Extrusion of Dissolved Oxygen by Exopolysaccharide From Leuconostoc mesenteroides and Its Implications in Relief of the Oxygen Stress

Strains of Leuconostoc are generally facultatively anaerobic and exposure to oxygen might be detrimental; therefore, strategies to combat the oxygen stress are essential for these bacteria to survive and flourish in the oxygenic atmosphere. Despite the extensive applications in industry, the fundamental issues concerning the aerobic life of Leuconostocs remain to be addressed. In this study, we have demonstrated that Leuconostoc mesenteroides CGMCC10064 cultivated in sucrose medium would acquire a growth advantage over that in glucose medium under oxygenic conditions, as reflected by more viable cells and less accumulation of reactive oxygen species. Further analysis showed that the growth advantage was dependent on exopolysaccharide (EPS) synthesized by a secreted glucansucrase. Determination of the dissolved oxygen in the culture suggested that the growth improvement was mediated by extrusion of dissolved oxygen from the aqueous circumstances. Growth experiments performed with the purified EPS showed that supplementation of 5 g/L EPS in the medium could improve the aerobic growth of L. mesenteroides by ∼10-fold. Moreover, the purified EPS was also effective in promoting the aerobic growth of oxygen-sensitive Lactobacillus and Bifidobacterium. These results demonstrate that EPS of L. mesenteroides plays a critical role in relief of the oxygen stress, and suggest the potential of the EPS in manufacture as well as preservation of oxygen-sensitive probiotics

Characterization of Aptamer-Protein Complexes by X-ray Crystallography and Alternative Approaches

Aptamers are oligonucleotide ligands, either RNA or ssDNA, selected for high-affinity binding to molecular targets, such as small organic molecules, proteins or whole microorganisms. While reports of new aptamers are numerous, characterization of their specific interaction is often restricted to the affinity of binding (KD). Over the years, crystal structures of aptamer-protein complexes have only scarcely become available. Here we describe some relevant technical issues about the process of crystallizing aptamer-protein complexes and highlight some biochemical details on the molecular basis of selected aptamer-protein interactions. In addition, alternative experimental and computational approaches are discussed to study aptamer-protein interactions.

Guidance on noncorticosteroid systemic immunomodulatory therapy in noninfectious uveitis: fundamentals of care for uveitis (focus) initiative

Topic: An international, expert-led consensus initiative to develop systematic, evidence-based recommendations for the treatment of noninfectious uveitis in the era of biologics. Clinical Relevance: The availability of biologic agents for the treatment of human eye disease has altered practice patterns for the management of noninfectious uveitis. Current guidelines are insufficient to assure optimal use of noncorticosteroid systemic immunomodulatory agents. Methods: An international expert steering committee comprising 9 uveitis specialists (including both ophthalmologists and rheumatologists) identified clinical questions and, together with 6 bibliographic fellows trained in uveitis, conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol systematic reviewof the literature (English language studies from January 1996 through June 2016; Medline [OVID], the Central Cochrane library, EMBASE,CINAHL,SCOPUS,BIOSIS, andWeb of Science). Publications included randomized controlled trials, prospective and retrospective studies with sufficient follow-up, case series with 15 cases or more, peer-reviewed articles, and hand-searched conference abstracts from key conferences. The proposed statements were circulated among 130 international uveitis experts for review.Atotal of 44 globally representativegroupmembersmet in late 2016 to refine these guidelines using a modified Delphi technique and assigned Oxford levels of evidence. Results: In total, 10 questions were addressed resulting in 21 evidence-based guidance statements covering the following topics: when to start noncorticosteroid immunomodulatory therapy, including both biologic and nonbiologic agents; what data to collect before treatment; when to modify or withdraw treatment; how to select agents based on individual efficacy and safety profiles; and evidence in specific uveitic conditions. Shared decision-making, communication among providers and safety monitoring also were addressed as part of the recommendations. Pharmacoeconomic considerations were not addressed. Conclusions: Consensus guidelines were developed based on published literature, expert opinion, and practical experience to bridge the gap between clinical needs and medical evidence to support the treatment of patients with noninfectious uveitis with noncorticosteroid immunomodulatory agents

Broad targeting of resistance to apoptosis in cancer

Apoptosis or programmed cell death is natural way of removing aged cells from the body. Most of the anti-cancer therapies trigger apoptosis induction and related cell death networks to eliminate malignant cells. However, in cancer, de-regulated apoptotic signaling, particularly the activation of an anti-apoptotic systems, allows cancer cells to escape this program leading to uncontrolled proliferation resulting in tumor survival, therapeutic resistance and recurrence of cancer. This resistance is a complicated phenomenon that emanates from the interactions of various molecules and signaling pathways. In this comprehensive review we discuss the various factors contributing to apoptosis resistance in cancers. The key resistance targets that are discussed include (1) Bcl-2 and Mcl-1 proteins; (2) autophagy processes; (3) necrosis and necroptosis; (4) heat shock protein signaling; (5) the proteasome pathway; (6) epigenetic mechanisms; and (7) aberrant nuclear export signaling. The shortcomings of current therapeutic modalities are highlighted and a broad spectrum strategy using approaches including (a) gossypol; (b) epigallocatechin-3-gallate; (c) UMI-77 (d) triptolide and (e) selinexor that can be used to overcome cell death resistance is presented. This review provides a roadmap for the design of successful anti-cancer strategies that overcome resistance to apoptosis for better therapeutic outcome in patients with cancer

A Positive Regulatory Loop between foxi3a and foxi3b Is Essential for Specification and Differentiation of Zebrafish Epidermal Ionocytes

BACKGROUND: Epidermal ionocytes play essential roles in the transepithelial transportation of ions, water, and acid-base balance in fish embryos before their branchial counterparts are fully functional. However, the mechanism controlling epidermal ionocyte specification and differentiation remains unknown. METHODOLOGY/PRINCIPAL FINDINGS: In zebrafish, we demonstrated that Delta-Notch-mediated lateral inhibition plays a vital role in singling out epidermal ionocyte progenitors from epidermal stem cells. The entire epidermal ionocyte domain of genetic mutants and morphants, which failed to transmit the DeltaC-Notch1a/Notch3 signal from sending cells (epidermal ionocytes) to receiving cells (epidermal stem cells), differentiates into epidermal ionocytes. The low Notch activity in epidermal ionocyte progenitors is permissive for activating winged helix/forkhead box transcription factors of foxi3a and foxi3b. Through gain- and loss-of-function assays, we show that the foxi3a-foxi3b regulatory loop functions as a master regulator to mediate a dual role of specifying epidermal ionocyte progenitors as well as of subsequently promoting differentiation of Na(+),K(+)-ATPase-rich cells and H(+)-ATPase-rich cells in a concentration-dependent manner. CONCLUSIONS/SIGNIFICANCE: This study provides a framework to show the molecular mechanism controlling epidermal ionocyte specification and differentiation in a low vertebrate for the first time. We propose that the positive regulatory loop between foxi3a and foxi3b not only drives early ionocyte differentiation but also prevents the complete blockage of ionocyte differentiation when the master regulator of foxi3 function is unilaterally compromised

Ni-based bimetallic heterogeneous catalysts for energy and environmental applications

Bimetallic catalysts have attracted extensive attention for a wide range of applications in energy production and environmental remediation due to their tunable chemical/physical properties. These properties are mainly governed by a number of parameters such as compositions of the bimetallic systems, their preparation method, and their morphostructure. In this regard, numerous efforts have been made to develop “designer” bimetallic catalysts with specific nanostructures and surface properties as a result of recent advances in the area of materials chemistry. The present review highlights a detailed overview of the development of nickel-based bimetallic catalysts for energy and environmental applications. Starting from a materials science perspective in order to obtain controlled morphologies and surface properties, with a focus on the fundamental understanding of these bimetallic systems to make a correlation with their catalytic behaviors, a detailed account is provided on the utilization of these systems in the catalytic reactions related to energy production and environmental remediation. We include the entire library of nickel-based bimetallic catalysts for both chemical and electrochemical processes such as catalytic reforming, dehydrogenation, hydrogenation, electrocatalysis and many other reactions

Protective Effects of Positive Lysosomal Modulation in Alzheimer's Disease Transgenic Mouse Models

Alzheimer's disease (AD) is an age-related neurodegenerative pathology in which defects in proteolytic clearance of amyloid β peptide (Aβ) likely contribute to the progressive nature of the disorder. Lysosomal proteases of the cathepsin family exhibit up-regulation in response to accumulating proteins including Aβ1–42. Here, the lysosomal modulator Z-Phe-Ala-diazomethylketone (PADK) was used to test whether proteolytic activity can be enhanced to reduce the accumulation events in AD mouse models expressing different levels of Aβ pathology. Systemic PADK injections in APPSwInd and APPswe/PS1ΔE9 mice caused 3- to 8-fold increases in cathepsin B protein levels and 3- to 10-fold increases in the enzyme's activity in lysosomal fractions, while neprilysin and insulin-degrading enzyme remained unchanged. Biochemical analyses indicated the modulation predominantly targeted the active mature forms of cathepsin B and markedly changed Rab proteins but not LAMP1, suggesting the involvement of enhanced trafficking. The modulated lysosomal system led to reductions in both Aβ immunostaining as well as Aβx-42 sandwich ELISA measures in APPSwInd mice of 10–11 months. More extensive Aβ deposition in 20-22-month APPswe/PS1ΔE9 mice was also reduced by PADK. Selective ELISAs found that a corresponding production of the less pathogenic Aβ1–38 occurs as Aβ1–42 levels decrease in the mouse models, indicating that PADK treatment leads to Aβ truncation. Associated with Aβ clearance was the elimination of behavioral and synaptic protein deficits evident in the two transgenic models. These findings indicate that pharmacologically-controlled lysosomal modulation reduces Aβ1–42 accumulation, possibly through intracellular truncation that also influences extracellular deposition, and in turn offsets the defects in synaptic composition and cognitive functions. The selective modulation promotes clearance at different levels of Aβ pathology and provides proof-of-principle for small molecule therapeutic development for AD and possibly other protein accumulation disorders

Mapping the Conformational Dynamics and Pathways of Spontaneous Steric Zipper Peptide Oligomerization

The process of protein misfolding and self-assembly into various, polymorphic aggregates is associated with a number of important neurodegenerative diseases. Only recently, crystal structures of several short peptides have provided detailed structural insights into -sheet rich aggregates, known as amyloid fibrils. Knowledge about early events of the formation and interconversion of small oligomeric states, an inevitable step in the cascade of peptide self-assembly, however, remains still limited

Matter manipulation with extreme terahertz light: Progress in the enabling THz technology

Terahertz (THz) light has proven to be a fine tool to probe and control quasi-particles and collective excitations in solids, to drive phase transitions and associated changes in material properties, and to study rotations and vibrations in molecular systems. In contrast to visible light, which usually carries excessive photon energy for collective excitations in condensed matter systems, THz light allows for direct coupling to low-energy (meV scale) excitations of interest, The development of light sources of strong-field few-cycle THz pulses in the 2000s opened the door to controlled manipulation of reactions and processes. Such THz pulses can drive new dynamic states of matter, in which materials exhibit properties entirely different from that of the equilibrium. In this review, we first systematically analyze known studies on matter manipulation with strong-field few-cycle THz light and outline some anticipated new results. We focus on how properties of materials can be manipulated by driving the dynamics of different excitations and how molecules and particles can be controlled in useful ways by extreme THz light. Around 200 studies are examined, most of which were done during the last five years. Secondly, we discuss available and proposed sources of strong-field few-cycle THz pulses and their state-of-the-art operation parameters. Finally, we review current approaches to guiding, focusing, reshaping and diagnostics of THz pulses. (C) 2019 The Author(s). Published by Elsevier B.V

Overview on Multienzymatic Cascades for the Production of Non-canonical α-Amino Acids

SM-R thanks the University of Granada for the support provided by project PPJI2017-1 and the European Cooperation in Science and Technology (COST Action CA15133). Authors are also grateful to the Andalusian Regional Government through Endocrinology & Metabolism Group (CTS-202).The 22 genetically encoded amino acids (AAs) present in proteins (the 20 standard AAs together with selenocysteine and pyrrolysine), are commonly referred as proteinogenic AAs in the literature due to their appearance in ribosome-synthetized polypeptides. Beyond the borders of this key set of compounds, the rest of AAs are generally named imprecisely as non-proteinogenic AAs, even when they can also appear in polypeptide chains as a result of post-transductional machinery. Besides their importance as metabolites in life, many of D-α- and L-α-“non-canonical” amino acids (NcAAs) are of interest in the biotechnological and biomedical fields. They have found numerous applications in the discovery of new medicines and antibiotics, drug synthesis, cosmetic, and nutritional compounds, or in the improvement of protein and peptide pharmaceuticals. In addition to the numerous studies dealing with the asymmetric synthesis of NcAAs, many different enzymatic pathways have been reported in the literature allowing for the biosynthesis of NcAAs. Due to the huge heterogeneity of this group of molecules, this review is devoted to provide an overview on different established multienzymatic cascades for the production of non-canonical D-α- and L-α-AAs, supplying neophyte and experienced professionals in this field with different illustrative examples in the literature. Whereas the discovery of new or newly designed enzymes is of great interest, dusting off previous enzymatic methodologies by a “back and to the future” strategy might accelerate the implementation of new or improved multienzymatic cascades.University of Granada PPJI2017-1European Cooperation in Science and Technology (COST) CA15133Andalusian Regional Government through Endocrinology & Metabolism Group CTS-20