Target-Templated Construction of Functional Proteomimetics Using Photo-Foldamer Libraries.

Current methods for proteomimetic engineering rely on structure-based design. Here we describe a design strategy that allows the construction of proteomimetics against challenging targets without a priori characterization of the target surface. Our approach employs (i) a 100-membered photoreactive foldamer library, the members of which act as local surface mimetics, and (ii) the subsequent affinity maturation of the primary hits using systems chemistry.

Insulin receptor substrate 1 is a novel member of EGFR signaling in pancreatic cells.

Pancreatic ductal adenocarcinoma is an extremely incurable cancer type characterized by cells with highly proliferative capacity and resistance against the current therapeutic options. Our study reveals that IRS1 acts as a bridging molecule between EGFR and IGFR/InsR signalization providing a potential mechanism for the interplay between signaling pathways and bypassing EGFR-targeted or IGFR/InsR-targeted therapies. The analysis of IRS1 phosphorylation status in four pancreatic cell lines identified the impact of EGFR signaling on IRS1 activation in comparison with InsR/IGFR signaling.

Predictive value analysis of the interaction network of Tks4 scaffold protein in colon cancer.

Background: Colorectal carcinoma (CRC) has emerged as one of the most widespread cancers and was the third leading cause of cancer-related mortality in 2020. The role of the podosomal protein Tks4 in tumor formation and progression is well established, including its involvement in gastric carcinoma and hepatocellular carcinoma; however, exploration of Tks4 and its associated EMT-regulating interactome in the context of colon cancer remains largely unexplored.

Methods: We conducted a comprehensive bioinformatic analysis to investigate the mRNA and protein expression levels of Tks4 and its associated partner molecules (CD2AP, GRB2, WASL, SRC, CTTN, and CAPZA1) across different tumor types.

Mapping protein binding sites by photoreactive fragment pharmacophores.

Fragment screening is a popular strategy of generating viable chemical starting points especially for challenging targets. Although fragments provide a better coverage of chemical space and they have typically higher chance of binding, their weak affinity necessitates highly sensitive biophysical assays. Here, we introduce a screening concept that combines evolutionary optimized fragment pharmacophores with the use of a photoaffinity handle that enables high hit rates by LC-MS-based detection.

Contribution of Noncovalent Recognition and Reactivity to the Optimization of Covalent Inhibitors: A Case Study on KRas.

Covalent drugs might bear electrophiles to chemically modify their targets and have the potential to target previously undruggable proteins with high potency. Covalent binding of drug-size molecules includes a noncovalent recognition provided by secondary interactions and a chemical reaction leading to covalent complex formation. Optimization of their covalent mechanism of action should involve both types of interactions.

Unveiling epithelial plasticity regulation in lung cancer: Exploring the cross-talk among Tks4 scaffold protein partners.

The epithelial-to-mesenchymal transition (EMT) represents a hallmark event in the evolution of lung cancer. This work aims to study a recently described EMT-regulating protein, Tks4, and to explore its potential as a prognostic biomarker in non-small cell lung cancer. In this study, we used CRISPR/Cas9 method to knockout (KO) Tks4 to study its functional roles in invadopodia formation, migration, and regulation of EMT marker expressions and we identified Tks4-interacting proteins.

Detection of plant cadmium toxicity by monitoring dielectric response of intact root systems on a fine timescale.

The root dielectric response was measured on a minute scale to assess its efficiency for monitoring short-term cadmium (Cd) toxicity non-destructively. Electrical capacitance (C), dissipation factor (D) and electrical conductance (G) were detected during the 24 to 168 h after Cd treatment (0, 20, 50 mg Cd kg substrate) in potted maize, cucumber and pea. Stress was also evaluated by measuring leaf chlorophyll content, F/F and stomatal conductance (g) in situ, and shoot and root mass and total root length after harvest.

Monitoring of plant water uptake by measuring root dielectric properties on a fine timescale: diurnal changes and response to leaf excision.

Background: The measurement of root dielectric response is a useful non-destructive method to evaluate root growth and function. Previous studies tracked root development throughout the plant growing cycle by single-time electrical measurements taken repeatedly. However, it is known that root conductivity and uptake activity can change rapidly, coupled with the day/night cycles of photosynthetic and transpiration rate.

Surface Modification of Titanate Nanotubes with a Carboxylic Arm for Further Functionalization Intended to Pharmaceutical Applications.

Nanotechnology is playing a significant role in modern life with tremendous potential and promising results in almost every domain, especially the pharmaceutical one. The impressive performance of nanomaterials is shaping the future of science and revolutionizing the traditional concepts of industry and research. Titanate nanotubes (TNTs) are one of these novel entities that became an appropriate choice to apply in several platforms due to their remarkable properties such as preparation simplicity, high stability, good biocompatibility, affordability and low toxicity.

Acquired Triazole Resistance Alters Pathogenicity-Associated Features in in an Isolate-Dependent Manner.

Fluconazole resistance is commonly encountered in , and the yeast frequently displays resistance to other standard drugs, which severely limits the number of effective therapeutic agents against this emerging pathogen. In this study, we aimed to investigate the effect of acquired azole resistance on the viability, stress response, and virulence of this species. Fluconazole-, posaconazole-, and voriconazole- resistant strains were generated from two susceptible clinical isolates (0381, 0387) and compared under various conditions.

Arsenic uptake and accumulation in bean and lettuce plants at different developmental stages.

The pattern of arsenic (As) uptake at different developmental stages in plants and its consequent influence on the growth of plants was investigated in bean and lettuce. Further, the human health risk from the consumption of these As-laced vegetables was determined. The irrigation water was contaminated with As at concentrations of 0.

Studying the Association of TKS4 and CD2AP Scaffold Proteins and Their Implications in the Partial Epithelial-Mesenchymal Transition (EMT) Process.

Colon cancer is a leading cause of death worldwide. Identification of new molecular factors governing the invasiveness of colon cancer holds promise in developing screening and targeted therapeutic methods. The Tyrosine Kinase Substrate with four SH3 domains (TKS4) and the CD2-associated protein (CD2AP) have previously been linked to dynamic actin assembly related processes and cancer cell migration, although their co-instructive role during tumor formation remained unknown.

Soil biological activity after a sixty-year fertilization practice in a wheat-maize crop rotation.

This study aimed to survey the long-term effects of fertilization practices on the functional diversity of the soil microbiota. A 60-year fertilization experiment with mineral fertilizers, farmyard manure and combined treatments was sampled in two consecutive years in maize (Zea mays L.) and wheat (Triticum aestivum L.

Iron deficiency in young basketball players: Is a 100 μg/L ferritin cut-off appropriate for iron supplementation?: Results of a randomized placebo-controlled study.

Background: Iron deficiency (ID) is one of the most common factors that may reduce sports performance, supplementation forms and doses are still not standardized in athletes. Our aim was to assess the iron status of young male basketball players and to study the effect of iron supplementation in a randomized placebo-controlled study.

Hypothesis: We hypothesized that due to the higher iron demand of athletes, the 100 μg/L ferritin cut-off may be appropriate to determine the non-anemic ID.

Estimation of the potential GDP by a new robust filter method.

The first purpose of this paper is to propose a theoretically new robust filter method to estimate non-observable macroeconomic indicators. The second purpose is to apply the proposed method to estimate the Hungarian potential GDP in 2000-2021. The novelty of the proposed filter method is that - unlike papers published so far - it does not require the stability of the dynamic model, only a partial stability condition must be satisfied.

Paraneoplastic Kelch-like protein 11 antibody-associated cerebellar and limbic encephalitis caused by metastatic "burned-out" seminoma - A scar(r)y phenomenon.

Introduction: The diagnosis of paraneoplastic neurologic syndromes is challenging when the primary tumor masquerades as scar tissue (i.e. "burned-out").

The impact of SARS-CoV-2 infection on the outcome of acute ischemic stroke-A retrospective cohort study.

Background: Acute ischemic stroke (AIS) is a common complication of severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) infection (COVID-19), but the prognosis of these patients is poorly understood.

Purpose: To explore the impact of COVID-19 on neurological outcomes in AIS patients.

Methods: A comparative retrospective cohort study was conducted in 32 consecutive AIS patients with and 51 without COVID-19 between the 1st of March 2020 and 1st of May 2021.

Iodine biofortification of bean (Phaseolus vulgaris L.) and pea (Pisum sativum L.) plants cultivated in three different soils.

An important challenge for mankind today is to find a plant-based source of iodine, instead of table salt, which would provide the recommended daily dosage of iodine. The aim of this work was to study the accumulation of iodine and the physiochemical changes in bean (Phaseolus vulgaris L.) and pea (Pisum sativum L.

[Early experiences with stentgrafts in the treatment of atherothrombotic diseases of the infrarenal aorta].

Introduction: Endovascular interventions have become the first-line treatment for peripheral arterial diseases. Athero-thrombotic disorders in the infrarenal aorta are also treated with open surgery, especially if it causes critical stenosis or embolization. The use of traditional stents leads to much more complications in such lesions; however, stentgrafts can provide excellent results.

A Novel Cell-Based Model for a Rare Disease: The Tks4-KO Human Embryonic Stem Cell Line as a Frank-Ter Haar Syndrome Model System.

Tyrosine kinase substrate with four SH3 domains (Tks4) scaffold protein plays roles in cell migration and podosome formation and regulates systemic mechanisms such as adult bone homeostasis and adipogenesis. Mutations in the Tks4 gene () cause a rare developmental disorder called Frank-Ter Haar syndrome (FTHS), which leads to heart abnormalities, bone tissue defects, and reduced adiposity. We aimed to produce a human stem cell-based in vitro FTHS model system to study the effects of the loss of the Tks4 protein in different cell lineages and the accompanying effects on the cell signalome.