Peroxi-electrocoagulation for Treatment of Trace Organic Compounds and Natural Organic Matter at Neutral pH

Iron-based oxidation technologies can be advantageous for mitigating trace organic compounds (TOrCs) during water and wastewater treatment due to their production of hydroxyl radicals. However, iron-based oxidation often occurs at acidic pH to promote Fenton\u27s reaction, which limits the processes\u27 feasibility for treatment applications. This study focused on utilizing iron-electrocoagulation (EC) paired with ex situ H2O2 addition (peroxi-electrocoagulation [EC:H2O2]) to promote oxidative reactions at neutral pH conditions. The hydroxyl radical probe para-chlorobenzoic acid (pCBA) was used to gauge oxidant activity and serve as a representative TOrC. The impact of water pH, current density, iron dose, H2O2 dose (i.e., [H2O2]initial/[Fe2+]generated ratio), and the presence of natural organic matter (NOM) were evaluated. Multivariable regressions showed that high levels of H2O2 relative to iron (i.e., [H2O2]initial/[Fe2+]generated ratio \u3e0.7) inhibited the rate of pCBA oxidation, likely due to additional radical quenching from extra H2O2. Oxidation of pCBA was confirmed at neutral pH conditions, indicating that EC:H2O2 may potentially serve as a multi-mechanistic treatment technology capable of oxidation. Experiments were also conducted in real-world water samples to gauge EC:H2O2 applications for treating groundwater, river water, and primary treated wastewater. Overall, H2O2 addition enhanced the oxidative degradation of TOrCs while still removing NOM. The one exception was the primary effluent sample, which had the highest degree of oxidant scavenging of all matrices tested. The electrical energy per order (EEO) metric demonstrated that EC:H2O2 is competitive with other TOrC oxidation technologies, with the added benefit of NOM mitigation in the same unit process

The trans-activation domain of the sporulation response regulator Spo0A revealed by X-ray crystallography

Sporulation in Bacillus involves the induction of scores of genes in a temporally and spatially co-ordinated programme of cell development. Its initiation is under the control of an expanded two-component signal transduction system termed a phosphorelay. The master control element in the decision to sporulate is the response regulator, Spo0A, which comprises a receiver or phosphoacceptor domain and an effector or transcription activation domain. The receiver domain of Spo0A shares sequence similarity with numerous response regulators, and its structure has been determined in phosphorylated and unphosphorylated forms. However, the effector domain (C-Spo0A) has no detectable sequence similarity to any other protein, and this lack of structural information is an obstacle to understanding how DNA binding and transcription activation are controlled by phosphorylation in Spo0A. Here, we report the crystal structure of C-Spo0A from Bacillus stearothermophilus revealing a single alpha -helical domain comprising six alpha -helices in an unprecedented fold. The structure contains a helix-turn-helix as part of a three alpha -helical bundle reminiscent of the catabolite gene activator protein (CAP), suggesting a mechanism for DNA binding. The residues implicated in forming the sigma (A)-activating region clearly cluster in a flexible segment of the polypeptide on the opposite side of the structure from that predicted to interact with DNA. The structural results are discussed in the context of the rich array of existing mutational data

The role of neoadjuvant and adjuvant treatment for adenocarcinoma of the upper gastrointestinal tract

Both locally advanced adenocarcinoma of the stomach and gastro-esophageal junction are associated with poor prognosis due to the lack of effective treatment. Recently multimodal treatment consisting of neoadjuvant chemotherapy in combination with radiotherapy is reported to improve survival when compared to surgery alone. Neoadjuvant therapy in these locally advanced tumors allows for early tumor responses and the extent of tumor regression that can be achieved is considered a significant prognostic factor. This, in turn, increases the resectability of these tumors. Also due to the high frequency of lymph node metastasis, patients with locally advanced adenocarcinoma should undergo a D2 lymphadenectomy. Postoperative chemoradiation and perioperative chemotherapy have been studied in gastric adenocarcinomas and showed a survival benefit. However, the surgical techniques used in these trials are no longer considered to be standard by today's surgical practice. In addition, there are no standard recommendations for adjuvant chemotherapy or chemoradiation after R0 resection and adequate lymph node dissection

Site-specific perturbations of alpha-synuclein fibril structure by the Parkinson's disease associated mutations A53T and E46K.

PMCID: PMC3591419This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Parkinson's disease (PD) is pathologically characterized by the presence of Lewy bodies (LBs) in dopaminergic neurons of the substantia nigra. These intracellular inclusions are largely composed of misfolded α-synuclein (AS), a neuronal protein that is abundant in the vertebrate brain. Point mutations in AS are associated with rare, early-onset forms of PD, although aggregation of the wild-type (WT) protein is observed in the more common sporadic forms of the disease. Here, we employed multidimensional solid-state NMR experiments to assess A53T and E46K mutant fibrils, in comparison to our recent description of WT AS fibrils. We made de novo chemical shift assignments for the mutants, and used these chemical shifts to empirically determine secondary structures. We observe significant perturbations in secondary structure throughout the fibril core for the E46K fibril, while the A53T fibril exhibits more localized perturbations near the mutation site. Overall, these results demonstrate that the secondary structure of A53T has some small differences from the WT and the secondary structure of E46K has significant differences, which may alter the overall structural arrangement of the fibrils

Crystal structures of self-assembled nanotubes from flexible macrocycles by weak interactions

8 páginas, 7 figuras, 2 tablas, 2 esquemas.Herein we report the crystal structures of tubular self-assemblies of flexible macrooligolides. The assembly is driven by the propensity of the macrocycles to create nearly flat structures displaying a void space within them and the cooperativity of weak directional interactions such as dipole–dipole interactions and CH***Ohydrogen bonds and non-directional interactions such as van der Waals contacts. The significance of the stereochemistry and the size of the cavity in the formation of the nanotubes are also studied.This research was supported by the Spanish MICINN-FEDER (CTQ2008-03334/BQU, CTQ2008-06806-C02-01/BQU and CTQ2008-06754-C04-01/PPQ), the MSC (RTICC RD06/0020/ 1046) and the Canary Islands FUNCIS (PI 01/06).Peer reviewe

HER2 Low Expression in Primary Male Breast Cancer

Katleen Nobbe,1 Melanie Erices-Leclercq,1 Frank Foerster,2,3 Robert Förster,4 Stephan E Baldus,5 Christian Rudlowski,1,6 Lars Schröder,7 Sabine Lubig1 1Breast Unit, Lutheran Hospital Bergisch Gladbach, Bergisch Gladbach, Germany; 2Department of Economical Sciences, University of Applied Sciences, Zwickau, Germany; 3Outpatient Department of Gynaecological Oncology and Palliative Care, Chemnitz, Germany; 4Institute for Radiation Oncology, Cantonal Hospital Winterthur, Winterthur, Switzerland; 5Institute for Pathology, Cytology and Molecular Pathology, Bergisch Gladbach, Germany; 6Department of Gynecology, University Hospital Bonn, Bonn, Germany; 7Department of Gynaecology and Obstetrics, Ketteler Krankenhaus, Offenbach, GermanyCorrespondence: Christian Rudlowski, Breast Unit, Lutheran Hospital Bergisch Gladbach, Ferrenbergstrasse 24, Bergisch Gladbach, 51465, Germany, Email [email protected]: The introduction of HER2-targeting antibody drug conjugates (ADCs) offers new treatment options for female breast cancer patients (FBC) expressing low levels of HER2 (HER2 low). No evidence was found that HER2 low describes a new FBC subtype. There is a lack of studies determining the impact of HER2 low in male breast cancer (MBC). In this study, we evaluate the prevalence of HER2 low in primary MBC and correlate the results with patient characteristics.Patients and Methods: In this study, histological specimens were obtained from 120 male patients diagnosed and treated for primary invasive breast cancer from 1995 to 2022 at Breast Cancer Units in Bergisch Gladbach, Chemnitz, and Zwickau, Germany. HER2 immunostaining and in situ hybridization were performed by central pathology and evaluated based on the ASCO/CAP guidelines. The correlation of expression of HER2 low with tumor biological characteristics and patient outcomes was investigated.Results: Out of all cases, four patients (3.3%) showed HER2 positivity (3+), 39 (32.5%) patients were classified as HER2 low, 7 (5.8%) were HER2 2+ (no amplification), 32 (26.7%) were HER2 1+, and 77 (64.2%) were classified as HER2 zero. Out of 77 HER2 zero cases, 47 tumors (61.0%) showed incomplete staining, with < 10% of tumor cells classified as HER2 ultralow. No statistical correlation between HER2 low and tumor biological characteristics and patients’ survival was found.Conclusion: Our findings show a notable, albeit lower, prevalence of HER2 low expression in primary MBC. However, tumors expressing HER2 low do not show specific tumor biological features to define a new breast cancer subtype in MBC. Our results suggest that a significant number of MBC patients could benefit from ADCs, as shown in FBC. Further studies are required to better understand HER2 low breast cancer, both generally and in MBC.Keywords: male breast cancer, HER2 low, prognosis, surviva

Fractional deuteration applied to biomolecular solid-state NMR spectroscopy

Solid-state Nuclear Magnetic Resonance can provide detailed insight into structural and dynamical aspects of complex biomolecules. With increasing molecular size, advanced approaches for spectral simplification and the detection of medium to long-range contacts become of critical relevance. We have analyzed the protonation pattern of a membrane-embedded ion channel that was obtained from bacterial expression using protonated precursors and D2O medium. We find an overall reduction of 50% in protein protonation. High levels of deuteration at Hα and Hβ positions reduce spectral congestion in (1H,13C,15N) correlation experiments and generate a transfer profile in longitudinal mixing schemes that can be tuned to specific resonance frequencies. At the same time, residual protons are predominantly found at amino-acid side-chain positions enhancing the prospects for obtaining side-chain resonance assignments and for detecting medium to long-range contacts. Fractional deuteration thus provides a powerful means to aid the structural analysis of complex biomolecules by solid-state NMR

Long non-coding RNAs defining major subtypes of B cell precursor acute lymphoblastic leukemia

BACKGROUND: Long non-coding RNAs (lncRNAs) have emerged as a novel class of RNA due to its diverse mechanism in cancer development and progression. However, the role and expression pattern of lncRNAs in molecular subtypes of B cell acute lymphoblastic leukemia (BCP-ALL) have not yet been investigated. Here, we assess to what extent lncRNA expression and DNA methylation is driving the progression of relapsed BCP-ALL subtypes and we determine if the expression and DNA methylation profile of lncRNAs correlates with established BCP-ALL subtypes. METHODS: We performed RNA sequencing and DNA methylation (Illumina Infinium microarray) of 40 diagnosis and 42 relapse samples from 45 BCP-ALL patients in a German cohort and quantified lncRNA expression. Unsupervised clustering was applied to ascertain and confirm that the lncRNA-based classification of the BCP-ALL molecular subtypes is present in both our cohort and an independent validation cohort of 47 patients. A differential expression and differential methylation analysis was applied to determine the subtype-specific, relapse-specific, and differentially methylated lncRNAs. Potential functions of subtype-specific lncRNAs were determined by using co-expression-based analysis on nearby (cis) and distally (trans) located protein-coding genes. RESULTS: Using an integrative Bioinformatics analysis, we developed a comprehensive catalog of 1235 aberrantly dysregulated BCP-ALL subtype-specific and 942 relapse-specific lncRNAs and the methylation profile of three subtypes of BCP-ALL. The 1235 subtype-specific lncRNA signature represented a similar classification of the molecular subtypes of BCP-ALL in the independent validation cohort. We identified a strong correlation between the DUX4-specific lncRNAs and genes involved in the activation of TGF-β and Hippo signaling pathways. Similarly, Ph-like-specific lncRNAs were correlated with genes involved in the activation of PI3K-AKT, mTOR, and JAK-STAT signaling pathways. Interestingly, the relapse-specific lncRNAs correlated with the activation of metabolic and signaling pathways. Finally, we found 23 promoter methylated lncRNAs epigenetically facilitating their expression levels. CONCLUSION: Here, we describe a set of subtype-specific and relapse-specific lncRNAs from three major BCP-ALL subtypes and define their potential functions and epigenetic regulation. The subtype-specific lncRNAs are reproducible and can effectively stratify BCP-ALL subtypes. Our data uncover the diverse mechanism of action of lncRNAs in BCP-ALL subtypes defining which lncRNAs are involved in the pathogenesis of disease and are relevant for the stratification of BCP-ALL subtypes