The diversity of stereochemical isomers present in glycans and glycoconjugates poses af ormidable challenge for comprehensive structural analysis.T ypically,s ophisticated mass spectrometry (MS)-based techniques are used in combination with chromatography or ion-mobility separation. However,c oexisting structurally similar isomers often render an unambiguous identification impossible.O ther powerful techniques such as gas-phase infrared (IR) spectroscopyh ave been limited to smaller glycans,since conformational flexibility and thermal activation during the measurement result in poor spectral resolution. This limitation can be overcome by using cold-ion spectroscopy. The vibrational fingerprints of cold oligosaccharide ions exhibit aw ealth of well-resolved absorption features that are diagnostic for minute structural variations.T he unprecedented resolution of cold-ion spectroscopy coupled with tandem MS may render this the key technology to unravel complex glycomes.Carbohydrates are ubiquitous in nature,and are historically associated with their prominent roles as structural scaffolds and energy sources within the cell. However,s horter chains, often referred to as oligosaccharides or glycans,a re also essential in numerous biological signaling processes.[1] The field of glycomics,w hich aims to comprehensively elucidate the structure and functions of glycans,i sc urrently profiting from technical breakthroughs in automated chemical synthesis and analysis but remains largely underexplored when compared to genomics and proteomics.T he inherent structural diversity of oligosaccharides creates major challenges for progress in glycobiology.Whereas DNAand proteins are exclusively assembled in alinear and template-driven fashion, glycans are non-template derived, branched, and exhibit complex stereo-and regiochemistry.Exploring the structure, shape,and resulting functions of oligosaccharides is difficult.Detailed structural analyses of glycans typically involve liquid chromatography (LC) and/or mass spectrometry (MS)-based techniques that require only small amounts of sample. [2] In addition to the molecular composition, sophisticated MS techniques such as sequential mass spectrometry (MS n )o r chemical derivatization can yield information about the sequence and connectivity of the constituting monosaccharide building blocks.[3] Ion-mobility mass spectrometry (IM-MS) has proven ap owerful tool to rapidly separate and identify the connectivity and configurational isomers of carbohydrates. [4] Combining MS and infrared (IR) spectroscopy provides av ery sensitive alternative by interrogating the vibrational modes of isolated molecules in the controlled environment of the gas phase.E xploring the characteristic absorption bands of molecules is ar outine means to deduce structural information concerning functional groups,hydrogen-bonding patterns,a nd preferred molecular conformations.A ss uch, gas-phase IR spectroscopy is aw ell-established tool for the structural analysis of peptides,proteins,and small mol...
Chagas disease is an endemic disease of the American continent caused by Trypanosoma cruzi and divided into six discrete typing units (TcI - TcVI). Nearly 10 million people harbour the infection representing a serious issue in public health. Epidemiological surveillance allowed us to detect a bat-related T. cruzi genotype (henceforth named TcBat) in a 5-year-old female living in a forest area in northwestern Colombia. Molecular tools determined a mixed infection of T. cruzi I and TcBat genotypes. This represents the first report of TcBat infection in humans; the epidemiological consequences of this finding are discussed herein.
Background Trypanosoma cruzi, the causative agent of Chagas disease, displays significant genetic variability revealed by six Discrete Typing Units (TcI-TcVI). In this pathology, oral transmission represents an emerging epidemiological scenario where different outbreaks associated to food/beverages consumption have been reported in Argentina, Bolivia, Brazil, Ecuador and Venezuela. In Colombia, six human oral outbreaks have been reported corroborating the importance of this transmission route. Molecular epidemiology of oral outbreaks is barely known observing the incrimination of TcI, TcII, TcIV and TcV genotypes.Methodology and Principal FindingsHigh-throughput molecular characterization was conducted performing MLMT (Multilocus Microsatellite Typing) and mtMLST (mitochondrial Multilocus Sequence Typing) strategies on 50 clones from ten isolates. Results allowed observing the occurrence of TcI, TcIV and mixed infection of distinct TcI genotypes. Thus, a majority of specific mitochondrial haplotypes and allelic multilocus genotypes associated to the sylvatic cycle of transmission were detected in the dataset with the foreseen presence of mitochondrial haplotypes and allelic multilocus genotypes associated to the domestic cycle of transmission.ConclusionsThese findings suggest the incrimination of sylvatic genotypes in the oral outbreaks occurred in Colombia. We observed patterns of super-infection and/or co-infection with a tailored association with the severe forms of myocarditis in the acute phase of the disease. The transmission dynamics of this infection route based on molecular epidemiology evidence was unraveled and the clinical and biological implications are discussed.
Here we present a combined experimental and theoretical study on the secondary structure of isolated proteins as a function of charge state. In infrared spectra of the proteins ubiquitin and cytochrome c, amide I (C=O stretch) and amide II (N–H bend) bands can be found at positions that are typical for condensed‐phase proteins. For high charge states a new band appears, substantially red‐shifted from the amide II band observed at lower charge states. The observations are interpreted in terms of Coulomb‐driven transitions in secondary structures from mostly helical to extended C5‐type hydrogen‐bonded structures. Support for this interpretation comes from simple energy considerations as well as from quantum chemical calculations on model peptides. This transition in secondary structure is most likely universal for isolated proteins that occur in mass spectrometric experiments.
Ultracold IR spectra of the protonated five amino acid peptide leu-enkephalin (Tyr-Gly-Gly-Phe-Leu) embedded in superfluid helium droplets have been recorded using a free-electron laser as radiation source. The results show resolved spectra, which are in good agreement with theoretical calculations, as well as with the available gas-phase data indicating that the helium environment does not induce a significant matrix-shift. In addition, the effect of the interaction between the charge and the peptide backbone has been further investigated by complexing protonated leu-enkephalin with one 18-crown-6 molecule. Good agreement between the experimental and theoretical results allow for an assignment of a preferred molecular structure.
BackgroundChagas disease is an anthropozoonosis caused by Trypanosoma cruzi. Two drugs are currently used for the etiological treatment of the disease: Nifurtimox (Lampit) and Benznidazole. This study presents a quasi-experimental trial (non-control group) of sixty-two patients who were treated for Chagas disease with Nifurtimox (Lampit), and were then followed for 30 months post-treatment. The safety of Nifurtimox (Lampit) for Chagas disease in this group of children primarily between 4 and 19 years old was also evaluated.Materials and methodsThe 62 patients included in the study were selected when resulted seropositive for two out of three fundamentally different serological tests. All children were treated during two months according to protocols established by WHO. Monitoring was performed every twenty days to evaluate treatment safety. In 43 patients, two different serological tests: ELISA and IFAT; and two parasitological tests: blood culture, and real time PCR, (qPCR) were performed to assess therapeutic response, defined as post-treatment serological negativization.Principal findingsAll patients completed the treatment successfully, and six patients abandoned the post-treatment follow-up. Adverse effects occurred in 74% of patients, but only 4.8% of cases required temporary suspension to achieve 100% adherence to the 60-day treatment, and all symptoms reverted after treatment completion. Both parasite load (measured through qPCR) and antibodies (ELISA absorbance) evidenced a significant median reduction 6 months after treatment from 6.2 to 0.2 parasite equivalents/mL, and from 0.6 to 0.2 absorbance units respectively (p<0.001). Serological negativization by ELISA was evident since 6 months post-treatment, whereas by IFAT only after 18 months. Serological negativization by the two tests (ELISA and IFAT) was 41.9% (95%CI: 26.5–57.3) after 30 months post-treatment. qPCR was positive in 88.3% of patients pre-treatment and only in 12.1% of patients after 30 months. Survival analysis indicated that only 26.3% (95%CI: 15.5–44.8) persisted with negative qPCR during the whole follow-up period.ConclusionsNifurtimox was very well tolerated and successfully reduced parasite load and antibody titers. Re-infection, lysed parasites or a lack of anti-parasitic activity could explain these persistently positive qPCR cases.
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