bluuebunny/crossref_metadata_2025 huggingface dataset:
Disaster-Related Shelter Surveillance During the Hurricane Harvey Response – Texas 2017
Authors: Schnall Amy Helene , Hanchey Arianna , Nakata Nicole , Wang Alice , Jeddy Zuha , Alva Herminia , Tan Christina , Boehmer Tegan , Bayleyegn Tesfaye , Casey-Lockyer Mary
Published: June 2019

Objectives:

Hurricane Harvey left a path of destruction in its wake, resulting in over 100 deaths and damaging critical infrastructure. During a disaster, public health surveillance is necessary to track emerging illnesses and injuries, identify at-risk populations, and assess the effectiveness of response efforts. The Centers for Disease Control and Prevention (CDC) and American Red Cross collaborate on shelter surveillance to monitor the health of the sheltered population and help guide response efforts.

Methods:

We analyzed data collected from 24 Red Cross shelters between August 25, 2017, and September 14, 2017. We described the aggregate morbidity data collected during Harvey compared with previous hurricanes (Gustav, Ike, and Sandy).

Results:

Over one-third (38%) of reasons for visit were for health care maintenance; 33% for acute illnesses, which includes respiratory conditions, gastrointestinal symptoms, and pain; 19% for exacerbation of chronic disease; 7% for mental health; and 4% for injury. The Red Cross treated 41% of clients within the shelters; however, reporting of disposition was often missed. These results are comparable to previous hurricanes.

Conclusion:

The capacity of Red Cross shelter staff to address the acute health needs of shelter residents is a critical resource for local public health agencies overwhelmed by the disaster. However, there remains room for improvement because reporting remained inconsistent.
Early intervention in psychosis in the North Lee Mental Health Services programme: a 5-year review
Authors: Lalevic G. , Scriven M. , O’Brien S.
Published: June 2019

Objectives

An Early Intervention in Psychosis (EIP) programme aims to engage patients in early assessment and phase-specific interventions which are the key elements of the Irish National Clinical Programme for psychosis. This study aims to describe and review the EIP programme offered by Cork’s North Lee Mental Health Services over a 5-year period.

Methods

A retrospective descriptive study design was adopted to describe and review the EIP programme, patient demographics and treatments offered in the service over a 5-year period.

Results

A total of 139 patients were accepted into the programme over the 5-year period. The mean age of onset was 30 years (median = 28, SD = 9.9), and the mean duration of untreated psychosis was 8 months (median = 2.5, SD = 15.3). Two-thirds of patients were single on initial assessment, had a history of substance misuse and were unemployed. The majority of the cohort engaged with the keyworkers and occupational therapy but did not complete the full psychological or family programmes offered. Hospital admission was required for 12% of the cohort.

Conclusions

Patients experiencing their first episode of psychosis can successfully be treated in the community with appropriate professional and family support. However, deficiencies were noted in physical health monitoring, as well as in the availability and engagement with family and psychological therapies. Properly resourced early interventions in psychosis teams are necessary to deliver services at internationally recognised standards.
Predicting Partisan Responsiveness: A Probabilistic Text Mining Time-Series Approach
Authors: Bustikova Lenka , Siroky David S. , Alashri Saud , Alzahrani Sultan
Published: June 2019

When do parties respond to their political rivals and when do they ignore them? This article presents a new computational framework to detect, analyze and predict partisan responsiveness by showing when parties on opposite poles of the political spectrum react to each other’s agendas and thereby contribute to polarization. Once spikes in responsiveness are detected and categorized using latent Dirichlet allocation, we utilize the terms that comprise the topics, together with a gradient descent solver, to assess the classifier’s predictive accuracy. Using 10,597 documents from the official websites of radical right and ethnic political parties in Slovakia (2004–2014), the analysis predicts which political issues will elicit partisan reactions, and which will be ignored, with an accuracy of 83% (F-measure) and outperforms both Random Forest and Naive Bayes classifiers. Subject matter experts validate the approach and interpret the results.
Does infusion time affect the retention of parenteral trace elements?
Authors: Ferrie Suzie
Published: June 2019

When readymade parenteral nutrition in multi-chamber bags is supplied without vitamins and minerals, these have to be added or given separately. Separate rapid infusion has logistical advantages but has been claimed to saturate tissue mechanisms, potentially increasing urine micronutrient losses. The present study compared urinary losses after fast (1 h) v. slow (10 h) trace elements infusion. The study enrolled thirty-nine consecutive patients who were starting parenteral nutrition postoperatively. One day’s dose of a complete intravenous micronutrient product was infused over 1 h and over 10 h, in random order, with a washout day after each infusion day. Urinary Zn, Mn, Se, Cr, Cu and Fe losses were measured by 24-h urine collection, recorded for each infusion day and subsequent washout day. For Zn, a dose of 100 μmol was given, and total urinary loss over the next 2 d was mean 40·6 (sd 23·8) μmol after the fast (1 h) infusion v. 33·4 (sd 25·4) μmol after the slow (10 h) infusion, that is, 7 % more of the 1-d dose was lost after fast infusion (P = 0·01). For Mn, after a dose of 1000 nmol, losses were 9·8 (sd 23·9) nmol after the fast infusion v. 22·1 (sd 47·2) nmol after the slow infusion, that is, 1 % more of the 1-d dose was lost after slow infusion (P = 0·04). There were no other significant differences: after 1 μmol Se, the losses were 1·5 (sd 0·6) μmol fast v. 1·3 (sd 0·5) μmol slow; after 200 nmol Cr, 257 (sd 92) μmol fast v. 246 (sd 107) nmol slow; after 8 μmol Cu, 1·6 (sd 1·4) μmol fast v. 1·5 (sd 1·3) μmol slow; and after 20 μmol Fe, 0·6 (sd 1·1) μmol fast v. 0·8 (sd 1·6) μmol slow (P > 0·05 for all). Overall, trace element retention appears to be minimally affected by infusion time.
The intonation of the Q-marking construction: A comparison of Hungarian and Slovenian
Authors: MYCOCK LOUISE
Published: June 2019

This paper examines the Q-marking construction: an interrogative construction in which a question phrase takes scope over a higher clause even though it appears in a lower clause. In this construction, the scope of a question phrase is extended by the presence of another word, the Q-marker, in a higher clause. While the syntax of this construction has been described and analysed in a number of works, its intonation is yet to receive commensurate attention. This paper presents data from two unrelated languages in which the Q-marking construction can be used to form questions: Hungarian and Slovenian. Data show that while the Q-marker shares properties with question words in Hungarian (they bear the same pitch accent), in Slovenian the Q-marker and question words bear distinct pitch accents. Furthermore, in Hungarian a direct intonational link exists between the Q-marker and a question phrase whose scope is extended, rather than an indirect one between the Q-marker and the entire lower clause in which the question phrase appears. The Slovenian data are compatible with the existence of either an indirect or a direct intonational link. These findings reveal hitherto unidentified dimensions of cross-linguistic variation, for which any analysis of the Q-marking construction must account.
Electron acoustic double layers in a magnetized plasma in the presence of superthermal particles
Authors: Dutta D. , Goswami K. S.
Published: June 2019

An analytical study of the small amplitude electron acoustic double layers in a magnetized plasma consisting of superthermal electrons and ions along with cold fluid electrons is discussed. The dispersion relation allows electron acoustic waves with the frequency within electron and ion gyro-frequency in the modelled plasma. In the process of study of the nonlinear structures, the Sagdeev pseudo-potential method for small amplitude regions is employed. The existence domains for the double layers are investigated in terms of the Mach numbers of the structures and the temperature ratios of the species for different ratios of their concentration. The effects of the compositional parameters on the nature and size of the double layers are also explored and it is observed that the plasma can support both compressive and rarefactive double layers depending on the values of those parameters and the Mach numbers.
Preservation amenity, research laboratory, or mineral reserve? International perspectives on the values of Antarctica
Authors: Tin Tina , Peden John , O’Reilly Jessica , Bastmeijer Kees , Maher Patrick T.
Published: June 2019

Inspired by notions of interest of humankind and intergenerational equity, we explored Antarctic perceptions of a subset of future generations—university students. Students at three universities in Canada, the Netherlands, and the USA were surveyed to determine the relationships between nationality, academic major, opinions on values of Antarctica, and support for a range of human activities in Antarctica (n = 618). Logistic regression was used to model the relationship of these variables with support for designation of Antarctica as a wilderness reserve, construction of new research stations, and mining. Compared with business and economics majors, biological sciences and natural resources/conservation majors were more likely to support wilderness designation and less likely to support mineral resource development. Nationality was not significantly associated with support for construction of new research stations and mineral resource development. Opinions on the value of Antarctica and support for activities also exhibited significant influences on dependent variables. Consistent with earlier studies of Antarctic scientists, personnel, tourists, and other members of the general public, university students valued Antarctica as one of the world’s last great wildernesses (66%), an important component of the Earth’s climate system (66%), and a science laboratory for the benefit of mankind (62%).
Big Data and Changing Concepts of the Human
Authors: Figdor Carrie
Published: June 2019

Big Data has the potential to enable unprecedentedly rigorous quantitative modeling of complex human social relationships and social structures. When such models are extended to non-human domains, they can undermine anthropocentric assumptions about the extent to which these relationships and structures are specifically human. Discoveries of relevant commonalities with non-humans may not make us less human, but they promise to challenge fundamental views of what it is to be human.
Forensic patients in state psychiatric hospitals: 1999–2016
Authors: Wik Amanda , Hollen Vera , Fisher William H.
Published: June 2019

Introduction.

In recent years mental health officials have reported a rise in the number of forensic patients present within their state psychiatric hospitals and the adverse impacts that these trends had on their hospitals. To date there have been no large-scale national studies conducted to determine if these trends are specific only to a few states or representative of a more global trend. The purpose of this study was to investigate these reported trends and their national prevalence.

Methods.

The forensic directors of each state behavioral health agency (including the District of Columbia) were sent an Excel spreadsheet that had two components: a questionnaire and data tables with information collected between 1996 and 2014 from the State Profiling System maintained by the National Association of State Mental Health Program Directors Research Institute. They were asked to verify and update these data and respond to the questionnaire.

Results.

Responses showed a 76% increase nationally in the number of forensic patients in state psychiatric hospitals between 1999 and 2014. The largest increase was for individuals who were court-committed after being found incompetent to stand trial and in need of inpatient restoration services.

Discussion.

The data reviewed here indicate that increases in forensic referrals to state psychiatric hospitals, while not uniform across all states, are nonetheless substantial.

Conclusion.

More research is needed to determine whether this multi-state trend is merely a coincidence of differing local factors occurring in many states, or a product of larger systemic factors affecting mental health agencies and the courts.
‘Nutrition is out of our control’: soldiers’ perceptions of their local food environment
Authors: Chukwura Chizoba L , Santo Theresa Jackson , Waters Clarice N , Andrews Anne
Published: June 2019

Objective:

To explore the perceptions of soldiers participating in a US Army Office of The Surgeon General’s worksite health promotion programme (WHPP) on the local food environment within their campus-style workplace.

Design:

Focus groups were conducted to evaluate the perceived effectiveness of the WHPP implementation. Further exploration of focus group data through thematic analysis focused on perceived contributions of the military campus-style food environment to soldiers’ nutrition behaviours.

Setting:

Three US Army installations located in the continental USA.

Participants:

Active duty soldiers (n 366) participating in one of the fifty-eight focus groups.

Results:

Soldiers shared a common belief of self-discipline and personal responsibility as the foothold to nutrition behaviour change. Soldiers described aspects of the military campus-style food environment as factors impeding achievement of optimal nutrition. Collectively, soldiers perceived the proximity and density of fast-food restaurants, lack of healthy alternatives on the installation and the cost of healthy food as inhibitors to choosing healthy foods. Overwhelmingly, soldiers also perceived time constraints as a factor contributing to unhealthy food choices.

Conclusions:

Although nutrition behaviour is individually driven, soldiers perceived the military campus-style food environment inhibits healthy decision making. Nutrition programming in military WHPP must integrate food environment changes to improve soldiers’ nutrition behaviour outcomes. Applicable to the military, food choice behaviour studies suggest environmental changes must be appealing to young adults. Considerations for environmental changes should include an increased portion size for healthy options, broadened use of soldiers’ daily food allowances on local produce and increased availability of grab-and-go options.
Wittener Ressourcenfragebogen (WIRF) – Ein mehrdimensionales Instrument zur subjektiven Ressourceneinschätzung
Authors: Victor Philipp Pascal , Schürmann Jan , Muermans Michaela Martha , Teismann Tobias , Willutzki Ulrike
Published: June 2019

Zusammenfassung. Der Wittener Ressourcenfragebogen (WIRF) ist ein mehrdimensionales Selbstbeurteilungsinstrument zur Erfassung individuell positiv bewerteter und funktionaler Aspekte, den Ressourcen einer Person. Ressourcen werden in den drei Kontexten Alltagsleben, Krisenbewältigung und aktuelle Probleme mittels jeweils drei Subskalen (Handlungsregulation, Entspannung und soziale Unterstützung) erfasst. Auf Grundlage zweier klinischer Stichproben (ambulante Psychotherapiepatientinnen und -patienten zu Therapiebeginn; KS-1: n = 144, KS-2: n = 274) wurden die psychometrischen Eigenschaften des WIRF bestimmt. Die Überprüfung der latenten Faktorstruktur erfolgte mittels konfirmatorischer Faktorenanalyse. Weiterhin wurden Korrelationen mit positiven (Wohlbefinden, soziale Unterstützung, Kohärenzgefühl, Ressourcen insgesamt) und problembezogenen Kriteriumsvariablen (Psychopathologie, Stress, psychische Inkongruenz) ermittelt. Zusätzlich wurden Vergleiche mit einer nicht-klinischen Stichprobe (NKS: n = 386) berechnet. Die interne Konsistenz der Skalen lag im klinischen Bereich bei α = .72 – .85. Die konfirmatorische Faktorenanalyse bestätigte die dreifaktorielle Struktur des WIRF in allen Kontexten befriedigend bis gut. Korrelationen mit den Kriteriumsvariablen lieferten Hinweise für eine zufriedenstellende Konstruktvalidität. Im Vergleich zur NKS gaben Patientinnen und Patienten signifikant weniger Ressourcen in allen Skalen an (d = 0.33 – 1.09). Schlussfolgerungen: Der WIRF stellt ein reliables und valides Selbstbeurteilungsinstrument zur Erfassung subjektiver Ressourcen in klinischen Stichproben dar. Zukünftige Studien zur Veränderungssensitivität und Prädiktionsrelevanz des Instruments sind notwendig.
New Perspectives on 2,000 Years of North Atlantic Climate Change
Authors: Stanley Sarah
Published: June 2019

A review of recent research advancements takes a deep dive into North Atlantic ocean circulation and its potential role in historical climate shifts.
On the Development of a Method for Updating an Empirical Climatological Ionospheric Model by Means of Assimilated vTEC Measurements From a GNSS Receiver Network
Authors: Pignalberi A. , Habarulema J.B. , Pezzopane M. , Rizzi R.
Published: June 2019

In this paper, a procedure for updating the International Reference Ionosphere (IRI) model by means of assimilated vertical total electron content (vTEC) measurements from a Global Navigational Satellite Systems (GNSS) receiver network is presented. This procedure stands as an additional implementation of the IRI UPdate (IRI UP) method, which is based on the assimilation of ionosonde derived F2 layer ionospheric characteristics. According to this, a mathematical procedure for obtaining foF2 and M(3000)F2 values from vTEC measurements is here proposed. Mathematical relationships between F2 layer characteristics and vTEC values have been derived using South African colocated ionosonde and GNSS stations. The same procedure can, however, be applied successfully in each region where such data are available. The goodness of the proposed IRI UP method, based on assimilated vTEC values, has been tested for several quiet and disturbed days in 2017 and 2018. IRI UP exhibits better performances than IRI for foF2, for most of the analyzed cases. Slight improvements are achieved in modeling hmF2 only for very disturbed periods in 2017. Due to the very good coverage of the terrestrial surface that GNSS receivers have achieved in recent years, we suggest that the method proposed here can be a good implementation of the IRI model for Space Weather nowcasting purposes, at least for foF2.
Coulomb pre-stress and fault bends are ignored yet vital factors for earthquake triggering and hazard
Authors: Mildon Z. K. , Roberts G. P. , Faure Walker J. P. , Toda S.
Published: June 2019

Successive locations of individual large earthquakes (Mw > 5.5) over years to centuries can be difficult to explain with simple Coulomb stress transfer (CST) because it is common for seismicity to circumvent nearest-neighbour along-strike faults where coseismic CST is greatest. We demonstrate that Coulomb pre-stress (the cumulative CST from multiple earthquakes and interseismic loading on non-planar faults) may explain this, evidenced by study of a 667-year historical record of earthquakes in central Italy. Heterogeneity in Coulomb pre-stresses across the fault system is >±50 bars, whereas coseismic CST is <±2 bars, so the latter will rarely overwhelm the former, explaining why historical earthquakes rarely rupture nearest neighbor faults. However, earthquakes do tend to occur where the cumulative coseismic and interseismic CST is positive, although there are notable examples where earthquake propagate across negatively stressed portions of faults. Hence Coulomb pre-stress calculated for non-planar faults is an ignored yet vital factor for earthquake triggering.
IL-33-mediated mast cell activation promotes gastric cancer through macrophage mobilization
Authors: Eissmann Moritz F. , Dijkstra Christine , Jarnicki Andrew , Phesse Toby , Brunnberg Jamina , Poh Ashleigh R. , Etemadi Nima , Tsantikos Evelyn , Thiem Stefan , Huntington Nicholas D. , Hibbs Margaret L. , Boussioutas Alex , Grimbaldeston Michele A. , Buchert Michael , O’Donoghue Robert J. J. , Masson Frederick , Ernst Matthias
Published: June 2019

The contribution of mast cells in the microenvironment of solid malignancies remains controversial. Here we functionally assess the impact of tumor-adjacent, submucosal mast cell accumulation in murine and human intestinal-type gastric cancer. We find that genetic ablation or therapeutic inactivation of mast cells suppresses accumulation of tumor-associated macrophages, reduces tumor cell proliferation and angiogenesis, and diminishes tumor burden. Mast cells are activated by interleukin (IL)-33, an alarmin produced by the tumor epithelium in response to the inflammatory cytokine IL-11, which is required for the growth of gastric cancers in mice. Accordingly, ablation of the cognate IL-33 receptor St2 limits tumor growth, and reduces mast cell-dependent production and release of the macrophage-attracting factors Csf2, Ccl3, and Il6. Conversely, genetic or therapeutic macrophage depletion reduces tumor burden without affecting mast cell abundance. Therefore, tumor-derived IL-33 sustains a mast cell and macrophage-dependent signaling cascade that is amenable for the treatment of gastric cancer.
Reduced subcutaneous adipogenesis in human hypertrophic obesity is linked to senescent precursor cells
Authors: Gustafson Birgit , Nerstedt Annika , Smith Ulf
Published: June 2019

Inappropriate expansion of the adipose cells in the subcutaneous adipose tissue (SAT) is a characteristic of hypertrophic obesity and of individuals with genetic predisposition for T2D (first-degree relatives; FDR). It is associated with insulin resistance, a dysfunctional, adipose tissue and reduced adipogenesis. We examined the regulation of adipogenesis in human SAT precursor cells and found ZNF521 to be a critical regulator of early adipogenic commitment and precursor cells leaving the cell cycle. However, neither altered upstream signalling nor lack of SAT progenitor cells could explain the reduced adipogenesis in hypertrophic obesity. Instead, we show that progenitor cells undergoing poor differentiation are characterized by senescence, inability to suppress p53/P16INK4 and secretion of factors reducing adipogenesis in non-senescent cells. We found aging, FDR and established T2D to be associated with increased progenitor cell senescence, reduced adipogenesis and hypertrophic expansion of the SAT adipose cells.
Thermoresponsive nanoemulsion-based gel synthesized through a low-energy process
Authors: Hashemnejad Seyed Meysam , Badruddoza Abu Zayed Md , Zarket Brady , Ricardo Castaneda Carlos , Doyle Patrick S.
Published: June 2019

Thermoresponsive nanoemulsions find utility in applications ranging from food to pharmaceuticals to consumer products. Prior systems have found limited translation to applications due to cytotoxicity of the compositions and/or difficulties in scaling-up the process. Here, we report a route to thermally gel an oil-in-water nanoemulsion using a small amount of FDA-approved amphiphilic triblock Pluronic copolymers which act as gelling agents. At ambient temperature the suspension displays liquid-like behavior, and quickly becomes an elastic gel at elevated temperatures. We propose a gelation mechanism triggered by synergistic action of thermally-induced adsorption of Pluronic copolymers onto the droplet interface and an increased micelle concentration in the aqueous solution. We demonstrate that the system’s properties can be tuned via many factors and report their rheological properties. The nanoemulsions are prepared using a low-energy process which offers an efficient route to scale-up. The nanoemulsion formulations are well-suited for use in cosmetics and pharmaceutical applications.
Molecular phenotyping of the surfaceome of migratory chondroprogenitors and mesenchymal stem cells using biotinylation, glycocapture and quantitative LC-MS/MS proteomic analysis
Authors: Matta Csaba , Boocock David J. , Fellows Christopher R. , Miosge Nicolai , Dixon James E. , Liddell Susan , Smith Julia , Mobasheri Ali
Published: June 2019

The complement of cell surface proteins, collectively referred to as the surfaceome, is a useful indicator of normal differentiation processes, and the development of pathologies such as osteoarthritis (OA). We employed biochemical and proteomic tools to explore the surfaceome and to define biomarkers in chondrogenic progenitor cells (CPC) derived from human OA knee articular cartilage. These cells have great therapeutic potential, but their unexplored biology limits their clinical application. We performed biotinylation combined with glycocapture and high throughput shotgun proteomics to define the surface proteome of human bone marrow mesenchymal stem cells (MSCs) and human CPCs. We prepared cell surface protein-enriched fractions from MSCs and CPCs, and then a proteomic approach was used to compare and evaluate protein changes between undifferentiated MSCs and CPCs. 1256 proteins were identified in the study, of which 791 (63%) were plasma membrane, cell surface or extracellular matrix proteins. Proteins constituting the surfaceome were annotated and categorized. Our results provide, for the first time, a repository of quantitative proteomic data on the surfaceome of two closely related cell types relevant to cartilage biology and OA. These results may provide novel insights into the transformation of the surfaceome during chondrogenic differentiation and phenotypic changes during OA development.
Analytical level set fabrication constraints for inverse design
Authors: Vercruysse Dries , Sapra Neil V. , Su Logan , Trivedi Rahul , Vučković Jelena
Published: June 2019

Inverse design methods produce nanophotonic devices with arbitrary geometries that show high efficiencies as well as novel functionalities. Ensuring fabricability during optimization of these unrestricted device geometries is a major challenge for these design methods. In this work, we construct a fabrication constraint penalty function for level set geometry representations of these devices. This analytical penalty function limits both the gap size and boundary curvature of a device. We incorporate this penalty in a fully automated optical design flow using a quasi-Newton optimization method. The performance of our design method is evaluated by designing a series of waveguide demultiplexers (WDM) and mode converters with various footprints and minimum feature sizes. Finally, we design and experimentally characterize three WDMs with a 80 nm, 120 nm and 160 nm feature size.
Direct measurement and analytical description of the mode alignment in inversely tapered silicon nano-resonators
Authors: Schmitt Sebastian W. , Schwarzburg Klaus , Dubourdieu Catherine
Published: June 2019

Inversely tapered silicon photonic resonators on silicon substrates were shown to host multiple high–Q whispering gallery modes and constitute versatile building blocks for CMOS compatible solid state lighting, optical sensing and modulator devices. So far, numerical analyses by the finite difference time domain method have been used to predict the height distribution of whispering gallery modes in such resonators. In this study, we provide an experimental evidence of this mode distribution along the resonator height by selectively exciting whispering gallery modes using cathodoluminescence spectroscopy. Further we derive analytical functions that permit to relate the height distribution of modes with a defined polarization, symmetry and effective refractive index to the geometrical shape of the inversely tapered resonators.
Chromatin Compaction by Small RNAs and the Nuclear RNAi Machinery in C. elegans
Authors: Fields Brandon D. , Kennedy Scott
Published: June 2019

DNA is organized and compacted into higher-order structures in order to fit within nuclei and to facilitate gene regulation. Mechanisms by which higher order chromatin structures are established and maintained are poorly understood. In C. elegans, nuclear-localized small RNAs engage the nuclear RNAi machinery to regulate gene expression and direct the post-translational modification of histone proteins. Here we confirm a recent report suggesting that nuclear small RNAs initiate or maintain chromatin compaction states in C. elegans germ cells. Additionally, we show that experimentally provided small RNAs are sufficient to direct chromatin compaction and that this compaction requires the small RNA-binding Argonaute NRDE-3, the pre-mRNA associated factor NRDE-2, and the HP1-like protein HPL-2. Our results show that small RNAs, acting via the nuclear RNAi machinery and an HP1-like protein, are capable of driving chromatin compaction in C. elegans.
Conversion of human and mouse fibroblasts into lung-like epithelial cells
Authors: Wong Amy P. , Shojaie Sharareh , Liang Qin , Xia Sunny , Di Paola Michelle , Ahmadi Saumel , Bilodeau Claudia , Garner Jodi , Post Martin , Duchesneau Pascal , Waddell Thomas K. , Bear Christine E. , Nagy Andras , Rossant Janet
Published: June 2019

Cell lineage conversion of fibroblasts to specialized cell types through transdifferentiation may provide a fast and alternative cell source for regenerative medicine. Here we show that transient transduction of fibroblasts with the four reprogramming factors (Oct4, Sox2, Klf4, and c-Myc) in addition to the early lung transcription factor Nkx2-1 (also known as Ttf1), followed by directed differentiation of the cells, can convert mouse embryonic and human adult dermal fibroblasts into induced lung-like epithelial cells (iLEC). These iLEC differentiate into multiple lung cell types in air liquid interface cultures, repopulate decellularized rat lung scaffolds, and form lung epithelia composed of Ciliated, Goblet, Basal, and Club cells after transplantation into immune-compromised mice. As proof-of-concept, differentiated human iLEC harboring the Cystic Fibrosis mutation dF508 demonstrated pharmacological rescue of CFTR function using the combination of lumacaftor and ivacaftor. Overall, this is a promising alternative approach for generation of patient-specific lung-like progenitors to study lung function, disease and future regeneration strategies.
Mutational mimics of allosteric effectors: a genome editing design to validate allosteric drug targets
Authors: Tang Qingling , Villar Maria T. , Artigues Antonio , Thyfault John P. , Apte Udayan , Zhu Hao , Peterson Kenneth R. , Fenton Aron W.
Published: June 2019

Development of drugs that allosterically regulate enzyme functions to treat disease is a costly venture. Amino acid susbstitutions that mimic allosteric effectors in vitro will identify therapeutic regulatory targets enhancing the likelihood of developing a disease treatment at a reasonable cost. We demonstrate the potential of this approach utilizing human liver pyruvate kinase (hLPYK) as a model. Inhibition of hLPYK was the first desired outcome of this study. We identified individual point mutations that: 1) mimicked allosteric inhibition by alanine, 2) mimicked inhibition by protein phosphorylation, and 3) prevented binding of fructose-1,6-bisphosphate (Fru-1,6-BP). Our second desired outcome was activation of hLPYK. We identified individual point mutations that: 1) prevented hLPYK from binding alanine, the allosteric inhibitor, 2) prevented inhibitory protein phosphorylation, or 3) mimicked allosteric activation by Fru-1,6-BP. Combining the three activating point mutations produced a constitutively activated enzyme that was unresponsive to regulators. Expression of a mutant hLPYK transgene containing these three mutations in a mouse model was not lethal. Thus, mutational mimics of allosteric effectors will be useful to confirm whether allosteric activation of hLPYK will control glycolytic flux in the diabetic liver to reduce hepatic glucose production and, in turn, reduce or prevent hyperglycemia.
Multidimensional diffusion MRI with spectrally modulated gradients reveals unprecedented microstructural detail
Authors: Lundell H. , Nilsson M. , Dyrby T. B. , Parker G. J. M. , Cristinacce P. L. Hubbard , Zhou F.-L. , Topgaard D. , Lasič S.
Published: June 2019

Characterization of porous media is essential in a wide range of biomedical and industrial applications. Microstructural features can be probed non-invasively by diffusion magnetic resonance imaging (dMRI). However, diffusion encoding in conventional dMRI may yield similar signatures for very different microstructures, which represents a significant limitation for disentangling individual microstructural features in heterogeneous materials. To solve this problem, we propose an augmented multidimensional diffusion encoding (MDE) framework, which unlocks a novel encoding dimension to assess time-dependent diffusion specific to structures with different microscopic anisotropies. Our approach relies on spectral analysis of complex but experimentally efficient MDE waveforms. Two independent contrasts to differentiate features such as cell shape and size can be generated directly by signal subtraction from only three types of measurements. Analytical calculations and simulations support our experimental observations. Proof-of-concept experiments were applied on samples with known and distinctly different microstructures. We further demonstrate substantially different contrasts in different tissue types of a post mortem brain. Our simultaneous assessment of restriction size and shape may be instrumental in studies of a wide range of porous materials, enable new insights into the microstructure of biological tissues or be of great value in diagnostics.
Involvement of Hsp90 and cyclophilins in intoxication by AIP56, a metalloprotease toxin from Photobacterium damselae subsp. piscicida
Authors: Rodrigues Inês S. , Pereira Liliana M. G. , Lisboa Johnny , Pereira Cassilda , Oliveira Pedro , dos Santos Nuno M. S. , do Vale Ana
Published: June 2019

AIP56 (apoptosis inducing protein of 56 kDa) is a key virulence factor secreted by virulent strains of Photobacterium damselae subsp. piscicida (Phdp), a Gram-negative bacterium that causes septicemic infections in several warm water marine fish species. AIP56 is systemically disseminated during infection and induces massive apoptosis of host macrophages and neutrophils, playing a decisive role in the disease outcome. AIP56 is a single-chain AB-type toxin, being composed by a metalloprotease A domain located at the N-terminal region connected to a C-terminal B domain, required for internalization of the toxin into susceptible cells. After binding to a still unidentified surface receptor, AIP56 is internalised through clathrin-mediated endocytosis, reaches early endosomes and translocates into the cytosol through a mechanism requiring endosomal acidification and involving low pH-induced unfolding of the toxin. At the cytosol, the catalytic domain of AIP56 cleaves NF-κB p65, leading to the apoptotic death of the intoxicated cells. It has been reported that host cytosolic factors, including host cell chaperones such as heat shock protein 90 (Hsp90) and peptidyl-prolyl cis/trans isomerases (PPIases), namely cyclophilin A/D (Cyp) and FK506-binding proteins (FKBP) are involved in the uptake of several bacterial AB toxins with ADP-ribosylating activity, but are dispensable for the uptake of other AB toxins with different enzymatic activities, such as Bacillus anthracis lethal toxin (a metalloprotease) or the large glycosylating toxins A and B of Clostridium difficile. Based on these findings, it has been proposed that the requirement for Hsp90/PPIases is a common and specific characteristic of ADP-ribosylating toxins. In the present work, we demonstrate that Hsp90 and the PPIases cyclophilin A/D are required for efficient intoxication by the metalloprotease toxin AIP56. We further show that those host cell factors interact with AIP56 in vitro and that the interactions increase when AIP56 is unfolded. The interaction with Hsp90 was also demonstrated in intact cells, at 30 min post-treatment with AIP56, suggesting that it occurs during or shortly after translocation of the toxin from endosomes into the cytosol. Based on these findings, we propose that the participation of Hsp90 and Cyp in bacterial toxin entry may be more disseminated than initially expected, and may include toxins with different catalytic activities.
NTHL1 biallelic mutations seldom cause colorectal cancer, serrated polyposis or a multi-tumor phenotype, in absence of colorectal adenomas
Authors: Belhadj Sami , Quintana Isabel , Mur Pilar , Munoz-Torres Pau M. , Alonso M. Henar , Navarro Matilde , Terradas Mariona , Piñol Virginia , Brunet Joan , Moreno Victor , Lázaro Conxi , Capellá Gabriel , Valle Laura
Published: June 2019

The cancer-predisposing syndrome caused by biallelic mutations in NTHL1 may not be a solely colorectal cancer (CRC) and polyposis syndrome but rather a multi-tumor recessive disease. The presence of ≤10 adenomas in several mutation carriers suggests a possible causal role of NTHL1 in hereditary or early-onset nonpolyposis CRC. The involvement of NTHL1 in serrated/hyperplastic polyposis remains unexplored. The aim of our study is to elucidate the role of NTHL1 in the predisposition to personal or familial history of multiple tumor types, familial/early-onset nonpolyposis CRC, and serrated polyposis. NTHL1 mutational screening was performed in 312 cancer patients with personal or family history of multiple tumor types, 488 with hereditary nonpolyposis CRC, and 96 with serrated/hyperplastic polyposis. While no biallelic mutation carriers were identified in patients with personal and/or family history of multiple tumor types or with serrated polyposis, one was identified among the 488 nonpolyposis CRC patients. The carrier of c.268C>T (p.Q90*) and 550-1G>A was diagnosed with CRC and meningioma at ages 37 and 45 respectively, being reclassified as attenuated adenomatous polyposis after the cumulative detection of 26 adenomas. Our findings suggest that biallelic mutations in NTHL1 rarely cause CRC, a personal/familial multi-tumor history, or serrated polyposis, in absence of adenomas.
Immunization with merozoite surface protein 2 fused to a Plasmodium-specific carrier protein elicits strain-specific and strain-transcending, opsonizing antibody
Authors: Eacret Jacqueline S. , Gonzales Donna M. , Franks Raymond G. , Burns James M.
Published: June 2019

Vaccine trials and cohort studies in Plasmodium falciparum endemic areas indicate that naturally-acquired and vaccine-induced antibodies to merozoite surface protein 2 (MSP2) are associated with resistance to malaria. These data indicate that PfMSP2 has significant potential as a component of a multi-antigen malaria vaccine. To overcome challenges encountered with subunit malaria vaccines, we established that the use of highly immunogenic rPfMSP8 as a carrier protein for leading vaccine candidates rPfMSP119 and rPfs25 facilitated antigen production, minimized antigenic competition and enhanced induction of functional antibodies. We applied this strategy to optimize a rPfMSP2 (3D7)-based subunit vaccine by producing unfused rPfMSP2 or chimeric rPfMSP2/8 in Escherichia coli. rPfMSP2 formed fibrils, which induced splenocyte proliferation in an antigen receptor-independent, TLR2-dependent manner. However, fusion to rPfMSP8 prevented rPfMSP2 amyloid-like fibril formation. Immunization of rabbits elicited high-titer anti-PfMSP2 antibodies that recognized rPfMSP2 of the 3D7 and FC27 alleles, as well as native PfMSP2. Competition assays revealed a difference in the specificity of antibodies induced by the two rPfMSP2-based vaccines, with evidence of epitope masking by rPfMSP2-associated fibrils. Rabbit anti-PfMSP2/8 was superior to rPfMSP2-elicited antibody at opsonizing P. falciparum merozoites for phagocytosis. These data establish rPfMSP8 as an effective carrier for a PfMSP2-based subunit malaria vaccine.
Predictability of a modified Mini- Nutritional- Assessment version on six-month and one-year mortality in hospitalized geriatric patients: a comparative analysis
Authors: Becker Lea , Volkert Dorothee , Christian Sieber Cornel , Gaßmann Karl-Günter , Ritt Martin
Published: June 2019

Recently we introduced a modified Mini Nutritional Assessment (MNA) Short Form (MNA-SF) and Long Form (MNA-SF) with operationalization of the ‘mobility’ and ‘neuropsychological problems’ items of the MNA using scores on Barthel Index mobility item and Mini Mental State Examination and Geriatric Depression Scale scores. We have now evaluated the abilities of this modified MNA-SF and MNA-LF to predict mortality in comparison with the standard MNA-SF and MNA-LF and the Nutritional Risk Screening 2002 (NRS 2002) and the Malnutrition Universal Screening Tool (MUST). A prospective analysis was performed in 240 hospitalised geriatric patients aged ≥ 65 years. Malnutrition and/or malnutrition risk were assessed using the modified MNA-SF and MNA-LF, the standard MNA-SF and MNA-LF, and the NRS 2002 and MUST. The modified MNA-SF and MNA-LF and the standard MNA-SF and MNA-LF assessments (all p < 0.05), but not NRS 2002 or MUST (all p ≥ 0.05), predicted six-month and/or one-year mortality. Prediction of six-month and/or one-year mortality by the modified MNA-SF was comparable with predictions by the standard MNA-SF and MNA-LF (all p ≥ 0.05). The modified MNA-LF showed better prediction of six-month and one-year mortality than the standard MNA-SF and MNA-LF (all p < 0.05). The modified MNA-LF (all adjusted p < 0.05), but none of the other instruments (all adjusted p ≥ 0.05), predicted six-month and one-year mortality independently of age, sex, frailty, comorbidity and ADL disability burden. The modified MNA-SF and MNA-LF emerged as potentially valuable tools for predicting mortality in patients hospitalised on geriatric wards.
Lupin (Lupinus spp.) seeds exert anthelmintic activity associated with their alkaloid content
Authors: Dubois O. , Allanic C. , Charvet C. L. , Guégnard F. , Février H. , Théry-Koné I. , Cortet J. , Koch C. , Bouvier F. , Fassier T. , Marcon D. , Magnin-Robert J. B. , Peineau N. , Courtot E. , Huau C. , Meynadier A. , Enguehard-Gueiffier C. , Neveu C. , Boudesocque-Delaye L. , Sallé G.
Published: June 2019

The growing range of drug resistant parasitic nematode populations threatens the sustainability of ruminant farming worldwide. In this context, nutraceuticals, animal feed that provides necessary dietary requirements while ensuring parasite control, could contribute to increase farming sustainability in developed and low resource settings. In this study, we evaluated the anthelmintic potential of lupin seed extracts against the major ruminant trichostrongylids, Haemonchus contortus and Teladorsagia circumcincta. In vitro observations showed that seed extracts from commercially available lupin varieties could significantly but moderately inhibit larval migration. This anthelmintic effect was mediated by the seed alkaloid content and was potent against both fully susceptible and multidrug resistant H. contortus isolates as well as a susceptible T. circumcincta isolate. Analytical chemistry revealed a set of four lupanine and sparteine-derivatives with anthelmintic activity, and electrophysiology assays on recombinant nematode acetylcholine receptors suggested an antagonistic mode of action for lupin alkaloids. An in vivo trial in H. contortus infected lupin-fed ewes and goats failed to demonstrate any direct anthelmintic effect of crude lupin seeds but infected lupin-fed goats suffered significantly less parasite-mediated blood losses. Altogether, our findings suggest that the anthelmintic potential of lupin remains limited. However, the potent alkaloids identified could lead to the development of novel drugs or may be used in combination with current anthelmintics to improve their efficacy.
Colour change and behavioural choice facilitate chameleon prawn camouflage against different seaweed backgrounds
Authors: Green Samuel D. , Duarte Rafael C. , Kellett Emily , Alagaratnam Natasha , Stevens Martin
Published: June 2019

Camouflage is driven by matching the visual environment, yet natural habitats are rarely uniform and comprise many backgrounds. Therefore, species often exhibit adaptive traits to maintain crypsis, including colour change and behavioural choice of substrates. However, previous work largely considered these solutions in isolation, whereas many species may use a combination of behaviour and appearance to facilitate concealment. Here we show that green and red chameleon prawns (Hippolyte varians) closely resemble their associated seaweed substrates to the vision of predatory fish, and that they can change colour to effectively match new backgrounds. Prawns also select colour-matching substrates when offered a choice. However, colour change occurs over weeks, consistent with seasonal changes in algal cover, whereas behavioural choice of matching substrates occurs in the short-term, facilitating matches within heterogeneous environments. We demonstrate how colour change and behaviour combine to facilitate camouflage against different substrates in environments varying spatially and temporally.
Synergies between mycorrhizal fungi and soil microbial communities increase plant nitrogen acquisition
Authors: Hestrin Rachel , Hammer Edith C. , Mueller Carsten W. , Lehmann Johannes
Published: June 2019

Nitrogen availability often restricts primary productivity in terrestrial ecosystems. Arbuscular mycorrhizal fungi are ubiquitous symbionts of terrestrial plants and can improve plant nitrogen acquisition, but have a limited ability to access organic nitrogen. Although other soil biota mineralize organic nitrogen into bioavailable forms, they may simultaneously compete for nitrogen, with unknown consequences for plant nutrition. Here, we show that synergies between the mycorrhizal fungus Rhizophagus irregularis and soil microbial communities have a highly non-additive effect on nitrogen acquisition by the model grass Brachypodium distachyon. These multipartite microbial synergies result in a doubling of the nitrogen that mycorrhizal plants acquire from organic matter and a tenfold increase in nitrogen acquisition compared to non-mycorrhizal plants grown in the absence of soil microbial communities. This previously unquantified multipartite relationship may contribute to more than 70 Tg of annually assimilated plant nitrogen, thereby playing a critical role in global nutrient cycling and ecosystem function.
Crystal structure of human endothelin ETB receptor in complex with peptide inverse agonist IRL2500
Authors: Nagiri Chisae , Shihoya Wataru , Inoue Asuka , Kadji Francois Marie Ngako , Aoki Junken , Nureki Osamu
Published: June 2019

Endothelin receptors (ETA and ETB) are G-protein-coupled receptors activated by endothelin-1 and are involved in blood pressure regulation. IRL2500 is a peptide-mimetic of the C-terminal tripeptide of endothelin-1, and has been characterized as a potent ETB-selective antagonist, which has preventive effects against brain edema. Here, we report the crystal structure of the human ETB receptor in complex with IRL2500 at 2.7 Å-resolution. The structure revealed the different binding modes between IRL2500 and endothelin-1, and provides structural insights into its ETB-selectivity. Notably, the biphenyl group of IRL2500 penetrates into the transmembrane core proximal to D2.50, thus stabilizing the inactive conformation. Using the newly-established constitutively active mutant, we clearly demonstrate that IRL2500 functions as an inverse agonist for the ETB receptor. The current findings will expand the chemical space of ETR antagonists and facilitate the design of inverse agonists for other class A GPCRs.