bluuebunny/crossref_metadata_2025 huggingface dataset:
Short-Selling Equity Exchange Traded Funds and Its Effect on Stock Market Liquidity
Authors: Karmaziene Egle , Sokolovski Valeri
Published: March 2021

We examine short selling of equity exchange traded funds (ETFs) using the 2008 short-sale ban. Contrasting the previously documented contractions in bearish strategies during the ban, we find a significant increase in short sales of the largest, most liquid ETF, the S&P 500 Spider. We offer evidence suggesting that this upsurge was driven primarily by investors circumventing the ban. We show that the ban’s detrimental effect on stock liquidity was around 30% less severe for the Spider’s constituents. Our results suggest that ETF shorts can substitute for short sales of individual stocks, thereby alleviating short-sale constraints’ adverse effect on liquidity.
Lost in translation: rethinking words about women in 1–2 Timothy
Authors: King Fergus J. , Lee Dorothy A.
Published: March 2021

St Paul and the tradition which follows in his wake have often fallen victim to the circumstances and ideologies of their interpreters: used as ambassadors for patriarchy by some and rejected as misogynistic by others. This article reviews some of the contentious passages in 1 and 2 Timothy and concludes that they both challenge the mores of their environment and resonate with other (deutero-)Pauline teachings. To ensure that such claims do not fall prey to circularity in their arguments, a methodology is developed and applied in which claims of resonance are not predicated on the content of other writings.
European Youth Work Policy and Young People’s Experience of Open Access Youth Work
Authors: ORD JON , CARLETTI MARC , MORCIANO DANIELE , SIURALA LASSE , DANSAC CHRISTOPHE , COOPER SUE , FYFE IAN , KÖTSI KAUR , SINISALO-JUHA EEVA , TARU MARTI , ZENTNER MANFRED
Published: March 2021

This article examines young people’s experiences of open access youth work in settings in the UK, Finland, Estonia, Italy and France. It analyses 844 individual narratives from young people, which communicate the impact of youthwork on their lives. These accounts are then analysed in the light of the European youth work policy goals. It concludes that it is encouraging that what young people identify as the positive impact of youth work are broadly consistent with many of these goals. There are however some disparities which require attention. These include the importance young people place on the social context of youth work, such as friendship, which is largely absent in EU youth work policy; as well as the importance placed on experiential learning. The paper also highlights a tension between ‘top down’ policy formulation and the ‘youth centric’ practices of youth work. It concludes with a reminder to policy makers that for youth work to remain successful the spaces and places for young people must remain meaningful to them ‘on their terms’.
Why they shared: recovering early arguments for sharing social scientific data
Authors: Hauptmann Emily
Published: March 2021

Argument

Most social scientists today think of data sharing as an ethical imperative essential to making social science more transparent, verifiable, and replicable. But what moved the architects of some of the U.S.’s first university-based social scientific research institutions, the University of Michigan’s Institute for Social Research (ISR), and its spin-off, the Inter-university Consortium for Political and Social Research (ICPSR), to share their data? Relying primarily on archived records, unpublished personal papers, and oral histories, I show that Angus Campbell, Warren Miller, Philip Converse, and others understood sharing data not as an ethical imperative intrinsic to social science but as a useful means to the diverse ends of financial stability, scholarly and institutional autonomy, and epistemological reproduction. I conclude that data sharing must be evaluated not only on the basis of the scientific ideals its supporters affirm, but also on the professional objectives it serves.
INCIDENTAL ACQUISITION OF MULTIWORD EXPRESSIONS THROUGH AUDIOVISUAL MATERIALS
Authors: Majuddin Elvenna , Siyanova-Chanturia Anna , Boers Frank
Published: March 2021

There has been limited research on the efficacy of captioned second language (L2) television in facilitating the incidental acquisition of multiword expressions (MWEs). The present study aims to fill this gap. Additionally, this study examines the role of typographic enhancement and repetition. One-hundred and twenty-two L2 learners were assigned to one of six conditions that differed in terms of caption condition (no captions, normal captions, enhanced captions) and the number of times they watched the same video (once, twice). The participants took a cued MWE form recall test before watching the video, immediately and 2 weeks after watching it. A content comprehension test was also administered. Compared to single viewing, repetition resulted in better content comprehension as well as better acquisition of MWEs. Both caption types positively influenced MWE recall relative to watching the video without captions, but typographic enhancement reduced the benefits of captions for content comprehension.
Controlling contamination in child maltreatment research: Impact on effect size estimates for child behavior problems measured throughout childhood and adolescence
Authors: Shenk Chad E. , Rausch Joseph R. , Shores Kenneth A. , Allen Elizabeth K. , Olson Anneke E.
Published: March 2021

Contamination, when members of a comparison or control condition are exposed to the event or intervention under scientific investigation, is a methodological phenomenon that downwardly biases the magnitude of effect size estimates. This study tested a novel approach for controlling contamination in observational child maltreatment research. Data from The Longitudinal Studies of Child Abuse and Neglect (LONGSCAN; N = 1354) were obtained to estimate the risk of confirmed child maltreatment on trajectories of internalizing and externalizing behaviors before and after controlling contamination. Baseline models, where contamination was uncontrolled, demonstrated a risk for greater internalizing (b = .29, p < .001, d = .40) and externalizing (b = .14, p = .040, d = .19) behavior trajectories. Final models, where contamination was controlled by separating the comparison condition into subgroups that did or did not self-report maltreatment, also demonstrated risks for greater internalizing (b = .37, p < .001, d = .51) and externalizing (b = .22, p = .028, d = .29) behavior trajectories. However, effect size estimates in final models were 27.5%–52.6% larger compared to baseline models. Controlling contamination in child maltreatment research can strengthen effect size estimates for child behavior problems, aiding future child maltreatment research design and analysis.
SPECIAL VALUES OF THE ZETA FUNCTION OF AN ARITHMETIC SURFACE
Authors: Flach Matthias , Siebel Daniel
Published: March 2021

We prove that the special-value conjecture for the zeta function of a proper, regular, flat arithmetic surface formulated in [6] at$s=1$is equivalent to the Birch and Swinnerton-Dyer conjecture for the Jacobian of the generic fibre. There are two key results in the proof. The first is the triviality of the correction factor of [6, Conjecture 5.12], which we show for arbitrary regular proper arithmetic schemes. In the proof we need to develop some results for the eh-topology on schemes over finite fields which might be of independent interest. The second result is a different proof of a formula due to Geisser, relating the cardinalities of the Brauer and the Tate–Shafarevich group, which applies to arbitrary rather than only totally imaginary base fields.
Valuation of long-term care options embedded in life annuities
Authors: Chen An , Fuino Michel , Sehner Thorsten , Wagner Joël
Published: March 2021

In most industrialised countries, one of the major societal challenges is the demographic change coming along with the ageing of the population. The increasing life expectancy observed over the last decades underlines the importance to find ways to appropriately cover the financial needs of the elderly. A particular issue arises in the area of health, where sufficient care must be provided to a growing number of dependent elderly in need of long-term care (LTC) services. In many markets, the offering of life insurance products incorporating care options and LTC insurance products is generally scarce. In our research, we therefore examine a life annuity product with an embedded care option potentially providing additional financial support to dependent persons. To evaluate the care option, we determine the minimum price that the annuity provider requires and the policyholder’s willingness to pay for the care option. For the latter, we employ individual utility functions taking account of the policyholder’s condition. We base our numerical study on recently developed transition probability data from Switzerland. Our findings give new and realistic insights into the nature and the utility of life annuity products proposing an embedded care option for tackling the financing of LTC needs.
A 1200 ka Stable Isotope Record From the Center of the Badain Jaran Desert, Northwestern China: Implications for the Variation and Interplay of the Westerlies and the Asian Summer Monsoon
Authors: Wang Fei , Li Zaijun , Sun Xiaoyun , Li Baofeng , Wang Xin , Chen Fahu
Published: March 2021

The variation and interplay of westerlies and the Asian summer monsoon (ASM) are important for understanding climate change in the Northern Hemisphere. Yet their spatial and temporal evolution is still debatable. Here, we present a stable isotopic record from the center of the Badain Jaran Desert, in Northwestern China, which records the variations and interplay of the two climate systems during the past 1200 ka. The results indicate that the westerlies dominated the Badain Jaran area at least from 1200 to 600 ka, and possibly earlier. Associated with ASM enhancement since 600 ka, the westerlies and ASM alternatively dominated the regional warm season precipitation during glacial‐interglacial cycles, respectively. Meanwhile, the δ18Ocarb of the Badain Jaran area showed high‐frequency fluctuations which may reveal the joint impact of ASM and westerlies on regional hydrology after 450 ka. Affected by the westerlies and ASM changes, the C4 plants stepwise expanded at 600, 450, and 300 ka. These stepwise variations of westerlies and ASM are response to the global climate change which significantly influenced the ASM at 600 and 450 ka, and westerlies at 300 ka, respectively. In addition, the uplift of the Pamir‐Tibetan Plateau during the middle Pleistocene also exerts a profound effect on westerlies and ASM pattern across the East Asia on a long‐term time scale.
Slip Rate of the Danghe Nan Shan Thrust Fault from 10Be Exposure Dating of Folded River Terraces: Implications for the Strain Distribution in Northern Tibet
Authors: Xu Q. , Hetzel R. , Hampel A. , Wolff R.
Published: March 2021

The northeastward motion of the Tibetan Plateau along the Altyn Tagh strike‐slip fault causes thrust faulting in three parallel mountain ranges (Qilian Shan, Daxue Shan, and Danghe Nan Shan) in the plateau interior, and leads to NNE‐directed crustal shortening and plateau growth. While slip rates at the plateau margin (i.e., along the Qilian Shan and the Altyn Tagh fault) are well constrained, rates of thrust faulting and the strain distribution in the plateau interior remain poorly resolved. Here, we use field investigations, a high‐resolution DEM, and 10Be exposure dating to quantify the shortening rate across the Danghe Nan Shan thrust fault from fluvial terraces, which are deformed by a growing NNE‐vergent anticline. 10Be exposure ages from two terrace levels range from 70 ± 5 to 92 ± 7 ka. When combined with uplift values of 37–68 m along the fold hinge, the 10Be ages yield a mean uplift rate of 0.6 ± 0.2 mm/year. Using the cross‐sectional area of the fold and the subsurface geometry of the listric thrust fault, we obtain a shortening rate of 0.8 ± 0.2 mm/year, which is consistent with the rate of elastic strain accumulation recorded by GPS data. Together with published fault slip rates and GPS data, our results indicate that northern Tibet experiences NNE‐directed shortening at a rate of ∼5 mm/year between the Qaidam Basin and the Hexi Corridor. In the plateau interior, this shortening is accommodated by several range‐bounding thrust faults and closely coupled with the eastward decrease in the slip rate of the Altyn Tagh fault.
Activation of the p11/SMARCA3/Neurensin-2 pathway in parvalbumin interneurons mediates the response to chronic antidepressants
Authors: Umschweif Gali , Medrihan Lucian , McCabe Kathryn A. , Sagi Yotam , Greengard Paul
Published: March 2021

The delayed behavioral response to chronic antidepressants depends on dynamic changes in the hippocampus. It was suggested that the antidepressant protein p11 and the chromatin remodeling factor SMARCA3 mediate this delayed response by inducing transcriptional changes in hippocampal neurons. However, what target genes are regulated by the p11/SMARCA3 complex to mediate the behavioral response to antidepressants, and what cell type mediates these molecular changes remain unknown. Here we report that the p11/SMARCA3 complex represses Neurensin-2 transcription in hippocampal parvalbumin-expressing interneurons after chronic treatment with Selective Serotonin Reuptake Inhibitors (SSRI). The behavioral response to antidepressants requires upregulation of p11, accumulation of SMARCA3 in the cell nucleus, and a consequent repression of Neurensin-2 transcription in these interneurons. We elucidate a functional role for p11/SMARCA3/Neurensin-2 pathway in regulating AMPA-receptor signaling in parvalbumin-expressing interneurons, a function that is enhanced by chronic treatment with SSRIs. These results link SSRIs to dynamic glutamatergic changes and implicate p11/SMARCA3/Neurensin-2 pathway in the development of more specific and efficient therapeutic strategies for neuropsychiatric disorders.
Unique and complementary suppression of cGAS-STING and RNA sensing- triggered innate immune responses by SARS-CoV-2 proteins
Authors: Rui Yajuan , Su Jiaming , Shen Si , Hu Ying , Huang Dingbo , Zheng Wenwen , Lou Meng , Shi Yifei , Wang Meng , Chen Shiqi , Zhao Na , Dong Qi , Cai Yong , Xu Rongzhen , Zheng Shu , Yu Xiao-Fang
Published: March 2021

The emergence of SARS-CoV-2 has resulted in the COVID-19 pandemic, leading to millions of infections and hundreds of thousands of human deaths. The efficient replication and population spread of SARS-CoV-2 indicates an effective evasion of human innate immune responses, although the viral proteins responsible for this immune evasion are not clear. In this study, we identified SARS-CoV-2 structural proteins, accessory proteins, and the main viral protease as potent inhibitors of host innate immune responses of distinct pathways. In particular, the main viral protease was a potent inhibitor of both the RLR and cGAS-STING pathways. Viral accessory protein ORF3a had the unique ability to inhibit STING, but not the RLR response. On the other hand, structural protein N was a unique RLR inhibitor. ORF3a bound STING in a unique fashion and blocked the nuclear accumulation of p65 to inhibit nuclear factor-κB signaling. 3CL of SARS-CoV-2 inhibited K63-ubiquitin modification of STING to disrupt the assembly of the STING functional complex and downstream signaling. Diverse vertebrate STINGs, including those from humans, mice, and chickens, could be inhibited by ORF3a and 3CL of SARS-CoV-2. The existence of more effective innate immune suppressors in pathogenic coronaviruses may allow them to replicate more efficiently in vivo. Since evasion of host innate immune responses is essential for the survival of all viruses, our study provides insights into the design of therapeutic agents against SARS-CoV-2.
Fear extinction learning and anandamide: an fMRI study in healthy humans
Authors: Spohrs Jennifer , Ulrich Martin , Grön Georg , Prost Michael , Plener Paul Lukas , Fegert Jörg Michael , Bindila Laura , Abler Birgit
Published: March 2021

Anxiety- and trauma-related disorders are severe illnesses with high prevalence. Current treatment options leave room for improvement and the endocannabinoid system (ECS) has become a key target in psychopharmacological research. Rodent models suggest an anxiolytic effect of endocannabinoids and demonstrated that the ECS is involved in the modulation of fear learning and aversive memory consolidation. So far, one prominent target was inhibition of fatty acid amino hydrolase (FAAH), the degrading enzyme of the endocannabinoid anandamide (AEA). Research in humans remains scarce, but genetic studies have found that the single-nucleotide polymorphism (SNP) FAAH C385A (rs324420) is associated with lower catabolic performance of FAAH and increased levels of AEA. Translational research on the ECS in fear learning processes is rare, yet crucial to understand the mechanisms involved. To address this lack of research, we designed a fear conditioning, extinction learning paradigm with 51 healthy, male humans who underwent functional magnetic resonance imaging (fMRI) before analysing baseline and task-related changes of AEA, as well as the FAAH polymorphism (rs324420). The results indicate higher AEA levels in AC-heterozygotes than in CC-individuals (SNP rs324420), but no difference between the groups during extinction learning. However, neural activation of the anterior cingulate cortex and anterior insular cortex during extinction learning correlated positively with AEA baseline levels, and task-related changes in AEA were found particularly during fear extinction, with a modulatory effect on neural activation related to extinction learning. Results indicate a putative role for AEA in fear extinction learning. Pre-treatment with AEA-enhancing drugs could promote extinction learning during psychotherapeutic interventions.
Depression treatment response to ketamine: sex-specific role of interleukin-8, but not other inflammatory markers
Authors: Kruse Jennifer L. , Vasavada Megha M. , Olmstead Richard , Hellemann Gerhard , Wade Benjamin , Breen Elizabeth C. , Brooks John O. , Congdon Eliza , Espinoza Randall , Narr Katherine L. , Irwin Michael R.
Published: March 2021

Inflammation plays a role in depression pathophysiology and treatment response, with effects varying by sex and therapeutic modality. Lower levels of interleukin(IL)-8 predict depression response to antidepressant medication and to electroconvulsive therapy (ECT), although ECT effects are specific to females. Whether IL-8 predicts depression response to ketamine and in a sex-specific manner is not known. Here, depressed patients (n = 46; female, n = 17) received open label infusion of ketamine (0.5 mg/kg over 40 min; NCT02165449). Plasma levels of IL-8 were evaluated at baseline and post-treatment. Baseline levels of IL-8 had a trending association with response to ketamine, depending upon sex (responder status × sex interaction: p = 0.096), in which lower baseline levels of IL-8 in females (p = 0.095) but not males (p = 0.96) trended with treatment response. Change in levels of IL-8 from baseline to post-treatment differed significantly by responder status (defined as ≥50% reduction in Hamilton Depression Rating Scale [HAM-D] Score), depending upon sex (responder status × sex × time interaction: F(1,42)=6.68, p = 0.01). In addition, change in IL-8 interacted with sex to predict change in HAM-D score (β = -0.63, p = 0.003); increasing IL-8 was associated with decreasing HAM-D score in females (p = 0.08) whereas the inverse was found in males (p = 0.02). Other inflammatory markers (IL-6, IL-10, tumor necrosis factor-α, C-reactive protein) were explored with no significant relationships identified. Given these preliminary findings, further evaluation of sex differences in the relationship between IL-8 and treatment response is warranted to elucidate mechanisms of response and aid in the development of personalized approaches to depression treatment.
The effect of nerve growth factor on supporting spatial memory depends upon hippocampal cholinergic innervation
Authors: Eu Wei Zheng , Chen Yu-Ju , Chen Wei-Ting , Wu Kuan-Yu , Tsai Cheng-Yu , Cheng Sin-Jhong , Carter Roderick N. , Huang Guo-Jen
Published: March 2021

Nerve growth factor (NGF) gene therapy has been used in clinical trials of Alzheimer’s disease. Understanding the underlying mechanisms of how NGF influences memory may help develop new strategies for treatment. Both NGF and the cholinergic system play important roles in learning and memory. NGF is essential for maintaining cholinergic innervation of the hippocampus, but it is unclear whether the supportive effect of NGF on learning and memory is specifically dependent upon intact hippocampal cholinergic innervation. Here we characterize the behavior and hippocampal measurements of volume, neurogenesis, long-term potentiation, and cholinergic innervation, in brain-specificNgf-deficient mice. Our results show that knockout mice exhibit increased anxiety, impaired spatial learning and memory, decreased adult hippocampal volume, neurogenesis, short-term potentiation, and cholinergic innervation. Overexpression ofNgfin the hippocampus ofNgfgene knockout mice rescued spatial memory and partially restored cholinergic innervations, but not anxiety. Selective depletion of hippocampal cholinergic innervation resulted in impaired spatial memory. However,Ngfoverexpression in the hippocampus failed to rescue spatial memory in mice with hippocampal-selective cholinergic fiber depletion. In conclusion, we demonstrate the impact ofNgfdeficiency in the brain and provide evidence that the effect of NGF on spatial memory is reliant on intact cholinergic innervations in the hippocampus. These results suggest that adequate cholinergic targeting may be a critical requirement for successful use ofNGFgene therapy of Alzheimer’s disease.
Cannabinoid receptor 1 signalling modulates stress susceptibility and microglial responses to chronic social defeat stress
Authors: Beins Eva C. , Beiert Thomas , Jenniches Imke , Hansen Jan N. , Leidmaa Este , Schrickel Jan W. , Zimmer Andreas
Published: March 2021

Psychosocial stress is one of the main environmental factors contributing to the development of psychiatric disorders. In humans and rodents, chronic stress is associated with elevated inflammatory responses, indicated by increased numbers of circulating myeloid cells and activation of microglia, the brain-resident immune cells. The endocannabinoid system (ECS) regulates neuronal and endocrine stress responses via the cannabinoid receptor 1 (CB1). CB1-deficient mice (Cnr1−/−) are highly sensitive to stress, but if this involves altered inflammatory responses is not known. To test this, we exposed Cnr1+/+ and Cnr1−/− mice to chronic social defeat stress (CSDS). Cnr1−/− mice were extremely sensitive to a standard protocol of CSDS, indicated by an increased mortality rate. Therefore, a mild CSDS protocol was established, which still induced a behavioural phenotype in susceptible Cnr1−/− mice. These mice also showed altered glucocorticoid levels after mild CSDS, suggesting dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis. Mild CSDS induced weak myelopoiesis in the periphery, but no recruitment of myeloid cells to the brain. In contrast, mild CSDS altered microglial activation marker expression and morphology in Cnr1−/− mice. These microglial changes correlated with the severity of the behavioural phenotype. Furthermore, microglia of Cnr1−/− mice showed increased expression of Fkbp5, an important regulator of glucocorticoid signalling. Overall, the results confirm that CB1 signalling protects the organism from the physical and emotional harm of social stress and implicate endocannabinoid-mediated modulation of microglia in the development of stress-related pathologies.
Physiological parameters of mental health predict the emergence of post-traumatic stress symptoms in physicians treating COVID-19 patients
Authors: Dolev T. , Zubedat S. , Brand Z. , Bloch B. , Mader E. , Blondheim O. , Avital A.
Published: March 2021

Lack of established knowledge and treatment strategies, and change in work environment, may altogether critically affect the mental health and functioning of physicians treating COVID-19 patients. Thus, we examined whether treating COVID-19 patients affect the physicians’ mental health differently compared with physicians treating non-COVID-19 patients. In this cohort study, an association was blindly computed between physiologically measured anxiety and attention vigilance (collected from 1 May 2014 to 31 May 31 2016) and self-reports of anxiety, mental health aspects, and sleep quality (collected from 20 April to 30 June 2020, and analyzed from 1 July to 1 September 2020), of 91 physicians treating COVID-19 or non-COVID-19 patients. As a priori hypothesized, physicians treating COVID-19 patients showed a relative elevation in both physiological measures of anxiety (95% CI: 2317.69–2453.44 versus 1982.32–2068.46; P < 0.001) and attention vigilance (95% CI: 29.85–34.97 versus 22.84–26.61; P < 0.001), compared with their colleagues treating non-COVID-19 patients. At least 3 months into the pandemic, physicians treating COVID-19 patients reported high anxiety and low quality of sleep. Machine learning showed clustering to the COVID-19 and non-COVID-19 subgroups with a high correlation mainly between physiological and self-reported anxiety, and between physiologically measured anxiety and sleep duration. To conclude, the pattern of attention vigilance, heightened anxiety, and reduced sleep quality findings point the need for mental intervention aimed at those physicians susceptible to develop post-traumatic stress symptoms, owing to the consequences of fighting at the forefront of the COVID-19 pandemic.
Quantification of biomarker functionality predicts patient outcomes
Authors: Larijani Banafshé , Miles James , Ward Stephen G. , Parker Peter J.
Published: March 2021

Implementation of a quantitative molecular imaging method (iFRET), which determines receptor–ligand interactions, has led to the finding that patients with a low extent of PD-1/PD-L1 interaction in metastatic NSCLC, and malignant melanoma, display significantly worsened overall survival compared to those with a high level of interaction.
MiR-127-3p targeting CISD1 regulates autophagy in hypoxic–ischemic cortex
Authors: Zhang Zi-Bin , Xiong Liu-Lin , Xue Lu-Lu , Deng Yan-Ping , Du Ruo-Lan , Hu Qiao , Xu Yang , Yang Si-Jin , Wang Ting-Hua
Published: March 2021

Neonatal hypoxic–ischemic (HI) injury derived from asphyxia during perinatal period, is a serious complication of neonatal asphyxia and the main cause of neonatal acute death and chronic neurological injury. Aberrant autophagy occurs in many nervous system diseases, but its role and underlying mechanism in HI injury is largely unknown. Here, we successfully constructed a newborn rat model of HI brain injury, and the knockout-miR-127-3p (KO-miR-127-3p) rats were structured by using CRISPR/Cas9. Subsequently, the in vitro functional experiments, in vivo zea-longa scores, as well as bioinformatics analyses and biological experiments were applied. The expression of autophagy-related proteins, including ATG12, P62, Beclin-1, LC3II in HI cortex with miR-127-3p knockout was significantly decreased, and autophagic vacuoles were disappeared. Moreover, miR-127-3p has a specific regulatory effect on CISD1 expression, another crucial molecule in autophagy process. Accordingly, the overexpression of CISD1 effectively inhibited the autophagic cell death and physiological dysfunction in the brain of HI injury, whereas si-CISD1 reversed the neuroprotective effects of KO-miR-127-3p. Our findings explained the underlying mechanism for HI injury, and miR-127-3p targeting CISD1 signal could be supposed as a new treatment strategy to prevent and treat HI injury.
Shc3 promotes hepatocellular carcinoma stemness and drug resistance by interacting with β-catenin to inhibit its ubiquitin degradation pathway
Authors: Liu Yun , Zhuang Hao , Cao Fang , Li Jie , Guo Yan , Zhang Jun , Zhao Qiang , Liu Yuanyuan
Published: March 2021

Hepatocellular carcinoma (HCC) is one of the most common cancers with an insidious onset, strong invasiveness, insensitivity to chemotherapy, and poor prognosis, thus makes clinical treatment challenging. The mechanisms require further elucidation for developing novel therapies and targeting drug resistance. Here, we observed high Shc3 expression in patients with chemoresistant and recurrent HCCs. Shc3 overexpression induced a significant increase in MDR1/P-glycoprotein expression, whereas Shc3 knockdown impaired this expression. Further, Shc3 inhibition significantly restored HCC cell sensitivity to doxorubicin and sorafenib. Mechanistically, Shc3 interacted with β-catenin, inhibited destruction complex stability, promoted β-catenin release, and dampened β-catenin ubiquitination. Shc3 bound β-catenin and facilitated its nuclear translocation, prompting the β-catenin/TCF pathway to elevate MDR1 transcription. β-catenin blockage abolished the discrepancy in drug resistance between Shc3-depleted HCC cells and control cells, which further validating that β-catenin is required for Shc3-mediated liver chemotherapy. We also determined the effect of Shc3 on the sensitivity of HCC to chemotherapy in vivo. Collectively, this study provides a potential strategy to target these pathways concurrently with systemic chemotherapy that can improve the clinical treatment of HCC.
Sirt1 coordinates with ERα to regulate autophagy and adiposity
Authors: Tao Zhipeng , Shi Limin , Parke Jane , Zheng Louise , Gu Wei , Dong X. Charlie , Liu Dongmin , Wang Zongwei , Olumi Aria F. , Cheng Zhiyong
Published: March 2021

Sex difference in adiposity has long been recognized but the mechanism remains incompletely understood. Previous studies suggested that adiposity was regulated by autophagy in response to energy status change. Here, we show that the energy sensor Sirt1 mediates sex difference in adiposity by regulating autophagy and adipogenesis in partnership with estrogen receptor α (ERα). Autophagy and adipogenesis were suppressed by Sirt1 activation or overexpression, which was associated with reduced sex difference in adiposity. Mechanistically, Sirt1 deacetylated and activated AKT and STAT3, resulting in suppression of autophagy and adipogenesis via mTOR-ULK1 and p55 cascades. ERα induced Sirt1 expression and inhibited autophagy in adipocytes, while silencing Sirt1 reversed the effects of ERα on autophagy and promoted adipogenesis. Moreover, Sirt1 deacetylated ERα, which constituted a positive feedback loop in the regulation of autophagy and adiposity. Our results revealed a new mechanism of Sirt1 regulating autophagy in adipocytes and shed light on sex difference in adiposity.
Human pluripotent stem cell-derived alveolar organoids for modeling pulmonary fibrosis and drug testing
Authors: Kim Jung-Hyun , An Geun Ho , Kim Ji-Young , Rasaei Roya , Kim Woo Jin , Jin Xiong , Woo Dong-Hun , Han Choongseong , Yang Se-Ran , Kim Jong-Hoon , Hong Seok-Ho
Published: March 2021

Detailed understanding of the pathogenesis and development of effective therapies for pulmonary fibrosis (PF) have been hampered by lack of in vitro human models that recapitulate disease pathophysiology. In this study, we generated alveolar organoids (AOs) derived from human pluripotent stem cells (hPSCs) for use as an PF model and for drug efficacy evaluation. Stepwise direct differentiation of hPSCs into alveolar epithelial cells by mimicking developmental cues in a temporally controlled manner was used to generate multicellular AOs. Derived AOs contained the expected spectrum of differentiated cells, including alveolar progenitors, type 1 and 2 alveolar epithelial cells and mesenchymal cells. Treatment with transforming growth factor (TGF-β1) induced fibrotic changes in AOs, offering a PF model for therapeutic evaluation of a structurally truncated form (NP-011) of milk fat globule-EGF factor 8 (MFG-E8) protein. The significant fibrogenic responses and collagen accumulation that were induced by treatment with TGF-β1 in these AOs were effectively ameliorated by treatment with NP-011 via suppression of extracellular signal-regulated kinase (ERK) signaling. Furthermore, administration of NP-011 reversed bleomycin-induced lung fibrosis in mice also via ERK signaling suppression and collagen reduction. This anti-fibrotic effect mirrored that following Pirfenidone and Nintedanib administration. Furthermore, NP-011 interacted with macrophages, which accelerated the collagen uptake for eliminating accumulated collagen in fibrotic lung tissues. This study provides a robust in vitro human organoid system for modeling PF and assessing anti-fibrotic mechanisms of potential drugs and suggests that modified MGF-E8 protein has therapeutic potential for treating PF.
2D printed multicellular devices performing digital and analogue computation
Authors: Mogas-Díez Sira , Gonzalez-Flo Eva , Macía Javier
Published: March 2021

Much effort has been expended on building cellular computational devices for different applications. Despite the significant advances, there are still several addressable restraints to achieve the necessary technological transference. These improvements will ease the development of end-user applications working out of the lab. In this study, we propose a methodology for the construction of printable cellular devices, digital or analogue, for different purposes. These printable devices are designed to work in a 2D surface, in which the circuit information is encoded in the concentration of a biological signal, the so-called carrying signal. This signal diffuses through the 2D surface and thereby interacts with different device components. These components are distributed in a specific spatial arrangement and perform the computation by modulating the level of the carrying signal in response to external inputs, determining the final output. For experimental validation, 2D cellular circuits are printed on a paper surface by using a set of cellular inks. As a proof-of-principle, we have printed and analysed both digital and analogue circuits using the same set of cellular inks but with different spatial topologies. The proposed methodology can open the door to a feasible and reliable industrial production of cellular circuits for multiple applications.
Author Correction: Experimental evidence for the existence of a second partially-ordered phase of ice VI
Authors: Yamane Ryo , Komatsu Kazuki , Gouchi Jun , Uwatoko Yoshiya , Machida Shinichi , Hattori Takanori , Ito Hayate , Kagi Hiroyuki
Published: March 2021

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-22085-4
Author Correction: High-resolution annotation of the mouse preimplantation embryo transcriptome using long-read sequencing
Authors: Qiao Yunbo , Ren Chao , Huang Shisheng , Yuan Jie , Liu Xingchen , Fan Jiao , Lin Jianxiang , Wu Susu , Chen Qiuzhen , Bo Xiaochen , Li Xiangyang , Huang Xingxu , Liu Zhen , Shu Wenjie
Published: March 2021

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-22148-6
Personalized cancer vaccine strategy elicits polyfunctional T cells and demonstrates clinical benefits in ovarian cancer
Authors: Tanyi Janos L. , Chiang Cheryl L.-L. , Chiffelle Johanna , Thierry Anne-Christine , Baumgartener Petra , Huber Florian , Goepfert Christine , Tarussio David , Tissot Stephanie , Torigian Drew A. , Nisenbaum Harvey L. , Stevenson Brian J. , Guiren Hajer Fritah , Ahmed Ritaparna , Huguenin-Bergenat Anne-Laure , Zsiros Emese , Bassani-Sternberg Michal , Mick Rosemarie , Powell Daniel J. , Coukos George , Harari Alexandre , Kandalaft Lana E.
Published: March 2021

T cells are important for controlling ovarian cancer (OC). We previously demonstrated that combinatorial use of a personalized whole-tumor lysate-pulsed dendritic cell vaccine (OCDC), bevacizumab (Bev), and cyclophosphamide (Cy) elicited neoantigen-specific T cells and prolonged OC survival. Here, we hypothesize that adding acetylsalicylic acid (ASA) and low-dose interleukin (IL)-2 would increase the vaccine efficacy in a recurrent advanced OC phase I trial (NCT01132014). By adding ASA and low-dose IL-2 to the OCDC-Bev-Cy combinatorial regimen, we elicited vaccine-specific T-cell responses that positively correlated with patients’ prolonged time-to-progression and overall survival. In the ID8 ovarian model, animals receiving the same regimen showed prolonged survival, increased tumor-infiltrating perforin-producing T cells, increased neoantigen-specific CD8+ T cells, and reduced endothelial Fas ligand expression and tumor-infiltrating T-regulatory cells. This combinatorial strategy was efficacious and also highlighted the predictive value of the ID8 model for future ovarian trial development.
Ligand modulation of the conformational dynamics of the A2A adenosine receptor revealed by single-molecule fluorescence
Authors: Fernandes Dennis D. , Neale Chris , Gomes Gregory-Neal W. , Li Yuchong , Malik Aimen , Pandey Aditya , Orazietti Alexander P. , Wang Xudong , Ye Libin , Scott Prosser R. , Gradinaru Claudiu C.
Published: March 2021

G protein-coupled receptors (GPCRs) are the largest class of transmembrane proteins, making them an important target for therapeutics. Activation of these receptors is modulated by orthosteric ligands, which stabilize one or several states within a complex conformational ensemble. The intra- and inter-state dynamics, however, is not well documented. Here, we used single-molecule fluorescence to measure ligand-modulated conformational dynamics of the adenosine A2A receptor (A2AR) on nanosecond to millisecond timescales. Experiments were performed on detergent-purified A2R in either the ligand-free (apo) state, or when bound to an inverse, partial or full agonist ligand. Single-molecule Förster resonance energy transfer (smFRET) was performed on detergent-solubilized A2AR to resolve active and inactive states via the separation between transmembrane (TM) helices 4 and 6. The ligand-dependent changes of the smFRET distributions are consistent with conformational selection and with inter-state exchange lifetimes ≥ 3 ms. Local conformational dynamics around residue 2296.31 on TM6 was measured using fluorescence correlation spectroscopy (FCS), which captures dynamic quenching due to photoinduced electron transfer (PET) between a covalently-attached dye and proximal aromatic residues. Global analysis of PET-FCS data revealed fast (150–350 ns), intermediate (50–60 μs) and slow (200–300 μs) conformational dynamics in A2AR, with lifetimes and amplitudes modulated by ligands and a G-protein mimetic (mini-Gs). Most notably, the agonist binding and the coupling to mini-Gs accelerates and increases the relative contribution of the sub-microsecond phase. Molecular dynamics simulations identified three tyrosine residues (Y112, Y2887.53, and Y2907.55) as being responsible for the dynamic quenching observed by PET-FCS and revealed associated helical motions around residue 2296.31 on TM6. This study provides a quantitative description of conformational dynamics in A2AR and supports the idea that ligands bias not only GPCR conformations but also the dynamics within and between distinct conformational states of the receptor.
Pancancer survival analysis of cancer hallmark genes
Authors: Nagy Ádám , Munkácsy Gyöngyi , Győrffy Balázs
Published: March 2021

Cancer hallmark genes are responsible for the most essential phenotypic characteristics of malignant transformation and progression. In this study, our aim was to estimate the prognostic effect of the established cancer hallmark genes in multiple distinct cancer types. RNA-seq HTSeq counts and survival data from 26 different tumor types were acquired from the TCGA repository. DESeq was used for normalization. Correlations between gene expression and survival were computed using the Cox proportional hazards regression and by plotting Kaplan–Meier survival plots. The false discovery rate was calculated to correct for multiple hypothesis testing. Signatures based on genes involved in genome instability and invasion reached significance in most individual cancer types. Thyroid and glioblastoma were independent of hallmark genes (61 and 54 genes significant, respectively), while renal clear cell cancer and low grade gliomas harbored the most prognostic changes (403 and 419 genes significant, respectively). The eight genes with the highest significance included BRCA1 (genome instability, HR 4.26, p < 1E−16), RUNX1 (sustaining proliferative signaling, HR 2.96, p = 3.1E−10) and SERPINE1 (inducing angiogenesis, HR 3.36, p = 1.5E−12) in low grade glioma, CDK1 (cell death resistance, HR = 5.67, p = 2.1E−10) in kidney papillary carcinoma, E2F1 (tumor suppressor, HR 0.38, p = 2.4E−05) and EREG (enabling replicative immortality, HR 3.23, p = 2.1E−07) in cervical cancer, FBP1 (deregulation of cellular energetics, HR 0.45, p = 2.8E−07) in kidney renal clear cell carcinoma and MYC (invasion and metastasis, HR 1.81, p = 5.8E−05) in bladder cancer. We observed unexpected heterogeneity and tissue specificity when correlating cancer hallmark genes and survival. These results will help to prioritize future targeted therapy development in different types of solid tumors.
Low dystrophin variability between muscles and stable expression over time in Becker muscular dystrophy using capillary Western immunoassay
Authors: Koeks Z. , Janson A. A. , Beekman C. , Signorelli M. , van Duyvenvoorde H. A. , van den Bergen J. C. , Hooijmans M. T. , Alleman I. , Hegeman I. M. , Verschuuren J. J. G. M. , v. Deutekom J. C. , Spitali P. , Datson N. A. , Niks E. H.
Published: March 2021

Becker muscular dystrophy (BMD) is the milder allelic variant of Duchenne muscular dystrophy, with higher dystrophin levels. To anticipate on results of interventions targeting dystrophin expression it is important to know the natural variation of dystrophin expression between different muscles and over time. Dystrophin was quantified using capillary Western immunoassay (Wes) in the anterior tibial (TA) muscle of 37 BMD patients. Variability was studied using two samples from the same TA biopsy site in nine patients, assessing nine longitudinal TA biopsies, and eight simultaneously obtained vastus lateralis (VL) muscle biopsies. Measurements were performed in duplicate with two primary antibodies. Baseline dystrophin levels were correlated to longitudinal muscle strength and functional outcomes. Results showed low technical variability and high precision for both antibodies. Dystrophin TA levels ranged from 4.8 to 97.7%, remained stable over a 3–5 year period, and did not correlate with changes in longitudinal muscle function. Dystrophin levels were comparable between TA and VL muscles. Intra-muscle biopsy variability was low (5.2% and 11.4% of the total variability of the two antibodies). These observations are relevant for the design of clinical trials targeting dystrophin production, and may urge the need for other biomarkers or surrogate endpoints.
Ants modulate stridulatory signals depending on the behavioural context
Authors: Masoni A. , Frizzi F. , Nieri R. , Casacci L. P. , Mazzoni V. , Turillazzi S. , Santini G.
Published: March 2021

Insect societies require an effective communication system to coordinate members’ activities. Although eusocial species primarily use chemical communication to convey information to conspecifics, there is increasing evidence suggesting that vibroacoustic communication plays a significant role in the behavioural contexts of colony life. In this study, we sought to determine whether stridulation can convey information in ant societies. We tested three main hypotheses using the Mediterranean ant Crematogaster scutellaris: (i) stridulation informs about the emitter’caste; (ii) workers can modulate stridulation based on specific needs, such as communicating the profitability of a food resource, or (iii) behavioural contexts. We recorded the stridulations of individuals from the three castes, restrained on a substrate, and the signals emitted by foragers workers feeding on honey drops of various sizes. Signals emitted by workers and sexuates were quantitatively and qualitatively distinct as was stridulation emitted by workers on different honey drops. Comparing across the experimental setups, we demonstrated that signals emitted in different contexts (restraining vs feeding) differed in emission patterns as well as certain parameters (dominant frequency, amplitude, duration of chirp). Our findings suggest that vibrational signaling represents a flexible communication channel paralleling the well-known chemical communication system.
Green propolis extract attenuates acute kidney injury and lung injury in a rat model of sepsis
Authors: Silveira Marcelo Augusto Duarte , Capcha José Manuel Condor , Sanches Talita Rojas , de Sousa Moreira Roberto , Garnica Margot S. , Shimizu Maria Heloisa , Berretta Andresa , Teles Flávio , Noronha Irene L. , Andrade Lúcia
Published: March 2021

Sepsis is the leading cause of acute kidney injury (AKI) and lung injury worldwide. Despite therapeutic advances, sepsis continues to be associated with high mortality. Because Brazilian green propolis (GP) has promising anti-inflammatory, antioxidant, and immunomodulatory properties, we hypothesized that it would protect kidneys and lungs in rats induced to sepsis by cecal ligation and puncture (CLP). Male Wistar rats were divided into groups—control (sham-operated); CLP (CLP only); and CLP + GP (CLP and treatment with GP at 6 h thereafter)—all receiving volume expansion and antibiotic therapy at 6 h after the procedures. By 24 h after the procedures, treatment with GP improved survival, attenuated sepsis-induced AKI, and restored renal tubular function. Whole-blood levels of reduced glutathione were higher in the CLP + GP group. Sepsis upregulated the Toll-like receptor 4/nuclear factor-kappa B axis in lung and renal tissues, as well as increasing inflammatory cytokine levels and macrophage infiltration; all of those effects were attenuated by GP. Treatment with GP decreased the numbers of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling-positive cells in renal and lung tissue, as well as protecting the morphology of the renal mitochondria. Our data open the prospect for clinical trials of the use of GP in sepsis.
SARS-CoV-2-induced humoral immunity through B cell epitope analysis in COVID-19 infected individuals
Authors: Yoshida Shota , Ono Chikako , Hayashi Hiroki , Fukumoto Shinya , Shiraishi Satoshi , Tomono Kazunori , Arase Hisashi , Matsuura Yoshiharu , Nakagami Hironori
Published: March 2021

The aim of this study is to understand adaptive immunity to SARS-CoV-2 through the analysis of B cell epitope and neutralizing activity in coronavirus disease 2019 (COVID-19) patients. We obtained serum from forty-three COVID-19 patients from patients in the intensive care unit of Osaka University Hospital (n = 12) and in Osaka City Juso Hospital (n = 31). Most individuals revealed neutralizing activity against SARS-CoV-2 assessed by a pseudotype virus-neutralizing assay.
The antibody production against the spike glycoprotein (S protein) or receptor-binding domain (RBD) of SARS-CoV-2 was elevated, with large individual differences, as assessed by ELISA. We observed the correlation between neutralizing antibody titer and IgG, but not IgM, antibody titer of COVID-19 patients. In the analysis of the predicted the linear B cell epitopes, hot spots in the N-terminal domain of the S protein were observed in the serum from patients in the intensive care unit of Osaka University Hospital. Overall, the analysis of antibody production and B cell epitopes of the S protein from patient serum may provide a novel target for the vaccine development against SARS-CoV-2.