Interfering with aggregated α-synuclein in advanced melanoma leads to a major upregulation of MHC class II proteins.

Melanoma is the most serious and deadly form of skin cancer and with progression to advanced melanoma, the intrinsically disordered protein α-synuclein is upregulated to high levels. While toxic to dopaminergic neurons in Parkinson's disease, α-synuclein is highly beneficial for primary and metastatic melanoma cells. To gain detailed insights into this exact opposite role of α-synuclein in advanced melanoma, we performed proteomic studies of high-level α-synuclein-expressing human melanoma cell lines that were treated with the diphenyl-pyrazole small-molecule compound anle138b, which binds to and interferes with the oligomeric structure of α-synuclein.

dsRNA formation leads to preferential nuclear export and gene expression.

When mRNAs have been transcribed and processed in the nucleus, they are exported to the cytoplasm for translation. This export is mediated by the export receptor heterodimer Mex67-Mtr2 in the yeast Saccharomyces cerevisiae (TAP-p15 in humans). Interestingly, many long non-coding RNAs (lncRNAs) also leave the nucleus but it is currently unclear why they move to the cytoplasm.

Genetic Variants Associated with the Age of Onset Identified by Whole-Exome Sequencing in Fatal Familial Insomnia.

Fatal familial insomnia (FFI) is a rare autosomal-dominant inherited prion disease with a wide variability in age of onset. Its causes are not known. In the present study, we aimed to analyze genetic risk factors other than the prion protein gene (), in FFI patients with varying ages of onset.

Elastin stabilization prevents impaired biomechanics in human pulmonary arteries and pulmonary hypertension in rats with left heart disease.

Pulmonary hypertension worsens outcome in left heart disease. Stiffening of the pulmonary artery may drive this pathology by increasing right ventricular dysfunction and lung vascular remodeling. Here we show increased stiffness of pulmonary arteries from patients with left heart disease that correlates with impaired pulmonary hemodynamics.

Engineered skeletal muscle recapitulates human muscle development, regeneration and dystrophy.

Background: Human pluripotent stem cell-derived muscle models show great potential for translational research. Here, we describe developmentally inspired methods for the derivation of skeletal muscle cells and their utility in skeletal muscle tissue engineering with the aim to model skeletal muscle regeneration and dystrophy in vitro.

Methods: Key steps include the directed differentiation of human pluripotent stem cells to embryonic muscle progenitors followed by primary and secondary foetal myogenesis into three-dimensional muscle.

Small and long RNA transcriptome of whole human cerebrospinal fluid and serum as compared to their extracellular vesicle fractions reveal profound differences in expression patterns and impacts on biological processes.

Background: Next generation sequencing (NGS) of human specimen is expected to improve prognosis and diagnosis of human diseases, but its sensitivity urges for well-defined sampling and standardized protocols in order to avoid error-prone conclusions.

Methods: In this study, large volumes of pooled human cerebrospinal fluid (CSF) were used to prepare RNA from human CSF-derived extracellular vesicles (EV) and from whole CSF, as well as from whole human serum and serum-derived EV. In all four fractions small and long coding and non-coding RNA expression was analyzed with NGS and transcriptome analyses.

Heat stress leads to rapid lipid remodeling and transcriptional adaptations in Nicotiana tabacum pollen tubes.

After reaching the stigma, pollen grains germinate and form a pollen tube that transports the sperm cells to the ovule. Due to selection pressure between pollen tubes, pollen grains likely evolved mechanisms to quickly adapt to temperature changes to sustain elongation at the highest possible rate. We investigated these adaptions in tobacco (Nicotiana tabacum) pollen tubes grown in vitro under 22°C and 37°C by a multi-omics approach including lipidomic, metabolomic, and transcriptomic analysis.

A novel single-cell RNA-sequencing approach and its applicability connecting genotype to phenotype in ageing disease.

Single cell multi-omics analysis has the potential to yield a comprehensive understanding of the cellular events that underlie the basis of human diseases. The cardinal feature to access this information is the technology used for single-cell isolation, barcoding, and sequencing. Most currently used single-cell RNA-sequencing platforms have limitations in several areas including cell selection, documentation and library chemistry.

Prdm12 modulates pain-related behavior by remodeling gene expression in mature nociceptors.

Prdm12 is a conserved epigenetic transcriptional regulator that displays restricted expression in nociceptors of the developing peripheral nervous system. In mice, Prdm12 is required for the development of the entire nociceptive lineage. In humans, PRDM12 mutations cause congenital insensitivity to pain, likely because of the loss of nociceptors.

Differences in synaptic vesicle pool behavior between male and female hippocampal cultured neurons.

A strong focus on sex-related differences has arisen recently in neurobiology, but most investigations focus on brain function in vivo, ignoring common experimental models like cultured neurons. A few studies have addressed morphological differences between male and female neurons in culture, but very few works focused on functional aspects, and especially on presynaptic function. To fill this gap, we studied here functional parameters of synaptic vesicle recycling in hippocampal cultures from male and female rats, which are a standard model system for many laboratories.

Toxicogenomic differentiation of functional responses to fipronil and imidacloprid in Daphnia magna.

Active substances of pesticides, biocides or pharmaceuticals can induce adverse side effects in the aquatic ecosystem, necessitating environmental hazard and risk assessment prior to substance registration. The freshwater crustacean Daphnia magna is a model organism for acute and chronic toxicity assessment representing aquatic invertebrates. However, standardized tests involving daphnia are restricted to the endpoints immobility and reproduction and thus provide only limited insights into the underlying modes-of-action.

Restructuring of the male mice peripheral circadian network after bariatric surgery.

Bariatric surgery is still the most effective long-term weight-loss therapy. Recent data indicate that surgical outcomes may be affected by diurnal food intake patterns. In this study, we aimed to investigate how surgery-induced metabolic adaptations (i.

Prognostic factor identification by screening changes in differentially expressed genes in oral squamous cell carcinoma.

Objective: This study was designed to identify changes in the expression of proteins occurring during the progression of oral squamous cell carcinoma (OSCC) and to validate their impact on patient prognosis.

Materials And Methods: The human OSCC cell line UPCI-SCC-040 was treated in vitro with TGF-β1, and transcriptome analysis of differentially expressed genes (DEGs) revealed putative candidates relative to untreated cells. The respective protein expression levels of the most important genes were immunohistochemically validated on a tissue microarray (TMA) containing tissue samples from 39 patients with OSCC and were correlated with disease-free survival (DFS) as the primary clinical endpoint.

Screening for potential targets to reduce stenosis in bioprosthetic heart valves.

Progressive stenosis is one of the main factors that limit the lifetime of bioprosthetic valved conduits. To improve long-term performance we aimed to identify targets that inhibit pannus formation on conduit walls. From 11 explanted, obstructed, RNAlater presevered pulmonary valved conduits, we dissected the thickened conduit wall and the thin leaflet to determine gene expression-profiles using ultra deep sequencing.

Post-transcriptional regulation by the exosome complex is required for cell survival and forebrain development via repression of P53 signaling.

Fine-tuned gene expression is crucial for neurodevelopment. The gene expression program is tightly controlled at different levels, including RNA decay. N-methyladenosine (m6A) methylation-mediated degradation of RNA is essential for brain development.

Toxicogenomic fin(ger)prints for thyroid disruption AOP refinement and biomarker identification in zebrafish embryos.

Endocrine disruption (ED) can trigger far-reaching effects on environmental populations, justifying a refusal of market approval for chemicals with ED properties. For the hazard assessment of ED effects on the thyroid system, regulatory decisions mostly rely on amphibian studies. Here, we used transcriptomics and proteomics for identifying molecular signatures of interference with thyroid hormone signaling preceding physiological effects in zebrafish embryos.

Long-term effects of empagliflozin on excitation-contraction-coupling in human induced pluripotent stem cell cardiomyocytes.

The SGLT2 inhibitor empagliflozin improved cardiovascular outcomes in patients with diabetes. As the cardiac mechanisms remain elusive, we investigated the long-term effects (up to 2 months) of empagliflozin on excitation-contraction (EC)-coupling in human cardiomyocytes derived from induced pluripotent stem cells (iPSC-CM) in a blinded manner. IPSC from 3 donors, differentiated into pure iPSC-CM (4 differentiations), were treated with a clinically relevant concentration of empagliflozin (0.

Maturational Changes in Mouse Cutaneous Touch and Piezo2-Mediated Mechanotransduction.

The age of studied animals has a profound impact on experimental outcomes in animal-based research. In mice, age influences molecular, morphological, physiological, and behavioral parameters, particularly during rapid postnatal growth and maturation until adulthood (at 12 weeks of age). Despite this knowledge, most biomedical studies use a wide-spanning age range from 4 to 12 weeks, raising concerns about reproducibility and potential masking of relevant age differences.

SUMOylation controls the neurodevelopmental function of the transcription factor Zbtb20.

SUMOylation is a dynamic post-translational protein modification that primarily takes place in cell nuclei, where it plays a key role in multiple DNA-related processes. In neurons, the SUMOylation-dependent control of a subset of neuronal transcription factors is known to regulate various aspects of nerve cell differentiation, development, and function. In an unbiased screen for endogenous SUMOylation targets in the developing mouse brain, based on a His -HA-SUMO1 knock-in mouse line, we previously identified the transcription factor Zinc finger and BTB domain-containing 20 (Zbtb20) as a new SUMO1-conjugate.

CRISPR-Mediated Activation of Endogenous Gene Expression in the Postnatal Heart.

Rationale: Genome editing by CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 is evolving rapidly. Recently, second-generation CRISPR/Cas9 activation systems based on nuclease inactive dead (d)Cas9 fused to transcriptional transactivation domains were developed for directing specific guide (g)RNAs to regulatory regions of any gene of interest, to enhance transcription. The application of dCas9 to activate cardiomyocyte transcription in targeted genomic loci in vivo has not been demonstrated so far.

ΔN-Tp63 Mediates Wnt/β-Catenin-Induced Inhibition of Differentiation in Basal Stem Cells of Mucociliary Epithelia.

Mucociliary epithelia provide a first line of defense against pathogens. Impaired regeneration and remodeling of mucociliary epithelia are associated with dysregulated Wnt/β-catenin signaling in chronic airway diseases, but underlying mechanisms remain elusive, and studies yield seemingly contradicting results. Employing the Xenopus mucociliary epidermis, the mouse airway, and human airway Basal cells, we characterize the evolutionarily conserved roles of Wnt/β-catenin signaling in vertebrates.

Transcription factor TAp73 and microRNA-449 complement each other to support multiciliogenesis.

Motile cilia serve vital functions in development, homeostasis, and regeneration. We recently demonstrated that TAp73 is an essential transcriptional regulator of respiratory multiciliogenesis. Here, we show that TAp73 is expressed in multiciliated cells (MCCs) of diverse tissues.

The IL-1 Pathway Is Hyperactive in Hidradenitis Suppurativa and Contributes to Skin Infiltration and Destruction.

Hidradenitis suppurativa (HS) (also designated acne inversa) is a chronic inflammatory disease characterized by painful purulent skin lesions and progressive destruction of skin architecture. Despite the high burden for the patients, pathogenetic pathways underlying HS alterations remain obscure. When we examined the HS cytokine pattern, IL-1β turned out to be a highly prominent cytokine, overexpressed even compared with psoriatic lesions.