and the Registered Persons Database. Between April 1, 1997, and March 31, 2001, we identified 4920 persons with a new diagnosis of right-sided colon cancer, of whom 2654 (53.9%) had had at least 1 colonoscopy within 3 years of their admission for surgical resection. Most (96.0%) had had their most recent colonoscopy up to 6 months before admission (detected cancers). However, 105 patients (4.0%) had their most recent colonoscopy between 6 and 36 months before admission to the hospital (missed cancers). Among persons undergoing resection for right-sided colon cancer, the miss rate of colonoscopy for detecting cancer in usual clinical practice was 4.0%.


Dialkylglycine decarboxylase structure: bifunctional active site and alkali metal sites.
The structure of the bifunctional, pyridoxal phosphate-dependent enzyme dialkylglycine decarboxylase was determined to 2.1-angstrom resolution. Model building suggests that a single cleavage site catalyzes both decarboxylation and transamination by maximizing stereoelectronic advantages and providing electrostatic and general base catalysis. The enzyme contains two binding sites for alkali metal ions. One is located near the active site and accounts for the dependence of activity on potassium ions. The other is located at the carboxyl terminus of an alpha helix. These sites help show how proteins can specifically bind alkali metals and how these ions can exert functional effects.


Verapamil and quinidine effects on PAH transport by isolated perfused renal tubules.
The effects of verapamil and quinidine on p-aminohippurate (PAH) transport by isolated perfused snake (Thamnophis spp.) distal-proximal renal tubules were studied. Addition of 5 X 10(-5) M verapamil or 1 X 10(-4) M quinidine to the bath reversibly depressed net PAH secretion (JnetPAH), apparent permeabilities of luminal (PL) and peritubular membranes (Pp) to PAH, and initial rate of PAH transport into cells at the peritubular membrane without affecting net fluid absorption (Jv), but simultaneously produced a threefold increase in cellular PAH concentration ( [PAH]cell). Addition of 5 X 10(-5) M verapamil to the perfusate reversibly depressed JnetPAH and PL without affecting [PAH]cell or Jv. Tetraethylammonium (1 X 10(-3) M) did not alter the effects of verapamil on PAH transport. The data indicate that verapamil and quinidine in the bath inhibit JnetPAH by inhibiting uptake into cells across peritubular membrane and efflux from cells across luminal and peritubular membranes and possibly by producing intracellular binding, verapamil in the perfusate inhibits JnetPAH by inhibiting efflux from cells across the luminal membrane and probably uptake into cells across the peritubular membrane, and the verapamil effects on JnetPAH do not depend on its entry into cells. The effects of verapamil may result primarily from inhibition of calcium entry into cells, but both verapamil and quinidine may have effects on PAH transport independent of effects on calcium.


Inhibitory effects of sulfobacin B on DNA polymerase and inflammation.
The sulfonolipid, sulfobacin B, is isolated from Chryseobacterium sp. and functions both as a von Willebrand factor receptor antagonist and a DNA polymerase (pol) α inhibitor. Previously, we chemically synthesized sulfobacin B by starting from L-cysteine. In this study, we investigated the inhibitory effects of chemically synthesized sulfobacin B on the activity of pols and other DNA metabolic enzymes. Sulfobacin B selectively inhibited the activity of all animal pol species: Among the pols tested, the inhibitory effect of the compound on pol λ activity was the strongest with IC50 values of 1.6 µM. However, sulfobacin B did not influence the activity of plant or prokaryotic pols, or that of the other DNA metabolic enzymes such as primase of pol α, RNA polymerase, polynucleotide kinase or deoxyribonuclease I. As we previously found a positive relationship between pol λ inhibition and anti-inflammation, we examined whether sulfobacin B could inhibit inflammatory responses. The compound caused a marked reduction in 12-O-tetradecanoylphorbol-13-acetate-induced acute inflammation in the mouse ear. In a cell culture system using mouse macrophages, sulfobacin B strongly inhibited the production of tumor necrosis factor (TNF)-α and the action of nuclear factor-κB induced by lipopolysaccharide (LPS). In an in vivo mouse model of LPS-induced acute inflammation, the intraperitoneal injection of sulfobacin B to mice led to the suppression of serum TNF-α production. These results indicate that sulfobacin B is a potential chemotherapeutic agent for inflammation.


Data management for prospective research studies using SAS software.
Maintaining data quality and integrity is important for research studies involving prospective data collection. Data must be entered, erroneous or missing data must be identified and corrected if possible, and an audit trail created. Using as an example a large prospective study, the Missouri Lower Respiratory Infection (LRI) Project, we present an approach to data management predominantly using SAS software. The Missouri LRI Project was a prospective cohort study of nursing home residents who developed an LRI. Subjects were enrolled, data collected, and follow-ups occurred for over three years. Data were collected on twenty different forms. Forms were inspected visually and sent off-site for data entry. SAS software was used to read the entered data files, check for potential errors, apply corrections to data sets, and combine batches into analytic data sets. The data management procedures are described. Study data collection resulted in over 20,000 completed forms. Data management was successful, resulting in clean, internally consistent data sets for analysis. The amount of time required for data management was substantially underestimated. Data management for prospective studies should be planned well in advance of data collection. An ongoing process with data entered and checked as they become available allows timely recovery of errors and missing data.


The Validity of YouTube Videos on Pediatric BLS and CPR.
There are few data regarding the validity of cardiopulmonary resuscitation (CPR) and basic life support (BLS) videos on YouTube in the medical literature, and those that do are only analyzing adult CPR videos. The present study aimed to determine the reliability and accuracy of pediatric CPR and BLS videos as to whether they are consistent with the 2010 CPR guidelines. YouTube was scanned in January 2015 using the key words "Pediatric CPR Pediatric BLS" without any filters. The raw data collected in the study included sources that uploaded the videos, the record time, the number of viewers in the study period, and inclusion of human or mannequins. Furthermore, the contents of the videos were evaluated as to whether they are consistent with the 2010 resuscitation guidelines. All videos were seen by two independent researchers (emergency physicians) and scored between 0 and 8. In total, 1,200 videos were evaluated regarding the exclusion criteria, which yielded 232 eligible ones. Most of the videos were found to be uploaded by individuals with unspecified credentials (34.1%). Of the videos, 15.5% have content inconsistent with the 2010 guidelines. The median score of all the videos are not high enough (5 [interquartile range (IQR), 4-7]), and only one-third of the videos have optimal quality with scores of 7 or 8. The downloaded number of videos compatible with guidelines was significantly higher relative to the videos not compatible with the guidelines (15,389 [IQR, 881-31515] versus 477 [IQR, 108-3,797); p = 0.0001). The videos downloaded more than 10,000 times had a higher score than the others (median scores of 7 and 5, respectively; p = 0.0001). Moderate numbers of YouTube videos purporting to be about pediatric life support have optimal quality, and few of them are perfect. Furthermore, YouTube videos uploaded by news programs with an insufficient quality have the highest download rates.


Epigenome-wide change and variation in DNA methylation in childhood: trajectories from birth to late adolescence.
DNA methylation (DNAm) is known to play a pivotal role in childhood health and development, but a comprehensive characterization of genome-wide DNAm trajectories across this age period is currently lacking. We have therefore performed a series of epigenome-wide association studies in 5019 blood samples collected at multiple time-points from birth to late adolescence from 2348 participants of two large independent cohorts. DNAm profiles of autosomal CpG sites (CpGs) were generated using the Illumina Infinium HumanMethylation450 BeadChip. Change over time was widespread, observed at over one-half (53%) of CpGs. In most cases, DNAm was decreasing (36% of CpGs). Inter-individual variation in linear trajectories was similarly widespread (27% of CpGs). Evidence for non-linear change and inter-individual variation in non-linear trajectories was somewhat less common (11 and 8% of CpGs, respectively). Very little inter-individual variation in change was explained by sex differences (0.4% of CpGs) even though sex-specific DNAm was observed at 5% of CpGs. DNAm trajectories were distributed non-randomly across the genome. For example, CpGs with decreasing DNAm were enriched in gene bodies and enhancers and were annotated to genes enriched in immune-developmental functions. In contrast, CpGs with increasing DNAm were enriched in promoter regions and annotated to genes enriched in neurodevelopmental functions. These findings depict a methylome undergoing widespread and often non-linear change throughout childhood. They support a developmental role for DNA methylation that extends beyond birth into late adolescence and has implications for understanding life-long health and disease. DNAm trajectories can be visualized at http://epidelta.mrcieu.ac.uk.


Altered Inhibitory Mechanisms in Parkinson's Disease: Evidence From Lexical Decision and Simple Reaction Time Tasks.
Although the motor signs of Parkinson's disease (PD) are well defined, nonmotor symptoms, including higher-level language deficits, have also been shown to be frequent in patients with PD. In the present study, we used a lexical decision task (LDT) to find out whether access to the mental lexicon is impaired in patients with PD, and whether task performance is affected by bradykinesia. Participants were 34 nondemented patients with PD, either without (off) medication (n = 16) or under optimum (on) medication (n = 18). A total of 19 age-matched control volunteers were also recruited. We recorded reaction times (RTs) to the LDT and a simple RT (control) task. In each task, stimuli were either visual or auditory. Statistical analyses consisted of repeated-measures analyses of variance and Tukey's HSD post hoc tests. In the LDT, participants with PD both off and on medication exhibited intact access to the mental lexicon in both modalities. In the visual modality, patients off medication were just as fast as controls when identifying real words, but slower when identifying pseudowords. In the visual modality of the control task, RTs for pseudowords were significantly longer for PD patients off medication than for controls, revealing an unexpected but significant lexicality effect in patients that was not observed in the auditory modality. Performances of patients on medication did not differ from those of age-matched controls. Motor execution was not slowed in patients with PD either off or on medication, in comparison with controls. Regarding lexical access, patients off medication seemed to (1) have difficulty inhibiting a cognitive-linguistic process (i.e., reading) when it was not required (simple reaction time task), and (2) exhibit a specific pseudoword processing deficit in the LDT, which may have been related to impaired lateral word inhibition within the mental lexicon. These deficits seemed to be compensated by medication.


Contrasting roles for IL-10 in protective immunity to different life cycle stages of intestinal nematode parasites.
Expulsion of the gastro-intestinal nematode Trichinella spiralis is associated with a pronounced mastocytosis mediated by a T helper (Th) 2 type response involving interleukin (IL)-4 and IL-13. Here we demonstrate that IL-10 is a key regulator of protective immune responses against T. spiralis in vivo. IL-10 knockout mice or normal mice treated with a neutralizing anti-IL-10 receptor antibody are highly susceptible to a primary T. spiralis infection and show significantly delayed adult worm expulsion. Depletion of IL-10 resulted in elevated Th1 and Th2 cytokine responses but significantly reduced numbers of mucosal mast cells in the jejunum. Interestingly, the increase in IFN-gamma detected in the absence of IL-10 resulted in increased immunity to larval stages. Hence, IL-10 has a negative effect on immunity to the tissue dwelling larval stages of T. spiralis but plays a significant biological role as an in vivo regulator of intestinal mast cell responses and is crucially involved in protection against adult stages of intestinal parasites in vivo.


Does good clinical practice at the primary care improve the outcome care for diabetic patients? Gender differences.
The Middle East region is predicted to have one of the highest prevalence of diabetes mellitus (DM) in the world. This is the first study in the region to assess treatment outcome of DM according to gender. To assess the quality and effectiveness of diabetes care provided to patients attending primary care settings according to gender in the State of Qatar. It is an observational cohort study. The survey was carried out in primary health care (PHC) centers in the State of Qatar. The study was conducted from January 2010 to August 2010 among diabetic patients attending (PHC) centers. Of the 2334 registered with diagnosed diabetes, 1705 agreed and gave their consent to take part in this study, thus giving a response rate of 73.1%. Face to face interviews were conducted using a structured questionnaire including socio-demographic, clinical and satisfaction score of the patients. Majority of subjects were diagnosed with type 2 DM (84.9%). A significantly larger proportion of females with DM were divorced or widowed (9.1%) in comparison to males with DM (3.4%; p<0.001). A significantly larger proportion of females were overweight (46.5%; p=0.009) and obese (29.5%; p=0.003) in comparison to males. Males reported significantly greater improvements in mean values of blood glucose (mmol/l) (-2.11 vs. -0.66; p=0.007), HbA1c (%) (-1.44 vs. -0.25; p=0.006), cholesterol (mmol/l) (-0.16 vs. 0.12; p=0.053) and systolic blood pressure (mmHg) (-9.04 vs. -6.62; p<0.001) in comparison to females. While there was a remarkable increase in male patients with normal range of fasting blood glucose (FBG; 51.6%) as compared to the FBG measurement 1 year before (28.5%: p<0.001) there was only a slight increase in females normal range FBG during this period from 28.0% to 30.4% (p=0.357). The present study revealed that the current form of PHC centers afforded to diabetic patients provided significantly improved outcomes for males, but only minor improved outcomes for females. This study reinforces calls for a gender-specific approach to diabetes care.


The burden of cancer attributable to modifiable risk factors: the Australian cancer-PAF cohort consortium.
To estimate the Australian cancer burden attributable to lifestyle-related risk factors and their combinations using a novel population attributable fraction (PAF) method that accounts for competing risk of death, risk factor interdependence and statistical uncertainty. 365 173 adults from seven Australian cohort studies. We linked pooled harmonised individual participant cohort data with population-based cancer and death registries to estimate exposure-cancer and exposure-death associations. Current Australian exposure prevalence was estimated from representative external sources. To illustrate the utility of the new PAF method, we calculated fractions of cancers causally related to body fatness or both tobacco and alcohol consumption avoidable in the next 10 years by risk factor modifications, comparing them with fractions produced by traditional PAF methods. Over 10 years of follow-up, we observed 27 483 incident cancers and 22 078 deaths. Of cancers related to body fatness (n=9258), 13% (95% CI 11% to 16%) could be avoided if those currently overweight or obese had body mass index of 18.5-24.9 kg/m2. Of cancers causally related to both tobacco and alcohol (n=4283), current or former smoking explains 13% (11% to 16%) and consuming more than two alcoholic drinks per day explains 6% (5% to 8%). The two factors combined explain 16% (13% to 19%): 26% (21% to 30%) in men and 8% (4% to 11%) in women. Corresponding estimates using the traditional PAF method were 20%, 31% and 10%. Our PAF estimates translate to 74 000 avoidable body fatness-related cancers and 40 000 avoidable tobacco- and alcohol-related cancers in Australia over the next 10 years (2017-2026). Traditional PAF methods not accounting for competing risk of death and interdependence of risk factors may overestimate PAFs and avoidable cancers. We will rank the most important causal factors and their combinations for a spectrum of cancers and inform cancer control activities.