Ubiquitin-derived artificial binding proteins targeting oncofetal fibronectin reveal scaffold plasticity by β-strand slippage.

Affilin proteins, artificial binding proteins based on the ubiquitin scaffold, have been generated by directed protein evolution to yield de-novo variants that bind the extra-domain B (EDB) of oncofetal fibronectin, an established marker of tumor neovasculature. The crystal structures of two EDB-specific Affilin variants reveal a striking structural plasticity of the ubiquitin scaffold, characterised by β-strand slippage, leading to different negative register shifts of the β5 strands. This process recruits amino acid residues from β5 towards the N-terminus to an adjacent loop region and subsequent residues into β5, respectively, remodeling the binding interface and leading to target specificity and affinity.

Fabrication and Characterization of PDMS Waveguides for Flexible Optrodes.

With the growth of optogenetic research, the demand for optical probes tailored to specific applications is ever rising. Specifically, for applications like the coiled cochlea of the inner ear, where planar, stiff, and nonconformable probes can hardly be used, transitioning from commonly used stiff glass fibers to flexible probes is required, especially for long-term use. Following this demand, polydimethylsiloxane (PDMS) with its lower Young's modulus compared to glass fibers can serve as material of choice.

Evaluation of mild pH elution protein A resins for antibodies and Fc-fusion proteins.

Protein A affinity chromatography is widely used as a capture step for monoclonal antibodies (mAb) and molecules that possess an Fc-domain, such as fusion proteins and bispecific antibodies. However, the use of low pH (3.0-4.

Acute PDE4 Inhibition Induces a Transient Increase in Blood Glucose in Mice.

cAMP-phosphodiesterase 4 (PDE4) inhibitors are currently approved for the treatment of inflammatory diseases. There is interest in expanding the therapeutic application of PDE4 inhibitors to metabolic disorders, as their chronic application induces weight loss in patients and animals and improves glucose handling in mouse models of obesity and diabetes. Unexpectedly, we have found that acute PDE4 inhibitor treatment induces a temporary increase, rather than a decrease, in blood glucose levels in mice.

Affilin-based retargeting of adenoviral vectors to the epidermal growth factor receptor.

Introduction: Treatment of head and neck squamous cell carcinomas (HNSCC) by oncolytic adenoviral vectors holds promise as an efficient anti-cancer therapy. The epidermal growth factor receptor (EGFR) represents an attractive target receptor since it is frequently overexpressed in many types of HNSCC.

Methods: To achieve EGFR-specific targeting by human adenovirus type 5 (HAdV-5) based vectors, the EGFR affinity ligand Affilin was covalently attached in a position specific manner either to the fiber or the hexon protein of the vector capsid.

Non-Selective PDE4 Inhibition Induces a Rapid and Transient Decrease of Serum Potassium in Mice.

The analysis of blood samples from mice treated with the PDE4 inhibitor Roflumilast revealed an unexpected reduction in serum potassium levels, while sodium and chloride levels were unaffected. Treatment with several structurally distinct PAN-PDE4 inhibitors, including Roflumilast, Rolipram, RS25344, and YM976 dose-dependently reduced serum potassium levels, indicating the effect is a class-characteristic property. PDE4 inhibition also induces hypothermia and hypokinesia in mice.

Real-time tracking of bioluminescent influenza A virus infection in mice.

Despite the availability of vaccines and antiviral therapies, seasonal influenza infections cause 400,000 human deaths on average per year. Low vaccine coverage and the occurrence of drug-resistant viral strains highlight the need for new and improved countermeasures. While influenza A virus (IAV) engineered to express a reporter gene may serve as a valuable tool for real-time tracking of viral infection, reporter gene insertion into IAV typically attenuates viral pathogenicity, hindering its application to research.

Assessment of PDE4 Inhibitor-Induced Hypothermia as a Correlate of Nausea in Mice.

Treatment with PAN-PDE4 inhibitors has been shown to produce hypothermia in multiple species. Given the growing body of evidence that links nausea and emesis to disturbances in thermoregulation in mammals, we explored PDE4 inhibitor-induced hypothermia as a novel correlate of nausea in mice. Using knockout mice for each of the four PDE4 subtypes, we show that selective inactivation of individual PDE4 subtypes does not produce hypothermia, which must instead require the concurrent inactivation of multiple (at least two) PDE4 subtypes.

Satellite-based time-series of sea-surface temperature since 1981 for climate applications.

A climate data record of global sea surface temperature (SST) spanning 1981-2016 has been developed from 4 × 10 satellite measurements of thermal infra-red radiance. The spatial area represented by pixel SST estimates is between 1 km and 45 km. The mean density of good-quality observations is 13 km yr.

Genome-wide identification of histone methylation (H3K9) and acetylation (H4K12) marks in two ecotypes of switchgrass (Panicum virgatum L.).

Background: Histone modifications play a significant role in the regulation of transcription and various biological processes, such as development and regeneration. Though a few genomic (including DNA methylation patterns) and transcriptomic studies are currently available in switchgrass, the genome-wide distribution of histone modifications has not yet been studied to help elucidate gene regulation and its application to switchgrass improvement.

Results: This study provides a comprehensive epigenomic analyses of two contrasting switchgrass ecotypes, lowland (AP13) and upland (VS16), by employing chromatin immunoprecipitation sequencing (ChIP-Seq) with two histone marks (suppressive- H3K9 and active- H4K12).

Immunohistochemical analysis of Bcl-2, nuclear S100A4, MITF and Ki67 for risk stratification of early-stage melanoma - A combined IHC score for melanoma risk stratification.

Background And Objectives: Overall survival (OS) in patients with early-stage malignant melanoma differs. To date, there are no established prognostic markers. We aimed to contribute to a better understanding of potential prognostic immunohistochemical markers for risk stratification.

AMPK Regulates the Epigenome through Phosphorylation of TET2.

Emerging evidence suggests that changes to cellular metabolism can regulate epigenetic modifications to alter gene expression. Recently in Nature, Wu et al. show that the metabolic regulator AMPK can phosphorylate and thus stabilize the epigenetic modifying enzyme TET2, defining a novel signaling link between metabolism and the epigenome.

In vivo RNAi screening identifies as a target for combination therapy with TKIs in BCP-ALL.

Despite the addition of tyrosine kinase inhibitors (TKIs) to the treatment of patients with B-cell precursor acute lymphoblastic leukemia ( BCP-ALL), relapse both with and without mutations is a persistent clinical problem. To identify -independent genetic mediators of response to the TKI dasatinib, we performed in vivo and in vitro RNA interference (RNAi) screens in a transplantable syngeneic mouse model of BCP-ALL. By using a novel combination of a longitudinal screen design and independent component analysis of screening data, we identified hairpins that have distinct behavior in different therapeutic contexts as well as in the in vivo vs in vitro settings.

Whole lesion histogram analysis of meningiomas derived from ADC values. Correlation with several cellularity parameters, proliferation index KI 67, nucleic content, and membrane permeability.

Purpose: To analyze several histopathological features and their possible correlations with whole lesion histogram analysis derived from ADC maps in meningioma.

Materials And Methods: The retrospective study involved 36 patients with primary meningiomas. For every tumor, the following histogram analysis parameters of apparent diffusion coefficient (ADC) were calculated: ADC, ADC, ADC, ADC, ADC, ADC percentiles: P10, P25, P75, P90, as well kurtosis, skewness, and entropy.

Outcome of Combined Treatment of Surgery and Adjuvant Radiotherapy in Merkel Cell Carcinoma.

In recent analyses of Merkel cell carcinoma, prognosis is poor even in stages I and II. We performed a monocentric retrospective study of 37 consecutive cases with Merkel cell carcinoma stage I to III treated with a combination of surgery and adjuvant radiation to evaluate progression-free and overall survival. The median primary tumour diameter was 17.

Dynamic reconfiguration of cortical functional connectivity across brain states.

Throughout each day, the brain displays transient changes in state, as evidenced by shifts in behavior and vigilance. While the electrophysiological correlates of brain states have been studied for some time, it remains unclear how large-scale cortico-cortical functional connectivity systematically reconfigures across states. Here, we investigate state-dependent shifts in cortical functional connectivity by recording local field potentials (LFPs) during spontaneous behavioral transitions in the ferret using chronically implanted micro-electrocorticographic (µECoG) arrays positioned over occipital, parietal, and temporal cortical regions.

Serial or Parallel Metastasis of Cutaneous Melanoma? A Study of the German Central Malignant Melanoma Registry.

For more than a century the Halstedian hypothesis of contiguous metastasis from the primary tumor through the lymphatics to distant sites shaped lymph node surgery for melanoma. We challenge this dogma of serial metastatic dissemination. A single-center series of 2,299 patients with cutaneous metastatic melanoma was investigated to analyze overall survival and distant metastasis-free survival of stage IV patients with or without primary lymphatic metastasis.

Acral lentiginous melanoma: a skin cancer with unfavourable prognostic features. A study of the German central malignant melanoma registry (CMMR) in 2050 patients.

Background: Acral lentiginous melanoma (ALM) is one of the four major subtypes in cutaneous melanoma (CM). Although ALM has a poorer prognosis than other CM subtypes, the prognostic factors associated with ALM have only been verified in small-sized cohorts because of the low incidence of ALM worldwide.

Objectives: To investigate the clinical characteristics of ALM and to evaluate their prognostic values based on a large dataset from the Central Malignant Melanoma Registry (CMMR) of the German Dermatologic Society.

Trans sectoral care of geriatric cancer patients based on comprehensive geriatric assessment and patient-reported quality of life - Results of a multicenter study to develop and pilot test a patient-centered interdisciplinary care concept for geriatric oncology patients (PIVOG).

Objectives: For older patients with cancer the maintenance of independence, functionality and health-related quality of life (HRQOL) is of great importance. Aiming to maintain HRQOL of older patients with cancer we developed an interdisciplinary care program based on comprehensive geriatric assessment (CGA) and patient-reported HRQOL comprising tailored supportive measures and telephone-based counseling during 6month aftercare.

Materials And Methods: Pilot-testing of the intervention took place in three centers at the University Hospital Halle to examine feasibility, acceptance and potential benefit.

Comparative transcriptome profiling of upland (VS16) and lowland (AP13) ecotypes of switchgrass.

Transcriptomes of two switchgrass genotypes representing the upland and lowland ecotypes will be key tools in switchgrass genome annotation and biotic and abiotic stress functional genomics. Switchgrass (Panicum virgatum L.) is an important bioenergy feedstock for cellulosic ethanol production.

Peritumoral Brain Edema in Meningiomas Depends on Aquaporin-4 Expression and Not on Tumor Grade, Tumor Volume, Cell Count, or Ki-67 Labeling Index.

Purpose: The aim of this study was to investigate to which degree the peritumoral brain edema in patients with meningiomas depends on aquaporin-4 (AQP4) expression, tumor grade, tumor volume, Ki-67 expression, and cell count.

Procedures: Thirty-three patients (25 women, 8 men; mean age 56.6 ± 16.