bluuebunny/crossref_metadata_2025 huggingface dataset:
Asymmetry in information acquisition—Exploring the principal–agent dyad of sport organizations and sport management higher education institutions
Authors: Wohlfart Olivia , Adam Sandy , Hovemann Gregor
Published: June 2021

This study is based on a metaphorical contract in sport management, whereby sport organizations (the principal) engage sport management higher education institutions (the agent) in qualifying graduates according to industry demands. There is asymmetry in the contract due to the lack of incentives for the principal to provide specific information and the agent’s ignorance about this information. A third party can acquire crucial information that sport management higher education institutions need to fulfil the contract. Based on a qualitative content analysis of 12 interviews with sport organization representatives, the study finds that sport management higher education institutions need to focus on either developing generic competencies or credibly signalling the value of sport management-specific competencies in their curriculum in order to efficiently fulfil the contract.
Sex/gender considerations in school-based interventions to promote children’s and adolescents’ physical activity
Authors: Schlund Annegret , Reimers Anne K. , Bucksch Jens , Linder Stephanie , Demetriou Yolanda
Published: June 2021

Physical inactivity is an increasing problem worldwide, but especially among girls. This difference by gender increases with age. Schools serve virtually all young people in most parts of the world and can thus play an important role in promoting physical activity. In this systematic review, we qualitatively and comprehensively assessed the treatment of sex/gender considerations (from study design to discussion of results) in 56 school-based intervention studies aiming to promote physical activity in children and adolescents. In all 56 studies, the factor of sex/gender was only rudimentarily considered, regardless of the effectiveness of the intervention. The meta-analysis revealed that the interventions had significant but relatively small effects with both girls and boys, along with high heterogeneity. To obtain better information about effective strategies that promote physical activity for both girls and boys equally, researchers conducting future intervention studies should pay attention to sex/gender differences and report on how they take this factor into account.
Studies on natural gas reserves multi-cycle growth law in Sichuan Basin based on multi-peak identification and peak parameter prediction
Authors: Li Haitao , Yu Guo , Fang Yizhu , Chen Yanru , Wang Chenyu , Zhang Dongming
Published: June 2021

Research on predicting the growth trend of natural gas reserves will help provide theoretical guidance for natural gas exploration in Sichuan Basin. The growth trend of natural gas reserves in Sichuan Basin is multi-cycle and complex. The multi-cyclic peak is screened by the original multi-cyclic peak judgment standard. Metabolically modified GM(1,3) gray prediction method is used to predict the multi-cycle model parameters. The multi-cycle Hubbert model and Gauss model are used to predict the growth trend of natural gas reserves. The research results show that: (1) The number of cycles of natural gas reserves curve during 1956–2018 is 13. Natural gas reserves will maintain the trend of rapid growth in the short term. (2) Metabolism modified GM(1,3) gray prediction model can improve the accuracy of model prediction. The prediction accuracy of Hubbert model is higher than that of Gauss model. By 2030, the cumulative proven level of natural gas will reach 52.34%. The Sichuan Basin will reach its peak of proven lifetime reserves in the next few years.
Insight on the inhibitive property of potassium ion on the stability of shale: a diffuse double-layer thickness (κ−1) perspective
Authors: AL-Bazali Talal
Published: June 2021

It is believed that potassium ions reduce the hydration energy and swelling of clays and thus promoting stability to shales. This belief was made based on volumetric and linear expansion data obtained from shale and KCl solutions interactions. However, swelling data alone is not adequate to mitigate wellbore instability in shale. Such data must be incorporated with mechanical and physicochemical data for complete and accurate wellbore instability analysis.

This paper presents clear experimental evidence showing that concentrated potassium chloride solutions tend to suppress shale swelling as higher concentration of potassium ions collapses the diffuse double layer of clay particles causing shale shrinkage which confirms the notion that the Debye length (κ−1) decreases as the ionic concentration increases.

Results show that there exists a KCl concentration threshold above which shale’s compressive strength deteriorates significantly. This concentration threshold was found to hover around 5% by weight. The amount of water and ions uptake into shale was quantified using gravimetric measurements. Significant potassium ions invasion into shale was experimentally measured as KCl solution concentration increased which proved the leaky nature of shale’s membrane. The reduction of shale’s compressive strength seems to be well correlated with the amount of ions uptake into shale. Moreover, data suggests that shale’s compressive strength was not significantly impacted by swelling. It was possible to gravimetrically separate osmotic water from associated water as shale interacted with KCl solutions. Results suggest that osmotic water is responsible for shale swelling since it is unattached to ions which makes it free to move around inside shale. On the other hand, data suggest that associated water does not contribute to shale swelling as it is bound to potassium ions which makes it unfree to move around. It is fair to state, based on our experimental data, that osmotic water is responsible for shale swelling while associated water contributes to shale’s compressive strength alteration.
Ultrasound and shear-wave elastography patterns of COVID-19 mRNA vaccine-related axillary, supra and subclavicular lymphadenopathy
Authors: D’Auria Divina , Fulgione Ludovica , Romeo Valeria , Stanzione Arnaldo , Maurea Simone , Brunetti Arturo
Published: June 2021

In this pictorial essay, we illustrate the ultrasound appearance of COVID-19 Pfizer-BioNTech vaccine-related lymph node abnormalities, which can occur at different stations ipsilateral to the site of vaccination, after either first or second vaccine dose and can represent a diagnostic dilemma when encountered in patients with underlying conditions. Typically, they appear as enlarged hypoechoic nodes with loss of fat hilum, increased hilar and cortical vascularization at color-Doppler, but low to intermediate cortical consistence at shear-wave elastography. Asymmetric or diffuse cortical thickening is also frequently encountered. They can be observed in patients without and with clinical symptoms, such as armpit pain, fever and fatigue.
Attack graph reachability: concept, analysis, challenges and issues
Authors: Al-Araji Zaid J , Ahmed Sharifah Sakinah Syad , Abdullah Raihana Syahirah , Mutlag Ammar Awad , Raheem Hayder Adil Abdul , Basri Siti Rohanah Hasan
Published: June 2021

An attack graph (AG) is an abstraction that represents the paths by which an attacker could break a security policy, leveraging interdependencies among discovered vulnerabilities. However, current AG implementations are inefficient on large-scale networks. The increase of the number of hosts in networks causes an increase in the time it takes to generate the AG, especially the calculation time and the complexity of determining reachability.

An attack graph (AG) is an abstraction that represents the paths by which an attacker could break a security policy, leveraging interdependencies among discovered vulnerabilities.

However, current AG implementations are inefficient on large-scale networks. The increase of the number of hosts in networks causes an increase in the time it takes to generate the AG, especially the calculation time and the complexity of determining reachability. In this article, the authors examine techniques that calculate the reachability using a matrix or a hyper-graph.
The Statues of Constantinople
Authors: Berger Albrecht
Published: June 2021

This Element discusses the ancient statues once set up in Byzantine Constantinople, with a special focus on their popular reception. From its foundation by Constantine the Great in 324, Constantinople housed a great number of statues which stood in the city on streets and public places, or were kept in several collections and in the Hippodrome. Almost all of them, except a number of newly made statues of reigning emperors, were ancient objects which had been brought to the city from other places. Many of these statues were later identified with persons other than those they actually represented, or received an allegorical (sometimes even an apocalyptical) interpretation. When the Crusaders of the Fourth Crusade conquered the city in 1204, almost all of the statues of Constantinople were destroyed or looted.
Board Dynamics
Authors: Stiles Philip
Published: June 2021

Boards of directors are at the apex of organisational decision-making and so are central in ensuring effective corporate governance. But boards are under increasing scrutiny due to the continuing prevalence of scandals and failures. Boards have been viewed as set up to fail because the demands placed upon them cannot effectively be delivered. In this Element, I examine this tension and look at the board as a working group, one which has an input, a process and an output. Through looking at the board as a group, the dynamics of how boards, and the potential for effective and ineffective operation, are highlighted. I conclude with outlining how the future of board dynamics may evolve.
The Knights Templar
Authors: Nicholson Helen J.
Published: June 2021

Over seven hundred years after the pope dissolved their Order, the Templars remain as controversial as ever. How could warriors also be monks? What did they really believe in? Why did they fail to protect the Holy Land? What impact did they have on society? Why were they dissolved-were they really heretics? Based on the medieval evidence and the latest research by modern scholars, this book surveys some key areas of the Templars' history. It argues that despite their wide landholdings and apparent power the Templars‘ influence depended on the patronage of popes and kings, and that they were destroyed when their most powerful patron had more to gain than lose from their dissolution.
Polynesia, 900–1600
Authors: Williams Madi
Published: June 2021

This book provides a concise overview of the history of Polynesia, focusing on New Zealand and its outlying islands, during the period 900–1600. It provides a thematic examination of Polynesia to avoid placing the region’s history into an inaccurate, linear Western chronology. The themes of movement and migration, adaptation and change, and development and expansion offer the optimal means of understanding Polynesia during this time. Through this innovative and unique perspective on Polynesian history, which has not been previously undertaken, the reader is encouraged to think about regions outside Europe in relation to the premodern period.
Infection Prevention Considerations for a Multi-Mission Convention Center Field Hospital in Baltimore, Maryland, During the COVID-19 Pandemic
Authors: Jones Jennifer A. , Siddiqui Zishan K. , Callahan Charles , Leekha Surbhi , Smyth Sharon , Preas Michael Anne , Ficke James R. , Cabunoc Marie Kristine F. , Kantsiper Melinda E. ,   the CONQUER COVID Consortium
Published: June 2021

The state of Maryland identified its first case of coronavirus disease 2019 (COVID-19) on March 5, 2020. The Baltimore Convention Center (BCCFH) quickly became a selected location to set up a 250-bed inpatient field hospital and alternate care site. In contrast to other field hospitals throughout the United States, the BCCFH remained open throughout the pandemic and took on additional COVID-19 missions, including community severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) diagnostic testing, monoclonal antibody infusions for COVID-19 outpatients, and community COVID-19 vaccinations.

To prevent the spread of pathogens during operations, infection prevention and control guidelines were essential to ensure the safety of staff and patients. Through multi-agency collaboration, use of infection prevention best practices, and answering what we describe as PPE-ESP, an operational framework was established to reduce infection risks for those providing or receiving care at the BCCFH during the COVID-19 pandemic.
Queer Rumors: Protestant Ministers, Unnatural Deeds, and Church Censure in the Twentieth-Century United States
Authors: Krivulskaya Suzanna
Published: June 2021

Over the course of the twentieth century, dozens of conservative Protestant ministers were accused of sexual deviance—including instances of same-sex acts and attractions. Protestant churches, in turn, experimented with employing various tactics to undermine and challenge such accusations. From silencing and secrecy to public censure and disassociation, denominational bodies labored to undermine evidence of queerness among their ministers. This essay surveys a one-hundred-year history of religious groups’ and institutions’ attempts at dealing with the uncomfortable but persistent allegations of not-quite-straightness among their leaders. This story accounts for how conservative Protestantism has been able to maintain its claims to a particular kind of sexual morality even as religious leaders themselves have repeatedly jeopardized this project.
TIME-INTEGRATED COLLECTION OF CO2FOR14C ANALYSIS FROM SOILS
Authors: Pedron Shawn , Xu X , Walker J C , Ferguson J C , Jespersen R G , Welker J M , Klein E S , Czimczik C I
Published: June 2021

We developed a passive sampler for time-integrated collection and radiocarbon (14C) analysis of soil respiration, a major flux in the global C cycle. It consists of a permanent access well that controls the CO2uptake rate and an exchangeable molecular sieve CO2trap. We tested how access well dimensions and environmental conditions affect collected CO2, and optimized cleaning procedures to minimize14CO2memory. We also deployed two generations of the sampler in Arctic tundra for up to two years, collecting CO2over periods of 3 days–2 months, while monitoring soil temperature, volumetric water content, and CO2concentration. The sampler collects CO2at a rate proportional to the length of a silicone tubing inlet (7–26 µg CO2-C day-1·m Si-1). With constant sampler dimensions in the field, CO2recovery is best explained by soil temperature. We retrieved 0.1–5.3 mg C from the 1st and 0.6–13 mg C from the 2nd generation samplers, equivalent to uptake rates of 2–215 (n=17) and 10–247 µg CO2-C day-1(n=20), respectively. The method blank is 8 ± 6 µg C (mean ± sd,n=8), with a radiocarbon content (fraction modern) ranging from 0.5875–0.6013 (n=2). The sampler enables more continuous investigations of soil C emission sources and is suitable for Arctic environments.
Effect of aminoethoxyvinylglycine (AVG) on quality, berry set and coloration of ‘Alphonse Lavallée’ table grapes
Authors: Babalık Zehra
Published: June 2021

The effect of different concentrations of aminoethoxyvinylglycine (AVG; 0 (control), 250, 500, 750 and 1000 mg/l), an ethylene biosynthesis inhibitor, on grape berry set and fruit quality was evaluated under vineyard conditions. Treatments were performed on ‘Alphonse Lavallée’ grape cultivar at full bloom stage for two years. Cluster and berry growth (length, width and weight), firmness, soluble solids content, yield, berry set, anthocyanin content and colour parameters were determined on treated and untreated (control) fruits. As a result of the study, the effects of AVG concentrations on firmness were not significant. When AVG applications were compared with control, it is determined that some quality properties were statistically affected, the others were not. Fruit set was increased by lower concentrations of AVG (250 mg/l) and anthocyanin content was increased by higher concentrations of AVG (750 mg/l).
On convex holes in d-dimensional point sets
Authors: Bukh Boris , Chao Ting-Wei , Holzman Ron
Published: June 2021

Given a finite set $A \subseteq \mathbb{R}^d$, points $a_1,a_2,\dotsc,a_{\ell} \in A$ form an $\ell$-hole in A if they are the vertices of a convex polytope, which contains no points of A in its interior. We construct arbitrarily large point sets in general position in $\mathbb{R}^d$ having no holes of size $O(4^dd\log d)$ or more. This improves the previously known upper bound of order $d^{d+o(d)}$ due to Valtr. The basic version of our construction uses a certain type of equidistributed point sets, originating from numerical analysis, known as (t,m,s)-nets or (t,s)-sequences, yielding a bound of $2^{7d}$. The better bound is obtained using a variant of (t,m,s)-nets, obeying a relaxed equidistribution condition.
TOROIDAL q-OPERS
Authors: Koroteev Peter , Zeitlin Anton M.
Published: June 2021

We define and study the space of q-opers associated with Bethe equations for integrable models of XXZ type with quantum toroidal algebra symmetry. Our construction is suggested by the study of the enumerative geometry of cyclic quiver varieties, in particular the ADHM moduli spaces. We define

$\left (\overline {GL}(\infty ),q\right )$
-opers with regular singularities and then, by imposing various analytic conditions on singularities, arrive at the desired Bethe equations for toroidal q-opers.
The “Lost” Personality Disorders and Their Relationships to the Alternative Model of Personality Disorders Among Older Adults
Authors: Stone Lisa E. , Segal Daniel L. , Coolidge Frederick L.
Published: June 2021

Abstract. Four personality disorders (PD) have become “lost” throughout the various editions of the DSM: Depressive, Passive-Aggressive, Sadistic, and Self-Defeating. The Alternative Model of Personality Disorders (AMPD) is a novel approach to PD classification, containing two diagnostic criteria: personality functioning and pathological personality traits. This study identifies the personality functioning and pathological personality trait features of the Lost PDs among older adults ( N = 202; Mage = 67.47 years). Results indicate that the Lost PDs related more strongly with the self-functioning domains (versus the interpersonal domains). Some pathological traits emerged in expected directions, whereas others did not, which is consistent with research on the traditional PDs. The AMPD appears to have mixed validity in capturing the Lost PDs in older adults, though overall it performed comparably well and warrants further examination.
Juno Detects Jupiter’s Highest-Energy Ions
Authors: Rehnberg Morgan
Published: June 2021

Trapped ions discovered at midlatitudes can have energies exceeding 100 megaelectron volts per nucleon. Their detection adds to our understanding of the powerful radiation environment around Jupiter.
Impact of Sea‐Ice Dynamics on the Spatial Distribution of Diatom Resting Stages in Sediments of the Pacific Arctic Region
Authors: Fukai Yuri , Matsuno Kohei , Fujiwara Amane , Suzuki Koji , Richlen Mindy L. , Fachon Evangeline , Anderson Donald M.
Published: June 2021

The Pacific Arctic region is characterized by seasonal sea‐ice, the spatial extent and duration of which varies considerably. In this region, diatoms are the dominant phytoplankton group during spring and summer. To facilitate survival during periods that are less favorable for growth, many diatom species produce resting stages that settle to the seafloor and can serve as a potential inoculum for subsequent blooms. Since diatom assemblage composition is closely related to sea‐ice dynamics, detailed studies of biophysical interactions are fundamental to understanding the lower trophic levels of ecosystems in the Pacific Arctic. One way to explore this relationship is by comparing the distribution and abundance of diatom resting stages with patterns of sea‐ice coverage. In this study, we quantified viable diatom resting stages in sediments collected during summer and autumn 2018 and explored their relationship to sea‐ice extent during the previous winter and spring. Diatom assemblages were clearly dependent on the variable timing of the sea‐ice retreat and accompanying light conditions. In areas where sea‐ice retreated earlier, open‐water species such as Chaetoceros spp. and Thalassiosira spp. were abundant. In contrast, proportional abundances of Attheya spp. and pennate diatom species that are commonly observed in sea‐ice were higher in areas where diatoms experienced higher light levels and longer day length in/under the sea‐ice. This study demonstrates that sea‐ice dynamics are an important determinant of diatom species composition and distribution in the Pacific Arctic region.
High spectro-temporal compression on a nonlinear CMOS-chip
Authors: Choi Ju Won , Sahin Ezgi , Sohn Byoung-Uk , Chen George F. R. , Ng Doris K. T. , Agarwal Anuradha M. , Kimerling Lionel C. , Tan Dawn T. H.
Published: June 2021

Optical pulses are fundamentally defined by their temporal and spectral properties. The ability to control pulse properties allows practitioners to efficiently leverage them for advanced metrology, high speed optical communications and attosecond science. Here, we report 11× temporal compression of 5.8 ps pulses to 0.55 ps using a low power of 13.3 W. The result is accompanied by a significant increase in the pulse peak power by 9.4×. These results represent the strongest temporal compression demonstrated to date on a complementary metal–oxide–semiconductor (CMOS) chip. In addition, we report the first demonstration of on-chip spectral compression, 3.0× spectral compression of 480 fs pulses, importantly while preserving the pulse energy. The strong compression achieved at low powers harnesses advanced on-chip device design, and the strong nonlinear properties of backend-CMOS compatible ultra-silicon-rich nitride, which possesses absence of two-photon absorption and 500× larger nonlinear parameter than in stoichiometric silicon nitride waveguides. The demonstrated work introduces an important new paradigm for spectro-temporal compression of optical pulses toward turn-key, on-chip integrated systems for all-optical pulse control.
KarMMa-RW: comparison of idecabtagene vicleucel with real-world outcomes in relapsed and refractory multiple myeloma
Authors: Jagannath Sundar , Lin Yi , Goldschmidt Hartmut , Reece Donna , Nooka Ajay , Senin Alicia , Rodriguez-Otero Paula , Powles Ray , Matsue Kosei , Shah Nina , Anderson Larry D. , Streetly Matthew , Wilson Kimberly , Le Hoa Van , Swern Arlene S. , Agarwal Amit , Siegel David S.
Published: June 2021

Patients with relapsed and refractory multiple myeloma (RRMM) who are triple-class exposed (to an immunomodulatory agent, proteasome inhibitor, and anti-CD38 antibody) have limited treatment options and there is no standard of care. Idecabtagene vicleucel (ide-cel, bb2121), a BCMA-directed CAR T-cell therapy, demonstrated efficacy in triple-class exposed RRMM patients in the KarMMa trial (NCT03361748). In this retrospective study (KarMMa-RW), patient-level data from triple-class exposed RRMM patients were merged into a single data model and compared with KarMMa using trimmed stabilized inverse probability of treatment weighting. Endpoints included overall response rate (ORR; primary), rate of very good partial response or better (≥VGPR), progression-free survival (PFS), and overall survival (OS). Of 1949 real-world triple-class exposed RRMM patients, 190 received subsequent (index) line of therapy and met KarMMa eligibility criteria (Eligible RRMM cohort). With a median follow-up of 13.3 months in KarMMa and 10.2 months in Eligible RRMM, ORR, and ≥VGPR were significantly improved in KarMMa versus Eligible RRMM (ORR, 76.4% vs 32.2%; ≥VGPR, 57.9% vs 13.7%; both P < 0.0001) as were PFS (11.6 vs 3.5 months; P = 0.0004) and OS (20.2 vs 14.7 months; P = 0.0006). This study demonstrated that ide-cel significantly improved responses and survival compared with currently available therapies in triple-class exposed RRMM.
Comprehensive understanding of anchorage-independent survival and its implication in cancer metastasis
Authors: Deng Zhong , Wang Huixue , Liu Jinlong , Deng Yuan , Zhang Nu
Published: June 2021

Detachment is the initial and critical step for cancer metastasis. Only the cells that survive from detachment can develop metastases. Following the disruption of cell–extracellular matrix (ECM) interactions, cells are exposed to a totally different chemical and mechanical environment. During which, cells inevitably suffer from multiple stresses, including loss of growth stimuli from ECM, altered mechanical force, cytoskeletal reorganization, reduced nutrient uptake, and increased reactive oxygen species generation. Here we review the impact of these stresses on the anchorage-independent survival and the underlying molecular signaling pathways. Furthermore, its implications in cancer metastasis and treatment are also discussed.
Long noncoding RNA AFAP1-AS1 promotes tumor progression and invasion by regulating the miR-2110/Sp1 axis in triple-negative breast cancer
Authors: Zhang Xiaohui , Li Fangyuan , Zhou Yidong , Mao Feng , Lin Yan , Shen Songjie , Li Yuntao , Zhang Sheng , Sun Qiang
Published: June 2021

Long noncoding ribonucleic acids (LncRNAs) have been found to be involved in the proliferation, apoptosis, invasion, migration, and other pathological processes of triple-negative breast cancer (TNBC). Expression of the lncRNA actin filament-associated protein 1 antisense RNA1 (AFAP1-AS1) has been found to be significantly higher in TNBC than in other subtypes or in normal tissue samples, but the specific mechanism by which AFAP1-AS1 affects the occurrence and development of TNBC is yet to be revealed. In this study, we used Cell Counting Kit-8 (CCK-8), colony formation, wound healing migration, Transwell invasion, and nude mouse xenograft assays to confirm the role of AFAP1-AS1 in the proliferation, migration of TNBC cells in vitro and in vivo. In addition, we performed bioinformatics analyses, reverse transcriptase quantitative polymerase chain reaction (RT-qPCR), western blot (WB), and dual-luciferase reporter assays (dual-LRA) to confirm interaction among AFAP1-AS1, micro-RNA 2110 (miR-2110), and Sp1 transcription factor (Sp1). We found that silencing AFAP1-AS1 and Sp1 or upregulating miR-2110 suppressed the proliferation, migration, and invasion of MDA–MB-231 and MDA–MB-468 cells in vitro as well as tumor growth in vivo. Mechanistically, the dual-LRA highlighted that miR-2110 was an inhibitory target of AFAP1-AS1, and that AFAP1-AS1 functioned as a miR-2110 sponge to increase Sp1 expression. AFAP1-AS1 silencing led to a reduction in Sp1 mRNA and protein levels, which could be reversed by joint transfection with miR-2110 inhibitor. Our findings demonstrated that AFAP1-AS1 could modulate the progression of breast cancer cells and affect tumorigenesis in mice by acting as a miR-2110 sponge, resulting in regulation of Sp1 expression. Therefore, AFAP1-AS1 could play a pivotal role in the treatment of TNBC.
Systematic analysis of exonic germline and postzygotic de novo mutations in bipolar disorder
Authors: Nishioka Masaki , Kazuno An-a , Nakamura Takumi , Sakai Naomi , Hayama Takashi , Fujii Kumiko , Matsuo Koji , Komori Atsuko , Ishiwata Mizuho , Watanabe Yoshinori , Oka Takashi , Matoba Nana , Kataoka Muneko , Alkanaq Ahmed N. , Hamanaka Kohei , Tsuboi Takashi , Sengoku Toru , Ogata Kazuhiro , Iwata Nakao , Ikeda Masashi , Matsumoto Naomichi , Kato Tadafumi , Takata Atsushi
Published: June 2021

Bipolar disorder is a severe mental illness characterized by recurrent manic and depressive episodes. To better understand its genetic architecture, we analyze ultra-rare de novo mutations in 354 trios with bipolar disorder. For germline de novo mutations, we find significant enrichment of loss-of-function mutations in constrained genes (corrected-P = 0.0410) and deleterious mutations in presynaptic active zone genes (FDR = 0.0415). An analysis integrating single-cell RNA-sequencing data identifies a subset of excitatory neurons preferentially expressing the genes hit by deleterious mutations, which are also characterized by high expression of developmental disorder genes. In the analysis of postzygotic mutations, we observe significant enrichment of deleterious ones in developmental disorder genes (P = 0.00135), including the SRCAP gene mutated in two unrelated probands. These data collectively indicate the contributions of both germline and postzygotic mutations to the risk of bipolar disorder, supporting the hypothesis that postzygotic mutations of developmental disorder genes may contribute to bipolar disorder.
Olfactory expression of trace amine-associated receptors requires cooperative cis-acting enhancers
Authors: Shah Ami , Ratkowski Madison , Rosa Alessandro , Feinstein Paul , Bozza Thomas
Published: June 2021

Olfactory sensory neurons express a large family of odorant receptors (ORs) and a small family of trace amine-associated receptors (TAARs). While both families are subject to so-called singular expression (expression of one allele of one gene), the mechanisms underlying TAAR gene choice remain obscure. Here, we report the identification of two conserved sequence elements in the mouse TAAR cluster (T-elements) that are required for TAAR gene expression. We observed that cell-type-specific expression of a TAAR-derived transgene required either T-element. Moreover, deleting either element reduced or abolished expression of a subset of TAAR genes, while deleting both elements abolished olfactory expression of all TAARs in cis with the mutation. The T-elements exhibit several features of known OR enhancers but also contain highly conserved, unique sequence motifs. Our data demonstrate that TAAR gene expression requires two cooperative cis-acting enhancers and suggest that ORs and TAARs share similar mechanisms of singular expression.
Hakai is required for stabilization of core components of the m6A mRNA methylation machinery
Authors: Bawankar Praveen , Lence Tina , Paolantoni Chiara , Haussmann Irmgard U. , Kazlauskiene Migle , Jacob Dominik , Heidelberger Jan B. , Richter Florian M. , Nallasivan Mohanakarthik P. , Morin Violeta , Kreim Nastasja , Beli Petra , Helm Mark , Jinek Martin , Soller Matthias , Roignant Jean-Yves
Published: June 2021

N6-methyladenosine (m6A) is the most abundant internal modification on mRNA which influences most steps of mRNA metabolism and is involved in several biological functions. The E3 ubiquitin ligase Hakai was previously found in complex with components of the m6A methylation machinery in plants and mammalian cells but its precise function remained to be investigated. Here we show that Hakai is a conserved component of the methyltransferase complex in Drosophila and human cells. In Drosophila, its depletion results in reduced m6A levels and altered m6A-dependent functions including sex determination. We show that its ubiquitination domain is required for dimerization and interaction with other members of the m6A machinery, while its catalytic activity is dispensable. Finally, we demonstrate that the loss of Hakai destabilizes several subunits of the methyltransferase complex, resulting in impaired m6A deposition. Our work adds functional and molecular insights into the mechanism of the m6A mRNA writer complex.
Community factors and excess mortality in first wave of the COVID-19 pandemic in England
Authors: Davies Bethan , Parkes Brandon L. , Bennett James , Fecht Daniela , Blangiardo Marta , Ezzati Majid , Elliott Paul
Published: June 2021

Risk factors for increased risk of death from COVID-19 have been identified, but less is known on characteristics that make communities resilient or vulnerable to the mortality impacts of the pandemic. We applied a two-stage Bayesian spatial model to quantify inequalities in excess mortality in people aged 40 years and older at the community level during the first wave of the pandemic in England, March-May 2020 compared with 2015–2019. Here we show that communities with an increased risk of excess mortality had a high density of care homes, and/or high proportion of residents on income support, living in overcrowded homes and/or with a non-white ethnicity. We found no association between population density or air pollution and excess mortality. Effective and timely public health and healthcare measures that target the communities at greatest risk are urgently needed to avoid further widening of inequalities in mortality patterns as the pandemic progresses.
Engineering an anti-HER2 biparatopic antibody with a multimodal mechanism of action
Authors: Kast Florian , Schwill Martin , Stüber Jakob C. , Pfundstein Svende , Nagy-Davidescu Gabriela , Rodríguez Josep M. Monné , Seehusen Frauke , Richter Christian P. , Honegger Annemarie , Hartmann Karen Patricia , Weber Thomas G. , Kroener Felix , Ernst Patrick , Piehler Jacob , Plückthun Andreas
Published: June 2021

The receptor tyrosine kinase HER2 acts as oncogenic driver in numerous cancers. Usually, the gene is amplified, resulting in receptor overexpression, massively increased signaling and unchecked proliferation. However, tumors become frequently addicted to oncogenes and hence are druggable by targeted interventions. Here, we design an anti-HER2 biparatopic and tetravalent IgG fusion with a multimodal mechanism of action. The molecule first induces HER2 clustering into inactive complexes, evidenced by reduced mobility of surface HER2. However, in contrast to our earlier binders based on DARPins, clusters of HER2 are thereafter robustly internalized and quantitatively degraded. This multimodal mechanism of action is found only in few of the tetravalent constructs investigated, which must target specific epitopes on HER2 in a defined geometric arrangement. The inhibitory effect of our antibody as single agent surpasses the combination of trastuzumab and pertuzumab as well as its parental mAbs in vitro and it is effective in a xenograft model.
High-throughput screening and rational design of biofunctionalized surfaces with optimized biocompatibility and antimicrobial activity
Authors: Fang Zhou , Chen Junjian , Zhu Ye , Hu Guansong , Xin Haoqian , Guo Kunzhong , Li Qingtao , Xie Liangxu , Wang Lin , Shi Xuetao , Wang Yingjun , Mao Chuanbin
Published: June 2021

Peptides are widely used for surface modification to develop improved implants, such as cell adhesion RGD peptide and antimicrobial peptide (AMP). However, it is a daunting challenge to identify an optimized condition with the two peptides showing their intended activities and the parameters for reaching such a condition. Herein, we develop a high-throughput strategy, preparing titanium (Ti) surfaces with a gradient in peptide density by click reaction as a platform, to screen the positions with desired functions. Such positions are corresponding to optimized molecular parameters (peptide densities/ratios) and associated preparation parameters (reaction times/reactant concentrations). These parameters are then extracted to prepare nongradient mono- and dual-peptide functionalized Ti surfaces with desired biocompatibility or/and antimicrobial activity in vitro and in vivo. We also demonstrate this strategy could be extended to other materials. Here, we show that the high-throughput versatile strategy holds great promise for rational design and preparation of functional biomaterial surfaces.
Highly metastatic claudin-low mammary cancers can originate from luminal epithelial cells
Authors: Rädler Patrick D. , Wehde Barbara L. , Triplett Aleata A. , Shrestha Hridaya , Shepherd Jonathan H. , Pfefferle Adam D. , Rui Hallgeir , Cardiff Robert D. , Perou Charles M. , Wagner Kay-Uwe
Published: June 2021

Claudin-low breast cancer represents an aggressive molecular subtype that is comprised of mostly triple-negative mammary tumor cells that possess stem cell-like and mesenchymal features. Little is known about the cellular origin and oncogenic drivers that promote claudin-low breast cancer. In this study, we show that persistent oncogenic RAS signaling causes highly metastatic triple-negative mammary tumors in mice. More importantly, the activation of endogenous mutant KRAS and expression of exogenous KRAS specifically in luminal epithelial cells in a continuous and differentiation stage-independent manner induces preneoplastic lesions that evolve into basal-like and claudin-low mammary cancers. Further investigations demonstrate that the continuous signaling of oncogenic RAS, as well as regulators of EMT, play a crucial role in the cellular plasticity and maintenance of the mesenchymal and stem cell characteristics of claudin-low mammary cancer cells.
Measurement of lipogenic flux by deuterium resolved mass spectrometry
Authors: Fu Xiaorong , Deja Stanisław , Fletcher Justin A. , Anderson Norma N. , Mizerska Monika , Vale Gonçalo , Browning Jeffrey D. , Horton Jay D. , McDonald Jeffrey G. , Mitsche Matthew A. , Burgess Shawn C.
Published: June 2021

De novo lipogenesis (DNL) is disrupted in a wide range of human disease. Thus, quantification of DNL may provide insight into mechanisms and guide interventions if it can be performed rapidly and noninvasively. DNL flux is commonly measured by 2H incorporation into fatty acids following deuterated water (2H2O) administration. However, the sensitivity of this approach is limited by the natural abundance of 13C, which masks detection of 2H by mass spectrometry. Here we report that high-resolution Orbitrap gas-chromatography mass-spectrometry resolves 2H and 13C fatty acid mass isotopomers, allowing DNL to be quantified using lower 2H2O doses and shorter experimental periods than previously possible. Serial measurements over 24-hrs in mice detects the nocturnal activation of DNL and matches a 3H-water method in mice with genetic activation of DNL. Most importantly, DNL is detected in overnight-fasted humans in less than an hour and is responsive to feeding during a 4-h study. Thus, 2H specific MS provides the ability to study DNL in settings that are currently impractical.
Design of COVID-19 staged alert systems to ensure healthcare capacity with minimal closures
Authors: Yang Haoxiang , Sürer Özge , Duque Daniel , Morton David P. , Singh Bismark , Fox Spencer J. , Pasco Remy , Pierce Kelly , Rathouz Paul , Valencia Victoria , Du Zhanwei , Pignone Michael , Escott Mark E. , Adler Stephen I. , Johnston S. Claiborne , Meyers Lauren Ancel
Published: June 2021

Community mitigation strategies to combat COVID-19, ranging from healthy hygiene to shelter-in-place orders, exact substantial socioeconomic costs. Judicious implementation and relaxation of restrictions amplify their public health benefits while reducing costs. We derive optimal strategies for toggling between mitigation stages using daily COVID-19 hospital admissions. With public compliance, the policy triggers ensure adequate intensive care unit capacity with high probability while minimizing the duration of strict mitigation measures. In comparison, we show that other sensible COVID-19 staging policies, including France’s ICU-based thresholds and a widely adopted indicator for reopening schools and businesses, require overly restrictive measures or trigger strict stages too late to avert catastrophic surges. As proof-of-concept, we describe the optimization and maintenance of the staged alert system that has guided COVID-19 policy in a large US city (Austin, Texas) since May 2020. As cities worldwide face future pandemic waves, our findings provide a robust strategy for tracking COVID-19 hospital admissions as an early indicator of hospital surges and enacting staged measures to ensure integrity of the health system, safety of the health workforce, and public confidence.
Brain structure is linked to the association between family environment and behavioral problems in children in the ABCD study
Authors: Gong Weikang , Rolls Edmund T. , Du Jingnan , Feng Jianfeng , Cheng Wei
Published: June 2021

Children’s behavioral problems have been associated with their family environments. Here, we investigate whether specific features of brain structures could relate to this link. Using structural magnetic resonance imaging of 8756 children aged 9-11 from the Adolescent Brain Cognitive Developmental study, we show that high family conflict and low parental monitoring scores are associated with children’s behavioral problems, as well as with smaller cortical areas of the orbitofrontal cortex, anterior cingulate cortex, and middle temporal gyrus. A longitudinal analysis indicates that psychiatric problems scores are associated with increased family conflict and decreased parental monitoring 1 year later, and mediate associations between the reduced cortical areas and family conflict, and parental monitoring scores. These results emphasize the relationships between the brain structure of children, their family environments, and their behavioral problems.
Enantioselective synthesis of tertiary boronic esters through catalytic asymmetric reversed hydroboration
Authors: Gao Tao-Tao , Lu Hou-Xiang , Gao Peng-Chao , Li Bi-Jie
Published: June 2021

Chiral tertiary boronic esters are important precursors to bioactive compounds and versatile synthetic intermediates to molecules containing quaternary stereocenters. The development of conjugate boryl addition to α,β-unsaturated amide has been hampered by the intrinsic low electrophilicity of the amide group. Here we show the catalytic asymmetric synthesis of enantioenriched tertiary boronic esters through hydroboration of β,β-disubstituted α,β-unsaturated amides. The Rh-catalyzed hydroboration occurs with previously unattainable selectivity to provide tertiary boronic esters in high enantioselectivity. This strategy opens a door for the hydroboration of inert Michael acceptors with high stereocontrol and may provide future applications in the synthesis of biologically active molecules.
Position-controlled quantum emitters with reproducible emission wavelength in hexagonal boron nitride
Authors: Fournier Clarisse , Plaud Alexandre , Roux Sébastien , Pierret Aurélie , Rosticher Michael , Watanabe Kenji , Taniguchi Takashi , Buil Stéphanie , Quélin Xavier , Barjon Julien , Hermier Jean-Pierre , Delteil Aymeric
Published: June 2021

Single photon emitters (SPEs) in low-dimensional layered materials have recently gained a large interest owing to the auspicious perspectives of integration and extreme miniaturization offered by this class of materials. However, accurate control of both the spatial location and the emission wavelength of the quantum emitters is essentially lacking to date, thus hindering further technological steps towards scalable quantum photonic devices. Here, we evidence SPEs in high purity synthetic hexagonal boron nitride (hBN) that can be activated by an electron beam at chosen locations. SPE ensembles are generated with a spatial accuracy better than the cubed emission wavelength, thus opening the way to integration in optical microstructures. Stable and bright single photon emission is subsequently observed in the visible range up to room temperature upon non-resonant laser excitation. Moreover, the low-temperature emission wavelength is reproducible, with an ensemble distribution of width 3 meV, a statistical dispersion that is more than one order of magnitude lower than the narrowest wavelength spreads obtained in epitaxial hBN samples. Our findings constitute an essential step towards the realization of top-down integrated devices based on identical quantum emitters in 2D materials.
Serum amyloid P component is an essential element of resistance against Aspergillus fumigatus
Authors: Doni Andrea , Parente Raffaella , Laface Ilaria , Magrini Elena , Cunha Cristina , Colombo Federico Simone , Lacerda João F. , Campos António , Mapelli Sarah N. , Petroni Francesca , Porte Rémi , Schorn Tilo , Inforzato Antonio , Mercier Toine , Lagrou Katrien , Maertens Johan , Lambris John D. , Bottazzi Barbara , Garlanda Cecilia , Botto Marina , Carvalho Agostinho , Mantovani Alberto
Published: June 2021

Serum amyloid P component (SAP, also known as Pentraxin 2; APCS gene) is a component of the humoral arm of innate immunity involved in resistance to bacterial infection and regulation of tissue remodeling. Here we investigate the role of SAP in antifungal resistance. Apcs−/− mice show enhanced susceptibility to A. fumigatus infection. Murine and human SAP bound conidia, activate the complement cascade and enhance phagocytosis by neutrophils. Apcs−/− mice are defective in vivo in terms of recruitment of neutrophils and phagocytosis in the lungs. Opsonic activity of SAP is dependent on the classical pathway of complement activation. In immunosuppressed mice, SAP administration protects hosts against A. fumigatus infection and death. In the context of a study of hematopoietic stem-cell transplantation, genetic variation in the human APCS gene is associated with susceptibility to invasive pulmonary aspergillosis. Thus, SAP is a fluid phase pattern recognition molecule essential for resistance against A. fumigatus.
Catalyst-free carbosilylation of alkenes using silyl boronates and organic fluorides via selective C-F bond activation
Authors: Zhou Jun , Jiang Bingyao , Fujihira Yamato , Zhao Zhengyu , Imai Takanori , Shibata Norio
Published: June 2021

A regioselective carbosilylation of alkenes has emerged as a powerful strategy to access molecules with functionalized silylated alkanes, by incorporating silyl and carbon groups across an alkene double bond. However, to the best of our knowledge, organic fluorides have never been used in this protocol. Here we disclose the catalyst-free carbosilylation of alkenes using silyl boronates and organic fluorides mediated by tBuOK. The main feature of this transformation is the selective activation of the C-F bond of an organic fluoride by the silyl boronate without undergoing potential side-reactions involving C-O, C-Cl, heteroaryl-CH, and even CF3 groups. Various silylated alkanes with tertiary or quaternary carbon centers that have aromatic, hetero-aromatic, and/or aliphatic groups at the β-position are synthesized in a single step from substituted or non-substituted aryl alkenes. An intramolecular variant of this carbosilylation is also achieved via the reaction of a fluoroarene with a ω-alkenyl side chain and a silyl boronate.
Arginine methylation of METTL14 promotes RNA N6-methyladenosine modification and endoderm differentiation of mouse embryonic stem cells
Authors: Liu Xiaona , Wang Hailong , Zhao Xueya , Luo Qizhi , Wang Qingwen , Tan Kaifen , Wang Zihan , Jiang Jia , Cui Jinru , Du Enhui , Xia Linjian , Du Wenyi , Chen Dahua , Xia Laixin , Xiao Shan
Published: June 2021

RNA N6-methyladenosine (m6A), the most abundant internal modification of mRNAs, plays key roles in human development and health. Post-translational methylation of proteins is often critical for the dynamic regulation of enzymatic activity. However, the role of methylation of the core methyltransferase METTL3/METTL14 in m6A regulation remains elusive. We find by mass spectrometry that METTL14 arginine 255 (R255) is methylated (R255me). Global mRNA m6A levels are greatly decreased in METTL14 R255K mutant mouse embryonic stem cells (mESCs). We further find that R255me greatly enhances the interaction of METTL3/METTL14 with WTAP and promotes the binding of the complex to substrate RNA. We show that protein arginine N-methyltransferases 1 (PRMT1) interacts with and methylates METTL14 at R255, and consistent with this, loss of PRMT1 reduces mRNA m6A modification globally. Lastly, we find that loss of R255me preferentially affects endoderm differentiation in mESCs. Collectively, our findings show that arginine methylation of METTL14 stabilizes the binding of the m6A methyltransferase complex to its substrate RNA, thereby promoting global m6A modification and mESC endoderm differentiation. This work highlights the crosstalk between protein methylation and RNA methylation in gene expression.