bluuebunny/crossref_metadata_2025 huggingface dataset:
Te–Li Exchange Reaction of Tellurophene‐Containing π‐Conjugated Polymer as Potential Synthetic Tool for Functional π‐Conjugated Polymers
Authors: Zheng Feng , Komatsuzaki Yusuke , Shida Naoki , Nishiyama Hiroki , Inagi Shinsuke , Tomita Ikuyoshi
Published: August 2019

On the basis of the facts that tellurophene‐containing π‐conjugated polymers are obtainable from organotitanium polymers and that the tellurium atoms in the tellurophene derivatives can be transformed into lithium atoms, the synthesis of reactive lithiated polymer precursor and its transformations into some functionalized π‐conjugated polymers are described. A regioregular organometallic polymer having 1,4‐dilithio‐1,3‐butadiene and 9,9‐dioctylfluorene‐2,7‐diyl units is generated by the reaction of a tellurophene‐containing polymer having the number‐average molecular weight (Mn) and molecular weight distribution (Mw/Mn) of 5890 and 1.9, respectively, with n‐butyllithium (2.4 equiv.) at −78 °C to −60 °C for 3 h. The lithiated polymer thus prepared is subjected to reactions with electrophiles to produce functionalized π‐conjugated polymers. For example, a π‐conjugated polymer possessing 1,4‐bis(tri‐n‐butylstannyl)‐1,3‐butadiene‐1,4‐diyl unit is obtained in 67% yield by the reaction with tri‐n‐butyltin chloride (2.4 equiv.) at −60 °C to ambient temperature for 12 h in tetrahydrofuran, whose Mn and Mw/Mn are estimated as 7320 and 2.5, respectively, by size exclusion chromatography. The absorption maximum and onset of the obtained polymer are observed at 380 and 465 nm, respectively, in the UV–vis spectrum, from which the optical band gap of the polymer is estimated as 2.67 eV.
Amiodarone use and the risk of acute pancreatitis: Influence of different exposure definitions
Authors: Hempenius Mirjam , Groenwold Rolf H.H. , de Boer Anthonius , Klungel Olaf H. , Gardarsdottir Helga
Published: August 2019

Purpose

The antiarrhythmic drug amiodarone has a long half‐life of 60 days, which is often ignored in observational studies. This study aimed to investigate the impact of different exposure definitions on the association between amiodarone use and the risk of acute pancreatitis.

Method

Using data from the Dutch PHARMO Database Network, incident amiodarone users were compared to incident users of a different type of antiarrhythmic drug. Eighteen different definitions were applied to define amiodarone exposure, including dichotomized, continuous and categorized cumulative definitions with lagged effects to account for the half‐life of amiodarone. For each exposure definition, a Cox proportional hazards model was used to estimate the hazard ratio (HR) of hospitalization for acute pancreatitis.

Results

This study included 15,378 starters of amiodarone and 21,394 starters of other antiarrhythmic drugs. Adjusted HRs for acute pancreatitis ranged between 1.21−1.43 for dichotomized definitions of exposure to amiodarone, between 1.13‐1.22 for dose definitions (per DDD) and between 0.52‐1.72 for cumulative dose definitions, depending on the category. Accounting for lagged effects had little impact on estimated HRs.

Conclusions

This study demonstrates the relative insensitivity of the association between amiodarone and the risk of acute pancreatitis against a broad range of different exposure definitions. Accounting for possible lagged effects had little impact, possibly because treatment switching and discontinuation was uncommon in this population.
Validity of hospital ICD‐10‐GM codes to identify acute liver injury in Germany
Authors: Timmer Antje , de Sordi Dominik , Kappen Sanny , Kohse Klaus Peter , Schink Tania , Perez‐Gutthann Susana , Jacquot Emmanuelle , Deltour Nicolas , Pladevall Manel
Published: August 2019

Purpose

Acute liver injury (ALI) is an important adverse drug reaction. We estimated the positive predictive values (PPVs) of ICD‐10‐GM codes of ALI used in an international postauthorisation safety study (PASS).

Methods

Analyses used routine data (2007 to 2016, adults) from a German academic hospital in a cross‐sectional design. Two algorithms from the PASS were applied to extract potential cases from the hospital information system: specific end point (A) (discharge diagnosis of liver disease–specific codes) and less specific end point (B) (discharge and outpatient‐specific and nonspecific codes suggestive of liver injury). ALI cases were confirmed on the basis of plasma liver enzyme activity elevation. Secondary analysis was performed following exclusion of cases with known cancer, chronic liver, biliary and pancreatic disease, heart failure, and alcohol‐related disorders, as applied in the PASS.

Results

On the basis of ICD codes: outcome A, 154 cases (143 with case notes and lab data for case verification); outcome B, 485 cases (357 with case notes and lab data). ALI was confirmed in 71 outcome A cases, PPV of 49.7% (95% confidence interval [CI], 41.2%‐58.1%), and 100 outcome B cases, PPV of 28.0% (95% CI, 23.4%‐33.0%). Applying exclusion criteria increased PPV (95% CI) to 62.7% (50.0%‐74.2%) for outcome A and 45.7% (37.2%‐54.3%) for outcome B.

Conclusions

In safety studies on hepatotoxicity based on routine data using ICD‐10‐GM discharge codes and when validation of potential cases is not feasible, only the more specific codes should be used to describe ALI, and competing diagnoses for liver injury should be excluded to avoid substantial misclassification.
Fast and Slow Stages of Lifetime Degradation by Boron–Oxygen Centers in Crystalline Silicon
Authors: Schmidt Jan , Bothe Karsten , Voronkov Vladimir V. , Falster Robert
Published: August 2019

A conflict between previous and recently published data on the two‐stage light‐induced degradation (LID) of carrier lifetime in boron‐doped oxygen‐containing crystalline silicon is addressed. The previous experiments showed the activation of two boron–oxygen recombination centers with strongly differing recombination properties for the fast and slow stages of LID, whereas more recent studies found only a single center for both stages. To resolve this controversy, the historic silicon samples of these previous examinations are re‐examined in this study after more than one decade. It is found that, in the historic samples, the fast stage can be either described by two different centers or a mixture of the two, depending on the duration of previous dark annealing. A possible solution is suggested based on the involvement of different activating impurities in the boron–oxygen defect. In dark‐annealed samples, the defect consisting of boron, oxygen, and the activation impurity is present in two latent configurations, which reconfigure during LID at a fast and a slow stage. In the examined historic silicon samples, which did not undergo a gettering pretreatment, a significant concentration of an additional boron–oxygen defect with a different kind of activating impurity attached exists. The historic and modern results are thus reconciled.
Management of vegetation encroachment by natural and induced channel avulsions: A physical model
Authors: Javernick Luke , Bertoldi Walter
Published: August 2019

Flow regulation and water abstractions may change the complex relationship between river hydraulics, morphology, and riparian vegetation. As a result, rivers are likely to decrease their dynamics, increase the amount of vegetation, and modify their habitat structure. Flood events provide a natural mechanism for removal of invasive vegetation and recreation of natural floodplain habitats. This work aims at evaluating and quantifying how gravel‐bed braided rivers naturally control vegetation encroachment through morphological processes and the impact of both naturally occurring and induced avulsions. Flume experiments were conducted in a 24‐m‐long x 1.6‐m‐wide channel filled with well‐sorted sand and constant longitudinal gradient at 0.01 m/m. Once a braided network developed, the flume was seeded with Eruca sativa at a density of 1.5 seeds/cm2 and grown until an approximate height of 1.1 cm. Experiments evaluated low‐, medium‐, and large‐flood events and documented morphological changes and impacts to vegetation at four intervals during the experiments. High‐resolution images captured approximately 3 m above the flume were used to produce accurate Structure‐from‐Motion‐derived topography and orthoimagery (average errors 2 mm). Vegetation dynamics were observed to be highly variable and depend on local morphological changes and bank erosion. Discharge is the first‐order control on vegetation removal, but our results show that occurrence of avulsions significantly increases vegetation removal. The experiments highlight that a relatively small amount of sediment relocation can be an effective tool to induce avulsions and reduce vegetation encroachment on regulated rivers.
Associations between subjective time perception and well‐being during stressful waiting periods
Authors: Rankin Kyla , Sweeny Kate , Xu Sandra
Published: August 2019

The passage of time is a subjective experience and can be easily distorted by concurrent emotions. Specifically, time seems to move particularly slowly when people are in a negative emotional state. The aim of the current studies was to evaluate the bidirectional relationship between subjective time perception and distress during stressful waiting periods, during which the slow passage of time may be particularly distressing. Across studies of undergraduate students awaiting a midterm exam grade (Study 1) and law graduates awaiting bar exam results (Studies 2 and 3), results revealed consistent links between distress and time perception across the waiting periods, with tentative evidence for bidirectional relationships between these experiences. That is, people who perceived time as moving slowly while they waited tended to report greater distress across the waiting period (particularly worry, anxiety, negative emotion, and poor coping), and people who reported greater distress tended to perceive time as moving more slowly. The links between distress and time perception suggest the possibility of downward spirals during stressful waiting periods, such that distress makes time seem to slow down, which then exacerbates distress. We discuss avenues for future research and potential remedies to derail the spiral of distress and time perception.
Low‐Temperature Electron Beam Deposition of Zn‐SnOx for Stable and Flexible Perovskite Solar Cells
Authors: Song Zonglong , Bi Wenbo , Zhuang Xinmeng , Wu Yanjie , Zhang Boxue , Chen Xinfu , Chen Cong , Dai Qilin , Song Hongwei
Published: August 2019

Perovskite solar cells (PSCs) attract tremendous interest due to their feasibility, high power conversion efficiency (PCE), light weight, and flexible architecture. However, some challenges are still present for cheap mass fabrication in commercial applications. Herein, efficient Zn‐SnOx electron transport layers (ETLs) are used by the low‐temperature (100 °C) electron beam (E‐beam) method. Doping Zn2+ in SnO2 improves conductivity, suppresses charge recombination, and optimizes the energy level structure of SnO2, leading to an improved PCE from 18.95% to 20.16%. More importantly, the PCE of the modified device is more than 80% of its initial values for 800 h in ambient air with a relative humidity of ≈40%. The flexible device exhibits a PCE of 15.25% and remains at an initial PCE of 83% after 100 bending cycles. The efficient and flexible PSCs are potentially used as wearable energy power sources. The low‐temperature preparation of ETL and the excellent performance of devices present great commercial potential for future applications.
Trade study to select best alternative for cable and pulley simulation for cranes on offshore vessels
Authors: Fotland Gaute , Haskins Cecilia , Rølvåg Terje
Published: August 2019

Cranes on offshore vessels are subjected to crane dynamics, structural couplings to the vessel, and environmental influence by waves and currents. The recent trend has been to use larger cranes on smaller vessels, which makes the lifting operation more complex and potentially dangerous. The use of digital twins (DTs) is emerging as one way to enable safer operations, real‐time simulation, and maintenance prediction. On offshore vessels, a DT can monitor the lifting operation to create a safer work environment. The SPADE (stakeholders, problem formulation, alternatives, decision making, and evaluation) model has been used as a framework toward the creation of a DT of cranes on offshore vessels. Several cases involving simulation of cranes revealed the lack of an adequate simulation of cable and pulleys suitable for use in a DT. The simulation is important for accurate results and for implementation in control systems. A trade study was performed to determine a numerical method adequate for cable and pulley simulation. The trade study identified the absolute nodal coordinate formulation in the framework of arbitrary Lagrangian–Eulerian as a promising numerical formulation.
Non-uniqueness for a critical heat equation in two dimensions with singular data
Authors: Ioku Norisuke , Ruf Bernhard , Terraneo Elide
Published: August 2019

Nonlinear heat equations in two dimensions with singular initial data are studied. In recent works nonlinearities with exponential growth of Trudinger–Moser type have been shown to manifest critical behavior: well-posedness in the subcritical case and non-existence for certain supercritical data. In this article we propose a specific model nonlinearity with Trudinger–Moser growth for which we obtain surprisingly complete results: a) for initial data strictly below a certain singular threshold function

\widetilde u

the problem is well-posed, b) for initial data above this threshold function

\widetilde u

, there exists no solution, c) for the singular initial datum

\widetilde u

there is non-uniqueness. The function

\widetilde u

is a weak stationary singular solution of the problem, and we show that there exists also a regularizing classical solution with the same initial datum

\widetilde u

.
Longitudinal analysis of risk factors for dementia based on Mild Cognitive Impairment Screen results and questionnaire responses from healthy Japanese individuals registered in an online database
Authors: Ogawa Masayo , Maruo Kazushi , Sone Daichi , Shimada Hiroyuki , Suzuki Keisuke , Watanabe Hiroshi , Matsuda Hiroshi , Mizusawa Hidehiro
Published: August 2019

Introduction

Despite an urgent need for developing remedial measures against dementia, no disease‐modifying drugs have been developed. Efficient protocols for participant recruitment need to be established for conducting clinical trials. To meet this need, a large‐scale online registry system, the Integrated Registry of Orange Plan (IROOP®), was created for healthy individuals. Although the risk factors for dementia have been discussed in our previous studies for a short interval of 6 months, some factors remain controversial. The present study aimed to explore factors affecting longitudinal changes in cognitive function for a longer interval of 18 months using the IROOP® data.

Methods

This study assessed the longitudinal changes in the collated data for predicting the risk of dementia and included 473 individuals (175 men and 298 women; mean age 59.6 ± 10.1 years) registered in the IROOP® between July 5, 2016 and January 15, 2018 who completed the initial questionnaire and brief assessment of cognitive function (Mild Cognitive Impairment Screen) at baseline and the regular questionnaire and the Mild Cognitive Impairment Screen at least once after baseline. Statistical analyses were performed using IBM SPSS, version 23.0, for Windows for demographic data and the MIXED procedure in SAS, version 9.4, for the linear mixed‐effect model. In each analysis, the statistical significance level was set at P < .05.

Results

Mood, sleep, quality of life, and medical histories including cognition were found to influence longitudinal changes in cognitive function.

Discussion

Given the multifactorial etiology of dementia, preventive measures targeting multiple domains are required for maintaining cognitive function, instead of focusing on one lifestyle factor.
Documenting Theatrical and Performative Philippines: Possibilities of a Task and a Practice
Authors: SERQUIÑA OSCAR TANTOCO
Published: August 2019

The writing of theatre history has been a challenging intellectual commitment in the Philippines. This mode of inquiry and inscription largely manifests more as a strand of general historiography than as a systematized and specialized critical practice in Philippine academe. No wonder, then, that Philippine theatre histories primarily come from academics whose disciplinary backgrounds are not solely in theatre arts per se but in a range of different but intersecting disciplines, such as film, literature, dance, anthropology, history and music. These historians have accounted for the medium's forms, geographies of production and performance, material aspects, lead practitioners, groups or organizations, and historical periods. They have thus far yielded a congeries of print materials: from the encyclopedia to the anthology or reader, the survey, up to the full-length book manuscript. More recently, theatre histories have also appeared in online catalogues or digital repositories.
Trajectories and Predictors of Children's Early-Starting Conduct Problems: Child, Family, Genetic, and Intervention Effects
Authors: Shaw Daniel S. , Galán Chardée A. , Lemery-Chalfant Kathryn , Dishion Thomas J. , Elam Kit K. , Wilson Melvin N. , Gardner Frances
Published: August 2019

Several research teams have previously traced patterns of emerging conduct problems (CP) from early or middle childhood. The current study expands on this previous literature by using a genetically-informed, experimental, and long-term longitudinal design to examine trajectories of early-emerging conduct problems and early childhood discriminators of such patterns from the toddler period to adolescence. The sample represents a cohort of 731 toddlers and diverse families recruited based on socioeconomic, child, and family risk, varying in urbanicity and assessed on nine occasions between ages 2 and 14. In addition to examining child, family, and community level discriminators of patterns of emerging conduct problems, we were able to account for genetic susceptibility using polygenic scores and the study's experimental design to determine whether random assignment to the Family Check-Up (FCU) discriminated trajectory groups. In addition, in accord with differential susceptibility theory, we tested whether the effects of the FCU were stronger for those children with higher genetic susceptibility. Results augmented previous findings documenting the influence of child (inhibitory control [IC], gender) and family (harsh parenting, parental depression, and educational attainment) risk. In addition, children in the FCU were overrepresented in the persistent low versus persistent high CP group, but such direct effects were qualified by an interaction between the intervention and genetic susceptibility that was consistent with differential susceptibility. Implications are discussed for early identification and specifically, prevention efforts addressing early child and family risk.
Co-occurring change in children's conduct problems and maternal depression: Latent class individual participant data meta-analysis of the Incredible Years parenting program
Authors: Leijten Patty , Gardner Frances , Melendez-Torres G.J. , Weeland Joyce , Hutchings Judy , Landau Sabine , McGilloway Sinéad , Overbeek Geertjan , van Aar Jolien , Menting Ankie , Orobio de Castro Bram , Berry Vashti , Gaspar Maria Filomena , Axberg Ulf , Mørch Willy-Tore , Scott Stephen
Published: August 2019

Children vary in the extent to which they benefit from parenting programs for conduct problems. How does parental mental health change if children benefit less or more? We assessed whether changes in conduct problems and maternal depressive symptoms co-occur following participation in the Incredible Years parenting program. We integrated individual participant data from 10 randomized trials (N= 1280; children aged 2–10 years) and distinguished latent classes based on families' baseline and post-test conduct problems and maternal depressive symptoms, using repeated measures latent class analysis (RMLCA) and latent transition analysis (LTA). Classes differed mainly in severity of conduct problems and depression (RMLCA; 4 classes). Conduct problems reduced in all classes. Depressive symptoms did not change in most classes, except in a class of families where conduct problems and depression were particularly severe. Incredible Years led to a greater likelihood of families with particularly severe conduct problems and depression moving to a class with mild problems (LTA; 3 classes). Our findings suggest that for the majority of families, children's conduct problems reduce, but maternal depressive symptoms do not, suggesting relative independence, with the exception of families with severe depression and severe conduct problems where changes for the better do co-occur.
Future Climate and Land Use Change Impacts on River Flows in the Tapajós Basin in the Brazilian Amazon
Authors: Farinosi Fabio , Arias Mauricio E. , Lee Eunjee , Longo Marcos , Pereira Fabio F. , Livino Angela , Moorcroft Paul R. , Briscoe John
Published: August 2019

Land conversion and changing climate are expected to significantly alter tropical forest hydrology. We used a land surface model integrated with a river routing scheme to analyze the hydrological alterations expected in the Tapajós River basin, a large portion of the Brazilian Amazon, caused by two environmental drivers: climate and land use. The model was forced with two future climate scenarios (years 2026–2045) from the Earth System Model HadGem2‐ES with moderate (+4.5 W/m2 radiative forcing value in the year 2100 with respect to preindustrial levels) and severe (+8.5 W/m2) representative atmospheric carbon dioxide pathways (Representative Concentration Pathways). We tested the sensitivity of our results to the uncertainty in future climate projections by running simulations with IPSL‐CM5 (wettest scenarios) and GISS‐E2 (driest scenarios). Human land use effects on vegetation were evaluated using a limited and an extreme deforestation scenario. Our analysis indicates that climate change is predicted to reduce river flows across seasons (up to 20%) and bring a considerable shift in flow seasonality toward a later onset (nearly 1.5 months) and increase in interannual variability. While land use change partially counteracts the climate‐driven diminishing trend in river flows, it is expected to contribute to a further increase in interannual and intraannual variability. From a water management perspective, the overall reduction of river flows and their increased variability, combined with the shift and the shortening of the wet season, could potentially affect the productivity of the large hydropower systems planned for the region and the growing demand for agricultural and transport expansion.
Biomarkers for response in major depression: comparing paroxetine and venlafaxine from two randomised placebo-controlled clinical studies
Authors: Carboni Lucia , McCarthy Dennis J. , Delafont Bruno , Filosi Michele , Ivanchenko Elena , Ratti Emiliangelo , Learned Susan M. , Alexander Robert , Domenici Enrico
Published: August 2019

The identification of biomarkers of response might speed drug development and set the premises to assist clinical practice in psychiatry. In this work, we evaluated a panel of peripheral biomarkers (including IL-6, IL-10, TNF-α, TNFRII, BDNF, CRP, MMP9 and PAI1) in depressed patients receiving paroxetine, venlafaxine, or placebo. Samples were obtained from two randomised placebo-controlled studies evaluating the efficacy and tolerability of a novel drug candidate, using either paroxetine or venlafaxine as active comparators. In both studies, the biomarker candidates were analysed in plasma collected at randomization and after 10 weeks of treatment with either placebo or active comparator (for a total of 106 and 108 subjects in the paroxetine and venlafaxine study, respectively). Data were obtained by multiplexing sandwich-ELISA system. Data were subjected to statistical analysis to assess their correlation with baseline severity and with response outcome. Increases in biomarker levels were correlated with reduction in depression severity for TNF-α, IL-6 IL-10 and CRP. Response to paroxetine treatment correlated with baseline IL-10, IL-6 and TNF-α levels, with the strongest signal being observed in males. In the venlafaxine study, a correlation was observed only between CRP level at randomisation and response, suggesting differences between the two active treatments and the two studies. Our investigations suggest that a combination of pro- and anti-inflammatory cytokines may predict response outcome in patients treated with paroxetine. The potential for IL-10, IL-6 and TNF-α as response biomarkers for a wider range of antidepressants warrants further investigations in clinical trials with other monoamine reuptake inhibitors.
Clinical and genetic characteristics of 14 patients from 13 Japanese families with RPGR-associated retinal disorder: report of eight novel variants
Authors: Mawatari Go , Fujinami Kaoru , Liu Xiao , Yang Lizhu , Yokokawa Yu-Fujinami , Komori Shiori , Ueno Shinji , Terasaki Hiroko , Katagiri Satoshi , Hayashi Takaaki , Kuniyoshi Kazuki , Miyake Yozo , Tsunoda Kazushige , Yoshitake Kazutoshi , Iwata Takeshi , Nao-i Nobuhisa ,   on behalf of the JEGC study group
Published: August 2019

Variants in the retinitis pigmentosa GTPase regulator (RPGR) gene are a major cause of X-linked inherited retinal disorder (IRD). We herein describe the clinical and genetic features of 14 patients from 13 Japanese families harboring RPGR variants in a nationwide cohort. Comprehensive ophthalmological examinations were performed to classify the patients into one of the phenotype subgroups: retinitis pigmentosa (RP) and cone rod dystrophy (CORD). The mean age of onset/at examination was 13.8/38.1 years (range, 0–50/11–72), respectively. The mean visual acuity in the right/left eye was 0.43/0.43 (range, 0.1–1.7/−0.08–1.52) LogMAR unit. Eight patients had RP, and six had CORD. Whole-exome sequencing with target analyses identified 13 RPGR variants in 730 families with IRD, including 8 novel variants. An association between the phenotype subgroup and the position of variants (cutoff of amino acid 950) was revealed. To conclude, the clinical and genetic spectrum of RPGR-associated retinal disorder was first illustrated in a Japanese population, with a high proportion of novel variants. These results suggest the distinct genetic background of RPGR in the Japanese population, in which the genotype–phenotype association was affirmed. This evidence should be helpful monitoring and counseling patients and in selecting patients for future therapeutic trials.
Phc2 controls hematopoietic stem and progenitor cell mobilization from bone marrow by repressing Vcam1 expression
Authors: Bae Joonbeom , Choi Sang-Pil , Isono Kyoichi , Lee Ji Yoon , Park Si-Won , Choi Chang-Yong , Han Jihye , Kim Sang-Hoon , Lee Han-Hyoung , Park Kyungmin , Jin Hyun Yong , Lee Suk Jun , Park Chung-Gyu , Koseki Haruhiko , Lee Young Sik , Chun Taehoon
Published: August 2019

The timely mobilization of hematopoietic stem and progenitor cells (HSPCs) is essential for maintaining hematopoietic and tissue leukocyte homeostasis. Understanding how HSPCs migrate between bone marrow (BM) and peripheral tissues is of great significance in the clinical setting, where therapeutic strategies for modulating their migration capacity determine the clinical outcome. Here, we identify an epigenetic regulator, Phc2, as a critical modulator of HSPC trafficking. The genetic ablation ofPhc2in mice causes a severe defect in HSPC mobilization through the derepression ofVcam1in bone marrow stromal cells (BMSCs), ultimately leading to a systemic immunodeficiency. Moreover, the pharmacological inhibition of VCAM-1 inPhc2-deficient mice reverses the symptoms. We further determine that Phc2-dependentVcam1repression in BMSCs is mediated by the epigenetic regulation of H3K27me3 and H2AK119ub. Together, our data demonstrate a cell-extrinsic role for Phc2 in controlling the mobilization of HSPCs by finely tuning their bone marrow niche.
Molecular basis for the binding and selective dephosphorylation of Na+/H+ exchanger 1 by calcineurin
Authors: Hendus-Altenburger Ruth , Wang Xinru , Sjøgaard-Frich Lise M. , Pedraz-Cuesta Elena , Sheftic Sarah R. , Bendsøe Anne H. , Page Rebecca , Kragelund Birthe B. , Pedersen Stine F. , Peti Wolfgang
Published: August 2019

Very little is known about how Ser/Thr protein phosphatases specifically recruit and dephosphorylate substrates. Here, we identify how the Na+/H+-exchanger 1 (NHE1), a key regulator of cellular pH homeostasis, is regulated by the Ser/Thr phosphatase calcineurin (CN). NHE1 activity is increased by phosphorylation of NHE1 residue T779, which is specifically dephosphorylated by CN. While it is known that Ser/Thr protein phosphatases prefer pThr over pSer, we show that this preference is not key to this exquisite CN selectivity. Rather a combination of molecular mechanisms, including recognition motifs, dynamic charge-charge interactions and a substrate interaction pocket lead to selective dephosphorylation of pT779. Our data identify T779 as a site regulating NHE1-mediated cellular acid extrusion and provides a molecular understanding of NHE1 substrate selection by CN, specifically, and how phosphatases recruit specific substrates, generally.
Class IIa HDACs regulate learning and memory through dynamic experience-dependent repression of transcription
Authors: Zhu Yongchuan , Huang Min , Bushong Eric , Phan Sebastien , Uytiepo Marco , Beutter Elizabeth , Boemer Daniel , Tsui Kristin , Ellisman Mark , Maximov Anton
Published: August 2019

The formation of new memories requires transcription. However, the mechanisms that limit signaling of relevant gene programs in space and time for precision of information coding remain poorly understood. We found that, during learning, the cellular patterns of expression of early response genes (ERGs) are regulated by class IIa HDACs 4 and 5, transcriptional repressors that transiently enter neuronal nuclei from cytoplasm after sensory input. Mice lacking these repressors in the forebrain have abnormally broad experience-dependent expression of ERGs, altered synaptic architecture and function, elevated anxiety, and severely impaired memory. By acutely manipulating the nuclear activity of class IIa HDACs in behaving animals using a chemical-genetic technique, we further demonstrate that rapid induction of transcriptional programs is critical for memory acquisition but these programs may become dispensable when a stable memory is formed. These results provide new insights into the molecular basis of memory storage.
PAWH1 and PAWH2 are plant-specific components of an Arabidopsis endoplasmic reticulum-associated degradation complex
Authors: Lin Liangguang , Zhang Congcong , Chen Yongwu , Wang Yi , Wang Dinghe , Liu Xiaolei , Wang Muyang , Mao Juan , Zhang Jianjun , Xing Weiman , Liu Linchuan , Li Jianming
Published: August 2019

Endoplasmic reticulum-associated degradation (ERAD) is a unique mechanism to degrade misfolded proteins via complexes containing several highly-conserved ER-anchored ubiquitin ligases such as HMG-CoA reductase degradation1 (Hrd1). Arabidopsis has a similar Hrd1-containing ERAD machinery; however, our knowledge of this complex is limited. Here we report two closely-related Arabidopsis proteins, Protein Associated With Hrd1-1 (PAWH1) and PAWH2, which share a conserved domain with yeast Altered Inheritance of Mitochondria24. PAWH1 and PAWH2 localize to the ER membrane and associate with Hrd1 via EMS-mutagenized Bri1 Suppressor7 (EBS7), a plant-specific component of the Hrd1 complex. Simultaneously elimination of two PAWHs constitutively activates the unfolded protein response and compromises stress tolerance. Importantly, the pawh1 pawh2 double mutation reduces the protein abundance of EBS7 and Hrd1 and inhibits degradation of several ERAD substrates. Our study not only discovers additional plant-specific components of the Arabidopsis Hrd1 complex but also reveals a distinct mechanism for regulating the Hrd1 stability.
Topological Lifshitz transitions and Fermi arc manipulation in Weyl semimetal NbAs
Authors: Yang H. F. , Yang L. X. , Liu Z. K. , Sun Y. , Chen C. , Peng H. , Schmidt M. , Prabhakaran D. , Bernevig B. A. , Felser C. , Yan B. H. , Chen Y. L.
Published: August 2019

Surface Fermi arcs (SFAs), the unique open Fermi-surfaces (FSs) discovered recently in topological Weyl semimetals (TWSs), are unlike closed FSs in conventional materials and can give rise to many exotic phenomena, such as anomalous SFA-mediated quantum oscillations, chiral magnetic effects, three-dimensional quantum Hall effect, non-local voltage generation and anomalous electromagnetic wave transmission. Here, by using in-situ surface decoration, we demonstrate successful manipulation of the shape, size and even the connections of SFAs in a model TWS, NbAs, and observe their evolution that leads to an unusual topological Lifshitz transition not caused by the change of the carrier concentration. The phase transition teleports the SFAs between different parts of the surface Brillouin zone. Despite the dramatic surface evolution, the existence of SFAs is robust and each SFA remains tied to a pair of Weyl points of opposite chirality, as dictated by the bulk topology.
Heterocellular gene signatures reveal luminal-A breast cancer heterogeneity and differential therapeutic responses
Authors: Poudel Pawan , Nyamundanda Gift , Patil Yatish , Cheang Maggie Chon U , Sadanandam Anguraj
Published: August 2019

Breast cancer is a highly heterogeneous disease. Although differences between intrinsic breast cancer subtypes have been well studied, heterogeneity within each subtype, especially luminal-A cancers, requires further interrogation to personalize disease management. Here, we applied well-characterized and cancer-associated heterocellular signatures representing stem, mesenchymal, stromal, immune, and epithelial cell types to breast cancer. This analysis stratified the luminal-A breast cancer samples into five subtypes with a majority of them enriched for a subtype (stem-like) that has increased stem and stromal cell gene signatures, representing potential luminal progenitor origin. The enrichment of immune checkpoint genes and other immune cell types in two (including stem-like) of the five heterocellular subtypes of luminal-A tumors suggest their potential response to immunotherapy. These immune-enriched subtypes of luminal-A tumors (containing only estrogen receptor positive samples) showed good or intermediate prognosis along with the two other differentiated subtypes as assessed using recurrence-free and distant metastasis-free patient survival outcomes. On the other hand, a partially differentiated subtype of luminal-A breast cancer with transit-amplifying colon-crypt characteristics showed poor prognosis. Furthermore, published luminal-A subtypes associated with specific somatic copy number alterations and mutations shared similar cellular and mutational characteristics to colorectal cancer subtypes where the heterocellular signatures were derived. These heterocellular subtypes reveal transcriptome and cell-type based heterogeneity of luminal-A and other breast cancer subtypes that may be useful for additional understanding of the cancer type and potential patient stratification and personalized medicine.
Essential ion binding residues for Na+ flow in stator complex of the Vibrio flagellar motor
Authors: Onoue Yasuhiro , Iwaki Masayo , Shinobu Ai , Nishihara Yasutaka , Iwatsuki Hiroto , Terashima Hiroyuki , Kitao Akio , Kandori Hideki , Homma Michio
Published: August 2019

The bacterial flagellar motor is a unique supramolecular complex which converts ion flow into rotational force. Many biological devices mainly use two types of ions, proton and sodium ion. This is probably because of the fact that life originated in seawater, which is rich in protons and sodium ions. The polar flagellar motor in Vibrio is coupled with sodium ion and the energy converting unit of the motor is composed of two membrane proteins, PomA and PomB. It has been shown that the ion binding residue essential for ion transduction is the conserved aspartic acid residue (PomB-D24) in the PomB transmembrane region. To reveal the mechanism of ion selectivity, we identified essential residues, PomA-T158 and PomA-T186, other than PomB-D24, in the Na+-driven flagellar motor. It has been shown that the side chain of threonine contacts Na+ in Na+-coupled transporters. We monitored the Na+-binding specific structural changes using ATR-FTIR spectroscopy. The signals were abolished in PomA-T158A and -T186A, as well as in PomB-D24N. Molecular dynamics simulations further confirmed the strong binding of Na+ to D24 and showed that T158A and T186A hindered the Na+ binding and transportation. The data indicate that two threonine residues (PomA-T158 and PomA-T186), together with PomB-D24, are important for Na+ conduction in the Vibrio flagellar motor. The results contribute to clarify the mechanism of ion recognition and conversion of ion flow into mechanical force.
Dynamics from elastic neutron-scattering via direct measurement of the running time-integral of the van Hove distribution function
Authors: Benedetto Antonio , Kearley Gordon J.
Published: August 2019

We present a new neutron-scattering approach to access the van Hove distribution function directly in the time domain, I(t), which reflects the system dynamics. Currently, I(t) is essentially determined from neutron energy-exchange. Our method consists of the straightforward measurement of the running time-integral of I(t), by computing the portion of scattered neutrons corresponding to species at rest within a time t, (conceptually elastic scattering). Previous attempts failed to recognise this connection. Starting from a theoretical standpoint, a practical realisation is assessed via numerical methods and an instrument simulation.
X-ray Crystallographic Structure and Oligomerization of Gloeobacter Rhodopsin
Authors: Morizumi Takefumi , Ou Wei-Lin , Van Eps Ned , Inoue Keiichi , Kandori Hideki , Brown Leonid S. , Ernst Oliver P.
Published: August 2019

Gloeobacter rhodopsin (GR) is a cyanobacterial proton pump which can be potentially applied to optogenetics. We solved the crystal structure of GR and found that it has overall similarity to the homologous proton pump from Salinibacter ruber, xanthorhodopsin (XR). We identified distinct structural characteristics of GR’s hydrogen bonding network in the transmembrane domain as well as the displacement of extracellular sides of the transmembrane helices relative to those of XR. Employing Raman spectroscopy and flash-photolysis, we found that GR in the crystals exists in a state which displays retinal conformation and photochemical cycle similar to the functional form observed in lipids. Based on the crystal structure of GR, we selected a site for spin labeling to determine GR’s oligomerization state using double electron–electron resonance (DEER) spectroscopy and demonstrated the pH-dependent pentamer formation of GR. Determination of the structure of GR as well as its pentamerizing propensity enabled us to reveal the role of structural motifs (extended helices, 3-omega motif and flipped B-C loop) commonly found among light-driven bacterial pumps in oligomer formation. Here we propose a new concept to classify these pumps based on the relationship between their oligomerization propensities and these structural determinants.
Multisensory learning between odor and sound enhances beta oscillations
Authors: Gnaedinger A. , Gurden H. , Gourévitch B. , Martin C.
Published: August 2019

Multisensory interactions are essential to make sense of the environment by transforming the mosaic of sensory inputs received by the organism into a unified perception. Brain rhythms allow coherent processing within areas or between distant brain regions and could thus be instrumental in functionally connecting remote brain areas in the context of multisensory interactions. Still, odor and sound processing relate to two sensory systems with specific anatomofunctional characteristics. How does the brain handle their association? Rats were challenged to discriminate between unisensory stimulation (odor or sound) and the multisensory combination of both. During learning, we observed a progressive establishment of high power beta oscillations (15–35 Hz) spanning on the olfactory bulb, the piriform cortex and the perirhinal cortex, but not the primary auditory cortex. In the piriform cortex, beta oscillations power was higher in the multisensory condition compared to the presentation of the odor alone. Furthermore, in the olfactory structures, the sound alone was able to elicit a beta oscillatory response. These findings emphasize the functional differences between olfactory and auditory cortices and reveal that beta oscillations contribute to the memory formation of the multisensory association.
Keratin 17 identifies the most lethal molecular subtype of pancreatic cancer
Authors: Roa-Peña Lucia , Leiton Cindy V. , Babu Sruthi , Pan Chun-Hao , Vanner Elizabeth A. , Akalin Ali , Bandovic Jela , Moffitt Richard A. , Shroyer Kenneth R. , Escobar-Hoyos Luisa F.
Published: August 2019

Although the overall five-year survival of patients with pancreatic ductal adenocarcinoma (PDAC) is dismal, there are survival differences between cases with clinically and pathologically indistinguishable characteristics, suggesting that there are uncharacterized properties that drive tumor progression. Recent mRNA sequencing studies reported gene-expression signatures that define PDAC molecular subtypes that correlate with differences in survival. We previously identified Keratin 17 (K17) as a negative prognostic biomarker in other cancer types. Here, we set out to determine if K17 is as accurate as molecular subtyping of PDAC to identify patients with the shortest survival. K17 mRNA was analyzed in two independent PDAC cohorts for discovery (n = 124) and validation (n = 145). Immunohistochemical localization and scoring of K17 immunohistochemistry (IHC) was performed in a third independent cohort (n = 74). Kaplan-Meier and Cox proportional-hazard regression models were analyzed to determine cancer specific survival differences in low vs. high mRNA K17 expressing cases. We established that K17 expression in PDACs defines the most aggressive form of the disease. By using Cox proportional hazard ratio, we found that increased expression of K17 at the IHC level is also associated with decreased survival of PDAC patients. Additionally, within PDACs of advanced stage and negative surgical margins, K17 at both mRNA and IHC level is sufficient to identify the subgroup with the shortest survival. These results identify K17 as a novel negative prognostic biomarker that could inform patient management decisions.
Reversibility of Age-related Oxidized Free NADH Redox States in Alzheimer’s Disease Neurons by Imposed External Cys/CySS Redox Shifts
Authors: Dong Yue , Sameni Sara , Digman Michelle A. , Brewer Gregory J.
Published: August 2019

Redox systems including extracellular cysteine/cystine (Cys/CySS), intracellular glutathione/oxidized glutathione (GSH/GSSG) and nicotinamide adenine dinucleotide reduced/oxidized forms (NADH/NAD+) are critical for maintaining redox homeostasis. Aging as a major risk factor for Alzheimer’s disease (AD) is associated with oxidative shifts, decreases in anti-oxidant protection and dysfunction of mitochondria. Here, we examined the flexibility of mitochondrial-specific free NADH in live neurons from non-transgenic (NTg) or triple transgenic AD-like mice (3xTg-AD) of different ages under an imposed extracellular Cys/CySS oxidative or reductive condition. We used phasor fluorescence lifetime imaging microscopy (FLIM) to distinguish free and bound NADH in mitochondria, nuclei and cytoplasm. Under an external oxidative stress, a lower capacity for maintaining mitochondrial free NADH levels was found in old compared to young neurons and a further decline with genetic load. Remarkably, an imposed Cys/CySS reductive state rejuvenated the mitochondrial free NADH levels of old NTg neurons by 71% and old 3xTg-AD neurons by 89% to levels corresponding to the young neurons. Using FLIM as a non-invasive approach, we were able to measure the reversibility of aging subcellular free NADH levels in live neurons. Our results suggest a potential reductive treatment to reverse the loss of free NADH in old and Alzheimer’s neurons.
Drift-diffusion explains response variability and capacity for tracking objects
Authors: Daneshi Asieh , Azarnoush Hamed , Towhidkhah Farzad , Gohari Amin , Ghazizadeh Ali
Published: August 2019

Being able to track objects that surround us is key for planning actions in dynamic environments. However, rigorous cognitive models for tracking of one or more objects are currently lacking. In this study, we asked human subjects to judge the time to contact (TTC) a finish line for one or two objects that became invisible shortly after moving. We showed that the pattern of subject responses had an error variance best explained by an inverse Gaussian distribution and consistent with the output of a biased drift-diffusion model. Furthermore, we demonstrated that the pattern of errors made when tracking two objects showed a level of dependence that was consistent with subjects using a single decision variable for reporting the TTC for two objects. This finding reveals a serious limitation in the capacity for tracking multiple objects resulting in error propagation between objects. Apart from explaining our own data, our approach helps interpret previous findings such as asymmetric interference when tracking multiple objects.
Generalised thresholding of hidden variable network models with scale-free property
Authors: Balogh Sámuel G. , Pollner Péter , Palla Gergely
Published: August 2019

The hidden variable formalism (based on the assumption of some intrinsic node parameters) turned out to be a remarkably efficient and powerful approach in describing and analyzing the topology of complex networks. Owing to one of its most advantageous property - namely proven to be able to reproduce a wide range of different degree distribution forms - it has become a standard tool for generating networks having the scale-free property. One of the most intensively studied version of this model is based on a thresholding mechanism of the exponentially distributed hidden variables associated to the nodes (intrinsic vertex weights), which give rise to the emergence of a scale-free network where the degree distribution p(k) ~ k−γ is decaying with an exponent of γ = 2. Here we propose a generalization and modification of this model by extending the set of connection probabilities and hidden variable distributions that lead to the aforementioned degree distribution, and analyze the conditions leading to the above behavior analytically. In addition, we propose a relaxation of the hard threshold in the connection probabilities, which opens up the possibility for obtaining sparse scale free networks with arbitrary scaling exponent.