Covalent Inhibitors of KEAP1 with Exquisite Selectivity.

The NRF2-KEAP1 interaction is central for cytoprotection against stresses, giving it high clinical significance. Covalent modification of KEAP1 is an efficient approach, but the covalent inhibitors used in the clinic carry undesired side effects originating in their moderate selectivity. Starting with a phenotypic screen, we identified a new covalent inhibitor chemotype that was optimized to deliver a series of potent and highly selective KEAP1 binders.

Effect of Irrigation on Sugarcane Morphophysiology in the Brazilian Cerrado.

Since sugarcane is semi-perennial, it has no escape from water stresses in the Brazilian Cerrado, and consequently, drought impacts plant growth and industrial quality. The objective of this study was to evaluate the morphophysiology and quality of the first ratoon of two sugarcane varieties submitted to irrigated and stressed treatments under field conditions. For the biometric characteristics, in general, significant decreases were observed under the stressed treatment for all periods, and only minor differences were detected between the studied cultivars.

PEC-PRO: A new prognostic score from a series of 87 patients with localized perivascular epithelioid cell neoplasms (PEComas) treated with curative intent.

Background: Perivascular epithelioid cell neoplasms (PEComas) encompass a heterogeneous family of mesenchymal tumors. Previously described clinicopathologic features aimed at distinguishing benign from malignant variants but lacked prognostic value.

Methods: This retrospective analysis examined clinicopathologic data from patients who had localized PEComa across French Sarcoma Network centers.

Decoding complexity in biomolecular recognition of DNA i-motifs with microarrays.

DNA i-motifs (iMs) are non-canonical C-rich secondary structures implicated in numerous cellular processes. Though iMs exist throughout the genome, our understanding of iM recognition by proteins or small molecules is limited to a few examples. We designed a DNA microarray containing 10976 genomic iM sequences to examine the binding profiles of four iM-binding proteins, mitoxantrone and the iMab antibody.

Use of Thermography to Evaluate Alternative Crops for Off-Season in the Cerrado Region.

Future predictions due to climate change are of decreases in rainfall and longer drought periods. The search for new tolerant crops is an important strategy. The objective of this study was to evaluate the effect of water stress on the physiology and productivity of crops with potential for growing in the off-season period in the Cerrado, and evaluate correlations with the temperature of the canopy obtained by means of thermography.

Twenty years of collaborative research to enhance community practice for cancer prevention and control.

The Cancer Prevention and Control Research Network (CPCRN) was established in 2002 to conduct applied research and undertake related activities to translate evidence into practice, with a special focus on the unmet needs of populations at higher risk of getting cancer and dying from it. A network of academic, public health and community partners, CPCRN is a thematic research network of the Prevention Research Centers Program at the Centers for Disease Control and Prevention (CDC). The National Cancer Institute's Division of Cancer Control and Population Sciences (DCCPS) has been a consistent collaborator.

DECODING COMPLEXITY IN BIOMOLECULAR RECOGNITION OF DNA I-MOTIFS.

DNA i-motifs (iMs) are non-canonical C-rich secondary structures implicated in numerous cellular processes. Though iMs exist throughout the genome, our understanding of iM recognition by proteins or small molecules is limited to a few examples. We designed a DNA microarray containing 10,976 genomic iM sequences to examine the binding profiles of four iM-binding proteins, mitoxantrone, and the iMab antibody.

Selective disruption of NRF2-KEAP1 interaction leads to NASH resolution and reduction of liver fibrosis in mice.

Background & Aims: Oxidative stress is recognized as a major driver of non-alcoholic steatohepatitis (NASH) progression. The transcription factor NRF2 and its negative regulator KEAP1 are master regulators of redox, metabolic and protein homeostasis, as well as detoxification, and thus appear to be attractive targets for the treatment of NASH.

Methods: Molecular modeling and X-ray crystallography were used to design S217879 - a small molecule that could disrupt the KEAP1-NRF2 interaction.

Investigating the clinical impact of dose-banding for weekly paclitaxel in patients with breast cancer: A retrospective and monocentric study.

Aims: Dose-banding (DB) consists in approximating the theoretical dose of anticancer drugs calculated according to the body surface area (Dose-BSA) of patients. This concept is supported by pharmacokinetic but not by clinical data. The aim of this study was to assess the clinical outcome of DB defined as dose-fitting up to ±10%.

Developing Capacity in Dissemination and Implementation Research in the Eastern Mediterranean Region: Evaluation of a Training Workshop.

Unlabelled: As the demand for dissemination and implementation (D&I) research grows globally, there is a need for D&I capacity building in regions where D&I science is underrepresented. The Workshop on Dissemination and Implementation Research in Health (WONDIRH) was aimed for participants in the Eastern Mediterranean region to (1) appreciate the complex process of bridging research and practice in a variety of real-world settings, and (2) develop research that balances rigor with relevance and employs study designs and methods appropriate for the complex processes involved in D&I. The present exploratory study investigates participants' satisfaction with the workshop, the enhancement of their self-rated confidence in D&I skills, as well as their intention to apply the learned content into practice.

Physiological Changes of Arabica Coffee under Different Intensities and Durations of Water Stress in the Brazilian Cerrado.

Coffee farmers have faced problems due to drought periods, with irrigation being necessary. In this sense, this study aimed to evaluate the responses to different levels and durations of water deficit in arabica coffee genotypes in the Cerrado region. The experiment consisted of three genotypes and five water regimes: full irrigation (FI 100 and FI 50-full irrigation with 100% and 50% replacement of evapotranspiration, respectively), water deficit (WD 100 and WD 50-water deficit from June to September, with 100% and 50% replacement of evapotranspiration, respectively) and rainfed (without irrigation).

Differences in the metabolic and functional mechanisms used to tolerate flooding in Guazuma ulmifolia (Lam.) from flood-prone Amazonian and dry Cerrado savanna populations.

Flood tolerance is crucial to the survival of tree species subject to long periods of flooding, such as those present in the Amazonian várzea. Tolerance can be mediated by adjustments of metabolism, physiology and morphology, reinforcing the need to investigate the physiological and biochemical mechanisms used by tropical tree species to survive this stress. Moreover, such mechanisms may vary between populations that are subjected to differences in the frequency of flooding events.

Altering the Double-Stranded DNA Specificity of the bZIP Domain of Zta with Site-Directed Mutagenesis at N182.

Zta, the Epstein-Barr virus bZIP transcription factor (TF), binds both unmethylated and methylated double-stranded DNA (dsDNA) in a sequence-specific manner. We studied the contribution of a conserved asparagine (N182) to sequence-specific dsDNA binding to four types of dsDNA: (i) dsDNA with cytosine in both strands ((DNA(C|C)), (ii, iii) dsDNA with 5-methylcytosine (5mC, ) or 5-hydroxymethylcytosine (5hmC, ) in one strand and cytosine in the second strand ((DNA(5mC|C) and DNA(5hmC|C)), and (iv) dsDNA with methylated cytosine in both strands in all CG dinucleotides ((DNA(5mCG)). We replaced asparagine with five similarly sized amino acids (glutamine (Q), serine (S), threonine (T), isoleucine (I), or valine (V)) and used protein binding microarrays to evaluate sequence-specific dsDNA binding.

Regulation and function of AP-1 in insulinoma cells and pancreatic β-cells.

Ca1.2 L-type voltage-gated Ca channels play a central role in pancreatic β-cells by integrating extracellular signals with intracellular signaling events leading to insulin secretion and altered gene transcription. Here, we investigated the intracellular signaling pathway following stimulation of Ca1.

Quinoa for the Brazilian Cerrado: Agronomic Characteristics of Elite Genotypes under Different Water Regimes.

Quinoa stands out as an excellent crop in the Cerrado region for cultivation in the off-season or irrigated winter season. Here, we tested the effects of different water regimes on the agronomic characteristics, physiology, and grain quality of different elite quinoa genotypes under field conditions. The experiment was conducted under field conditions at Embrapa Cerrados (Planaltina, DF, Brazil).

Structural basis for glucocorticoid receptor recognition of both unmodified and methylated binding sites, precursors of a modern recognition element.

The most common form of DNA methylation involves the addition of a methyl group to a cytosine base in the context of a cytosine-phosphate-guanine (CpG) dinucleotide. Genomes from more primitive organisms are more abundant in CpG sites that, through the process of methylation, deamination and subsequent mutation to thymine-phosphate-guanine (TpG) sites, can produce new transcription factor binding sites. Here, we examined the evolutionary history of the over 36 000 glucocorticoid receptor (GR) consensus binding motifs in the human genome and identified a subset of them in regulatory regions that arose via a deamination and subsequent mutation event.

Gold Nanostar Spatial Distribution Impacts the Surface-Enhanced Raman Scattering Detection of Uranyl on Amidoximated Polymers.

The plasmonic properties of carboxylated gold nanostars distributed on amidoximated polyacrylonitrile (AO PAN) electrospun polymer films scale with surface-enhanced Raman scattering (SERS) intensities for coordinated uranium(VI) oxide (uranyl) species. This two-step plasmonic sensor first isolates uranyl from solution using functionalized polymers; then carboxylated gold nanostars are subsequently deposited for SERS. Spatially resolved localized surface plasmon resonance (LSPR) and SERS facilitate correlated nanostar optical density and uranyl quantification.

Improving Evidence-Based Program Repositories: Introducing the Evidence-Based Cancer Control Programs (EBCCP) Web Repository.

To reduce the research to practice gap, promoting the utility of evidence-based repositories is essential among both practitioners and researchers. Organizing these repositories to address the needs of these audiences requires a user-centered design approach as proposed recently in an article by Harden et al, 2020. This commentary builds on the proposed solutions to introduce a recently redesigned Evidence-Based Cancer Control Programs (EBCCP) web repository (formerly Research-Tested Intervention Programs (RTIPs)) from the National Cancer Institute.

REL Domain of NFATc2 Binding to Five Types of DNA Using Protein Binding Microarrays.

NFATc2 is a DNA binding protein in the Rel family transcription factors, which binds a motif better when both cytosines in the dinucleotide are methylated. Using protein binding microarrays (PBMs), we examined the DNA binding of NFATc2 to three additional types of DNA: single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) with either 5-methylcytosine (5mC, ) or 5-hydroxymethylcytosine (5hmC, ) in one strand and a cytosine in the second strand. , the complement of the core motif, is better bound as ssDNA compared to dsDNA.

Transient Delivery of A-C/EBP Protein Perturbs Differentiation of 3T3-L1 Cells and Induces Preadipocyte Marker Genes.

Transformation of committed 3T3-L1 preadipocytes to lipid-laden adipocytes involves the timely appearance of numerous transcription factors (TFs); foremost among them, C/EBPβ is expressed during the early phases of differentiation. Here, we describe liposome-mediated protein transfection approach to rapidly downregulate C/EBPβ by A-C/EBP protein inhibitor. Signals from EGFP-tagged A-C/EBP protein were observed in 3T3-L1 cells within 2 h of transfections, whereas for A-C/EBP gene transfections, equivalent signals appeared in 48 h.

Characterization of raffinose metabolism genes uncovers a wild Arachis galactinol synthase conferring tolerance to abiotic stresses.

Raffinose family oligosaccharides (RFOs) are implicated in plant regulatory mechanisms of abiotic stresses tolerance and, despite their antinutritional proprieties in grain legumes, little information is available about the enzymes involved in RFO metabolism in Fabaceae species. In the present study, the systematic survey of legume proteins belonging to five key enzymes involved in the metabolism of RFOs (galactinol synthase, raffinose synthase, stachyose synthase, alpha-galactosidase, and beta-fructofuranosidase) identified 28 coding-genes in Arachis duranensis and 31 in A. ipaënsis.

bZIP Dimers CREB1, ATF2, Zta, ATF3|cJun, and cFos|cJun Prefer to Bind to Some Double-Stranded DNA Sequences Containing 5-Formylcytosine and 5-Carboxylcytosine.

In mammalian cells, 5-methylcytosine (5mC) occurs in genomic double-stranded DNA (dsDNA) and is enzymatically oxidized to 5-hydroxymethylcytosine (5hmC), then to 5-formylcytosine (5fC), and finally to 5-carboxylcytosine (5caC). These cytosine modifications are enriched in regulatory regions of the genome. The effect of these oxidative products on five bZIP dimers (CREB1, ATF2, Zta, ATF3|cJun, and cFos|cJun) binding to five types of dsDNA was measured using protein binding microarrays.

Custom G4 Microarrays Reveal Selective G-Quadruplex Recognition of Small Molecule BMVC: A Large-Scale Assessment of Ligand Binding Selectivity.

G-quadruplexes (G4) are considered new drug targets for human diseases such as cancer. More than 10,000 G4s have been discovered in human chromatin, posing challenges for assessing the selectivity of a G4-interactive ligand. 3,6-bis(1-Methyl-4-vinylpyridinium) carbazole diiodide (BMVC) is the first fluorescent small molecule for G4 detection in vivo.

Custom DNA Microarrays Reveal Diverse Binding Preferences of Proteins and Small Molecules to Thousands of G-Quadruplexes.

Single-stranded DNA (ssDNA) containing four guanine repeats can form G-quadruplex (G4) structures. While cellular proteins and small molecules can bind G4s, it has been difficult to broadly assess their DNA-binding specificity. Here, we use custom DNA microarrays to examine the binding specificities of proteins, small molecules, and antibodies across ∼15,000 potential G4 structures.