bluuebunny/crossref_metadata_2025 huggingface dataset:
Cytoplasmic versus nuclear THR alpha expression determines survival of ovarian cancer patients
Authors: Ditsch Nina , Heublein Sabine , Jeschke Udo , Sattler Cornelia , Kuhn Christina , Hester Anna , Czogalla Bastian , Trillsch Fabian , Mahner Sven , Engel Jutta , Mayr Doris , Schmoeckel Elisa
Published: June 2020

Purpose

Thyroid hormone receptors (THR) have manifold functions and are involved in the carcinogenesis of several tumor types. Within this study, we aimed to investigate the expression pattern (nuclear versus cytoplasmic) of the THR alpha and its impact on patients survival in ovarian cancer (OvCa).

Methods

The presence of the thyroid hormone receptors THRα, THRα1 and − 2 was investigated in 156 ovarian cancer samples using immunohistochemistry (IHC) using semi-quantitative immunoreactivity (IR) scores and correlated with clinical, pathological data, subtype of ovarian cancer, clinical data, staining of 20 already described OvCa marker proteins and overall survival (OS).

Results

Among all subtypes of OvCa, clear cell carcinomas showed the highest THRα expression. Furthermore, nuclear THRα was associated with a reduced survival in this subtype. However, nuclear expressed THRα1 turned out to be a positive prognosticator for all subtypes of OvCa patients. Nuclear THRα2 is a positive prognosticator for OvCa patients of the serous subtype. In contrast, cytoplasmic expression THRα2 was associated with a reduced OS in all subtypes of OvCa patients; while, cytoplasmic expression of THRα1 is associated with reduced OS in mucinous OvCa patients only. In addition, THRα expression correlates with gonadotropin receptors, steroid hormone receptors, TA-MUC1 and glycodelin.

Conclusion

Depending on nuclear or cytoplasmic expression, our study shows that THRα and its isoforms 1 and 2 provide different prognostic information for ovarian cancer patients. Further investigations should analyze if THRs may represent new endocrine targets for the treatment of ovarian cancer.
Modeling intracranial aneurysm stability and growth: an integrative mechanobiological framework for clinical cases
Authors: Teixeira Frederico S. , Neufeld Esra , Kuster Niels , Watton Paul N.
Published: June 2020

We present a novel patient-specific fluid-solid-growth framework to model the mechanobiological state of clinically detected intracranial aneurysms (IAs) and their evolution. The artery and IA sac are modeled as thick-walled, non-linear elastic fiber-reinforced composites. We represent the undulation distribution of collagen fibers: the adventitia of the healthy artery is modeled as a protective sheath whereas the aneurysm sac is modeled to bear load within physiological range of pressures. Initially, we assume the detected IA is stable and then consider two flow-related mechanisms to drive enlargement: (1) low wall shear stress; (2) dysfunctional endothelium which is associated with regions of high oscillatory flow. Localized collagen degradation and remodelling gives rise to formation of secondary blebs on the aneurysm dome. Restabilization of blebs is achieved by remodelling of the homeostatic collagen fiber stretch distribution. This integrative mechanobiological modelling workflow provides a step towards a personalized risk-assessment and treatment of clinically detected IAs.
Certified Efficient Global Roundness Evaluation
Authors: Schöpfer Frank , Chernov Alexey
Published: June 2020

We propose and analyze a global search algorithm for the computation of the minimum zone sphericity (circularity) error of a given set. The formulation is valid in any dimension and covers both finite sets of data points as well as infinite sets like polygonal chains or triangulations of surfaces. We derive theoretical estimates for the cost to reach a desired accuracy, and validate the performance of the algorithm with various numerical experiments.
When does math anxiety in parents and teachers predict math anxiety and math achievement in elementary school children? The role of gender and grade year
Authors: Szczygieł Monika
Published: June 2020

The study investigated the relationship between math anxiety in parents and teachers and math anxiety and math achievement in first- to third-grade children. The results indicate that math anxiety in fathers (but not mothers and teachers) is associated with math anxiety in first-grade children and third-grade girls. Math anxiety in mothers and teachers (but not fathers) explains the level of math achievement in third-grade children. The research results indicate the importance of adults in shaping pupils’ math anxiety and math achievement, but these relationships vary depending on gender and the grade year. The obtained outcomes generally suggest that adults’ math anxiety is not a social source of children’s math anxiety, but it can be considered a source of low math achievement among children in the final grade of early school education.
Charge Carriers in Commercial Photocatalysts: Fractal Kinetics and Effect of “Inert” Additives
Authors: Günnemann Carsten , Curti Mariano , Sieland Fabian , Bahnemann Detlef W.
Published: June 2020

High photon conversion efficiencies and low-cost materials are crucial for implementing photocatalytic solutions in large scale applications. To improve the conversion efficiencies, knowledge on the lifetime and dynamics of photogenerated charge carriers is fundamental, for which transient absorption spectroscopy has provided important insights. Regarding the cost of the materials, one approach to decrease it is mixing the photocatalyst with cheaper additives while avoiding a significant loss in its activity. In this short review we summarize the findings of our group dealing with both aspects. A new model to fit transient absorption decays, based on fractal kinetics, is discussed. The model has been applied to the transient decays of TiO2 mixtures with binary particle size distributions and of TiO2 mixtures with a priori inert additives. In both cases, the insights obtained from the model were crucial to explain the photocatalytic activities of the mixtures.
Calbindin Deficits May Underlie Dissociable Effects of 5-HT6 and mGlu7 Antagonists on Glutamate and Cognition in a Dual-Hit Neurodevelopmental Model for Schizophrenia
Authors: Shortall Sinead E. , Brown Angus M. , Newton-Mann Eliot , Dawe-Lane Erin , Evans Chanelle , Fowler Maxine , King Madeleine V.
Published: June 2020

Despite several compounds entering clinical trials for the negative and cognitive symptoms of schizophrenia, few have progressed beyond phase III. This is partly attributed to a need for improved preclinical models, to understand disease and enable predictive evaluation of novel therapeutics. To this end, one recent approach incorporates “dual-hit” neurodevelopmental insults like neonatal phencyclidine plus isolation rearing (PCP-Iso). Glutamatergic dysfunction contributes to schizophrenia pathophysiology and may represent a treatment target, so we used enzyme-based microsensors to evaluate basal- and drug-evoked glutamate release in hippocampal slices from rats that received neonatal PCP and/or isolation rearing. 5-HT6 antagonist-evoked glutamate release (thought to be mediated indirectly via GABAergic disinhibition) was reduced in PCP-Iso, as were cognitive effects of a 5-HT6 antagonist in a hippocampal glutamate-dependent novel object discrimination task. Yet mGlu7 antagonist-evoked glutamatergic and cognitive responses were spared. Immunohistochemical analyses suggest these findings (which mirror the apparent lack of clinical response to 5-HT6 antagonists in schizophrenia) are not due to reduced hippocampal 5-HT input in PCP-Iso, but may be explained by reduced calbindin expression. This calcium-binding protein is present in a subset of GABAergic interneurons receiving preferential 5-HT innervation and expressing 5-HT6 receptors. Its loss (in schizophrenia and PCP-Iso) would be expected to reduce interneuron firing and potentially prevent further 5-HT6 antagonist-mediated disinhibition, without impacting on responses of VIP-expressing interneurons to mGlu7 antagonism. This research highlights the importance of improved understanding for selection of appropriate preclinical models, especially where disease neurobiology impacts on cells mediating the effects of potential therapeutics.
Comprehensive assessment of multiple tryptophan metabolites as potential biomarkers for immune checkpoint inhibitors in patients with non-small cell lung cancer
Authors: Karayama M. , Masuda J. , Mori K. , Yasui H. , Hozumi H. , Suzuki Y. , Furuhashi K. , Fujisawa T. , Enomoto N. , Nakamura Y. , Inui N. , Suda T. , Maekawa M. , Sugimura H. , Takada A.
Published: June 2020

Purpose

Tryptophan metabolites have immunomodulatory functions, suggesting possible roles in cancer immunity.

Methods

Plasma tryptophan metabolites were measured using liquid chromatography/mass spectrometry before immune checkpoint inhibitors (ICIs) in patients with non-small cell lung cancer (NSCLC).

Results

The 19 patients with NSCLC had significantly lower levels of tryptophan (p = 0.002) and xanthurenic acid (p = 0.032), and a significantly higher level of 3-hydroxyanthranilic acid (3-HAA) (p = 0.028) compared with the 10 healthy volunteers. The patients achieving objective responses had significantly lower levels of 3-HAA than those who did not (p = 0.045). Receiver operating characteristic analyses determined that the cutoff value of 3-HAA for objective response was 35.4 pmol/mL (sensitivity: 87.5% and specificity: 83.3%). The patients with 3-HAA < 35.4 pmol/mL had significantly longer median progression-free survival (7.0 months) than those without (1.6 months, p = 0.022).

Conclusions

Tryptophan metabolites may have a potential for predicting the efficacy of ICIs.

Registration number

University Hospital Medical Information Network Clinical Trial Registry 000026140.
A method for constructing sliding windows leak from noisy cache timing information
Authors: Ueno Rei , Takahashi Junko , Hayashi Yu-ichi , Homma Naofumi
Published: June 2020

This paper presents a method for constructing an operation sequence of sliding window exponentiation from the noisy cache information of RSA, which can be used for a cache attack using sliding windows leak (SWL). An SWL attack can retrieve the secret keys of RSA with non-negligible probability if the SWL is correctly captured. However, in practice, it is not always possible for an attacker to acquire a complete and correct operation sequence from cache information observation. In this paper, we first show that the capture errors in an operation sequence can be evaluated based on the Levenshtein distance between correct and estimated sequences. The dynamic time warping algorithm is employed for quantitative evaluation. Then, we present a method of accurately estimating a complete and correct operation sequence from noisy sequences obtained through multiple observations. Furthermore, we show the effectiveness of the proposed method through a set of experiments performed using RSA software in Libgcrypt. As a result, we can identify the correct operation sequence from approximately 100 observations of cache traces.
Attachment to God among Bereaved Jewish Parents: Exploring Differences by Denominational Affiliation
Authors: Frei-Landau Rivi , Tuval-Mashiach Rivka , Silberg Tamar , Hasson-Ohayon Ilanit
Published: June 2020

While much research has been devoted to examining individual differences in one's interpersonal attachment, very little research has been devoted to examining individual differences in one's attachment to God (ATG). Particularly, how ATG dimensions relate to different religious denominations (RD). To explore the relationship between ATG dimensions (avoidance/anxiety) and Jewish RDs. As the attachment theory was conceptualized to understand human reaction to separation and loss, the current study examined the relationship between ATG and RD among bereaved parents. Seventy-seven bereaved Jewish parents completed questionnaires referring to their RD and ATG. The results revealed different relationships between ATG and RD for each of the two ATG dimensions. Avoidant ATG was negatively correlated with RD in a linear order, whereas the relationship between the anxious ATG and RD was quadratic, revealing the highest levels of attachment-anxiety among participants affiliated with the traditional RD (“ Masorti”). Methodologically, these findings support the argument that ATG dimensions are distinct and separable from each other. Additionally, the findings highlight the importance of considering participants’ RD when exploring their ATG, as different denomination-based manifestations of ATG do exist. Clinical implications include using RD to detect bereaved parents at risk (i.e., traditional ones), due to their high anxious ATG dimension.
Corpus literacy instruction in language teacher education: Investigating Arab EFL student teachers’ immediate beliefs and long-term practices
Authors: Abdel Latif Muhammad M. M.
Published: June 2020

With the increasing recognition of the pedagogical applications of corpus linguistics, there has been a growing interest in developing teachers’ corpus literacy to popularize the use of corpora in language education. This longitudinal study investigated Arab Gulf EFL student teachers’ immediate and long-term responses to corpus literacy instruction. After teaching a corpus literacy component to two classes of student teachers in a graduate computer-assisted language learning course they attended, the author collected focus group data about their views on this instruction and their own expected future uses of corpora in language learning, teaching and research. Two years later, a group of these student teachers (n= 19) responded to a follow-up questionnaire exploring their beliefs about corpus literacy integration and their multiple uses of corpora. The student teachers reported very positive immediate and long-term perceptions of corpus literacy instruction, but it was found that such instruction has not brought about all the desired changes in their long-term uses of online corpora as a linguistic and pedagogical resource, or their attitudes towards doing corpus-based TESOL research. However, it is expected that the popularization benefits gained from corpus literacy integration could lead to better future developments in using corpora for language education and research purposes in the target context.
The Erber: tracing global trade through a London building
Authors: Milne Sarah A.
Published: June 2020

Through a case-study of one significant courtyard house owned by the Drapers’ Company and known as ‘The Erber’, this article argues that mercantile livery companies supported London's growing centrality within an expanding network of trade through the use and development of corporate properties. The micro-history at the heart of this article reveals that the ‘everyday’ built environment of sixteenth- and seventeenth-century London was shaped not just by the city elite. Also relevant to that process were the different sorts of tenants of the Drapers’ Company, who benefited from the expansion at all levels of London's mercantile activity. The trickle-down effects of global mercantilism affected spaces small and large. The investigation of the Erber highlights the domestic implications of global commercial expansion.
Zur gesundheitlichen Lage von Kindern im Kita-Alter in Deutschland
Authors: Mauz Elvira , Kuntz Benjamin , Gutsche Johanna , Hoffmann Robert , Krug Susanne , Poethko-Müller Christina , Richter Almut , Jordan Susanne
Published: June 2020

Zusammenfassung. Kindertageseinrichtungen (Kitas) sind das zentrale Setting für Gesundheitsförderung und Prävention bei Kindern im Vorschulalter. Der Erziehungs- und Bildungsauftrag der Kita umfasst auch gesundheitliche Aspekte. Der Beitrag zeigt ausgewählte Ergebnisse zum Gesundheitszustand und dem Gesundheitsverhalten von Kindern im Alter bis zu 6 Jahren, die auf aktuellen bundesweit repräsentativen Daten der „Studie zur Gesundheit von Kindern und Jugendlichen in Deutschland (KiGGS)“ basieren. Die große Mehrheit der Kinder wächst gesund auf, allerdings zeigen sich deutliche Handlungsbedarfe für Gesundheitsaspekte im Bereich von Ernährung, Bewegung und der psychischen Gesundheit. Das Ausmaß der Bedarfe ist abhängig vom sozioökonomischen Status der Familien. Der frühen Bildung im Setting Kita kommt eine bedeutsame Rolle zu, da hier Kinder unabhängig von ihrem familiären Hintergrund erreicht werden können. Dies kann dazu beitragen, das Präventionspotenzial im Hinblick auf die Reduzierung von Gesundheitsproblemen wie Adipositas oder psychischen Auffälligkeiten weiter auszuschöpfen.
Subjektiver Handlungsbedarf und Maßnahmen aufgrund psychischer Auffälligkeiten im Kindergartenalter
Authors: Hoffer Rieke
Published: June 2020

Zusammenfassung. Kindergartenkinder mit psychischen Auffälligkeiten sind darauf angewiesen, dass ihre Probleme bemerkt werden, damit sie Hilfe und Unterstützung erhalten. In einer Fragebogenstudie mit quantitativen und qualitativen Elementen wurden 255 Eltern von Kindern von drei bis sechs Jahren und deren frühpädagogische Fachkräfte mit einem standardisierten Instrument zur Erhebung psychischer Probleme (Verhaltensskalen für das Kindergartenalter, VSK, Koglin & Petermann, 2016 ) befragt. In ergänzenden offenen Textfeldern gaben Eltern und Fachkräfte an, ob aus ihrer Sicht Handlungsbedarf aufgrund des Verhaltens des Kindes bestehe, und, wenn ja, aus welchen Gründen, welche Maßnahmen durchgeführt wurden. Die Ergebnisse zeigten bei Eltern und Fachkräften einen nur geringen Zusammenhang zwischen auffälligen Werten und subjektivem Handlungsbedarf. Als Gründe für Handlungsbedarf wurden von beiden Gruppen v.a. externalisierende Verhaltensweisen und der Mangel an sozialen Kompetenzen angegeben. Als Maßnahmen wurden von Eltern am häufigsten die Inanspruchnahme verschiedener professioneller Unterstützungsangebote benannt (36,6%). Die Fachkräfte gaben die Kooperation mit den Eltern (36,0%) und die Zusammenarbeit mit diversen externen Kooperationspartnern als häufigste Maßnahmen an (36,0%). Implikationen für die pädagogische Praxis sind v.a. die Fokussierung in Aus- und Weiterbildung auf Kompetenzen zum Erkennen auch emotionaler Probleme sowie eine intensive Vernetzung von Kindertageseinrichtungen mit Akteuren aus Sozialpädiatrischen Zentren und kinderpsychotherapeutischem Fachpersonal.
Soil Greenhouse Gas Fluxes From Maize Production Under Different Soil Fertility Management Practices in East Africa
Authors: Macharia Joseph M. , Pelster David E. , Ngetich Felix K. , Shisanya Chris A. , Mucheru‐Muna Monicah , Mugendi Daniel N.
Published: June 2020

In sub‐Saharan Africa (SSA), few studies have quantified greenhouse gas (GHG) emissions following application of soil amendments, for development of accurate national GHG inventories. Therefore, this study quantified soil GHG emissions using static chambers for two maize cropping seasons (one full year) of four different soil amendments in the central highlands of Kenya. The four treatments were (i) animal manure, (ii) inorganic fertilizer, (iii) combined animal manure and inorganic fertilizer, and (iv) a no‐N control (no amendment) laid out in a randomized complete block design. Cumulative annual soil fluxes (February 2017 to February 2018) ranged from −1.03 ± 0.19 kg CH4‐C ha−1 yr−1 from the manure inorganic fertilizer treatment to −0.09 ± 0.03 kg CH4‐C ha−1 yr−1 from the manure treatment, 1,391 ± 74 kg CO2‐C ha−1 yr−1 from the control treatment to 3,574 ± 113 kg CO2‐C ha−1 yr−1 from the manure treatment, and 0.13 ± 0.08 to 1.22 ± 0.12 kg N2O‐N ha−1 yr−1 in the control and manure treatments, respectively. Animal manure amendment produced the highest cumulative CO2 emissions (P < 0.001), N2O emissions (P < 0.001), and maize yields (P = 0.002) but the lowest N2O yield‐scaled emission (YSE) (0.5 g N2O–N kg−1 grain yield). Manure combined with inorganic fertilizer had the highest cumulative CH4 uptake (P < 0.001) and N2O YSE (2.2 g N2O–N kg−1 grain yield). Our results indicate that while the use of animal manure may increase total GHG emissions, the concurrent increase in maize yields results in reduced yield‐scaled GHG emissions.
Frequently Dry Waterways Still Contribute to Carbon Emissions
Authors: Derouin Sarah
Published: June 2020

A new international collaboration found that dry inland waters—no matter where they were located—contributed significant global carbon dioxide emissions.
Is Climate Variability Organized?
Authors: Franzke Christian , Yuan Naiming
Published: June 2020

Most climate variability is organized by a simple principle—scaling laws—allowing us to understand past and future climate change.
Different Peak Response Time of Daytime Thermospheric Neutral Species to the 27‐Day Solar EUV Flux Variations
Authors: Ren Dexin , Lei Jiuhou , Wang Wenbin , Burns Alan , Luan Xiaoli , Dou Xiankang
Published: June 2020

Previous work suggested that the peak response time of the mass densities of atomic oxygen (O) and molecular nitrogen (N2) in the thermosphere had more than a 1‐day difference relative to the peak of the 27‐day periodic variation of solar extreme ultraviolet (EUV) flux. In this study, we used the Thermosphere Ionosphere Electrodynamic General Circulation Model (TIEGCM) to explore the physical mechanisms responsible for the different peak response times of the daytime thermospheric neutral species. It was found that the peak response time of O or N2 mass density corresponds to the time of equilibrium between the contributions from the barometric effect and the change in its abundance. The peak response time of O is shorter than that of thermospheric temperature Tn, due to a dynamic change in the circulation that acts to cancel out the contribution from the barometric process prior to the peak of Tn. On the contrary, the change of N2 abundance contributes further to a decrease of N2 mass density on a constant pressure surface when the thermosphere is expanding. The change of chemical loss leads to a longer peak response time of N2 abundance than that due to barometric motion. Therefore, an equilibrium is reached after the barometric effect turns from expansion (contraction) to contraction (expansion), so that the peak response time of N2 is longer than that of Tn. Moreover, the meridional circulation in the thermosphere modulates the latitudinal dependence of the peak response time of thermospheric neutral species.
Biochemical activity of RAGs is impeded by Dolutegravir, an HIV integrase inhibitor
Authors: Nilavar Namrata M. , Paranjape Amita M. , Raghavan Sathees C.
Published: June 2020

HIV is a retrovirus that infects CD4+ T lymphocytes in human beings and causes immunodeficiency. In the recent years, various therapies have been developed against HIV, including targeting the HIV specific protein, integrase, responsible for integration of HIV cDNA into host DNA. Although, integrase is specific to HIV, it has functional and structural similarity with RAG1, one of the partner proteins associated with V(D)J recombination, a process by which immune diversity is generated in humans. Currently, there are three HIV integrase inhibitors: Elvitegravir, Dolutegravir, and Raltegravir, in the market which have been approved by the FDA (USA). All three drugs are used in anti-retroviral therapy (ART). Previously, we showed that amongst the HIV inhibitors, Elvitegravir could significantly decrease B cell maturation in vivo and inhibit the physiological activities of RAGs in vitro, unlike Raltegravir. In the present study, we address the effect of second-generation integrase inhibitor, Dolutegravir on RAG activities. Binding and nicking studies showed that, Dolutegravir could decrease the binding efficiency of RAG1 domains and cleavage on DNA substrates, but not as considerably as Elvitegravir. Thus, we show that although the integrase inhibitors such as Elvitegravir show an affinity towards RAG1, the newer molecules may have lesser side-effects.
Nuclear interacting SET domain protein 1 inactivation impairs GATA1-regulated erythroid differentiation and causes erythroleukemia
Authors: Leonards Katharina , Almosailleakh Marwa , Tauchmann Samantha , Bagger Frederik Otzen , Thirant Cécile , Juge Sabine , Bock Thomas , Méreau Hélène , Bezerra Matheus F. , Tzankov Alexandar , Ivanek Robert , Losson Régine , Peters Antoine H. F. M. , Mercher Thomas , Schwaller Juerg
Published: June 2020

The nuclear receptor binding SET domain protein 1 (NSD1) is recurrently mutated in human cancers including acute leukemia. We show that NSD1 knockdown alters erythroid clonogenic growth of human CD34+hematopoietic cells. Ablation ofNsd1in the hematopoietic system of mice induces a transplantable erythroleukemia. In vitro differentiation ofNsd1−/−erythroblasts is majorly impaired despite abundant expression of GATA1, the transcriptional master regulator of erythropoiesis, and associated with an impaired activation of GATA1-induced targets. Retroviral expression of wildtype NSD1, but not a catalytically-inactive NSD1N1918QSET-domain mutant induces terminal maturation ofNsd1−/−erythroblasts. Despite similar GATA1 protein levels, exogenous NSD1 but not NSDN1918Qsignificantly increases the occupancy of GATA1 at target genes and their expression. Notably, exogenous NSD1 reduces the association of GATA1 with the co-repressor SKI, and knockdown of SKI induces differentiation ofNsd1−/−erythroblasts. Collectively, we identify the NSD1 methyltransferase as a regulator of GATA1-controlled erythroid differentiation and leukemogenesis.
Water stable molecular n-doping produces organic electrochemical transistors with high transconductance and record stability
Authors: Paterson Alexandra F. , Savva Achilleas , Wustoni Shofarul , Tsetseris Leonidas , Paulsen Bryan D. , Faber Hendrik , Emwas Abdul Hamid , Chen Xingxing , Nikiforidis Georgios , Hidalgo Tania C. , Moser Maximillian , Maria Iuliana Petruta , Rivnay Jonathan , McCulloch Iain , Anthopoulos Thomas D. , Inal Sahika
Published: June 2020

From established to emergent technologies, doping plays a crucial role in all semiconducting devices. Doping could, theoretically, be an excellent technique for improving repressively low transconductances in n-type organic electrochemical transistors – critical for advancing logic circuits for bioelectronic and neuromorphic technologies. However, the technical challenge is extreme: n-doped polymers are unstable in electrochemical transistor operating environments, air and water (electrolyte). Here, the first demonstration of doping in electron transporting organic electrochemical transistors is reported. The ammonium salt tetra-n-butylammonium fluoride is simply admixed with the conjugated polymer poly(N,N’-bis(7-glycol)-naphthalene-1,4,5,8-bis(dicarboximide)-co-2,2’-bithiophene-co-N,N’-bis(2-octyldodecyl)-naphthalene-1,4,5,8-bis(dicarboximide), and found to act as a simultaneous molecular dopant and morphology-additive. The combined effects enhance the n-type transconductance with improved channel capacitance and mobility. Furthermore, operational and shelf-life stability measurements showcase the first example of water-stable n-doping in a polymer. Overall, the results set a precedent for doping/additives to impact organic electrochemical transistors as powerfully as they have in other semiconducting devices.
Functional annotation of rare structural variation in the human brain
Authors: Han Lide , Zhao Xuefang , Benton Mary Lauren , Perumal Thaneer , Collins Ryan L. , Hoffman Gabriel E. , Johnson Jessica S. , Sloofman Laura , Wang Harold Z. , Stone Matthew R. ,   CommonMind Consortium, Akbarian Schahram , Bendl Jaroslav , Breen Michael , Brennand Kristen J. , Brown Leanne , Browne Andrew , Buxbaum Joseph D. , Charney Alexander , Chess Andrew , Couto Lizette , Crawford Greg , Devillers Olivia , Devlin Bernie , Dobbyn Amanda , Domenici Enrico , Filosi Michele , Flatow Elie , Francoeur Nancy , Fullard John , Gil Sergio Espeso , Girdhar Kiran , Gulyás-Kovács Attila , Gur Raquel , Hahn Chang-Gyu , Haroutunian Vahram , Hauberg Mads Engel , Huckins Laura , Jacobov Rivky , Jiang Yan , Johnson Jessica S. , Kassim Bibi , Kim Yungil , Klei Lambertus , Kramer Robin , Lauria Mario , Lehner Thomas , Lewis David A. , Lipska Barbara K. , Montgomery Kelsey , Park Royce , Rosenbluh Chaggai , Roussos Panos , Ruderfer Douglas M. , Senthil Geetha , Shah Hardik R. , Sloofman Laura , Song Lingyun , Stahl Eli , Sullivan Patrick , Visintainer Roberto , Wang Jiebiao , Wang Ying-Chih , Wiseman Jennifer , Xia Eva , Zhang Wen , Zharovsky Elizabeth , Brennand Kristen J. , Brand Harrison , Sieberts Solveig K. , Marenco Stefano , Peters Mette A. , Lipska Barbara K. , Roussos Panos , Capra John A. , Talkowski Michael , Ruderfer Douglas M.
Published: June 2020

Structural variants (SVs) contribute to many disorders, yet, functionally annotating them remains a major challenge. Here, we integrate SVs with RNA-sequencing from human post-mortem brains to quantify their dosage and regulatory effects. We show that genic and regulatory SVs exist at significantly lower frequencies than intergenic SVs. Functional impact of copy number variants (CNVs) stems from both the proportion of genic and regulatory content altered and loss-of-function intolerance of the gene. We train a linear model to predict expression effects of rare CNVs and use it to annotate regulatory disruption of CNVs from 14,891 independent genome-sequenced individuals. Pathogenic deletions implicated in neurodevelopmental disorders show significantly more extreme regulatory disruption scores and if rank ordered would be prioritized higher than using frequency or length alone. This work shows the deleteriousness of regulatory SVs, particularly those altering CTCF sites and provides a simple approach for functionally annotating the regulatory consequences of CNVs.
Heavy N+ ion transfer in doubly charged N2Ar van der Waals cluster
Authors: Zhu XiaoLong , Hu XiaoQing , Yan ShunCheng , Peng YiGeng , Feng WenTian , Guo DaLong , Gao Yong , Zhang ShaoFeng , Cassimi Amine , Xu JiaWei , Zhao DongMei , Dong DaPu , Hai Bang , Wu Yong , Wang JianGuo , Ma X.
Published: June 2020

Van der Waals clusters are weakly bound atomic/molecular systems and are an important medium for understanding micro-environmental chemical phenomena in bio-systems. The presence of neighboring atoms may open channels otherwise forbidden in isolated atoms/molecules. In hydrogen-bond clusters, proton transfer plays a crucial role, which involves mass and charge migration over large distances within the cluster and results in its fragmentation. Here we report an exotic transfer channel involving a heavy N+ ion observed in a doubly charged cluster produced by 1 MeV Ne8+ ions: (N2Ar)2+→N++NAr+. The neighboring Ar atom decreases the $${\mathrm{N}}_2^{2 + }$$

N

2

2
+

barrier height and width, resulting in significant shorter lifetimes of the metastable molecular ion state $${\mathrm{N}}_2^{2 + }$$

N

2

2
+

($${{\mathrm{X}}^{1}}{\Sigma _{{\mathrm{g}}}^{+}}$$

X

1

Σ

g

+

). Consequently, the breakup of the covalent N+−N+ bond, the tunneling out of the N+ ion from the $${\mathrm{N}}_2^{2 + }$$

N

2

2
+

potential well, as well as the formation of an N−Ar+ bound system take place almost simultaneously, resulting in a Coulomb explosion of N+ and NAr+ ion pairs.
ARS2/MAGL signaling in glioblastoma stem cells promotes self-renewal and M2-like polarization of tumor-associated macrophages
Authors: Yin Jinlong , Kim Sung Soo , Choi Eunji , Oh Young Taek , Lin Weiwei , Kim Tae-Hoon , Sa Jason K. , Hong Jun Hee , Park Se Hwan , Kwon Hyung Joon , Jin Xiong , You Yeonhee , Kim Ji Hye , Kim Hyunggee , Son Jaekyoung , Lee Jeongwu , Nam Do-Hyun , Choi Kui Son , Shi Bingyang , Gwak Ho-Shin , Yoo Heon , Iavarone Antonio , Kim Jong Heon , Park Jong Bae
Published: June 2020

The interplay between glioblastoma stem cells (GSCs) and tumor-associated macrophages (TAMs) promotes progression of glioblastoma multiforme (GBM). However, the detailed molecular mechanisms underlying the relationship between these two cell types remain unclear. Here, we demonstrate that ARS2 (arsenite-resistance protein 2), a zinc finger protein that is essential for early mammalian development, plays critical roles in GSC maintenance and M2-like TAM polarization. ARS2 directly activates its novel transcriptional target MGLL, encoding monoacylglycerol lipase (MAGL), to regulate the self-renewal and tumorigenicity of GSCs through production of prostaglandin E2 (PGE2), which stimulates β-catenin activation of GSC and M2-like TAM polarization. We identify M2-like signature downregulated by which MAGL-specific inhibitor, JZL184, increased survival rate significantly in the mouse xenograft model by blocking PGE2 production. Taken together, our results suggest that blocking the interplay between GSCs and TAMs by targeting ARS2/MAGL signaling offers a potentially novel therapeutic option for GBM patients.
Autophagy controls the induction and developmental decline of NMDAR-LTD through endocytic recycling
Authors: Shen Hongmei , Zhu Huiwen , Panja Debabrata , Gu Qinhua , Li Zheng
Published: June 2020

NMDA receptor-dependent long-term depression (NMDAR-LTD) is a long-lasting form of synaptic plasticity. Its expression is mediated by the removal of AMPA receptors from postsynaptic membranes. Under basal conditions, endocytosed AMPA receptors are rapidly recycled back to the plasma membrane. In NMDAR-LTD, however, they are diverted to late endosomes for degradation. The mechanism for this switch is largely unclear. Additionally, the inducibility of NMDAR-LTD is greatly reduced in adulthood. The underlying mechanism and physiological significance of this phenomenon are elusive. Here, we report that autophagy inhibition is essential for the induction and developmental dampening of NMDAR-LTD. Autophagy is inhibited during NMDAR-LTD to decrease endocytic recycling. Autophagy inhibition is both necessary and sufficient for LTD induction. In adulthood, autophagy is up-regulated to make LTD induction harder, thereby preventing the adverse effect of excessive LTD on memory consolidation. These findings reveal the unrecognized functions of autophagy in synaptic plasticity, endocytic recycling, and memory.
Angiopoietin-2–integrin α5β1 signaling enhances vascular fatty acid transport and prevents ectopic lipid-induced insulin resistance
Authors: Bae Hosung , Hong Ki Yong , Lee Choong-kun , Jang Cholsoon , Lee Seung-Jun , Choe Kibaek , Offermanns Stefan , He Yulong , Lee Hyuek Jong , Koh Gou Young
Published: June 2020

Proper storage of excessive dietary fat into subcutaneous adipose tissue (SAT) prevents ectopic lipid deposition-induced insulin resistance, yet the underlying mechanism remains unclear. Here, we identify angiopoietin-2 (Angpt2)–integrin α5β1 signaling as an inducer of fat uptake specifically in SAT. Adipocyte-specific deletion of Angpt2 markedly reduced fatty acid uptake and storage in SAT, leading to ectopic lipid accumulation in glucose-consuming organs including skeletal muscle and liver and to systemic insulin resistance. Mechanistically, Angpt2 activated integrin α5β1 signaling in the endothelium and triggered fatty acid transport via CD36 and FATP3 into SAT. Genetic or pharmacological inhibition of the endothelial integrin α5β1 recapitulated adipocyte-specific Angpt2 knockout phenotypes. Our findings demonstrate the critical roles of Angpt2–integrin α5β1 signaling in SAT endothelium in regulating whole-body fat distribution for metabolic health and highlight adipocyte–endothelial crosstalk as a potential target for prevention of ectopic lipid deposition-induced lipotoxicity and insulin resistance.
Robust leaf trait relationships across species under global environmental changes
Authors: Cui Erqian , Weng Ensheng , Yan Enrong , Xia Jianyang
Published: June 2020

Recent studies show coordinated relationships between plant leaf traits and their capacity to predict ecosystem functions. However, how leaf traits will change within species and whether interspecific trait relationships will shift under future environmental changes both remain unclear. Here, we examine the bivariate correlations between leaf economic traits of 515 species in 210 experiments which mimic climate warming, drought, elevated CO2, and nitrogen deposition. We find divergent directions of changes in trait-pairs between species, and the directions mostly do not follow the interspecific trait relationships. However, the slopes in the logarithmic transformed interspecific trait relationships hold stable under environmental changes, while only their elevations vary. The elevation changes of trait relationship are mainly driven by asymmetrically interspecific responses contrary to the direction of the leaf economic spectrum. These findings suggest robust interspecific trait relationships under global changes, and call for linking within-species responses to interspecific coordination of plant traits.
Adenovector 26 encoded prefusion conformation stabilized RSV-F protein induces long-lasting Th1-biased immunity in neonatal mice
Authors: van der Fits Leslie , Bolder Renske , Heemskerk-van der Meer Marjolein , Drijver Joke , van Polanen Yolinda , Serroyen Jan , Langedijk Johannes P. M. , Schuitemaker Hanneke , Saeland Eirikur , Zahn Roland
Published: June 2020

While RSV is a major cause of respiratory morbidity in infants, vaccine development is hindered by the immaturity and Th2-bias of the infant immune system and the legacy of enhanced respiratory disease (ERD) after RSV infection following immunization with formalin inactivated (FI)-RSV vaccine in earlier clinical trials. Preclinical studies have demonstrated that an adenoviral vector-based RSV F vaccine candidate (Ad26.RSV.FA2) induces Th1-biased protective immune responses, without signs of ERD upon subsequent RSV challenge. We here developed an Ad26 vector encoding the RSV F protein stabilized in its prefusion conformation (Ad26.RSV.preF). In adult mice, Ad26.RSV.preF induced superior, Th1-biased IgG2a-dominated humoral responses as compared to Ad26.RSV.FA2, while maintaining the strong Th1-biased cellular responses. Similar to adult mice, Ad26.RSV.preF induced robust and durable humoral immunity in neonatal mice, again characterized by IgG2a-dominated RSV F-binding antibodies, and high and stable virus-neutralizing titers. In addition, vaccine-elicited cellular immune responses were durable and characterized by IFN-γ-producing CD4+ and CD8+ T cells, with a profound Th1 bias. In contrast, immunization of neonatal mice with FI-RSV resulted in IgG1 RSV F-binding antibodies associated with a Th2 phenotype, no detectable virus-neutralizing antibodies, and a Th2-biased cellular response. These results are supportive for the clinical development of Ad26.RSV.preF for use in infants.
Distribution and conservation of species is misestimated if biotic interactions are ignored: the case of the orchid Laelia speciosa
Authors: Flores-Tolentino Mayra , García-Valdés Raúl , Saénz-Romero Cuauhtémoc , Ávila-Díaz Irene , Paz Horacio , Lopez-Toledo Leonel
Published: June 2020

The geographic distribution of species depends on their relationships with climate and on the biotic interactions of the species. Ecological Niche Models (ENMs) mainly consider climatic variables only and may tend to overestimate these distributions, especially for species strongly restricted by biotic interactions. We identified the preference ofLaelia speciosafor different host tree species and include this information in an ENM. The effect of habitat loss and climate change on the distribution of these species was also estimated. AlthoughL. speciosawas recorded as epiphyte at six tree species, 96% of the individuals were registered at one single species (Quercus deserticola), which indicated a strong biotic interaction. We included the distribution of this host tree as a biotic variable in the ENM ofL. speciosa. The contemporary distribution ofL. speciosais 52,892 km2, which represent 4% of Mexican territory and only 0.6% of the distribution falls within protected areas. Habitat loss rate for L. speciosaduring the study period was 0.6% per year. Projections for 2050 and 2070 under optimistic and pessimistic climate change scenarios indicated a severe reduction in its distribution. Climaticaly suitable areas will also shift upwards (200–400 m higher). When estimating the distribution of a species, including its interactions can improve the performance of the ENMs, allowing for more  accurate estimates of the actual distribution of the species, which in turn allows for better conservation strategies.
Genetic variations in catechol-O-methyltransferase gene are associated with levodopa response variability in Chinese patients with Parkinson’s disease
Authors: Zhao Cuiping , Wang Yihua , Zhang Bin , Yue Yaoxian , Zhang Jianyuan
Published: June 2020

Catechol-O-methyltransferase (COMT) is one of the main enzymes in dopamine metabolism and is reported to be associated with susceptibility to Parkinson’s disease (PD) and pharmacotherapy. However, researchers mostly focus on the most common polymorphism, rs4680. In this case-control study, we investigated the association of SNPs other than rs4680 with the levodopa (L-dopa) response and other clinical features in Chinese PD patients. Eleven single nucleotide polymorphisms (SNPs) in the COMT gene were genotyped, and clinical data were collected. Patients with the TT genotype of rs165728 or rs174699 had larger daily levodopa equivalent doses (LEDs) than the patients with CC and CT genotypes under the dominant model (p = 0.01421 for rs165728 and p = 0.02302 for rs174699). Under the dominant model, the patients with GG at rs4680 G > A had a lower occurrence of dyskinesia than those with AA and AG (p = 0.0196). Patients with CC at rs4633 had a lower occurrence of dyskinesia than those with TT and TC (p = 0.0429) under the dominant model. The frequencies of the rs174675 T and rs933271 C alleles were higher in PD patients than in the controls (p < 0.05). Our primary results showed the possible association of SNPs other than the most common functional rs4680 in COMT with interindividual variance in the L-dopa daily dose and susceptibility to dyskinesia in Chinese patients, although this was an exploratory study based on a small sample size. Larger and more randomized samples are necessary for further investigation.
Identification of key genes and modules in response to Cadmium stress in different rice varieties and stem nodes by weighted gene co-expression network analysis
Authors: Wang Qi , Zeng Xiannan , Song Qiulai , Sun Yu , Feng Yanjiang , Lai Yongcai
Published: June 2020

Soil cadmium (Cd) pollution threatens food safety. This study aimed to identify genes related to Cd accumulation in rice. Low- (Shennong 315, short for S315) and high- (Shendao 47, short for S47) Cd-accumulative rice cultivars were incubated with CdCl2·2.5H2O. RNA-seq and weighted gene co-expression network analysis (WGCNA) were performed to identify the modules and genes associated with Cd-accumulative traits of rice. After Cd stress treatment, the Cd content in various tissues of S315 was significantly higher than that of S47. In the stem nodes, the Cd distribution results of the two varieties indicated that the unelongated nodes near the root (short for node A) had a stronger ability to block Cd transfer upwards than the panicle node (short for node B). Cd stress induced huge changes in gene expression profiles. After analyzing the differentially expressed genes (DEGs) in significantly correlated WGCNA modules, we found that genes related to heavy metal transportation had higher expression levels in node A than that in node B, such as Copper transporter 6 (OS04G0415600), Zinc transporter 10 (OS06G0566300), and some heavy-metal associated proteins (OS11G0147500, OS03G0861400, and OS10G0506100). In the comparison results between S315 and S47, the expression of chitinase (OS03G0679700 and OS06G0726200) was increased by Cd treatment in S315. In addition, OsHSPs (OS05G0460000, OS08G0500700), OsHSFC2A (OS02G0232000), and OsDJA5 (OS03G0787300) were found differentially expressed after Cd treatment in S315, but changed less in S47. In summary, different rice varieties have different processes and intensities in response to Cd stress. The node A might function as the key tissue for blocking Cd upward transport into the panicle via vigorous processes, including of heavy metal transportation, response to stress, and cell wall.
Association between oral health and incidence of pneumonia: a population-based cohort study from Korea
Authors: Son Minkook , Jo Sangyong , Lee Ji Sung , Lee Dong Hyun
Published: June 2020

Pneumonia is related to oral health of the elderly and intensive care unit patients. However, studies on the relationship between overall oral health and pneumonia in the general population have been limited. The purpose of this study was to investigate the association between oral health and pneumonia using a nationwide population-based Korean cohort database. Data from 122,251 participants who underwent health screening and oral examinations in 2004 or 2005 were analyzed. Cox proportional hazard regression analysis was performed to evaluate the association between oral health and pneumonia. The risk of pneumonia increased significantly in groups with a higher number of dental caries and missing teeth, with respective adjusted hazard ratios (HRs) and 95% confidence interval (CI) of 1.265 (1.086–1.473; p = 0.0025) and 1.218 (1.113–1.332; p < 0.0001), and decreased significantly in frequent tooth brushing and regular professional dental cleaning groups, with respective adjusted HRs and 95% CI of 0.853 (0.786–0.926; p = 0.0001) and 0.920 (0.855–0.990; p = 0.0255). In addition, regardless of age and comorbidities, oral health status and oral hygiene behaviors were associated with pneumonia. The results indicate that improved oral health may reduce the risk of pneumonia in the general population.
Age-different extent of resection for clinical IA non-small cell lung cancer: analysis of nodal metastasis
Authors: Deng Han-Yu , Zhou Jie , Wang Ru-Lan , Jiang Rui , Qiu Xiao-Ming , Zhu Da-Xing , Tang Xiao-Jun , Zhou Qinghua
Published: June 2020

Whether age has any impact on the risk of lymph node (LN) metastasis in patients with early-stage non-small cell lung cancer (NSCLC) remains controversial. Therefore, we aimed to objectively compare the risk of LN metastasis between elderly and young patients so as to justify for age-different extent of surgical resection for treating these patients. We retrospectively collected clinical data of patients undergoing lobectomy or segmentectomy with systematic hilar and mediastinal LN dissection for clinical stage IA peripheral NSCLC from January 2015 to December 2018. Both multivariate logistic regression analysis and propensity score-matched (PSM) analysis were applied to compare the risk of LN metastasis between elderly (>65 years old) and young (≤65 years old) patients. We finally included a total of 590 patients for analysis (142 elderly patients and 448 young patients). In the analysis of unmatched cohorts, young patients tended to have higher rates of hilar/intrapulmonary LN (13.4% VS 9.2%) and mediastinal LN metastasis (10.5% VS 6.3%) than elderly patients. In the multivariate analysis, age was found to be an independent predictor of both hilar/intrapulmonary (Odds ratio(OR) = 2.065, 95%confidence interval(CI): 1.049–4.064, P = 0.036) and mediastinal (OR = 2.400, 95%CI: 1.083–5.316, P = 0.031) LN metastasis. Moreover, in the analysis of well-matched cohorts generated by PSM analysis, young patients had significantly higher rates of hilar/intrapulmonary (18.8% VS 9.4%, P = 0.039) and mediastinal LN metastasis (17.1% VS 6.0%, P = 0.008) than elderly patients. Therefore, age remains to be an independent predictor of LN metastasis in early-stage NSCLC and age-different extent of surgical resection may be justified for these patients.