Why Are Left-Handed G-Quadruplexes Scarce?

G-quadruplexes (G4s) are nucleic acid structures crucial for the regulation of gene expression and genome maintenance. While they hold promise as nanodevice components, achieving desired G4 folds requires understanding the interplay between stability and structural properties, like helicity. Although right-handed G4 structures dominate the experimental data, the molecular basis for this preference over left-handed helicity is unclear. To address this, we employ all-atom molecular dynamics simulations and quantum chemical methods. Our results reveal that right-handed G4s exhibit greater thermodynamic and kinetic stability as a result of favorable sugar-phosphate backbone conformations in guanine tracts. Moreover, while hydrogen-bonding patterns influence helicity-specific G4 loop conformations, they minimally affect stability differences. We also elucidate the strong correlation between helicity and the strand progression direction, essential for G4 structures. These findings deepen our understanding of G4s, providing molecular-level insights into their structural and energetic preferences, which could inform the design of novel nanodevices.

Mechanism of recognition of parallel G-quadruplexes by DEAH/RHAU helicase DHX36 explored by molecular dynamics simulations.

Because of high stability and slow unfolding rates of G-quadruplexes (G4), cells have evolved specialized helicases that disrupt these non-canonical DNA and RNA structures in an ATP-dependent manner. One example is DHX36, a DEAH-box helicase, which participates in gene expression and replication by recognizing and unwinding parallel G4s. Here, we studied the molecular basis for the high affinity and specificity of DHX36 for parallel-type G4s using all-atom molecular dynamics simulations. By computing binding free energies, we found that the two main G4-interacting subdomains of DHX36, DSM and OB, separately exhibit high G4 affinity but they act cooperatively to recognize two distinctive features of parallel G4s: the exposed planar face of a guanine tetrad and the unique backbone conformation of a continuous guanine tract, respectively. Our results also show that DSM-mediated interactions are the main contributor to the binding free energy and rely on making extensive van der Waals contacts between the GXXXG motifs and hydrophobic residues of DSM and a flat guanine plane. Accordingly, the sterically more accessible 5'-G-tetrad allows for more favorable van der Waals and hydrophobic interactions which leads to the preferential binding of DSM to the 5'-side. In contrast to DSM, OB binds to G4 mostly through polar interactions by flexibly adapting to the 5'-terminal guanine tract to form a number of strong hydrogen bonds with the backbone phosphate groups. We also identified a third DHX36/G4 interaction site formed by the flexible loop missing in the crystal structure.

Solvothermal synthesis and structural characterization of three polyoxotitanium-organic acid clusters.

Three new titanium oxo-clusters Ti4O2(OiPr)10(OOCPhMe)2 (I), Ti6O4(OEt)8(OOCPhMe)8 (II) and Ti6O6(OEt)6(OOCCHPh2)6 (III) were obtained by easy one-step solvothermal reactions of titanium(iv) isopropoxide, alcohols and carboxylic acids. The three compounds were characterized by single-crystal and powder X-ray diffraction, TGA/DSC, optical and electron microscopy, and FTIR and NMR spectroscopy. X-ray powder diffraction and spectroscopy confirmed the purity of the compounds. Structural analysis indicates that in all compounds the titanium(iv) ions are six-coordinated (distorted octahedra). (I) is a tetranuclear complex containing a Ti4(µ4-O)(µ2-O) core, which is linked by two (µ2-OOCPhMe), four (µ2-OiPr) and six OiPr ligands. (II) and (III) are hexanuclear complexes with different cores, respectively Ti6(µ3-O)2(µ2-O)2 and Ti6(µ3-O)6. The coordination sphere of the Ti atoms is filled by eight (µ2-OOCPhMe), two (µ2-OEt) and six OEt in (II) and six (µ2-OOCHPh2) and six OEt in (III). Different steric hindrance of substituents attached to the carboxyl group or different concentrations lead to three main different cluster geometries with two ligands. The tetranuclear and the hexanuclear clusters were obtained with the OOCPhMe ligand, while the hexagonal prism cluster was obtained with the OOCCHPh2 ligand. Hirshfeld surface calculations indicated that the packing is driven by C-O⋯H-C weak hydrogen bonds. The clusters can be used as molecular models of organic molecules bonded to titania surface, used in organic photovoltaic (dye sensitized solar cells) or other optoelectronic applications.

Beyond the Hippocampus and the SVZ: Adult Neurogenesis Throughout the Brain.

Convincing evidence has repeatedly shown that new neurons are produced in the mammalian brain into adulthood. Adult neurogenesis has been best described in the hippocampus and the subventricular zone (SVZ), in which a series of distinct stages of neuronal development has been well characterized. However, more recently, new neurons have also been found in other brain regions of the adult mammalian brain, including the hypothalamus, striatum, substantia nigra, cortex, and amygdala. While some studies have suggested that these new neurons originate from endogenous stem cell pools located within these brain regions, others have shown the migration of neurons from the SVZ to these regions. Notably, it has been shown that the generation of new neurons in these brain regions is impacted by neurologic processes such as stroke/ischemia and neurodegenerative disorders. Furthermore, numerous factors such as neurotrophic support, pharmacologic interventions, environmental exposures, and stem cell therapy can modulate this endogenous process. While the presence and significance of adult neurogenesis in the human brain (and particularly outside of the classical neurogenic regions) is still an area of debate, this intrinsic neurogenic potential and its possible regulation through therapeutic measures present an exciting alternative for the treatment of several neurologic conditions. This review summarizes evidence in support of the classic and novel neurogenic zones present within the mammalian brain and discusses the functional significance of these new neurons as well as the factors that regulate their production. Finally, it also discusses the potential clinical applications of promoting neurogenesis outside of the classical neurogenic niches, particularly in the hypothalamus, cortex, striatum, substantia nigra, and amygdala.

Compliant flooring to prevent fall-related injuries in older adults: A scoping review of biomechanical efficacy, clinical effectiveness, cost-effectiveness, and workplace safety.

BACKGROUND: Compliant flooring, broadly defined as flooring systems or floor coverings with some level of shock absorbency, may reduce the incidence and severity of fall-related injuries in older adults; however, a lack of synthesized evidence may be limiting widespread uptake. METHODS: Informed by the Arksey and O'Malley framework and guided by a Research Advisory Panel of knowledge users, we conducted a scoping review to answer: what is presented about the biomechanical efficacy, clinical effectiveness, cost-effectiveness, and workplace safety associated with compliant flooring systems that aim to prevent fall-related injuries in healthcare settings? We searched academic and grey literature databases. Any record that discussed a compliant flooring system and at least one of biomechanical efficacy, clinical effectiveness, cost-effectiveness, or workplace safety was eligible for inclusion. Two independent reviewers screened and abstracted records, charted data, and summarized results. RESULTS: After screening 3611 titles and abstracts and 166 full-text articles, we included 84 records plus 56 companion (supplementary) reports. Biomechanical efficacy records (n = 50) demonstrate compliant flooring can reduce fall-related impact forces with minimal effects on standing and walking balance. Clinical effectiveness records (n = 20) suggest that compliant flooring may reduce injuries, but may increase risk for falls. Preliminary evidence suggests that compliant flooring may be a cost-effective strategy (n = 12), but may also result in increased physical demands for healthcare workers (n = 17). CONCLUSIONS: In summary, compliant flooring is a promising strategy for preventing fall-related injuries from a biomechanical perspective. Additional research is warranted to confirm whether compliant flooring (i) prevents fall-related injuries in real-world settings, (ii) is a cost-effective intervention strategy, and (iii) can be installed without negatively impacting workplace safety. Avenues for future research are provided, which will help to determine whether compliant flooring is recommended in healthcare environments.

Compliant flooring to prevent fall-related injuries: a scoping review protocol.

INTRODUCTION: Fall-related injuries can have serious consequences for older adults, including increased risk of dependence in daily activities and mortality. Compliant flooring is a passive intervention that may reduce the incidence and severity of fall-related injuries in healthcare settings, including acute and long-term care, but few sites have implemented compliant flooring, in part because synthesised evidence about key performance aspects has not been available. METHODS AND ANALYSIS: We will conduct a scoping review to address the question: what is presented about the biomechanical efficacy, clinical effectiveness, cost-effectiveness, and workplace safety associated with compliant flooring systems that aim to prevent fall-related injuries? We will conduct a comprehensive and systematic literature search of academic databases (AgeLine, CINAHL, EBM Reviews, MEDLINE (Ovid), SportDiscus and Web of Science) and grey literature (clinical trial registries, theses/dissertations, abstracts/conference proceedings and relevant websites). 2 team members will independently screen records (first titles and abstracts, then full text) and extract data from included records. Numerical and narrative analyses will be presented by theme (biomechanical efficacy, clinical effectiveness, cost-effectiveness, workplace safety). ETHICS AND DISSEMINATION: This scoping review responds to the information needs of healthcare decision-makers tasked with preventing fall-related injuries. This review will summarise evidence about compliant flooring as a potential intervention for preventing fall-related injuries in older adults and identify gaps in evidence and new avenues for research. Results will be especially useful in long-term care, but also applicable in acute care, assisted living and home care. We will disseminate the review's findings via open-access publications, conference presentations, a webinar, a Stakeholder Symposium and a Knowledge-to-Action Report.