bluuebunny/crossref_metadata_2025 huggingface dataset:
Melatonin MT1 and MT2 receptor ERK signaling is differentially dependent on Gi/o and Gq/11 proteins
Authors: Chen Min , Cecon Erika , Karamitri Angeliki , Gao Wenwen , Gerbier Romain , Ahmad Raise , Jockers Ralf
Published: February 2020

G protein‐coupled receptors (GPCRs) transmit extracellular signals into cells by activating G protein‐ and β‐arrestin‐dependent pathways. Extracellular signal‐regulated kinases (ERKs) play a central role in integrating these different linear inputs coming from a variety of GPCRs to regulate cellular functions. Here, we investigated human melatonin MT1 and MT2 receptors signaling through the ERK1/2 cascade by employing different biochemical techniques together with pharmacological inhibitors and siRNA molecules. We show that ERK1/2 activation by both receptors is exclusively G protein‐dependent, without any participation of β‐arrestin1/2 in HEK293 cells. ERK1/2 activation by MT1 is only mediated though Gi/o proteins, while MT2 is dependent on the cooperative activation of Gi/o and Gq/11 proteins. In the absence of Gq/11 proteins, however, MT2‐induced ERK1/2 activation switches to a β‐arrestin1/2‐dependent mode. The signaling cascade downstream of G proteins is the same for both receptors and involves activation of the PI3K/PKCζ/c‐Raf/MEK/ERK cascade. The differential G protein dependency of MT1‐ and MT2‐mediated ERK activation was confirmed at the level of EGR1 and FOS gene expression, two ERK1/2 target genes. Gi/o/Gq/11 cooperativity was also observed in Neuroscreen‐1 cells expressing endogenous MT2, whereas in the mouse retina, where MT2 is engaged into MT1/MT2 heterodimers, ERK1/2 signaling is exclusively Gi/o‐dependent. Collectively, our data reveal differential signaling modes of MT1 and MT2 in terms of ERK1/2 activation, with an unexpected Gi/o/Gq/11 cooperativity exclusively for MT2. The plasticity of ERK activation by MT2 is highlighted by the switch to a β‐arrestin1/2‐dependent mode in the absence of Gq/11 proteins and by the switch to a Gi/o mode when engaged into MT1/MT2 heterodimers, revealing a new mechanism underlying tissue‐specific responses to melatonin.
Rediscovery of the lost little dogwood Cornus wardiana (Cornaceae)—Its phylogenetic and morphological distinction and implication in the origin of the Arctic‐Sino‐Himalayan disjunction
Authors: Wahlsteen Eric , Zhou Wenbin , Xiang Qiuyun (Jenny) , Rushforth Keith
Published: February 2020

The dwarf dogwoods (subgenus Arctocrania) have been widely known to consist of three circumboreal species Cornus suecica, Cornus canadensis, and Cornus unalaschkensis. A fourth putative species was discovered from the northern Myanmar in 1937, but it had never been formally reported on. Here, we formally report the species on the basis of phylogenetic and morphological evidence and name it Cornus wardiana Rushforth & Wahlsteen (sp. nov.). We conducted phylogenetic and morphometric analyses to determine its evolutionary relationship and differentiation from the existing relatives. We dated the phylogeny using molecular data and conducted a biogeographic analysis to gain insights into the evolution and biogeography of the Arctic‐Sino‐Himalayan disjunction. The phylogenetic analysis used sequences of the nrITS and plastid matK and rbcL genes and included all four dwarf dogwoods and 20 other species representing the three other major lineages of Cornus and the outgroup. The morphometric analyses included 60 populations and 102 specimens of dwarf dogwood, representing the entire range of the subgenus. The results showed that C. wardiana diverged first within subgenus Arctocrania in the Miocene, from a wide‐spread ancestor. Results from principal component analysis and discriminant analysis also showed that the Myanmar samples are well separated from the others. Taken together, these results suggest that the dwarf dogwood lineage split from the big‐bracted dogwoods in Asia or Asia‐western North America during the late Paleocene and spread widely to form a Eurasia‐North America distribution; the Arctic‐Sino‐Himalayan disjunction was the result of southward migration in the Miocene followed by extinction in the intervening highland areas.
Convergent recruitment of 5′‐hydroxylase activities by CYP75B flavonoid B‐ring hydroxylases for tricin biosynthesis in Medicago legumes
Authors: Lui Andy C. W. , Lam Pui Ying , Chan Kwun Ho , Wang Lanxiang , Tobimatsu Yuki , Lo Clive
Published: February 2020

Tricin (3′,5′‐dimethoxylated flavone) is a predominant flavonoid amongst monocots but occurs only in isolated and unrelated dicot lineages. Although tricin biosynthesis has been intensively studied in monocots, it has remained largely elusive in tricin‐accumulating dicots.

We investigated a subgroup of cytochrome P450 (CYP) 75B subfamily flavonoid B‐ring hydroxylases (FBHs) from two tricin‐accumulating legumes, Medicago truncatula and alfalfa (Medicago sativa), by phylogenetic, molecular, biochemical and mutant analyses.

Five Medicago cytochrome P450 CYP75B FBHs are phylogenetically distant from other legume CYP75B members. Among them, MtFBH‐4, MsFBH‐4 and MsFBH‐10 were expressed in tricin‐accumulating vegetative tissues. In vitro and in planta analyses demonstrated that these proteins catalyze 3′‐ and 5′‐hydroxylations critical to tricin biosynthesis. A key amino acid polymorphism, T492G, at their substrate recognition site 6 domain is required for the novel 5′‐hydroxylation activities. Medicago truncatula mtfbh‐4 mutants were tricin‐deficient, indicating that MtFBH‐4 is indispensable for tricin biosynthesis.

Our results revealed that these Medicago legumes had acquired the tricin pathway through molecular evolution of CYP75B FBHs subsequent to speciation from other nontricin‐accumulating legumes. Moreover, their evolution is independent of that of grass‐specific CYP75B apigenin 3′‐hydroxylases/chrysoeriol 5′‐hydroxylases dedicated to tricin production and Asteraceae CYP75B flavonoid 3′,5′‐hydroxylases catalyzing the production of delphinidin‐based pigments.
Dynamic exploits: calculative asymmetries in the on‐demand economy
Authors: Shapiro Aaron
Published: February 2020

On‐demand service firms secure market power by cultivating and operationalising calculative asymmetries between the platform and labour. In this article, I analyse dynamic (or ‘surge’) pricing as an exemplary calculative technique. I show how the asymmetrical application of price‐setting allows firms to leverage control at the aggregate level while maintaining the façade of autonomy at the individual level, thereby legitimising workers’ classification as independent contractors but solving the coordination problems that the classification introduces. The article complements and extends previous critical research into the platform or ‘on‐demand’ service economy by analysing how management scientists model and simulate on‐demand marketplaces. I consider management science to be a calculative technique for optimising operational efficiency. A critical review of management science provides novel insights into platforms’ efforts to monopolise calculative agency at the expense of other market participants. The article concludes by considering implications for broader critiques of platform labour management.
The role of stress mindset in support provision
Authors: Nguyen Thao T. T. , Neff Lisa A. , Williamson Hannah C.
Published: February 2020

To better understand the antecedents of support provision within relationships, this study examined the potential role of a novel individual difference; spouses' stress mindset (i.e., beliefs about whether stress‐is‐enhancing or stress‐is‐debilitating). As individuals with a stress‐is‐enhancing mindset often underestimate other's stress, we hypothesized that those with a stress‐is‐enhancing mindset will generally provide less and worse support compared to individuals with a stress‐is‐debilitating mindset. The results revealed few significant associations and the associations that were significant were contrary to predictions. For example, wives with a stress‐is‐enhancing mindset provided more support, and husbands who perceived their partner as having a more stress‐is‐enhancing mindset provided better support. Further research is needed to replicate these results and determine whether stress mindset has interpersonal consequences.
Child Electronic Growth Monitoring System: An innovative and sustainable approach for establishing the Kaduna Infant Development (KID) Study in Nigeria
Authors: Kana Musa A. , Ahmed Jenifer , Ashiru Abdullahi Y. , Jibrin Salamatu , Sunday Ashel Dache , Shehu Kamaludeen , Safiyan Halimah , Kantiyok Christiana , Yusuf Hauwa'u Evelyn , Ibrahim Jimoh M. , Musa Shuaibu , Baduku Tokan S. , Tabari Abdulkadir M. , Barros Henrique , London Stephanie J.
Published: February 2020

Background

Developing countries bear the burden of childhood stunting but lack resources for cohort studies to develop preventive strategies. To enable future prospective studies, we designed and tested the Child Electronic Growth Monitoring System (CEGROMS) using a readily available electronic data capture platform, the Research Electronic Data Capture (REDCap).

Objectives

To demonstrate the feasibility of using CEGROMS for data collection for a pilot study for the Kaduna Infant Development (KID) Birth Cohort Study in Nigeria.

Methods

CEGROMS consists of the data capture form for growth monitoring, a central cloud server, electronic tablets, and desktop computer. We implemented the pilot study in 2017‐2019 at the Barau Dikko Teaching Hospital, Kaduna, Nigeria. Odds ratios (OR) and 95% confidence intervals (CI) were calculated for completeness of baseline data (relative to individuals with incomplete data) and completion of follow‐up at different time points (relative to individuals with no follow‐up visit) by the participant characteristics. Complete data were defined as date of birth, sex, and birthweight recorded at recruitment.

Results

Among 3152 infant records in CEGROMS, 2789 (88.5%) had complete data. Of these, 1905 (68.3%) had at least one follow‐up visit. The main determinants of data completeness were health facility delivery (OR 19.17, 95% CI 13.65, 26.92) and tertiary education (OR 3.54, 95% CI 2.69, 4.67). Follow‐up was greater for women with tertiary education (OR 1.33, 95% CI 1.06, 1.51 for at least one visit). Maternal education is associated with completeness and follow‐up (following adjustments for parity and employment).

Conclusions

The CEGROMS electronic data collection system enables complete and consistent data collection. The data will enable design of strategies to improve follow‐up in the future implementation of the birth cohort study.
miR‐142‐5P regulates triglyceride by targeting CTNNB1 in goat mammary epithelial cells
Authors: Sui MeiXia , Wang ZongWei , Xi Dan , Wang HanHai
Published: February 2020

MicroRNAs (miRNAs) regulate genes through post‐transcriptional regulation by targeting the 3′‐UTR of mRNA to downregulate gene expression. Several reports have indicated that miRNA regulation can affect many physiological processes, including immune function, apoptosis, cell proliferation and differentiation, and milk fat metabolism. In this study, miR‐142‐5P promoted milk fat metabolism, and inhibition of miR‐142‐5P suppressed milk fat metabolism both in vivo and in vitro. The luciferase and Western blot assays indicated that catenin beta‐1 (CTNNB1) is a potential target for miR‐142‐5P. In addition, CTNNB1 inhibited milk fat metabolism. In summary, miR‐142‐5P may promote milk fat metabolism by inhibiting CTNNB1 expression.
Reconstructing facade semantic models using hierarchical topological graphs
Authors: Wang Yuefeng , Fan Hongchao , Zhou Guoqing
Published: February 2020

Semantic information in 3D building models is of vital importance for various applications in terms of smart cities. To infer the semantic information and localize the components on building facades, this article proposes a novel approach to model facades with semantics by constructing hierarchical topological graphs. This method utilizes the topological characteristics of building facades. In the first‐layer layout graph, the algorithm takes the nearest cluster as the vertex and the distance between components as the edge. Thus, a topology graph is generated for the facade. The proposed algorithm is divided into three steps. First, the topology graph is obtained by calculating the spacing between the components. It is reasonable to calculate the topological graph by encoding the topological edges. If this calculation is not effective, the topology is justified by adjusting the spacing between components. Finally, the vertices in the graph are used to repair the occluded parts of the facade. In the second‐layer graph, a grid is constructed according to the first‐layer graph. Then, the attributes of the nodes are used to reconstruct the facade. The experimental results show that this method has a high accuracy of 90% and that the average time consumption is 6 s.
Household flooring associated with reduced infant diarrhoeal illness in Zimbabwe in households with and without WASH interventions
Authors: Koyuncu Aybüke , Kang Dufour Mi‐Suk , Watadzaushe Constancia , Dirawo Jeffrey , Mushavi Angela , Padian Nancy , Cowan Frances , McCoy Sandra I.
Published: February 2020

Objectives

Diarrhoeal illness is a leading cause of childhood morbidity and mortality and has long‐term negative impacts on child development. Although flooring, water and sanitation have been identified as important routes of transmission of diarrhoeal pathogens, research examining variability in the association between flooring and diarrhoeal illness by water and sanitation is limited.

Methods

We utilised cross‐sectional data collected for the evaluation of Zimbabwe’s Prevention of Mother‐to‐Child HIV transmission programme in 2014 and 2017–18. Mothers of infants 9–18 months of age self‐reported the household's source of drinking water and type of sanitation facility, as well as infant diarrhoeal illness in the four weeks prior to the survey. Household flooring was assessed using interviewer observation, and households in which the main material of flooring was dirt/earthen were classified as having unimproved flooring, and those with solid flooring (e.g. cement) were classified as having improved flooring.

Results

Mothers of infants living in households with improved flooring were less likely to report diarrhoeal illness in the last four weeks (PDa = −4.8%, 95% CI: −8.6, −1.0). The association between flooring and diarrhoeal illness did not vary by the presence of improved/unimproved water (pRERI = 0.91) or sanitation (pRERI = 0.76).

Conclusions

Our findings support the hypothesis that household flooring is an important pathway for the transmission of diarrhoeal pathogens, even in settings where other aspects of sanitation are sub‐optimal. Improvements to household flooring do not require behaviour change and may be an effective and expeditious strategy for reducing childhood diarrhoeal illness irrespective of household access to improved water and sanitation.
Anti‐platelet antibody immunoassays in childhood immune thrombocytopenia: a systematic review
Authors: Schmidt David E. , Lakerveld Anke J. , Heitink‐Pollé Katja M. J. , Bruin Marrie C. A. , Vidarsson Gestur , Porcelijn Leendert , de Haas Masja
Published: February 2020

Background

In adult immune thrombocytopenia (ITP), an acquired autoimmune bleeding disorder, anti‐platelet autoantibody testing may be useful as a rule‐in test. Childhood ITP has different disease characteristics, and the diagnostic and prognostic value of anti‐platelet antibody testing remains uncertain.

Objective

To systematically review the diagnostic accuracy of anti‐platelet autoantibody testing in childhood ITP.

Methods

PubMed and EMBASE were searched for studies evaluating immunoassays in childhood ITP. Study quality was assessed (QUADAS2), and evidence was synthesized descriptively.

Results

In total, 40 studies (1606 patients) were identified. Nine studies reported sufficient data to determine diagnostic accuracy measures. Anti‐platelet IgG antibody testing showed a moderate sensitivity (0·36–0·80 platelet‐associated IgG [direct test]; 0·19–0·39 circulating IgG [indirect test]). In studies that reported control data, including patients with non‐immune thrombocytopenia, specificity was very good (0·80–1·00). Glycoprotein‐specific immunoassays showed comparable sensitivity (three studies) and predominantly identified IgG anti‐GP IIb/IIIa antibodies, with few IgG anti‐GP Ib/IX antibodies. Anti‐platelet IgM antibodies were identified in a substantial proportion of children (sensitivity 0·62–0·64 for direct and indirect tests).

Conclusion

The diagnostic evaluation of IgG and IgM anti‐platelet antibodies may be useful as a rule‐in test for ITP. In children with insufficient platelets for a direct test, indirect tests may be performed instead. A negative test does not rule out the diagnosis of ITP. Future studies should evaluate the value of anti‐platelet antibody tests in thrombocytopenic children with suspected ITP.
The Evaluation of School Administrators' Views on the Need for Professional Development of Teachers regarding the Use of Technology in Physics Classes
Authors: Uzal Gurcan , Erdem Aytekin
Published: February 2020

The aim of the study is to investigate the school administrators' views on the professional development needs of teachers regarding the use of technology in physics classes. The participants of the study were 121 executive teachers from the city of Kocaeli. The data for the research was obtained using the survey model and was compiled with the help of a five point Likert type scale. The data collected by a scale with the reliability coefficient of 0.92 were analyzed using descriptive and inferential statistical techniques. As a result of the analysis, it was found that the administrators completely agreed with the use of the LCD panels in the teaching of physics subjects, while only agreeing with the other items. In addition, the opinions of school administrators regarding the professional development needs of teachers for the use of technology in physics classes does not differ according to demographic characteristics, but significantly do however, according to gender and experience. In light of the results, recommendations were made for researchers, administrators and the Ministry of National Education.
Widespread diversity in the transcriptomes of functionally divergent limb tendons
Authors: Disser Nathaniel P. , Ghahramani Gregory C. , Swanson Jacob B. , Wada Susumu , Chao Max L. , Rodeo Scott A. , Oliver David J. , Mendias Christopher L.
Published: February 2020

Key points

Tendon is a hypocellular, matrix‐rich tissue that has been excluded from comparative transcriptional atlases. These atlases have provided important knowledge about biological heterogeneity between tissues, and our study addresses this important gap.

We performed measures on four of the most studied tendons, the Achilles, forepaw flexor, patellar and supraspinatus tendons of both mice and rats. These tendons are functionally distinct and are also among the most commonly injured, and therefore of important translational interest.

Approximately one‐third of the filtered transcriptome was differentially regulated between Achilles, forepaw flexor, patellar and supraspinatus tendons within either mice or rats. Nearly two‐thirds of the transcripts that are expressed in anatomically similar tendons were different between mice and rats.

The overall findings from this study identified that although tendons across the body share a common anatomical definition based on their physical location between skeletal muscle and bone, tendon is a surprisingly genetically heterogeneous tissue.

Tendon is a functionally important connective tissue that transmits force between skeletal muscle and bone. Previous studies have evaluated the architectural designs and mechanical properties of different tendons throughout the body. However, less is known about the underlying transcriptional differences between tendons that may dictate their designs and properties. Therefore, our objective was to develop a comprehensive atlas of the transcriptome of limb tendons in adult mice and rats using systems biology techniques. We selected the Achilles, forepaw digit flexor, patellar, and supraspinatus tendons due to their divergent functions and high rates of injury and tendinopathies in patients. Using RNA sequencing data, we generated the Comparative Tendon Transcriptional Database (CTTDb) that identified substantial diversity in the transcriptomes of tendons both within and across species. Approximately 30% of filtered transcripts were differentially regulated between tendons of a given species, and nearly 60% of the filtered transcripts present in anatomically similar tendons were different between species. Many of the genes that differed between tendons and across species are important in tissue specification and limb morphogenesis, tendon cell biology and tenogenesis, growth factor signalling, and production and maintenance of the extracellular matrix. This study indicates that tendon is a surprisingly heterogenous tissue with substantial genetic variation based on anatomical location and species.
Three new Aceria spp. (Acari: Trombidiformes: Eriophyoidea) associated to Artemisia spp. (Compositae) from South Khorasan province, East Iran

Authors: Honarmand Arash , Sadeghi-namaghi Hussein , Lillo Enrico De
Published: February 2020

During the field surveys of eriophyoid mites associated to plant species of Artemisia L. (Compositae) from semi-arid and arid environment in East Iran (Birjand, South Khorasan, Iran 2016-2017), three new Aceria spp. (Acari: Trombidiformes: Eriophyidae) were collected. They are Aceria gallartae sp. nov. on Artemisia sieberi Besser, Aceria khaniensis sp. nov. on A. tournefortiana Rchb., and Aceria alghoorii sp. nov. on A. scoparia Waldst. & Kitam., which are illustrated and described herein.
International standardization and metrology as tools to address the comparability and reproducibility challenges in XPS measurements
Authors: Unger Wolfgang E. S.
Published: February 2020

The status of standardization related to x-ray photoelectron spectroscopy (XPS, ESCA) at ASTM International (Subcommittee E42.03) and ISO (TC 201) is presented and commented upon in a structured manner. The survey also identifies other active bodies, here VAMAS Technical Working Area 2 and the Surface Analysis Working Group at the International Meter Convention, contributing to prestandardization research and metrology of XPS and reports their specific activities. It is concluded that existing standardization is delivering good practices in the use of XPS and has a high potential to avoid the recently observed erroneous use, misapplications, and misinterpretation by new and inexperienced users of the method—which seems to be the main reason for the “reproducibility crisis” in the field of XPS applications. A need for a more proactive publicizing of international documentary standards by experienced XPS users, specifically those who are involved in standardization, is identified. Because the existing portfolio of standards addressing the use of XPS is not complete, future standardization projects planned or already ongoing are mentioned. The way the standardization bodies are identifying future needs is shortly explained.
A cell atlas of human thymic development defines T cell repertoire formation
Authors: Park Jong-Eun , Botting Rachel A. , Domínguez Conde Cecilia , Popescu Dorin-Mirel , Lavaert Marieke , Kunz Daniel J. , Goh Issac , Stephenson Emily , Ragazzini Roberta , Tuck Elizabeth , Wilbrey-Clark Anna , Roberts Kenny , Kedlian Veronika R. , Ferdinand John R. , He Xiaoling , Webb Simone , Maunder Daniel , Vandamme Niels , Mahbubani Krishnaa T. , Polanski Krzysztof , Mamanova Lira , Bolt Liam , Crossland David , de Rita Fabrizio , Fuller Andrew , Filby Andrew , Reynolds Gary , Dixon David , Saeb-Parsy Kourosh , Lisgo Steven , Henderson Deborah , Vento-Tormo Roser , Bayraktar Omer A. , Barker Roger A. , Meyer Kerstin B. , Saeys Yvan , Bonfanti Paola , Behjati Sam , Clatworthy Menna R. , Taghon Tom , Haniffa Muzlifah , Teichmann Sarah A.
Published: February 2020

Thymus development, cell by cell

The human thymus is the organ responsible for the maturation of many types of T cells, which are immune cells that protect us from infection. However, it is not well known how these cells develop with a full immune complement that contains the necessary variation to protect us from a variety of pathogens. By performing single-cell RNA sequencing on more than 250,000 cells, Park
et al.
examined the changes that occur in the thymus over the course of a human life. They found that development occurs in a coordinated manner among immune cells and with their developmental microenvironment. These data allowed for the creation of models of how T cells with different specific immune functions develop in humans.

Science
, this issue p.
eaay3224
Bumble bees display cross-modal object recognition between visual and tactile senses
Authors: Solvi Cwyn , Gutierrez Al-Khudhairy Selene , Chittka Lars
Published: February 2020

These bees have “seen” that before

Humans excel at mental imagery, and we can transfer those images across senses. For example, an object out of view, but for which we have a mental image, can still be recognized by touch. Such cross-modal recognition is highly adaptive and has been recently identified in other mammals, but whether it is widespread has been debated. Solvi
et al.
tested for this behavior in bumble bees, which are increasingly recognized as having some relatively advanced cognitive skills (see the Perspective by von der Emde and Burt de Perera). They found that the bees could identify objects by shape in the dark if they had seen, but not touched, them in the light, and vice versa, demonstrating a clear ability to transmit recognition across senses.

Science
, this issue p.
910
; see also p.
850
Angiotensin and biased analogs induce structurally distinct active conformations within a GPCR
Authors: Wingler Laura M. , Skiba Meredith A. , McMahon Conor , Staus Dean P. , Kleinhenz Alissa L. W. , Suomivuori Carl-Mikael , Latorraca Naomi R. , Dror Ron O. , Lefkowitz Robert J. , Kruse Andrew C.
Published: February 2020

Choosing the drug to fit the protein

Many approved drugs bind to G protein–coupled receptors (GPCRs). A challenge in targeting GPCRs is that different ligands preferentially activate different signaling pathways. Two papers show how biased signaling arises for the angiotensin II type 1 receptor that couples to two signaling partners (G proteins and arrestins). Suomivuori
et al.
used large-scale atomistic simulations to show that coupling to the two pathways is through two distinct GPCR conformations and that extracellular ligands favor one or the other conformation. Wingler
et al.
present crystal structures of the same receptor bound to ligands with different bias profiles. These structures show conformational changes in and around the binding pocket that match those observed in simulations. This work could provide a framework for the rational design of drugs that are more effective and have fewer side effects.

Science
, this issue p.
881
, p.
888
Structure of CD20 in complex with the therapeutic monoclonal antibody rituximab
Authors: Rougé Lionel , Chiang Nancy , Steffek Micah , Kugel Christine , Croll Tristan I. , Tam Christine , Estevez Alberto , Arthur Christopher P. , Koth Christopher M. , Ciferri Claudio , Kraft Edward , Payandeh Jian , Nakamura Gerald , Koerber James T. , Rohou Alexis
Published: February 2020

Clustering for the kill

Cluster of differentiation 20 (CD20) is a membrane protein that defines most B cell populations and is the target of therapeutic antibodies to treat malignancies and autoimmune disorders. Rougé
et al.
present the structure of CD20 bound to the antibody rituximab that activates the complement system to kill B cells. CD20 forms a dimer and each monomer binds one rituximab antigen-binding fragment (Fab) to give 2:2 stoichiometry. The compact packing between Fab arms and CD20 gives rise to circular assemblies with a diameter similar to that of antibody hexamers known to recruit the first component of the complement cascade.

Science
, this issue p.
1224
How mycorrhizal associations drive plant population and community biology
Authors: Tedersoo Leho , Bahram Mohammad , Zobel Martin
Published: February 2020

The pervasive power of mycorrhizas

Associations between plants and symbiotic fungi—mycorrhizas—are ubiquitous in plant communities. Tedersoo
et al.
review recent developments in mycorrhizal research, revealing the complex and pervasive nature of this largely invisible interaction. Complex networks of mycorrhizal hyphae connect the root systems of individual plants, regulating nutrient flow and competitive interactions between and within plant species, controlling seedling establishment, and ultimately influencing all aspects of plant community ecology and coexistence.

Science
, this issue p.
eaba1223
Disassembling 2D van der Waals crystals into macroscopic monolayers and reassembling into artificial lattices
Authors: Liu Fang , Wu Wenjing , Bai Yusong , Chae Sang Hoon , Li Qiuyang , Wang Jue , Hone James , Zhu X.-Y.
Published: February 2020

Larger monolayers with gold tapes

Although the exfoliation of monolayers of materials such as transition metal dichalcogenides produces high-quality electronic materials with low defect densities, the size of the monolayers is limited to the micrometer scale. Liu
et al.
modified this method by creating atomically flat gold layers on polymer supports. The strong van der Waals adhesion of the gold layer allowed monolayers to be exfoliated on the centimeter scale. Multilayers could be reassembled to artificial structures, such as a MoSe
2
/WSe
2
single-crystal bilayer with a twist angle chosen to quench intralayer exciton formation.

Science
, this issue p.
903
A Membrane-Bound Transcription Factor is Proteolytically Regulated by the AAA+ Protease FtsH in Staphylococcus aureus
Authors: Yeo Won-Sik , Anokwute Chiamara , Marcadis Philip , Levitan Marcus , Ahmed Mahmoud , Bae Yeun , Kim Kyeongkyu , Kostrominova Tatiana , Liu Qian , Bae Taeok
Published: February 2020

Staphylococcus aureus
is an important pathogenic bacterium causing various diseases in humans. In the bacterium, transcription is typically regulated by the transcription factors located in the cytoplasm. In this study, we report an atypical transcription factor identified in
S. aureus
. Unlike most other transcription factors, the newly identified transcription factor is located in the cytoplasmic membrane, and its activity is proteolytically controlled by the membrane-bound AAA+ protease FtsH. The newly identified MTF, named MbtS, has the potential to regulate the transcription of over 200 genes. This study provides a molecular mechanism by which a protease affects bacterial transcription and illustrates the diversity of the bacterial transcriptional regulation.
High-Throughput Fluorescence-Based Screen Identifies the Neuronal MicroRNA miR-124 as a Positive Regulator of Alphavirus Infection
Authors: López Paula , Girardi Erika , Mounce Bryan C. , Weiss Amélie , Chane-Woon-Ming Béatrice , Messmer Mélanie , Kaukinen Pasi , Kopp Arnaud , Bortolamiol-Becet Diane , Fendri Ali , Vignuzzi Marco , Brino Laurent , Pfeffer Sébastien
Published: February 2020

Arthropod-borne (arbo) viruses are part of a class of pathogens that are transmitted to their final hosts by insects. Because of climate change, the habitat of some of these insects, such as mosquitoes, is shifting, thereby facilitating the emergence of viral epidemics. Among the pathologies associated with arbovirus infection, neurological diseases such as meningitis and encephalitis represent a significant health burden. Using a genome-wide miRNA screen, we identified neuronal miR-124 as a positive regulator of the Sindbis and chikungunya alphaviruses. We also showed that this effect was in part direct, thereby opening novel avenues to treat alphavirus infections.
Concurrent Control of the Kaposi's Sarcoma-Associated Herpesvirus Life Cycle through Chromatin Modulation and Host Hedgehog Signaling: a New Prospect for the Therapeutic Potential of Lipoxin A4
Authors: Asha Kumari , Balfe Natalie , Sharma-Walia Neelam
Published: February 2020

The latent-to-lytic switch in KSHV infection is one of the critical events regulated by the major replication and transcription activator KSHV protein called RTA. Chromatin modification of the viral genome determines the phase of the viral life cycle in the host. Here, we report that LXA4 interacts with a host chromatin modulator, especially SMARCB1, which upregulates the KSHV ORF50 promoter. SMARCB1 has also been recognized to be a tumor suppressor protein which controls many tumorigenic events associated with the hedgehog (hh) signaling pathway. We also observed that LXA4 treatment reduces PD-L1 expression and that PD-L1 expression is an important immune evasion strategy used by KSHV for its survival and maintenance in the host. Our study underscores the role of LXA4 in KSHV biology and emphasizes that KSHV is strategic in downregulating LXA4 secretion in the host to establish latency. This study also uncovers the therapeutic potential of LXA4 and its targetable receptor, AhR, in KSHV’s pathogenesis.
Impact of rituximab on anthropometric indices among childhood steroid-dependent nephrotic syndromes
Authors: Sinha Rajiv , Banerjee Sushmita , Mukherjee Anwesha , Akhtar Shakil , Pradhan Subal
Published: February 2020

Background

There is scarcity of data on impact of rituximab on anthropometrical parameters (weight, height and body mass index i.e. BMI SD score (SDS)) among children with steroid-dependent nephrotic syndromes (SDNS).

Methods

Multicentre retrospective review.

Results

102 children with SDNS (male: 63%; n=64), median age 7 (IQR: 4.3–9.6) years, received a total of 217 rituximab infusions (total 110 cycles). At median follow-up of 2.1 (IQR: 1.3–2.8) years, 58 (57%) children were off steroids and a significant fall in steroid threshold for relapse was noted (median 0.6; IQR 0.4–0.9 to median 0.3; IQR 0.12 - 0.5 mg/kg/alternate day, p=0.005). Anthropometric parameters (BMI SDS: 0.92±1.8 to 0.25±1.47, p=0.003; weight SDS: 0.20±1.6 to −0.11±1.3, p=0.01; and height SDS: −0.93±1.88 to −0.45±1.54, p=0.04) as well as obesity (38% to 20%, p=0.003) and short stature (11% to 3%, p=0.02) improved. Results remained significant even when analysis was restricted to children ≤12 years (n=88), (BMI SDS: 0.97±1.98 to 0.25±1.5, p=0.001; weight SDS: 0.33±1.6 to 0.02±1.2, p=0.01; and height SDS: −0.67±1.84 to −0.186±1.42, p=0.001).

Conclusions

Use of rituximab resulted in significant steroid sparing effect with an improvement in both growth and obesity parameters.
Automated identification of malignancy in whole-slide pathological images: identification of eyelid malignant melanoma in gigapixel pathological slides using deep learning
Authors: Wang Linyan , Ding Longqian , Liu Zhifang , Sun Lingling , Chen Lirong , Jia Renbing , Dai Xizhe , Cao Jing , Ye Juan
Published: February 2020

Background/Aims

To develop a deep learning system (DLS) that can automatically detect malignant melanoma (MM) in the eyelid from histopathological sections with colossal information density.

Methods

Setting: Double institutional study.

Study population: We retrospectively reviewed 225 230 pathological patches (small section cut from pathologist-labelled area from an H&E image), cut from 155 H&E-stained whole-slide images (WSI).

Observation procedures: Labelled gigapixel pathological WSIs were used to train and test a model designed to assign patch-level classification. Using malignant probability from a convolutional neural network, the patches were embedded back into each WSI to generate a visualisation heatmap and leveraged a random forest model to establish a WSI-level diagnosis.

Main outcome measure(s): For classification, the area under the receiver operating characteristic curve (AUC), accuracy, sensitivity and specificity were used to evaluate the efficacy of the DLS in detecting MM.

Results

For patch diagnosis, the model achieved an AUC of 0.989 (95% CI 0.989 to 0.991), with an accuracy, sensitivity and specificity of 94.9%, 94.7% and 95.3%, respectively. We displayed the lesion area on the WSIs as graded by malignant potential. For WSI, the obtained sensitivity, specificity and accuracy were 100%, 96.5% and 98.2%, respectively, with an AUC of 0.998 (95% CI 0.994 to 1.000).

Conclusion

Our DLS, which uses artificial intelligence, can automatically detect MM in histopathological slides and highlight the lesion area on WSIs using a probabilistic heatmap. In addition, our approach has the potential to be applied to the histopathological sections of other tumour types.
Cohort study of high maternal body mass index and the risk of adverse pregnancy and delivery outcomes in Scotland
Authors: Doi Lawrence , Williams Andrew James , Marryat Louise , Frank John
Published: February 2020

Objective

To examine the association between high maternal weight status and complications during pregnancy and delivery.

Setting

Scotland.

Participants

Data from 132 899 first-time singleton deliveries in Scotland between 2008 and 2015 were used. Women with overweight and obesity were compared with women with normal weight. Associations between maternal body mass index and complications during pregnancy and delivery were evaluated.

Outcome measures

Gestational diabetes, gestational hypertension, pre-eclampsia, placenta praevia, placental abruption, induction of labour, elective and emergency caesarean sections, pre-term delivery, post-term delivery, low Apgar score, small for gestational age and large for gestational age.

Results

In the multivariable models controlling for potential confounders, we found that, compared with women with normal weight, the odds of the following outcomes were significantly increased for women with overweight and obesity (overweight adjusted ORs; 95% CI, followed by the same for women with obesity): gestational hypertension (1.61; 1.49 to 1.74), (2.48; 2.30 to 2.68); gestational diabetes (2.14; 1.86 to 2.46), (8.25; 7.33 to 9.30); pre-eclampsia (1.46; 1.32 to 1.63) (2.07; 1.87 to 2.29); labour induction (1.28; 1.23 to 1.33), (1.69; 1.62 to 1.76) and emergency caesarean section (1.82; 1.74 to 1.91), (3.14; 3.00 to 3.29).

Conclusions

Women with overweight and obesity in Scotland are at greater odds of adverse pregnancy and delivery outcomes. The odds of these conditions increases with increasing body mass index. Health professionals should be empowered and trained to deliver promising dietary and lifestyle interventions to women at risk of overweight and obesity prior to conception, and control excessive weight gain in pregnancy.
Association between employment status and risk of all-cause and cause-specific mortality: a population-based prospective cohort study
Authors: Nie Jing , Wang Jianglin , Aune Dagfinn , Huang Wentao , Xiao Dong , Wang Yafeng , Chen Xiong
Published: February 2020

Background

Unemployment has been reported to be associated with an increased risk of mortality. While most available studies focused on the effects of temporary unemployment on mortality, it remains unclear whether similar trends can be found in subjects who were never employed or are retirement. Therefore, this study examined the associations between temporary unemployment, never employed and retirement, integrating the risk of all-cause and cause-specific mortality in US adults.

Methods

Data from the National Health Interview Survey from 2001 to 2013 Linked Mortality files through 31 December 2015 were used. A total of 282 364 participants aged 18 to 65 years were included. Their employment status was categorised into four groups: employed, never employed, temporary unemployed and retired.

Results

During the mean follow-up time of 8.2 years, 12 645 subjects died from a variety of causes. Compared with employed participants, temporary unemployed, never employed or retired participants faced an increased risk of mortality for all-cause (temporary unemployed HR 1.76, 95% CI 1.67 to 1.86; never employed HR 1.63, 95% CI 1.47 to 1.81; retired HR 1.27, 95% CI 1.17 to 1.37). Cause-specific mortality analysis showed that compared with employed participants, temporary unemployed or never employed participants faced a significantly increased risk of mortality from cancer, cardiovascular disease, chronic lower respiratory disease, diabetes and kidney disease.

Conclusion

This study showed that retired, temporary unemployed and never employed participants aged 18 to 65 years were strongly associated with higher mortality, indicating that both temporary and long-term unemployment are associated with a higher risk of mortality and adversely affect longevity.
Brain iron deposition is linked with cognitive severity in Parkinson’s disease
Authors: Thomas George Edward Calver , Leyland Louise Ann , Schrag Anette-Eleonore , Lees Andrew John , Acosta-Cabronero Julio , Weil Rimona Sharon
Published: February 2020

Background

Dementia is common in Parkinson’s disease (PD) but measures that track cognitive change in PD are lacking. Brain tissue iron accumulates with age and co-localises with pathological proteins linked to PD dementia such as amyloid. We used quantitative susceptibility mapping (QSM) to detect changes related to cognitive change in PD.

Methods

We assessed 100 patients with early-stage to mid-stage PD, and 37 age-matched controls using the Montreal Cognitive Assessment (MoCA), a validated clinical algorithm for risk of cognitive decline in PD, measures of visuoperceptual function and the Movement Disorders Society Unified Parkinson’s Disease Rating Scale part 3 (UPDRS-III). We investigated the association between these measures and QSM, an MRI technique sensitive to brain tissue iron content.

Results

We found QSM increases (consistent with higher brain tissue iron content) in PD compared with controls in prefrontal cortex and putamen (p<0.05 corrected for multiple comparisons). Whole brain regression analyses within the PD group identified QSM increases covarying: (1) with lower MoCA scores in the hippocampus and thalamus, (2) with poorer visual function and with higher dementia risk scores in parietal, frontal and medial occipital cortices, (3) with higher UPDRS-III scores in the putamen (all p<0.05 corrected for multiple comparisons). In contrast, atrophy, measured using voxel-based morphometry, showed no differences between groups, or in association with clinical measures.

Conclusions

Brain tissue iron, measured using QSM, can track cognitive involvement in PD. This may be useful to detect signs of early cognitive change to stratify groups for clinical trials and monitor disease progression.
Combat Application Tourniquet fares well in a chemical, biological, radiological or nuclear dress state
Authors: Beaven Alastair , Sellon E , Ballard M , Parker P
Published: February 2020

Introduction

There is a need for a military tourniquet to control catastrophic haemorrhage in a chemical, biological, radiological or nuclear (CBRN) threat environment. No published data exist as to the efficacy of tourniquets while wearing British military CBRN individual protective equipment (IPE).

Methods

12 volunteers from the counter CBRN instructors’ course allowed testing on 24 legs. A Combat Application Tourniquet (C-A-T) was applied to all volunteers at the level of the midthigh. 12 legs were tested while wearing CBRN IPE (both operator and simulated casualty), and the control group of 12 legs was tested while wearing conventional combat dress state (both operator and simulated casualty). The order of leg laterality and dress state were sequenced according to a prerandomised system. Efficacy was measured via use of an ultrasound probe at the popliteal artery. Tourniquets were considered effective if arterial flow was completely occluded on ultrasound imaging. Data were collected on time to successful application, failure of tourniquets and pain scores as rated by the visual analogue scale (1–10).

Results

There were no failures of tourniquet application in the CBRN group, and two failures (17%) in the control group. Failures were pain threshold exceeded (n=1) and tourniquet internal strap failure (n=1). The mean application time for the CBRN group was 28.5 s (SD 11.7) and 23.7 s (SD 9.8) for the conventional combat group. There was no statistically significant difference (p=0.27). The median CBRN pain score was 2.0 (IQR 2.0–3.5). The median control pain score was 4.0 (IQR 3–6). This was a statistically significant difference (p=0.002).

Conclusion

C-A-Ts applied to simulated casualties in CBRN IPE at the midthigh are at least as efficacious as those applied to the midthigh in a conventional combat dress state. The pain experienced was less in CBRN IPE than when in a conventional combat dress state.
Losartan may attenuate altitude-related sleep disturbance
Authors: Clarke Alexander , Ladha C , Wright A , Pattinson K
Published: February 2020

Introduction

Sleep disturbance is common at high altitude and likely driven by an exaggerated peripheral chemoreceptor response which leads to apnoeic episodes and arousal. We hypothesised that this heightened response is in part mediated through angiotensin II receptors in the carotid body. To examine this link, we studied the effect of angiotensin II receptor blocker on sleep disturbance.

Methods

Twenty participants paired by age, gender and ACE phenotype ascended to the Whymper Hut (5000 m) on Chimborazo in the Ecuadorean Andes as part of a double-blinded randomised placebo-controlled study of physiological mechanisms. Subjects were randomised to either losartan 100 mg daily or placebo. The primary outcome of sleep efficiency was measured using wrist-mounted actigraphs. One pair was excluded from analysis after descending before the end of the study due to acute mountain sickness.

Results

There was a significantly different response to altitude between the two groups (F=3.274, p=0.029), as a decline in sleep efficiency in the placebo group (F=10.259, p<0.001) was not replicated in the angiotensin II receptor blocker group (F=0.459, p=0.713).

Conclusion

The absence of any significant sleep disturbance in the intervention group suggests that peripheral chemoreceptor hypersensitivity is largely mediated by angiotensin II receptor activation. However, further research is needed to confirm our findings and to study the potential mechanisms of action.