bluuebunny/crossref_metadata_2025 huggingface dataset:
Cross-fitted instrument: a blueprint for one-sample Mendelian Randomization
Authors: Denault William R.P. , Bohlin Jon , Page Christian M. , Burgess Stephen , Jugessur Astanand
Published: May 2021

Bias from weak instruments may undermine the ability to estimate causal effects in instrumental variable regression (IVR). We present here a simple solution for handling weak instrument bias by introducing a new type of instrumental variable called ‘cross-fitted instrument’ (CFI). CFI splits the data at random and estimates the impact of the instrument on the exposure in each partition. The estimates are then used to perform an IVR on each partition. We adapt CFI to Mendelian randomization (MR) and term this adaptation ‘Cross-Fitting for Mendelian Randomization’ (CFMR). A major advantage of CFMR is its use of all the available data to select genetic instruments, as opposed to traditional two-sample MR where a large part of the data is only used for instrument selection. Consequently, CFMR has the potential to enhance the power of MR in a meta-analysis setting by enabling an unbiased one-sample MR to be performed in each cohort prior to meta-analyzing the results across all the cohorts. In a similar fashion, CFMR enables a cross-ethnic MR analysis by accounting for ethnic heterogeneity, which is particularly important in consortia-led meta-analyses where the participating cohorts might be of different ethnicities. To our knowledge, there are currently no MR approach that can account for such heterogeneity. Finally, CFMR enables the application of MR to exposures that are rare or difficult to measure, which would normally preclude their analysis in the regular two-sample MR setting.

Key messages

We develop a new method to enable an unbiased one-sample Mendelian Randomization.

The new method provides the same power as the standard two-sample Mendelian Randomization approach and does not require summary statistics from a genome-wide association study in an independent cohort.

Our approach enables a cross-ethnic instrumental variable regression to account for heterogeneity in a sample consisting of multiple ethnicities.
A 3D molecular map of the cavefish neural plate illuminates eyefield organization and its borders in vertebrates
Authors: Agnès François , Torres-Paz Jorge , Michel Pauline , Rétaux Sylvie
Published: May 2021

The vertebrate retinas originate from a specific anlage in the anterior neural plate called the eyefield. The eyefield shares its anterior border with the prospective telencephalon and is in contact ventrally and posteriorly with hypothalamic and diencephalic precursors. Eyefield identity is conferred by a set of “eye transcription factors”, whose combinatorial expression has not been precisely characterized. Here, we use the dimorphic teleost speciesAstyanax mexicanus, which develops proper eyes in the wild type and smaller colobomatous eyes in the blind cavefish embryo, to unravel the molecular anatomy of the eyefield and its micro-evolutionary variations in the twoAstyanaxmorphs. Using a series of markers (Rx3, Pax6, CxCr4b, Zic1, Lhx2, Emx3, Nkx2.1), we draw a comparative 3D expression map at the end of gastrulation/onset of neurulation, which highlights hyper-regionalization of the eyefield into sub-territories of distinct sizes, shapes, cell identities and putative fates along the three body axes. We also discover sub-domains within the prospective telencephalon, and we characterize cell identities at the frontiers of the eyefield. Analyses at the tissue scale and single cell level show variations in volumes and shapes of eyefield subdivisions as well as cellular gene expression levels and identity changes in cavefish. The ventro-medial border and the anterior border of the eyefield contain cells co-expressing hypothalamic and telencephalic marker, respectively, in cavefish embryos. Altogether, we provide a new model of eyefield patterning in 3D and suggest a developmental origin for the emergence of the coloboma phenotype in the natural mutant cavefish embryo.
Members of theLegionella pneumophilaSde Family Target Tyrosine Residues for Phosphoribosyl-Linked Ubiquitination
Authors: Zhang Mengyun , McEwen Joseph M. , Sjoblom Nicole M. , Kotewicz Kristin M. , Isberg Ralph R. , Scheck Rebecca A.
Published: May 2021

Legionella pneumophilaestablishes a replication vacuole by translocating hundreds of protein effectors through a type IV secretion system (T4SS). Among these translocated effectors are members of the Sde family, which catalyze phosphoribosyl-linked ubiquitination (pR-Ub) of host targets. Previous work has posited that Sde proteins solely target serine (Ser) residues within acceptor protein substrates. We show here that SdeC-mediated pR-Ub modification results from a stepwise reaction that also modifies tyrosine (Tyr) residues. Unexpectedly, the presence of an HA tag on Ub resulted in poly-pR-ubiquitination, consistent with the HA tag acting as an acceptor target. Interrogation of phosphoribosyl-linked HA-Ub revealed that Tyr4 was the preferred targeted residue, based on LC-MS/MS analysis of the crosslinked product. Further analysis using synthetic HA variants revealed promiscuous modification of Tyr, as crosslinking was prevented only by constructing a triple mutant in which all three Tyr within the HA sequence were substituted with Phe. Although previous work has indicated that Ser is the sole acceptor residue, we found no evidence of Ser preference over Tyr using Tyr->Ser replacement mutants. This work demonstrates that pR-ubiquitination by the Sde family is not limited to Ser-modification as previously proposed, and broadens the potential sites targeted by this family.
Precision environmental health monitoring by longitudinal exposome and multi-omics profiling
Authors: Gao Peng , Shen Xiaotao , Zhang Xinyue , Jiang Chao , Zhang Sai , Zhou Xin , Schüssler-Fiorenza Rose Sophia Miryam , Snyder Michael
Published: May 2021

Conventional environmental health studies primarily focused on limited environmental stressors at the population level, which lacks the power to dissect the complexity and heterogeneity of individualized environmental exposures. Here we integrated deep-profiled longitudinal personal exposome and internal multi-omics to systematically investigate how the exposome shapes an individual’s phenome. We annotated thousands of chemical and biological components in the personal exposome cloud and found they were significantly correlated with thousands of internal biomolecules, which was further cross validated using corresponding clinical data. In particular, our results showed that agrochemicals (e.g., carcinogenic pesticides, fungicides, and herbicides) and fungi predominated in the highly diverse and dynamic personal exposome, and the biomolecules and pathways related to the individual’s immune system, kidneys, and liver were highly correlated with the personal external exposome. Overall, our findings demonstrate dynamic interactions between the personal exposome and internal multi-omics and provide important insights into the impact of the environmental exposome on precision health.
Discovery of an Antarctic ascidian-associated uncultivated Verrucomicrobia with antimelanoma palmerolide biosynthetic potential
Authors: Murray Alison E. , Lo Chien-Chi , Daligault Hajnalka E. , Avalon Nicole E. , Read Robert W. , Davenport Karen W. , Higham Mary L. , Kunde Yuliya , Dichosa Armand E.K. , Baker Bill J. , Chain Patrick S.G.
Published: May 2021

The Antarctic marine ecosystem harbors a wealth of biological and chemical innovation that has risen in concert over millennia since the isolation of the continent and formation of the Antarctic circumpolar current. Scientific inquiry into the novelty of marine natural products produced by Antarctic benthic invertebrates led to the discovery of a bioactive macrolide, palmerolide A, that has specific activity against melanoma and holds considerable promise as an anticancer therapeutic. While this compound was isolated from the Antarctic ascidian Synoicum adareanum, its biosynthesis has since been hypothesized to be microbially mediated, given structural similarities to microbially-produced hybrid non-ribosomal peptide-polyketide macrolides. Here, we describe a metagenome-enabled investigation aimed at identifying the biosynthetic gene cluster (BGC) and palmerolide A-producing organism. A 74 Kbp candidate BGC encoding the multi-modular enzymatic machinery (hybrid Type I-trans-AT polyketide synthase-non-ribosomal peptide synthetase and tailoring functional domains) was identified and found to harbor key features predicted as necessary for palmerolide A biosynthesis. Surveys of ascidian microbiome samples targeting the candidate BGC revealed a high correlation between palmerolide-gene targets and a single 16S rRNA gene variant (R=0.83 – 0.99). Through repeated rounds of metagenome sequencing followed by binning contigs into metagenome-assembled genomes, we were able to retrieve a near-complete genome (10 contigs) of the BGC-producing organism, a novel verrucomicrobium within the Opitutaceae family that we propose here as Candidatus Synoicihabitans palmerolidicus. The refined genome assembly harbors five highly similar BGC copies, along with structural and functional features that shed light on the host-associated nature of this unique bacterium.

Importance

Palmerolide A has potential as a chemotherapeutic agent to target melanoma. We interrogated the microbiome of the Antarctic ascidian, Synoicum adareanum, using a cultivation-independent high-throughput sequencing and bioinformatic strategy. The metagenome-encoded biosynthetic machinery predicted to produce palmerolide A was found to be associated with the genome of a member of the S. adareanum core microbiome. Phylogenomic analysis suggests the organism represents a new deeply-branching genus, Candidatus Synoicihabitans palmerolidicus, in the Opitutaceae family of the Verrucomicrobia phylum. The Ca. S. palmerolidicus 4.29 Mb genome encodes a repertoire of carbohydrate-utilizing and transport pathways enabling its ascidian-associated lifestyle. The palmerolide-producer’s genome also contains five distinct copies of the large palmerolide biosynthetic gene cluster that may provide structural complexity of palmerolide variants.
Structure-based design of a highly stable, covalently-linked SARS-CoV-2 spike trimer with improved structural properties and immunogenicity
Authors: Olmedillas Eduardo , Mann Colin J. , Peng Weiwei , Wang Ying-Ting , Avalos Ruben Diaz , Bedinger Dan , Valentine Kristen , Shafee Norazizah , Schendel Sharon L. , Yuan Meng , Lang Guojun , Rouet Romain , Christ Daniel , Jiang Weidong , Wilson Ian A. , Germann Tim , Shresta Sujan , Snijder Joost , Saphire Erica Ollmann
Published: May 2021

The continued threat of SARS-CoV-2 to global health necessitates development of improved research tools and vaccines. We present an improved SARS-CoV-2 spike ectodomain, “VFLIP”, bearing five proline substitutions, a flexible cleavage site linker, and an inter-protomer disulfide bond. VFLIP displays significantly improved stability, high-yield production and retains its trimeric state without exogenous trimerization motifs. High-resolution cryo-EM and glycan profiling reveal that the VFLIP quaternary structure and glycosylation mimic the native spike on the viral surface. Further, VFLIP has enhanced affinity and binding kinetics relative to other stabilized spike proteins for antibodies in the Coronavirus Immunotherapeutic Consortium (CoVIC), and mice immunized with VFLIP exhibit potent neutralizing antibody responses against wild-type and B.1.351 live SARS-CoV-2. Taken together, VFLIP represents an improved tool for diagnostics, structural biology, antibody discovery, and vaccine design.
Cecropins contribute toDrosophilahost defence against fungal and Gram-negative bacterial infection
Authors: Carboni A. , Hanson M.A. , Lindsay S.A. , Wasserman S.A. , Lemaitre B.
Published: May 2021

Cecropins are small helical secreted peptides with antimicrobial activity that are widely distributed among insects. Genes encoding Cecropins are strongly induced upon infection, pointing to their role in host-defence. InDrosophila, fourCecropingenes clustered in the genome (CecA1, CecA2, CecBandCecC) are expressed upon infection downstream of the Toll and Imd pathways. In this study, we generated a short deletionΔCecA-Cremoving the wholeCecropinlocus. Using theΔCecA-Cdeficiency alone or in combination with other antimicrobial peptide (AMP) mutations, we addressed the function of Cecropins in the systemic immune response.ΔCecA-Cflies were viable and resisted challenge with various microbes as wild-type. However, removingΔCecA-Cin flies already lacking ten other AMP genes revealed a role for Cecropins in defence against Gram-negative bacteria and fungi. Measurements of pathogen loads confirm that Cecropins contribute to the control of certain Gram-negative bacteria, notablyEnterobacter cloacaeandProvidencia heimbachae. Collectively, our work provides the first genetic demonstration of a role for Cecropins in insect host defence, and confirms theirin vivoactivity primarily against Gram-negative bacteria and fungi. Generation of a fly line (ΔAMP14) that lacks fourteen immune inducible AMPs provides a powerful tool to address the function of these immune effectors in host-pathogen interactions and beyond.
Teaching with the case method: opportunities and problems since the COVID-19 pivot to online
Authors: Gómez García Luis Demetrio , Alba Cabañas Marisleidy
Published: May 2021

Purpose

This paper aims to detect the opportunities and problems when teaching with cases since the COVID-19 pivot to online.

Design/methodology/approach

From a qualitative phenomenological approach, both authors reflect on the pivot to online case method teaching in their master’s level courses in Colombia and the Dominican Republic.

Findings

The reflection allowed the authors to validate that the questions before and during the debate and the voting are resources equally valuable for discussing cases in the traditional classroom and online. However, the authors observe a pivot to teaching with cases online from the COVID-19 pandemic in aspects such as teamwork requiring more time in online class due to internet problems or students’ slowing down. The instructor’s viewing of teamwork is intermittent and causes feeling out of control. Working with cameras on or off generates different results in the students, in the teaching-learning process and in the results, which require the instructor’s good judgement decisions. The online discussion planning and organisation demand flexibility and empathy by the instructor, to promote a more significant student-student interaction, which, in the experience, is limited in the virtual environment. Finally, working with cases online generates and requires additional skills in the instructors to those of the traditional classroom.

Originality/value

The study’s originality consists of identifying the main divergences between face-to-face and online teaching with the case method, from the COVID-19 pivot to online. The study’s value is to warn instructors of problems that may arise in online teaching with the case method, for which recommendations are made.
The Mortensen-Pissarides model and the empirical facts of housing markets
Authors: Lisi Gaetano
Published: May 2021

Purpose

This paper aims to explain the main empirical facts of housing markets, notably the trade-off between housing price and time-on-the-market, the positive correlation between housing price and the number of contracts traded during a given period (i.e. the trading volume) and the existence of price dispersion.

Design/methodology/approach

This theoretical paper makes use of a search and matching model. Search and matching, indeed, are two fundamental characteristics of the trading process in the housing market, and, thus, the search-and-matching models have become the new economic approach to the analysis of real estate markets.

Findings

This paper shows that a slightly modified version of the baseline search and matching model à la Mortensen-Pissarides can explain the main empirical facts of housing markets. There are two key mechanisms that allow to achieve this notable goal: a simple formalisation of the (reasonable) assumption that buyers today are potential sellers tomorrow (and vice versa); and the direct relationship between market tightness and house price, derived by the standard matching model and underestimated by the related literature.

Research limitations/implications

The developed theoretical model only studies the equilibrium conditions. Indeed, it would be interesting to also study the disequilibrium in housing markets.

Practical implications

The explanation of the main empirical facts of housing markets is embodied in the same and relatively simple theoretical model.

Originality/value

In addition to the explanation of the main empirical facts of housing markets, the developed theoretical model can generate an upward sloping Beveridge curve in the housing market (the positive relation between home-seekers and vacant houses). Instead, according to a recent criticism in the related literature, a model à la Mortensen-Pissarides inherently generates a (empirically unrealistic) downward sloping Beveridge curve.
The Nexus Between Energy and Trade in South Asia: A Panel Analysis
Authors: Ahmed Azreen Benazir Abdullah , Amin Sakib , Harvie Charles , Nepal Rabindra
Published: May 2021

Following Sadorsky (Energy Economics, 2011, 33, 739), we examine the nexus between energy and trade in South Asia in a panel framework using annual data from 1990 to 2015. Given the cross‐sectional dependency issue, we use robust second‐generation panel econometric methods for the analysis. We find that variables are stationary at the first difference and cointegrated in the long run. The Dumitrescu‐Hurlin panel causality test shows a long‐run unidirectional causality from trade openness to energy consumption but not vice versa. Moreover, the panel symmetric and asymmetric estimation techniques reveal that energy consumption rises by 0.47 per cent on average and 0.83 per cent, with a 1 per cent rise in trade openness in the long run. However, a negative shock of similar magnitude reduces energy consumption by 0.37 per cent. We further fortify the panel results in the country‐level data with robust methods. We recommend energy efficiency and conservation policies and renewable energy technology augmentation policies through bilateral or multilateral trade strategies for sustainable development in the selected South Asian countries.
9000 years of changes in peat organic matter composition in Store Mosse (Sweden) traced using FTIR‐ATR
Authors: Martínez Cortizas Antonio , Sjöström Jenny K. , Ryberg Eleonor E. , Kylander Malin E. , Kaal Joeri , López‐Costas Olalla , Álvarez Fernández Noemi , Bindler Richard
Published: May 2021

Store Mosse (the ‘Great Bog’ in Swedish) is one of the most extensive bog complexes in southern Sweden (~77 km2), where pioneering palaeoenvironmental research has been carried out since the early 20th century. This includes, for example, vegetation changes, carbon and nitrogen dynamics, peat decomposition, atmospheric metal pollution, mineral dust deposition, dendrochronology, and tephrochronology. Even though organic matter (OM) represents the bulk of the peat mass and its compositional change has the potential to provide crucial ecological information on bog responses to environmental factors, peat OM molecular composition has not been addressed in detail. Here, a 568‐cm‐deep peat sequence was studied at high resolution, by attenuated reflectance Fourier‐transform infrared spectroscopy (FTIR‐ATR) in the mid‐infrared region (4000–400 cm–1). Principal components analysis was performed on selected absorbances and change‐point modelling was applied to the records to determine the timing of changes. Four components accounted for peat composition: (i) depletion/accumulation of labile (i.e. carbohydrates) and recalcitrant (i.e. lignin and other aromatics, aliphatics, organic acids and some N compounds) compounds, due to peat decomposition; (ii) variations in N compounds and carbohydrates; (iii) residual variation of lignin and organic acids; and (iv) residual variation of aliphatic structures. Peat decomposition showed two main patterns: a long‐term trend highly correlated to peat age (r = 0.87), and a short‐term trend, which showed five main phases of increased decomposition (at ~8.4–8.1, ~7.0–5.6, ~3.5–3.1, ~2.7–2.1 and ~1.6–1.3 ka) – mostly corresponding to drier climate and its effect on bog hydrology. The high peat accumulation event (~5.6–3.9 ka), described in earlier studies, is characterized by the lowest degree of peat decomposition of the whole record. Given that FTIR‐ATR is a quick, non‐destructive, cost‐effective technique, our results indicate that it can be applied in a systematic way (including multicore studies) to peat research and provide relevant information on the evolution of peatlands.
RAG enhances BCR‐ABL1‐positive leukemic cell growth through its endonuclease activity in vitro and in vivo
Authors: Yuan Meng , Wang Yang , Qin Mengting , Zhao Xiaohui , Chen Xiaodong , Li Dandan , Miao Yinsha , Otieno Odhiambo Wood , Liu Huasheng , Ma Yunfeng , Ji Yanhong
Published: May 2021

BCR‐ABL1 gene fusion associated with additional DNA lesions involves the pathogenesis of chronic myelogenous leukemia (CML) from a chronic phase (CP) to a blast crisis of B lymphoid (CML‐LBC) lineage and BCR‐ABL1+ acute lymphoblastic leukemia (BCR‐ABL1+ ALL). The recombination‐activating gene RAG1 and RAG2 (collectively, RAG) proteins that assemble a diverse set of antigen receptor genes during lymphocyte development are abnormally expressed in CML‐LBC and BCR‐ABL1+ ALL. However, the direct involvement of dysregulated RAG in disease progression remains unclear. Here, we generate human wild‐type (WT) RAG and catalytically inactive RAG‐expressing BCR‐ABL1+ and BCR‐ABL1− cell lines, respectively, and demonstrate that BCR‐ABL1 specifically collaborates with RAG recombinase to promote cell survival in vitro and in xenograft mice models. WT RAG‐expressing BCR‐ABL1+ cell lines and primary CD34+ bone marrow cells from CML‐LBC samples maintain more double‐strand breaks (DSB) compared to catalytically inactive RAG‐expressing BCR‐ABL1+ cell lines and RAG‐deficient CML‐CP samples, which are measured by γ‐H2AX. WT RAG‐expressing BCR‐ABL1+ cells are biased to repair RAG‐mediated DSB by the alternative non–homologous end joining pathway (a‐NHEJ), which could contribute genomic instability through increasing the expression of a‐NHEJ‐related MRE11 and RAD50 proteins. As a result, RAG‐expressing BCR‐ABL1+ cells decrease sensitivity to tyrosine kinase inhibitors (TKI) by activating BCR‐ABL1 signaling but independent of the levels of BCR‐ABL1 expression and mutations in the BCR‐ABL1 tyrosine kinase domain. These findings identify a surprising and novel role of RAG in the functional specialization of disease progression in BCR‐ABL1+ leukemia through its endonuclease activity.
Understanding the lived experience of connection to nature
Authors: Furness Ella
Published: May 2021

There are multiple theoretical understandings of connection to nature. Often, scholars define a connection to nature as being the outcome of a process of awakening “biophilia.” They may also define it as the maturation or development of an “ecological self,” where one sees nature as part of oneself, or as an awareness of oneself as a member of a wider biotic community. Using evidence from longitudinal in‐depth interviewing and participant observation, this article examines these differing conceptualizations of connection to nature in lived experience. We find that feeling connected to nature is about feeling an affinity for, and that one belongs within, a wider web of nonhuman relationships. This sense of feeling connected to nature is unstable; it may be felt and then recede according to the circumstances in which people live and their competing priorities. The difficulty of sustaining consistent close relationships with nature in everyday life presents some challenges to the hope that enabling people to feel connected to nature will induce reliable pro‐environmental behavior. Relationships with nature fluctuate, and it is necessary to examine how a connection to nature can be nurtured at every stage of life.
Presence of donor specific HLA class 2 antibodies (DSA class 2) is associated with development of graft fibrosis more than 10 years after liver transplantation–a retrospective single center study
Authors: Sultani Bejan , Marget Matthias , Briem‐Richter Andrea , Herrmann Jochen , Meisner Sebastian , Grabhorn Enke Freya , Ozga Ann‐Kathrin , Weidemann Sören , Herden Uta , Fischer Lutz , Sterneck Martina
Published: May 2021

Here the impact of donor specific human leukocyte antigen (HLA) class 2 antibodies (DSA cl 2) on long term outcome after liver transplantation (LT) was investigated. Altogether 156 (44 pediatric and 112 adult) LT recipients were included in the study. Graft fibrosis was assessed by liver elastography and biopsy. DSA cl 2 were determined by Luminex technology. 46% of LT recipients were positive for DSA cl 2 after a median follow‐up of 15 years. In the multivariate analysis DSA cl 2 were significantly associated with immunosuppressive monotherapy (OR 5.42; 95% CI: 1.02–28.90; p = .048). Compared to DSA cl 2 negative patients, positive recipients had significantly more graft fibrosis based on the liver stiffness (mean 9.4 ± 9.0 kPa vs. 6.5 ± 6.3 kPa; p < .002) and fibrosis stages determined by liver elastography (p = .016) and the performed liver biopsies (p = .002). Also, a significantly higher incidence of chronic rejections (11% vs. 2%; p = .045) and graft losses (6% vs. 0%; p = .043) were found. In the multivariate regression analysis DSA cl 2 were significantly associated with graft fibrosis (OR 4.57; 95% CI 1.59–13.10; p = .005). So, these data suggest that development of DSA cl 2 occurs more often with immunosuppressive monotherapy and may ultimately result in chronic rejection and graft fibrosis.
Comprehensive in vitro pro‐arrhythmic assays demonstrate that omecamtiv mecarbil has low pro‐arrhythmic risk
Authors: Qu Yusheng , Gao BaoXi , Arimura Ziva , Fang Mei , Vargas Hugo M.
Published: May 2021

Omecamtiv mecarbil (OM) is a myosin activator (myotrope), developed as a potential therapeutic agent for heart failure with reduced ejection fraction. To characterize the potential pro‐arrhythmic risk of this novel sarcomere activator, we evaluated OM in a series of International Conference on Harmonization S7B core and follow‐up assays, including an in silico action potential (AP) model. OM was tested in: (i) hERG, Nav1.5 peak, and Cav1.2 channel assays; (ii) in silico computation in a human ventricular AP (hVAP) population model; (iii) AP recordings in canine cardiac Purkinje fibers (PF); and (iv) electrocardiography analysis in isolated rabbit hearts (IRHs). OM had low potency in the hERG (half‐maximal inhibitory concentration [IC50] = 125.5 µM) and Nav1.5 and Cav1.2 assays (IC50 > 300 µM). These potency values were used as inputs to investigate the occurrence of repolarization abnormalities (biomarkers of pro‐arrhythmia) in an hVAP model over a wide range of OM concentrations. The outcome of hVAP analysis indicated low pro‐arrhythmia risk at OM concentration up to 30 µM (100‐fold the effective free therapeutic plasma concentration). In the isolated canine PF assay, OM shortened AP duration (APD)60 and APD90 significantly from 3 to 30 µM. In perfused IRH, ventricular repolarization (corrected QT and corrected JT intervals) was decreased significantly at greater than or equal to 1 µM OM. In summary, the comprehensive proarrhythmic assessment in human and non‐rodent cardiac models provided data indicative that OM did not delay ventricular repolarization at therapeutic relevant concentrations, consistent with clinical findings.
Epidermolysis bullosa dystrophica pretibialis – Clinical snapshot and management of a rare orphan disease
Authors: Will Lisa Marlen , Reichrath Jörg , Vogt Thomas
Published: May 2021

If blistering occurs in childhood, the possibility of hereditary epidermolysis bullosa should be considered even if the symptoms are mild. Besides clinical and histological examination, molecular genetic screening is diagnostically relevant. For localized forms, symptomatic, topical therapy options are currently still the primary choice. Of particular interest is the new option of topical therapy with diacerein 1 % cream. In the case of a pronounced clinical picture with extracutaneous organ involvement, multidisciplinary management is required.

In the future, new forms of therapy such as autologous epidermal stem cell transplantation and gene therapeutic procedures may be applied. Human genetic counselling is indispensable.
Golden mussel (Limnoperna fortunei) survival during winter at the northern invasion front implies a potential high‐latitude distribution
Authors: Xia Zhiqiang , Barker Justin R. , Zhan Aibin , Haffner Gordon Douglas , MacIsaac Hugh J.
Published: May 2021

Aim

Golden mussel Limnoperna fortunei is an invasive bivalve in many freshwater ecosystems in Asia and South America. Cold winter temperatures are expected to restrict its spread to high‐latitude areas. Cold tolerance and potential distribution of this species remain largely unstudied because the most extensively studied populations occur in tropical and sub‐tropical areas. We sought to investigate cold tolerance of golden mussels and to model their potential distribution at higher latitudes.

Location

China, Global.

Methods

We investigated overwintering survival of caged golden mussels in a reservoir located at the northern invasion front in north China. We then determined the lowest water temperature at which mussel filtering occurred in laboratory. Finally, we modelled relative environmental suitability globally based on Maximum Entropy using the species’ most updated occurrence records.

Results

Golden mussels in a northern invasion front reservoir could survive over a course of 6 days at <1°C, or 41 days at <2°C, or 108 days at <5°C, with 27% survival overall. Caged mussels were inaccessible to local predators and reproduced, with the subsequent population size increasing in early summer by ~280%, representing a potential source population. Laboratory tests demonstrated that the lowest water temperature at which mussels could filter water was 5.5°C, and 50% of individuals became active when temperature rose to 7.5–8.0°C. Species distribution modelling illustrated a potential distribution of golden mussels at higher latitude than presently found. Models that considered updated high‐latitude occurrence records predicted a significantly larger suitable area than currently exists, including near the lower Laurentian Great Lakes.

Main conclusions

Our findings suggest enhanced cold tolerance of golden mussels and wider potential distribution than currently exists. We emphasize the importance of examining samples from invasion fronts when developing distribution predictions for spreading invasive species.
Effect of empagliflozin on cardiorenal outcomes and mortality according to body mass index: A subgroup analysis of the EMPA‐REG OUTCOME trial with a focus on Asia
Authors: Ji Qiuhe , Ji Linong , Mu Yiming , Zhao Jiajun , Zinman Bernard , Wanner Christoph , George Jyothis T. , Zwiener Isabella , Ueki Kohjiro , Yokote Koutaro , Ogawa Wataru , Johansen Odd Erik
Published: May 2021

Aim

To investigate whether the cardiorenal benefits of the sodium‐glucose co‐transporter‐2 inhibitor empagliflozin are affected by body mass index (BMI) in type 2 diabetes patients with established cardiovascular (CV) disease, including Asians.

Methods

In this exploratory analysis of the EMPA‐REG OUTCOME trial, we used Cox regression to evaluate the effects of empagliflozin on all‐cause mortality, hospitalization for heart failure (HHF) or CV death, and incident or worsening nephropathy by baseline BMI category.

Results

Of the 7020 participants (1517 Asians [21.6%]), 934 (13.3%), 2465 (35.1%) and 3621 (51.6%) had a BMI of less than 25, 25 to less than 30, and 30 kg/m2 or higher, respectively. Overall, hazard ratios for empagliflozin versus placebo for all‐cause mortality, HHF or CV death, and incident or worsening nephropathy were 0.68 (95% CI 0.57, 0.82), 0.66 (0.55, 0.79) and 0.61 (0.53, 0.70), respectively, and were consistent across BMI categories (P values for interaction between treatment and BMI were .6772, .3087 and .6265, respectively). Results were similar in Asians using these BMI categories and categories of less than 24, 24 to less than 28, and 28 kg/m2 or higher.

Conclusion

Empagliflozin reduced cardiorenal and mortality risk regardless of BMI at baseline, including in Asians with a lower BMI.
The impact of resveratrol on skin wound healing, scarring, and aging
Authors: Hecker Andrzej , Schellnegger Marlies , Hofmann Elisabeth , Luze Hanna , Nischwitz Sebastian Philipp , Kamolz Lars‐Peter , Kotzbeck Petra
Published: May 2021

Resveratrol is a well‐known antioxidant that harbours many health beneficial properties. Multiple studies associated the antioxidant, anti‐inflammatory, and cell protective effects of resveratrol. These diverse effects of resveratrol are also potentially involved in cutaneous wound healing, scarring, and (photo‐)aging of the skin. Hence, this review highlighted the most relevant studies involving resveratrol in wound healing, scarring, and photo‐aging of the skin. A systematic review was performed and the database PubMed was searched for suitable publications. Only original articles in English that investigated the effects of resveratrol in wound healing, scarring, and (photo‐)aging of the skin were analysed. The literature search yielded a total of 826 studies, but only 41 studies met the inclusion criteria. The included studies showed promising results that resveratrol might be a feasible treatment approach to support wound healing, counteract excessive scarring, and even prevent photo‐aging of the skin. Resveratrol represents an interesting and promising novel therapy regime but to confirm resveratrol‐associated effects, more evidence based in vitro and in vivo studies are needed.
Tacit Knowledge in Painting: From Studio to Classroom
Authors: Marinkovic Branka
Published: May 2021

This article discusses research that employed practice‐led and action research methods to study the tacit knowledge of painting practice and its application to teaching. Polanyi’s theory of tacit knowledge is used to analyse the non‐verbal, experience‐based knowledge of painting to construct a discursive relationship between the dual practices of painting and teaching. The research was undertaken in the context of a twelve‐week class in landscape painting for adults in a non‐profit art school. Within the context of the class, a series of paintings was created and documented. By analysing the focal and subsidiary knowledge of the painting processes, several distinct patterns of action and thinking emerged. These patterns were synthesised into three modes of thinking that integrate the mind, body and materials. The outcome of the study is a preliminary model that describes painting as a dynamic multi‐modal thinking process, integrating visual perception, material actions and expressive ways of thinking. The discussion includes a detailed description of the research methods, the data analysis, the application in teaching, and the embodied nature of cognition in the painting process.
Brain FDG‐PET findings in glutamic acid decarboxylase antibody‐associated epilepsy
Authors: Mongay‐Ochoa Neus , Sala‐Padró Jacint , Reynés‐Llompart Gabriel , Rodríguez‐Bel Laura , Jaraba Sònia , Morandeira Francisco , Falip Mercè
Published: May 2021

Background and Purpose

Glutamic acid decarboxylase antibodies (GAD‐Ab) are sometimes associated with chronic drug‐resistant focal epilepsy. Clinically, it may manifest as mesial temporal lobe epilepsy (mTLE), with GAD‐Ab patients difficult to distinguish. Therefore, the aim of this study is to compare brain metabolism of patients with mTLE and high serum titers of GAD‐Ab (>2000 UI/ml) to those with mTLE and hippocampal sclerosis (HS) and confirmed GAD‐ab negativity.

Methods

Images from PET studies were normalized to an SPM 12 template. Voxel to voxel comparisons were made using a two‐sample one‐tailedt‐test.

Results

In both patients with GAD‐Ab and controls (mTLE‐HS), hypometabolism in mesial temporal lobe areas was observed. When comparing the two groups, GAD‐Ab patients had statistically significant reduced metabolism in both insulae and medial inferior frontal‐hypothalamus area (p< 0.001).

Conclusions

Hypometabolism in mesial temporal lobe areas together with hypometabolism in insulae and medial inferior frontal‐hypothalamus may be characteristic of patients with epilepsy and GAD‐ab. This PET pattern could be a useful diagnostic tool to identify GAD‐Ab patients.
Explaining Unfavorable Attitudes Toward Religious Out‐Groups Among Three Major Religions
Authors: Kanol Eylem
Published: May 2021

Considering intensifying sectarian conflicts in recent years and increasing interreligious violence around the globe, there is a need to further our understanding of negative attitudes toward religious out‐groups. To investigate the driving factors behind these negative attitudes among members of the three major Abrahamic religions, I employ original data derived from a survey fielded among 10,046 respondents in eight countries (Cyprus, Germany, Israel, Kenya, Lebanon, Palestine, Turkey, and the USA). A rich body of literature documents the relationship between religious fundamentalism and prejudice. Other scholars have investigated out‐group hostility using an intergroup relations perspective, focusing on contact theory, and more recently, on discrimination. While controlling for other relevant factors such as demographic and socioeconomic variables, I investigate the role of religiosity and intergroup relations in explaining unfavorable interreligious attitudes. The results suggest that unfavorable attitudes toward religious out‐groups are most strongly associated with religious fundamentalism. This finding is robust across religious groups.
A rare case of a necrotized urethral prolapse in a postmenopausal woman with acute urinary retention
Authors: Abuhasanein Suleiman , Holmin Emelie , Swärd Jesper , Ruplys Rimgaudas , Sagen Erik
Published: May 2021

Case

Urethral prolapse (UP) is a rare condition with unknown etiology. We reported on an 86‐year‐old woman with a normal BMI and cystocele, presented with acute urinary retention and perineal pain. A residual urine of 950 mL was measured and released by an indwelling catheter. The physical examination revealed 2 × 3 cm severely sore and purple polyp around the urethral meatus with signs of necrosis. A diagnosis of a strangulated urethral prolapse was stated.

Outcome

The patient was admitted to the Department of Urology, and treated with surgical excision using the four‐quadrant excisional technique. The histopathological examination revealed a non‐keratinized, inflammatory squamous epithelium. At a follow‐up visit, the patient remained asymptomatic and a complete anatomical resolution was achieved.

Conclusion

UP is an uncommon, sometimes misdiagnosed condition. The management is controversial and to date no consensus exists. This clinical picture is sufficient for diagnosis and surgical excision of the prolapsed urethral mucosa is reasonable if there are signs of strangulation.
Effective behavior change techniques to promote physical activity in adults with overweight or obesity: A systematic review and meta‐analysis
Authors: Carraça Eliana , Encantado Jorge , Battista Francesca , Beaulieu Kristine , Blundell John , Busetto Luca , van Baak Marleen , Dicker Dror , Ermolao Andrea , Farpour‐Lambert Nathalie , Pramono Adriyan , Woodward Euan , Bellicha Alice , Oppert Jean‐Michel
Published: May 2021

Multicomponent behavior change interventions are typically used in weight management, but results are largely heterogeneous and modest. Determining which techniques (behavior change technique [BCTs]) are more effective in changing behavior is thus required. This study aimed to identify the most effective BCTs for increasing physical activity (PA) in digital and face‐to‐face behavior change interventions in adults with overweight/obesity. Four databases were searched for eligible studies until October 2019. BCTs were coded using BCTTv1 and MBCT taxonomies. Sixty‐two RCTs were included. Meta‐regressions were performed to explore BCTs' moderating role. Five BCTs showed significant moderator effects on PA in digital interventions: goal setting behavior, goal setting outcome, graded tasks, social incentive, and self‐monitoring of behavior (adjusted R2's = 0.15–0.51). One BCT showed significant moderator effects on PA in face‐to‐face interventions, behavioral practice and rehearsal (adjusted R2 = 0.22). Multivariate and sensitivity analysis generally led to similar findings. Effective BCTs for increasing PA in adults with overweight/obesity in digital and face‐to‐face interventions seem to differ. Evidence suggests that using goal setting, social incentive, and graded tasks might help improve PA in digital interventions while avoiding inconsistent self‐monitoring of behavior. In face‐to‐face interventions, prompting behavioral practice and rehearsal might lead to better PA outcomes. Still, further studies are needed. Implications of the current findings are discussed.
Luminogenic D‐Luciferin Derivatives as OATP1B1 and 1B3 Substrates in No‐wash Assays†
Authors: Ma Dongping , Wang Hui , Ugo Tim , Mustafa Dana , Zhou Wenhui , Cali James J.
Published: May 2021

The human hepatic organic ion transporting polypeptides OATP1B1 and ‐1B3 are uptake transporters that influence the disposition of several small molecule drugs and perpetrate certain adverse drug‐drug interactions. To predict these in vivo effects, in vitro systems are used to screen new drug entities as potential transporter substrates or inhibitors. To simplify such studies, we synthesized luminogenic derivatives of the OATP1B1 and ‐1B3 substrate D‐luciferin to test as probe substrates in a rapid, no‐wash optical approach for substrate and inhibitor identification and characterization. Each derivative is a pro‐luciferin containing a self‐immolating trimethyl lock quinone linker that is sensitive to intracellular reducing environments that cause the release of free luciferin in proportion to the amount of probe taken up by the transporter. A subsequent luciferin‐limited luciferase reaction produces light in proportion to transporter activity. We tested the derivatives in HEK293 cells that overexpress OATP1B1 or OATP1B3 by transient transfection or viral transduction. Derivatives were identified that showed OATP‐dependent uptake that was time and concentration dependent, saturable and sensitive to inhibition by known OATP1B1 and ‐1B3 substrates and inhibitors. These luminogenic transporter probes enabled an add‐only multi‐well plate protocol suitable for automation and high throughput screening.
Linear Acceleration at Head Impact in Collegiate Divers: A Pilot Study
Authors: Wood Tyler A. , Tablerion Jake M. , Ballard Randy A. , Zimmerman Jerrad , Sosnoff Jacob J.
Published: May 2021

There is minimal biomechanical research examining head impacts in noncollision sport, such as diving. This pilot study quantified the number of head impacts and magnitude of linear head acceleration in collegiate divers. Three participants wore instrumented swim caps for 10 practice sessions. A total of 1,271 dives were recorded and analyzed. Acceleration at impact ranged from 24.1g to 33.3g for 1-m dives and from 31.6g to 38.4g for 3-m dives. Simple main effects were observed for dive type (p > .001) and dive distance (p > .001). The current data suggest diving athletes experience considerable head acceleration, yet more research is needed to understand the potential implications.
Physical Performance Differences Between Spanish Selected and Nonselected Para-Footballers With Cerebral Palsy for the National Team
Authors: Peña-González Iván , Sarabia José M. , Roldan Alba , Manresa-Rocamora Agustín , Moya-Ramón Manuel
Published: May 2021

In regular football, the players’ selection process involves an objective assessment based on their anthropometric and physical performance. However, available literature focused on players’ selection process in cerebral palsy (CP) football is scarce. Purpose: To describe the anthropometrical and physical performance profiles of the International Spanish CP footballers and to compare them with the remaining CP football players from the national competition. Method: A total of 75 CP football players from the Spanish CP Football National Competition (classified into the 3 existing classes: football class [FT] 1 = 38; FT2 = 29; FT3 = 8) participated in the study. Participants were divided into 2 groups: selected players (n = 15) and nonselected players (n = 60) for the national team. Anthropometrical data and physical performance (countermovement jump, 20-m sprint, modified agility T-test [MAT], and dribbling test) were collected. Results: There were significant differences in the 20-m sprint, MAT, and dribbling for the total sample and in MAT and dribbling for FT2 and FT3 classes between selected players and nonselected players (P < .05), but there were no differences for FT1. The MAT and dribbling showed a positive correlation and a high percentage of player selection prediction. Conclusion: Change-of-direction ability (ie, MAT) and dribbling skills are important when performing the selection process, as they allow the evaluation of important aspects of the game, but they may also provide the technical staff with an idea of the functionality and the physical performance of the players in each sport class.
Examining the Relationship Between Parental Stress and Girls’ and Boys’ Physical Activity Among Racially/Ethnically Diverse and Immigrant/Refugee Populations
Authors: Berge Jerica M. , Cheatom Octavia , Fertig Angela R. , Tate Allan , Trofholz Amanda , Brito Junia N. , Shippee Nathan
Published: May 2021

Given the high prevalence of overweight/obesity and the low prevalence of engaging in physical activity in children, it is important to identify barriers that impede child physical activity. One potential barrier is parental stress. The current study examined the association between parental stress levels and girls’ and boys’ moderate to vigorous physical activity. Children aged 5–7 years and their families (n = 150) from 6 racial/ethnic groups (n = 25 each Black, Hispanic, Hmong, Native American, Somali, and White families) were recruited for the Family Matters mixed-methods study in 2015 through primary care clinics in Minneapolis and St Paul, MN. Two in-home visits were carried out with families 10 days apart for data collection, with an 8-day observational period in between when children wore accelerometers. Higher parental stress levels were associated with fewer minutes of moderate to vigorous physical activity in girls (P < .05) compared with boys. On average, girls with a parent reporting a stress rating of 10 engaged in 24 minutes less of physical activity per day than girls with a parent with a stress rating of 1. The results suggest that parental stress may reduce girls’ engagement in physical activity. The implications of these results include targeting parental stress and coping skills in future physical activity interventions. In addition, when addressing child physical activity in health care visits with parents and daughters, providers may want to focus their anticipatory guidance on parental stress and coping skills in addition to providing resources to help parents manage stress.
Interrogating hot electrons in tunnel junctions
Authors: Martín-Moreno Luis
Published: May 2021

Electronic transport reveals excited-carrier energy distribution in plasmonic nanostructures
Fiction meets the near future

Burn-In: A Novel of the
Real
Robotic Revolution

P. W. Singer and August Cole
Houghton Mifflin Harcourt, 2020. 432 pp.
Authors: Lucas George
Published: May 2021

An action-packed thriller explores the implications of emerging technologies
Beth Cindy Levine (1960–2020)
Authors: Virgin Herbert W. , Cuervo Ana Maria , Xavier Ramnik J.
Published: May 2021

Visionary physician scientist who linked autophagy to disease