bluuebunny/crossref_metadata_2025 huggingface dataset:
Semantic Bottlenecks: Quantifying and Improving Inspectability of Deep Representations
Authors: Losch Max , Fritz Mario , Schiele Bernt
Published: September 2021

Today’s deep learning systems deliver high performance based on end-to-end training but are notoriously hard to inspect. We argue that there are at least two reasons making inspectability challenging: (i) representations are distributed across hundreds of channels and (ii) a unifying metric quantifying inspectability is lacking. In this paper, we address both issues by proposing Semantic Bottlenecks (SB), which can be integrated into pretrained networks, to align channel outputs with individual visual concepts and introduce the model agnostic Area Under inspectability Curve (AUiC) metric to measure the alignment. We present a case study on semantic segmentation to demonstrate that SBs improve the AUiC up to six-fold over regular network outputs. We explore two types of SB-layers in this work. First, concept-supervised SB-layers (SSB), which offer inspectability w.r.t. predefined concepts that the model is demanded to rely on. And second, unsupervised SBs (USB), which offer equally strong AUiC improvements by restricting distributedness of representations across channels. Importantly, for both SB types, we can recover state of the art segmentation performance across two different models despite a drastic dimensionality reduction from 1000s of non aligned channels to 10s of semantics-aligned channels that all downstream results are based on.
Identification and structural characterization of three psychoactive substances, phenylpiperazines (pBPP and 3,4-CFPP) and a cocaine analogue (troparil), in collected samples
Authors: Popławska Magdalena , Bednarek Elżbieta , Naumczuk Beata , Błażewicz Agata
Published: September 2021

Purpose

New psychoactive substances (NPSs) still appear on the market, mainly due to their legal status. This situation indicates and alarms that permanent recognition of the designer drug scene should be conducted. In this paper, we describe the detection of three psychoactive substances in samples collected from drug users.

Methods

Qualitative characterization was performed using liquid chromatography–high-resolution tandem mass spectrometry with a quadrupole time-of-flight analyzer, gas chromatography with mass spectrometry and nuclear magnetic resonance spectroscopy.

Results

In this study, we reported the detection and structural elucidation of three psychoactive substances: 1-(4-bromophenyl)piperazine (pBPP), 1-(3-chloro-4-fluorophenyl)piperazine (3,4-CFPP) and methyl 8-methyl-3-phenyl-8-azabicyclo[3.2.1]octane-4-carboxylate (troparil).

Conclusions

To the best of our knowledge, this is the first report that presents an identification methodology for these substances found in illegal products. Comprehensive characterization of the NPSs presented in this paper facilitates their detection and identification by forensic and clinical laboratories.
Inverse Correlation Between Alzheimer’s Disease and Cancer: Short Overview
Authors: Zabłocka Agnieszka , Kazana Wioletta , Sochocka Marta , Stańczykiewicz Bartłomiej , Janusz Maria , Leszek Jerzy , Orzechowska Beata
Published: September 2021

The negative association between Alzheimer’s disease (AD) and cancer suggests that susceptibility to one disease may protect against the other. When biological mechanisms of AD and cancer and relationship between them are understood, the unsolved problem of both diseases which still touches the growing human population could be overcome. Actual information about biological mechanisms and common risk factors such as chronic inflammation, age-related metabolic deregulation, and family history is presented here. Common signaling pathways, e.g., p53, Wnt, role of Pin1, and microRNA, are discussed as well. Much attention is also paid to the potential impact of chronic viral, bacterial, and fungal infections that are responsible for the inflammatory pathway in AD and also play a key role to cancer development. New data about common mechanisms in etiopathology of cancer and neurological diseases suggests new therapeutic strategies. Among them, the use of nilotinib, tyrosine kinase inhibitor, protein kinase C, and bexarotene is the most promising.
Influenza A Virus (H1N1) Infection Induces Glycolysis to Facilitate Viral Replication
Authors: Ren Lehao , Zhang Wanju , Zhang Jing , Zhang Jiaxiang , Zhang Huiying , Zhu Yong , Meng Xiaoxiao , Yi Zhigang , Wang Ruilan
Published: September 2021

Viruses depend on host cellular metabolism to provide the energy and biosynthetic building blocks required for their replication. In this study, we observed that influenza A virus (H1N1), a single-stranded, negative-sense RNA virus with an eight-segmented genome, enhanced glycolysis both in mouse lung tissues and in human lung epithelial (A549) cells. In detail, the expression of hexokinase 2 (HK2), the first enzyme in glycolysis, was upregulated in H1N1-infected A549 cells, and the expression of pyruvate kinase M2 (PKM2) and pyruvate dehydrogenase kinase 3 (PDK3) was upregulated in H1N1-infected mouse lung tissues. Pharmacologically inhibiting the glycolytic pathway or targeting hypoxia-inducible factor 1 (HIF-1), the central transcriptional factor critical for glycolysis, significantly reduced H1N1 replication, revealing a requirement for glycolysis during H1N1 infection. In addition, pharmacologically enhancing the glycolytic pathway further promoted H1N1 replication. Furthermore, the change of H1N1 replication upon glycolysis inhibition or enhancement was independent of interferon signaling. Taken together, these findings suggest that influenza A virus induces the glycolytic pathway and thus facilitates efficient viral replication. This study raises the possibility that metabolic inhibitors, such as those that target glycolysis, could be used to treat influenza A virus infection in the future.
The value of additional data for public transport origin–destination matrix estimation
Authors: Ait-Ali Abderrahman , Eliasson Jonas
Published: September 2021

Passenger origin–destination data is an important input for public transport planning. In recent years, new data sources have become increasingly common through the use of the automatic collection of entry counts, exit counts and link flows. However, collecting such data can be sometimes costly. The value of additional data collection hence has to be weighed against its costs. We study the value of additional data for estimating time-dependent origin–destination matrices, using a case study from the London Piccadilly underground line. Our focus is on how the precision of the estimated matrix increases when additional data on link flow, destination count and/or average travel distance is added, starting from origin counts only. We concentrate on the precision of the most policy-relevant estimation outputs, namely, link flows and station exit flows. Our results suggest that link flows are harder to estimate than exit flows, and only using entry and exit data is far from enough to estimate link flows with any precision. Information about the average trip distance adds greatly to the estimation precision. The marginal value of additional destination counts decreases only slowly, so a relatively large number of exit station measurement points seem warranted. Link flow data for a subset of links hardly add to the precision, especially if other data have already been added.
A Psychosocial Support Program for Young Adult Childhood Cancer Survivors in Austria: a Qualitative Evaluation Study
Authors: Pletschko Thomas , Krottendorfer Kerstin , Schlifelner Juliana , Schwarzinger Agathe , Fohn-Erhold Verena , Weiler-Wichtl Liesa , Kienesberger Anita , Leiss Ulrike
Published: September 2021

Many adolescents and young adult (AYAs) childhood cancer survivors face disease- or therapy-related late-effects, which limit their participation in various areas of daily life. AYAs are often left alone in our health care system, and many worry about their ability to cope with long-term sequelae, and some are even lost to follow-up. Therefore, in the present study, a targeted aftercare program was developed and evaluated with the goal of facilitating three important “life skills”: (1) self-perception, (2) social interaction and conflict management, and (3) self-conscious communication of support needs. A total of n = 13 participants (19.2–30.2 years, mean age 22.8 years) completed a 3-day aftercare seminar, at the end of which each participant wrote a reflection letter (“letter to my future self”), elaborating on observed effects of the seminar, applicability of the given information in daily life, and the direct impact of the seminar on their individual circumstances. The reflection letters were analyzed using qualitative content analysis. All target life skills were mentioned in the reflection letters. The participants reported individual benefits from the program especially with respect to self-perception and self-confidence, giving and taking feedback, and acceptance of personal strengths and weaknesses. Moreover, the feeling of “not being alone” was associated with the survivors’ experience of emotional and social support. This evaluation highlights the potential of a one weekend aftercare seminar to address important life skills that are known to positively influence health behavior in AYAs. The detailed description of the seminar can serve as a basis for making this kind of aftercare accessible for other people in similar circumstances.
Synthesis and study of aroylethyl(ethyl)-xanthates as stabilizers of polymeric materials
Authors: Akchurina Tanzila , Sardarova Sabira , Efendiyeva Khuraman , Eyvazova Irada , Farzaliyev Vagif , Sujayev Afsun
Published: September 2021

The number of aroylethyl (ethyl)xanthates have been synthesized by the reaction of the exchange decomposition of β-dimethylaminopropiophenone hydrochlorides with potassium xanthate containing several functional groups (C=O, C=S, C–OH), which determine the use of these xanthates as stabilizers with internal synergy to polymeric materials. It was shown that the thermal stability of the compounds, depending on the nature of the substituent in the benzene ring of the molecule was observed in the temperature range of 149–196 °C. It was revealed that aroylethyl(ethyl)xanthates had a stabilizing effect due to the suppression of thermo-oxidative destruction of polyethylene; they increased the induction period of polyethylene oxidation by 2–6 times, and the oxidation rate was reduced by about 3–9 times. Among the studied compounds, 4-hydroxybenzoylethyl (ethyl)xanthate had the greatest stabilizing effect. The study of the mechanism of the stabilizing action of the compounds showed that xanthates react with cumene hydroperoxide (CHP), which proceeded through the stage of formation of an intermediate product that actively decomposed CHP, i.e., the oxidation chain was terminated by the decomposition of the CHP not by the initial xanthates but by their transformation products.
Pro-environmental habits: An underexplored research agenda in sustainability science
Authors: Linder Noah , Giusti Matteo , Samuelsson Karl , Barthel Stephan
Published: September 2021

Habits are the fundamental basis for many of our daily actions and can be powerful barriers to behavioural change. Still, habits are not included in most narratives, theories, and interventions applied to sustainable behaviour. One reason societies struggle to reach policy goals and people fail to change towards more pro-environmental lifestyles might be that many behaviours are now bound by strong habits that override knowledge and intentions to act. In this perspective article, we provide three arguments for why pro-environmental habits are a needed research agenda in sustainability science: (1) habit theory highlights how behaviour is heavily reliant on automatic processes, (2) the environmental context sets boundary conditions for behaviour, shape habits, and cues action responses, and (3) our habits and past behaviour shape our values and self-identity. These arguments highlight the transformative potential of looking at sustainable behaviours through a habit lens. We believe a research agenda on pro-environmental habits could generate a more holistic understanding of sustainable behaviours and complement today’s dominating approaches which emphasize reasoned decisions and intrinsic motivations such as values, norms, and intentions to understand and predict pro-environmental behaviour. We highlight evident knowledge gaps and practical benefits of considering habit theory to promote pro-environmental behaviours, and how habit architecture could be utilized as a strong leverage point when designing, modifying, and building urban environments.
Protecting the Empire's Humanity
Authors: Laidlaw Zoë
Published: September 2021

Rooted in the extraordinary archive of Quaker physician and humanitarian activist, Dr Thomas Hodgkin, this book explores the efforts of the Aborigines' Protection Society to expose Britain's hypocrisy and imperial crimes in the mid-nineteenth century. Hodgkin's correspondents stretched from Liberia to Lesotho, New Zealand to Texas, Jamaica to Ontario, and Bombay to South Australia; they included scientists, philanthropists, missionaries, systematic colonizers, politicians and indigenous peoples themselves. Debating the best way to protect and advance indigenous rights in an era of burgeoning settler colonialism, they looked back to the lessons and limitations of anti-slavery, lamented the imperial government's disavowal of responsibility for settler colonies, and laid out elaborate (and patronizing) plans for indigenous 'civilization'. Protecting the Empire's Humanity reminds us of the complexity, contradictions and capacious nature of British colonialism and metropolitan 'humanitarianism', illuminating the broad canvas of empire through a distinctive set of British and Indigenous campaigners.
Hyperbolicity of renormalization for dissipative gap mappings
Authors: CLARK TREVOR , GOUVEIA MÁRCIO
Published: September 2021

A gap mapping is a discontinuous interval mapping with two strictly increasing branches that have a gap between their ranges. They are one-dimensional dynamical systems, which arise in the study of certain higher dimensional flows, for example the Lorenz flow and the Cherry flow. In this paper, we prove hyperbolicity of renormalization acting on

$C^3$

dissipative gap mappings, and show that the topological conjugacy classes of infinitely renormalizable gap mappings are

$C^1$

manifolds.
Effective for Whom? Ethnic Identity and Nonviolent Resistance
Authors: MANEKIN DEVORAH , MITTS TAMAR
Published: September 2021

A growing literature finds that nonviolence is more successful than violence in effecting political change. We suggest that a focus on this association is incomplete, because it obscures the crucial influence of ethnic identity on campaign outcomes. We argue that because of prevalent negative stereotypes associating minority ethnic groups with violence, such groups are perceived as more violent even when resisting nonviolently, increasing support for their repression and ultimately hampering campaign success. We show that, cross-nationally, the effect of nonviolence on outcomes is significantly moderated by ethnicity, with nonviolence increasing success only for dominant groups. We then test our argument using two experiments in the United States and Israel. Study 1 finds that nonviolent resistance by ethnic minorities is perceived as more violent and requiring more policing than identical resistance by majorities. Study 2 replicates and extends the results, leveraging the wave of racial justice protests across the US in June 2020 to find that white participants are perceived as less violent than Black participants when protesting for the same goals. These findings highlight the importance of ethnic identity in shaping campaign perceptions and outcomes, underscoring the obstacles that widespread biases pose to nonviolent mobilization.
General v. specific vulnerabilities: polygenic risk scores and higher-order psychopathology dimensions in the Adolescent Brain Cognitive Development (ABCD) Study
Authors: Waszczuk Monika A. , Miao Jiaju , Docherty Anna R. , Shabalin Andrey A. , Jonas Katherine G. , Michelini Giorgia , Kotov Roman
Published: September 2021

Background

Polygenic risk scores (PRSs) capture genetic vulnerability to psychiatric conditions. However, PRSs are often associated with multiple mental health problems in children, complicating their use in research and clinical practice. The current study is the first to systematically test which PRSs associate broadly with all forms of childhood psychopathology, and which PRSs are more specific to one or a handful of forms of psychopathology.

Methods

The sample consisted of 4717 unrelated children (mean age = 9.92, s.d. = 0.62; 47.1% female; all European ancestry). Psychopathology was conceptualized hierarchically as empirically derived general factor (p-factor) and five specific factors: externalizing, internalizing, neurodevelopmental, somatoform, and detachment. Partial correlations explored associations between psychopathology factors and 22 psychopathology-related PRSs. Regressions tested which level of the psychopathology hierarchy was most strongly associated with each PRS.

Results

Thirteen PRSs were significantly associated with the general factor, most prominently Chronic Multisite Pain-PRS (r = 0.098), ADHD-PRS (r = 0.079), and Depression-PRS (r = 0.078). After adjusting for the general factor, Depression-PRS, Neuroticism-PRS, PTSD-PRS, Insomnia-PRS, Chronic Back Pain-PRS, and Autism-PRS were not associated with lower order factors. Conversely, several externalizing PRSs, including Adventurousness-PRS and Disinhibition-PRS, remained associated with the externalizing factor (|r| = 0.040–0.058). The ADHD-PRS remained uniquely associated with the neurodevelopmental factor (r = 062).

Conclusions

PRSs developed to predict vulnerability to emotional difficulties and chronic pain generally captured genetic risk for all forms of childhood psychopathology. PRSs developed to predict vulnerability to externalizing difficulties, e.g. disinhibition, tended to be more specific in predicting behavioral problems. The results may inform translation of existing PRSs to pediatric research and future clinical practice.
Condensed Internet-delivered prolonged exposure provided soon after trauma: a randomised trial
Authors: Bragesjö Maria , Arnberg Filip K. , Olofsdotter Lauri Klara , Aspvall Kristina , Särnholm Josefin , Andersson Erik
Published: September 2021

Background

Exposure to trauma is common and can have a profoundly negative impact on mental health. Interventions based on trauma-focused cognitive behavioural therapy have shown promising results to facilitate recovery. The current trial evaluated whether a novel, scalable and digital early version of the intervention, Condensed Internet-Delivered Prolonged Exposure (CIPE), is effective in reducing post-traumatic stress symptoms.

Method

A single-site randomised controlled trial with self-referred adults (N = 102) exposed to trauma within the last 2 months. The participants were randomised to 3 weeks of CIPE or a waiting list (WL) for 7 weeks. Assessments were conducted at baseline, week 1–3 (primary endpoint), week 4–7 (secondary endpoint) and at 6-month follow-up. The primary outcome measure was PTSD Checklist for DSM-5 (PCL-5).

Results

The main analysis according to the intention-to-treat principle indicated statistically significant reductions in symptoms of post-traumatic stress in the CIPE group as compared to the WL group. The between-group effect size was moderate at week 3 (bootstrapped d = 0.70; 95% CI 0.33–1.06) and large at week 7 (bootstrapped d = 0.83; 95% CI 0.46–1.19). Results in the intervention group were maintained at the 6-month follow-up. No severe adverse events were found.

Conclusions

CIPE is a scalable intervention that may confer early benefits on post-traumatic stress symptoms in survivors of trauma. The next step is to compare this intervention to an active control group and also investigate its effects when implemented in regular care.
Genotyping indicates marked heterogeneity of tuberculosis transmission in the United States, 2009–2018
Authors: Rodriguez Carly A. , Li Tenglong , Self Julie L. , Jenkins Helen E. , Horsburgh Charles R. , White Laura F.
Published: September 2021

Heterogeneity in the number of secondary tuberculosis (TB) cases per source case, the effective reproductive number, R, is important in modelling prevention strategies' impact on incidence.

We estimated mean R (Rm) and calculate the dispersion parameter of this distribution, k, using surveillance and genotyping data for U.S. cases during 2009–2018. We modelled transmission assuming cases in a cluster have matching genotypes and share characteristics related to geography, temporal proximity (i.e. serial interval) and time since U.S. arrival among non-U.S.-born persons.

Complete data were available for 55 330/85 958 cases. Varying the serial interval and geographic proximity used to derive clusters, we consistently estimated Rm<1.0 and k < 0.08; the low value of k indicates a small number of source cases produce a disproportionate number of secondary cases.

U.S. TB reproductive number has a highly skewed distribution, indicating a minority of source cases disproportionately contribute to transmission.
Percutaneous treatment of a double-drainage scimitar-like syndrome
Authors: Meliota Giovanni , Zaza Pierluigi , Vairo Ugo
Published: September 2021

Scimitar syndrome is a rare variant of anomalous right pulmonary vein connection to the inferior vena cava and it is associated with other cardiopulmonary anomalies. It generally requires surgery and sometimes it may go unrecognised into adulthood. We report a unique case of a scimitar syndrome variant in a young adult, who was successfully treated percutaneously, after the first misdiagnosis of arrhythmogenic ventricular cardiomyopathy. The cardiac magnetic resonance unveiled the uncommon anatomical pattern, avoiding surgical repair. Cross-sectional imaging is extremely useful in the diagnosis and treatment planning of CHD in adults.
Analytical Three-Dimensional Field Ion Microscopy of an Amorphous Glass FeBSi
Authors: Klaes Benjamin , Renaux Jeoffrey , Lardé Rodrigue , Delaroche Fabien , Morgado Felipe F , Stephenson Leigh T , Gault Baptiste , Vurpillot François
Published: September 2021

Three-dimensional field ion microscopy is a powerful technique to analyze material at a truly atomic scale. Most previous studies have been made on pure, crystalline materials such as tungsten or iron. In this article, we study more complex materials, and we present the first images of an amorphous sample, showing the capability to visualize the compositional fluctuations compatible with theoretical medium order in a metallic glass (FeBSi), which is extremely challenging to observe directly using other microscopy techniques. The intensity of the spots of the atoms at the moment of field evaporation in a field ion micrograph can be used as a proxy for identifying the elemental identity of the imaged atoms. By exploiting the elemental identification and positioning information from field ion images, we show the capability of this technique to provide imaging of recrystallized phases in the annealed sample with a superior spatial resolution compared with atom probe tomography.
Sleepwalking into the ‘Post-Racial’: Social Policy and Research-Led Teaching
Authors: Phillips Coretta , Williams Fiona
Published: September 2021

Research-led teaching is the sine qua non of the 21stcentury university. To understand its possibilities for teaching and learning about race in Social Policy requires, as a first step, interrogating the epistemological and theoretical core of the discipline, as well as its organisational dynamics. Using parts of Emirbayer and Desmond’s (2012) framework of disciplinary reflexivity, this article traces the discipline’s habits of thought but also its lacunae in the production of racial knowledge. This entails focusing on its different forms of institutionalised and epistemological whiteness, and what has shaped the omission or marginalisation of a full understanding of the racialisation of welfare subjects and regimes in the discipline. Throughout, the article offers alternative analyses and thinking that fully embrace the historical and contemporary role of race, racism, and nation in lived realities, institutional processes, and global racial orders. It concludes with pointers towards a re-envisioning of Social Policy, within a framework in which postcolonial and intersectional theory and praxis are championed. Only then might a decolonised curriculum be possible in which race is not peripheral to core teaching and learning.
Colonial Disparities in Higher Education: Explaining Racial Inequality for Māori Youth in Aotearoa New Zealand
Authors: Mayeda David , France Alan , Pukepuke Tepora , Cowie Lucy , Chetty Marilyn
Published: September 2021

While recent research shows a gradual increase of young Māori in Higher Education it remains the case that inequality amongst the Indigenous population remains entrenched and institutionalised. This article explains how national governments in Aotearoa New Zealand have failed to address the colonial disparities and inequalities in the Higher Education system. In this process we will show, through the lens of historical privilege and institutional racism, how these processes continue to shape and frame both opportunities and experiences for Māori youth. The article will also highlight what strategies are needed if a more inclusive Higher Education system is to be developed that addresses the disparities that young Māori encounter.
First Full Vector Archeomagnetic Data From Northern Mexico
Authors: Tchibinda Madingou B. , Perrin M. , Hervé G. , Hernàndez Cardona A. , Alva‐Valdivia L. M. , Cruz Antillón R.
Published: September 2021

Several regional secular variation curves of the geomagnetic field have been proposed for Mexico over the last millennia. Despite a fairly large number of archeomagnetic data, these curves remain imprecise because of an uneven quality and geographic distribution, with a lack of data in Northern Mexico. Nine pottery kilns were sampled in Casas de Fuego, an archeological site in the Chihuahua state. These kilns belong to the Casas Grandes culture and were in use between 1250 and 1450 CE. Rock magnetic experiments indicate that the main magnetic phase is a Ti‐poor titanomagnetite in the SD range. Mean characteristic directions per kiln were estimated by alternating field and/or thermal demagnetization, and archeointensities with the Thellier‐Thellier protocol, after correction for anisotropy and cooling effects. The nine directions and eight intensities agree with data from USA and Mexico but do not support the peak in inclination modeled by the Mexican secular variation curve around 1200–1300 CE. For the last millennium, the Western North American curve is consistent with the SHAWQ2k global model, and better reflects the secular variation in Northern Mexico. For intensity, neither the SHAWQ2k model nor the regional intensity curve can depict the rapid secular variation that likely occurs circa 1500 CE. The Casas de Fuego results are the first full vector determinations obtained in Northern Mexico.
Programmed cell death 10 promotes metastasis and epithelial-mesenchymal transition of hepatocellular carcinoma via PP2Ac-mediated YAP activation
Authors: Sun Bo , Zhong Fang-Jing , Xu Cong , Li Yi-Ming , Zhao Yan-Rong , Cao Mo-Mo , Yang Lian-Yue
Published: September 2021

Tumour metastasis is the main cause of postoperative tumour recurrence and mortality in patients with hepatocellular carcinoma (HCC), but the underlying mechanism remains unclear. Accumulating evidence has demonstrated that programmed cell death 10 (PDCD10) plays an important role in many biological processes. However, the role of PDCD10 in HCC progression is still elusive. In this study, we aimed to explore the clinical significance and molecular function of PDCD10 in HCC. PDCD10 is significantly upregulated in HCC, which also correlates with aggressive clinicopathological characteristics and predicts poor prognosis of HCC patients after liver resection. High PDCD10 expression promotes HCC cell proliferation, migration, and invasion in vitro and tumour growth, metastasis in vivo. In addition, PDCD10 could facilitate epithelial-to-mesenchymal transition (EMT) of HCC cells. In terms of the mechanism, PDCD10 directly binds to the catalytic subunit of protein phosphatase 2A (PP2Ac) and increases its enzymatic activity, leading to the interaction of YAP and dephosphorylation of the YAP protein. This interaction contributes to YAP nuclear translocation and transcriptional activation. PP2Ac is necessary for PDCD10-mediated HCC progression. Knocking down PP2Ac abolished the tumour-promoting role of PDCD10 in the migration, invasion and EMT of HCC. Moreover, a PP2Ac inhibitor (LB100) could restrict tumour growth and metastasis of HCC with high PDCD10 expression. Collectively, PDCD10 promotes EMT and the progression of HCC by interacting with PP2Ac to promote YAP activation, which provides new insight into the mechanism of cancer metastasis. PDCD10 may be a potential prognostic biomarker and therapeutic target for HCC.
Single-cell RNA-Seq reveals transcriptional heterogeneity and immune subtypes associated with disease activity in human myasthenia gravis
Authors: Jin Wanlin , Yang Qi , Peng Yuyao , Yan Chengkai , Li Yi , Luo Zhaohui , Xiao Bo , Xu Liqun , Yang Huan
Published: September 2021

Myasthenia gravis (MG) is a rare autoimmune disease. Although the impact of immune cell disorder in MG has been extensively studied, little is known about the transcriptomes of individual cells. Here, we assessed the transcriptional profiles of 39,243 cells by single-cell sequencing and identified 13 major cell clusters, along with 39 subgroups of cells derived from patients with new-onset myasthenia gravis and healthy controls. We found that B cells, CD4+T cells, and monocytes exhibited more heterogeneity in MG patients. CD4+T cells were expanded in MG patients. We reclustered B cells and CD4+T cells, and predict their essential regulators. Further analyses demonstrated that B cells in MG exhibited higher transcriptional activity towards plasma cell differentiation, CD4+T cell subsets were unbalanced, and inflammatory pathways of monocytes were highly activated. Notably, we discovered a disease-relevant subgroup, CD180−B cells. Increased CD180−B cells in MG are indicative of a high IgG composition and were associated with disease activity and the anti-AChR antibody. Together, our data further the understanding of the cellular heterogeneity involved in the pathogenesis of MG and provide large cell-type-specific markers for subsequent research.
Development and biological characterization of a clinical gene transfer vector for the treatment of MAK-associated retinitis pigmentosa
Authors: Tucker Budd A. , Burnight Erin R. , Cranston Cathryn M. , Ulferts Mallory J. , Luse Meagan A. , Westfall Trudi , Scott C. Anthony , Marsden Autumn , Gibson-Corley Katherine , Wiley Luke A. , Han Ian C. , Slusarski Diane C. , Mullins Robert F. , Stone Edwin M.
Published: September 2021

By combining next generation whole exome sequencing and induced pluripotent stem cell (iPSC) technology we found that an Alu repeat inserted in exon 9 of the MAK gene results in a loss of normal MAK transcript and development of human autosomal recessive retinitis pigmentosa (RP). Although a relatively rare cause of disease in the general population, the MAK variant is enriched in individuals of Jewish ancestry. In this population, 1 in 55 individuals are carriers and one third of all cases of recessive RP is caused by this gene. The purpose of this study was to determine if a viral gene augmentation strategy could be used to safely restore functional MAK protein as a step toward a treatment for early stage MAK-associated RP. Patient iPSC-derived photoreceptor precursor cells were generated and transduced with viral vectors containing the MAK transcript. One week after transduction, transcript and protein could be detected via rt-PCR and western blotting respectively. Using patient-derived fibroblast cells and mak knockdown zebra fish we demonstrate that over-expression of the retinal MAK transgene restored the cells ability to regulate primary cilia length. In addition, the visual defect in mak knockdown zebrafish was mitigated via treatment with the retinal MAK transgene. There was no evidence of local or systemic toxicity at 1-month or 3-months following subretinal delivery of clinical grade vector into wild type rats. The findings reported here will help pave the way for initiation of a phase 1 clinical trial for the treatment of patients with MAK-associated RP.
Glycan remodeled erythrocytes facilitate antigenic characterization of recent A/H3N2 influenza viruses
Authors: Broszeit Frederik , van Beek Rosanne J. , Unione Luca , Bestebroer Theo M. , Chapla Digantkumar , Yang Jeong-Yeh , Moremen Kelley W. , Herfst Sander , Fouchier Ron A. M. , de Vries Robert P. , Boons Geert-Jan
Published: September 2021

During circulation in humans and natural selection to escape antibody recognition for decades, A/H3N2 influenza viruses emerged with altered receptor specificities. These viruses lost the ability to agglutinate erythrocytes critical for antigenic characterization and give low yields and acquire adaptive mutations when cultured in eggs and cells, contributing to recent vaccine challenges. Examination of receptor specificities of A/H3N2 viruses reveals that recent viruses compensated for decreased binding of the prototypic human receptor by recognizing α2,6-sialosides on extended LacNAc moieties. Erythrocyte glycomics shows an absence of extended glycans providing a rationale for lack of agglutination by recent A/H3N2 viruses. A glycan remodeling approach installing functional receptors on erythrocytes, allows antigenic characterization of recent A/H3N2 viruses confirming the cocirculation of antigenically different viruses in humans. Computational analysis of HAs in complex with sialosides having extended LacNAc moieties reveals that mutations distal to the RBD reoriented the Y159 side chain resulting in an extended receptor binding site.
Slow update of internal representations impedes synchronization in autism
Authors: Vishne Gal , Jacoby Nori , Malinovitch Tamar , Epstein Tamir , Frenkel Or , Ahissar Merav
Published: September 2021

Autism is a neurodevelopmental disorder characterized by impaired social skills, motor and perceptual atypicalities. These difficulties were explained within the Bayesian framework as either reflecting oversensitivity to prediction errors or – just the opposite – slow updating of such errors. To test these opposing theories, we administer paced finger-tapping, a synchronization task that requires use of recent sensory information for fast error-correction. We use computational modelling to disentangle the contributions of error-correction from that of noise in keeping temporal intervals, and in executing motor responses. To assess the specificity of tapping characteristics to autism, we compare performance to both neurotypical individuals and individuals with dyslexia. Only the autism group shows poor sensorimotor synchronization. Trial-by-trial modelling reveals typical noise levels in interval representations and motor responses. However, rate of error correction is reduced in autism, impeding synchronization ability. These results provide evidence for slow updating of internal representations in autism.
Aluminum nitride nanophotonics for beyond-octave soliton microcomb generation and self-referencing
Authors: Liu Xianwen , Gong Zheng , Bruch Alexander W. , Surya Joshua B. , Lu Juanjuan , Tang Hong X.
Published: September 2021

Frequency microcombs, alternative to mode-locked laser and fiber combs, enable miniature rulers of light for applications including precision metrology, molecular fingerprinting and exoplanet discoveries. To enable frequency ruling functions, microcombs must be stabilized by locking their carrier-envelope offset frequency. So far, the microcomb stabilization remains compounded by the elaborate optics external to the chip, thus evading its scaling benefit. To address this challenge, here we demonstrate a nanophotonic chip solution based on aluminum nitride thin films, which simultaneously offer optical Kerr nonlinearity for generating octave soliton combs and quadratic nonlinearity for enabling heterodyne detection of the offset frequency. The agile dispersion control of crystalline aluminum nitride photonics permits high-fidelity generation of solitons with features including 1.5-octave spectral span, dual dispersive waves, and sub-terahertz repetition rates down to 220 gigahertz. These attractive characteristics, aided by on-chip phase-matched aluminum nitride waveguides, allow the full determination of the offset frequency. Our proof-of-principle demonstration represents an important milestone towards fully integrated self-locked microcombs for portable optical atomic clocks and frequency synthesizers.
Sequential actions of EOMES and T-BET promote stepwise maturation of natural killer cells
Authors: Zhang Jiang , Le Gras Stéphanie , Pouxvielh Kevin , Faure Fabrice , Fallone Lucie , Kern Nicolas , Moreews Marion , Mathieu Anne-Laure , Schneider Raphaël , Marliac Quentin , Jung Mathieu , Berton Aurore , Hayek Simon , Vidalain Pierre-Olivier , Marçais Antoine , Dodard Garvin , Dejean Anne , Brossay Laurent , Ghavi-Helm Yad , Walzer Thierry
Published: September 2021

EOMES and T-BET are related T-box transcription factors that control natural killer (NK) cell development. Here we demonstrate that EOMES and T-BET regulate largely distinct gene sets during this process. EOMES is dominantly expressed in immature NK cells and drives early lineage specification by inducing hallmark receptors and functions. By contrast, T-BET is dominant in mature NK cells, where it induces responsiveness to IL-12 and represses the cell cycle, likely through transcriptional repressors. Regardless, many genes with distinct functions are co-regulated by the two transcription factors. By generating two gene-modified mice facilitating chromatin immunoprecipitation of endogenous EOMES and T-BET, we show a strong overlap in their DNA binding targets, as well as extensive epigenetic changes during NK cell differentiation. Our data thus suggest that EOMES and T-BET may distinctly govern, via differential expression and co-factors recruitment, NK cell maturation by inserting partially overlapping epigenetic regulations.
Quantum state tomography of molecules by ultrafast diffraction
Authors: Zhang Ming , Zhang Shuqiao , Xiong Yanwei , Zhang Hankai , Ischenko Anatoly A. , Vendrell Oriol , Dong Xiaolong , Mu Xiangxu , Centurion Martin , Xu Haitan , Miller R. J. Dwayne , Li Zheng
Published: September 2021

Ultrafast electron diffraction and time-resolved serial crystallography are the basis of the ongoing revolution in capturing at the atomic level of detail the structural dynamics of molecules. However, most experiments capture only the probability density of the nuclear wavepackets to determine the time-dependent molecular structures, while the full quantum state has not been accessed. Here, we introduce a framework for the preparation and ultrafast coherent diffraction from rotational wave packets of molecules, and we establish a new variant of quantum state tomography for ultrafast electron diffraction to characterize the molecular quantum states. The ability to reconstruct the density matrix, which encodes the amplitude and phase of the wavepacket, for molecules of arbitrary degrees of freedom, will enable the reconstruction of a quantum molecular movie from experimental x-ray or electron diffraction data.
Genetic basis and adaptation trajectory of soybean from its temperate origin to tropics
Authors: Dong Lidong , Fang Chao , Cheng Qun , Su Tong , Kou Kun , Kong Lingping , Zhang Chunbao , Li Haiyang , Hou Zhihong , Zhang Yuhang , Chen Liyu , Yue Lin , Wang Lingshuang , Wang Kai , Li Yongli , Gan Zhuoran , Yuan Xiaohui , Weller James L. , Lu Sijia , Kong Fanjiang , Liu Baohui
Published: September 2021

Soybean (Glycine max) serves as a major source of protein and edible oils worldwide. The genetic and genomic bases of the adaptation of soybean to tropical regions remain largely unclear. Here, we identify the novel locus Time of Flowering 16 (Tof16), which confers delay flowering and improve yield at low latitudes and determines that it harbors the soybean homolog of LATE ELONGATED HYPOCOTYL (LHY). Tof16 and the previously identified J locus genetically additively but independently control yield under short-day conditions. More than 80% accessions in low latitude harbor the mutations of tof16 and j, which suggests that loss of functions of Tof16 and J are the major genetic basis of soybean adaptation into tropics. We suggest that maturity and yield traits can be quantitatively improved by modulating the genetic complexity of various alleles of the LHY homologs, J and E1. Our findings uncover the adaptation trajectory of soybean from its temperate origin to the tropics.
Parity associates with chromosomal damage in uterine leiomyomas
Authors: Kuisma Heli , Bramante Simona , Rajamäki Kristiina , Sipilä Lauri J. , Kaasinen Eevi , Kaukomaa Jaana , Palin Kimmo , Mäkinen Netta , Sjöberg Jari , Sarvilinna Nanna , Taipale Jussi , Kauppi Liisa , Tumiati Manuela , Hassinen Antti , Pitkäniemi Janne , Jalkanen Jyrki , Heikkinen Sanna , Pasanen Annukka , Heikinheimo Oskari , Bützow Ralf , Välimäki Niko , Aaltonen Lauri A.
Published: September 2021

Mechanical forces in a constrained cellular environment were recently established as a facilitator of chromosomal damage. Whether this could contribute to tumorigenesis is not known. Uterine leiomyomas are common neoplasms that display relatively few chromosomal aberrations. We hypothesized that if mechanical forces contribute to chromosomal damage, signs of this could be seen in uterine leiomyomas from parous women. We examined the karyotypes of 1946 tumors, and found a striking overrepresentation of chromosomal damage associated with parity. We then subjected myometrial cells to physiological forces similar to those encountered during pregnancy, and found this to cause DNA breaks and a DNA repair response. While mechanical forces acting in constrained cellular environments may thus contribute to neoplastic degeneration, and genesis of uterine leiomyoma, further studies are needed to prove possible causality of the observed association. No evidence for progression to malignancy was found.
Computational synthesis of substrates by crystal cleavage
Authors: Paul Joshua T. , Galdi Alice , Parzyck Christopher , M. Shen Kyle , Maxson Jared , Hennig Richard G.
Published: September 2021

The discovery of substrate materials has been dominated by trial and error, opening the opportunity for a systematic search. We generate bonding networks for materials from the Materials Project and systematically break up to three bonds in the networks for three-dimensional crystals. Successful cleavage reduces the bonding network to two periodic dimensions. We identify 4693 symmetrically unique cleavage surfaces across 2133 bulk crystals, 4626 of which have a maximum Miller index of one. We characterize the likelihood of cleavage by creating monolayers of these surfaces and calculating their thermodynamic stability using density functional theory to discover 3991 potential substrates. Following, we identify distinct trends in the work of cleavage and relate them to bonding in the three-dimensional precursor. We illustrate the potential impact of the substrate database by identifying several improved epitaxial substrates for the transparent conductor BaSnO3. The open-source databases of predicted and commercial substrates are available at MaterialsWeb.org.
Changes in cortical gene expression in the muscarinic M1 receptor knockout mouse: potential relevance to schizophrenia, Alzheimer’s disease and cognition
Authors: Dean Brian , Scarr Elizabeth
Published: September 2021

Postmortem and neuroimaging studies show low levels of cortical muscarinic M1 receptors (CHRM1) in patients with schizophrenia which is significant because CHRM signalling has been shown to change levels of gene expression and cortical gene expression is altered in schizophrenia. We decided to identify CHRM1-mediated changes in cortical gene expression by measuring levels of RNA in the cortex of the Chrm1−/−mouse (n = 10), where there would be no signalling by that receptor, and in wild type mouse (n = 10) using the Affymetrix Mouse Exon 1.0 ST Array. We detected RNA for 15,501 annotated genes and noncoding RNA of which 1,467 RNAs were higher and 229 RNAs lower in the cortex of the Chrm1−/−mouse. Pathways and proteins affected by the changes in cortical gene expression in the Chrm1−/−are linked to the molecular pathology of schizophrenia. Our human cortical gene expression data showed 47 genes had altered expression in Chrm1−/−mouse and the frontal pole from patients with schizophrenia with the change in expression of 44 genes being in opposite directions. In addition, genes with altered levels of expression in the Chrm1−/−mouse have been shown to affect amyloid precursor protein processing which is associated with the pathophysiology of Alzheimer’s disease, and 69 genes with altered expression in the Chrm1−/−mouse are risk genes associated with human cognitive ability. Our findings argue CHRM1-mediated changes in gene expression are relevant to the pathophysiologies of schizophrenia and Alzheimer’s disease and the maintenance of cognitive ability in humans.
Unique clinical features and long term follow up of survivors of sudden cardiac death in an Asian multicenter study
Authors: Huang Pang-Shuo , Cheng Jen-Fang , Ko Wen-Chin , Chang Shu-Hsuan , Lin Tin-Tse , Chen Jien-Jiun , Chiu Fu-Chun , Lin Lian-Yu , Lai Ling-Ping , Lin Jiunn-Lee , Tsai Chia-Ti
Published: September 2021

There has been no long-term clinical follow-up data of survivors or victims of sudden cardiac death (SCD). The Taiwan multi-center sudden arrhythmia death syndrome follow-up and clinical study (TFS-SADS) is a collaborative multi-center study with median follow-up time 43 months. In this cohort, the clinical characteristics of these SADS patients were compared with those with ischemic heart disease (IHD). In this SCD cohort, around half (42%) were patients with IHD, which was different from Caucasian SCD cohorts. Among those with normal heart, most had Brugada syndrome (BrS). Compared to those with SADS, patients with IHD were older, more males and more comorbidities, more arrhythmic death, and lower left ventricular ejection fraction. In the long-term follow-up, patients with SADS had a better survival than those with IHD (p < 0.001). In the Cox regression analysis to identify the independent predictors of mortality, older age, lower LVEF, prior myocardial infarction and history of out-of-hospital cardiac arrest were associated with higher mortality and beta blocker use and idiopathic ventricular fibrillation or tachycardia (IVF/IVT) with a better survival during follow-up. History of prior MI was associated with more arrhythmic death. Several distinct features of SCD were found in the Asia–Pacific region, such as higher proportion of SADS, poorer prognosis of LQTS and better prognosis of IVF/IVT. Patients with SADS had a better survival than those with IHD. For those with SADS, patients with channelopathy had a better survival than those with cardiomyopathy.