bluuebunny/crossref_metadata_2025 huggingface dataset:
A Framework to Assist School Psychologists and Counsellors in Recommending Quality Apps for Supporting Diabetes Self-Management: An Illustrative Assessment Using Content Analysis
Authors: Furlonger Brett , Ostojic Marko , Chung Jasmine , Philips Katrina , Busacca Margherita , Moore Dennis , Anderson Angelika
Published: October 2018

A framework was examined to assist school psychologists and counsellors in recommending quality apps for supporting diabetes self-management. A content analysis was undertaken to assess behaviour change strategies in Apple and Android smartphone apps for the self-management of type 2 diabetes. The Behaviour Change Technique Taxonomy was used to assess the presence of behaviour change strategies, while the Mobile App Rating Scale was used to assess overall app quality. Raters found, on average, 7.13 behaviour change techniques out of a possible 93, indicating few behaviour change techniques in apps for the self-management of Type 2 diabetes. Analysis indicated that apps of a higher overall quality tended to incorporate more behaviour change strategies. It was concluded that mental-health professionals are advantaged if they are able to assess and refine selection tools for matching apps with the needs of students with diabetes.
Relationships Between Adult Attachment Dimensions and Patient-Physician Relationship Quality
Authors: McWilliams Lachlan A.
Published: October 2018

Positive associations between attachment insecurity and indicators of poorer patient-physician relationship quality have been found in samples of patients consulting with physicians for a variety of specific medical conditions or needs. The current study was the first to investigate associations between adult attachment characteristics and relationship quality with family physicians. University students (N = 239) completed measures assessing attachment and their relationships with their family physician. Attachment avoidance was associated with poor affective relationship quality and with greater communication difficulties. Attachment anxiety was associated with greater communication difficulties, but was unrelated to affective relationship quality. Those with insecure attachment, particularly those with high levels of avoidance, have poorer relationships with their family physicians than those with more secure attachment.
Estimating development and temperature thresholds of Ephestia kuehniella: toward improving a mass production system
Authors: Pakyari H. , Amir-Maafi M. , Moghadamfar Z. , Zalucki M.
Published: October 2018

The development of the Mediterranean flour moth, Ephestia kuehniella (Zeller), was evaluated at 10, 15, 17.5, 20, 22.5, 25, 27.5, 30 and 32.5°C with no lighting. None successfully completed development at 10 and 32.5°C. The total development time from egg to adult emergence was 164, 140, 98, 76, 61, 62 and 50 days, respectively, at the remaining temperatures. The developmental rate of E. kuehniella was described by the common linear model and six non-linear models. The lower temperature threshold for the immature stages and the thermal constant for E. kuehniella were 9°C and 1111 degree-days (DD) to complete development from egg to newly emerged adult. Non-linear models estimated the lower and upper thermal thresholds (Tmin and Tmax) and optimal temperature (Topt). The values of Tmax calculated by three nonlinear models ranged from 34°C to 46°C; Topt for each stage of development varied from 24 and 31°C, consistent with the temperature (30°C) at which the most rapid development occurred. Information on the threshold temperatures for development and thermal requirements can be utilized to predict E. kuehniella population dynamics and phenology and to evaluate optimal temperature conditions for mass rearing in stored products.
The Role of Teaching in Language Revival and Revitalization Movements
Authors: Shah Sheena , Brenzinger Matthias
Published: October 2018

Teaching is the main or even only way to pass on ancestral languages when intergenerational language transmission no longer takes place. The main reason for the interruption of natural language transmission is an increasing weakening of community bonds due to intermarriage, migration, and mobility. The formal or informal teaching of ancestral languages is therefore at the core of language revival and language revitalization movements. The article reviews favorable conditions and supportive factors for the teaching of ancestral languages from different parts of the world, and highlights the important role of dedicated community members in these endeavors.
Combining local knowledge and field surveys to determine status and threats to Timneh Parrots Psittacus timneh in Guinea-Bissau
Authors: LOPES DANIEL C. , MARTIN ROWAN O. , HENRIQUES MOHAMED , MONTEIRO HAMILTON , CARDOSO PAULO , TCHANTCHALAM QUINTINO , PIRES ANTÓNIO J. , REGALLA AISSA , CATRY PAULO
Published: October 2018

Timneh ParrotsPsittacus timnehare a threatened species endemic to the moist forests of West Africa. In 2016, they were categorised as ‘Endangered’ on the IUCN Red List, due to suspected rapid population declines driven by habitat loss and heavy trapping for the pet trade. Systematic assessments of the status of populations are lacking for much of their range and addressing this knowledge shortfall has been identified as a priority action. We combined multiple research approaches to investigate the distribution, trends and threats to Timneh Parrots in Guinea Bissau, where the species is restricted to the islands of the Bijagós archipelago and Pecixe. Direct observational surveys were conducted along line transects on 19 islands. A total of 69 groups were observed on eight of these islands, with the majority (78%) seen on just two islands. Forty-two interviews were conducted with local community members on 24 islands. Interviewees reported the species to occur on 20 islands and that populations are generally perceived to have declined in recent decades. Based on these findings and existing data we conclude that Timneh Parrots occur on 22 of the 32 islands considered and estimate the national population in Guinea-Bissau to be in the order of several hundred individuals, with perhaps half of the parrots occurring on the islands of João Vieira and Meio. Investigations into the factors linked to inter-island variation in parrot densities indicate that densities are highest on the islands which are most remote from permanent human settlements. These findings suggest that human activities including habitat modification and trapping have been important in driving population declines in Guinea-Bissau. We consider the implications of these findings for the conservation of Timneh Parrots.
Professional implications of introducing artificial intelligence in healthcare: an evaluation using radiation medicine as a testing ground
Authors: Gillan Caitlin , Milne Emily , Harnett Nicole , Purdie Thomas G. , Jaffray David A. , Hodges Brian
Published: October 2018

Aim

This study will evaluate radiation medicine professionals’ perceptions of clinical and professional risks and benefits, and the evolving roles and responsibilities with artificial intelligence (AI).

Methods

Radiation oncologists (ROs), medical physicists (MPs), treatment planners (TP-RTTs) and treatment delivery radiation therapists (TD-RTTs) at a cancer centre in preliminary stages of implementing an AI-enabled treatment planning system were invited to participate in uniprofessional focus groups. Semi-structured scripts addressed the perceptions of AI, including thoughts regarding changing roles and competencies. Sessions were audiorecorded, transcribed and coded thematically through consensus-building.

Results

A total of 24 participants (four ROs, five MPs, seven TP-RTTs and eight TD-RTTs) were engaged in four focus groups of 58 minutes average duration (range 54–61 minutes). Emergent themes addressed AI’s impact on quality of care, changing professional tasks and changing competency requirements. Time-consuming repetitive tasks such as delineating targets, generating treatment plans and quality assurance were thought conducive to offloading to AI. Outcomes data and adaptive planning would be incorporated into clinical decision-making. Changing workload would necessitate changing skills, prioritising plan evaluation over generation and increasing interprofessional communication. All groups discussed AI reducing the need for TP-RTTs, though displacement was thought more likely than replacement.

Conclusions

It is important to consider how professionals perceive AI to be proactive in informing change, as gains in quality and efficiency will require new workflows, skills and education.
Human rights, humanitarianism, and the practices of humanity
Authors: Barnett Michael
Published: October 2018

This article uses the concept of international practices to explore the distinctions between human rights and humanitarianism in the contemporary period and, in turn, uses this exploration to comment on the concept of international practices. First section proposes to advance the theoretical and empirical utility of the concept of practices by parsing it into the ‘problem’ that sets the story in motion, what counts as competent action, background knowledge, and meanings. Second section applies this framework to the relationship between human rights and humanitarianism. Beginning in the 1990s, they began responding to many of the same material realities, which unleashed two, interrelated, processes, but had different ways of understanding competent action, background knowledge, and meanings. They began to revise their practices not only in response to new challenges but also to how the other evolved, generating new distinctions. These points of distinction were structured by different kinds of suffering and informed their contrasting narratives of precarity in the case of humanitarianism, and progress in human rights. The conclusion considers how this discussion of human rights and humanitarianism redirects contemporary research on international practices.
Photonic waveguide to free-space Gaussian beam extreme mode converter
Authors: Kim Sangsik , Westly Daron A. , Roxworthy Brian J. , Li Qing , Yulaev Alexander , Srinivasan Kartik , Aksyuk Vladimir A.
Published: October 2018

Integration of photonic chips with millimeter-scale atomic, micromechanical, chemical, and biological systems can advance science and enable new miniaturized hybrid devices and technology. Optical interaction via small evanescent volumes restricts performance in applications such as gas spectroscopy, and a general ability to photonically access optical fields in large free-space volumes is desired. However, conventional inverse tapers and grating couplers do not directly scale to create wide, high-quality collimated beams for low-loss diffraction-free propagation over many millimeters in free space, necessitating additional bulky collimating optics and expensive alignment. Here, we develop an extreme mode converter, which is a compact planar photonic structure that efficiently couples a 300 nm × 250 nm silicon nitride high-index single-mode waveguide to a well-collimated near surface-normal Gaussian beam with an ≈160 µm waist, which corresponds to an increase in the modal area by a factor of >105. The beam quality is thoroughly characterized, and propagation over 4 mm in free space and coupling back into a single-mode photonic waveguide with low loss via a separate identical mode converter is demonstrated. To achieve low phase error over a beam area that is >100× larger than that of a typical grating coupler, our approach separates the two-dimensional mode expansion into two sequential separately optimized stages, which create a fully expanded and well-collimated Gaussian slab mode before out-coupling it into free space. Developed at 780 nm for integration with chip-scale atomic vapor cell cavities, our design can be adapted for visible, telecommunication, or other wavelengths. The technique can be expanded to more arbitrary phase and intensity control of both large-diameter, free-space optical beams and wide photonic slab modes.
Uncovering the complex genetics of human character
Authors: Zwir Igor , Arnedo Javier , Del-Val Coral , Pulkki-Råback Laura , Konte Bettina , Yang Sarah S. , Romero-Zaliz Rocio , Hintsanen Mirka , Cloninger Kevin M. , Garcia Danilo , Svrakic Dragan M. , Rozsa Sandor , Martinez Maribel , Lyytikäinen Leo-Pekka , Giegling Ina , Kähönen Mika , Hernandez-Cuervo Helena , Seppälä Ilkka , Raitoharju Emma , de Erausquin Gabriel A. , Raitakari Olli , Rujescu Dan , Postolache Teodor T. , Sung Joohon , Keltikangas-Järvinen Liisa , Lehtimäki Terho , Cloninger C. Robert
Published: October 2018

Human personality is 30–60% heritable according to twin and adoption studies. Hundreds of genetic variants are expected to influence its complex development, but few have been identified. We used a machine learning method for genome-wide association studies (GWAS) to uncover complex genotypic–phenotypic networks and environmental interactions. The Temperament and Character Inventory (TCI) measured the self-regulatory components of personality critical for health (i.e., the character traits of self-directedness, cooperativeness, and self-transcendence). In a discovery sample of 2149 healthy Finns, we identified sets of single-nucleotide polymorphisms (SNPs) that cluster within particular individuals (i.e., SNP sets) regardless of phenotype. Second, we identified five clusters of people with distinct profiles of character traits regardless of genotype. Third, we found 42 SNP sets that identified 727 gene loci and were significantly associated with one or more of the character profiles. Each character profile was related to different SNP sets with distinct molecular processes and neuronal functions. Environmental influences measured in childhood and adulthood had small but significant effects. We confirmed the replicability of 95% of the 42 SNP sets in healthy Korean and German samples, as well as their associations with character. The identified SNPs explained nearly all the heritability expected for character in each sample (50 to 58%). We conclude that self-regulatory personality traits are strongly influenced by organized interactions among more than 700 genes despite variable cultures and environments. These gene sets modulate specific molecular processes in brain for intentional goal-setting, self-reflection, empathy, and episodic learning and memory.
Parallel phylogeography of Prochlorococcus and Synechococcus
Authors: Kent Alyssa G , Baer Steven E , Mouginot Céline , Huang Jeremy S , Larkin Alyse A , Lomas Michael W , Martiny Adam C
Published: October 2018

The globally abundant marine Cyanobacteria Prochlorococcus and Synechococcus share many physiological traits but presumably have different evolutionary histories and associated phylogeography. In Prochlorococcus, there is a clear phylogenetic hierarchy of ecotypes, whereas multiple Synechococcus clades have overlapping physiologies and environmental distributions. However, microbial traits are associated with different phylogenetic depths. Using this principle, we reclassified diversity at different phylogenetic levels and compared the phylogeography. We sequenced the genetic diversity of Prochlorococcus and Synechococcus from 339 samples across the tropical Pacific Ocean and North Atlantic Ocean using a highly variable phylogenetic marker gene (rpoC1). We observed clear parallel niche distributions of ecotypes leading to high Pianka’s Index values driven by distinct shifts at two transition points. The first transition point at 6°N distinguished ecotypes adapted to warm waters but separated by macronutrient content. At 39°N, ecotypes adapted to warm, low macronutrient vs. colder, high macronutrient waters shifted. Finally, we detected parallel vertical and regional single-nucleotide polymorphism microdiversity within clades from both Prochlorococcus and Synechococcus, suggesting uniquely adapted populations at very specific depths, as well as between the Atlantic and Pacific Oceans. Overall, this study demonstrates that Prochlorococcus and Synechococcus have shared phylogenetic organization of traits and associated phylogeography.
Dianhydrogalactitol induces replication-dependent DNA damage in tumor cells preferentially resolved by homologous recombination
Authors: Zhai Beibei , Steinø Anne , Bacha Jeffrey , Brown Dennis , Daugaard Mads
Published: October 2018

1,2:5,6-Dianhydrogalactitol (DAG) is a bifunctional DNA-targeting agent causing N7-guanine alkylation and inter-strand DNA crosslinks currently in clinical trial for treatment of glioblastoma. While preclinical studies and clinical trials have demonstrated antitumor activity of DAG in a variety of malignancies, understanding the molecular mechanisms underlying DAG-induced cytotoxicity is essential for proper clinical qualification. Using non-small cell lung cancer (NSCLC) as a model system, we show that DAG-induced cytotoxicity materializes when cells enter S phase with unrepaired N7-guanine DNA crosslinks. In S phase, DAG-mediated DNA crosslink lesions translated into replication-dependent DNA double-strand breaks (DSBs) that subsequently triggered irreversible cell cycle arrest and loss of viability. DAG-treated NSCLC cells attempt to repair the DSBs by homologous recombination (HR) and inhibition of the HR repair pathway sensitized NSCLC cells to DAG-induced DNA damage. Accordingly, our work describes a molecular mechanism behind N7-guanine crosslink-induced cytotoxicity in cancer cells and provides a rationale for using DAG analogs to treat HR-deficient tumors.
Exosomal 15-LO2 mediates hypoxia-induced pulmonary artery hypertension in vivo and in vitro
Authors: Zhang Min , Xin Wei , Ma Cui , Zhang Hongyue , Mao Min , Liu Ying , Zheng Xiaodong , Zhang Lixin , Yu Xiufeng , Li Huajian , Zhu Daling
Published: October 2018

Our previous studies have shown that 15-LO2/15-HETE induced by hypoxia played an important role in pulmonary arterial hypertension (PH). However, the transportations of 15-LO2/15-HETE among the cells remain elusive. In this study, we investigated the specific involvement of 15-LO2-containing exosomes in the overproliferation of pulmonary artery endothelial cells (PAECs) induced by hypoxia and the underlying mechanism. In vitro, 15-LO2 was abundantly expressed and enriched in exosomes secreted from hypoxic PAECs, which subsequently activated the STAT3 signaling pathway, resulting in a robust increase in PAECs proliferation. In vivo treatment with the exosomes inhibitor GW4869 protected the pulmonary vascular homeostasis from dysfunctional and abnormal remodeling. Moreover, 15-LO2 was ubiquitinated under hypoxia, and further inhibition of the ubiquitin-proteasome system significantly suppressed PAECs proliferation, suggesting that ubiquitination of 15-LO2 may contribute to its sorting into exosomes. Overall, these findings indicate a previously unrecognized effect of exosomes and the cargo 15-LO2 in pulmonary vascular homeostasis on the pathogenesis of PH.
Selective toxicity of tumor treating fields to melanoma: an in vitro and in vivo study
Authors: Jo Yunhui , Hwang Sang-Gu , Jin Yeung Bae , Sung Jiwon , Jeong Youn Kyoung , Baek Jeong Hwa , Cho Jae-Min , Kim Eun Ho , Yoon Myonggeun
Published: October 2018

Tumor treating fields (TTFs) are a newly developed cancer therapy technology using an alternating electric field that may be a possible candidate for overcoming the limitations of conventional treatment methods currently used in cancer treatment. Although clinical results using TTFs appear promising, concerns regarding side effects must be clarified to demonstrate the effectiveness of this treatment method. To investigate the side effects of TTF treatment, the damage to normal cell lines and normal tissue of a mouse model was compared with the damage to tumor cells and tumors in a mouse model after TTF treatment. No serious damage was found in the normal cells and normal tissues of the mouse model, suggesting that the side effects of TTF treatment may not be serious. Our evidence based on in vitro and in vivo experiments suggests that TTF may cause selective damage to cancer cells, further demonstrating the potential of TTF as an attractive alternative to conventional cancer treatment modalities.
YL064 directly inhibits STAT3 activity to induce apoptosis of multiple myeloma cells
Authors: Wang Yingying , Wu Linlin , Cai Haiyan , Lei Hu , Ma Chun-Min , Yang Li , Xu Hanzhang , Zhu Qi , Yao Zhujun , Wu Yingli
Published: October 2018

Aberrant activation of signal transducer and activator of transcription 3 (STAT3) plays a critical role in the proliferation and survival of multiple myeloma. And inactivation of STAT3 is considered a promising strategy for the treatment of multiple myeloma. Here we show that the sinomenine derivative YL064 could selectively reduce the cell viability of multiple myeloma cell lines and primary multiple myeloma cells. Moreover, YL064 also induces cell death of myeloma cells in the presence of stromal cells. Western blot analysis showed that YL064 inhibited the constitutive activation and IL-6-induced activation of STAT3, reflected by the decreased phosphorylation of STAT3 on Tyr705. Consistent with this, YL064 inhibited the nuclear translocation of STAT3 and the expression of STAT3 target genes, such as cyclin D1 and Mcl-1. Using biotin- and FITC-labeled YL064, we found that YL064 could pull-down STAT3 from myeloma cells and colocalized with STAT3, suggesting that YL064 directly targets STAT3. Cellular thermal shift assay further demonstrated the engagement of YL064 to STAT3 in cells. Molecular docking studies indicated that YL064 may interact with STAT3 in its SH2 domain, thereby inhibiting the dimerization of STAT3. Finally, YL064 inhibited the growth of human myeloma xenograft in vivo. Taken together, this study demonstrated that YL064 may be a promising candidate compound for the treatment of multiple myeloma by directly targeting STAT3.
Metastatic adrenocortical carcinoma displays higher mutation rate and tumor heterogeneity than primary tumors
Authors: Gara Sudheer Kumar , Lack Justin , Zhang Lisa , Harris Emerson , Cam Margaret , Kebebew Electron
Published: October 2018

Adrenocortical cancer (ACC) is a rare cancer with poor prognosis and high mortality due to metastatic disease. All reported genetic alterations have been in primary ACC, and it is unknown if there is molecular heterogeneity in ACC. Here, we report the genetic changes associated with metastatic ACC compared to primary ACCs and tumor heterogeneity. We performed whole-exome sequencing of 33 metastatic tumors. The overall mutation rate (per megabase) in metastatic tumors was 2.8-fold higher than primary ACC tumor samples. We found tumor heterogeneity among different metastatic sites in ACC and discovered recurrent mutations in several novel genes. We observed 37–57% overlap in genes that are mutated among different metastatic sites within the same patient. We also identified new therapeutic targets in recurrent and metastatic ACC not previously described in primary ACCs.
Meta-analysis of effects of exclusive breastfeeding on infant gut microbiota across populations
Authors: Ho Nhan T. , Li Fan , Lee-Sarwar Kathleen A. , Tun Hein M. , Brown Bryan P. , Pannaraj Pia S. , Bender Jeffrey M. , Azad Meghan B. , Thompson Amanda L. , Weiss Scott T. , Azcarate-Peril M. Andrea , Litonjua Augusto A. , Kozyrskyj Anita L. , Jaspan Heather B. , Aldrovandi Grace M. , Kuhn Louise
Published: October 2018

Previous studies on the differences in gut microbiota between exclusively breastfed (EBF) and non-EBF infants have provided highly variable results. Here we perform a meta-analysis of seven microbiome studies (1825 stool samples from 684 infants) to compare the gut microbiota of non-EBF and EBF infants across populations. In the first 6 months of life, gut bacterial diversity, microbiota age, relative abundances of Bacteroidetes and Firmicutes, and predicted microbial pathways related to carbohydrate metabolism are consistently higher in non-EBF than in EBF infants, whereas relative abundances of pathways related to lipid metabolism, vitamin metabolism, and detoxification are lower. Variation in predicted microbial pathways associated with non-EBF infants is larger among infants born by Caesarian section than among those vaginally delivered. Longer duration of exclusive breastfeeding is associated with reduced diarrhea-related gut microbiota dysbiosis. Furthermore, differences in gut microbiota between EBF and non-EBF infants persist after 6 months of age. Our findings elucidate some mechanisms of short and long-term benefits of exclusive breastfeeding across different populations.
A hippocampal circuit linking dorsal CA2 to ventral CA1 critical for social memory dynamics
Authors: Meira Torcato , Leroy Felix , Buss Eric W. , Oliva Azahara , Park Jung , Siegelbaum Steven A.
Published: October 2018

Recent results suggest that social memory requires the dorsal hippocampal CA2 region as well as a subset of ventral CA1 neurons. However, it is unclear whether dorsal CA2 and ventral CA1 represent parallel or sequential circuits. Moreover, because evidence implicating CA2 in social memory comes largely from long-term inactivation experiments, the dynamic role of CA2 in social memory remains unclear. Here, we use pharmacogenetics and optogenetics in mice to acutely and reversibly silence dorsal CA2 and its projections to ventral hippocampus. We show that dorsal CA2 activity is critical for encoding, consolidation, and recall phases of social memory. Moreover, dorsal CA2 contributes to social memory by providing strong excitatory input to the same subregion of ventral CA1 that contains the subset of neurons implicated in social memory. Thus, our studies provide new insights into a dorsal CA2 to ventral CA1 circuit whose dynamic activity is necessary for social memory.
An intrinsic association between olfactory identification and spatial memory in humans
Authors: Dahmani Louisa , Patel Raihaan M. , Yang Yiling , Chakravarty M. Mallar , Fellows Lesley K. , Bohbot Véronique D.
Published: October 2018

It was recently proposed that olfaction evolved to aid navigation. Consistent with this hypothesis, olfactory identification and spatial memory are linked to overlapping brain areas which include the orbitofrontal cortex and hippocampus. However, the relationship between these two processes has never been specifically investigated. Here, we show that olfactory identification covaries with spatial memory in humans. We also found that the cortical thickness of the left medial orbitofrontal cortex, and the volume of the right hippocampus, predict both olfactory identification and spatial memory. Finally, we demonstrate deficits in both olfactory identification and spatial memory in patients with lesions of the medial orbitofrontal cortex. Our findings reveal an intrinsic relationship between olfaction and spatial memory that is supported by a shared reliance on the hippocampus and medial orbitofrontal cortex. This relationship may find its roots in the parallel evolution of the olfactory and hippocampal systems.
Interface-mediated hygroelectric generator with an output voltage approaching 1.5 volts
Authors: Huang Yaxin , Cheng Huhu , Yang Ce , Zhang Panpan , Liao Qihua , Yao Houze , Shi Gaoquan , Qu Liangti
Published: October 2018

Hygroelectricity is proposed as a means to produce electric power from air by absorbing gaseous or vaporous water molecules, which are ubiquitous in the atmosphere. Here, using a synergy between a hygroscopic bulk graphene oxide with a heterogeneous structure and interface mediation between electrodes/materials with Schottky junctions, we develop a high-performance hygroelectric generator unit with an output voltage approaching 1.5 V. High voltage (e.g., 18 V with 15 units) can be easily reached by simply scaling up the number of hygroelectric generator units in series, enough to drive commercial electronic devices. This work provides insight for the design and development of hygroelectric generators that may promote the efficient conversion of potential energy in the environmental atmosphere to electricity for practical applications.
Genetic signature to provide robust risk assessment of psoriatic arthritis development in psoriasis patients
Authors: Patrick Matthew T. , Stuart Philip E. , Raja Kalpana , Gudjonsson Johann E. , Tejasvi Trilokraj , Yang Jingjing , Chandran Vinod , Das Sayantan , Callis-Duffin Kristina , Ellinghaus Eva , Enerbäck Charlotta , Esko Tõnu , Franke Andre , Kang Hyun M. , Krueger Gerald G. , Lim Henry W. , Rahman Proton , Rosen Cheryl F. , Weidinger Stephan , Weichenthal Michael , Wen Xiaoquan , Voorhees John J. , Abecasis Gonçalo R. , Gladman Dafna D. , Nair Rajan P. , Elder James T. , Tsoi Lam C.
Published: October 2018

Psoriatic arthritis (PsA) is a complex chronic musculoskeletal condition that occurs in ~30% of psoriasis patients. Currently, no systematic strategy is available that utilizes the differences in genetic architecture between PsA and cutaneous-only psoriasis (PsC) to assess PsA risk before symptoms appear. Here, we introduce a computational pipeline for predicting PsA among psoriasis patients using data from six cohorts with >7000 genotyped PsA and PsC patients. We identify 9 new loci for psoriasis or its subtypes and achieve 0.82 area under the receiver operator curve in distinguishing PsA vs. PsC when using 200 genetic markers. Among the top 5% of our PsA prediction we achieve >90% precision with 100% specificity and 16% recall for predicting PsA among psoriatic patients, using conditional inference forest or shrinkage discriminant analysis. Combining statistical and machine-learning techniques, we show that the underlying genetic differences between psoriasis subtypes can be used for individualized subtype risk assessment.
Physical descriptor for the Gibbs energy of inorganic crystalline solids and temperature-dependent materials chemistry
Authors: Bartel Christopher J. , Millican Samantha L. , Deml Ann M. , Rumptz John R. , Tumas William , Weimer Alan W. , Lany Stephan , Stevanović Vladan , Musgrave Charles B. , Holder Aaron M.
Published: October 2018

The Gibbs energy, G, determines the equilibrium conditions of chemical reactions and materials stability. Despite this fundamental and ubiquitous role, G has been tabulated for only a small fraction of known inorganic compounds, impeding a comprehensive perspective on the effects of temperature and composition on materials stability and synthesizability. Here, we use the SISSO (sure independence screening and sparsifying operator) approach to identify a simple and accurate descriptor to predict G for stoichiometric inorganic compounds with ~50 meV atom−1 (~1 kcal mol−1) resolution, and with minimal computational cost, for temperatures ranging from 300–1800 K. We then apply this descriptor to ~30,000 known materials curated from the Inorganic Crystal Structure Database (ICSD). Using the resulting predicted thermochemical data, we generate thousands of temperature-dependent phase diagrams to provide insights into the effects of temperature and composition on materials synthesizability and stability and to establish the temperature-dependent scale of metastability for inorganic compounds.
A mechanoelectrical mechanism for detection of sound envelopes in the hearing organ
Authors: Nuttall Alfred L. , Ricci Anthony J. , Burwood George , Harte James M. , Stenfelt Stefan , Cayé-Thomasen Per , Ren Tianying , Ramamoorthy Sripriya , Zhang Yuan , Wilson Teresa , Lunner Thomas , Moore Brian C. J. , Fridberger Anders
Published: October 2018

To understand speech, the slowly varying outline, or envelope, of the acoustic stimulus is used to distinguish words. A small amount of information about the envelope is sufficient for speech recognition, but the mechanism used by the auditory system to extract the envelope is not known. Several different theories have been proposed, including envelope detection by auditory nerve dendrites as well as various mechanisms involving the sensory hair cells. We used recordings from human and animal inner ears to show that the dominant mechanism for envelope detection is distortion introduced by mechanoelectrical transduction channels. This electrical distortion, which is not apparent in the sound-evoked vibrations of the basilar membrane, tracks the envelope, excites the auditory nerve, and transmits information about the shape of the envelope to the brain.
Unravelling the structure of glycosyl cations via cold-ion infrared spectroscopy
Authors: Mucha Eike , Marianski Mateusz , Xu Fei-Fei , Thomas Daniel A. , Meijer Gerard , von Helden Gert , Seeberger Peter H. , Pagel Kevin
Published: October 2018

Glycosyl cations are the key intermediates during the glycosylation reaction that covalently links building blocks during the synthetic assembly of carbohydrates. The exact structure of these ions remained elusive due to their transient and short-lived nature. Structural insights into the intermediate would improve our understanding of the reaction mechanism of glycosidic bond formation. Here, we report an in-depth structural analysis of glycosyl cations using a combination of cold-ion infrared spectroscopy and first-principles theory. Participating C2 protective groups form indeed a covalent bond with the anomeric carbon that leads to C1-bridged acetoxonium-type structures. The resulting bicyclic structure strongly distorts the ring, which leads to a unique conformation for each individual monosaccharide. This gain in mechanistic understanding fundamentally impacts glycosynthesis and will allow to tailor building blocks and reaction conditions in the future.
Optimizing the utilization of aluminum adjuvants in vaccines: you might just get what you want
Authors: HogenEsch Harm , O’Hagan Derek T. , Fox Christopher B.
Published: October 2018

Aluminum-containing adjuvants have been used for over 90 years to enhance the immune response to vaccines. Recent work has significantly advanced our understanding of the physical, chemical, and biological properties of these adjuvants, offering key insights on underlying mechanisms. Given the long-term success of aluminum adjuvants, we believe that they should continue to represent the “gold standard” against which all new adjuvants should be compared. New vaccine candidates that require adjuvants to induce a protective immune responses should first be evaluated with aluminum adjuvants before other more experimental approaches are considered, since use of established adjuvants would facilitate both clinical development and the regulatory pathway. However, the continued use of aluminum adjuvants requires an appreciation of their complexities, in combination with access to the necessary expertise to optimize vaccine formulations. In this article, we will review the properties of aluminum adjuvants and highlight those elements that are critical to optimize vaccine performance. We will discuss how other components (excipients, TLR ligands, etc.) can affect the interaction between adjuvants and antigens, and impact the potency of vaccines. This review provides a resource and guide, which will ultimately contribute to the successful development of newer, more effective and safer vaccines.
Dual-controlled optogenetic system for the rapid down-regulation of protein levels in mammalian cells
Authors: Baaske Julia , Gonschorek Patrick , Engesser Raphael , Dominguez-Monedero Alazne , Raute Katrin , Fischbach Patrick , Müller Konrad , Cachat Elise , Schamel Wolfgang W. A. , Minguet Susana , Davies Jamie A. , Timmer Jens , Weber Wilfried , Zurbriggen Matias D.
Published: October 2018

Optogenetic switches are emerging molecular tools for studying cellular processes as they offer higher spatiotemporal and quantitative precision than classical, chemical-based switches. Light-controllable gene expression systems designed to upregulate protein expression levels meanwhile show performances superior to their chemical-based counterparts. However, systems to reduce protein levels with similar efficiency are lagging behind. Here, we present a novel two-component, blue light-responsive optogenetic OFF switch (‘Blue-OFF’), which enables a rapid and quantitative down-regulation of a protein upon illumination. Blue-OFF combines the first light responsive repressor KRAB-EL222 with the protein degradation module B-LID (blue light-inducible degradation domain) to simultaneously control gene expression and protein stability with a single wavelength. Blue-OFF thus outperforms current optogenetic systems for controlling protein levels. The system is described by a mathematical model which aids in the choice of experimental conditions such as light intensity and illumination regime to obtain the desired outcome. This approach represents an advancement of dual-controlled optogenetic systems in which multiple photosensory modules operate synergistically. As exemplified here for the control of apoptosis in mammalian cell culture, the approach opens up novel perspectives in fundamental research and applications such as tissue engineering.
Temperature-mediated invocation of the vacuum state for switchable ultrawide-angle and broadband deflection
Authors: Serebryannikov Andriy E. , Lakhtakia Akhlesh , Aalizadeh Majid , Ozbay Ekmel , Vandenbosch Guy A. E.
Published: October 2018

Temperature-mediated appearance and disappearance of a deflection grating in a diffracting structure is possible by employing InSb as the grating material. InSb transits from the dielectric state to the plasmonic state in the terahertz regime as the temperature increases, this transition being reversible. An intermediate state is the vacuum state in which the real part of the relative permittivity of InSb equals unity while the imaginary part is much smaller. Then the grating virtually disappears, deflection being impossible as only specular reflection can occur. This ON/OFF switching of deflection and relevant angular filtering are realizable over wide ranges of frequency and incidence angle by a temperature change of as low as 20 K. The vacuum state of InSb invoked for ON/OFF switching of deflection and relevant angular filtering can also be obtained for thermally tunable materials other than InSb as well as by using non-thermal mechanisms.
Porcine Reproductive and Respiratory Syndrome Virus strains with Higher Virulence Cause Marked Protein Profile Changes in MARC-145 Cells
Authors: Chen Zhi , Liu Shaoning , Zhang Shujin , Zhang Yuyu , Yu Jiang , Sun Wenbo , Chen Lei , Du Yijun , Wang Jinbao , Li Yubao , Wu Jiaqiang
Published: October 2018

Porcine reproductive and respiratory syndrome is an infectious disease that causes serious economic losses to the swine industry worldwide. To better understand the pathogenesis of the porcine reproductive and respiratory syndrome virus (PRRSV), three PRRSV strains with different molecular markers and virulence were used to infect MARC-145 cells. A total of 1804 proteins were identified, and 233 altered proteins and 72 signaling pathways involved in the proteomic profiling of virus-infected MARC-145 cells increased with the virulence of the PRRSV strain. The three types of viral strains shared a common pathway—the electron transport reaction in mitochondria—in the infected-MARC-145 cells. Moreover, the antisense pathway was the most variable of all significant signaling pathways for the highly virulent SX-1 strain, indicating that this unique pathway may be connected to the high virulence of the SX-1 strain. Our study is the first attempt to provide a proteome profile of MARC-145 cells infected with PRRSV strains with different virulence, and these findings will facilitate a deep understanding of the interactions between this virus and its host.
Circadian monitoring as an aging predictor
Authors: Martinez-Nicolas A. , Madrid J. A. , García F. J. , Campos M. , Moreno-Casbas M. T. , Almaida-Pagán P. F. , Lucas-Sánchez A. , Rol M. A.
Published: October 2018

The ageing process is associated with sleep and circadian rhythm (SCR) frailty, as well as greater sensitivity to chronodisruption. This is essentially due to reduced day/night contrast, decreased sensitivity to light, napping and a more sedentary lifestyle. Thus, the aim of this study is to develop an algorithm to identify a SCR phenotype as belonging to young or aged subjects. To do this, 44 young and 44 aged subjects were recruited, and their distal skin temperature (DST), activity, body position, light, environmental temperature and the integrated variable TAP rhythms were recorded under free-living conditions for five consecutive workdays. Each variable yielded an individual decision tree to differentiate between young and elderly subjects (DST, activity, position, light, environmental temperature and TAP), with agreement rates of between 76.1% (light) and 92% (TAP). These decision trees were combined into a unique decision tree that reached an agreement rate of 95.3% (4 errors out of 88, all of them around the cut-off point). Age-related SCR changes were very significant, thus allowing to discriminate accurately between young and aged people when implemented in decision trees. This is useful to identify chronodisrupted populations that could benefit from chronoenhancement strategies.
Naturally Occurring Variations Modulate the Activity of the HPV33 Early Promoter and its Affinity for the E2 Transcription Factor
Authors: Alvarez Jennifer , Gagnon David , Coutlée François , Archambault Jacques
Published: October 2018

The human papillomavirus (HPV) Long Control Region (LCR) encompasses the early promoter (EP) that drives transcription of the E6 and E7 oncogenes in keratinocytes and HPV-associated cancers. In this study, the transcriptional activities of the HPV33 EP from the prototype LCR and from eight variants representative of the worldwide diversity of the virus were examined in primary human keratinocytes (PHK) and in the HeLa cervical carcinoma cell line by luciferase reporter-gene assays. Remarkably, the two variations with the greatest effect on the EP in PHK were C7732G and a 79-bp deletion that were associated with high-grade cervical lesions and persistent infections, respectively, in epidemiological studies. In contrast, the three variations most active in HeLa cells were C7537A, A7874C and A7879G. A7874C, which lies within an E2-binding sequence, is also shown to increase the activity and binding of E2 at this site. Collectively, these results indicate that naturally-occurring variations affect the HPV33 EP differentially in PHK than in cancer cells and, furthermore, that they can also alter its regulation by E2. These findings provide a molecular basis for rationalizing the results of previous epidemiological studies and for understanding the contribution of LCR polymorphisms to the oncogenicity and persistence of HPV33 infections.
AIMP3 Deletion Induces Acute Radiation Syndrome-like Phenotype in Mice
Authors: Kim Doyeun , Kim Sunmi , Oh Youngsun , Park Songhwa , Jeon Yoon , Kim Hongtae , Lee Ho , Kim Sunghoon
Published: October 2018

Genomes are mostly protected from constant DNA-damaging threats, either internal or external, which ultimately sustain the organism. Herein, we report that AIMP3, a previously demonstrated tumour suppressor, plays an essential role in maintaining genome integrity in adult mice. Upon induction of the temporal systemic deletion of AIMP3 by tamoxifen in adult mice, the animals developed an acute radiation syndrome-like phenotype, typified by scleroderma, hypotrophy of haematopoietic cells and organs, and intestinal failure. Induction of γH2AX, an early marker of DNA double-strand breaks, was observed in the spleen, intestine, and the highly replicating embryonic cortex. In addition, sub-lethal irradiation of AIMP3 mKO mice dramatically affected organ damage and survival. Using isolated MEFs from conditional KO mice or AIMP3 knockdown cells, we confirmed the presence of spontaneously occurring DNA double-strand breaks by COMET assay and γH2AX induction. Furthermore, γH2AX removal was delayed, and homologous DNA repair activity was significantly reduced. Reduction of RPA foci formation and subsequent Rad51 foci formation probably underlie the significant reduction in homologous recombination activity in the absence of AIMP3. Together, our data demonstrate that AIMP3 plays a role in genome stability through the DNA repair process.
Using long term mortality to determine which perioperative risk factors of mortality following hip and knee replacement may be causal
Authors: Hunt Linda P. , Whitehouse Michael R. , Howard Peter W. , Ben-Shlomo Yoav , Blom Ashley W.
Published: October 2018

Observational studies have identified surgical factors that are associated with a reduced risk of mortality after joint replacement. It is not clear whether these are causal or reflect patient selection. Data on the first primary hip (n = 424,156) and knee replacements (n = 469,989) performed for osteoarthritis in the National Joint Registry were analysed. Flexible parametric survival modelling was used to determine if risk factors for mortality in the perioperative period persisted. To explore selection bias, standardised mortality ratios were calculated for all-cause, respiratory and smoking related cancer mortality using population rates. Selection was apparent for hip resurfacing, combined spinal and general anaesthetic and unicondylar knee implants; reduced mortality was observed for many years for both all and other causes of mortality with a waning effect. Mechanical thromboprophylaxis was also suggestive of selection although patients receiving aspirin had sustained reduced mortality, possibly due to to a cardioprotective effect. Posterior approach for hips was ambiguous with a possible causal component. Spinal anaesthesia was suggestive of a causal effect. We are reliant on observational data when it is not feasible to undertake randomised trials. Our approach of looking at long term mortality risks for perioperative interventions provides further insights to differentiate causal interventions from selection. We recommend the use of aspirin chemothromboprophylaxis, the posterior approach and spinal anaesthetic in total hip replacement due to the apparent causal effect on reduced mortality.
Peptide-oligonucleotide conjugates exhibiting pyrimidine-X cleavage specificity efficiently silence miRNA target acting synergistically with RNase H
Authors: Patutina O. A. , Bazhenov M. A. , Miroshnichenko S. K. , Mironova N. L. , Pyshnyi D. V. , Vlassov V. V. , Zenkova M. A.
Published: October 2018

Taking into account the important role of miRNA in carcinogenesis, oncogenic miRNAs are attractive molecules for gene-targeted therapy. Here, we developed a novel series of peptide-oligonucleotide conjugates exhibiting ribonuclease activity targeted to highly oncogenic miRNAs miR-21 and miR-17. When designing the conjugates, we enhanced both nuclease resistance of the targeted oligodeoxyribonucleotide by introducing at its 3′-end mini-hairpin structure displaying high thermostability and robustness against nuclease digestion and the efficiency of its functioning by attachment of the catalytic construction (amide)NH2-Gly(ArgLeu)4-TCAA displaying ribonuclease activity to its 5′-end. Designed miRNases efficiently cleaved miRNA targets, exhibiting Pyr-X specificity, and cleavage specificity had strong dependence on the miRNA sequence in the site of peptide location. In vitro, designed miRNases do not prevent cleavage of miRNA bound with the conjugate by RNase H, and more than an 11-fold enhancement of miRNA cleavage by the conjugate is observed in the presence of RNase H. In murine melanoma cells, miRNase silences mmu-miR-17 with very high efficiency as a result of miR-17 cleavage by miRNase and by recruited RNase H. Thus, miRNases provide a system of double attack of the miRNA molecules, significantly increasing the efficiency of miRNA downregulation in the cells in comparison with antisense oligonucleotide.