bluuebunny/crossref_metadata_2025 huggingface dataset:
The Role of Vascular Injury and Congestion in the Pathogenesis of Cirrhosis: the Congestive Escalator and the Parenchymal Extinction Sequence
Authors: Wanless Ian R.
Published: January 2020

Purpose of Review

Current research into the pathogenesis of cirrhosis is largely dominated by investigations of hepatocellular injury and fibrogenesis, mostly in short-term experimental models. Cirrhosis in the human evolves for decades with histologic features that are very different from the models studied, dominated by hepatic vein obstruction and congestion. This is a clue that the mechanisms operating in the human are different from those in most animal models.

Recent Findings

This paper presents an updated “vascular hypothesis” with previously unpublished observations that provide a more complete understanding of the pathogenesis of chronic liver disease in the human: (1) a definition of parenchymal extinction emphasizing the importance of sinusoidal destruction, (2) analysis of the temporal evolution of parenchymal extinction lesions, (3) new data to quantify hepatic vein obstruction, (4) a “congestive escalator” hypothesis to explain how vascular obstruction occurs, beginning with sinusoidal endothelial cell injury, fluid translocation, and vascular compression by mechanics known as “compartment syndrome,” (5) a “nested cone model” of hepatic vein anatomy that predisposes to compartment syndrome in the human, and (6) a proposal for the mechanism of collagen formation in response to congestion (“congestive fibrosis”).

The guiding principle in this model is that flow has to be vented to keep pressure gradients within the physiological range. Vascular obstruction causes tissue congestion which induces further vascular obstruction that drives a congestive escalator leading to progressive parenchymal extinction. This model may be applicable to all types of cirrhosis found in the human.
SEOM clinical guideline for the management of immune-related adverse events in patients treated with immune checkpoint inhibitors (2019)
Authors: Majem M. , García-Martínez E. , Martinez M. , Muñoz-Couselo E. , Rodriguez-Abreu D. , Alvarez R. , Arance A. , Berrocal A. , de la Cruz-Merino L. , Lopez-Martin J. A.
Published: January 2020

The use of immune checkpoint inhibitors has emerged as an effective treatment option for patients with several tumor types. By increasing the activity of the immune system, they can induce inflammatory side effects, which are often termed immune-related adverse events. These are pathophysiologically unique toxicities, compared with those from other anticancer therapies. In addition, the spectrum of the target organs is very broad. Immune-inflammatory adverse events can be life threatening. Prompt diagnosis and pharmacological intervention are instrumental to avoid progression to severe manifestations. Consequently, clinicians require new skills to successfully diagnose and manage these events. These SEOM guidelines have been developed with the consensus of ten medical oncologists. Relevant studies published in peer-review journals were used for the guideline elaboration. The Infectious Diseases Society of America grading system was used to assign levels of evidence and grades of recommendation.
SEOM clinical guideline for treatment of kidney cancer (2019)
Authors: Lázaro M. , Valderrama B. P. , Suárez C. , de-Velasco G. , Beato C. , Chirivella I. , González-del-Alba A. , Laínez N. , Méndez-Vidal M. J. , Arranz J. A.
Published: January 2020

In this article, we review de state of the art on the management of renal cell carcinoma (RCC) and provide recommendations on diagnosis and treatment. Recent advances in molecular biology have allowed the subclassification of renal tumours into different histologic variants and may help to identify future prognostic and predictive factors. For patients with localized disease, surgery is the treatment of choice with nephron-sparing surgery recommended when feasible. No adjuvant therapy has demonstrated a clear benefit in overall survival. Considering the whole population of patients with advanced disease, the combination of axitinib with either pembrolizumab or avelumab increase response rate and progression-free survival, compared to sunitinib, but a longer overall survival has only been demonstrated so far with the pembrolizumab combo. For patients with IMDC intermediate and poor prognosis, nephrectomy should not be considered mandatory. In this subpopulation, the combination of ipilimumab and nivolumab has also demonstrated a superior response rate and overall survival vs. sunitinib. In patients progressing to one or two antiangiogenic tyrosine-kinase inhibitors, both nivolumab and cabozantinib in monotherapy have shown benefit in overall survival compared to everolimus. Although no clear sequence can be recommended, medical oncologists and patients should be aware of the recent advances and new strategies that improve survival and quality of life in patients with metastatic RCC.
Complete assignment of Ala, Ile, LeuProS, Met and ValProS methyl groups of the protruding domain from human norovirus GII.4 Saga
Authors: Müller-Hermes Christoph , Creutznacher Robert , Mallagaray Alvaro
Published: January 2020

Attachment of human noroviruses to histo blood group antigens (HBGAs) is thought to be essential for infection, although how this binding event promotes infection is unknown. Recent studies have shown that 60% of all GII.4 epidemic strains may undergo a spontaneous post-translational modification (PTM) in an amino acid located adjacent to the binding pocket for HBGAs. This transformation proceeds with an estimated half-life of 1–2 days under physiological conditions, dramatically affecting HBGA recognition. The surface-exposed position of this PTM and its sequence conservation suggests a relevant role in immune escape and host-cell recognition. As a first step towards the understanding of the biological implications of this PTM at atomic resolution, we report the complete assignment of methyl resonances of a MILProSVProSA methyl-labeled sample of a 72 kDa protruding domain from a GII.4 Saga human norovirus strain. Assignments were obtained from methyl–methyl NOESY experiments combined with site-directed mutagenesis and automated assignment. This data provides the basis for a detailed characterization of the PTM-driven modulation of immune recognition in human norovirus on a molecular level.
Peer Mentors for People with Advanced Cancer: Lessons Learnt from Recruiting and Training Peer Mentors for a Feasibility Randomized Controlled Trial
Authors: Walshe Catherine , Roberts Diane , Calman Lynn , Appleton Lynda , Croft Robert , Perez Algorta Guillermo , Skevington Suzanne , Lloyd-Williams Mari , Grande Gunn
Published: January 2020

Peer mentors may offer distinctive forms of support to people with advanced cancer. Whilst peer mentor programmes are known, little is understood about recruiting and training peer mentors to support those with advanced cancer. The purpose of this study is to determine the feasibility of recruiting and training peer mentors for a novel peer mentor intervention to promote well-being in people with advanced cancer. Feasibility study testing proactive introduction to a trained peer mentor for 12 weeks in the context of a randomized controlled two-arm trial and nested qualitative process evaluation was used. Peer mentors have/had cancer, recruited via an open call. Two-day training included a new bespoke module on coping with cancer. Descriptive recruitment and training data were captured, supplemented by qualitative interviews, analysed thematically. Forty-eight people expressed interest, mostly female (69%), with breast cancer (32%), and recruited via social media (49%). Twelve people completed training, with attrition often due to availability or mentors’ own health; many had advanced cancer themselves. They wanted to ‘give something back’, but also formed supportive bonds with fellow mentors. It is feasible to recruit and train people with lived experience of cancer to be peer mentors, but those with particular characteristics may predominate. Broad social media based recruitment may have merit in widening the pool of potential peer mentors.
Advancing health equity through CTSA programs: Opportunities for interaction between health equity, dissemination and implementation, and translational science
Authors: Yousefi Nooraie Reza , Kwan Bethany M. , Cohn Elizabeth , AuYoung Mona , Clarke Roberts Megan , Adsul Prajakta , Shelton Rachel C.
Published: January 2020

Dissemination and implementation (D&I) science is dedicated to studying how to effectively translate and apply research in real-world contexts. There has been increasing interest in health equity within the D&I field to ensure the equitable implementation of evidence-based programs/practices across a range of diverse populations and settings. At the same time, health equity researchers recognize the potential of D&I science to promote the more widespread dissemination, implementation, and sustainment of evidence-based interventions to address health inequities. The National Center for Accelerating Clinical and Translational Science Clinical and Translational Science Award (CTSA) Program has been a champion for community engagement and translational scholarship in its mission to improve individual and population health. The overall CTSA infrastructure and resources within and among CTSA hubs are well-equipped to facilitate a health equity focus to D&I across the phases of translational research. This paper proposes a framework that demonstrates the interaction and opportunities between health equity and D&I science and highlights how CTSAs can support and facilitate wider efforts in translational research with a focus on equitable D&I.
Timely interventions: Temporality and peacebuilding
Authors: Christie Ryerson , Algar-Faria Gilberto
Published: January 2020

While there has been a long engagement with the impact of time on peacebuilding policies and practice, this engagement has to date focused predominately on issues of short- versus long-term initiatives, and of waning donor support for such initiatives. More recently, the critical peacebuilding turn has focused attention on the politics of the everyday as being essential to emancipatory endeavours enacted through localisation. Yet despite this, time itself has not been the subject of analysis, and the politics of time have not been integrated into the study of peacebuilding. This article, drawing both on historical institutionalist and on critical international studies analyses of temporality, provides a framework for analysing the impacts of time on the potential to achieve emancipatory peace. Drawing on extensive fieldwork in Bosnia and Herzegovina and in Cambodia, this article asserts that a focus on Policy Time, Liberal Political Time, and Intergenerational Time highlights how peacebuilding initiatives are framed by disparate timescapes that limit the visibility of local chronopolitics, and that this in turn restricts local empowerment and resistances.
Understanding unmet health-care need among older Ghanaians: a gendered analysis
Authors: Kuuire Vincent Z. , Tenkorang Eric Y. , Amegbor Prince M. , Rosenberg Mark
Published: January 2020

Health insurance schemes are important for bridging gaps in health-care needs between the rich and poor, especially in contexts where poverty is higher among seniors (persons aged 65 years and above). In this study we examined (a) gender-based predictors of unmet health-care need among seniors and (b) whether access was influenced by wealth status (measured by income quintiles). Gender-specific negative log–log regression models were fitted to data from the Study on Global Ageing and Health to examine associations between unmet health-care need and health insurance status controlling for theoretically relevant covariates. Insurance status was an important determinant of men and women's unmet health-care need but the relationship was moderated by income quintile for women and not men. While occupation was important for men, religion, marital status and income quintile were significantly associated with women's unmet health-care need. Based on the observed gender differences, we recommend the implementation of programmes aimed at improving the economic situation of older people, particularly women.
Moral Distress among Disaster Responders: What is it?
Authors: Gustavsson Martina E. , Arnberg Filip K. , Juth Niklas , von Schreeb Johan
Published: January 2020

Introduction:

Current research of moral distress is mainly derived from challenges within high-resource health care settings, and there is lack of clarity among the different definitions. Disaster responders are prone to a range of moral challenges during the work, which may give rise to moral distress. Further, organizations have considered increased drop-out rates and sick leaves among disaster responders as consequences of moral distress. Therefore, initiatives have been taken to address and understand the impacts of moral distress and its consequences for responders. Since there is unclarity among the different definitions, a first step is to understand the concept of moral distress and its interlinkages within the literature related to disaster responders.

Hypothesis/Problem:

To examine how disaster responders are affected by moral challenges, systematic knowledge is needed about the concepts related to moral distress. This paper aims to elucidate how the concept of moral distress in disaster response is defined and explained in the literature.

Methods:

The paper opted to systematically map the existing literature through the methods of a scoping review. The searches derived documents which were screened regarding specific inclusion criteria. The included 16 documents were analyzed and collated according to their definitions of moral distress or according to their descriptions of moral distress.

Results:

The paper provides clarity among the different concepts and definitions of moral distress within disaster response. Several concepts exist that describe the outcomes of morally challenging situations, centering on situations when individuals are prevented from acting in accordance with their moral values. Their specific differences suggest that to achieve greater clarity in future work, moral stress and moral distress should be distinguished.

Conclusion:

Based on the findings, a conceptual model of the development of moral distress was developed, which displays a manifestation of moral distress with the interplay between the responder and the context. The overview of the different concepts in this model can facilitate future research and be used to illuminate how the concepts are interrelated.
Transfer learning for Turkish named entity recognition on noisy text
Authors: Kağan Akkaya Emre , Can Burcu
Published: January 2020

In this article, we investigate using deep neural networks with different word representation techniques for named entity recognition (NER) on Turkish noisy text. We argue that valuable latent features for NER can, in fact, be learned without using any hand-crafted features and/or domain-specific resources such as gazetteers and lexicons. In this regard, we utilize character-level, character n-gram-level, morpheme-level, and orthographic character-level word representations. Since noisy data with NER annotation are scarce for Turkish, we introduce a transfer learning model in order to learn infrequent entity types as an extension to the Bi-LSTM-CRF architecture by incorporating an additional conditional random field (CRF) layer that is trained on a larger (but formal) text and a noisy text simultaneously. This allows us to learn from both formal and informal/noisy text, thus improving the performance of our model further for rarely seen entity types. We experimented on Turkish as a morphologically rich language and English as a relatively morphologically poor language. We obtained an entity-level F1 score of 67.39% on Turkish noisy data and 45.30% on English noisy data, which outperforms the current state-of-art models on noisy text. The English scores are lower compared to Turkish scores because of the intense sparsity in the data introduced by the user writing styles. The results prove that using subword information significantly contributes to learning latent features for morphologically rich languages.
Are cover crop mixtures better at suppressing weeds than cover crop monocultures?
Authors: Smith Richard G. , Warren Nicholas D. , Cordeau Stéphane
Published: January 2020

Cover crops are increasingly being used for weed management, and planting them as diverse mixtures has become an increasingly popular strategy for their implementation. While ecological theory suggests that cover crop mixtures should be more weed suppressive than cover crop monocultures, few experiments have explicitly tested this for more than a single temporal niche. We assessed the effects of cover crop mixtures (5- or 6-species and 14-species mixtures) and monocultures on weed abundance (weed biomass) and weed suppression at the time of cover crop termination. Separate experiments were conducted in Madbury, NH, from 2014 to 2017 for each of three temporal cover-cropping niches: summer (spring planting–summer termination), fall (summer planting–fall termination), and spring (fall planting–subsequent spring termination). Regardless of temporal niche, mixtures were never more weed suppressive than the most weed-suppressive cover crop grown as a monoculture, and the more diverse mixture (14 species) never outperformed the less diverse mixture. Mean weed-suppression levels of the best-performing monocultures in each temporal niche ranged from 97% to 98% for buckwheat (Fagopyrum esculentum Moench) in the summer niche and forage radish (Raphanus sativus L. var. niger J. Kern.) in the fall niche, and 83% to 100% for triticale (×Triticosecale Wittm. ex A. Camus [Secale × Triticum]) in the winter–spring niche. In comparison, weed-suppression levels for the mixtures ranged from 66% to 97%, 70% to 90%, and 67% to 99% in the summer, fall, and spring niches, respectively. Stability of weed suppression, measured as the coefficient of variation, was two to six times greater in the best-performing monoculture compared with the most stable mixture, depending on the temporal niche. Results of this study suggest that when weed suppression is the sole objective, farmers are more likely to achieve better results planting the most weed-suppressive cover crop as a monoculture than a mixture.
Once Again on Preliminary Reference Earth Model
Authors: Guliyev H. H. , Javanshir R. J.
Published: January 2020

We studied the isotropic ball using data of Preliminary Reference Earth Model (PREM). It is shown that such a ball should be either destructed or gone into a more stable equilibrium state with uneven distributed deformation under thermobaric condition of the inner core. Body elastic waves with real velocities cannot propagate in it. This manuscript is devoted to study the situation from the standpoint of nonlinear geomechanics. A number of necessary principles of Mechanics of Deformable Solid Body (MDSB) is given at the beginning of the analysis. A brief review of the published latest experimental work is performed. It is established that proper attention to the role of the MDSB principles in micro‐scale (nano) experiments of the physical level has not been given. Deformation properties of solid bodies are emphasized in microscale and macroscale. Application of linear acoustoelasticity and extrapolation of Birch's linear law of the inner core and use of an idea on variability of elasticity moduli with the increase of pressure and temperature have contributed to obtained pseudo data for the geological medium of the Earth's core instead of linear data on the physicomechanical properties. It is proposed that parallel to elimination of the indicated disadvantages, collection, processing and interpretation should be performed using nonclassically linearized approach. This set of necessary actions is offered as the “key” of geomechanical analysis. The proper application will allow conducting similar analysis concerning other solid‐state structures of the Earth.
Studying Sequences of Initial Breakdown Pulses in Cloud‐to‐Ground Lightning Flashes
Authors: Karunarathne Nilmini , Marshall Thomas C. , Karunarathne Sumedhe , Stolzenburg Maribeth
Published: January 2020

The properties of the first 5–12 classic initial breakdown pulses (IBPs) of three cloud‐to‐ground (CG) lightning flashes were determined using a modified transmission line model. As part of the modeling, the current with respect to time of each IBP was determined from the measured electric field changes at multiple sites using three theoretical methods called Hilbert transform, Hertzian dipole, and matrix inversion. In the transmission line modeling the length of each IBP was estimated from high‐speed video data of the IBPs. The modeling provided the following properties of the larger classic IBPs in each flash: peak current, velocity, total charge, charge moment, radiated power, and total energy dissipated for successive IB pulses in three developing lightning flashes. For the main initial leader channel in the three CG flashes (and for one long branch), IBP peak current was largest for the first or second classic IBP and declined mostly monotonically with successive IBPs. For the same channels, IBP current velocity was smallest for the first classic IBP and increased mostly monotonically with successive IBPs. The smallest velocities were (2.0, 2.5, 2.5, 3.0) × 107 m/s, respectively, while the largest velocities were (9.2, 12.2, 11.5, 12.0) × 107 m/s, respectively. These data support earlier hypotheses that it is the classic IB pulses during initial leader of normal negative CG flashes that change the nonconductive air into an ionized path that is sufficiently long and conductive to start the stepped leader.
Intelligent control of mode-locked femtosecond pulses by time-stretch-assisted real-time spectral analysis
Authors: Pu Guoqing , Yi Lilin , Zhang Li , Luo Chao , Li Zhaohui , Hu Weisheng
Published: January 2020

Mode-locked fiber lasers based on nonlinear polarization evolution can generate femtosecond pulses with different pulse widths and rich spectral distributions for versatile applications through polarization tuning. However, a precise and repeatable location of a specific pulsation regime is extremely challenging. Here, by using fast spectral analysis based on a time-stretched dispersion Fourier transform as the spectral discrimination criterion, along with an intelligent polarization search algorithm, for the first time, we achieved real-time control of the spectral width and shape of mode-locked femtosecond pulses; the spectral width can be tuned from 10 to 40 nm with a resolution of ~1.47 nm, and the spectral shape can be programmed to be hyperbolic secant or triangular. Furthermore, we reveal the complex, repeatable transition dynamics of the spectrum broadening of femtosecond pulses, including five middle phases, which provides deep insight into ultrashort pulse formation that cannot be observed with traditional mode-locked lasers.
Characterization of a sponge microbiome using an integrative genome-centric approach
Authors: Engelberts J Pamela , Robbins Steven J , de Goeij Jasper M , Aranda Manuel , Bell Sara C , Webster Nicole S
Published: January 2020

Marine sponges often host diverse and species-specific communities of microorganisms that are critical for host health. Previous functional genomic investigations of the sponge microbiome have focused primarily on specific symbiont lineages, which frequently make up only a small fraction of the overall community. Here, we undertook genome-centric analysis of the symbiont community in the model species Ircinia ramosa and analyzed 259 unique, high-quality metagenome-assembled genomes (MAGs) that comprised 74% of the I. ramosa microbiome. Addition of these MAGs to genome trees containing all publicly available microbial sponge symbionts increased phylogenetic diversity by 32% within the archaea and 41% within the bacteria. Metabolic reconstruction of the MAGs showed extensive redundancy across taxa for pathways involved in carbon fixation, B-vitamin synthesis, taurine metabolism, sulfite oxidation, and most steps of nitrogen metabolism. Through the acquisition of all major taxa present within the I. ramosa microbiome, we were able to analyze the functional potential of a sponge-associated microbial community in unprecedented detail. Critical functions, such as carbon fixation, which had previously only been assigned to a restricted set of sponge-associated organisms, were actually spread across diverse symbiont taxa, whereas other essential pathways, such as ammonia oxidation, were confined to specific keystone taxa.
Lipoic acid decreases breast cancer cell proliferation by inhibiting IGF-1R via furin downregulation
Authors: Farhat Diana , Léon Sophie , Ghayad Sandra E. , Gadot Nicolas , Icard Philippe , Le Romancer Muriel , Hussein Nader , Lincet Hubert
Published: January 2020

Background

Breast cancer is the second most common cancer in the world. Despite advances in therapies, the mechanisms of resistance remain the underlying cause of morbidity and mortality. Lipoic acid (LA) is an antioxidant and essential cofactor in oxidative metabolism. Its potential therapeutic effects have been well documented, but its mechanisms of action (MOA) are not fully understood.

Methods

The aim of this study is to validate the inhibitory LA effect on the proliferation of various breast cancer cell lines and to investigate the MOA that may be involved in this process. We tested LA effects by ex vivo studies on fresh human mammary tumour samples.

Results

We demonstrate that LA inhibits the proliferation and Akt and ERK signalling pathways of several breast cancer cells. While searching for upstream dysregulations, we discovered the loss of expression of IGF-1R upon exposure to LA. This decrease is due to the downregulation of the convertase, furin, which is implicated in the maturation of IGF-1R. Moreover, ex vivo studies on human tumour samples showed that LA significantly decreases the expression of the proliferation marker Ki67.

Conclusion

LA exerts its anti-proliferative effect by inhibiting the maturation of IGF-1R via the downregulation of furin.
Synergistic anti-methicillin-resistant Staphylococcus aureus (MRSA) activity and absolute stereochemistry of 7,8-dideoxygriseorhodin C
Authors: Miller Bailey W. , Torres Joshua P. , Tun Jortan O. , Flores Malem S. , Forteza Imelda , Rosenberg Gary , Haygood Margo G. , Schmidt Eric W. , Concepcion Gisela P.
Published: January 2020

The emergence of antibiotic resistance necessitates not only the identification of new compounds with antimicrobial properties, but also new strategies and combination therapies to circumvent this growing problem. Here, we report synergistic activity against methicillin-resistant Staphylococcus aureus (MRSA) of the β-lactam antibiotic oxacillin combined with 7,8-dideoxygriseorhodin C in vitro. Ongoing efforts to identify antibiotics from marine mollusk-associated bacteria resulted in the isolation of 7,8-dideoxygriseorhodin C from a Streptomyces sp. strain cultivated from a marine gastropod tissue homogenate. Despite the long history of 7,8-dideoxygriseorhodin C in the literature, the absolute configuration has never been previously reported. A comparison of measured and calculated ECD spectra resolved the configuration of the spiroketal carbon C6, and 2D ROESY NMR spectroscopy established the absolute configuration as 6s,6aS. The compound is selective against Gram-positive bacteria including MRSA and Enterococcus faecium with an MIC range of 0.125–0.5 μg ml−1. Moreover, the compound synergizes with oxacillin against MRSA as observed in the antimicrobial microdilution and time-kill assays. Simultaneous treatment of the compound with oxacillin resulted in an approximately tenfold decrease in MIC with a combination index of <0.5, indicating synergistic anti-MRSA activity.
Eukaryotic transcription factors can track and control their target genes using DNA antennas
Authors: Castellanos Milagros , Mothi Nivin , Muñoz Victor
Published: January 2020

Eukaryotic transcription factors (TF) function by binding to short 6-10 bp DNA recognition sites located near their target genes, which are scattered through vast genomes. Such process surmounts enormous specificity, efficiency and celerity challenges using a molecular mechanism that remains poorly understood. Combining biophysical experiments, theory and bioinformatics, we dissect the interplay between the DNA-binding domain of Engrailed, a Drosophila TF, and the regulatory regions of its target genes. We find that Engrailed binding affinity is strongly amplified by the DNA regions flanking the recognition site, which contain long tracts of degenerate recognition-site repeats. Such DNA organization operates as an antenna that attracts TF molecules in a promiscuous exchange among myriads of intermediate affinity binding sites. The antenna ensures a local TF supply, enables gene tracking and fine control of the target site’s basal occupancy. This mechanism illuminates puzzling gene expression data and suggests novel engineering strategies to control gene expression.
Longitudinal assessment of tumor development using cancer avatars derived from genetically engineered pluripotent stem cells
Authors: Koga Tomoyuki , Chaim Isaac A. , Benitez Jorge A. , Markmiller Sebastian , Parisian Alison D. , Hevner Robert F. , Turner Kristen M. , Hessenauer Florian M. , D’Antonio Matteo , Nguyen Nam-phuong D. , Saberi Shahram , Ma Jianhui , Miki Shunichiro , Boyer Antonia D. , Ravits John , Frazer Kelly A. , Bafna Vineet , Chen Clark C. , Mischel Paul S. , Yeo Gene W. , Furnari Frank B.
Published: January 2020

Many cellular models aimed at elucidating cancer biology do not recapitulate pathobiology including tumor heterogeneity, an inherent feature of cancer that underlies treatment resistance. Here we introduce a cancer modeling paradigm using genetically engineered human pluripotent stem cells (hiPSCs) that captures authentic cancer pathobiology. Orthotopic engraftment of the neural progenitor cells derived from hiPSCs that have been genome-edited to contain tumor-associated genetic driver mutations revealed by The Cancer Genome Atlas project for glioblastoma (GBM) results in formation of high-grade gliomas. Similar to patient-derived GBM, these models harbor inter-tumor heterogeneity resembling different GBM molecular subtypes, intra-tumor heterogeneity, and extrachromosomal DNA amplification. Re-engraftment of these primary tumor neurospheres generates secondary tumors with features characteristic of patient samples and present mutation-dependent patterns of tumor evolution. These cancer avatar models provide a platform for comprehensive longitudinal assessment of human tumor development as governed by molecular subtype mutations and lineage-restricted differentiation.
Tunable anomalous Hall conductivity through volume-wise magnetic competition in a topological kagome magnet
Authors: Guguchia Z. , Verezhak J. A. T. , Gawryluk D. J. , Tsirkin S. S. , Yin J.-X. , Belopolski I. , Zhou H. , Simutis G. , Zhang S.-S. , Cochran T. A. , Chang G. , Pomjakushina E. , Keller L. , Skrzeczkowska Z. , Wang Q. , Lei H. C. , Khasanov R. , Amato A. , Jia S. , Neupert T. , Luetkens H. , Hasan M. Z.
Published: January 2020

Magnetic topological phases of quantum matter are an emerging frontier in physics and material science. Along these lines, several kagome magnets have appeared as the most promising platforms. Here, we explore magnetic correlations in the kagome magnet Co3Sn2S2. Using muon spin-rotation, we present evidence for competing magnetic orders in the kagome lattice of this compound. Our results show that while the sample exhibits an out-of-plane ferromagnetic ground state, an in-plane antiferromagnetic state appears at temperatures above 90 K, eventually attaining a volume fraction of 80% around 170 K, before reaching a non-magnetic state. Strikingly, the reduction of the anomalous Hall conductivity (AHC) above 90 K linearly follows the disappearance of the volume fraction of the ferromagnetic state. We further show that the competition of these magnetic phases is tunable through applying either an external magnetic field or hydrostatic pressure. Our results taken together suggest the thermal and quantum tuning of Berry curvature induced AHC via external tuning of magnetic order.
The Red Sea Deep Water is a potent source of atmospheric ethane and propane
Authors: Bourtsoukidis E. , Pozzer A. , Sattler T. , Matthaios V. N. , Ernle L. , Edtbauer A. , Fischer H. , Könemann T. , Osipov S. , Paris J.-D. , Pfannerstill E. Y. , Stönner C. , Tadic I. , Walter D. , Wang N. , Lelieveld J. , Williams J.
Published: January 2020

Non-methane hydrocarbons (NMHCs) such as ethane and propane are significant atmospheric pollutants and precursors of tropospheric ozone, while the Middle East is a global emission hotspot due to  extensive oil and gas production. Here we compare in situ hydrocarbon measurements, performed around the Arabian Peninsula, with global model simulations that include current emission inventories (EDGAR) and state-of-the-art atmospheric circulation and chemistry mechanisms (EMAC model). While measurements of high mixing ratios over the Arabian Gulf are adequately simulated, strong underprediction by the model was found over the northern Red Sea. By examining the individual sources in the model and by utilizing air mass back-trajectory investigations and Positive Matrix Factorization (PMF) analysis, we deduce that Red Sea Deep Water (RSDW) is an unexpected, potent source of atmospheric NMHCs. This overlooked underwater source is comparable with total anthropogenic emissions from entire Middle Eastern countries, and significantly impacts the regional atmospheric chemistry.
Observation of persistent species temperature separation in inertial confinement fusion mixtures
Authors: Haines Brian M. , Shah R. C. , Smidt J. M. , Albright B. J. , Cardenas T. , Douglas M. R. , Forrest C. , Glebov V. Yu , Gunderson M. A. , Hamilton C. E. , Henderson K. C. , Kim Y. , Lee M. N. , Murphy T. J. , Oertel J. A. , Olson R. E. , Patterson B. M. , Randolph R. B. , Schmidt D. W.
Published: January 2020

The injection and mixing of contaminant mass into the fuel in inertial confinement fusion (ICF) implosions is a primary factor preventing ignition. ICF experiments have recently achieved an alpha-heating regime, in which fusion self-heating is the dominant source of yield, by reducing the susceptibility of implosions to instabilities that inject this mass. We report the results of unique separated reactants implosion experiments studying pre-mixed contaminant as well as detailed high-resolution three-dimensional simulations that are in good agreement with experiments. At conditions relevant to mixing regions in high-yield implosions, we observe persistent chunks of contaminant that do not achieve thermal equilibrium with the fuel throughout the burn phase. The assumption of thermal equilibrium is made in nearly all computational ICF modeling and methods used to infer levels of contaminant from experiments. We estimate that these methods may underestimate the amount of contaminant by a factor of two or more.
Scalable spin–photon entanglement by time-to-polarization conversion
Authors: Vasconcelos Rui , Reisenbauer Sarah , Salter Cameron , Wachter Georg , Wirtitsch Daniel , Schmiedmayer Jörg , Walther Philip , Trupke Michael
Published: January 2020

The realization of quantum networks and quantum computers relies on the scalable generation of entanglement, for which spin-photon interfaces are strong candidates. Current proposals to produce entangled-photon states with such platforms place stringent requirements on the physical properties of the photon emitters, limiting the range and performance of suitable physical systems. We propose a scalable protocol, which significantly reduces the constraints on the emitter. We use only a single optical transition and an asymmetric polarizing interferometer. This device converts the entanglement from the experimentally robust time basis via a path degree of freedom into a polarization basis, where quantum logic operations can be performed. The fundamental unit of the proposed protocol is realized experimentally in this work, using a nitrogen-vacancy center in diamond. This classically assisted protocol greatly widens the set of physical systems suited for scalable entangled-photon generation and enables performance enhancement of existing platforms.
A novel repetitive head impact exposure measurement tool differentiates player position in National Football League
Authors: Karton Clara , Blaine Hoshizaki T. , Gilchrist Michael D.
Published: January 2020

American-style football participation poses a high risk of repetitive head impact (RHI) exposure leading to acute and chronic brain injury. The complex nature of symptom expression, human predisposition, and neurological consequences of RHI limits our understanding of what constitutes as an injurious impact affecting the integrity of brain tissue. Video footage of professional football games was reviewed and documentation made of all head contact. Frequency of impact, tissue strain magnitude, and time interval between impacts was used to quantify RHI exposure, specific to player field position. Differences in exposure characteristics were found between eight different positions; where three unique profiles can be observed. Exposure profiles provide interpretation of the relationship between the traumatic event(s) and how tissue injury is manifested and expressed. This study illustrates and captures an objective measurement of RHI on the field, a critical component in guiding public policy and guidelines for managing exposure.
Sub-wavelength annular-slit-assisted superoscillatory lens for longitudinally-polarized super-resolution focusing
Authors: Kim Hyuntai , Rogers Edward T. F.
Published: January 2020

A binary metallic superoscillatory lens assisted with annular subwavelength slits is proposed, which generates a longitudinally-polarized super-resolution focal point. The annular slits are designed to selectively transmit radially-polarized light. Simulations using the finite element method show a 0.24 λ focal spot with 21.8 dB of polarization purity and only 0.342 dB reduction in efficiency compared to a standard superoscillatory lens.
Ultra High Field fMRI of Human Superior Colliculi Activity during Affective Visual Processing
Authors: Wang Yuxi C. , Bianciardi Marta , Chanes Lorena , Satpute Ajay B.
Published: January 2020

Research on rodents and non-human primates has established the involvement of the superior colliculus in defensive behaviours and visual threat detection. The superior colliculus has been well-studied in humans for its functional roles in saccade and visual processing, but less is known about its involvement in affect. In standard functional MRI studies of the human superior colliculus, it is challenging to discern activity in the superior colliculus from activity in surrounding nuclei such as the periaqueductal gray due to technological and methodological limitations. Employing high-field strength (7 Tesla) fMRI techniques, this study imaged the superior colliculus at high (0.75 mm isotropic) resolution, which enabled isolation of the superior colliculus from other brainstem nuclei. Superior colliculus activation during emotionally aversive image viewing blocks was greater than that during neutral image viewing blocks. These findings suggest that the superior colliculus may play a role in shaping subjective emotional experiences in addition to its visuomotor functions, bridging the gap between affective research on humans and non-human animals.
Viscosity-adjustable grease matrices for serial nanocrystallography
Authors: Sugahara Michihiro , Motomura Koji , Suzuki Mamoru , Masuda Tetsuya , Joti Yasumasa , Numata Keiji , Tono Kensuke , Yabashi Makina , Ishikawa Tetsuya
Published: January 2020

Serial femtosecond crystallography (SFX) has enabled determination of room temperature structures of proteins with minimum radiation damage. A highly viscous grease matrix acting as a crystal carrier for serial sample loading at a low flow rate of ~0.5 μl min−1 was introduced into the beam path of X-ray free-electron laser. This matrix makes it possible to determine the protein structure with a sample consumption of less than 1 mg of the protein. The viscosity of the matrix is an important factor in maintaining a continuous and stable sample column from a nozzle of a high viscosity micro-extrusion injector for serial sample loading. Using conventional commercial grease (an oil-based, viscous agent) with insufficient control of viscosity in a matrix often gives an unexpectedly low viscosity, providing an unstable sample stream, with effects such as curling of the stream. Adjustment of the grease viscosity is extremely difficult since the commercial grease contains unknown compounds, which may act as unexpected inhibitors of proteins. This study introduces two novel grease matrix carriers comprising known compounds with a viscosity higher than that of conventional greases, to determine the proteinase K structure from nano-/microcrystals.
Risk of active tuberculosis development in contacts exposed to infectious tuberculosis in congregate settings in Korea
Authors: Park Shin Young , Han Sunmi , Kim Young-Man , Kim Jieun , Lee Sodam , Yang Jiyeon , Kim Un-Na , Park Mi-sun
Published: January 2020

Contact investigation is an important and effective active case-finding strategy, but there is a lack of research on congregate settings in countries with an intermediate incidence. This study determined the incidence of and risk factors for tuberculosis (TB) development after exposure in congregate settings. This retrospective cohort study included 116,742 contacts identified during the investigation of 2,609 TB cases diagnosed from January to December 2015. We searched the Korean National Tuberculosis Surveillance System TB registry to identify contacts that developed active TB during follow-up until May 2018. During the mean observation period of 2.9 years, 499 of 116,742 contacts (0.4%) developed new active TB. From these contacts, 404 (81.0%) developed TB within 2 years after exposure. The 2-year Kaplan-Meier cumulative risk for TB was the highest in contacts aged ≥65 years [1%; 95% confidence interval (CI), 0.8–1.3]. Contacts with LTBI who completed chemoprophylaxis exhibited a lower risk of active TB development than those without chemoprophylaxis (adjusted hazard ratio, 0.16; 95% CI, 0.08–0.29). Aggressive contact investigation is effective for the early detection and prevention of TB in congregate settings. The risk of progression to active TB among contacts with LTBI can be minimised by the completion of chemoprophylaxis.
Advanced identification of global bioactivity hotspots via screening of the metabolic fingerprint of entire ecosystems
Authors: Mueller Constanze , Kremb Stephan , Gonsior Michael , Brack-Werner Ruth , Voolstra Christian R. , Schmitt-Kopplin Philippe
Published: January 2020

Natural products (NP) are a valuable drug resource. However, NP-inspired drug leads are declining, among other reasons due to high re-discovery rates. We developed a conceptual framework using the metabolic fingerprint of entire ecosystems (MeE) to facilitate the discovery of global bioactivity hotspots. We assessed the MeE of 305 sites of diverse aquatic ecosystems, worldwide. All samples were tested for antiviral effects against the human immunodeficiency virus (HIV), followed by a comprehensive screening for cell-modulatory activity by High-Content Screening (HCS). We discovered a very strong HIV-1 inhibition mainly in samples taken from fjords with a strong terrestrial input. Multivariate data integration demonstrated an association of a set of polyphenols with specific biological alterations (endoplasmic reticulum, lysosomes, and NFkB) caused by these samples. Moreover, we found strong HIV-1 inhibition in one unrelated oceanic sample closely matching to HIV-1-inhibitory drugs on a cytological and a chemical level. Taken together, we demonstrate that even without physical purification, a sophisticated strategy of differential filtering, correlation analysis, and multivariate statistics can be employed to guide chemical analysis, to improve de-replication, and to identify ecosystems with promising characteristics as sources for NP discovery.
PreDBA: A heterogeneous ensemble approach for predicting protein-DNA binding affinity
Authors: Yang Wenyi , Deng Lei
Published: January 2020

The interaction between protein and DNA plays an essential function in various critical natural processes, like DNA replication, transcription, splicing, and repair. Studying the binding affinity of proteins to DNA helps to understand the recognition mechanism of protein-DNA complexes. Since there are still many limitations on the protein-DNA binding affinity data measured by experiments, accurate and reliable calculation methods are necessarily required. So we put forward a computational approach in this paper, called PreDBA, that can forecast protein-DNA binding affinity effectively by using heterogeneous ensemble models. One hundred protein-DNA complexes are manually collected from the related literature as a data set for protein-DNA binding affinity. Then, 52 sequence and structural features are obtained. Based on this, the correlation between these 52 characteristics and protein-DNA binding affinity is calculated. Furthermore, we found that the protein-DNA binding affinity is affected by the DNA molecule structure of the compound. We classify all protein-DNA compounds into five classifications based on the DNA structure related to the proteins that make up the protein-DNA complexes. In each group, a stacked heterogeneous ensemble model is constructed based on the obtained features. In the end, based on the binding affinity data set, we used the leave-one-out cross-validation to evaluate the proposed method comprehensively. In the five categories, the Pearson correlation coefficient values of our recommended method range from 0.735 to 0.926. We have demonstrated the advantages of the proposed method compared to other machine learning methods and currently existing protein-DNA binding affinity prediction approach.
Novel Alzheimer’s disease subtypes identified using a data and knowledge driven strategy
Authors: Mitelpunkt Alexis , Galili Tal , Kozlovski Tal , Bregman Noa , Shachar Netta , Markus-Kalish Mira , Benjamini Yoav
Published: January 2020

The population of adults with Alzheimer’s disease (AD) varies in needs and outcomes. The heterogeneity of current AD diagnostic subgroups impedes the use of data analytics in clinical trial design and translation of findings into improved care. The purpose of this project was to define more clinically-homogeneous groups of AD patients and link clinical characteristics with biological markers. We used an innovative big data analysis strategy, the 3C strategy, that incorporates medical knowledge into the data analysis process. A large set of preprocessed AD Neuroimaging Initiative (ADNI) data was analyzed with 3C. The data analysis yielded 6 new disease subtypes, which differ from the assigned diagnosis types and present different patterns of clinical measures and potential biomarkers. Two of the subtypes, “Anosognosia dementia” and “Insightful dementia”, differentiate between severe participants based on clinical characteristics and biomarkers. The “Uncompensated mild cognitive impairment (MCI)” subtype, demonstrates clinical, demographic and imaging differences from the “Affective MCI” subtype. Differences were also observed between the “Worried Well” and “Healthy” clusters. The use of data-driven analysis yielded sub-phenotypic clinical clusters that go beyond current diagnoses and are associated with biomarkers. Such homogenous sub-groups can potentially form the basis for enhancement of brain medicine research.