bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of model resolution on geometric simulations of antibody aggregation
Authors: Manavi Kasra , Jacobson Bruna , Hoard Brittany , Tapia Lydia
Published: May 2016

It is estimated that allergies afflict up to 40% of the world's population. A primary mediator for allergies is the aggregation of antigens and IgE antibodies bound to cell-surface receptors, FcεRI. Antibody/antigen aggregate formation causes stimulation of mast cells and basophils, initiating cellular degranulation and releasing immune mediators which produce an allergic or anaphylactic response. Understanding the shape and structure of these aggregates can provide critical insights into the allergic response. We have previously developed methods to geometrically model, simulate and analyze antibody aggregation inspired by rigid body robotic motion simulations. Our technique handles the large size and number of molecules involved in aggregation, providing an advantage over traditional simulations such as molecular dynamics (MD) and coarse-grained energetic models. In this paper, we study the impact of model resolution on simulations of geometric structures using both our previously developed Monte Carlo simulation and a novel application of rule-based modeling. These methods complement each other, the former providing explicit geometric detail and the latter providing a generic representation where multiple resolutions can be captured. Our exploration is focused on two antigens, a man-made antigen with three binding sites, DF3, and a common shrimp allergen (antigen), Pen a 1. We find that impact of resolution is minimal for DF3, a small globular antigen, but has a larger impact on Pen a 1, a rod-shaped molecule. The volume reduction caused by the loss in resolution allows more binding site accessibility, which can be quantified using a rule-based model with implicit geometric input. Clustering analysis of our simulation shows good correlation when compared with available experimental results. Moreover, collisions in all-atom reconstructions are negligible, at around 0.2% at 90% reduction.
Wavelet neural network-based H∞trajectory tracking for robot manipulators using fast terminal sliding mode control
Authors: Panwar Vikas
Published: May 2016

This paper focuses on fast terminal sliding mode control (FTSMC) of robot manipulators using wavelet neural networks (WNN) with guaranteed H∞tracking performance. The FTSMC for trajectory tracking is employed to drive the tracking error of the system to converge to an equilibrium point in finite time. The tracking error arrives at the sliding surface in finite time and then converges to zero in finite time along the sliding surface. To deal with the case of uncertain and unknown robot dynamics, a WNN is proposed to fully compensate the robot dynamics. The online tuning algorithms for the WNN parameters are derived using Lyapunov approach. To attenuate the effect of approximation errors to a prescribed level, H∞tracking performance is proposed. It is shown that the proposed WNN is able to learn the system dynamics with guaranteed H∞tracking performance and finite time convergence for trajectory tracking. Finally, the simulation results are performed on a 3D-Microbot manipulator to show the effectiveness of the controller.
Chlamydiaprevalence in Polish pig herds
Authors: RYPUŁA K. , KUMALA A. , PŁONECZKA-JANECZKO K. , KARUGA-KUŹNIEWSKA E. , DUDEK K. , CHORBIŃSKI P.
Published: May 2016

Chlamydiae are frequently encountered intracellular Gram-negative bacteria. In pigs, these bacteria in combination with other pathogens contribute to the induction of a multi-aetiological syndrome. One of the major characteristics ofChlamydiaspp. is their ability to cause prolonged, often subclinical infections. While the economic consequences ofChlamydiaspp. infections in pig farms are not fully established, we know that reproductive disorders and other syndromes correlated withChlamydiainfection can lead to financial loss as a result of a reduction in pork production. Additionally,Chlamydiaspp. presents a potential zoonotic hazard, therefore determining the prevalence ofChlamydiain pig populations is critical. In the present study 97 pig herds from Poland were involved. To determine the prevalence ofChlamydiaPCR and CFT tests were used. In total 797 vaginal samples, 797 conjunctival samples, and 235 serum samples were collected and tested. The study took place from 2011 to 2014. We foundChlamydiaspp. present in 71·2% of all tested farms. The percentage of animals testing positive on any given farm varied from 20% to 100%.
The Neuropsychology of Risky Sexual Behavior
Authors: Ross J. Megan , Duperrouzel Jacqueline , Vega Melanie , Gonzalez Raul
Published: May 2016

Objectives:Engagement in risky sexual behavior (RSB) is a significant public health concern. A growing body of literature is elucidating the role of brain systems and neuropsychological constructs implicated in RSB, which may pave the way for novel insights and prevention efforts.Methods:In this article, we review studies incorporating neuropsychology into the study of RSB across the lifespan. The review of the literature on the neuropsychology of RSB is separated into three different sections by age of participants. Background is presented on research associating RSB with neurocognitive processes and the brain systems involved. Given the overlap between RSBs and substance use, studies addressing these problems in tandem are also discussed.Results:Neurocognitive constructs are implicated in RSB, including impulsivity, decision-making, and working memory.Discussion:Thus far, evidence suggest that neuropsychological factors are associated with engagement in RSB. More research on the influence of neuropsychological factors on engagement in RSB is necessary and may help inform future prevention efforts. (JINS, 2016,22, 586–594)
A VARIATIONAL PROBLEM FOR CURVES ON FINSLER SURFACES
Authors: SABAU SORIN V. , SHIBUYA KAZUHIRO
Published: May 2016

We study the variational problem for $N$-parallel curves on a Finsler surface by means of exterior differential systems using Griffiths’ method. We obtain the conditions when these curves are extremals of a length functional and write the explicit form of Euler–Lagrange equations for this type of variational problem.
Identifying and addressing the support needs of family caregivers of people with motor neurone disease using the Carer Support Needs Assessment Tool
Authors: Aoun Samar M. , Deas Kathleen , Kristjanson Linda J. , Kissane David W.
Published: May 2016

Objective:

Family caregivers of people with motor neurone disease (MND) experience adverse health outcomes as a result of their caregiving experience. This may be alleviated if their support needs are identified and addressed in a systematic and timely manner. The objective of the present study was to assess the feasibility and relevance of the Carer Support Needs Assessment Tool (CSNAT) in home-based care during the period of caregiving from the perspectives of the family caregivers of people with MND and their service providers.

Method:

The study was conducted during 2014 in Western Australia. Some 30 family caregivers and 4 care advisors participated in trialing the CSNAT intervention, which involved two visits from care advisors (6–8 weeks apart) to identify and address support needs. The feedback from family caregivers was obtained via telephone interviews and that of care advisors via a self-administered questionnaire.

Results:

A total of 24 caregivers completed the study (80% completion rate) and identified the highest support priorities as “knowing what to expect in the future,” “knowing who to contact if concerned,” and “equipment to help care.” The majority found that this assessment process adequately addressed their needs and gave them a sense of validation, reassurance, and empowerment. Care advisors advocated the CSNAT approach as an improvement over standard practice, allowing them to more clearly assess needs, to offer a more structured follow-up, and to focus on the caregiver and family.

Significance of Results:

The CSNAT approach for identifying and addressing family caregivers' support needs was found to be relevant and feasible by MND family caregivers and care advisors. The tool provided a formal structure to facilitate discussions with family caregivers and thus enable needs to be addressed. Such discussions can also inform an evidence base for the ongoing development of services, ensuring that new and improved services are designed to meet the explicit needs of the family caregivers of people with a motor neurone disease.
NO JUSTICE, NO PEACE
Authors: Durán Robert J.
Published: May 2016

This article provides a thematic overview of a subset of controversial officer involved shootings that have occurred in Denver, Colorado during a period of thirty years (1983-2012). Determining whether a shooting was legally justified involved multiple participants, including local, national, and international representatives. The primary stakeholders were City and County District Attorneys regarding whether to file criminal charges against the officer, and Managers of Safety for whether officers acted within police departmental policy. Although most cases were processed without conflict, a small number were challenged by members of the community based on thematic reasons of shooting individuals who had not committed a crime, violating continuum of force standards, and entrusting law enforcement officers with the power to use deadly force both off-duty and while working secondary jobs. Despite outcome legitimacy vested in a small number of public officials, community members often reported a lack of justice and accountability. They struggled to get public officials to take notice and implement systematic change. Reviewing controversial shootings highlights the multiple issues involved in protecting law enforcement officers from encountering criminal charges, and in essence the procurement of colonial control. Critical Race Theory (interest convergence and storytelling), Social Dominance Theory, along with the historical framework of W. E. B. Du Bois, were utilized to explore a number of officer-involved shootings that continue to produce disparate outcomes by race, class, and gender.
DECOLONIZING SOUTH AFRICAN SOCIOLOGY
Authors: Mangcu Xolela
Published: May 2016

On 14 June 2014 the Council of the University of Cape Town (UCT) voted to change race-based affirmative action in student admissions. The Council was ratifying an earlier decision by the predominantly White University Senate. According to the new policy race would be considered as only one among several factors, with the greater emphasis now being economic disadvantage. This paper argues that the new emphasis on economic disadvantage is a reflection of a long-standing tendency among left-liberal White academics to downplay race and privilege economic factors in their analysis of disadvantage in South Africa. The arguments behind the decision were that (1) race is an unscientific concept that takes South Africa back to apartheid-era thinking, and (2) that race should be replaced by class or economic disadvantage. These arguments are based on the assumption that race is a recent product of eighteenth century racism, and therefore an immoral and illegitimate social concept.

Drawing on the non-biologistic approaches to race adopted by W. E. B. Du Bois, Tiyo Soga, Pixley ka Seme, S. E. K. Mqhayi, and Steve Biko, this paper argues that awareness of Black perspectives on race as a historical and cultural concept should have led to an appreciation of race as an integral part of people’s identities, particularly those of the Black students on campus. Instead of engaging with these Black intellectual traditions, White academics railroaded their decisions through the governing structures. This decision played a part in the emergence of the #RhodesMustFall movement at UCT.

This paper argues that South African sociology must place Black perspectives on race at the center of its curriculum. These perspectives have been expressed by Black writers since the emergence of a Black literary culture in the middle of the nineteenth century. These perspectives constitute what Henry Louis Gates, Jr. calls a shared “text of Blackness” (Gates 2014, p. 140). This would provide a practical example of the decolonization of the curriculum demanded by students throughout the university system.
Evaluating the Impact of Maryland's Healthy Air Act
Authors: Cook Terri
Published: May 2016

Reducing emissions of short-lived gaseous sulfur pollutants from power plants had an immediate, local benefit, but controlling longer-lasting harmful particulate matter will require regional action.
Preparing Children With Autism Spectrum Disorders for Overnight Sleep Studies: A Case Series
Authors: Paasch Valerie , Leibowitz Lucy , Accardo Jennifer , Slifer Keith
Published: May 2016

Children with neurodevelopmental disorders (NDD) are at increased risk for having sleep problems, including sleep-related breathing disorders such as obstructive sleep apnea (OSA). Because of their increased risk for OSA, children with NDD may require a polysomnogram (PSG, or sleep study). PSG involves a number of sensors that may be difficult for children with NDD to tolerate because of their difficulties with anxiety, behavioral regulation, communication, and increased sensitivity to environmental stimulation. When trying to help a child complete a PSG, sedation and restraint are not preferred ways to gain cooperation and compliance. Behavioral interventions using simulated medical procedures, exposure therapy, distraction, and counterconditioning can help children succeed with a variety of challenging medical procedures. This case series describes a behavioral intervention used to help 3 children with autism spectrum disorders learn to tolerate PSG without the use of sedation or restraint. All 3 participants successfully completed the behavioral desensitization sessions, as well as their PSG. The results are discussed in terms of their apparent utility, limitations of the case studies presented, need for empirical validation in future experimental studies, and recommendations for future practice and research.
Development and Initial Feasibility Testing of Brief Cognitive-Behavioral Therapy for Insomnia in Adolescents With Comorbid Conditions
Authors: Palermo Tonya M. , Bromberg Maggie H. , Beals-Erickson Sarah , Law Emily F. , Durkin Lindsay , Noel Melanie , Chen Maida
Published: May 2016

Insomnia is highly prevalent in the adolescent population and frequently occurs in the context of other medical or mental health concerns. Efficacy of cognitive–behavioral therapy for insomnia (CBT-I) has been determined in adults with comorbid conditions. However, there are limited data applying CBT-I to adolescents with comorbid conditions. Therefore, the purpose of this study was to (a) develop and refine a 4-session CBT-I intervention for adolescents with co-occurring medical and mental health conditions, and (b) evaluate feasibility and acceptability of applying the intervention to adolescents and their parents. Forty participants (ages 11 to 18 years) were recruited from 2 pediatric specialty clinics representing a range of physical and psychiatric comorbidities (e.g., depression, chronic pain, anxiety). Adolescents and parents attended 4 treatment sessions of CBT-I delivered individually or conjointly to adolescent and parent. Daily sleep diaries were completed during the treatment period. Preliminary findings demonstrated a high level of feasibility and acceptability of treatment. Compliance with treatment visits was high, with 34 of the 40 families (85%) completing all 4 sessions. Youth and parents were highly engaged in therapy sessions as rated by treating therapists. On the Treatment Evaluation Inventory, parents’ and teens’ mean scores indicated high treatment acceptability ( M = 38.8, SD = 5.2; M = 36.8, SD = 4.6, respectively). The preliminary data suggest that CBT-I is feasible to implement to treat insomnia in adolescents with co-occurring health and mental health conditions. Future studies are needed to evaluate intervention efficacy on sleep and functional outcomes in youth.
The blind men and the AML elephant: can we feel the progress?
Authors: Tauro S
Published: May 2016

The pharmacological therapy of non-promyelocytic acute myeloid leukemia (AML) has remained unchanged for over 40 years with an anthracycline–cytarabine combination forming the backbone of induction treatments. Nevertheless, the survival of younger patients has increased due to improved management of the toxicity of therapies including stem cell transplantation. Older patients and those with infirmity that precludes treatment-intensification have, however, not benefited from improvements in supportive care and continue to experience poor outcomes. An increased understanding of the genomic heterogeneity of AML raises the possibility of treatment-stratification to improve prognosis. Thus, efforts to identify agents with non-conventional anti-leukemic effects have paralleled those aiming to optimize leukemia cell-kill with conventional chemotherapy, resulting in a number of randomized controlled trials (RCT). In the last 18 months, RCTs investigating the effects of vosaroxin, azacitidine and gemtuzumab ozogamycin and daunorubicin dose have been reported with some studies indicating a statistically significant survival benefit with the investigational agent compared with standard therapy and potentially, a new era in AML therapeutics. Given the increasing costs of cancer care, a review of these studies, with particular attention to the magnitude of clinical benefit with the newer agents would be useful, especially for physicians treating patients in single-payer health systems.
Dietary metabolites and the gut microbiota: an alternative approach to control inflammatory and autoimmune diseases
Authors: Richards James L , Yap Yu Anne , McLeod Keiran H , Mackay Charles R , Mariño Eliana
Published: May 2016

It is now convincingly clear that diet is one of the most influential lifestyle factors contributing to the rise of inflammatory diseases and autoimmunity in both developed and developing countries. In addition, the modern 'Western diet' has changed in recent years with increased caloric intake, and changes in the relative amounts of dietary components, including lower fibre and higher levels of fat and poor quality of carbohydrates. Diet shapes large‐bowel microbial ecology, and this may be highly relevant to human diseases, as changes in the gut microbiota composition are associated with many inflammatory diseases. Recent studies have demonstrated a remarkable role for diet, the gut microbiota and their metabolites—the short‐chain fatty acids (SCFAs)—in the pathogenesis of several inflammatory diseases, such as asthma, arthritis, inflammatory bowel disease, colon cancer and wound‐healing. This review summarizes how diet, microbiota and gut microbial metabolites (particularly SCFAs) can modulate the progression of inflammatory diseases and autoimmunity, and reveal the molecular mechanisms (metabolite‐sensing G protein‐coupled receptor (GPCRs) and inhibition of histone deacetylases (HDACs)). Therefore, considerable benefit could be achieved simply through the use of diet, probiotics and metabolites for the prevention and treatment of inflammatory diseases and autoimmunity.
Phylogenetic network analysis applied to pig gut microbiota identifies an ecosystem structure linked with growth traits
Authors: Ramayo-Caldas Yuliaxis , Mach Nuria , Lepage Patricia , Levenez Florence , Denis Catherine , Lemonnier Gaetan , Leplat Jean-Jacques , Billon Yvon , Berri Mustapha , Doré Jöel , Rogel-Gaillard Claire , Estellé Jordi
Published: May 2016

The ecological interactions within the gut microbial communities are complex and far from being fully understood. Here we report the first study that aims at defining the interaction network of the gut microbiota in pigs and comparing it with the enterotype-like clustering analysis. Fecal microbiota of 518 healthy piglets was characterized by 16S ribosomal RNA gene sequencing. Two networks were constructed at the genus and operational taxonomic unit levels. Within-network interactions mirrored the human gut microbiota relationships, with a strong co-exclusion between Prevotella and Ruminococcus genera, and were consistent with the two enterotype-like clusters identified in the pig microbiota. Remarkably, the cluster classification of the individuals was significantly associated with the body weight at 60 days of age (P=0.005) and average daily gain (P=0.027). To the best of our knowledge, this is the first study to provide an integrated overview of the porcine gut microbiota that suggests a conservation of the ecological community interactions and functional architecture between humans and pig. Moreover, we show that the microbial ecosystems and porcine growth traits are linked, which allows us to foresee that the enterotype concept may have an important role in the animal production industry.
Fragmentation of magnetism in artificial kagome dipolar spin ice
Authors: Canals Benjamin , Chioar Ioan-Augustin , Nguyen Van-Dai , Hehn Michel , Lacour Daniel , Montaigne François , Locatelli Andrea , Menteş Tevfik Onur , Burgos Benito Santos , Rougemaille Nicolas
Published: May 2016

Geometrical frustration in magnetic materials often gives rise to exotic, low-temperature states of matter, such as the ones observed in spin ices. Here we report the imaging of the magnetic states of a thermally active artificial magnetic ice that reveal the fingerprints of a spin fragmentation process. This fragmentation corresponds to a splitting of the magnetic degree of freedom into two channels and is evidenced in both real and reciprocal space. Furthermore, the internal organization of both channels is interpreted within the framework of a hybrid spin–charge model that directly emerges from the parent spin model of the kagome dipolar spin ice. Our experimental and theoretical results provide insights into the physics of frustrated magnets and deepen our understanding of emergent fields through the use of tailor-made magnetism.
An organelle-specific protein landscape identifies novel diseases and molecular mechanisms
Authors: Boldt Karsten , van Reeuwijk Jeroen , Lu Qianhao , Koutroumpas Konstantinos , Nguyen Thanh-Minh T. , Texier Yves , van Beersum Sylvia E. C. , Horn Nicola , Willer Jason R. , Mans Dorus A. , Dougherty Gerard , Lamers Ideke J. C. , Coene Karlien L. M. , Arts Heleen H. , Betts Matthew J. , Beyer Tina , Bolat Emine , Gloeckner Christian Johannes , Haidari Khatera , Hetterschijt Lisette , Iaconis Daniela , Jenkins Dagan , Klose Franziska , Knapp Barbara , Latour Brooke , Letteboer Stef J. F. , Marcelis Carlo L. , Mitic Dragana , Morleo Manuela , Oud Machteld M. , Riemersma Moniek , Rix Susan , Terhal Paulien A. , Toedt Grischa , van Dam Teunis J. P. , de Vrieze Erik , Wissinger Yasmin , Wu Ka Man , Apic Gordana , Beales Philip L. , Blacque Oliver E. , Gibson Toby J. , Huynen Martijn A. , Katsanis Nicholas , Kremer Hannie , Omran Heymut , van Wijk Erwin , Wolfrum Uwe , Kepes François , Davis Erica E. , Franco Brunella , Giles Rachel H. , Ueffing Marius , Russell Robert B. , Roepman Ronald ,   UK10K Rare Diseases Group, Al-Turki Saeed , Anderson Carl , Antony Dinu , Barroso Inês , Bentham Jamie , Bhattacharya Shoumo , Carss Keren , Chatterjee Krishna , Cirak Sebahattin , Cosgrove Catherine , Danecek Petr , Durbin Richard , Fitzpatrick David , Floyd Jamie , Reghan Foley A. , Franklin Chris , Futema Marta , Humphries Steve E. , Hurles Matt , Joyce Chris , McCarthy Shane , Mitchison Hannah M. , Muddyman Dawn , Muntoni Francesco , O'Rahilly Stephen , Onoufriadis Alexandros , Payne Felicity , Plagnol Vincent , Raymond Lucy , Savage David B. , Scambler Peter , Schmidts Miriam , Schoenmakers Nadia , Semple Robert , Serra Eva , Stalker Jim , van Kogelenberg Margriet , Vijayarangakannan Parthiban , Walter Klaudia , Whittall Ros , Williamson Kathy
Published: May 2016

Cellular organelles provide opportunities to relate biological mechanisms to disease. Here we use affinity proteomics, genetics and cell biology to interrogate cilia: poorly understood organelles, where defects cause genetic diseases. Two hundred and seventeen tagged human ciliary proteins create a final landscape of 1,319 proteins, 4,905 interactions and 52 complexes. Reverse tagging, repetition of purifications and statistical analyses, produce a high-resolution network that reveals organelle-specific interactions and complexes not apparent in larger studies, and links vesicle transport, the cytoskeleton, signalling and ubiquitination to ciliary signalling and proteostasis. We observe sub-complexes in exocyst and intraflagellar transport complexes, which we validate biochemically, and by probing structurally predicted, disruptive, genetic variants from ciliary disease patients. The landscape suggests other genetic diseases could be ciliary including 3M syndrome. We show that 3M genes are involved in ciliogenesis, and that patient fibroblasts lack cilia. Overall, this organelle-specific targeting strategy shows considerable promise for Systems Medicine.
Behavioural traits propagate across generations via segregated iterative-somatic and gametic epigenetic mechanisms
Authors: Mitchell Emma , Klein Shifra L. , Argyropoulos Kimon V. , Sharma Ali , Chan Robin B. , Toth Judit Gal , Barboza Luendreo , Bavley Charlotte , Bortolozzi Analia , Chen Qiuying , Liu Bingfang , Ingenito Joanne , Mark Willie , Dudakov Jarrod , Gross Steven , Di Paolo Gilbert , Artigas Francesc , van den Brink Marcel , Toth Miklos
Published: May 2016

Parental behavioural traits can be transmitted by non-genetic mechanisms to the offspring. Although trait transmission via sperm has been extensively researched, epidemiological studies indicate the exclusive/prominent maternal transmission of many non-genetic traits. Since maternal conditions impact the offspring during gametogenesis and through fetal/early-postnatal life, the resultant phenotype is likely the aggregate of consecutive germline and somatic effects; a concept that has not been previously studied. Here, we dissected a complex maternally transmitted phenotype, reminiscent of comorbid generalized anxiety/depression, to elementary behaviours/domains and their transmission mechanisms in mice. We show that four anxiety/stress-reactive traits are transmitted via independent iterative-somatic and gametic epigenetic mechanisms across multiple generations. Somatic/gametic transmission alters DNA methylation at enhancers within synaptic genes whose functions can be linked to the behavioural traits. Traits have generation-dependent penetrance and sex specificity resulting in pleiotropy. A transmission-pathway-based concept can refine current inheritance models of psychiatric diseases and facilitate the development of better animal models and new therapeutic approaches.
Argonaute-associated short introns are a novel class of gene regulators
Authors: Hansen Thomas B. , Venø Morten T. , Jensen Trine I. , Schaefer Anne , Damgaard Christian K. , Kjems Jørgen
Published: May 2016

MicroRNAs (miRNAs) are short (∼22 nucleotides) regulators of gene expression acting by direct base pairing to 3′-UTR target sites in messenger RNAs. Mature miRNAs are produced by two sequential endonucleolytic cleavages facilitated by Drosha in the nucleus and Dicer in the cytoplasm. A subclass of miRNAs, termed mirtrons, derives from short introns and enters the miRNA biogenesis pathway as Dicer substrates. Here we uncover a third biogenesis strategy that, similar to mirtron biogenesis, initiates from short introns but bypasses Dicer cleavage. These short introns (80–100 nucleotides), coined agotrons, are associated with and stabilized by Argonaute (Ago) proteins in the cytoplasm. Some agotrons are completely conserved in mammalian species, suggesting that they are functionally important. Furthermore, we demonstrate that the agotrons are capable of repressing mRNAs with seed-matching target sequences in the 3′-UTR. These data provide evidence for a novel RNA regulator of gene expression, which bypasses the canonical miRNA biogenesis machinery.
Evidence that phytochrome functions as a protein kinase in plant light signalling
Authors: Shin Ah-Young , Han Yun-Jeong , Baek Ayoung , Ahn Taeho , Kim Soo Young , Nguyen Thai Son , Son Minky , Lee Keun Woo , Shen Yu , Song Pill-Soon , Kim Jeong-Il
Published: May 2016

It has been suggested that plant phytochromes are autophosphorylating serine/threonine kinases. However, the biochemical properties and functional roles of putative phytochrome kinase activity in plant light signalling are largely unknown. Here, we describe the biochemical and functional characterization of Avena sativa phytochrome A (AsphyA) as a potential protein kinase. We provide evidence that phytochrome-interacting factors (PIFs) are phosphorylated by phytochromes in vitro. Domain mapping of AsphyA shows that the photosensory core region consisting of PAS-GAF-PHY domains in the N-terminal is required for the observed kinase activity. Moreover, we demonstrate that transgenic plants expressing mutant versions of AsphyA, which display reduced activity in in vitro kinase assays, show hyposensitive responses to far-red light. Further analysis reveals that far-red light-induced phosphorylation and degradation of PIF3 are significantly reduced in these transgenic plants. Collectively, these results suggest a positive relationship between phytochrome kinase activity and photoresponses in plants.
Patient-specific factors influence somatic variation patterns in von Hippel–Lindau disease renal tumours
Authors: Fei Suzanne S. , Mitchell Asia D. , Heskett Michael B. , Vocke Cathy D. , Ricketts Christopher J. , Peto Myron , Wang Nicholas J. , Sönmez Kemal , Linehan W. Marston , Spellman Paul T.
Published: May 2016

Cancer development is presumed to be an evolutionary process that is influenced by genetic background and environment. In laboratory animals, genetics and environment are variables that can largely be held constant. In humans, it is possible to compare independent tumours that have developed in the same patient, effectively constraining genetic and environmental variation and leaving only stochastic processes. Patients affected with von Hippel–Lindau disease are at risk of developing multiple independent clear cell renal carcinomas. Here we perform whole-genome sequencing on 40 tumours from six von Hippel-Lindau patients. We confirm that the tumours are clonally independent, having distinct somatic single-nucleotide variants. Although tumours from the same patient show many differences, within-patient patterns are discernible. Single-nucleotide substitution type rates are significantly different between patients and show biases in trinucleotide mutation context. We also observe biases in chromosome copy number aberrations. These results show that genetic background and/or environment can influence the types of mutations that occur.
Modelled drift patterns of fish larvae link coastal morphology to seabird colony distribution
Authors: Sandvik Hanno , Barrett Robert T. , Erikstad Kjell Einar , Myksvoll Mari S. , Vikebø Frode , Yoccoz Nigel G. , Anker-Nilssen Tycho , Lorentsen Svein-Håkon , Reiertsen Tone K. , Skarðhamar Jofrid , Skern-Mauritzen Mette , Systad Geir Helge
Published: May 2016

Colonial breeding is an evolutionary puzzle, as the benefits of breeding in high densities are still not fully explained. Although the dynamics of existing colonies are increasingly understood, few studies have addressed the initial formation of colonies, and empirical tests are rare. Using a high-resolution larval drift model, we here document that the distribution of seabird colonies along the Norwegian coast can be explained by variations in the availability and predictability of fish larvae. The modelled variability in concentration of fish larvae is, in turn, predicted by the topography of the continental shelf and coastline. The advection of fish larvae along the coast translates small-scale topographic characteristics into a macroecological pattern,viz.the spatial distribution of top-predator breeding sites. Our findings provide empirical corroboration of the hypothesis that seabird colonies are founded in locations that minimize travel distances between breeding and foraging locations, thereby enabling optimal foraging by central-place foragers.
From a retrovirus infection of mice to a long noncoding RNA that induces proto-oncogene transcription and oncogenesis via an epigenetic transcription switch
Authors: Garen Alan
Published: May 2016

Here I review the properties of the mouse retroelement VL30-1, which apparently derived from retrotranspostions of a founder VL30 retrovirus that infected the mouse germline after the mouse–human speciation. The VL30-1 gene is transcribed as a long noncoding RNA (lncRNA) with an essential host function in an epigenetic transcription switch (ETS) that regulates transcription of multiple genes, including proto-oncogenes that control cell proliferation and oncogenesis. The ETS involves the tumor suppressor protein PSF that has a DNA-binding domain (DBD) and two RNA-binding domains (RBDs). The DBD binds to promoters that have a DBD-binding sequence and switches off transcription, and the RBDs bind lncRNAs that have a RBD-binding sequence, releasing PSF and switching on transcription. VL30-1 lncRNA has two RBD-binding sequences, apparently acquired by mutations during retrotranspositions of the founder retrovirus, which drive proto-oncogene transcription and oncogenesis via the ETS. VL30-1 lncRNA is a seminal example of the key role of endogenous retroviruses (ERVs) and their retroelements in the evolution of transcription regulatory systems.
NADPH oxidase is implicated in the pathogenesis of oxidative phosphorylation dysfunction in mice fed a high-fat diet
Authors: García-Ruiz Inmaculada , Solís-Muñoz Pablo , Fernández-Moreira Daniel , Grau Montserrat , Muñoz-Yagüe Teresa , Solís-Herruzo José A.
Published: May 2016

The aim of this study was to evaluate the role of NADPH oxidase (NADPHox) in the pathogenesis of oxidative phosphorylation (OXPHOS) dysfunction as found in mice fed a high-fat diet (HFD). C57BL/6J mice were distributed in four groups: WT/SCD: six wild-type (WT) mice fed a standard chow diet (SCD); WT/HFD, six WT mice fed a HFD; NOX2−/−/SCD, six NADPHox-deficient mice on a SCD; (4) NOX2−/−/HFD, six NADPHox-deficient mice on a HFD. After 32 weeks, we studied the liver for: histology; OXPHOS complex activity; fully assembled OXPHOS complexes and their subunits; gene expression of OXPHOS subunits; oxidative and nitrosative stress; and oxidative DNA damage. In the liver of WT/HFD mice, we found a significant decreased in the activity of all OXPHOS complexes, in fully assembled complexes, in the amount of OXPHOS subunits and in gene expression of mitochondrial DNA-encoded subunits. 8-hydroxy-2′-deoxyguanosine was only increased in mitochondrial DNA. The liver of NOX−/−/HFD mice showed mild steatosis but no non-alcoholic steatohepatitis (NASH) lesions were found. OXPHOS activity, OXPHOS subunits and assembly of subunits into OXPHOS complexes were normal in these mice. We conclude that this study shows that NADPH deficiency protects mice from developing OXPHOS dysfunction and NASH caused by a HFD.
Intracellular chromobody delivery by mesoporous silica nanoparticles for antigen targeting and visualization in real time
Authors: Chiu Hsin-Yi , Deng Wen , Engelke Hanna , Helma Jonas , Leonhardt Heinrich , Bein Thomas
Published: May 2016

Chromobodies have recently drawn great attention as bioimaging nanotools. They offer high antigen binding specificity and affinity comparable to conventional antibodies, but much smaller size and higher stability. Chromobodies can be used in live cell imaging for specific spatio-temporal visualization of cellular processes. To date, functional application of chromobodies requires lengthy genetic manipulation of the target cell. Here, we develop multifunctional large-pore mesoporous silica nanoparticles (MSNs) as nanocarriers to directly transport chromobodies into living cells for antigen-visualization in real time. The multifunctional large-pore MSNs feature high loading capacity for chromobodies and are efficiently taken up by cells. By functionalizing the internal MSN surface with nitrilotriacetic acid-metal ion complexes, we can control the release of His6-tagged chromobodies from MSNs in acidified endosomes and observe successful chromobody-antigen binding in the cytosol. Hence, by combining the two nanotools, chromobodies and MSNs, we establish a new powerful approach for chromobody applications in living cells.
Modeling and fitting protein-protein complexes to predict change of binding energy
Authors: Dourado Daniel F.A.R. , Flores Samuel Coulbourn
Published: May 2016

It is possible to accurately and economically predict change in protein-protein interaction energy upon mutation (ΔΔG), when a high-resolution structure of the complex is available. This is of growing usefulness for design of high-affinity or otherwise modified binding proteins for therapeutic, diagnostic, industrial, and basic science applications. Recently the field has begun to pursue ΔΔG prediction for homology modeled complexes, but so far this has worked mostly for cases of high sequence identity. If the interacting proteins have been crystallized in free (uncomplexed) form, in a majority of cases it is possible to find a structurally similar complex which can be used as the basis for template-based modeling. We describe how to use MMB to create such models, and then use them to predict ΔΔG, using a dataset consisting of free target structures, co-crystallized template complexes with sequence identify with respect to the targets as low as 44%, and experimental ΔΔG measurements. We obtain similar results by fitting to a low-resolution Cryo-EM density map. Results suggest that other structural constraints may lead to a similar outcome, making the method even more broadly applicable.
The recombined cccDNA produced using minicircle technology mimicked HBV genome in structure and function closely
Authors: Guo Xiaoyan , Chen Ping , Hou Xiaohu , Xu Wenjuan , Wang Dan , Wang Tian-yan , Zhang Liping , Zheng Gang , Gao Zhi-liang , He Cheng-Yi , Zhou Boping , Chen Zhi-Ying
Published: May 2016

HBV covalently closed circular DNA (cccDNA) is drug-resistant and responsible for viral persistence. To facilitate the development of anti-cccDNA drugs, we developed a minicircle DNA vector (MC)-based technology to produce large quantity of recombined cccDNA (rcccDNA) resembling closely to its wild-type counterpart both in structure and function. The rcccDNA differed to the wild-type cccDNA (wtcccDNA) only in that it carried an extra 36-bp DNA recombinant product attR upstream of the preC/C gene. Using a procedure similar to standard plasmid production, milligrams of rcccDNA can be generated in common laboratories conveniently. The rcccDNA demonstrated many essential biological features of wtcccDNA, including: (1) undergoing nucleation upon nucleus entry; (2) serving as template for production of all HBV RNAs and proteins; (3) deriving virions capable of infecting tree shrew, and subsequently producing viral mRNAs, proteins, rcccDNA and infectious virions. As an example to develop anti-cccDNA drugs, we used the Crispr/Cas9 system to provide clear-cut evidence that rcccDNA was cleaved by this DNA editing tool in vitro. In summary, we have developed a convenient technology to produce large quantity of rcccDNA as a surrogate of wtcccDNA for investigating HBV biology and developing treatment to eradicate this most wide-spreading virus.
CD3brightCD56+ T cells associate with pegylated interferon-alpha treatment nonresponse in chronic hepatitis B patients
Authors: Guo Chuang , Shen Xiaokun , Fu Binqing , Liu Yanyan , Chen Yongyan , Ni Fang , Ye Ying , Sun Rui , Li Jiabin , Tian Zhigang , Wei Haiming
Published: May 2016

Chronic hepatitis B (CHB) infection is a serious and prevalent health concern worldwide and the development of effective drugs and strategies to combat this disease is urgently needed. Currently, pegylated interferon-alpha (peg-IFNα) and nucleoside/nucleotide analogues (NA) are the most commonly prescribed treatments. However, sustained response rates in patients remain low and the reasons are not well understood. Here, we observed that CHB patients preferentially harbored CD3brightCD56+ T cells, a newly identified CD56+ T cell population. Patients with this unique T cell population exhibited relatively poor responses to peg-IFNα treatment. CD3brightCD56+ T cells expressed remarkably high levels of the inhibitory molecule NKG2A as well as low levels of CD8. Even if patients were systematically treated with peg-IFNα, CD3brightCD56+ T cells remained in an inhibitory state throughout treatment and exhibited suppressed antiviral function. Furthermore, peg-IFNα treatment rapidly increased inhibitory TIM-3 expression on CD3brightCD56+ T cells, which negatively correlated with IFNγ production and might have led to their dysfunction. This study identified a novel CD3brightCD56+ T cell population preferentially shown in CHB patients and indicated that the presence of CD3brightCD56+ T cells in CHB patients may be useful as a new indicator associated with poor therapeutic responses to peg-IFNα treatment.
Network Meta-Analysis of the Effectiveness of Neoadjuvant Endocrine Therapy for Postmenopausal, HR–Positive Breast Cancer
Authors: Wang Wei , Liu Chenghao , Zhou Wenbin , Xia Tiansong , Xie Hui , Wang Shui
Published: May 2016

In clinical practice, it is necessary to define an optimal choice from many different therapeutic regimens. This study aimed to assess the efficacy and safety of neoadjuvant endocrine therapy (NET) for breast cancer patients. Randomized clinical trials were included. Nine studies comprising 2133 patients were included in the final analysis. Network meta-analysis showed that everolimus plus letrozole was more easily accepted by patients than exemestane (≥20wks) (odds ratio (OR): 856697.02, 95% confidence intervals (95%CI): 1.88 to 87242934...); exemestane (≥20wks) had worse acceptability than letrozole (OR: 0.00, 95%CI: 0.00 to 0.98). Letrozole produced a better clinical objective response (COR) than tamoxifen (OR: 1.99, 95%CI: 1.04 to 3.80). The incidence of fatigue between the anastrozole plus gefitinib group and the everolimus plus letrozole group was significantly different (OR: 0.08, 95%CI: 0.01 to 0.83). The exemestane (<20wks) plus celecoxib group had fewer hot flushes than others. Ranking showed the everolimus plus letrozole was most likely rank first in comparisons of COR and acceptability, and had a 64% possibility to rank first after stochastic multi-criteria acceptability analysis. In conclusion, our study showed that letrozole plus everolimus is the most effective treatment for postmenopausal, hormone receptor-positive breast cancer in the neoadjuvant setting.
Coldest Temperature Extreme Monotonically Increased and Hottest Extreme Oscillated over Northern Hemisphere Land during Last 114 Years
Authors: Zhou Chunlüe , Wang Kaicun
Published: May 2016

Most studies on global warming rely on global mean surface temperature, whose change is jointly determined by anthropogenic greenhouse gases (GHGs) and natural variability. This introduces a heated debate on whether there is a recent warming hiatus and what caused the hiatus. Here, we presented a novel method and applied it to a 5° × 5° grid of Northern Hemisphere land for the period 1900 to 2013. Our results show that the coldest 5% of minimum temperature anomalies (the coldest deviation) have increased monotonically by 0.22 °C/decade, which reflects well the elevated anthropogenic GHG effect. The warmest 5% of maximum temperature anomalies (the warmest deviation), however, display a significant oscillation following the Atlantic Multidecadal Oscillation (AMO), with a warming rate of 0.07 °C/decade from 1900 to 2013. The warmest (0.34 °C/decade) and coldest deviations (0.25 °C/decade) increased at much higher rates over the most recent decade than last century mean values, indicating the hiatus should not be interpreted as a general slowing of climate change. The significant oscillation of the warmest deviation provides an extension of previous study reporting no pause in the hottest temperature extremes since 1979, and first uncovers its increase from 1900 to 1939 and decrease from 1940 to 1969.
Identification of P-Rex1 as an anti-inflammatory and anti-fibrogenic target for pulmonary fibrosis
Authors: Liang Qing , Cheng Ni , Zhang Gufang , Liang Yurong , Qian Feng , Wu Dianqing , Ye Richard D.
Published: May 2016

Pulmonary fibrosis (PF) leads to progressive and often irreversible loss of lung functions, posing a health threat with no effective cure. We examined P-Rex1, a PI3K- and G protein βγ-regulated guanine nucleotide exchange factor (GEF) of the Rac small GTPase, for its potential involvement in PF. In a bleomycin-induced PF model, mice deficient in p-rex1 had well-preserved alveolar structure and survived significantly better than their wild type (WT) littermates. The p-rex1−/− mice expressed significantly less proinflammatory cytokines and chemokines and had reduced leukocyte infiltration in the lung tissue than their WT littermates. P-Rex1 was detected in lung fibroblasts of WT mice and its genetic deletion attenuated TGFβ-1-stimulated lung fibroblast migration, Rac1 activation and p38 MAPK phosphorylation. The p-rex1−/− mice showed significantly reduced pathological changes including the expression of α-smooth muscle actin, fibronectin and TGFβ-1 compared with their WT controls. Expression of a GEF-deficient P-Rex1 mutant effectively blocked Smads-dependent transcriptional activation, suggesting that P-Rex1 is a downstream mediator of TGFβ-1 signaling. These findings identify P-Rex1 as a novel player of PF, suggesting that targeting P-Rex1 may simultaneously block the inflammatory and fibrogenic processes of PF.
Novel Locus for Paroxysmal Kinesigenic Dyskinesia Mapped to Chromosome 3q28-29
Authors: Liu Ding , Zhang Yumiao , Wang Yu , Chen Chanjuan , Li Xin , Zhou Jinxia , Song Zhi , Xiao Bo , Rasco Kevin , Zhang Feng , Wen Shu , Li Guoliang
Published: May 2016

Paroxysmal kinesigenic dyskinesia (PKD) is characterized by recurrent and brief attacks of dystonia or chorea precipitated by sudden movements. It can be sporadic or familial. Proline-Rich Transmembrane Protein 2 (PRRT2) has been shown to be a common causative gene of PKD. However, less than 50% of patients with primary PKD harbor mutations in PRRT2. The aim of this study is to use eight families with PKD to identify the pathogenic PRRT2 mutations, or possible novel genetic cause of PKD phenotypes. After extensive clinical investigation, direct sequencing and mutation analysis of PRRT2 were performed on patients from eight PKD families. A genome-wide STR and SNP based linkage analysis was performed in one large family that is negative for pathogenic PRRT2 mutations. Using additional polymorphic markers, we identified a novel gene locus on chromosome 3q in this PRRT2-mutation-negative PKD family. The LOD score for the region between markers D3S1314 and D3S1256 is 3.02 and we proposed to designate this locus as Episodic Kinesigenic Dyskinesia (EKD3). Further studies are needed to identify the causative gene within this locus.