bluuebunny/crossref_metadata_2025_split huggingface dataset:
Endothelial Dnmt3a controls placenta vascularization and function to support fetal growth
Authors: Gehrs Stephanie , Jakab Moritz , Gutjahr Ewgenija , Gu Zuguang , Weichenhan Dieter , Mogler Carolin , Schlesner Matthias , Plass Christoph , Augustin Hellmut G. , Schlereth Katharina 
Published: July 2022

AbstractThe fetoplacental capillary network is of vital importance for proper nourishment during early development. Inadequate maternal-fetal circulation has emerged as one of the main pathophysiological features of placental insufficiency. Meta-analysis of human placental endothelial cells (EC) revealed that downregulation of the de novo DNA methyltransferase 3A (DNMT3A) is associated with preeclampsia. However, mechanistic insights into functional consequences of altered DNA methylation patterns during placental vascular development remain elusive. Here, we investigated the role of Dnmt3a in the vasculature during murine placenta development. Spatial and temporal expression analyses revealed an induction of Dnmt3a in the mature labyrinth layer. The global and endothelium-specific loss (ECKO) of Dnmt3a resulted in reduced placental vascularization and fetal growth restriction. EC deleted for Dnmt3a demonstrated extensive loss of DNA methylation, particularly close to angiogenesis related genes. Loss of DNA methylation decreased the angiogenic capacity of EC in vitro and in vivo. Collectively, these data identify DNMT3A as the main DNA methyltransferase in the human and murine placental vasculature and characterize its importance for physiological endothelial function. The Dnmt3a-dependent regulation of genes related to placenta insufficiency validates Dnmt3a ECKO mice as an epigenetically driven mouse model of placenta insufficiency with potential translational relevance.
PEPseq Quantifies Transcriptome-Wide Changes in Protein Occupancy and Reveals Selective Translational Repression After Translational Stress
Authors: Trendel Jakob , Boileau Etienne , Jochem Marco , Dieterich Christoph , Krijgsveld Jeroen 
Published: July 2022

AbstractPost-transcriptional gene regulation is accomplished by the interplay of the transcriptome with RNA-binding proteins, which occurs in a dynamic manner in response to altered cellular conditions. Recording the combined occupancy of all proteins binding to the transcriptome offers the opportunity to interrogate if a particular treatment leads to any interaction changes, pointing to sites in RNA that undergo post-transcriptional regulation. Here, we establish a method to monitor protein occupancy in a transcriptome-wide fashion by RNA sequencing. To this end, peptide-enhanced pull-down for RNA sequencing (or PEPseq) uses metabolic RNA labelling with 4-thiouridine (4SU) for light-induced protein-RNA crosslinking, and N-hydroxysuccinimide (NHS) chemistry to isolate protein-crosslinked RNA fragments across all long RNA biotypes. We use PEPseq to investigate changes in protein occupancy during the onset of arsenite-induced translational stress in human cells and reveal evidence for ribosome stalling and depletion from stress granules for a distinct set of mRNAs, many coding for ribosomal proteins. We use quantitative proteomics to demonstrate that translation of these mRNAs remains repressed during the initial hours of recovery after arsenite stress. Thus, we present PEPseq as a discovery platform for the unbiased investigation of post-transcriptional regulation.
Targeting triple-negative breast cancer with β1-integrin binding aptamer
Authors: Pleiko Karlis , Haugas Maarja , Parfejevs Vadims , Pantelejevs Teodors , Parisini Emilio , Teesalu Tambet , Riekstina Una 
Published: July 2022

ABSTRACTTargeted therapies have increased the treatment options for triple-negative breast cancer patients. However, the paucity of targetable biomarkers and tumour heterogeneity have limited the ability of precision-guided interventions to live up to their full potential. As affinity targeting ligands, aptamers show high selectivity towards target molecules. Compared to antibodies, aptamers have lower molecular weight, increased stability during transportation, reduced immunogenicity, and increased tissue uptake. Recently, we reported the discovery of GreenB1 aptamer that is internalized in cultured triple-negative MDA-MB-231 human breast cancer cells. We show that the GreenB1 aptamer specifically targets β1-integrin, a protein previously linked to breast cancer cell invasiveness and migration. Aptamer binds to β1-integrin with low nanomolar affinity. GreenB1 homes in the orthotopic 4T1 triple-negative breast cancer lesions modelled in mice. Our findings suggest potential applications for the GreenB1-guided precision agents for the diagnosis and therapy of triple-negative breast cancer.
A unique peptide recognition mechanism by the human relaxin family peptide receptor 4 (RXFP4)
Authors: Chen Yan , Zhou Qingtong , Wang Jiang , Xu Youwei , Wang Yun , Yan Jiahui , Wang Yibing , Zhu Qi , Zhao Fenghui , Li Chenghao , Chen Chuan-Wei , Cai Xiaoqing , Bathgate Ross A.D. , Shen Chun , Xu H. Eric , Yang Dehua , Liu Hong , Wang Ming-Wei 
Published: July 2022

AbstractMembers of the insulin superfamily regulate a variety of biological processes through two types of target-specific but structurally conserved peptides, insulin/insulin-like growth factors and relaxin/insulin-like peptides. The latter bind to the human relaxin family peptide receptors (RXFPs), which are class A G protein-coupled receptors (GPCRs), to exert pleiotropic actions. Here, we report three cryo-electron microscopy structures of RXFP4–Giprotein complexes in the presence of the endogenous ligand insulin-like peptide 5 (INSL5) or one of the two small molecule agonists, compound 4 and DC591053, both were discovered through medicinal chemistry efforts. The B chain of INSL5 adopts a single α-helix that penetrates into the orthostatic pocket, while the A chain sits above the orthosteric pocket to interact with the extracellular surface of RXFP4, revealing a unique peptide-binding mode previously unknown. Together with mutagenesis and functional analyses, the key determinants responsible for the peptidomimetic agonism and subtype selectivity were identified. DC591053 selectively mimicked the action of INSL5 at RXFP4 whereas compound 4 activated both RXFP3 and RXFP4. Comparison of peptide binding modes within the insulin superfamily displayed diverse interaction mechanisms distinct to each type of the peptides. Our findings not only provide valuable insights into ligand recognition and subtype selectivity among class A GPCRs, but also expand the knowledge of signaling mechanisms in the insulin superfamily.
A clade of RHH proteins ubiquitous in Sulfolobales and their viruses regulates cell cycle progression
Authors: Li X , Lozano-Madueño C , Martínez-Alvarez L , Peng X 
Published: July 2022

ABSTRACTCell cycle regulation is crucial for all living organisms and is often targeted by viruses to facilitate their own propagation, yet cell cycle progression control is largely underexplored in archaea. In this work, we reveal a cell cycle regulator (aCcr1) carrying a ribbon-helix-helix (RHH) domain and ubiquitous in the crenarchaeal order Sulfolobales and their viruses. Overexpression of several aCcr1 members including gp21 of rudivirus SIRV2 and its host homolog SiL_0190 of S. islandicus LAL14/1 results in impairment of cell division, evidenced by growth retardation, cell enlargement and an increase in cellular DNA content. Additionally, both gp21 and SiL_0190 can bind to the motif AGTATTA conserved in the promoter of several genes involved in cell division, DNA replication and cellular metabolism thereby repressing or inducing their transcription. Our results suggest that aCcr1 silences cell division and drives progression to the S-phase in Sulfolobales, a function exploited by viruses to facilitate viral propagation.
A multispecific antibody prevents immune escape and confers pan-SARS-CoV-2 neutralization
Authors: Misasi John , Wei Ronnie R. , Wang Lingshu , Pegu Amarendra , Wei Chih-Jen , Oloniniyi Olamide K. , Zhou Tongqing , Moliva Juan I. , Zhao Bingchun , Choe Misook , Yang Eun Sung , Zhang Yi , Boruszczak Marika , Chen Man , Leung Kwan , Li Juan , Yang Zhi-Yong , Andersen Hanne , Carlton Kevin , Godbole Sucheta , Harris Darcy R. , Henry Amy R. , Ivleva Vera B. , Lei Paula , Liu Cuiping , Longobardi Lindsay , Merriam Jonah S. , Nase Danielle , Olia Adam S. , Pessaint Laurent , Porto Maciel , Shi Wei , Wolff Jeremy J. , Douek Daniel C. , Suthar Mehul S. , Gall Jason , Koup Richard A. , Kwong Peter D. , Mascola John R. , Nabel Gary J. , Sullivan Nancy J. 
Published: July 2022

Summary ParagraphDespite effective countermeasures, SARS-CoV-2 persists worldwide due to its ability to diversify and evade human immunity1. This evasion stems from amino-acid substitutions, particularly in the receptor-binding domain of the spike, that confer resistance to vaccines and antibodies2–16. To constrain viral escape through resistance mutations, we combined antibody variable regions that recognize different receptor binding domain (RBD) sites17,18into multispecific antibodies. Here, we describe multispecific antibodies, including a trispecific that prevented virus escape >3000-fold more potently than the most effective clinical antibody or mixtures of the parental antibodies. Despite being generated before the evolution of Omicron, this trispecific antibody potently neutralized all previous variants of concern and major Omicron variants, including the most recent BA.4/BA.5 strains at nanomolar concentrations. Negative stain electron microscopy revealed that synergistic neutralization was achieved by engaging different epitopes in specific orientations that facilitated inter-spike binding. An optimized trispecific antibody also protected Syrian hamsters against Omicron variants BA.1, BA.2 and BA.5, each of which uses different amino acid substitutions to mediate escape from therapeutic antibodies. Such multispecific antibodies decrease the likelihood of SARS-CoV-2 escape, simplify treatment, and maximize coverage, providing a strategy for universal antibody therapies that could help eliminate pandemic spread for this and other pathogens.
Seven principles to ensure future-ready accounting graduates – a model for future research and practice
Authors: De Villiers Rouxelle 
Published: July 2022

Purpose
The business environment is changing and education at university business schools does not appear to keep pace. This paper aims to identify principles to guide educators in preparing accounting students for automation and artificial intelligence and sets an agenda for future research.

Design/methodology/approach
The seven principles are derived from an extensive literature review and the analysis of qualitative data from focus groups, thought leader discussions, interviews and workshops.

Findings
The derived seven Cs model includes: critical, conceptual thinking and the spirit of enquiry; complicate, grapple and fail; create, innovate and experience; concise communication; collaboration; consciousness, respectfulness and ethical fibre; and curiosity, lifelong learning and specialized generalists. An inclusive list of future research topics related to the seven Cs model is provided to aid researchers’ agendas.

Research limitations/implications
Although every attempt was made to base this study purely on expert opinions, as reflected in journal articles, conference papers, interviews and focus groups, it is impossible to prevent author biases from slipping into the interpretation and reflection involved in creating the model. Readers will also find some overlap in terms of the accounting business competencies development model’s seven Cs, due to the inter-related nature of the concepts and because the various definitions of concepts have some habits of the mind and social competencies in common.

Practical implications
The seven principles will help business schools and higher education policymakers guide future education developments with a focus on new competencies and reframed skills, as opposed to new knowledge. The model ensures that scholars and graduates have insight into the essential knowledge, attributes and skills that apply to the diverse nature of accounting vocations and can adapt to unanticipated changes.

Social implications
This new model can be used by business schools to ensure that graduates can fully contribute to a society impacted by automation and artificial intelligence by entering the workplace with the requisite skills. It also responds to critics’ fears about the role of business schools in preparing graduates for the future of work.

Originality/value
The paper contributes in two ways. First, rather than focussing on particular issues or the shortcomings of current education, it identifies broad-based principles from a literature review, interviews, focus groups and workshops. Second, it sets an agenda for future research.
Long‐term experimental drought alters floral scent and pollinator visits in a Mediterranean plant community despite overall limited impacts on plant phenotype and reproduction
Authors: Jaworski Coline C. , Geslin Benoît , Zakardjian Marie , Lecareux Caroline , Caillault Pauline , Nève Gabriel , Meunier Jean‐Yves , Dupouyet Sylvie , Sweeney Aoife C. T. , Lewis Owen T. , Dicks Lynn V. , Fernandez Catherine 
Published: July 2022

Abstract

Pollinators are declining globally, with climate change implicated as an important driver. Climate change can induce phenological shifts and reduce floral resources for pollinators, but little is known about its effects on floral attractiveness and how this might cascade to affect pollinators, pollination functions and plant fitness.

We used an in situ long‐term drought experiment to investigate multiple impacts of reduced precipitation in a natural Mediterranean shrubland, a habitat where climate change is predicted to increase the frequency and intensity of droughts. Focusing on three insect‐pollinated plant species that provide abundant rewards and support a diversity of pollinators (Cistus albidus, Salvia rosmarinus and Thymus vulgaris), we investigated the effects of drought on a suite of floral traits including nectar production and floral scent. We also measured the impact of reduced rainfall on pollinator visits, fruit set and germination in S. rosmarinus and C. albidus.

Drought altered floral emissions of all three plant species qualitatively, and reduced nectar production in T. vulgaris only. Apis mellifera and Bombus gr. terrestris visited more flowers in control plots than drought plots, while small wild bees visited more flowers in drought plots than control plots. Pollinator species richness did not differ significantly between treatments. Fruit set and seed set in S. rosmarinus and C. albidus did not differ significantly between control and drought plots, but seeds from drought plots had slower germination for S. rosmarinus and marginally lower germination success in C. albidus.

Synthesis. Overall, we found limited but consistent impacts of a moderate experimental drought on floral phenotype, plant reproduction and pollinator visits. Increased aridity under climate change is predicted to be stronger than the level assessed in the present study. Drought impacts will likely be stronger and this could profoundly affect the structure and functioning of plant–pollinator networks in Mediterranean ecosystems.
Therapeutic management and outcomes in inflammatory bowel diseases, 2010 to 2017 in cohorts from Denmark, Sweden and Norway
Authors: Zhao Mirabella , Lirhus Sandre , Lördal Mikael , Langholz Ebbe , Knudsen Torben , Voutilainen Markku , Høivik Marte Lie , Moum Bjorn , Anisdahl Karoline , Sæbø Borghild , Haiko Paula , Malmgren Carolina , Coskun Mehmet , Melberg Hans Olav , Burisch Johan 
Published: July 2022

SummaryBackgroundDespite the increasing use of biologics in patients with inflammatory bowel disease (IBD), real‐world data about outcomes in the era of biologics remain inconclusive.AimsTo investigate trends in surgeries, hospitalisations and medication use in patients with IBD in a multinational, population‐based cohortMethodsWe included 42,894 patients with ulcerative colitis (UC) and 24,864 with Crohn's disease (CD) who were diagnosed between 2010 and 2017 in Denmark, Norway and Sweden. We extracted data about surgeries, hospitalisations and medications from national registries and compared across countries and diagnosis years.ResultsBetween 2010 and 2017, 2‐year surgery rates were 4‐7% in UC and 10‐15% in CD and were stable over time. Two‐year hospitalisation rates increased in Denmark (UC: 20% to 35%; CD: 27% to 32%) but were stable in Norway and Sweden (fluctuating between 33% and 37% in UC, and 46% and 52% in CD). Two‐year rates of biologic use increased in both UC (7% to 16% in Denmark, 8% to 18% in Norway) and CD (22% to 26% in Denmark; 21% to 35% in Norway). Two‐year rates of immunomodulator use increased in Norway (from 14% to 23% in UC; 37% to 45% in CD) and Sweden (from 41% to 52% in CD), but were stable in Denmark (between 17% and 21% in UC; 39% to 46% in CD).ConclusionBetween 2010 and 2017, surgery rates among Scandinavian patients with IBD remained stable, with no clear changes in hospitalisation rates despite the increasing use of immunomodulators and biologics.
An archaeometric study of the Konya basin metallic ware through FTIR and XRD analysis with chemometrics: Central Anatolian Early Bronze Age ceramics
Authors: Tarhan İsmail , Massa Michele , Tuna Yusuf , Şahin Fatma 
Published: July 2022

AbstractFourier‐transform infrared, X‐ray diffraction and chemometrics were used to characterize the mineralogical composition and firing conditions of 59 Early Bronze Age ceramic sherds from the Konya Plain (Turkey). These include the Konya Basin Metallic Ware (KBMW) and a control group of contemporary local products. The analysis indicates significant differences in mineral inclusions and firing temperatures, with KBMW generally being fired above 800°C and characterized by standardized fabric recipes. Assessed together with other published evidence, these results indicate a high degree of specialization in the production of KBMW ceramic assemblages in central Anatolia during the third millennium BCE.
A meta‐analysis on observed paternal and maternal sensitivity
Authors: Deneault Audrey‐Ann , Cabrera Natasha J. , Bureau Jean‐François 
Published: July 2022

AbstractTwo meta‐analyses were conducted (N = 10,980 child–father dyads) with 93 studies published between 1983–2020, primarily in North America and Europe, on observed parental sensitivity to children (3–180 months; 48% girls; 14% non‐White) in partnered mothers and fathers. The first meta‐analysis found higher maternal mean levels of observed sensitivity, with a small effect size (d = −.27). Differences between parents were larger with micro coding and triadic/family assessments. Differences narrowed as a function of publication year and were not significant in European samples. The second meta‐analysis identified a moderate correlation between observed maternal and paternal sensitivity (r = .23 after adjusting for probable publication bias). Correlations were larger in Middle Eastern samples and with composite sensitivity scales.
Monkeypox: key pointers for dermatologists
Authors: Kawsar Anusuya , Hussain Khawar , Roberts Nerys 
Published: July 2022

Abstract
The current monkeypox epidemic is a major public health concern as the global outbreak continues to grow. We present a case report to highlight the salient points for dermatologists. Human monkeypox is a zoonosis caused by monkeypox virus, belonging to the Orthopoxvirus genus and is a close relative of the variola virus. Pleomorphic skin lesions appear ranging from macules, papules, vesicles, pustules, some of which may appear umbilicated before crusting over. Dermatologists play a key role in early recognition of new cases, aiding diagnoses leading to prevention of disease spread through identification and isolation, contact tracing and education.
Comparison of reproductive outcomes in subclinical hypothyroidism women with high‐normal versus low‐normal thyroid‐stimulating hormone levels after treatment with levothyroxine
Authors: Zhang Yuchao , Liu Yanli , Li Zhen , Guan Yichun 
Published: July 2022

AbstractObjectiveReproductive outcomes in euthyroid women with high‐normal thyroid‐stimulating hormone (TSH) levels are comparable to those in euthyroid women with low TSH levels; however, few studies have investigated whether strictly controlled TSH levels after levothyroxine (LT4) treatment impair reproductive outcomes in infertile women with subclinical hypothyroidism (SCH). This study aimed to investigate the impact of high‐normal versus low‐normal TSH levels on reproductive outcomes in women undergoing their first in vitro fertilisation and embryo transfer (IVF‐ET) cycle.DesignThis was a retrospective cohort study. Patients were divided into low‐normal (TSH < 2.5 mIU/L, and ≥0.27 mIU/L) and high‐normal (TSH ≥ 2.5 mIU/L, and <4.2 mIU/L) groups based on TSH levels after LT4 treatment. TSH levels after LT4 treatment and before ovarian stimulation were recorded. Reproductive outcomes were compared between the low‐normal and high‐normal TSH groups and between the euthyroid and LT4‐treated groups.ResultsA total of 6002 women, 548 of whom were LT4‐treated women, were finally included in this study. Among the LT4‐treated women, 129 women had low‐normal TSH levels, and 167 women had high‐normal TSH levels. The clinical pregnancy rate, miscarriage rate, and live birth rate were comparable between the low‐normal and high‐normal groups (all p > .05). When adjusted by age, anti‐Mullerian hormone (AMH) levels, infertility duration, transferred embryos, and dose and duration of LT4 treatment, high‐normal TSH levels neither significantly decreased miscarriage (adjusted odds ratio [aOR] = 2.27, 95% confidence interval [CI] = 0.77–6.69, p = .14) nor increased clinical pregnancy (aOR = 1.15, 95% CI = 0.70–1.89, p = .57 or live birth (aOR = 0.97, 95% CI = 0.60–1.59, p = .92). Similar obstetric outcomes were observed between the low‐normal and high‐normal TSH groups after LT4 treatment and between the euthyroid and LT4‐treated groups (all p ≥ .05).ConclusionsHigh‐normal TSH levels did not have adverse effects on clinical and obstetric outcomes when compared with low‐normal TSH levels after LT4 treatment. However, whether it is appropriate to set 2.5 mIU/L as the goal of treatment before IVF/ICSI remains to be determined in further well‐designed studies.
A Process Model for Dashboard Onboarding
Authors: Dhanoa Vaishali , Walchshofer Conny , Hinterreiter Andreas , Stitz Holger , Groeller Eduard , Streit Marc 
Published: July 2022

AbstractDashboards are used ubiquitously to gain and present insights into data by means of interactive visualizations. To bridge the gap between non‐expert dashboard users and potentially complex datasets and/or visualizations, a variety of onboarding strategies are employed, including videos, narration, and interactive tutorials. We propose a process model for dashboard onboarding that formalizes and unifies such diverse onboarding strategies. Our model introduces the onboarding loop alongside the dashboard usage loop. Unpacking the onboarding loop reveals how each onboarding strategy combines selected building blocks of the dashboard with an onboarding narrative. Specific means are applied to this narration sequence for onboarding, which results in onboarding artifacts that are presented to the user via an interface. We concretize these concepts by showing how our process model can be used to describe a selection of real‐world onboarding examples. Finally, we discuss how our model can serve as an actionable blueprint for developing new onboarding systems.