Chemical synthesis of site-selective advanced glycation end products in α-synuclein and its fragments

\ua9 2024 The Royal Society of Chemistry.Advanced glycation end products (AGEs) arise from the Maillard reaction between dicarbonyls and proteins, nucleic acids, or specific lipids. Notably, AGEs are linked to aging and implicated in various disorders, spanning from cancer to neurodegenerative diseases. While dicarbonyls like methylglyoxal preferentially target arginine residues, lysine-derived AGEs, such as N(6)-(1-carboxymethyl)lysine (CML) and N(6)-(1-carboxyethyl)lysine (CEL), are also abundant. Predicting protein glycation in vivo proves challenging due to the intricate nature of glycation reactions. In vitro, glycation is difficult to control, especially in proteins that harbor multiple glycation-prone amino acids. α-Synuclein (aSyn), pivotal in Parkinson\u27s disease and synucleinopathies, has 15 lysine residues and is known to become glycated at multiple lysine sites. To understand the influence of glycation in specific regions of aSyn on its behavior, a strategy for site-specific glycated protein production is imperative. To fulfill this demand, we devised a synthetic route integrating solid-phase peptide synthesis, orthogonal protection of amino acid side-chain functionalities, and reductive amination strategies. This methodology yielded two disease-related N-terminal peptide fragments, each featuring five and six CML and CEL modifications, alongside a full-length aSyn protein containing a site-selective E46CEL modification. Our synthetic approach facilitates the broad introduction of glycation motifs at specific sites, providing a foundation for generating glycated forms of synucleinopathy-related and other disease-relevant proteins

Evidence of Bordetella pertussis infection in vaccinated 1-year-old Danish children

We measured IgA and IgG antibodies to pertussis toxin (PT) and filamentous hemagglutinin (FHA) in sera from 203 1-year-old children who had received one to three doses of a monocomponent PT toxoid vaccine. Ten children (5%) had IgA antibody to PT indicating recent infection; seven of these children had received three doses of vaccine. PT IgA responders did not have significantly longer coughing episodes than PT IgA non-responders. Since an IgA antibody response occurs in only ∼50% of infected children, the actual infection rate in our cohort is estimated to ∼10%. The apparent high Bordetella pertussis infection rate in Danish infants suggests that the monocomponent PT toxoid vaccine used in Denmark has limited efficacy against B. pertussis infection. A prospective immunization study comparing a multi-component vaccine with the present monocomponent PT toxoid vaccine should be undertaken

Bordetella pertussis, Finland and France

We used pulsed-field gel electrophoresis analysis and genotyping to compare clinical isolates of Bordetella pertussis recovered since the early 1990s in Finland and France, 2 countries with similar histories of long-term mass vaccination with whole-cell pertussis vaccines. Isolates from both countries were similar genetically but varied temporally

Semi-supervised multi-task learning for predicting interactions between HIV-1 and human proteins

Motivation: Protein–protein interactions (PPIs) are critical for virtually every biological function. Recently, researchers suggested to use supervised learning for the task of classifying pairs of proteins as interacting or not. However, its performance is largely restricted by the availability of truly interacting proteins (labeled). Meanwhile, there exists a considerable amount of protein pairs where an association appears between two partners, but not enough experimental evidence to support it as a direct interaction (partially labeled)

Ozone profiles in the high-latitude stratosphere and lower mesosphere measured by the Improved Limb Atmospheric Spectrometer (ILAS)-II: comparison with other satellite sensors and ozonesondes

A solar occultation sensor, the Improved Limb Atmospheric Spectrometer (ILAS)-II, measured 5890 vertical profiles of ozone concentrations in the stratosphere and lower mesosphere and of other species from January to October 2003. The measurement latitude coverage was 54–71°N and 64–88°S, which is similar to the coverage of ILAS (November 1996 to June 1997). One purpose of the ILAS-II measurements was to continue such high-latitude measurements of ozone and its related chemical species in order to help accurately determine their trends. The present paper assesses the quality of ozone data in the version 1.4 retrieval algorithm, through comparisons with results obtained from comprehensive ozonesonde measurements and four satellite-borne solar occultation sensors. In the Northern Hemisphere (NH), the ILAS-II ozone data agree with the other data within ±10% (in terms of the absolute difference divided by its mean value) at altitudes between 11 and 40 km, with the median coincident ILAS-II profiles being systematically up to 10% higher below 20 km and up to 10% lower between 21 and 40 km after screening possible suspicious retrievals. Above 41 km, the negative bias between the NH ILAS-II ozone data and the other data increases with increasing altitude and reaches 30% at 61–65 km. In the Southern Hemisphere, the ILAS-II ozone data agree with the other data within ±10% in the altitude range of 11–60 km, with the median coincident profiles being on average up to 10% higher below 20 km and up to 10% lower above 20 km. Considering the accuracy of the other data used for this comparative study, the version 1.4 ozone data are suitably used for quantitative analyses in the high-latitude stratosphere in both the Northern and Southern Hemisphere and in the lower mesosphere in the Southern Hemisphere

A topological Dirac insulator in a quantum spin Hall phase : Experimental observation of first strong topological insulator

When electrons are subject to a large external magnetic field, the conventional charge quantum Hall effect \cite{Klitzing,Tsui} dictates that an electronic excitation gap is generated in the sample bulk, but metallic conduction is permitted at the boundary. Recent theoretical models suggest that certain bulk insulators with large spin-orbit interactions may also naturally support conducting topological boundary states in the extreme quantum limit, which opens up the possibility for studying unusual quantum Hall-like phenomena in zero external magnetic field. Bulk Bi$_{1-x}$Sb$_x$ single crystals are expected to be prime candidates for one such unusual Hall phase of matter known as the topological insulator. The hallmark of a topological insulator is the existence of metallic surface states that are higher dimensional analogues of the edge states that characterize a spin Hall insulator. In addition to its interesting boundary states, the bulk of Bi$_{1-x}$Sb$_x$ is predicted to exhibit three-dimensional Dirac particles, another topic of heightened current interest. Here, using incident-photon-energy-modulated (IPEM-ARPES), we report the first direct observation of massive Dirac particles in the bulk of Bi$_{0.9}$Sb$_{0.1}$, locate the Kramers' points at the sample's boundary and provide a comprehensive mapping of the topological Dirac insulator's gapless surface modes. These findings taken together suggest that the observed surface state on the boundary of the bulk insulator is a realization of the much sought exotic "topological metal". They also suggest that this material has potential application in developing next-generation quantum computing devices.Comment: 16 pages, 3 Figures. Submitted to NATURE on 25th November(2007

Clinical Definitions of Pertussis: Summary of a Global Pertussis Initiative Roundtable Meeting, February 2011

Existing clinical case definitions of pertussis are decades old and based largely on clinical presentation in infants and children, yet an increasing burden is borne by adolescents and adults who may manifest distinct signs/symptoms. Therefore, a “one-size-fits-all” clinical case definition is no longer appropriate. Seeking to improve pertussis diagnosis, the Global Pertussis Initiative (GPI) developed an algorithm that delineates the signs/symptoms of pertussis most common to 3 age groups: 0–3 months, 4 months to 9 years, and ≥10 years. These case definitions are based on clinical presentation alone, but do include recommendations on laboratory diagnostics. Until pertussis can be accurately diagnosed, its burden will remain underestimated, making the introduction of epidemiologically appropriate preventive strategies difficult. The proposed definitions are intended to be widely applicable and to encourage the expanded use of laboratory diagnostics. Determination of their utility and their sensitivity and/or specificity versus existing case definitions is required