Molecular Background of Pi Deficiency-Induced Root Hair Growth in Brassica carinata – A Fasciclin-Like Arabinogalactan Protein Is Involved

Formation of longer root hairs under limiting phosphate (P) conditions can increase the inorganic P (Pi) uptake. Here, regulatory candidate genes for Pi deficiency-induced root hair growth were identified by comparison of massive analysis of cDNA ends (MACE) provided expression profiles of two Brassica carinata cultivars (cv.) differing in their root hair response to Pi deficiency: cv. Bale develops longer root hairs under Pi deficiency, but not cv. Bacho. A split-root experiment was conducted for the differentiation between locally and systemically regulated genes. Furthermore, plants were exposed to nitrogen and potassium deficiency to identify P-specific reacting genes. The latter were knocked out by CRISPR/Cas9 and the effect on the root hair length was determined. About 500 genes were differentially expressed under Pi deficiency in cv. Bale, while these genes did not respond to the low P supply in cv. Bacho. Thirty-three candidate genes with a potential regulatory role were selected and the transcriptional regulation of 30 genes was confirmed by quantitative PCR. Only five candidate genes seemed to be either exclusively regulated locally (two) or systemically (three), whereas 25 genes seemed to be involved in both local and systemic signaling pathways. Potassium deficiency affected neither the root hair length nor the expression of the 30 candidate genes. By contrast, both P and nitrogen deficiency increased the root hair length, and both affected the transcript levels in 26 cases. However, four genes reacted specifically to Pi starvation. These genes and, additionally, INORGANIC PHOSPHATE TRANSPORTER 1 (BcPHT1) were targeted by CRISPR/Cas9. However, even if the transcript levels of five of these genes were clearly decreased, FASCICLIN-LIKE ARABINOGALACTAN PROTEIN 1 (BcFLA1) was the only gene whose downregulation reduced the root hair length in transgenic hairy roots under Pi-deficient conditions. To the best of our knowledge, this is the first study describing a fasciclin-like arabinogalactan protein with a predicted role in the Pi deficiency-induced root hair elongation

Histone deacetylase activity is essential for the expression of HoxA9 and for endothelial commitment of progenitor cells

The regulation of acetylation is central for the epigenetic control of lineage-specific gene expression and determines cell fate decisions. We provide evidence that the inhibition of histone deacetylases (HDACs) blocks the endothelial differentiation of adult progenitor cells. To define the mechanisms by which HDAC inhibition prevents endothelial differentiation, we determined the expression of homeobox transcription factors and demonstrated that HoxA9 expression is down-regulated by HDAC inhibitors. The causal involvement of HoxA9 in the endothelial differentiation of adult progenitor cells is supported by the finding that HoxA9 overexpression partially rescued the endothelial differentiation blockade induced by HDAC inhibitors. Knockdown and overexpression studies revealed that HoxA9 acts as a master switch to regulate the expression of prototypical endothelial-committed genes such as endothelial nitric oxide synthase, VEGF-R2, and VE-cadherin, and mediates the shear stress–induced maturation of endothelial cells. Consistently, HoxA9-deficient mice exhibited lower numbers of endothelial progenitor cells and showed an impaired postnatal neovascularization capacity after the induction of ischemia. Thus, HoxA9 is regulated by HDACs and is critical for postnatal neovascularization

SARS-CoV-2 Variant of Concern B.1.1.7: Diagnostic Sensitivity of Three Antigen-Detecting Rapid Tests.

Funder: Foundation for Innovative New DiagnosticsFunder: World Health OrganizationFunder: Ministry of Science, Research and Culture, State of Baden Wuerttemberg, German

Targeting inflammation to reduce cardiovascular disease risk: a realistic clinical prospect?

Data from basic science experiments is overwhelmingly supportive of the causal role of immune-inflammatory response(s) at the core of atherosclerosis, and therefore the theoretical potential to manipulate the inflammatory response to prevent cardiovascular events. However, extrapolation to humans requires care and we still lack definitive evidence to show that interfering in immune-inflammatory processes may safely lessen clinical atherosclerosis. In this review, we discuss key therapeutic targets in the treatment of vascular inflammation, placing basic research in to a wider clinical perspective, as well as identifying outstanding questions

Von Offener Wissenschaft zu Zugänglicher Wissenschaft ⁄ Diskussionspapier

Dieses Diskussionspapier richtet sich an die bestehende Open Science Community bzw. an alle Interessierten, die sich dazuzählen. Es will mit vier Perspektiven zu einer anderen Sicht auf Offene Wissenschaft beitragen, Anregungen zur Reflexion von Konzepten und Praktiken Offener Wissenschaft geben, Problemfelder aufzeigen und Fragen als Denkanstöße formulieren. Wie zugänglich sind die Ansätze Offener Wissenschaft bzw. Open Science eigentlich, und für wen? Inwieweit werden die als normatives Ideal einer modernen Form des Betreibens von Wissenschaft formulierten Ansprüche an Offenheit tatsächlich eingelöst? Welche Bevölkerungsgruppen werden von Kommunikationsaktivitäten und einer Einladung zur Mitwirkung angesprochen, wer nimmt es tatsächlich in Anspruch? Inwieweit betreffen die immer noch bestehenden Hindernisse für Open Science in Form von Strukturen und Anreizsystemen in der Wissenschaft manche Menschen besonders, und inwieweit können Open Science Ansätze selbst ausschließend wirken? Und wie kann Open-Science ganz praktisch einladender und zugänglicher gestaltet werden? Dieses Diskussionspapier entstand im Rahmen des Fellow-Projektes von Philipp Schrögel im Jahrgang 2019 des Fellowship Freies Wissen von Wikimedia Deutschland, dem Stifterverband und der VolkswagenStiftung, in Zusammenarbeit mit Svenja Rühland von innOsci, dem Forum offene Innovationskultur, einem Projekt des Stifterverbandes und des Bundesministeriums für Bildung und Forschung

Histone deacetylase (HDAC) inhibitors in recent clinical trials for cancer therapy

Heritable changes in gene expression that are not based upon alterations in the DNA sequence are defined as epigenetics. The most common mechanisms of epigenetic regulation are the methylation of CpG islands within the DNA and the modification of amino acids in the N-terminal histone tails. In the last years, it became evident that the onset of cancer and its progression may not occur only due to genetic mutations but also because of changes in the patterns of epigenetic modifications. In contrast to genetic mutations, which are almost impossible to reverse, epigenetic changes are potentially reversible. This implies that they are amenable to pharmacological interventions. Therefore, a lot of work in recent years has focussed on the development of small molecule enzyme inhibitors like DNA-methyltransferase inhibitors or inhibitors of histone-modifying enzymes. These may reverse misregulated epigenetic states and be implemented in the treatment of cancer or other diseases, e.g., neurological disorders. Today, several epigenetic drugs are already approved by the FDA and the EMEA for cancer treatment and around ten histone deacetylase (HDAC) inhibitors are in clinical development. This review will give an update on recent clinical trials of the HDAC inhibitors used systemically that were reported in 2009 and 2010 and will present an overview of different biomarkers to monitor the biological effects

Endothelial progenitor cells and integrins: adhesive needs

In the last decade there have been multiple studies concerning the contribution of endothelial progenitor cells (EPCs) to new vessel formation in different physiological and pathological settings. The process by which EPCs contribute to new vessel formation in adults is termed postnatal vasculogenesis and occurs via four inter-related steps. They must respond to chemoattractant signals and mobilize from the bone marrow to the peripheral blood; home in on sites of new vessel formation; invade and migrate at the same sites; and differentiate into mature endothelial cells (ECs) and/or regulate pre-existing ECs via paracrine or juxtacrine signals. During these four steps, EPCs interact with different physiological compartments, namely bone marrow, peripheral blood, blood vessels and homing tissues. The success of each step depends on the ability of EPCs to interact, adapt and respond to multiple molecular cues. The present review summarizes the interactions between integrins expressed by EPCs and their ligands: extracellular matrix components and cell surface proteins present at sites of postnatal vasculogenesis. The data summarized here indicate that integrins represent a major molecular determinant of EPC function, with different integrin subunits regulating different steps of EPC biology. Specifically, integrin α4β1 is a key regulator of EPC retention and/or mobilization from the bone marrow, while integrins α5β1, α6β1, αvβ3 and αvβ5 are major determinants of EPC homing, invasion, differentiation and paracrine factor production. β2 integrins are the major regulators of EPC transendothelial migration. The relevance of integrins in EPC biology is also demonstrated by many studies that use extracellular matrix-based scaffolds as a clinical tool to improve the vasculogenic functions of EPCs. We propose that targeted and tissue-specific manipulation of EPC integrin-mediated interactions may be crucial to further improve the usage of this cell population as a relevant clinical agent

In Vitro Differentiation of Embryonic and Adult Stem Cells into Hepatocytes: State of the Art

Stem cells are a unique source of self-renewing cells within the human body. Before the end of the last millennium, adult stem cells, in contrast to their embryonic counterparts, were considered to be lineage-restricted cells or incapable of crossing lineage boundaries. However, the unique breakthrough of muscle and liver regeneration by adult bone marrow stem cells at the end of the 1990s ended this long-standing paradigm. Since then, the number of articles reporting the existence of multipotent stem cells in skin, neuronal tissue, adipose tissue, and bone marrow has escalated, giving rise, both in vivo and in vitro, to cell types other than their tissue of origin. The phenomenon of fate reprogrammation and phenotypic diversification remains, though, an enigmatic and rare process. Understanding how to control both proliferation and differentiation of stem cells and their progeny is a challenge in many fields, going from preclinical drug discovery and development to clinical therapy. In this review, we focus on current strategies to differentiate embryonic, mesenchymal(-like), and liver stem/progenitor cells into hepatocytes in vitro. Special attention is paid to intracellular and extracellular signaling, genetic modification, and cell-cell and cell-matrix interactions. In addition, some recommendations are proposed to standardize, optimize, and enrich the in vitro production of hepatocyte-like cells out of stem/progenitor cells

Comprehensive assessments and related interventions to enhance the long-term outcomes of child, adolescent and young adult cancer survivors – presentation of the CARE for CAYA-Program study protocol and associated literature review

Background Improved, multimodal treatment strategies have been shown to increase cure rates in cancer patients. Those who survive cancer as a child, adolescent or young adult (CAYA), are at a higher risk for therapy-, or disease-related, late or long-term effects. The CARE for CAYA-Program has been developed to comprehensively assess any potential future problems, to offer need-based preventative interventions and thus to improve long-term outcomes in this particularly vulnerable population. Methods The trial is designed as an adaptive trial with an annual comprehensive assessment followed by needs stratified, modular interventions, currently including physical activity, nutrition and psycho-oncology, all aimed at improving the lifestyle and/or the psychosocial situation of the patients. Patients, aged 15–39 years old, with a prior cancer diagnosis, who have completed tumour therapy and are in follow-up care, and who are tumour free, will be included. At baseline (and subsequently on an annual basis) the current medical and psychosocial situation and lifestyle of the participants will be assessed using a survey compiled of various validated questionnaires (e.g. EORTC QLQ C30, NCCN distress thermometer, PHQ-4, BSA, nutrition protocol) and objective parameters (e.g. BMI, WHR, co-morbidities like hyperlipidaemia, hypertension, diabetes), followed by basic care (psychological and lifestyle consultation). Depending on their needs, CAYAs will be allocated to preventative interventions in the above-mentioned modules over a 12-month period. After 1 year, the assessment will be repeated, and further interventions may be applied as needed. During the initial trial phase, the efficacy of this approach will be compared to standard care (waiting list with intervention in the following year) in a randomized study. During this phase, 530 CAYAs will be included and 320 eligible CAYAs who are willing to participate in the interventions will be randomly allocated to an intervention. Overall, 1500 CAYAs will be included and assessed. The programme is financed by the innovation fund of the German Federal Joint Committee and will be conducted at 14 German sites. Recruitment began in January 2018. Discussion CAYAs are at high risk for long-term sequelae. Providing structured interventions to improve lifestyle and psychological situation may counteract against these risk factors. The programme serves to establish uniform regular comprehensive assessments and need-based interventions to improve long-term outcome in CAYA survivors. Trial registration Registered at the German Clinical Trial Register (ID: DRKS00012504, registration date: 19th January 2018)