bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractThe 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.ImportancePalmerolide 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

SUMMARYThe 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

ABSTRACTCecropins 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.
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

AbstractBCR‐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

AbstractThere 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

AbstractHere 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

AbstractOmecamtiv 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

SummaryIf 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

AbstractAimGolden 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.LocationChina, Global.MethodsWe 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.ResultsGolden 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 conclusionsOur 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.