Streptococcus Pneumoniae Secretes Hydrogen Peroxide Leading to DNA Damage and Apoptosis in Lung Cells

Streptococcus pneumoniae is a leading cause of pneumonia and one of the most common causes of death globally. The impact of S. pneumoniae on host molecular processes that lead to detrimental pulmonary consequences is not fully understood. Here, we show that S. pneumoniae induces toxic DNA double-strand breaks (DSBs) in human alveolar epithelial cells, as indicated by ataxia telangiectasia mutated kinase (ATM)-dependent phosphorylation of histone H2AX and colocalization with p53-binding protein (53BP1). Furthermore, results show that DNA damage occurs in a bacterial contact-independent fashion and that Streptococcus pyruvate oxidase (SpxB), which enables synthesis of H[subscript 2]O[subscript 2], plays a critical role in inducing DSBs. The extent of DNA damage correlates with the extent of apoptosis, and DNA damage precedes apoptosis, which is consistent with the time required for execution of apoptosis. Furthermore, addition of catalase, which neutralizes H[subscript 2]O[subscript 2], greatly suppresses S. pneumoniae-induced DNA damage and apoptosis. Importantly, S. pneumoniae induces DSBs in the lungs of animals with acute pneumonia, and H[subscript 2]O[subscript 2] production by S. pneumoniae in vivo contributes to its genotoxicity and virulence. One of the major DSBs repair pathways is nonhomologous end joining for which Ku70/80 is essential for repair. We find that deficiency of Ku80 causes an increase in the levels of DSBs and apoptosis, underscoring the importance of DNA repair in preventing S. pneumoniae-induced genotoxicity. Taken together, this study shows that S. pneumoniae-induced damage to the host cell genome exacerbates its toxicity and pathogenesis, making DNA repair a potentially important susceptibility factor in people who suffer from pneumonia

Supramolecular chemistry enables vat photopolymerization 3D printing of novel water-soluble tablets

Vat photopolymerization has garnered interest from pharmaceutical researchers for the fabrication of personalised medicines, especially for drugs that require high precision dosing or are heat labile. However, the 3D printed structures created thus far have been insoluble, limiting printable dosage forms to sustained-release systems or drug-eluting medical devices which do not require dissolution of the printed matrix. Resins that produce water-soluble structures will enable more versatile drug release profiles and expand potential applications. To achieve this, instead of employing cross-linking chemistry to fabricate matrices, supramolecular chemistry may be used to impart dynamic interaction between polymer chains. In this study, water-soluble drug-loaded printlets (3D printed tablets) are fabricated via digital light processing (DLP) 3DP for the first time. Six formulations with varying ratios of an electrolyte acrylate monomer, [2-(acryloyloxy)ethyl]trimethylammonium chloride (TMAEA), and a co-monomer, 1-vinyl-2-pyrrolidone (NVP), were prepared to produce paracetamol-loaded printlets. 1H NMR spectroscopy analysis confirmed the integration of TMAEA and NVP in the polymer, and residual TMAEA monomers were found to be present only in trace amounts (0.71 - 1.37 %w/w). The apparent molecular mass of the photopolymerised polymer was found to exceed 300,000 Da with hydrodynamic radii of 15 - 20 nm, estimated based on 1H DOSY NMR measurements The loaded paracetamol was completely released from the printlets between 45 minutes to 5 hours. In vivo single-dose acute toxicity studies in rats suggest that the printlets did not cause any tissue damage. The findings reported in this study represent a significant step towards the adoption of vat photopolymerization-based 3DP to produce personalised medicines

Architecture of Heptagonal Metallo-macrocycles via Embedding Metal Nodes Into Its Rigid Backbone

Metal-organic macrocycles have received increasing attention not only due to their versatile applications such as molecular recognition, compounds encapsulation, anti-bacteria and others, but also for their important role in the study of structure-property relationship at nano scale. However, most of the constructions utilize benzene ring as the backbone, which restricts the ligand arm angle in the range of 60, 120 and 180 degrees. Thus, the topologies of most metallo-macrocycles are limited as triangles and hexagons, and explorations of using other backbones with large angles and the construction of metallo-macrocycles with more than six edges are very rare. In this study, we present a novel strategy for self-assembly two giant heptagonal metallo-macrocycles with an inner diameter of 5 nm, by embedding metal nodes into the ligand backbone and regulating the ligand arm angle. By complexing with metal ions, the angle between two arms at the 4,4” position of the central terpyridine (tpy) was extended, resulting in ring expansion of the metallo-macrocycle. This approach enabled the construction of giant and more complex metallo- macrocycles that could not be achieved with traditional benzene ring backbones. The characterization of complex molecules often requires the use of multiple techniques, such as multi-dimensional and multinuclear NMR and multidimensional mass spectrometry analysis. Here, we also utilized transmission electron microscopy (TEM) and ultra-high vacuum (∼E-10 torr) low-temperature (∼77 K) scanning tunneling microscopy (UHV-LT-STM) to characterize complex supramolecules. The resulting metallo-macrocycles formed hierarchical self-assembled nanotube structures at larger densities, which is observed by TEM, while UHV-LT-STM was used for direct visualization of individual complex supramolecules deposited on an Au(111) substrate. Our findings indicate that UHV-LT-STM is an effective methodology for characterizing supramolecules at a single molecule level, providing more details of the molecular structure that is difficult to resolve by the resolution of TEM.https://digitalcommons.odu.edu/gradposters2023_sciences/1005/thumbnail.jp

High Stability Positron Beam Generation Based on Ultra-intense Laser

Relativistic positron beams were generated by laser wakefield electrons bombarding on solid target. Very stable positron beams were generated in our experiments. The total yield of positrons is about 4.4 x 10(8)/shot. The energy spectra of positrons and electrons obey quasi-Maxwell distribution. Compared with the direct method, the indirect method produces positrons (38.5 MeV) and electrons (50.5 MeV) with much higher slope temperature

Phenomenology of Higgs bosons in the Zee-Model

To generate small neutrino masses radiatively, the Zee-model introduces two Higgs doublets and one weak-singlet charged Higgs boson to its Higgs sector. From analyzing the renormalization group equations, we determine the possibile range of the lightest CP-even Higgs boson ($h$) mass and the Higgs boson self-couplings as a function of the cut-off scale beyond which either some of the coupling constants are strong enough to invalidate the perturbative analysis or the stability of the electroweak vacuum is no longer guaranteed. Using the results obtained from the above analysis, we find that the singlet charged Higgs boson can significantly modify the partial decay width of $h \to \gamma \gamma$ via radiative corrections, and its collider phenomenology can also be drastically different from that of the charged Higgs bosons in the usual two-Higgs-doublet models.Comment: Added a paragraph and a figure in Section V, corrected typos, added references. (RevTeX, 45 pages, 16 figures included.) To appear in Physical Review