bluuebunny/crossref_metadata_2025 huggingface dataset:
Prospective comparative study of the evolution of probable
Alzheimer's disease and Parkinson's disease dementia
Authors: STERN YAAKOV , TANG MING-XIN , JACOBS DIANE M. , SANO MARY , MARDER KAREN , BELL KAREN , DOONEIEF GEORGE , SCHOFIELD PETER , CÔTÉ LUCIEN
Published: September 2019

No previous comparison of test performance in probable
Alzheimer's disease (pAD) and Parkinson's disease
(PD) dementia has provided information about potential
differences in the dementing process. This study compared
the evolution of cognitive changes associated with these
dementias. Generalized estimating equations (GEE) applied
to regression analyses with repeated measures were used
to evaluate cognitive changes over 1 to 3 years prior
to the point when dementia was diagnosed in 40 matched
pairs of patients with incident pAD and PD dementia. Both
groups' performance declined on the Short Blessed,
Selective Reminding Test (SRT; total recall, long-term
retrieval, and delayed recall), Boston Naming Test, Category
Fluency, and Similarities. The decline on naming and SRT
delayed recall was more rapid in the PD dementia group,
suggesting that these performance deficits emerge earlier
in the development of pAD. The PD dementia group performed
worse on Category Fluency throughout the follow-up period,
suggesting either that dementia is overlaid on this preexisting
performance deficit or that this type of executive deficit
is an early manifestation of dementia in PD. The pAD group
performed more poorly throughout the follow-up period on
SRT delayed recognition, consistent with a pAD-specific
encoding deficit. We conclude that while pAD and PD dementia
are similar in many respects, differences in their evolution
support previous observation of unique features in the
2 dementias and suggest different underlying pathologies.
(JINS, 1998, 4, 279–284.)
Normative data for a brief neuropsychological battery administered
to English- and Spanish-speaking community-dwelling elders
Authors: STRICKS LAURIE , PITTMAN JOHN , JACOBS DIANE M. , SANO MARY , STERN YAAKOV
Published: September 2019

The use of neuropsychological tests in non-English-speaking
populations and among those with less education has been
limited because most tests have been standardized for English-speaking
populations with relatively high levels of education. In
effort to establish norms, a battery of neuropsychological
tests was administered, in either English or Spanish, to
995 normal elders with a wide range of educational attainment,
residing in the community of Washington Heights–Inwood
in northern Manhattan. Results indicate that age, education,
and language all influence test performance and should
be considered when evaluating neuropsychological measures.
(JINS, 1998, 4, 311–318.)
Verbal learning and memory in alcohol abusers and polysubstance
abusers with concurrent alcohol abuse
Authors: BONDI MARK W. , DRAKE ANGELA I. , GRANT IGOR
Published: September 2019

To define the combined effects of drug and alcohol
abuse on verbal learning and memory, 70 alcoholic and 80
polysubstance abuse (PSA) individuals with concurrent alcohol
abuse were compared on a list learning task, the California
Verbal Learning Test (CVLT). Despite demonstrating similar
learning strategies, response styles, and error patterns,
the PSA group nonetheless exhibited significantly greater
recall deficits than the alcoholic group on the CVLT. These
deficits were particularly evident in those who were heaviest
abusers of cocaine. PSA participants did not, however,
evidence greater recognition memory deficits. This pattern
of greater deficits on recall than on recognition memory,
as well as poor consolidation, is consistent with the initiation–retrieval
difficulties of patient groups with subcortical dysfunction.
It is concluded that the combined use of alcohol and drugs,
cocaine in particular, may compound memory difficulties
beyond what is typically observed in alcoholic individuals.
(JINS, 1998, 4, 319–328.)
China's fiscal decentralization and environmental quality: theory and an empirical study
Authors: Hao Yu , Chen Yu-Fu , Liao Hua , Wei Yi-Ming
Published: September 2019

As a wide-reaching institutional reform, China's fiscal decentralization was launched in the early 1980s to encourage provincial economic growth by granting more financial autonomy to provincial governments. In this paper, the impact of fiscal decentralization on China's environmental quality is investigated both theoretically and empirically. A neoclassical model is developed based on the primary characteristics of China's fiscal decentralization. Using provincial panel data for the period 1995-2015, a two-equation regression model is employed to empirically verify the three propositions of the theoretical model: (1) there exists an inverted-U shaped relationship between fiscal decentralization and GDP per capita; (2) fiscal decentralization is positively related to GDP per capita at the steady state; (3) there is an inverted-U shaped Environmental Kuznets Curve relationship between pollution emissions and economic growth.
Novelistic essay: on the form of Wang Shu’s PhD thesis, ‘Fictionalising Cities’
Authors: Xinleng Gaojin , Hale Jonathan , Wang Qi
Published: September 2019

In 2012 the Chinese architect Wang Shu won the distinguished Pritzker Architecture Prize. Since then, his buildings and his architectural thinking have received increasing international attention. Among his many written works, Wang’s PhD thesis ‘Fictionalising Cities’ – completed in 2000 under the supervision of Professor Jiwei Lu at Tongji University in Shanghai – is widely considered the definitive statement of his architectural thought and methodology. It comprises a structuralist study of the city and its architecture, doing so through the development of two key themes. The first is Wang’s theoretical discussion of the application of structuralist-semiotic approaches to architecture, urban research, and other areas in the humanities, and the second is his reading of the Chinese city and China’s landscape architecture tradition in the light of this theoretical discussion. Wang believes that traditional Chinese cities have their own structure, components and rules of combination, and refers to them as instances of ‘texture city’ (), a term that proposes an analogy between Roland Barthes’s notion of text and the city, both of which are understood as a ‘fabric of signifiers’.
OVERVIEW OF NONLINEAR MACROECONOMETRIC EMPIRICAL MODELS
Authors: Granger Clive W.J.
Published: September 2019

A survey of nonlinear multivariate macro empirical models is attempted. Although theory may suggest that nonlinearity is to be expected, empirical studies have difficulty in discovering strong consistent effects. Regime switching techniques appear to be the most successful and evidence of nonlinearity is most found for interest rates. Most of the studies emphasize model fitting rather than model evaluation, which limits their usefulness.
MULTIVARIATE STAR ANALYSIS OF MONEY–OUTPUT RELATIONSHIP
Authors: Rothman Philip , van Dijk Dick , Philip Hans
Published: September 2019

This paper investigates the potential for nonlinear Granger causality from money to output. Using a standard four-variable linear (subset) vector error-correction model (VECM), we first show that the null hypothesis of linearity can be rejected against the alternative of smooth-transition autoregressive nonlinearity. An interesting result from this stage of the analysis is that the yearly growth rate of money is identified as one of the variables that may govern the switching between regimes. Smooth-transition VECM's (STVECM's) are then used to examine whether there is nonlinear Granger causality in the money–output relationship in the sense that lagged values of money enter the model's output equation as regressors. We evaluate this type of nonlinear Granger causality with both in-sample and out-of-sample analyses. For the in-sample analysis, we compare alternative models using the Akaike information criteria, which can be interpreted as a predictive accuracy test. The results show that allowing for both nonlinearity and for money–output causality leads to considerable improvement in model's in-sample performance. By contrast, the out-of-sample forecasting results do not suggest that money is nonlinearly Granger causal for output. They also show that, according to several criteria, the linear VECM's dominate the STVECM's. However, these forecast improvements seldomly are statistically significant at conventional levels.
VECTOR AUTOREGRESSIVE PROCESSES WITH NONLINEAR TIME TRENDS IN COINTEGRATING RELATIONS
Authors: Ripatti Antti , Pentti
Published: September 2019

We extend the conventional cointegrated VAR model to allow for general nonlinear deterministic trends. These nonlinear trends can be used to model gradual structural changes in the intercept term of the cointegrating relations. A general asymptotic theory of estimation and statistical inference is reviewed and a diagnostic test for the correct specification of an employed nonlinear trend is developed. The methods are applied to Finnish interest-rate data. A smooth level shift of the logistic form between the own-yield of broad money and the short-term money market rate is found appropriate for these data. The level shift is motivated by the deregulation of issuing certificates of deposit and its inclusion in the model solves the puzzle of the “missing cointegration vector” found in a previous study.
SOVEREIGN DEFAULT, TRADE, AND TERMS OF TRADE
Authors: Gu Grace Weishi
Published: September 2019

Sovereign defaults are associated with income and trade reductions and terms-of-trade deterioration. This paper develops a two-country model to study the interactions between income, trade, terms of trade, and foreign-debt default risk and default events. Such default risk and events are costly because they adversely affect the demand for a borrower country’s intermediate goods exports and its income. Consequently, trade flows change due to the income loss and consumption home bias. The defaulter’s terms of trade also deteriorate endogenously, which accelerates its income and trade losses. The model produces procyclical imports, exports, terms of trade, and other empirical features of emerging countries’ business cycles and default episodes.
MULTIVARIATE NONLINEAR FORECASTING Using Financial Information to Forecast the Real Sector
Authors: Jaditz Ted , Riddick Leigh A. , Sayers Chera L.
Published: September 2019

Previous work shows that financial series contain important
information on the current state of the economy and expectations for the
future. Further, numerous papers find links between the financial sectors and
the real sectors of the economy. We add to those findings by exploring whether
financial variables help to forecast the
growth rate of industrial production.
We evaluate linear and nonlinear forecasting methods using out-of-sample
forecasting performance. We compare
autoregressive models, error-correcting
models, and multivariate nearest-neighbor
regression models, and we explore the
use of optimally combined forecasts. We find that no single forecasting
technique appears to outperform any other method, and the evidence for
persistent nonlinear patterns is weak.
However, although nonparametric methods
do not offer significant improvements in
forecast accuracy by themselves, more accurate forecasts are obtained when the
nonlinear forecasts are optimally combined. Our results indicate that
financial information can statistically improve the forecasts of the real
sector in these combined models, but the magnitude of the improvement in
root-mean-squared error is small.
Borrowing and shift-induced interference: Contrasting patterns in French–Germanic contact in Brussels and Strasbourg
Authors: Treffers-Daller Jeanine
Published: September 2019

(The reader is referred to the previous issue of Bilingualism for the full text of the article.)
Cultural adaptations of CBT: a summary and discussion of the Special Issue on Cultural Adaptation of CBT
Authors: Naeem Farooq
Published: September 2019

Cognitive behavioural therapy (CBT) in its current form might not be acceptable to service users from a variety of backgrounds. Therefore, it makes sense to adapt CBT when working with diverse populations. Contributors to this special issue of theCognitive Behaviour Therapisthave tackled the issues around the cultural adaptation of CBT from various perspectives, using a variety of methods, and have addressed topics ranging from cultural adaptation to improving access to CBT. Here, I briefly summarize and discuss the papers in this special issue. I start with a systematic review of CBT for social anxiety across cultures. Seven articles cover aspects of adaptation of therapies for people from different backgrounds. Three papers discuss the issues of gender and sexuality when using CBT, while another three papers focus on refugees, asylum seekers and the homeless, and two papers describe the application of CBT with religious populations. Finally, there are seven papers on issues related to service delivery, practice and training and supervision when working with a diverse population. Collectively, papers in this special issue provide us with sufficient evidence that cultural considerations play a vital role when using CBT, offer practical suggestions for improving cultural competence and most importantly, can catalyse future research. However, the full potential of culturally adapted interventions will not be realized until and unless access to CBT is improved. Therefore, there is a need to build robust evidence to convince funders, policy makers and service managers.
Countering Misperceptions to Reduce Prejudice: An Experiment on Attitudes toward Muslim Americans
Authors: Williamson Scott
Published: September 2019

Muslim Americans constitute one of the United States’ most vulnerable minority groups, facing frequent discrimination from both the public and the government. Despite this vulnerability, few studies evaluate interventions for reducing prejudice against Muslim Americans. Building from an insightful literature on the sources of prejudice against Muslim Americans, this paper tests whether attitudes can be improved with information countering misperceptions of the community as particularly foreign, threatening, and disloyal to the United States. The experimental treatment modestly improved attitudes, including among some subgroups predisposed to prejudice against Muslim Americans. However, the treatment struggled to change policy views, and it demonstrated some vulnerability to social desirability bias and priming on terrorism threats. The findings suggest that information campaigns addressing misperceptions can help to reduce prejudice on the margins, but primarily in less politicized contexts.
Phase Relations of a Depleted Peridotite Fluxed by a CO2‐H2O Fluid—Implications for the Stability of Partial Melts Versus Volatile‐Bearing Mineral Phases in the Cratonic Mantle
Authors: Saha Sriparna , Dasgupta Rajdeep
Published: September 2019

We present phase‐equilibria experiments of a K‐bearing, depleted peridotite (Mg# 92) fluxed with a mixed CO2‐H2O fluid (0.5 wt.% CO2 and 0.94 wt.% H2O in the bulk) to gain insight into the stability of volatile‐bearing partial melts versus volatile‐bearing mineral phases in a depleted peridotite system. Experiments were performed at 850–1150 °C and 2–4 GPa using a piston‐cylinder and a multianvil apparatus. Olivine, orthopyroxene, clinopyroxene, and spinel/garnet are present at all experimental conditions. Textural confirmation of partial melt is made at temperatures as low as 1000 °C at 2 GPa, 950 °C at 3 GPa, and 1000 °C at 4 GPa marking the onset of melting at 900–1000 °C at 2 GPa, 850–950 °C at 3 GPa, and 950–1000 °C at 3 GPa. Phlogopite and magnesite breakdown at 900–1000 °C at 2 GPa, 950–1000 °C at 3 GPa, and 1000–1050 °C at 4 GPa. Comparison with previously published experiments in depleted peridotite system with identical CO2‐H2O content introduced via a silicic melt show that introduction of CO2‐H2O as fluid lowers the temperature of phlogopite breakdown by 150–200 °C at 2–4 GPa and stabilizes partial melts at lower temperatures. Our study thus, shows that the volatile‐bearing phase present in the cratonic mantle is controlled by bulk composition and is affected by the process of volatile addition during craton formation in a subduction zone. In addition, volatile introduction via melt versus aqueous fluid, leads to different proportion of anhydrous phases such as olivine and orthopyroxene. Considering the agent of metasomatism is thus critical to evaluate how the bulk composition of depleted peridotite is modified, leading to potential stability of volatile‐bearing phases as the cause of anomalously low shear wave velocity in mantle domains such as mid lithospheric discontinuities beneath continents.
A Darcy‐Brinkman‐Biot Approach to Modeling the Hydrology and Mechanics of Porous Media Containing Macropores and Deformable Microporous Regions
Authors: Carrillo Francisco J. , Bourg Ian C.
Published: September 2019

The coupled hydrology and mechanics of soft porous materials (such as clays, hydrogels, membranes, and biofilms) is an important research area in several fields, including water and energy technologies as well as biomedical engineering. Well‐established models based on poromechanics theory exist for describing these coupled properties, but these models are not adapted to describe systems with more than one characteristic length scale, that is, systems that contain both macropores and micropores. In this paper, we expand upon the well‐known Darcy‐Brinkman formulation of fluid flow in two‐scale porous media to develop a “Darcy‐Brinkman‐Biot” formulation: a general coupled system of equations that approximates the Navier‐Stokes equations in fluid‐filled macropores and resembles the equations for poroelasticity in microporous regions. We parameterized and validated our model for systems that contain either plastic (swelling clay) or elastic microporous regions. In particular, we used our model to predict the permeability of an idealized siliciclastic sedimentary rock as a function of pore water salinity and clay content. Predicted permeability values are well described by a single parametric relation between permeability and clay volume fraction that agrees with existing experimental data sets. Our novel formulation captures the coupled hydro‐chemo‐mechanical properties of sedimentary rocks and other deformable porous media in a manner that can be readily implemented within the framework of Digital Rock Physics.
Temperature as competitive strategy determining factor in pulse-fed aerobic bioreactors
Authors: Stouten Gerben Roelandt , Hogendoorn Carmen , Douwenga Sieze , Kilias Estelle Silvia , Muyzer Gerard , Kleerebezem Robbert
Published: September 2019

Exposing a microbial community to alternating absence and presence of carbon substrate in aerobic conditions is an effective strategy for enrichment of storage polymers (polyhydroxybutyrate, PHB) producing microorganisms. In this work we investigate to which extent intermediate storage polymer production is a temperature independent microbial competition determining factor. Eight parallel bioreactors were operated in the temperature range of 20–40 °C, but intermediate storage polymer production was only obtained at 25–35 °C. Besides PHB production and consumption, cell decay and subsequent cryptic growth on lysis products was found to determine process properties and the microbial community structure at all operational temperatures. At 40 °C decay processes cannot be overcome with additional energy from storage polymers, and fast-growing microorganisms dominate the system. At 20 °C, highly competitive communities with ambiguous storage properties were enriched. The results described here demonstrate that a rigorous experimental approach could aid in the understanding of competitive strategies in microbial communities.
Drivers of human gut microbial community assembly: coadaptation, determinism and stochasticity
Authors: Oliphant Kaitlyn , Parreira Valeria R , Cochrane Kyla , Allen-Vercoe Emma
Published: September 2019

Microbial community assembly is a complex process shaped by multiple factors, including habitat filtering, species assortment and stochasticity. Understanding the relative importance of these drivers would enable scientists to design strategies initiating a desired reassembly for e.g., remediating low diversity ecosystems. Here, we aimed to examine if a human fecal-derived defined microbial community cultured in bioreactors assembled deterministically or stochastically, by completing replicate experiments under two growth medium conditions characteristic of either high fiber or high protein diets. Then, we recreated this defined microbial community by matching different strains of the same species sourced from distinct human donors, in order to elucidate whether coadaptation of strains within a host influenced community dynamics. Each defined microbial ecosystem was evaluated for composition using marker gene sequencing, and for behavior using 1H-NMR-based metabonomics. We found that stochasticity had the largest influence on the species structure when substrate concentrations varied, whereas habitat filtering greatly impacted the metabonomic output. Evidence of coadaptation was elucidated from comparisons of the two communities; we found that the artificial community tended to exclude saccharolytic Firmicutes species and was enriched for metabolic intermediates, such as Stickland fermentation products, suggesting overall that polysaccharide utilization by Firmicutes is dependent on cooperation.
Gene set enrichment analysis to create polygenic scores: a developmental examination of aggression
Authors: Elam Kit K. , Clifford Sierra , Shaw Daniel S. , Wilson Melvin N. , Lemery-Chalfant Kathryn
Published: September 2019

Previous approaches for creating polygenic risk scores (PRSs) do not explicitly consider the biological or developmental relevance of the genetic variants selected for inclusion. We applied gene set enrichment analysis to meta-GWAS data to create developmentally targeted, functionally informed PRSs. Using two developmentally matched meta-GWAS discovery samples, separate PRSs were formed, then examined in time-varying effect models of aggression in a second, longitudinal sample of children (n = 515, 49% female) in early childhood (2–5 years old), and middle childhood (7.5–10.5 years old). Functional PRSs were associated with aggression in both the early and middle childhood models.
Epigenome-wide association study of depression symptomatology in elderly monozygotic twins
Authors: Starnawska A. , Tan Q. , Soerensen M. , McGue M. , Mors O. , Børglum A. D. , Christensen K. , Nyegaard M. , Christiansen L.
Published: September 2019

Depression is a severe and debilitating mental disorder diagnosed by evaluation of affective, cognitive and physical depression symptoms. Severity of these symptoms strongly impacts individual’s quality of life and is influenced by a combination of genetic and environmental factors. One of the molecular mechanisms allowing for an interplay between these factors is DNA methylation, an epigenetic modification playing a pivotal role in regulation of brain functioning across lifespan. The aim of this study was to investigate if there are DNA methylation signatures associated with depression symptomatology in order to identify molecular mechanisms contributing to pathophysiology of depression. We performed an epigenome-wide association study (EWAS) of continuous depression symptomatology score measured in a cohort of 724 monozygotic Danish twins (346 males, 378 females). Through EWAS analyses adjusted for sex, age, flow-cytometry based blood cell composition, and twin relatedness structure in the data we identified depression symptomatology score to be associated with blood DNA methylation levels in promoter regions of neuropsin (KLK8, p-value = 4.7 × 10−7) and DAZ associated protein 2 (DAZAP2, p-value = 3.13 × 10−8) genes. Other top associated probes were located in gene bodies of MAD1L1 (p-value = 5.16 × 10−6), SLC29A2 (p-value = 6.15 × 10−6) and AKT1 (p-value = 4.47 × 10−6), all genes associated before with development of depression. Additionally, the following three measures (a) DNAmAge (calculated with Horvath and Hannum epigenetic clock estimators) adjusted for chronological age, (b) difference between DNAmAge and chronological age, and (c) DNAmAge acceleration were not associated with depression symptomatology score in our cohort. In conclusion, our data suggests that depression symptomatology score is associated with DNA methylation levels of genes implicated in response to stress, depressive-like behaviors, and recurrent depression in patients, but not with global DNA methylation changes across the genome.
ER stress-linked autophagy stabilizes apoptosis effector PERP and triggers its co-localization with SERCA2b at ER–plasma membrane junctions
Authors: McDonnell Samantha J. , Spiller David G. , White Michael R. H. , Prior Ian A. , Paraoan Luminita
Published: September 2019

Specific molecular interactions that underpin the switch between ER stress-triggered autophagy-mediated cellular repair and cellular death by apoptosis are not characterized. This study reports the unexpected interaction elicited by ER stress between the plasma membrane (PM)-localized apoptosis effector PERP and the ER Ca2+ pump SERCA2b. We show that the p53 effector PERP, which specifically induces apoptosis when expressed above a threshold level, has a heterogeneous distribution across the PM of un-stressed cells and is actively turned over by the lysosome. PERP is upregulated following sustained starvation-induced autophagy, which precedes the onset of apoptosis indicating that PERP protein levels are controlled by a lysosomal pathway that is sensitive to cellular physiological state. Furthermore, ER stress stabilizes PERP at the PM and induces its increasing co-localization with SERCA2b at ER–PM junctions. The findings highlight a novel crosstalk between pro-survival autophagy and pro-death apoptosis pathways and identify, for the first time, accumulation of an apoptosis effector to ER–PM junctions in response to ER stress.
Association between habitual yogurt consumption and newly diagnosed non-alcoholic fatty liver disease
Authors: Zhang Shunming , Fu Jingzhu , Zhang Qing , Liu Li , Lu Min , Meng Ge , Yao Zhanxin , Wu Hongmei , Xia Yang , Bao Xue , Gu Yeqing , Sun Shaomei , Wang Xing , Zhou Ming , Jia Qiyu , Song Kun , Wu Yuntang , Xiang Huiling , Niu Kaijun
Published: September 2019

Background/Objectives

Many studies have suggested that probiotics may be applied as a therapeutic agent for non-alcoholic fatty liver disease (NAFLD). However, the effects of frequent yogurt consumption (as a natural probiotic source) on NAFLD remain poorly understood. This study was to examine the association of habitual yogurt consumption with newly diagnosed NAFLD in the general adult population.

Subject/Methods

Overall, 24,389 adults were included in this cross-sectional study. Yogurt consumption was estimated by using a validated self-administered food frequency questionnaire. NAFLD was diagnosed by abdominal ultrasonography. We used logistic regression models to assess the association between yogurt consumption categories and newly diagnosed NAFLD.

Results

The multivariable odds ratios with 95% confidence interval of newly diagnosed NAFLD were 1.00 (0.88, 1.14) for 1 time/week, 0.91 (0.81, 1.02) for 2–3 times/week, and 0.86 (0.76, 0.98) for ≥4 times/week (P for trend = 0.01), compared with those who consumed <1 time/week yogurt. The inverse association was observed in a sensitivity analysis.

Conclusion

Higher yogurt consumption was inversely associated with the prevalence of newly diagnosed NAFLD. These results are needed to be confirmed in randomized controlled trials or prospective studies.
Single-cell transcriptomics reveals multi-step adaptations to endocrine therapy
Authors: Hong Sung Pil , Chan Thalia E. , Lombardo Ylenia , Corleone Giacomo , Rotmensz Nicole , Bravaccini Sara , Rocca Andrea , Pruneri Giancarlo , McEwen Kirsten R. , Coombes R. Charles , Barozzi Iros , Magnani Luca
Published: September 2019

Resistant tumours are thought to arise from the action of Darwinian selection on genetically heterogenous cancer cell populations. However, simple clonal selection is inadequate to describe the late relapses often characterising luminal breast cancers treated with endocrine therapy (ET), suggesting a more complex interplay between genetic and non-genetic factors. Here, we dissect the contributions of clonal genetic diversity and transcriptional plasticity during the early and late phases of ET at single-cell resolution. Using single-cell RNA-sequencing and imaging we disentangle the transcriptional variability of plastic cells and define a rare subpopulation of pre-adapted (PA) cells which undergoes further transcriptomic reprogramming and copy number changes to acquire full resistance. We find evidence for sub-clonal expression of a PA signature in primary tumours and for dominant expression in clustered circulating tumour cells. We propose a multi-step model for ET resistance development and advocate the use of stage-specific biomarkers.
The structural basis of lipid scrambling and inactivation in the endoplasmic reticulum scramblase TMEM16K
Authors: Bushell Simon R. , Pike Ashley C. W. , Falzone Maria E. , Rorsman Nils J. G. , Ta Chau M. , Corey Robin A. , Newport Thomas D. , Christianson John C. , Scofano Lara F. , Shintre Chitra A. , Tessitore Annamaria , Chu Amy , Wang Qinrui , Shrestha Leela , Mukhopadhyay Shubhashish M. M. , Love James D. , Burgess-Brown Nicola A. , Sitsapesan Rebecca , Stansfeld Phillip J. , Huiskonen Juha T. , Tammaro Paolo , Accardi Alessio , Carpenter Elisabeth P.
Published: September 2019

Membranes in cells have defined distributions of lipids in each leaflet, controlled by lipid scramblases and flip/floppases. However, for some intracellular membranes such as the endoplasmic reticulum (ER) the scramblases have not been identified. Members of the TMEM16 family have either lipid scramblase or chloride channel activity. Although TMEM16K is widely distributed and associated with the neurological disorder autosomal recessive spinocerebellar ataxia type 10 (SCAR10), its location in cells, function and structure are largely uncharacterised. Here we show that TMEM16K is an ER-resident lipid scramblase with a requirement for short chain lipids and calcium for robust activity. Crystal structures of TMEM16K show a scramblase fold, with an open lipid transporting groove. Additional cryo-EM structures reveal extensive conformational changes from the cytoplasmic to the ER side of the membrane, giving a state with a closed lipid permeation pathway. Molecular dynamics simulations showed that the open-groove conformation is necessary for scramblase activity.
Replication stress triggers microsatellite destabilization and hypermutation leading to clonal expansion in vitro
Authors: Matsuno Yusuke , Atsumi Yuko , Shimizu Atsuhiro , Katayama Kotoe , Fujimori Haruka , Hyodo Mai , Minakawa Yusuke , Nakatsu Yoshimichi , Kaneko Syuzo , Hamamoto Ryuji , Shimamura Teppei , Miyano Satoru , Tsuzuki Teruhisa , Hanaoka Fumio , Yoshioka Ken-ichi
Published: September 2019

Mismatch repair (MMR)-deficient cancers are characterized by microsatellite instability (MSI) and hypermutation. However, it remains unclear how MSI and hypermutation arise and contribute to cancer development. Here, we show that MSI and hypermutation are triggered by replication stress in an MMR-deficient background, enabling clonal expansion of cells harboring ARF/p53-module mutations and cells that are resistant to the anti-cancer drug camptothecin. While replication stress-associated DNA double-strand breaks (DSBs) caused chromosomal instability (CIN) in an MMR-proficient background, they induced MSI with concomitant suppression of CIN via a PARP-mediated repair pathway in an MMR-deficient background. This was associated with the induction of mutations, including cancer-driver mutations in the ARF/p53 module, via chromosomal deletions and base substitutions. Immortalization of MMR-deficient mouse embryonic fibroblasts (MEFs) in association with ARF/p53-module mutations was ~60-fold more efficient than that of wild-type MEFs. Thus, replication stress-triggered MSI and hypermutation efficiently lead to clonal expansion of cells with abrogated defense systems.
An electrostatic switching mechanism to control the lipid transfer activity of Osh6p
Authors: Lipp Nicolas-Frédéric , Gautier Romain , Magdeleine Maud , Renard Maxime , Albanèse Véronique , Čopič Alenka , Drin Guillaume
Published: September 2019

A central assumption is that lipid transfer proteins (LTPs) bind transiently to organelle membranes to distribute lipids in the eukaryotic cell. Osh6p and Osh7p are yeast LTPs that transfer phosphatidylserine (PS) from the endoplasmic reticulum (ER) to the plasma membrane (PM) via PS/phosphatidylinositol-4-phosphate (PI4P) exchange cycles. It is unknown how, at each cycle, they escape from the electrostatic attraction of the PM, highly anionic, to return to the ER. Using cellular and in vitro approaches, we show that Osh6p reduces its avidity for anionic membranes once it captures PS or PI4P, due to a molecular lid closing its lipid-binding pocket. Thus, Osh6p maintains its transport activity between ER- and PM-like membranes. Further investigations reveal that the lid governs the membrane docking and activity of Osh6p because it is anionic. Our study unveils how an LTP self-limits its residency time on membranes, via an electrostatic switching mechanism, to transfer lipids efficiently.
Anti-relapse neurons in the infralimbic cortex of rats drive relapse-suppression by drug omission cues
Authors: Laque Amanda , L. De Ness Genna , Wagner Grant E. , Nedelescu Hermina , Carroll Ayla , Watry Debbie , M. Kerr Tony , Koya Eisuke , Hope Bruce T. , Weiss Friedbert , Elmer Greg I. , Suto Nobuyoshi
Published: September 2019

Drug addiction is a chronic relapsing disorder of compulsive drug use. Studies of the neurobehavioral factors that promote drug relapse have yet to produce an effective treatment. Here we take a different approach and examine the factors that suppress—rather than promote—relapse. Adapting Pavlovian procedures to suppress operant drug response, we determined the anti-relapse action of environmental cues that signal drug omission (unavailability) in rats. Under laboratory conditions linked to compulsive drug use and heightened relapse risk, drug omission cues suppressed three major modes of relapse-promotion (drug-predictive cues, stress, and drug exposure) for cocaine and alcohol. This relapse-suppression is, in part, driven by omission cue-reactive neurons, which constitute small subsets of glutamatergic and GABAergic cells, in the infralimbic cortex. Future studies of such neural activity-based cellular units (neuronal ensembles/memory engram cells) for relapse-suppression can be used to identify alternate targets for addiction medicine through functional characterization of anti-relapse mechanisms.
Capillary orbits
Authors: Gauthier Anaïs , van der Meer Devaraj , Snoeijer Jacco H. , Lajoinie Guillaume
Published: September 2019

Millimeter-sized objects trapped at a liquid surface distort the interface by their weight, which in turn attracts them towards each other. This ubiquitous phenomenon, colloquially called the “Cheerios effect” is seen in the clumping of cereals in a breakfast bowl, and turns out to be a highly promising route towards controlled self-assembly of colloidal particles at the water surface. Here, we study capillary attraction between levitating droplets, maintained in an inverse Leidenfrost state above liquid nitrogen. We reveal that the drops spontaneously orbit around each other – mirroring a miniature celestial system. In this unique situation of negligible friction, the trajectories are solely shaped by the Cheerios-interaction potential, which we obtain directly from the droplet’s dynamics. Our findings offer an original perspective on contactless and contamination-free droplet cryopreservation processing, where the Leidenfrost effect and capillarity would be used in synergy to vitrify and transport biological samples.
Nano-confined crystallization of organic ultrathin nanostructure arrays with programmable geometries
Authors: Gao Hanfei , Qiu Yuchen , Feng Jiangang , Li Shuang , Wang Huijie , Zhao Yuyan , Wei Xiao , Jiang Xiangyu , Su Yewang , Wu Yuchen , Jiang Lei
Published: September 2019

Fabricating ultrathin organic semiconductor nanostructures attracts wide attention towards integrated electronic and optoelectronic applications. However, the fabrication of ultrathin organic nanostructures with precise alignment, tunable morphology and high crystallinity for device integration remains challenging. Herein, an assembly technique for fabricating ultrathin organic single-crystal arrays with different sizes and shapes is achieved by confining the crystallization process in a sub-hundred nanometer space. The confined crystallization is realized by controlling the deformation of the elastic topographical templates with tunable applied pressures, which produces organic nanostructures with ordered crystallographic orientation and controllable thickness from less than 10 nm to ca. 1 μm. The generality is verified for patterning various typical solution-processable materials with long-range order and pure orientation, including organic small molecules, polymers, metal-halide perovskites and nanoparticles. It is anticipated that this technique with controlling the crystallization kinetics by the governable confined space could facilitate the electronic integration of organic semiconductors.
YAP1 subgroup supratentorial ependymoma requires TEAD and nuclear factor I-mediated transcriptional programmes for tumorigenesis
Authors: Pajtler Kristian W. , Wei Yiju , Okonechnikov Konstantin , Silva Patricia B. G. , Vouri Mikaella , Zhang Lei , Brabetz Sebastian , Sieber Laura , Gulley Melissa , Mauermann Monika , Wedig Tatjana , Mack Norman , Imamura Kawasawa Yuka , Sharma Tanvi , Zuckermann Marc , Andreiuolo Felipe , Holland Eric , Maass Kendra , Körkel-Qu Huiqin , Liu Hai-Kun , Sahm Felix , Capper David , Bunt Jens , Richards Linda J. , Jones David T. W. , Korshunov Andrey , Chavez Lukas , Lichter Peter , Hoshino Mikio , Pfister Stefan M. , Kool Marcel , Li Wei , Kawauchi Daisuke
Published: September 2019

YAP1 fusion-positive supratentorial ependymomas predominantly occur in infants, but the molecular mechanisms of oncogenesis are unknown. Here we show YAP1-MAMLD1 fusions are sufficient to drive malignant transformation in mice, and the resulting tumors share histo-molecular characteristics of human ependymomas. Nuclear localization of YAP1-MAMLD1 protein is mediated by MAMLD1 and independent of YAP1-Ser127 phosphorylation. Chromatin immunoprecipitation-sequencing analyses of human YAP1-MAMLD1-positive ependymoma reveal enrichment of NFI and TEAD transcription factor binding site motifs in YAP1-bound regulatory elements, suggesting a role for these transcription factors in YAP1-MAMLD1-driven tumorigenesis. Mutation of the TEAD binding site in the YAP1 fusion or repression of NFI targets prevents tumor induction in mice. Together, these results demonstrate that the YAP1-MAMLD1 fusion functions as an oncogenic driver of ependymoma through recruitment of TEADs and NFIs, indicating a rationale for preclinical studies to block the interaction between YAP1 fusions and NFI and TEAD transcription factors.
Enhanced ion tolerance of electrokinetic locomotion in polyelectrolyte-coated microswimmer
Authors: Zhan Xiaojun , Wang Jizhuang , Xiong Ze , Zhang Xuan , Zhou Ying , Zheng Jing , Chen Jianan , Feng Shien-Ping , Tang Jinyao
Published: September 2019

Over the last decade, researchers have endeavored to mimic the naturally motile microorganisms and develop artificial nano/microswimmers, which propel themselves in aqueous media. However, most of these nano/microswimmers are propelled by the self-electrophoretic mechanism, which has one critical incompetency: the inability to operate in a high concentration electrolyte solution, such as the most important body fluid, blood. This ionic quenching behavior is well backed by the classical Helmholtz–Smoluchowski theory and seems to be an insurmountable challenge which has shadowed the otherwise promising biomedical applications for artificial nano/microswimmers. Here, we propose that the active nano/microswimmer’s self-electrophoresis is fundamentally different from the passive nanoparticle electrophoresis. By significantly increasing the Dukhin number with polyelectrolyte coating and geometry optimization, a favorable deviation from the Helmholtz–Smoluchowski behavior can be realized, and ion tolerance is enhanced by over 100 times for a visible light-powered self-electrophoretic microswimmer.
The marginal cells of the Caenorhabditis elegans pharynx scavenge cholesterol and other hydrophobic small molecules
Authors: Kamal Muntasir , Moshiri Houtan , Magomedova Lilia , Han Duhyun , Nguyen Ken C. Q. , Yeo May , Knox Jessica , Bagg Rachel , Won Amy M. , Szlapa Karolina , Yip Christopher M. , Cummins Carolyn L. , Hall David H. , Roy Peter J.
Published: September 2019

The nematode Caenorhabditis elegans is a bacterivore filter feeder. Through the contraction of the worm’s pharynx, a bacterial suspension is sucked into the pharynx’s lumen. Excess liquid is then shunted out of the buccal cavity through ancillary channels made by surrounding marginal cells. We find that many worm-bioactive small molecules (a.k.a. wactives) accumulate inside of the marginal cells as crystals or globular spheres. Through screens for mutants that resist the lethality associated with one crystallizing wactive we identify a presumptive sphingomyelin-synthesis pathway that is necessary for crystal and sphere accumulation. We find that expression of sphingomyelin synthase 5 (SMS-5) in the marginal cells is not only sufficient for wactive accumulation but is also important for absorbing exogenous cholesterol, without which C. elegans cannot develop. We conclude that sphingomyelin-rich marginal cells act as a sink to scavenge important nutrients from filtered liquid that might otherwise be shunted back into the environment.
Effects of the serine protease inhibitor rBmTI-A in an experimental mouse model of chronic allergic pulmonary inflammation
Authors: Florencio Ariana Corrêa , de Almeida Robson S. , Arantes-Costa Fernanda M. , Saraiva-Romanholo Beatriz M. , Duran Adriana F. , Sasaki Sérgio D. , Martins Mílton A. , Lopes Fernanda D. T. Q. S. , Tibério Iolanda F. L. C. , Leick Edna A.
Published: September 2019

To evaluate whether a recombinant serine protease inhibitor (rBmTI-A) modulates inflammation in an experimental model of chronic allergic lung inflammation. Balb/c mice were divided into four groups: SAL (saline), OVA (sensitized with ovalbumin), SAL + rBmTI-A (control treated with rBmTI-A) and OVA + rBmTI-A (sensitized with ovalbumin and treated with rBmTI-A). The animals received an intraperitoneal injection of saline or ovalbumin, according to the group. The groups received inhalation with saline or ovalbumin and were treated with rBmTI-A or saline by nasal instillation. After 29 days, we evaluated the respiratory mechanics; bronchoalveolar lavage fluid (BALF); cytokines; MMP-9, TIMP-1; eosinophils; collagen and elastic fibre expression in the airways; and the trypsin-like, MMP-1, and MMP-9 lung tissue proteolytic activity. Treatment with rBmTI-A reduced the trypsin-like proteolytic activity, the elastance and resistance maximum response, the polymorphonuclear cells, IL-5, IL-10, IL-13 and IL-17A in the BALF, the expression of IL-5, IL-13, IL-17, CD4+, MMP-9, TIMP-1, eosinophils, collagen and elastic fibres in the airways of the OVA + rBmTI-A group compared to the OVA group (p < 0.05). rBmTI-A attenuated bronchial hyperresponsiveness, inflammation and remodelling in this experimental model of chronic allergic pulmonary inflammation. This inhibitor may serve as a potential therapeutic tool for asthma treatment.
River channel conveyance capacity adjusts to modes of climate variability
Authors: Slater L. J. , Khouakhi A. , Wilby R. L.
Published: September 2019

River networks are typically treated as conduits of fixed discharge conveyance capacity in flood models and engineering design, despite knowledge that alluvial channel networks adjust their geometry, conveyance, planform, extent and drainage density over time in response to shifts in the magnitude and frequency of streamflows and sediment supply. Consistent relationships between modes of climate variability conducive to wetter-/drier-than-average conditions and changes in channel conveyance have never been established, hindering geomorphological prediction over interannual to multidecadal timescales. This paper explores the relationship between river channel conveyance/geometry and three modes of climate variability (the El Niño–Southern Oscillation, Atlantic Multidecadal Oscillation, and Arctic Oscillation) using two-, five- and ten-year medians of channel measurements, streamflow, precipitation and climate indices over seven decades in 67 United States rivers. We find that in two thirds of these rivers, channel capacity undergoes coherent phases of expansion/contraction in response to shifts in catchment precipitation and streamflow, driven by climate modes with different periodicities. Understanding the sensitivity of channel conveyance to climate modes would enable better river management, engineering design, and flood predictability over interannual to multidecadal timescales.
A20 deficiency in hematopoietic stem cells causes lymphopenia and myeloproliferation due to elevated Interferon-γ signals
Authors: Nakagawa Masahiro Marshall , Rathinam Chozha Vendan
Published: September 2019

Inflammation and inflammatory cytokines have been shown to exert both positive and negative effects on hematopoietic stem cells (HSCs) and hematopoiesis. While the significance of inflammation driven hematopoiesis has begun to unfold, molecular players that regulate this phenomenon remain largely unknown. In the present study, we identified A20 as a critical regulator of inflammation controlled hematopoietic cell fate decisions of HSCs. A20 deficiency in HSCs leads to increased differentiation of myeloid cells and myeloproliferation. Analysis of erythroid lineage cells of A20 deficient mice indicated a striking reduction of erythrocytes in the bone marrow (BM), but elevated numbers in the spleen. Loss of A20 in HSCs causes a severe blockade of B cell differentiation in the BM and absence of peripheral B cells in the spleen, liver and blood. T cell differentiation studies revealed a reduction of both T cell progenitors and differentiated T cells in the thymus and altered T cell numbers in the spleens of A20 mutant mice. Analysis of lineage committed progenitors of the myeloid, erythroid and lymphoid lineages specified an altered composition in the A20 deficient BM. Genetic studies identified that specific loss of A20 in the myeloid lineage cells results in myeloproliferation. Bone marrow transplantation studies and mixed bone marrow chimera studies suggested an involvement of inflammatory cytokines, particularly interferon (IFN)- γ, in the onset of myeloproliferation and lymphopenia of A20 deficient mice. Finally, ablation of IFNγ signals in A20 deficient mice rescued the hematopoietic defects. In essence, these studies highlight a previously unknown role for A20 in the restriction of inflammation driven pathologic hematopoiesis. We believe that our studies based on A20 mutant mice will be helpful in understanding the pathophysiology and in the treatment of patients with A20 (TNFAIP3) mutations.