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Spectrochimica Acta. Part A, Molecular... Jun 2024The impact of microbial infections is increasing over time, and it is one of the major reasons for death in both developed and developing countries. colistin is...
The impact of microbial infections is increasing over time, and it is one of the major reasons for death in both developed and developing countries. colistin is considered as the antibiotic of last choice for infections brought by major multidrug-resistant (MDR), gram-negative bacteria such as Enterobacter species, Acinetobacter species, and Pseudomonas aeruginosa. Existing approaches to diagnose these resistant species are relatively slow and take up to 2 to 3 days. In this work, we propose a novel interdisciplinary method based on Raman spectroscopy and heavy water to identify colistin-resistant microbes. Our hypothesis is based on the fact that resistant bacteria will be metabolically active in the culture medium containing antibiotics and heavy water, and these bacteria will take up deuterium instead of hydrogen to newly synthesized lipids and proteins. This effect will generate a 'C - D' bond-specific Raman spectral marker. Successful identification of this band in the spectral profile can confirm the presence of colistin-resistant bacteria. We have validated the efficacy of this approach in identifying colistin-resistant bacteria spiked in artificial urine and have compared sensitivity at different bacterial concentrations. Overall findings suggest that heavy water can potentially serve as a suitable Raman probe for identifying metabolically active colistin-resistant bacteria via urine under clinically implementable time and can be used in clinical settings after validation.
PubMed: 38941753
DOI: 10.1016/j.saa.2024.124723 -
JACS Au Jun 2024Deuterium-labeled α-amino acids are useful in research related to drug discovery and biomedical science. However, a high degree of site selectivity and...
Deuterium-labeled α-amino acids are useful in research related to drug discovery and biomedical science. However, a high degree of site selectivity and stereoselectivity in the deuterium incorporation process is still difficult to achieve. Herein, we report a new enantioselective deuteration method at the α-position of several amino acids without external chiral sources. The proposed deuteration methods (NaOEt and EtOD) are highly selective and simple. Additionally, we provide a mechanistic study for this enantioretentive deuteration.
PubMed: 38938805
DOI: 10.1021/jacsau.4c00185 -
Nature Communications Jun 2024Hydrogen bond symmetrisation is the phenomenon where a hydrogen atom is located at the centre of a hydrogen bond. Theoretical studies predict that hydrogen bonds in ice...
Hydrogen bond symmetrisation is the phenomenon where a hydrogen atom is located at the centre of a hydrogen bond. Theoretical studies predict that hydrogen bonds in ice VII eventually undergo symmetrisation upon increasing pressure, involving nuclear quantum effect with significant isotope effect and drastic changes in the elastic properties through several intermediate states with varying hydrogen distribution. Despite numerous experimental studies conducted, the location of hydrogen and hence the transition pressures reported up to date remain inconsistent. Here we report the atomic distribution of deuterium in DO ice using neutron diffraction above 100 GPa and observe the transition from a bimodal to a unimodal distribution of deuterium at around 80 GPa. At the transition pressure, a significant narrowing of the peak widths of 110 is also observed, attributed to the structural relaxation by the change of elastic properties.
PubMed: 38937434
DOI: 10.1038/s41467-024-48932-8 -
Journal of the American Chemical Society Jun 2024Using real-time mass spectrometric (MS) monitoring, we demonstrate one-step, catalyst-free spontaneous oxidation of various alcohols (ROH) to key reactive intermediates...
Using real-time mass spectrometric (MS) monitoring, we demonstrate one-step, catalyst-free spontaneous oxidation of various alcohols (ROH) to key reactive intermediates for the formation of ROO compounds on the surface of water microdroplets surrounded by alcohol vapor, carried out under ambient conditions. These organic peroxides (POs) can act as important secondary organic aerosols (SOA). We used hydrogen-deuterium exchange by spraying DO instead of HO to learn about the reaction mechanism, and the results demonstrate the crucial role of the water-air interface in microdroplet chemistry. We find that the formation of POs relies on electron transfer occurring at the microdroplet interface, which generates hydrogen atoms and hydroxyl radicals that lead to a cascade of radical reactions. This electron transfer is believed to be driven by two factors: (1) the emergence of a strong electrostatic potential on the microdroplet's surface; and (2) the partial solvation of ions at the interface. Mass spectra reveal that the formation of POs is dependent on the alcohol structure, with tertiary alcohols showing a higher tendency to form organic peroxides than secondary alcohols, which in turn are more reactive than primary alcohols.
PubMed: 38935892
DOI: 10.1021/jacs.4c04092 -
The Journal of Chemical Physics Jun 2024Ice XIX and ice XV are both partly hydrogen-ordered counterparts to disordered ice VI. The ice XIX → XV transition represents the only order-to-order transition in ice...
Ice XIX and ice XV are both partly hydrogen-ordered counterparts to disordered ice VI. The ice XIX → XV transition represents the only order-to-order transition in ice physics. Using Raman and dielectric spectroscopies, we investigate the ambient-pressure kinetics of the two individual steps in this transition in real time (of hours), that is, ice XIX → transient ice VI (the latter called VI‡) and ice VI‡ → ice XV. Hydrogen-disordered ice VI‡ appears intermittent between 101 and 120 K, as inferred from the appearance and subsequent disappearance of the ice VI Raman marker bands. A comparison of the rate constants for the H2O ices reported here with those from D2O samples [Thoeny et al., J. Chem. Phys. 156, 154507 (2022)] reveals a large kinetic isotope effect for the ice XIX decay, but a much smaller one for the ice XV buildup. An enhancement of the classical overbarrier rate through quantum tunneling for the former can provide a possible explanation for this finding. The activation barriers for both transitions are in the 18-24 kJ/mol range, which corresponds to the energy required to break a single hydrogen bond. These barriers do not show an H/D isotope effect and are the same, no matter whether they are derived from Raman scattering or from dielectric spectroscopy. These findings favor the notion that a dipolar reorientation, involving the breakage of a hydrogen bond, is the rate determining step at the order-to-order transition.
PubMed: 38934633
DOI: 10.1063/5.0211427 -
The Journal of Physiology Jun 2024
PubMed: 38932599
DOI: 10.1113/JP286506 -
Molecules (Basel, Switzerland) Jun 2024An untargeted metabolomic study identified four potential lung cancer diagnostic biomarkers in human urine. One of the potential biomarkers was an unidentified feature...
An untargeted metabolomic study identified four potential lung cancer diagnostic biomarkers in human urine. One of the potential biomarkers was an unidentified feature possessing a / value of 561+. "561+" was isolated from human urine and tentatively identified as 27-nor-5β-cholestane-3α,7α,12α,24,25 pentol glucuronide with unknown C24,25 stereochemistry using H NMR and mass spectrometry. In a prior report, the C24,25 stereochemistry of the aglycone, 27-nor-5β-cholestane-3α,7α,12α,24,25 pentol, was found to be 24,25 through GC analysis of the acetonide-TMS derivative. An authentic sample was prepared and found not to have the same stereochemistry as "561+". To identify the C24,25 stereochemistry, four C24,C25 diastereoisomeric alcohols of 27-nor-5β-cholestane-3α,7α,12α,24,25 pentol were prepared from chiral amino acids. Using an LCMS method, the C24,C25 stereochemistry of the "561+" aglycone was determined to be 24,25. With the correct aglycone in hand, it was coupled with glucuronic acid to complete the first reported synthesis of 27-nor-5β-cholestane-3α,7α,12α,24,25S pentol glucuronide. Deuterium labeled 27-nor-5β-cholestane-3α,7α,12α,24,25 pentol was also synthesized for use as an internal standard for MS quantitation.
Topics: Humans; Lung Neoplasms; Biomarkers, Tumor; Glucuronides; Deuterium; Male; Female
PubMed: 38930845
DOI: 10.3390/molecules29122781 -
Biomolecular NMR Assignments Jun 2024Adalimumab is a therapeutic monoclonal antibody developed to target human TNF an important mediator of immune-mediated inflammatory diseases such as rheumatoid...
Adalimumab is a therapeutic monoclonal antibody developed to target human TNF an important mediator of immune-mediated inflammatory diseases such as rheumatoid arthritis, amongst others. The 48 kDa Fab fragment of adalimumab was produced in Escherichia coli using a single chain approach to allow complete isotopic incorporation of deuterium, carbon-13 and nitrogen-15 along with the protonated isoleucine-d, valine and leucine methyl groups. Here we report the near complete resonance assignment of the polypeptide backbone and the methyl groups of isoleucine, leucine and valine residues.
PubMed: 38926254
DOI: 10.1007/s12104-024-10187-1 -
Aging Cell Jun 2024The rationale for the use of metformin as a treatment to slow aging was largely based on data collected from metabolically unhealthy individuals. For healthspan...
The rationale for the use of metformin as a treatment to slow aging was largely based on data collected from metabolically unhealthy individuals. For healthspan extension metformin will also be used in periods of good health. To understand the potential context specificity of metformin treatment on skeletal muscle, we used a rat model (high-capacity runner/low-capacity runner [HCR/LCR]) with a divide in intrinsic aerobic capacity. Outcomes of metformin treatment differed based on baseline intrinsic mitochondrial function, oxidative capacity of the muscle (gastroc vs soleus), and the mitochondrial population (intermyofibrillar vs. subsarcolemmal). Metformin caused lower ADP-stimulated respiration in LCRs, with less of a change in HCRs. However, a washout of metformin resulted in an unexpected doubling of respiratory capacity in HCRs. These improvements in respiratory capacity were accompanied by mitochondrial remodeling that included increases in protein synthesis and changes in morphology. Our findings raise questions about whether the positive findings of metformin treatment are broadly applicable.
PubMed: 38923664
DOI: 10.1111/acel.14235 -
Molecular Pharmaceutics Jun 2024Reversible self-association (RSA) of therapeutic proteins presents major challenges in the development of high-concentration formulations, especially those intended for...
Reversible self-association (RSA) of therapeutic proteins presents major challenges in the development of high-concentration formulations, especially those intended for subcutaneous administration. Understanding self-association mechanisms is therefore critical to the design and selection of candidates with acceptable developability to advance to clinical trials. The combination of experiments and in silico modeling presents a powerful tool to elucidate the interface of self-association. RSA of monoclonal antibodies has been studied extensively under different solution conditions and have been shown to involve interactions for both the antigen-binding fragment and the crystallizable fragment. Novel modalities such as bispecific antibodies, antigen-binding fragments, single-chain-variable fragments, and diabodies constitute a fast-growing class of antibody-based therapeutics that have unique physiochemical properties compared to monoclonal antibodies. In this study, the RSA interface of a diabody-interleukin 22 fusion protein (FP-1) was studied using hydrogen-deuterium exchange coupled with mass spectrometry (HDX-MS) in combination with in silico modeling. Taken together, the results show that a complex solution behavior underlies the self-association of FP-1 and that the interface thereof can be attributed to a specific segment in the variable light chain of the diabody. These findings also demonstrate that the combination of HDX-MS with in silico modeling is a powerful tool to guide the design and candidate selection of novel biotherapeutic modalities.
PubMed: 38922328
DOI: 10.1021/acs.molpharmaceut.4c00169