bluuebunny/crossref_metadata_2025 huggingface dataset:
Should Talmy’s motion typology be expanded to visual
motion?
Authors: Kawachi Kazuhiro
Published: February 2020

This chapter addresses the question of whether or
not Talmy’s (1985, 1991, 2000b) motion typology should be expanded
to visual motion (Matsumoto
2001, 2017;
Slobin 2009; Cifuentes-Férez 2014), by
examining how Sidaama (Cushitic; Ethiopia) expresses (i)
self-agentive/non-agentive motion, (ii) agentive motion, and (iii)
fictive motion along a visual emanation path. It shows that although
this language closely follows the verb-framed pattern in expressing
(i) and (ii), it does not do so in expressing (iii), as in many
other verb-framed languages. A possible reason for this is that
(iii) is not conceptualized as a macro-event, whereas Talmy’s
typology is built on expression patterns of macro-events. This study
also observes that there are other types of events to which Talmy’s
typology does not apply, presumably for the same reason: they are
not really macro-events.
The construction of heterogeneous and fluid identities
Authors: Li Luyao , Huang Jing
Published: February 2020

This paper presents a case study of identity construction and performance by examining the dynamic translanguaging
practices of a Chinese student in the UK on a widely-used social media platform, WeChat. Drawing on data from WeChat Moment posts,
chatting records, face-to-face interviews and online interviews over a period of 10 months, the study discusses identity
construction in a digital world with a particular focus on heterogeneity and fluidity. The main findings include the following two
points. First, the participant is the epitome of his world; he selects and manipulates linguistic and other semiotic resources
indicating his beliefs, attitudes and life trajectory, and he actively, creatively, critically and strategically uses resources
from his communicative repertoire to construct heterogeneous and fluid self-identities in his interactions with others. Second,
the participant actively creates a virtual translanguaging space on WeChat, within which his new and old identities and different
knowledge meet, integrate and fuse. The findings of this research provide detailed insights of digital translanguaging practices
of WeChat users and contribute to a comprehensive understanding of identity (re)construction and (re)formation of an increasing
number of overseas Chinese students.
From Hero to Superhero
Authors: Unceta Gómez Luis
Published: February 2020

This paper offers an analysis of the interpretative keys of the
character of the superhero in comic books, in comparison with those of the
hero of Classical Antiquity. It is not only that both characters come to
play similar functions in their respective fictional universes, but there is
also a genetic link between the latter and the former. And this relationship
is two-way, since this dependency determines the contemporary rewritings of
the ancient hero in comic books. Taking El héroe
(The Hero), by the Spanish scriptwriter David Rubín, as
a case study, this paper tries to exemplify that relationship, according to
which an ancient hero such as Hercules immediately evokes the typical
features of the superhero of comic book.
Horrible deaths, grotesque deaths
Authors: Bartolomé Gómez Jesús
Published: February 2020

The aim of this essay is to analyze several instances of the
reversal of the hero’s glorious death, the critical moment of his/her
career. In order to achieve this goal, I have selected some of most
outstanding passages from Lucan’s Civil War, for instance
Sceva’s aristeia (6.138–262), and the episode of the
Asbyte’s death by the flavian epicist Silius Italicus
(Punica 2.189–210).

After having studied the resources employed by the Roman writers,
I compare them with the means of description of the grotesque deaths in the
TV series Spartacus (2010–2013), a product of mass culture
alien to the academic world. Both the similarities and the differences
raised by this comparison are relevant to understanding the meaning of this
kind of representation.
Pedagogical linguistics
Authors: Bardovi-Harlig Kathleen
Published: February 2020

The positive effects of instruction on the acquisition of second-language pragmatics has been well documented by numerous recent published studies (81 in the 10 years betweenRose, 2005, andBardovi-Harlig, 2015), but we have yet to see a corresponding increase in the teaching of pragmatics in second and foreign language classrooms or language textbooks. This article explores some of the potential causes for the lack of implementation of pragmatics instruction in second and foreign language classrooms (Skyes, 2013) and suggests means of overcoming such challenges. Pedagogical linguistics, in the form of pedagogical pragmatics, offers insight into meeting the challenges of limited theoretical support for curricular development, lack of authentic input in teaching materials, lack of instructor knowledge, and lack of reference books and pedagogical resources for teachers. The final challenge for pedagogical linguistics and pragmatics researchers is conveying relevant research findings to teachers; means for accomplishing this are discussed in the final section of the article.
Kazakh particle ğoj as an existential
operator
Authors: Christopher Nadezda
Published: February 2020

This paper is devoted to the Kazakh particle
ğoj, its syntactic distribution, pragmatic
contribution and semantics. Two syntactically distinct types of
ğoj are distinguished: a post-nominal copula-type
ğoj and a post-predicative particle
ğoj. The speaker using either particle in her
utterance indicates to her hearer that (some of) the information she
provides has been previously shared, or should be treated as such.
In post-predicative position, ğoj is never
obligatory and can follow any type of predicate – verbal or
nominal – as long as it is either narrowly focused, or is a part of
a wider focus phrase. Both types of ğoj contribute
similar pragmatic effects of contrastivity and givenness (or
pragmatic presupposition). Especially, the proposition
p followed by post-predicative
ğoj is assumed to belong to the Common Ground,
whether it had been explicitly added there during the preceding
exchange or not. Drawing on the comparison with Russian
že and Tundra Yukaghir particle
mə(r)=, it is shown that
ğoj should be treated as an existential
operator stating the existence of p inside of the
Common Ground.
From focus marking to illocutionary modification
Authors: Favaro Marco
Published: February 2020

This paper investigates the polyfunctionality of
the Italian adverb solo ‘only’. Beside its
prototypical use as an exclusive focus particle, the adverb
solo has developed some secondary uses which
have not yet been investigated: connective uses (uses as a
conjunctional adverb and as a discourse marker) and illocutive uses
(use as an illocutionary operator tied to specific speech-act
types). By analyzing the different contexts of occurrence and
possible paths of semantic change, the meaning variation of
solo is described and a synchronic
categorization is laid out. Particular attention has been devoted to
its illocutive uses, the meaning of which displays a complex
interrelationship between features pertaining to the information
structure level (focus marking, common ground management) and
features connected to the speech-act domain (marking of the
illocutionary force and speech-act specification in an interpersonal
perspective).
Types and functions of wa-marked DPs and their
structural distribution in a Japanese sentence
Authors: Nakamura Koichiro
Published: February 2020

This paper is devoted to the Japanese particle
wa. We argue that a Japanese sentence has a CP
peripheral structure, in which multiple wa-marked
phrases can sit. The left peripheral structure in CP territory
includes Topic Phrases (TopP) that host Thematic Topics (TT) in
sentence-initial positions or Contrastive Topics (CT) elsewhere.
These topics correspond to DPs marked with the particle
wa. We argue that a Japanese sentence can
involve multiple wa-marked phrases. In addition,
the left peripheral structure also involves one Focus Phrase (FocP),
the locus for Exhaustive Identificational-Focus (EI-Focus) elements.
This FocP is the slot for focally-stressed
WA-marked DPs. Our crucial point is that, unlike
wa-marked phrases, a Japanese sentence has only
one WA-marked phrase.
Is the information-structural contribution of modal particles in
the syntax, in discourse structure, or in both?
Authors: Waltereit Richard
Published: February 2020

Traditionally, information structure belongs to
sentence structure, whereas discourse particles operate at the level
of discourse structure (Hansen
1998a). Modal particles, by contrast, belong to sentence
structure, too. They are also widely recognized as making a
significant contribution to information structure. At the same time,
a distinction between modal particles and discourse particles on
semantic or otherwise functional grounds is notoriously difficult
and controversial (Hansen
1998a; Waltereit
& Detges 2007). Recently, Ozerov (2015) has suggested that at least
some of what is traditionally thought of as information structure
need not, in fact, be encoded at the level of sentence grammar, but
may be more appropriately regarded as reflecting
discourse-structuring techniques. A re-examination of modal
particles would seem to be well-suited to make a contribution to
this debate, since it has long been recognized that modal particles
are sensitive to syntactic constraints (such as position and
sentence type) while having a discourse-related function. In this
paper, I will look at the French modal particle quand
même (Waltereit
2004). This particle, originally a concessive adverb
meaning, roughly, ‘nevertheless’, has come to develop, from the end
of the 19th century, two modal particle uses which can perhaps be
approximately described by the meaning ‘anyway’ with a
forward-looking and a backward-looking nuance, respectively,
alongside further discourse-level differences. This shows that modal
particles may encode, alongside sentence-level information
structure, also discourse-level information structure.
Modal particles in Basque
Authors: Monforte Sergio
Published: February 2020

The interaction between modal particles and
information structure has received no attention within Basque
linguistics. Although the standard behaviour of modal particles in
Basque shows, no connection with information structure, in this
article I present two dialectal uses only found in Eastern Basque
where the discourse particle ote interacts with
focus: on the one hand, ote, which can behave as a
weak adverb in these varieties, is only licensed when there is
narrow focus occupying the Focus Phrase. On the other hand, the
particle can attach wh-words creating a
configuration also found in languages such as German or Japanese as
will be discussed throughout the article; this combination seems to
attract emphasis for intensity cross-linguistically.
The NP-Strategy for Expressing Reciprocity
Authors: Bar-Asher Siegal Elitzur A.
Published: February 2020

This book provides a comprehensive treatment of the syntax and semantics of a single linguistic phenomenon – the NP-strategy for expressing reciprocity – in synchronic, diachronic, and typological perspectives. It challenges the assumption common in the typological, syntactic, and semantic literature, namely that so-called reciprocal constructions encode symmetric relations. Instead, they are analyzed as constructions encoding unspecified relations. In effect, it provides a new proposal for the truth-conditional semantics of these constructions. More broadly, this book introduces new ways of bringing together historical linguistics and formal semantics, demonstrating how, on the one hand, the inclusion of historical data concerning the sources of reciprocal constructions enriches their synchronic analysis; and how, on the other hand, an analysis of the syntax and the semantics of these constructions serves as a key for understanding their historical origins.
Conditional and residual trends of singular hot days in Europe
Authors: Jézéquel Aglaé , Bevacqua Emanuele , d’Andrea Fabio , Thao Soulivanh , Vautard Robert , Vrac Mathieu , Yiou Pascal
Published: February 2020

The influence of anthropogenic climate change on both mean and extremely hot temperatures in Europe has been demonstrated in a number of studies. There is a growing consensus that high temperature extremes have increased more rapidly than the regional mean in central Europe, while the difference between extreme and mean trends is not significant in other European regions. However, it is less clear how to quantify the changes in different processes leading to heat extremes. Extremely hot temperatures are associated to a large extent with specific types of atmospheric circulation. Here we investigate how the temperature associated with atmospheric patterns leading to extremely hot days in the present could evolve in the future. We propose a methodology to calculate conditional trends tailored to the circulation patterns of specific days by computing the evolution of the temperature for days with a similar circulation to the day of interest. We also introduce the concept of residual trends, which compare the conditional trends to regional mean temperature trends. We compute these trends for two case studies of the hottest days recorded in two different European regions (corresponding to the heat-waves of summer 2003 and 2010). We use the NCEP reanalysis dataset, an ensemble of CMIP5 models, and a large ensemble of a single coupled model (CESM), in order to account for different sources of uncertainty. We also evaluate how bias correction of climate simulations influences the results.
H1N1 influenza virus interaction with a porous layer of silicon nanowires
Authors: Gonchar Kirill A , Agafilushkina Svetlana N , Moiseev Daniil V , Bozhev Ivan V , Manykin Anatolij A , Kropotkina Ekaterina A , Gambaryan Alexandra S , Osminkina Liubov A
Published: February 2020

Here, the non-specific interaction of the H1N1 influenza virus with a porous layer of silicon nanowires (PSi NWs) was studied by transmission and scanning electron microscopy (TEM, SEM, respectively) and optical spectroscopy. PSi NW layer with a thickness of about 200 nm was fabricated by metal-assisted chemical etching of p-type highly doped crystalline silicon wafers, and consist of porous nanowires with a diameter of 50–200 nm, and a distance between the nanowires of 100–200 nm. It was shown that during the adsorption of viruses, viral particles with a diameter of about 100 nm bind to the porous surface of the nanowires. This interaction was revealed using TEM, SEM, and causes wavelength shifts in the Fabry–Perot fringes in the reflection spectrum of visible light from the PSi NW layer. The results show that thin layers of PSi NWs are a promising nanomaterial for creating filters and sensors for binding and detection of viruses.
Casting for the Public Good: BAME Casting in British Film and Television in the 2010s
Authors: Geraghty Christine
Published: February 2020

This article examines changes in casting practices which have begun to put black, Asian, and minority ethnic actors more regularly on British screens and in more significant parts. In the context of calls for improving BAME involvement at all levels of the film and television industry, I look in particular at how colour-blind casting has begun to have an impact on British cinema. The article looks initially at how calls for the campaign for changes entwine with the British tradition of public service broadcasting and examines the socially conscious criteria for casting introduced by the BBC and the BFI in 2016. I suggest that some of the ambiguous expectations of audiences in relation to colour-blind casting are similar to the potentially contradictory aspirations placed on institutions which receive public funding. In order to examine these issues in some detail, I draw on textual and paratextual analysis to demonstrate how frames of reference for understanding new approaches to casting can be found in recent period adaptations, a British genre strongly associated with whiteness by actors and critics. The examples discussed span the decade: Wuthering Heights (Arnold, 2011), Lady Macbeth (Oldroyd, 2016), and Mary Queen of Scots (Rourke, 2018). The analysis demonstrates that while casting for the public good is becoming more common it nevertheless remains a complicated and controversial strategy.
Developmental and molecular characterization of novel staminodes in Aquilegia
Authors: Meaders Clara , Min Ya , Freedberg Katherine J , Kramer Elena
Published: February 2020

Background and Aims

The ranunculid model system Aquilegia is notable for the presence of a fifth type of floral organ, the staminode, which appears to be the result of sterilization and modification of the two innermost whorls of stamens. Previous studies have found that the genetic basis for the identity of this new organ is the result of sub- and neofunctionalization of floral organ identity gene paralogues; however, we do not know the extent of developmental and molecular divergence between stamens and staminodes.

Methods

We used histological techniques to describe the development of the Aquilegia coerulea ‘Origami’ staminode relative to the stamen filament. These results have been compared with four other Aquilegia species and the closely related genera Urophysa and Semiaquilegia. As a complement, RNA sequencing has been conducted at two developmental stages to investigate the molecular divergence of the stamen filaments and staminodes in A. coerulea ‘Origami’.

Key Results

Our developmental study has revealed novel features of staminode development, most notably a physical interaction along the lateral margin of adjacent organs that appears to mediate their adhesion. In addition, patterns of abaxial/adaxial differentiation are observed in staminodes but not stamen filaments, including asymmetric lignification of the adaxial epidermis in the staminodes. The comparative transcriptomics are consistent with the observed lignification of staminodes and indicate that stamen filaments are radialized due to overexpression of adaxial identity, while the staminodes are expanded due to the balanced presence of abaxial identity.

Conclusions

These findings suggest a model in which the novel staminode identity programme interacts with the abaxial/adaxial identity pathways to produce two whorls of laterally expanded organs that are highly differentiated along their abaxial/adaxial axis. While the ecological function of Aquilegia staminodes remains to be determined, these data are consistent with a role in protecting the early carpels from herbivory and/or pathogens.
Prevention of Umbilical Sagging After Medium Definition Liposuction
Authors: Borille Giuliano , Neves Patrícia M A , Filho Gustavo P , Kim Roy , Miotto Gabriele
Published: February 2020

Background

The loss of the umbilical vertical axis, causing a horizontal shape deformity after liposuction, is a current aesthetic issue. The use of energy devices, such as LASER and VASER, has been advocated as an option for improving skin retraction, but no data are available on the prevention of umbilical sagging.

Objectives

The authors sought to describe a technique for preventing umbilical deformities after medium definition liposuction employing suction-assisted liposuction.

Methods

Over a period of 31 months, 62 patients underwent medium definition liposuction with direct needle fixation of the umbilical stalk to prevent horizontal umbilical deformities. All patients underwent surgery performed by a single surgeon (G.B.). All patients underwent objective measurements of the umbilical shape before and after the procedure utilizing digital image measurements by Mirror Image software, version 6.0 (Fairfield, NJ). Statistical analysis was performed with IBM SPSS Statistics V26. The mean age of the patients was 28.8 years. The follow-up evaluation was performed 2 weeks and 9 months postoperatively.

Results

Over a period of 31 months, 60 patients (96.7%) who underwent abdominal etching liposuction showed maintenance of (n = 9, 14.5%) or improvements in the umbilical shape 9 months postoperatively (n = 51, 82.2%, P < 0.05). Two patients (3.2%) experienced worsening of the umbilical shape after surgery despite suture fixation.

Conclusions

Horizontal shape deformities of the umbilicus after liposuction can be improved by utilizing direct needle fixation of the umbilical stalk. The approach has been shown to be effective, safe, and reproducible for the prevention of umbilical sagging in selected patients.

Level of Evidence: 4
Immune cell infiltration-based signature for prognosis and immunogenomic analysis in breast cancer
Authors: Wang Shiyuan , Zhang Qi , Yu Chunlu , Cao Yiyin , Zuo Yongchun , Yang Lei
Published: February 2020

Breast cancer is one of the most human malignant diseases and the leading cause of cancer-related death in the world. However, the prognostic and therapeutic benefits of breast cancer patients cannot be predicted accurately by the current stratifying system. In this study, an immune-related prognostic score was established in 22 breast cancer cohorts with a total of 6415 samples. An extensive immunogenomic analysis was conducted to explore the relationships between immune score, prognostic significance, infiltrating immune cells, cancer genotypes and potential immune escape mechanisms. Our analysis revealed that this immune score was a promising biomarker for estimating overall survival in breast cancer. This immune score was associated with important immunophenotypic factors, such as immune escape and mutation load. Further analysis revealed that patients with high immune scores exhibited therapeutic benefits from chemotherapy and immunotherapy. Based on these results, we can conclude that this immune score may be a useful tool for overall survival prediction and treatment guidance for patients with breast cancer.
OrgDyn: feature- and model-based characterization of spatial and temporal organoid dynamics
Authors: Hasnain Zaki , Fraser Andrew K , Georgess Dan , Choi Alex , Macklin Paul , Bader Joel S , Peyton Shelly R , Ewald Andrew J , Newton Paul K
Published: February 2020

Organoid model systems recapitulate key features of mammalian tissues and enable high throughput experiments. However, the impact of these experiments may be limited by manual, non-standardized, static or qualitative phenotypic analysis. OrgDyn is an open-source and modular pipeline to quantify organoid shape dynamics using a combination of feature- and model-based approaches on time series of 2D organoid contour images. Our pipeline consists of (i) geometrical and signal processing feature extraction, (ii) dimensionality reduction to differentiate dynamical paths, (iii) time series clustering to identify coherent groups of organoids and (iv) dynamical modeling using point distribution models to explain temporal shape variation. OrgDyn can characterize, cluster and model differences among unique dynamical paths that define diverse final shapes, thus enabling quantitative analysis of the molecular basis of tissue development and disease.

Availability and Implementation

https://github.com/zakih/organoidDynamics (BSD 3-Clause License).

Supplementary information

Supplementary data are available at Bioinformatics online.
Multiway generalized canonical correlation analysis
Authors: Gloaguen Arnaud , Philippe Cathy , Frouin Vincent , Gennari Giulia , Dehaene-Lambertz Ghislaine , Le Brusquet Laurent , Tenenhaus Arthur
Published: February 2020

Regularized generalized canonical correlation analysis (RGCCA) is a general multiblock data analysis framework that encompasses several important multivariate analysis methods such as principal component analysis, partial least squares regression, and several versions of generalized canonical correlation analysis. In this article, we extend RGCCA to the case where at least one block has a tensor structure. This method is called multiway generalized canonical correlation analysis (MGCCA). Convergence properties of the MGCCA algorithm are studied, and computation of higher-level components are discussed. The usefulness of MGCCA is shown on simulation and on the analysis of a cognitive study in human infants using electroencephalography (EEG).
Unique shoot architecture in the leafy liverwortHerzogianthus vaginatus(Herzogianthaceae): insights into novel growth patterns in Jungermanniidae
Authors: Renner Matt A M , Salter Joshua
Published: February 2020

All studied leafy liverworts have shoots with leaf to underleaf ratios of either 2:1 or 1:1. These ratios are the product of growth by either helical or pendular segmentation of the tetrahedral apical cell. Here we report that Herzogianthus vaginatus has a leaf to underleaf ratio approaching 3:1 on primary shoots, and on secondary shoots the ratio is closer to 4:1. These ratios are incompatible with the simple helical or pendular growth patterns found in other leafy liverworts. Further, the sequence of leaves and underleaves on Herzogianthus shoots is not wholly regular, which is previously unrecorded. We assess potential growth models that may explain the leaf to underleaf ratios and architecture of Herzogianthus shoots, including (1) branch modification, (2) merophyte or leaf-initial duplication and (3) changes in segmentation sequences. We compared leaf sequences produced by pendular and helical segmentation and a range of non-standard models, with sequences observed on shoots of Herzogianthus. Structure allows us to discriminate between the many alternative growth models, because each make testable predictions about leaf and underleaf sequences. We propose that Herzogianthus possesses growth processes unique among leafy liverworts, in which the direction of helication periodically and, sometimes irregularly, reverses. This, in combination with the secondary shoots having different growth patterns from primary shoots, emphasizes that Herzogianthus warrants detailed histological study to test our proposition.
Phylogenetics of the mycoheterotrophic genusThismia(Thismiaceae: Dioscoreales) with a focus on the Old World taxa: delineation of novel natural groups and insights into the evolution of morphological traits
Authors: Shepeleva Ekaterina A , Schelkunov Mikhail I , Hroneš Michal , Sochor Michal , Dančák Martin , Merckx Vincent Sft , Kikuchi Izai Abs , Chantanaorrapint Sahut , Suetsugu Kenji , Tsukaya Hirokazu , Mar Shek S , Luu Hong Truong , Li Hong-Qing , Logacheva Maria D , Nuraliev Maxim S
Published: February 2020

Thismia is a genus of > 80 mycoheterotrophic species characterized by a peculiar appearance and complex floral morphology. A significant proportion of the species and morphological diversity of Thismia has only been uncovered in the past two decades, and new discoveries continue to be made. Given that many new data have recently become available, and the most comprehensive taxonomic revision of the genus from 1938 addresses less than half of the currently known species, previous hypotheses for species relationships and infrageneric taxonomic classification in Thismia was in need of review. Extensive molecular phylogenetic studies of Thismia at the genus level have never been presented. We investigate the phylogenetic relationships of 41 species (and one variety) of Thismia from the Old World. Our study comprises 68 specimens (for 28 of which the data were newly generated), including outgroup taxa broadly representing Thismiaceae (= Burmanniaceae p.p. sensuAPG IV, 2016), and is based on two nuclear and one mitochondrial marker. We use maximum likelihood and Bayesian inference to infer relationships among the taxa. We also constructed a morphological dataset of 12 mostly floral characters, comparing these characters to hypotheses based on molecular evidence to identify putative synapomorphies for major clades and to discuss hypotheses regarding the evolution of structural traits in the genus. Our analyses indicate that the majority of currently accepted infrageneric taxa of Thismia are polyphyletic. We find support for the monophyly of the Old World group, in which we recognize five well-supported lineages (clades); the only New World species studied appears to be related to the Neotropical genus Tiputinia. Ancestral state reconstructions demonstrate that the evolution of most morphological characters was homoplastic, but we identify characters that provide each of the five clades of Old World Thismia with a unique morphological description. The geographical distribution of the species under study is also shown to be consistent with the major clades. Our investigation provides a phylogenetic basis for the development of a novel sectional classification of Thismia reflecting morphological and geographical traits.
Novel congenital disorder of O-linked glycosylation caused by GALNT2 loss of function
Authors: Zilmer Monica , Edmondson Andrew C , Khetarpal Sumeet A , Alesi Viola , Zaki Maha S , Rostasy Kevin , Madsen Camilla G , Lepri Francesca R , Sinibaldi Lorenzo , Cusmai Raffaella , Novelli Antonio , Issa Mahmoud Y , Fenger Christina D , Abou Jamra Rami , Reutter Heiko , Briuglia Silvana , Agolini Emanuele , Hansen Lars , Petäjä-Repo Ulla E , Hintze John , Raymond Kimiyo M , Liedtke Kristen , Stanley Valentina , Musaev Damir , Gleeson Joseph G , Vitali Cecilia , O’Brien W Timothy , Gardella Elena , Rubboli Guido , Rader Daniel J , Schjoldager Katrine T , Møller Rikke S
Published: February 2020

Congenital disorders of glycosylation are a growing group of rare genetic disorders caused by deficient protein and lipid glycosylation. Here, we report the clinical, biochemical, and molecular features of seven patients from four families with GALNT2-congenital disorder of glycosylation (GALNT2-CDG), an O-linked glycosylation disorder. GALNT2 encodes the Golgi-localized polypeptide N-acetyl-d-galactosamine-transferase 2 isoenzyme. GALNT2 is widely expressed in most cell types and directs initiation of mucin-type protein O-glycosylation. All patients showed loss of O-glycosylation of apolipoprotein C-III, a non-redundant substrate for GALNT2. Patients with GALNT2-CDG generally exhibit a syndrome characterized by global developmental delay, intellectual disability with language deficit, autistic features, behavioural abnormalities, epilepsy, chronic insomnia, white matter changes on brain MRI, dysmorphic features, decreased stature, and decreased high density lipoprotein cholesterol levels. Rodent (mouse and rat) models of GALNT2-CDG recapitulated much of the human phenotype, including poor growth and neurodevelopmental abnormalities. In behavioural studies, GALNT2-CDG mice demonstrated cerebellar motor deficits, decreased sociability, and impaired sensory integration and processing. The multisystem nature of phenotypes in patients and rodent models of GALNT2-CDG suggest that there are multiple non-redundant protein substrates of GALNT2 in various tissues, including brain, which are critical to normal growth and development.
Identification of an amino-terminus determinant critical for ryanodine receptor/Ca2+ release channel function
Authors: Seidel Monika , de Meritens Camille Rabesahala , Johnson Louisa , Parthimos Dimitris , Bannister Mark , Thomas Nia Lowri , Ozekhome-Mike Esizaze , Lai Francis Anthony , Zissimopoulos Spyros
Published: February 2020

Aims 

The cardiac ryanodine receptor (RyR2), which mediates intracellular Ca2+ release to trigger cardiomyocyte contraction, participates in development of acquired and inherited arrhythmogenic cardiac disease. This study was undertaken to characterize the network of inter- and intra-subunit interactions regulating the activity of the RyR2 homotetramer.

Methods and results 

We use mutational investigations combined with biochemical assays to identify the peptide sequence bridging the β8 with β9 strand as the primary determinant mediating RyR2 N-terminus self-association. The negatively charged side chains of two aspartate residues (D179 and D180) within the β8–β9 loop are crucial for the N-terminal inter-subunit interaction. We also show that the RyR2 N-terminus domain interacts with the C-terminal channel pore region in a Ca2+-independent manner. The β8–β9 loop is required for efficient RyR2 subunit oligomerization but it is dispensable for N-terminus interaction with C-terminus. Deletion of the β8–β9 sequence produces unstable tetrameric channels with subdued intracellular Ca2+ mobilization implicating a role for this domain in channel opening. The arrhythmia-linked R176Q mutation within the β8–β9 loop decreases N-terminus tetramerization but does not affect RyR2 subunit tetramerization or the N-terminus interaction with C-terminus. RyR2R176Q is a characteristic hypersensitive channel displaying enhanced intracellular Ca2+ mobilization suggesting an additional role for the β8–β9 domain in channel closing.

Conclusion 

These results suggest that efficient N-terminus inter-subunit communication mediated by the β8–β9 loop may constitute a primary regulatory mechanism for both RyR2 channel activation and suppression.
Genome-wide association study on coronary artery disease in type 1 diabetes suggests beta-defensin 127 as a risk locus
Authors: Antikainen Anni A V , Sandholm Niina , Trégouët David-Alexandre , Charmet Romain , McKnight Amy Jayne , Ahluwalia Tarunveer S , Syreeni Anna , Valo Erkka , Forsblom Carol , Gordin Daniel , Harjutsalo Valma , Hadjadj Samy , Maxwell Alexander P , Rossing Peter , Groop Per-Henrik
Published: February 2020

Aims

Diabetes is a known risk factor for coronary artery disease (CAD). There is accumulating evidence that CAD pathogenesis differs for individuals with type 1 diabetes (T1D). However, the genetic background has not been extensively studied. We aimed to discover genetic loci increasing CAD susceptibility, especially in T1D, to examine the function of these discoveries and to study the role of the known risk loci in T1D.

Methods and results

We performed the largest genome-wide association study to date for CAD in T1D, comprising 4869 individuals with T1D (cases/controls: 941/3928). Two loci reached genome-wide significance, rs1970112 in CDKN2B-AS1 [odds ratio (OR) = 1.32, P = 1.50 × 10−8], and rs6055069 on DEFB127 promoter (OR = 4.17, P = 2.35 × 10−9), with consistent results in survival analysis. The CDKN2B-AS1 variant replicated (P = 0.04) when adjusted for diabetic kidney disease in three additional T1D cohorts (cases/controls: 434/3123). Furthermore, we explored the function of the lead discoveries with a cardio-phenome-wide analysis. Among the eight suggestive loci (P < 1 × 10−6), rs70962766 near B3GNT2 associated with central blood pressure, rs1344228 near CNTNAP5 with intima media thickness, and rs2112481 on GRAMD2B promoter with serum leucocyte concentration. Finally, we calculated genetic risk scores for individuals with T1D with the known susceptibility loci. General population risk variants were modestly but significantly associated with CAD also in T1D (P = 4.21 × 10−7).

Conclusion

While general population CAD risk loci had limited effect on the risk in T1D, for the first time, variants at the CDKN2B-AS1 locus were robustly associated with CAD in individuals with T1D. The novel finding on β-defensin DEFB127 promoter provides a link between diabetes, infection susceptibility, and CAD, although pending on future confirmation.
Theoretical signature of a cavern created by an underground nuclear explosion in 2-D exploration seismic data
Authors: Ortiz-Aguilar Stephany , De Basabe Jonas D , Gonzalez-Escobar Mario , Magar Vanesa
Published: February 2020

The proliferation of nuclear tests is a problem that threatens the safety and health of everybody. In order to tackle this problem, the UN is promoting the Comprehensive Nuclear-Test-Ban Treaty (CTBT), which includes protocols for monitoring and On-Site Inspections (OSI). The purpose of OSI is to verify if a nuclear test has been carried out by identifying with a geophysical technique the presence of a cavern, hole or some device that indicates the violation of the treaty. In this context, it is desirable to be able to use exploration-seismology techniques to detect caverns created by an underground nuclear explosion. However, there is scarce information about the seismic signature of this type of cavern. We present the results of elastic wave propagation simulations, in the time domain, with a cavern created by an underground nuclear explosion. The wave equation is solved using the spectral element method with 4th order basis functions and quadrilateral elements. We show the results for models with cavities and caverns corresponding to explosions of 1, 20 and 100 kilotons, and obtain seismic traces in which we can observe the effect of the structures. We conclude that caverns created by nuclear explosions can be detected using seismic data and distinguished from caves because they behave like two concentric diffractor bodies, as opposed to caves-like diffractors.
Disturbed genomic imprinting and its relevance for human reproduction: causes and clinical consequences
Authors: Elbracht Miriam , Mackay Deborah , Begemann Matthias , Kagan Karl Oliver , Eggermann Thomas
Published: February 2020

BACKGROUND

Human reproductive issues affecting fetal and maternal health are caused by numerous exogenous and endogenous factors, of which the latter undoubtedly include genetic changes. Pathogenic variants in either maternal or offspring DNA are associated with effects on the offspring including clinical disorders and nonviable outcomes. Conversely, both fetal and maternal factors can affect maternal health during pregnancy. Recently, it has become evident that mammalian reproduction is influenced by genomic imprinting, an epigenetic phenomenon that regulates the expression of genes according to their parent from whom they are inherited. About 1% of human genes are normally expressed from only the maternally or paternally inherited gene copy. Since numerous imprinted genes are involved in (embryonic) growth and development, disturbance of their balanced expression can adversely affect these processes.

OBJECTIVE AND RATIONALE

This review summarises current our understanding of genomic imprinting in relation to human ontogenesis and pregnancy and its relevance for reproductive medicine.

SEARCH METHODS

Literature databases (Pubmed, Medline) were thoroughly searched for the role of imprinting in human reproductive failure. In particular, the terms ‘multilocus imprinting disturbances, SCMC, NLRP/NALP, imprinting and reproduction’ were used in various combinations.

OUTCOMES

A range of molecular changes to specific groups of imprinted genes are associated with imprinting disorders, i.e. syndromes with recognisable clinical features including distinctive prenatal features. Whereas the majority of affected individuals exhibit alterations at single imprinted loci, some have multi-locus imprinting disturbances (MLID) with less predictable clinical features. Imprinting disturbances are also seen in some nonviable pregnancy outcomes, such as (recurrent) hydatidiform moles, which can therefore be regarded as a severe form of imprinting disorders. There is growing evidence that MLID can be caused by variants in the maternal genome altering the imprinting status of the oocyte and the embryo, i.e. maternal effect mutations. Pregnancies of women carrying maternal affect mutations can have different courses, ranging from miscarriages to birth of children with clinical features of various imprinting disorders.

WIDER IMPLICATIONS

Increasing understanding of imprinting disturbances and their clinical consequences have significant impacts on diagnostics, counselling and management in the context of human reproduction. Defining criteria for identifying pregnancies complicated by imprinting disorders facilitates early diagnosis and personalised management of both the mother and offspring. Identifying the molecular lesions underlying imprinting disturbances (e.g. maternal effect mutations) allows targeted counselling of the family and focused medical care in further pregnancies.
NOX1 Regulates Collective and Planktonic Cell Migration: Insights From Patients With Pediatric-Onset IBD and NOX1 Deficiency
Authors: Khoshnevisan Razieh , Anderson Michael , Babcock Stephen , Anderson Sierra , Illig David , Marquardt Benjamin , Sherkat Roya , Schröder Katrin , Moll Franziska , Hollizeck Sebastian , Rohlfs Meino , Walz Christoph , Adibi Peyman , Rezaei Abbas , Andalib Alireza , Koletzko Sibylle , Muise Aleixo M , Snapper Scott B , Klein Christoph , Thiagarajah Jay R , Kotlarz Daniel
Published: February 2020

Background

Genetic defects of pediatric-onset inflammatory bowel disease (IBD) provide critical insights into molecular factors controlling intestinal homeostasis. NOX1 has been recently recognized as a major source of reactive oxygen species (ROS) in human colonic epithelial cells. Here we assessed the functional consequences of human NOX1 deficiency with respect to wound healing and epithelial migration by studying pediatric IBD patients presenting with a stop-gain mutation in NOX1.

Methods

Functional characterization of the NOX1 variant included ROS generation, wound healing, 2-dimensional collective chemotactic migration, single-cell planktonic migration in heterologous cell lines, and RNA scope and immunohistochemistry of paraffin-embedded patient tissue samples.

Results

Using exome sequencing, we identified a stop-gain mutation in NOX1 (c.160C>T, p.54R>*) in patients with pediatric-onset IBD. Our studies confirmed that loss-of-function of NOX1 causes abrogated ROS activity, but they also provided novel mechanistic insights into human NOX1 deficiency. Cells that were NOX1-mutant showed impaired wound healing and attenuated 2-dimensional collective chemotactic migration. High-resolution microscopy of the migrating cell edge revealed a reduced density of filopodial protrusions with altered focal adhesions in NOX1-deficient cells, accompanied by reduced phosphorylation of p190A. Assessment of single-cell planktonic migration toward an epidermal growth factor gradient showed that NOX1 deficiency is associated with altered migration dynamics with loss of directionality and altered cell-cell interactions.

Conclusions

Our studies on pediatric-onset IBD patients with a rare sequence variant in NOX1 highlight that human NOX1 is involved in regulating wound healing by altering epithelial cytoskeletal dynamics at the leading edge and directing cell migration.
Intersections of machine learning and epidemiological methods for health services research
Authors: Rose Sherri
Published: February 2020

The field of health services research is broad and seeks to answer questions about the health care system. It is inherently interdisciplinary, and epidemiologists have made crucial contributions. Parametric regression techniques remain standard practice in health services research with machine learning techniques currently having low penetrance in comparison. However, studies in several prominent areas, including health care spending, outcomes and quality, have begun deploying machine learning tools for these applications. Nevertheless, major advances in epidemiological methods are also as yet underleveraged in health services research. This article summarizes the current state of machine learning in key areas of health services research, and discusses important future directions at the intersection of machine learning and epidemiological methods for health services research.
Summer Outbreak of Severe RSV-B Disease, Minnesota, 2017 Associated with Emergence of a Genetically Distinct Viral Lineage
Authors: Thielen Beth K , Bye Erica , Wang Xiong , Maroushek Stacene , Friedlander Hannah , Bistodeau Sarah , Christensen Jaime , Reisdorf Erik , Shilts Meghan H , Martin Karen , Como-Sabetti Kathryn , Strain Anna K , Ferrieri Patricia , Lynfield Ruth
Published: February 2020

Background

Respiratory syncytial virus (RSV) typically causes winter outbreaks in temperate climates. During summer 2017, the Minnesota Department of Health received a report of increased cases of severe RSV-B infection.

Methods

We compared characteristics of summer 2017 cases with those of 2014–2018 summers. To understand the genetic relatedness among viruses, we performed high-throughput sequencing of RSV from patients with a spectrum of illness from sites in Minnesota and Wisconsin.

Results

From May to September 2017, 58 RSV cases (43 RSV-B) were reported compared to 20–29 cases (3–7 RSV-B) during these months in other years. Median age and frequency of comorbidities were similar, but 55% (24/43) were admitted to the ICU in 2017 compared to 12% in preceding 3 years (odds ratio, 4.84, P < .01). Sequencing was performed on 137 specimens from March 2016 to March 2018. Outbreak cases formed a unique clade sharing a single conserved nonsynonymous change in the SH gene. We observed increased cases during the following winter season, when the new lineage was the predominant strain.

Conclusions

We identified an outbreak of severe RSV-B disease associated with a new genetic lineage among urban Minnesota children during a time of expected low RSV circulation.
Identification of relevant performance indicators for district healthcare systems in Ethiopia: a systematic review and expert opinion
Authors: Yesuf Elias Ali , Woldie Mirkuzie , Haile-Mariam Damen , Koller Daniela , Früschl Gönter , Grill Eva
Published: February 2020

Purpose

To identify potential performance indicators relevant for district healthcare systems of Ethiopia.

Data sources

Public Library of Medicine and Agency for Healthcare Research and Quality of the United States of America, Organization for Economic Cooperation and Development Library and Google Scholar were searched.

Study selection

Expert opinions, policy documents, literature reviews, process evaluations and observational studies published between 1990 and 2015 were considered for inclusion. Participants were national- and local-healthcare systems. The phenomenon of interest was the performance of healthcare systems. The Joanna Briggs Institute tools were adapted and used for critical appraisal of records.

Data extraction

Indicators of performance were extracted from included records and summarized in a narrative form. Then, experts rated the relevance of the indicators. Relevance of an indicator is its agreement with priority health objectives at the national and district level in Ethiopia.

Results of data synthesis

A total of 11 206 titles were identified. Finally, 22 full text records were qualitatively synthesized. Experts rated 39 out of 152 (25.7%) performance indicators identified from the literature to be relevant for district healthcare systems in Ethiopia. For example, access to primary healthcare, tuberculosis (TB) treatment rate and infant mortality rate were found to be relevant.

Conclusion

Decision-makers in Ethiopia and potentially in other low-income countries can use multiple relevant indicators to measure the performance of district healthcare systems. Further research is needed to test the validity of the indicators.
How Cyber Crime Damages Lives
Authors: Cooper Martin
Published: February 2020

Sean O’Neil from Bedfordshire Police investigates fraud and helps people and organisations avoid falling victim. He shows Martin Cooper MBCS behind the statistics as he explores the true human cost of online crime.
What's Really Happening in Data Protection?
Authors: Melsom Blair
Published: February 2020

Jeremy Holt is the senior partner of Clark Holt Commercial Solicitors, specialising in IT law. He talks to Blair Melsom AMBCS about data breaches, Brexit and nurturing the next generation of talent.
5 Steps to a Better Tech Fit in Mergers & Acquisitions
Authors: Zubairov Renat
Published: February 2020

Mergers and acquisitions (M&As) are expensive activities. They are arguably the largest undertaking a business can make - and, writes Renat Zubairov CEO of elastic.io - unsuccessful attempts can be enormously costly in time, money and reputation.
Data in Transit
Authors: Cox Peter
Published: February 2020

Peter Cox, CEO and Founder of UM Labs, explores VoIP and messaging systems and explains why organisations need to ensure high levels of security around data-in-transit, warning that failure to do so may lead to GDPR compliance issues.