Synthesis of colicin Ia neoglycoproteins: tools towards glyco-engineering of bacterial cell surfaces.

Colicins are antimicrobial proteins produced by certain strains of that function as offensive weapons against closely-related competitor strains. Their bactericidal properties and narrow bacterial targeting range has made them of therapeutic interest. Furthermore, the applications of engineered non-bactericidal colicins are of interest as a cell surface-directed protein anchor for decorating with biomolecules.

Mannose-Presenting "Glyco-Colicins" Convert the Bacterial Cell Surface into a Multivalent Adsorption Site for Adherent Bacteria.

Biofilm formation is integral to the pathogenesis of numerous adherent bacteria and contributes to antimicrobial resistance (AMR). The rising threat of AMR means the need to develop novel nonbactericidal antiadhesion approaches against such bacteria is more urgent than ever. Both adherent-invasive (AIEC, implicated in inflammatory bowel disease) and uropathogenic (UPEC, responsible for ∼80% of urinary tract infections) adhere to terminal mannose sugars on epithelial glycoproteins through the FimH adhesin on their type 1 pilus.

Structural basis of DNA packaging by a ring-type ATPase from an archetypal viral system.

Many essential cellular processes rely on substrate rotation or translocation by a multi-subunit, ring-type NTPase. A large number of double-stranded DNA viruses, including tailed bacteriophages and herpes viruses, use a homomeric ring ATPase to processively translocate viral genomic DNA into procapsids during assembly. Our current understanding of viral DNA packaging comes from three archetypal bacteriophage systems: cos, pac and phi29.

Over 10 years "Health and Technology".

Over 10 years ago, in August 2011, this IUPESM and Springer journal "Health and Technology" published its first issue. In this editorial paper we give an overview on the origins, the developments, the achievements and the future of this journal.

Subcellular dynamics and functional activity of the cleaved intracellular domain of the Na channel β1 subunit.

The voltage-gated Na channel β1 subunit, encoded by SCN1B, regulates cell surface expression and gating of α subunits and participates in cell adhesion. β1 is cleaved by α/β and γ-secretases, releasing an extracellular domain and intracellular domain (ICD), respectively. Abnormal SCN1B expression/function is linked to pathologies including epilepsy, cardiac arrhythmia, and cancer.

Transverse Magnetic Tweezers Allowing Coincident Epi-Fluorescence Microscopy on Horizontally Extended DNA.

Longitudinal magnetic tweezers (L-MT) have seen wide-scale adoption as the tool of choice for stretching and twisting a single DNA molecule. They are also used to probe topological changes in DNA as a result of protein binding and enzymatic activity. However, in the longitudinal configuration, the DNA molecule is extended perpendicular to the imaging plane.

A Tale of Two Bioconjugations: pH Controlled Divergent Reactivity of Protein α-oxo-Aldehydes in Competing α-oxo-Mannich and Catalyst-Free Aldol Ligations.

Site-selective chemical methods for protein bioconjugation have revolutionized the fields of cell and chemical biology through the development of novel protein/enzyme probes bearing fluorescent, spectroscopic, or even toxic cargos. Herein, we report two new methods for the bioconjugation of α-oxo aldehyde handles within proteins using small molecule aniline and/or phenol probes. The "α-oxo-Mannich" and "catalyst-free aldol" ligations both compete for the electrophilic α-oxo aldehyde, which displays pH divergent reactivity proceeding through the "Mannich" pathway at acidic pH to afford bifunctionalized bioconjugates, and the "catalyst-free aldol" pathway at neutral pH to afford monofunctionalized bioconjugates.

Pathophysiological mechanisms of bradycardia in patients with anorexia nervosa.

Background: The purpose of this investigation was to examine heart rate variability (HRV), interbeat interval (IBI), and their interrelationship in healthy controls, bradycardic hyperpolarization-activated cyclic nucleotide-gated channel 4 () mutation carriers, and patients with anorexia nervosa (AN). We tested the hypothesis that neural mechanisms cause bradycardia in patients with AN. Therefore, we assumed that saturation of the HRV/IBI relationship as a consequence of sustained parasympathetic control of the sinus node is exclusively detectable in patients with AN.

Periscope Proteins are variable-length regulators of bacterial cell surface interactions.

Changes at the cell surface enable bacteria to survive in dynamic environments, such as diverse niches of the human host. Here, we reveal "Periscope Proteins" as a widespread mechanism of bacterial surface alteration mediated through protein length variation. Tandem arrays of highly similar folded domains can form an elongated rod-like structure; thus, variation in the number of domains determines how far an N-terminal host ligand binding domain projects from the cell surface.

Multicolor Mechanofluorophores for the Quantitative Detection of Covalent Bond Scission in Polymers.

The fracture of polymer materials is a multiscale process starting with the scission of a single molecular bond advancing to a site of failure within the bulk. Quantifying the bonds broken during this process remains a big challenge yet would help to understand the distribution and dissipation of macroscopic mechanical energy. We here show the design and synthesis of fluorogenic molecular optical force probes (mechanofluorophores) covering the entire visible spectrum in both absorption and emission.

Developments in Mannose-Based Treatments for Uropathogenic Escherichia coli-Induced Urinary Tract Infections.

During their lifetime almost half of women will experience a symptomatic urinary tract infection (UTI) with a further half experiencing a relapse within six months. Currently UTIs are treated with antibiotics, but increasing antibiotic resistance rates highlight the need for new treatments. Uropathogenic Escherichia coli (UPEC) is responsible for the majority of symptomatic UTI cases and thus has become a key pathological target.

Diagnosis and management of an inappropriate sinus tachycardia in adolescence based upon a Holter ECG: A retrospective analysis of 479 patients.

Inappropriate sinus tachycardia (IST) is a common disease of the autonomic nervous system in children and adults. Diagnosis and treatment of IST in adolescents is not well defined. In this retrospective study, we tested our hypothesis regarding autonomic dysfunction in childhood by analyzing 24-h heart rate variability (HRV) in 479 children, with a mean age of 13.

Vγ9Vδ2 T Cells: Can We Re-Purpose a Potent Anti-Infection Mechanism for Cancer Therapy?

Cancer therapies based on in vivo stimulation, or on adoptive T cell transfer of Vγ9Vδ2 T cells, have been tested in the past decades but have failed to provide consistent clinical efficacy. New, promising concepts such as γδ Chimeric Antigen Receptor (CAR) -T cells and γδ T-cell engagers are currently under preclinical evaluation. Since the impact of factors, such as the relatively low abundance of γδ T cells within tumor tissue is still under investigation, it remains to be shown whether these effector T cells can provide significant efficacy against solid tumors.

Anti-Stokes Stress Sensing: Mechanochemical Activation of Triplet-Triplet Annihilation Photon Upconversion.

The development of methods to detect damage in macromolecular materials is of paramount importance to understand their mechanical failure and the structure-property relationships of polymers. Mechanofluorophores are useful and sensitive molecular motifs for this purpose. However, to date, tailoring of their optical properties remains challenging and correlating emission intensity to force induced material damage and the respective events on the molecular level is complicated by intrinsic limitations of fluorescence and its detection techniques.

Omega-3 Fatty Acid Supplementation Improves Heart Rate Variability in Obese Children.

Obese children and adolescents are at high risk of developing cardiovascular diseases later in life. We hypothesized that cardiovascular prophylaxis with omega-3 fatty acids could benefit them. In our study, 20 children and adolescents (mean body mass index percentile: 99.

Intermembrane crosstalk drives inner-membrane protein organization in Escherichia coli.

Gram-negative bacteria depend on energised protein complexes that connect the two membranes of the cell envelope. However, β-barrel outer-membrane proteins (OMPs) and α-helical inner-membrane proteins (IMPs) display quite different organisation. OMPs cluster into islands that restrict their lateral mobility, while IMPs generally diffuse throughout the cell.

Nickel-Catalyzed Alkoxy-Alkyl Interconversion with Alkylborane Reagents through C-O Bond Activation of Aryl and Enol Ethers.

A nickel-catalyzed alkylation of polycyclic aromatic methyl ethers as well as methyl enol ethers with B-alkyl 9-BBN and trialkylborane reagents that involves the cleavage of stable C(sp )-OMe bonds is described. The transformation has a wide substrate scope and good chemoselectivity profile while proceeding under mild reaction conditions; it provides a versatile way to form C(sp )-C(sp ) bonds that does not suffer from β-hydride elimination. Furthermore, a selective and sequential alkylation process by cleavage of inert C-O bonds is presented to demonstrate the advantage of this method.

In situ mechanical and molecular investigations of collagen/apatite biomimetic composites combining Raman spectroscopy and stress-strain analysis.

Unlabelled: We report the design, fabrication and application of a novel micro-electromechanical device coupled to a confocal Raman microscope that enables in situ molecular investigations of micro-fibers under uniaxial tensile load. This device allows for the mechanical study of micro-fibers with diameters in the range between 10 and 100μm and lengths of several hundred micrometers. By exerting forces in the mN range, the device enables an important force range to be accessed between that of atomic force microscopy and macroscopic stress-strain measurement devices.

The tripeptide KdPT ameliorates ongoing psoriasis-like skin inflammation in murine and human skin.

Psoriasis is a chronic inflammatory disease appearing as scaly erythematous cutaneous lesions, which are characterized by parakeratosis and acanthosis as well as the infiltration of immune cells, such as T helper-1 and T helper-17 cells. Here, we demonstrated that KdPT, a tripeptide structurally related to the C-terminal amino acids of alpha-melanocyte-stimulating hormone, which was previously shown to exhibit anti-inflammatory effects in intestinal inflammation, ameliorated ongoing disease in the mouse model of imiquimod-induced psoriasis-like skin inflammation and in the small xenotransplant mouse model of psoriasis. We could show that systemic KdPT treatment significantly reduced hyperkeratosis and acanthosis in murine as well as human skin.

Transverse Magnetic Tweezers Allowing Coincident Epifluorescence Microscopy on Horizontally Extended DNA.

Longitudinal magnetic tweezers (L-MT) have seen wide-scale adoption as the tool-of-choice for stretching and twisting a single DNA molecule. They are also used to probe topological changes in DNA as a result of protein binding and enzymatic activity. However, in the longitudinal configuration, the DNA molecule is extended perpendicular to the imaging plane.

Protein-protein interactions and the spatiotemporal dynamics of bacterial outer membrane proteins.

It has until recently been unclear whether outer membrane proteins (OMPs) of Gram-negative bacteria are organized or distributed randomly. Studies now suggest promiscuous protein-protein interactions (PPIs) between β-barrel OMPs in Escherichia coli govern their local and global dynamics, engender spatiotemporal patterning of the outer membrane into micro-domains and are the basis of β-barrel protein turnover. We contextualize these latest advances, speculate on areas of bacterial cell biology that might be influenced by the organization of OMPs into supramolecular assemblies, and highlight the new questions and controversies this revised view of the bacterial outer membrane raises.

The Lipid-Modifying Enzyme SMPDL3B Negatively Regulates Innate Immunity.

Lipid metabolism and receptor-mediated signaling are highly intertwined processes that cooperate to fulfill cellular functions and safeguard cellular homeostasis. Activation of Toll-like receptors (TLRs) leads to a complex cellular response, orchestrating a diverse range of inflammatory events that need to be tightly controlled. Here, we identified the GPI-anchored Sphingomyelin Phosphodiesterase, Acid-Like 3B (SMPDL3B) in a mass spectrometry screening campaign for membrane proteins co-purifying with TLRs.

A Conserved Circular Network of Coregulated Lipids Modulates Innate Immune Responses.

Lipid composition affects the biophysical properties of membranes that provide a platform for receptor-mediated cellular signaling. To study the regulatory role of membrane lipid composition, we combined genetic perturbations of sphingolipid metabolism with the quantification of diverse steps in Toll-like receptor (TLR) signaling and mass spectrometry-based lipidomics. Membrane lipid composition was broadly affected by these perturbations, revealing a circular network of coregulated sphingolipids and glycerophospholipids.