bluuebunny/crossref_metadata_2025 huggingface dataset:
Die außen- und sicherheitspolitischen Positionen der SPD: Sozialdemokratische Außenpolitik ist multilaterale Außenpolitik
Authors: Heinrich Gabriela
Published: May 2021

Die internationale Ordnung ist in den vergangenen Jahren zunehmend volatil geworden. Bereits vorliegende Trends – Populismus, Angriffe auf die multilaterale Ordnung, Digitalisierung und Automatisierung, die Klimakrise – haben sich teils dramatisch verschärft. In dieser zunehmend unsteten Welt ist ein souveränes Europa mehr denn je Dreh- und Angelpunkt der Rolle Deutschlands in der Welt. In diesem Rahmen können wir den Multilateralismus stärken, die transatlantische Partnerschaft weiterentwickeln und neuen Herausforderungen (digitale Souveränität, aufstrebende Mächte) begegnen.
Experiences and perspectives of self‐compassion from young adult children of parents with mental illness
Authors: Dunkley‐Smith Addy J. , Reupert Andrea E. , Ling Mathew , Sheen Jade A.
Published: May 2021

Introduction

In adolescents and young adults, self‐compassion has been positively associated with wellbeing and negatively associated with psychological distress. One population of youth who may draw particular benefit from self‐compassion are those who have parents with mental illness. This qualitative study explored the perspectives and experiences of self‐compassion among a group of young adult children of parents with mental illness.

Methods

A purposive sample of ten Australian emerging adults aged 18–25 years (3 men, 6 women and 1 non‐binary person) participated in individual semi‐structured telephone interviews. Interpretative Phenomenological Analysis was used to examine and interpret participants’ experiences and perspectives of self‐compassion.

Results

Participants described self‐compassion as personally relevant and beneficial, although difficult to engage in. Some participants had learnt about, and actively practiced self‐compassion, and offered advice for others. Conversely, others described self‐compassion as difficult to practice and outlined barriers to self‐compassion, from society and family life. Although participants identified common negative social conceptions of self‐compassion, they articulated how self‐compassion could be valuable for those who have parents with mental illness.

Conclusions

Results indicate the perceived importance of self‐compassion along with barriers and facilitators of self‐compassion for young adults who have parents with a mental illness. Implications for clinical practice and suggestions for future research are presented.
Improving cognitive functions in adolescents with learning difficulties: A feasibility study on the potential use of telerehabilitation during Covid‐19 pandemic in Italy
Authors: Maggio Maria Grazia , Foti Cuzzola Marilena , Calatozzo Patrizia , Marchese Domenicaroberta , Andaloro Adriana , Calabrò Rocco Salvatore
Published: May 2021

Introduction. Learning disabilities are due to genetic and/or neurobiological factors that alter brain functioning by affecting one or more cognitive processes related to learning. This study aimed to assess the efficacy of cognitive telerehabilitation in adolescents with learning disabilities to overcome the treatment problems related to the COVID‐19 pandemic lockdown. Methods. Twenty‐four patients diagnosed with Unspecified Learning Disability (mean ± SD age: 18.2 ± 2.9 years; 50% male) were enrolled in this study. The patients were assessed by a neuropsychological evaluation at the beginning and at the end of the program. All patients received cognitive treatment via a specific telehealth app to stimulate the cognitive skills related to learning. The treatment lasted four weeks, with a daily training (lasting up to 60 min), for five days a week. Results. Our young patients reported a statistically significant improvement in the main cognitive domains that are usually compromised in learning disabilities, including sustained and selective attention, shifting of attention, control of interference, memory and speed of information processing. Moreover, the patients showed a good usability and motivation during the training. Conclusions. Our study has shown that telerehabilitation could be a valid tool for the rehabilitation of specific cognitive skills in adolescents with learning difficulties.
Continuing Collagenase Clostridium Histolyticum Injections Among Initial Nonresponders Results in Significant Curvature Improvements in the Majority of Peyronie’s Disease Men
Authors: Alom Manaf , Burgon Holli , Ziegelmann Matthew , Köhler Tobias , Helo Sevann , Trost Landon
Published: May 2021

Background

It is currently unclear if men with Peyronie’s Disease (PD) who achieve minimal benefits with the first 2 series of Collagenase Clostridium Histolyticum (CCH) injections should continue with additional injections.

Aim

To analyze curvature improvements from the final two series of CCH injections based on amount of improvement during the first 2 series.

Methods

A prospective registry was analyzed of all men undergoing CCH injections for PD at a single institution. Men were included if they had completed a full 4 series (8 injections) of CCH and had baseline, interval (after 2 series), and/or final (after 4 series) curvature assessments available. Men were stratified into cohorts using baseline-to-interval assessments of ≤10° (or ≤20%) and >10° (or >20%), and improvements were compared using interval-to-final assessments.

Outcomes

The primary outcome was interval-to-final curvature improvements stratified by ≤10°/>10° or ≤20%/>20% improvements achieved during the baseline-to-interval period. Secondary outcomes included analyses of demographic and pathophysiologic variables to determine associations with significant improvements during the final 2 CCH series.

RESULTS

A total of 296 PD men were identified as receiving at least one CCH injection, of whom 175 had baseline-to-interval, 84 interval-to-final, and 115 with baseline-to-final measurements. Mean age was 56.6, PD duration 28.6 months, baseline curvature 63.4°, hourglass deformity 36.2%, and calcification 20%. Mean overall curve improvement was −21.5° (33.1%). Among men who experienced ≤20% improvements after 2 series, the mean subsequent curvature change was -24.6% during the final two series (vs +4.3% of those with >20% initial improvement, P< .001), and they were 2.7x more likely to experience >20% subsequent curve improvements. Thirty-one percent of those who achieved >10° during the first 2 series experienced benefits during the final 2 series compared to 70% of men who had ≤10° improvement initially. No demographic or pathophysiological variables predicted likelihood for improvements during the final 2 series of injections.

Clinical Implications

Men who fail to achieve significant benefits with 2 series of CCH injections may benefit from completing the final 2 series.

Strengths and Limitations

Strengths including a relatively large, prospective series. Limitations include a single center, nonrandomization, nonblinded assessments, and restriction to men who completed eight injections.

CONCLUSIONS

In the current series, approximately 2/3 of men who fail to achieve >10° or 20% curve improvements with an initial 2 series of CCH injections achieved >10° or 20% improvements with the subsequent 2 series.
Stethoscope hygiene: A call to action. Recommendations to update the CDC guidelines
Authors: Kalra Sarathi , Amin Alpesh , Albert Nancy , Cadwell Cindy , Edmonson Cole , Gaynes Robert , Hand Mary , Marinella Mark , Morely Colleen , Sieck Sandra , Vasudevan Rajiv S.
Published: May 2021

Healthcare-acquired infections are a tremendous challenge to the US medical system. Stethoscopes touch many patients, but current guidance from the Centers for Disease Control and Prevention does not support disinfection between each patient. Stethoscopes are rarely disinfected between patients by healthcare providers. When cultured, even after disinfection, stethoscopes have high rates of pathogen contamination, identical to that of unwashed hands. The consequence of these practices may bode poorly in the coronavirus 2019 disease (COVID-19) pandemic. Alternatively, the CDC recommends the use of disposable stethoscopes. However, these instruments have poor acoustic properties, and misdiagnoses have been documented. They may also serve as pathogen vectors among staff sharing them. Disposable aseptic stethoscope diaphragm barriers can provide increased safety without sacrificing stethoscope function. We recommend that the CDC consider the research regarding stethoscope hygiene and effective solutions to contemporize this guidance and elevate stethoscope hygiene to that of the hands, by requiring stethoscope disinfection or change of disposable barrier between every patient encounter.
LATE CHALCOLITHIC CERAMIC DEVELOPMENT IN SOUTHERN IRAQI KURDISTAN: THE STRATIGRAPHIC SOUNDING AT KANI SHAIE
Authors: Renette Steve , Jayyab Khaled Abu , Gibbon Elizabeth , Lewis Michael P. , Abdullkarim Qadir Zana , Cabral Ricardo , Tomé André G.
Published: May 2021

Kani Shaie is a small archaeological site in the Kurdistan Region of Iraq, centrally located in the Bazian Basin, a narrow valley at the western edge of the Zagros Mountains along the major route between Kirkuk and Sulaymaniyah. Its main mound was inhabited almost continuously from the fifth to the middle of the third millennium, c. 5000–2500 B.C.E. This period of Mesopotamian prehistory, corresponding to the Chalcolithic and Early Bronze Age, witnessed major transformations such as initial urbanism and intensification of interregional interaction networks. The recent resurgence of fieldwork in the Kurdistan Region of Iraq is beginning to reveal local trajectories that do not always match the established chronological framework, which is largely based on changes in ceramic technology and styles observed in northern Mesopotamia. Here, we discuss the ceramic sequence retrieved from a step trench at Kani Shaie spanning the entire Late Chalcolithic (c. 4600–3100 B.C.E.). A bottom-up approach to potting traditions at the site allows an initial assessment of the relationship between local communities in the Zagros foothills and large-scale developments in the Mesopotamian world. We argue that the evidence from Kani Shaie reflects a long process in which different communities of practice made active choices of adopting, adapting, or rejecting non-local cultural practices.
Verb argument structure overgeneralisations for the English intransitive and transitive constructions: grammaticality judgments and production priming
Authors: BIDGOOD AMY , PINE JULIAN , ROWLAND CAROLINE , SALA GIOVANNI , FREUDENTHAL DANIEL , AMBRIDGE BEN
Published: May 2021

We used a multi-method approach to investigate how children avoid (or retreat from) argument structure overgeneralisation errors (e.g., *You giggled me). Experiment 1 investigated how semantic and statistical constraints (preemption and entrenchment) influence children’s and adults’ judgments of the grammatical acceptability of 120 verbs in transitive and intransitive sentences. Experiment 2 used syntactic priming to elicit overgeneralisation errors from children (aged 5–6) to investigate whether the same constraints operate in production. For judgments, the data showed effects of preemption, entrenchment, and semantics for all ages. For production, only an effect of preemption was observed, and only for transitivisation errors with intransitive-only verbs (e.g., *The man laughed the girl). We conclude that preemption, entrenchment, and semantic effects are real, but are obscured by particular features of the present production task.
Monumental Structures and Volcanic Activities: Excavating the Campana at San Andrés in the Zapotitán Valley, El Salvador
Authors: Ichikawa Akira
Published: May 2021

This article presents stratigraphic data and radiocarbon dates combined with Bayesian modeling from San Andrés in the Zapotitán Valley, El Salvador, focusing on the Campana Structure, the largest and longest-used monumental structure at the site. These data refine the regional chronology of the valley and provide insights into the emergence, development, and abandonment of this pivotal center in southeastern Mesoamerica and its potential links to three related volcanic eruptions: Ilopango, Loma Caldera, and El Boquerón. These distinct volcanic events had pronounced effects on local people who innovated new monumental construction projects and used new volcanic debris as construction material after major eruptions. It is suggested that these monumental public building projects played an important role in the post-disaster recovery of societies by helping foster a sense of corporate identity. The use of volcanic material in constructions at San Andrés and the building of these massive structures may also have helped keep these events alive in the communal memory.
Following the Old Road: Organizational Imprinting and the Regional Development of Russia
Authors: Nykänen Nooa
Published: May 2021

In this article, I draw from organizational imprinting theory to illuminate the impact of the Soviet legacy on contemporary Russian economic geography and regional policy. I argue that central coordination in the creation and regulation of Russian urban agglomerations is connected to a socialist imprinted paradigm associated with the Soviet economic regionalization model and territorial-production complexes (TPCs). I conduct a qualitative historical study to analyze the role of the foundational environment and the dynamics in the development of this imprint. I propose that this imprint effect is prone to reproduction in contemporary regional development strategies and community-based paradigms due to exaptation and cultural-cognitive persistence. The article extends the literature of socialist imprinting by demonstrating how imprints may emerge, transform, and affect localized organizational communities in transition economies and highlights the role of imprinted paradigms in policymaking and regional development.
What is partial ambiguity?
Authors: Berger Loïc
Published: May 2021

This paper reflects on the notion of partial ambiguity. Using a framework decomposing ambiguity into distinct layers of analysis, among which are risk and model uncertainty, and allowing for different attitudes toward these layers, I show that partial ambiguity may prove less desirable than full ambiguity, even under ambiguity aversion. This observation poses difficulties for interpreting the notion of partial ambiguity in relation to the partial information available to determine the potential compositions of an ambiguous urn. Two Ellsberg-style thought experiments are described to challenge the meaning of partial ambiguity further, and an alternative interpretation, based on a more ambiguous relation, is discussed.
THE CONTRIBUTIONS OF IMPLICIT-STATISTICAL LEARNING APTITUDE TO IMPLICIT SECOND-LANGUAGE KNOWLEDGE
Authors: Godfroid Aline , Kim Kathy MinHye
Published: May 2021

This study addresses the role of domain-general mechanisms in second-language learning and knowledge using an individual differences approach. We examine the predictive validity of implicit-statistical learning aptitude for implicit second-language knowledge. Participants (n = 131) completed a battery of four aptitude measures and nine grammar tests. Structural equation modeling revealed that only the alternating serial reaction time task (a measure of implicit-statistical learning aptitude) significantly predicted learners’ performance on timed, accuracy-based language tests, but not their performance on reaction-time measures. These results inform ongoing debates about the nature of implicit knowledge in SLA: they lend support to the validity of timed, accuracy-based language tests as measures of implicit knowledge. Auditory and visual statistical learning were correlated with medium strength, while the remaining implicit-statistical learning aptitude measures were not correlated, highlighting the multicomponential nature of implicit-statistical learning aptitude and the corresponding need for a multitest approach to assess its different facets.
The foreign exchange market in Barcelona at the beginning of the fifteenth century
Authors: Orlandi Angela , Toscano Giacomo
Published: May 2021

Based on the reconstruction of the monetary flows of a merchant-banking company operating in Barcelona at the beginning of the fifteenth century, this study aims to understand the reasons behind exchange-rate variations in the local currency with respect to the principal European markets, as well as the modalities and predictability of such oscillations. By using real rather than ‘hearsay’ rates, we present new assessments of the seasonal character of exchange rates and their sensitivity to conditions of currency abundance or shortage. In addition, econometric analysis shows that exchange-rate volatility was quite modest and dependent on geographic and macroeconomic factors, such as the system of commercial flows.
Reconfigurable diplexer using hybrid couplers and perturbed TE012 cavities
Authors: Laplanche E. , Tantot O. , Delhote N. , Verdeyme S. , Perigaud A. , Pacaud D. , Carpentier L.
Published: May 2021

A continuously tunable Ku-band waveguide diplexer is proposed in this paper. This diplexer is based on a hybrid coupler topology and is composed of an input filter centered at 11.9 GHz with a 200 MHz bandwidth, a pair of ladder-type hybrid couplers, and a pair of tunable filters. This diplexer can provide two bandpass channels (channels 1 and 2) that can continuously go from a state where the bandwidths of channels 1 and 2 are maximum (up to 140 MHz) and minimum (down to 40 MHz), respectively, to another configuration where the bandwidth of channel 1 is the largest and the bandwidth of channel 2 is the narrowest. We propose a tunable filter based on TE012 mode circular cavities that are perturbed by low-loss dielectric inserts to obtain such performance. The resonant frequency of these cavities can be continuously tuned between 11.8 and 12 GHz due to the linear movement of the dielectric perturber. The design process for these components is presented and a breadboard device has been manufactured and measured to prove the concept. Different measured configurations of the diplexer are demonstrated, showing that the 200 MHz operating bandpass between 11.8 and 12 GHz can be efficiently separated into two tunable channels. The measured bandwidth of channels 1 and 2 in the manufactured diplexer can be tuned from 135 to 40 MHz (and vice versa) while maintaining an average guard band between the channels of approximately 26 ± 7 MHz. The obtained bandwidth tuning ratios are 3.2 for the highest channel and 3.1 for the lowest channel.
Abiotic Drivers of a Deep Cyanobacteria Layer in a Stratified and Eutrophic Lake
Authors: Taylor J. , Hondzo M. , Voller V. R.
Published: May 2021

Harmful algal blooms (HABs), in particular those consisting of the cyanobacteria Microcystis, are becoming increasingly more common across the globe. Despite the growing body of evidence that suggests vertical heterogeneity of Microcystis can be a precursor to HAB formation, the abiotic drivers of vertical distribution of Microcystis are poorly understood in the field environment. The prediction of subsurface cyanobacteria is also pertinent because subsurface concentrations are not easily recognizable to the public or lake system managers, creating a risk of exposure to harmful algal toxins. High‐frequency temporal and vertical data were collected from a research station anchored in a stratified and eutrophic lake for five months. Using a combination of dimensional analysis and machine learning approaches, data show that the magnitude of the subsurface Microcystis concentration peak and the center of gravity of the deep cyanobacteria layer are statistically significantly mediated by the thermal structure of the lake. The peak subsurface cyanobacteria biovolume is related to the thermocline depth and temperature, whereas the center of gravity of the subsurface cyanobacteria biovolume is related to the mixed layer depth and temperature. Furthermore, our data suggest there is a seasonal evolution of the subsurface cyanobacteria center of gravity that could potentially indicate timing of HAB onset. Based on easily measured parameters associated with the vertical lake temperature profile and meteorological conditions, we provide evidence of predictable trends in subsurface cyanobacteria variables.
Global Patterns in Cratonic Mid‐Lithospheric Discontinuities From Sp Receiver Functions
Authors: Krueger Hannah E. , Gama Isabella , Fischer Karen M.
Published: May 2021

The goal of this study is to constrain the origins of layering in the seismic velocity structure within the cratonic mantle lithosphere (i.e. mid‐lithospheric discontinuities [MLDs]). For long‐lived stations in cratons worldwide, we calculated S‐to‐P converted phase receiver function stacks using time domain deconvolution and a k‐means algorithm to select robust, consistent receiver functions. Negative MLDs appear in only 50% of the receiver function stacks, indicating that negative MLDs are common but intermittent. The negative MLDs correspond to shear velocity drops of 1%–4%, which could be caused by layers of minerals created by metasomatism, although vertical layering in seismic anisotropy cannot be ruled out. In craton interiors, negative MLDs have a lower amplitude (<3% velocity drops) and can be explained by metasomatism of the original Archean mantle. Negative MLD amplitudes increase with decreasing upper mantle shear velocity (toward the outer margins of the cratons), but do not depend on the age of the craton. Thus, negative MLD amplitudes are not dominated by age‐related variations in the cratonic mantle composition, and, instead, are more strongly correlated with proximity to tectonic and metasomatic activity that occurred long after craton formation. Negative MLDs are less numerous among stations that have Paleoproterozoic and Archean thermotectonic ages, consistent with the view that shallow release of slab‐derived fluids during early “warm” subduction was less favorable for negative MLD formation. We also observe velocity gradients below 150 km at stations in craton boundaries and interiors, indicating the presence of seismic velocity changes at the cratonic lithosphere‐asthenosphere boundary and/or Lehmann discontinuity.
Dissolved Fe Supply to the Central Gulf of Alaska Is Inferred to Be Derived From Alaskan Glacial Dust That Is Not Resolved by Dust Transport Models
Authors: Crusius John
Published: May 2021

Re‐examination of previously published dissolved iron time‐series data from Ocean Station Papa in the central Gulf of Alaska (GoA) reveals 33%–70% increases in the dissolved iron inventories occurring between September and February of successive years, implying a source of Fe to this region during autumn or early winter. Because I can virtually rule out many possible iron sources at this time of year, I suggest Alaskan glacial dust is the likely iron source. Large plumes of such dust are known to be generated regularly in the autumn by anomalous offshore winds and channeled through mountain gaps, simultaneously from several locations spanning ∼1,000 km of the northern Gulf of Alaska coastline. Large dust flux events occur when below‐freezing, low‐humidity air temperatures persist for many days during the autumn. I suggest that existing state‐of‐the‐art global dust models fail to reproduce this Alaskan dust flux because the model spatial resolution is too coarse to resolve the high winds through the narrow mountain gaps that generate the dust. Future work that could help to confirm this Fe source to the central GoA includes time‐series profiles of iron concentrations, and ancillary information from sensor‐equipped profiling floats. If this mechanism of Fe supply to the central GoA were confirmed, it would imply this Alaskan dust is transported ≥1,100 km from the coast, more than twice as far as has been visually documented from satellite observations.
Novel Alzheimer’s disease risk variants identified based on whole-genome sequencing of APOE ε4 carriers
Authors: Park Jong-Ho , Park Inho , Youm Emilia Moonkyung , Lee Sejoon , Park June-Hee , Lee Jongan , Lee Dong Young , Byun Min Soo , Lee Jun Ho , Yi Dahyun , Chung Sun Ju , Park Kye Won , Choi Nari , Kim Seong Yoon , Yoon Woon , An Hoyoung , Kim Ki woong , Choi Seong Hye , Jeong Jee Hyang , Kim Eun-Joo , Kang Hyojin , Lee Junehawk , Kim Younghoon , Lee Eunjung Alice , Seo Sang Won , Na Duk L. , Kim Jong-Won
Published: May 2021

Alzheimer’s disease (AD) is a progressive neurodegenerative disease associated with a complex genetic etiology. Besides the apolipoprotein E ε4 (APOE ε4) allele, a few dozen other genetic loci associated with AD have been identified through genome-wide association studies (GWAS) conducted mainly in individuals of European ancestry. Recently, several GWAS performed in other ethnic groups have shown the importance of replicating studies that identify previously established risk loci and searching for novel risk loci. APOE-stratified GWAS have yielded novel AD risk loci that might be masked by, or be dependent on, APOE alleles. We performed whole-genome sequencing (WGS) on DNA from blood samples of 331 AD patients and 169 elderly controls of Korean ethnicity who were APOE ε4 carriers. Based on WGS data, we designed a customized AD chip (cAD chip) for further analysis on an independent set of 543 AD patients and 894 elderly controls of the same ethnicity, regardless of their APOE ε4 allele status. Combined analysis of WGS and cAD chip data revealed that SNPs rs1890078 (P = 6.64E−07) and rs12594991 (P = 2.03E−07) in SORCS1 and CHD2 genes, respectively, are novel genetic variants among APOE ε4 carriers in the Korean population. In addition, nine possible novel variants that were rare in individuals of European ancestry but common in East Asia were identified. This study demonstrates that APOE-stratified analysis is important for understanding the genetic background of AD in different populations.
KDM4A regulates myogenesis by demethylating H3K9me3 of myogenic regulatory factors
Authors: Zhu Qi , Liang Feng , Cai Shufang , Luo Xiaorong , Duo Tianqi , Liang Ziyun , He Zuyong , Chen Yaosheng , Mo Delin
Published: May 2021

Histone lysine demethylase 4A (KDM4A) plays a crucial role in regulating cell proliferation, cell differentiation, development and tumorigenesis. However, little is known about the function of KDM4A in muscle development and regeneration. Here, we found that the conditional ablation of KDM4A in skeletal muscle caused impairment of embryonic and postnatal muscle formation. The loss of KDM4A in satellite cells led to defective muscle regeneration and blocked the proliferation and differentiation of satellite cells. Myogenic differentiation and myotube formation in KDM4A-deficient myoblasts were inhibited. Chromatin immunoprecipitation assay revealed that KDM4A promoted myogenesis by removing the histone methylation mark H3K9me3 at MyoD, MyoG and Myf5 locus. Furthermore, inactivation of KDM4A in myoblasts suppressed myoblast differentiation and accelerated H3K9me3 level. Knockdown of KDM4A in vitro reduced myoblast proliferation through enhancing the expression of the cyclin-dependent kinase inhibitor P21 and decreasing the expression of cell cycle regulator Cyclin D1. Together, our findings identify KDM4A as an important regulator for skeletal muscle development and regeneration, orchestrating myogenic cell proliferation and differentiation.
Fast photothermal spatial light modulation for quantitative phase imaging at the nanoscale
Authors: Robert Hadrien M. L. , Holanová Kristýna , Bujak Łukasz , Vala Milan , Henrichs Verena , Lánský Zdeněk , Piliarik Marek
Published: May 2021

Spatial light modulators have become an essential tool for advanced microscopy, enabling breakthroughs in 3D, phase, and super-resolution imaging. However, continuous spatial-light modulation that is capable of capturing sub-millisecond microscopic motion without diffraction artifacts and polarization dependence is challenging. Here we present a photothermal spatial light modulator (PT-SLM) enabling fast phase imaging for nanoscopic 3D reconstruction. The PT-SLM can generate a step-like wavefront change, free of diffraction artifacts, with a high transmittance and a modulation efficiency independent of light polarization. We achieve a phase-shift > π and a response time as short as 70 µs with a theoretical limit in the sub microsecond range. We used the PT-SLM to perform quantitative phase imaging of sub-diffractional species to decipher the 3D nanoscopic displacement of microtubules and study the trajectory of a diffusive microtubule-associated protein, providing insights into the mechanism of protein navigation through a complex microtubule network.
Club cell-specific role of programmed cell death 5 in pulmonary fibrosis
Authors: Park Soo-Yeon , Hong Jung Yeon , Lee Soo Yeon , Lee Seung-Hyun , Kim Mi Jeong , Kim Soo Yeon , Kim Kyung Won , Shim Hyo Sup , Park Moo Suk , Lee Chun Geun , Elias Jack A. , Sohn Myung Hyun , Yoon Ho-Geun
Published: May 2021

Idiopathic pulmonary fibrosis (IPF) causes progressive fibrosis and worsening pulmonary function. Prognosis is poor and no effective therapies exist. We show that programmed cell death 5 (PDCD5) expression is increased in the lungs of patients with IPF and in mouse models of lung fibrosis. Lung fibrosis is significantly diminished by club cell-specific deletion of Pdcd5 gene. PDCD5 mediates β-catenin/Smad3 complex formation, promoting TGF-β-induced transcriptional activation of matricellular genes. Club cell Pdcd5 knockdown reduces matricellular protein secretion, inhibiting fibroblast proliferation and collagen synthesis. Here, we demonstrate the club cell-specific role of PDCD5 as a mediator of lung fibrosis and potential therapeutic target for IPF.
Caspase-8 deficiency induces a switch from TLR3 induced apoptosis to lysosomal cell death in neuroblastoma
Authors: Locquet Marie-Anaïs , Ichim Gabriel , Bisaccia Joseph , Dutour Aurelie , Lebecque Serge , Castets Marie , Weber Kathrin
Published: May 2021

In cancer cells only, TLR3 acquires death receptor properties by efficiently triggering the extrinsic pathway of apoptosis with Caspase-8 as apical protease. Here, we demonstrate that in the absence of Caspase-8, activation of TLR3 can trigger a form of programmed cell death, which is distinct from classical apoptosis. When TLR3 was activated in the Caspase-8 negative neuroblastoma cell line SH-SY5Y, cell death was accompanied by lysosomal permeabilization. Despite caspases being activated, lysosomal permeabilization as well as cell death were not affected by blocking caspase-activity, positioning lysosomal membrane permeabilization (LMP) upstream of caspase activation. Taken together, our data suggest that LMP with its deadly consequences represents a “default” death mechanism in cancer cells, when Caspase-8 is absent and apoptosis cannot be induced.
Feasibility of predicting allele specific expression from DNA sequencing using machine learning
Authors: Zhang Zhenhua , van Dijk Freerk , de Klein Niek , van Gijn Mariëlle E , Franke Lude H , Sinke Richard J , Swertz Morris A , van der Velde K Joeri
Published: May 2021

Allele specific expression (ASE) concerns divergent expression quantity of alternative alleles and is measured by RNA sequencing. Multiple studies show that ASE plays a role in hereditary diseases by modulating penetrance or phenotype severity. However, genome diagnostics is based on DNA sequencing and therefore neglects gene expression regulation such as ASE. To take advantage of ASE in absence of RNA sequencing, it must be predicted using only DNA variation. We have constructed ASE models from BIOS (n = 3432) and GTEx (n = 369) that predict ASE using DNA features. These models are highly reproducible and comprise many different feature types, highlighting the complex regulation that underlies ASE. We applied the BIOS-trained model to population variants in three genes in which ASE plays a clinically relevant role: BRCA2, RET and NF1. This resulted in predicted ASE effects for 27 variants, of which 10 were known pathogenic variants. We demonstrated that ASE can be predicted from DNA features using machine learning. Future efforts may improve sensitivity and translate these models into a new type of genome diagnostic tool that prioritizes candidate pathogenic variants or regulators thereof for follow-up validation by RNA sequencing. All used code and machine learning models are available at GitHub and Zenodo.
Drop homotopic effects of masseter-muscle pain on somatosensory sensitivity in healthy participants
Authors: Hayakawa Hidetoshi , Iida Takashi , Honda-Sakaki Mika , Masuda Manabu , Svensson Peter , Komiyama Osamu
Published: May 2021

Current pain classifications use 1.0-kg palpation of the masseter muscle to distinguish between “pain patients” and “healthy controls” but a thorough understanding of the normal physiological responses to various somatosensory stimuli is lacking. The aim of this study was to investigate somatosensory function of the skin over the masseter muscle in healthy participants that were divided into a masseter pain prone group (MPP) (n = 22) and non-MPP group (n = 22), according to the response to a 1.0-kg palpation. Quantitative sensory testing (QST) was performed at the skin above the right masseter muscle (homotopic). In an additional experiment, 13 individuals each from MPP and non-MPP received application of 60% topical lidocaine tape to the skin over the masseter muscle for 30 min. Immediately after, mechanical pain sensitivity (MPS), dynamic mechanical allodynia, and pressure pain threshold were tested. Homotopic MPS was significantly higher and PPTs significantly lower in MPP than in N-MPP (P < 0.05). Strikingly, no other differences in QST outcomes were observed between the groups (P > 0.05). After lidocaine application, no significant differences in homotopic MPS were observed between groups. The presence or absence of acute provoked pain in masseter muscle is exclusively associated with differences in homotopic MPS which is decreased following topical anesthesia.
Watching sports and depressive symptoms among older adults: a cross-sectional study from the JAGES 2019 survey
Authors: Tsuji Taishi , Kanamori Satoru , Watanabe Ryota , Yokoyama Meiko , Miyaguni Yasuhiro , Saito Masashige , Kondo Katsunori
Published: May 2021

The current study investigated the relationship between the frequency of watching sports and depressive symptoms among older adults. This study used cross-sectional data from the Japan Gerontological Evaluation Study, a nationwide mail survey of 21,317 older adults. Depressive symptoms were defined as a Geriatric Depression Scale score of ≥ 5. Participants were queried regarding the average frequency at which they watched sports on-site and via TV/Internet over the past year. Among the 21,317 participants, 4559 (21.4%) had depressive symptoms, while 4808 (22.6%) and 16,576 (77.8%) watched sports on-site and via TV/Internet at least once a year, respectively. Older adults who watched sports on-site a few times/year (prevalence ratio, 0.70; 95% confidence interval, 0.65–0.74) or 1–3 times/month (0.66, 0.53–0.82) were less likely to have depressive symptoms compared to non-spectators after adjusting for frequency of playing sports, exercise activities, and other potential confounders. Meanwhile, a dose–response relationship was confirmed for watching via TV/Internet (prevalence ratio of 0.86, 0.79, and 0.71 for a few times/year, 1–3 times/month, and ≥ 1 time/week, respectively). This study suggested that watching sports on-site or via TV/Internet, regardless of whether they regularly engage in sports, may reduce the risk of depressive symptoms among older adults.
Patient-derived tumor xenograft and organoid models established from resected pancreatic, duodenal and biliary cancers
Authors: Pham Nhu-An , Radulovich Nikolina , Ibrahimov Emin , Martins-Filho Sebastiao N. , Li Quan , Pintilie Melania , Weiss Jessica , Raghavan Vibha , Cabanero Michael , Denroche Robert E. , Wilson Julie M. , Metran-Nascente Cristiane , Borgida Ayelet , Hutchinson Shawn , Dodd Anna , Begora Michael , Chadwick Dianne , Serra Stefano , Knox Jennifer J. , Gallinger Steven , Hedley David W. , Muthuswamy Lakshmi , Tsao Ming-Sound
Published: May 2021

Patient-derived xenograft (PDX) and their xenograft-derived organoid (XDO) models that recapitulate the genotypic and phenotypic landscape of patient cancers could help to advance research and lead to improved clinical management. PDX models were established from 276 pancreato-duodenal and biliary cancer resections. Initial, passage 0 (P0) engraftment rates were 59% (118/199) for pancreatic, 86% (25/29) for duodenal, and 35% (17/48) for biliary ductal tumors. Pancreatic ductal adenocarcinoma (PDAC), had a P0 engraftment rate of 62% (105/169). KRAS mutant and wild-type PDAC models were molecularly profiled, and XDO models were generated to perform initial drug response evaluations. Subsets of PDAC PDX models showed global copy number variants and gene expression profiles that were retained with serial passaging, and they showed a spectrum of somatic mutations represented in patient tumors. PDAC XDO models were established, with a success rate of 71% (10/14). Pathway activation of KRAS-MAPK in PDXs was independent of KRAS mutational status. Four wild-type KRAS models were characterized by one with EGFR (L747-P753 del), two with BRAF alterations (N486_P490del or V600E), and one with triple negative KRAS/EGFR/BRAF. Model OCIP256, characterized by BRAF (N486-P490 del), had activated phospho-ERK. A combination treatment of a pan-RAF inhibitor (LY3009120) and a MEK inhibitor (trametinib) effectively suppressed phospho-ERK and inhibited growth of OCIP256 XDO and PDX models. PDAC/duodenal adenocarcinoma have high success rates forming PDX/organoid and retaining their phenotypic and genotypic features. These models may be effective tools to evaluate novel drug combination therapies.
Decreased vascular smooth muscle contractility in Hutchinson–Gilford Progeria Syndrome linked to defective smooth muscle myosin heavy chain expression
Authors: von Kleeck Ryan , Castagnino Paola , Roberts Emilia , Talwar Shefali , Ferrari Giovanni , Assoian Richard K.
Published: May 2021

Children with Hutchinson–Gilford Progeria Syndrome (HGPS) suffer from multiple cardiovascular pathologies due to the expression of progerin, a mutant form of the nuclear envelope protein Lamin A. Progerin expression has a dramatic effect on arterial smooth muscle cells (SMCs) and results in decreased viability and increased arterial stiffness. However, very little is known about how progerin affects SMC contractility. Here, we studied the LaminAG609G/G609G mouse model of HGPS and found reduced arterial contractility at an early age that correlates with a decrease in smooth muscle myosin heavy chain (SM-MHC) mRNA and protein expression. Traction force microscopy on isolated SMCs from these mice revealed reduced force generation compared to wild-type controls; this effect was phenocopied by depletion of SM-MHC in WT SMCs and overcome by ectopic expression of SM-MHC in HGPS SMCs. Arterial SM-MHC levels are also reduced with age in wild-type mice and humans, suggesting a common defect in arterial contractility in HGPS and normal aging.
Comparison between selective caudal fixed screw construct and all variable screw construct in anterior cervical discectomy and fusion
Authors: Yang Jae Jun , Park Sehan , Park Seongyun
Published: May 2021

This retrospective comparative study aimed to compare the efficacy of selective caudal fixed screw constructs with all variable screw constructs in anterior cervical discectomy and fusion (ACDF). Thirty-five patients who underwent surgery using selective caudal fixed screw construct (SF group) were compared with 44 patients who underwent surgery using all variable constructs (AV group). The fusion rate, subsidence, adjacent level ossification development (ALOD), adjacent segmental disease (ASD), and plate-adjacent disc space distance were assessed. The one-year fusion rates assessed by computed tomography bone bridging and interspinous motion as well as the significant subsidence rate did not differ significantly between the AV and SF groups. The ALOD and ASD rates and plate-adjacent disc space distances did not significantly differ between the two groups at both the cranial and caudal adjacent levels. The number of operated levels was significantly associated with pseudarthrosis in the logistic regression analysis. The stability provided by the locking mechanism of the fixed screw did not lead to an increased fusion rate at the caudal level. Therefore, the screw type should be selected based on individual patient’s anatomy and surgeon’s experience without concern for increased complications caused by screw type.
Distribution of genetic alterations in high-risk early-stage cervical cancer patients treated with postoperative radiation therapy
Authors: Murakami Naoya , Asami Yuka , Yoshida Hiroshi , Takayanagi Daisuke , Hirose Sou , Kuno Ikumi , Takahashi Kazuaki , Matsuda Maiko , Shimada Yoko , Yamano Shotaro , Sunami Kuniko , Honda Takayuki , Nakahara Tomomi , Watanabe Tomoko , Okuma Kae , Kuroda Takafumi , Kohno Takashi , Kato Tomoyasu , Shiraishi Kouya , Itami Jun
Published: May 2021

Somatic genetic alteration analysis was performed for post-hysterectomy high-risk early-stage uterine cervical cancer patients who underwent post-operative radiation therapy. Post-operative radiation therapy was performed for patients with pathological features of pelvic lymph node metastasis, parametrium invasion, or positive vaginal margin, which corresponded to the post-operative high-risk category. DNA was extracted from paraffin-embedded surgical specimens, and 50 somatic hotspot genetic alternations were detected using Ion AmpliSeq Cancer Hotspot Panel. The existence of actionable mutation was assessed based on OncoKB evidence level > 3A. Between January 2008 and November 2019, 89 patients who underwent abdominal radical hysterectomy followed by post-operative radiation therapy were identified. The follow-up period for living patients was 82.3 months (range 9.3–153.9), and the 5-year relapse-free survival and overall survival rates were 72.6% and 85.9%, respectively. The most frequently detected somatic mutation was PIK3CA (26 [29.2%] patients); however, no prognostic somatic genetic alterations were identified. Actionable mutations were detected in 30 (33.7%) patients. Actionable mutations were detected in approximately one-third of patients, suggesting that precision medicine can be offered to patients with post-operative high-risk uterine cervical cancer in the near future.
Prediction of velocity profile of water based copper nanofluid in a heated porous tube using CFD and genetic algorithm
Authors: Ciano Tiziana , Ferrara Massimiliano , Babanezhad Meisam , Khan Afrasyab , Marjani Azam
Published: May 2021

The heat transfer improvements by simultaneous usage of the nanofluids and metallic porous foams are still an attractive research area. The Computational fluid dynamics (CFD) methods are widely used for thermal and hydrodynamic investigations of the nanofluids flow inside the porous media. Almost all studies dedicated to the accurate prediction of the CFD approach. However, there are not sufficient investigations on the CFD approach optimization. The mesh increment in the CFD approach is one of the challenging concepts especially in turbulent flows and complex geometries. This study, for the first time, introduces a type of artificial intelligence algorithm (AIA) as a supplementary tool for helping the CFD. According to the idea of this study, the CFD simulation is done for a case with low mesh density. The artificial intelligence algorithm uses learns the CFD driven data. After the intelligence achievement, the AIA could predict the fluid parameters for the infinite number of nodes or dense mesh without any limitations. So, there is no need to solve the CFD models for further nodes. This study is specifically focused on the genetic algorithm-based fuzzy inference system (GAFIS) to predict the velocity profile of the water-based copper nanofluid turbulent flow in a porous tube. The most intelligent GAFIS could perform the most accurate prediction of the velocity. Hence, the intelligence of GAFIS is tested for different values of cluster influence range (CIR), squash factor(SF), accept ratio (AR) and reject ratio (RR), the population size (PS), and the percentage of crossover (PC). The maximum coefficient of determination (~ 0.97) was related to the PS of 30, the AR of 0.6, the PC of 0.4, CIR of 0.15, the SF 1.15, and the RR of 0.05. The GAFIS prediction of the fluid velocity was in great agreement with the CFD. In the most intelligent condition, the velocity profile predicted by GAFIS was similar to the CFD. The nodes increment from 537 to 7671 was made by the GAFIS. The new predictions of the GAFIS covered all CFD results.
Author Correction: Calcium ion-induced formation of β-sheet/-turn structure leading to alteration of osteogenic activity of bone morphogenetic protein-2
Authors: Zhang Wenjing , He Hongyan , Tian Yu , Gan Qi , Zhang Jing , Yuan Yuan , Liu Changsheng
Published: May 2021

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Live-cell imaging of glucose-induced metabolic coupling of β and α cell metabolism in health and type 2 diabetes
Authors: Wang Zhongying , Gurlo Tatyana , Matveyenko Aleksey V. , Elashoff David , Wang Peiyu , Rosenberger Madeline , Junge Jason A. , Stevens Raymond C. , White Kate L. , Fraser Scott E. , Butler Peter C.
Published: May 2021

Type 2 diabetes is characterized by β and α cell dysfunction. We used phasor-FLIM (Fluorescence Lifetime Imaging Microscopy) to monitor oxidative phosphorylation and glycolysis in living islet cells before and after glucose stimulation. In healthy cells, glucose enhanced oxidative phosphorylation in β cells and suppressed oxidative phosphorylation in α cells. In Type 2 diabetes, glucose increased glycolysis in β cells, and only partially suppressed oxidative phosphorylation in α cells. FLIM uncovers key perturbations in glucose induced metabolism in living islet cells and provides a sensitive tool for drug discovery in diabetes.
CD28 engagement inhibits CD73-mediated regulatory activity of CD8+ T cells
Authors: Lai Yo-Ping , Kuo Lu-Cheng , Lin Been-Ren , Lin Hung-Ju , Lin Chih-Yu , Chen Yi-Ting , Hsiao Pei-Wen , Chang Huan-Tsung , Ko Patrick Chow-In , Chen Hsiao-Chin , Chang Hsiang-Yu , Lu Jean , Ho Hong-Nerng , Wu-Hsieh Betty A. , Kung John T. , Chen Shu-Ching
Published: May 2021

CD28 is required for T cell activation as well as the generation of CD4+Foxp3+ Treg. It is unclear, however, how CD28 costimulation affects the development of CD8+ T cell suppressive function. Here, by use of Hepa1.6.gp33 in vitro killing assay and B16.gp33 tumor mouse model we demonstrate that CD28 engagement during TCR ligation prevents CD8+ T cells from becoming suppressive. Interestingly, our results showed that ectonucleotidase CD73 expression on CD8+ T cells is upregulated in the absence of CD28 costimulation. In both murine and human tumor-bearing hosts, CD73 is upregulated on CD28−CD8+ T cells that infiltrate the solid tumor. UPLC-MS/MS analysis revealed that CD8+ T cells activation without CD28 costimulation produces elevated levels of adenosine and that CD73 mediates its production. Adenosine receptor antagonists block CD73-mediated suppression. Our data support the notion that CD28 costimulation inhibits CD73 upregulation and thereby prevents CD8+ T cells from becoming suppressive. This study uncovers a previously unidentified role for CD28 costimulation in CD8+ T cell activation and suggests that the CD28 costimulatory pathway can be a potential target for cancer immunotherapy.