Keenepatterson0899

Homochirality is a common feature of amino acids and carbohydrates, and its origin is still unknown. Meanwhile, right-handed helices are ubiquitous in nature. Are these two phenomena intrinsically correlated? Here, we propose that homochirality of amino acids and nucleotide sugars originated from the handedness of helices. We show that right-handed 310-helix and α-helix favor the l-chiral form for amino acids, but for deoxyribose sugars, right-handed helices prefer the d-chiral form instead. Our analyses unveil strong cooperativity effects dominated by electrostatic interactions. This work not only resolves the mystery of homochirality by providing a unified explanation for the origin of homochirality in proteins and DNA using helical secondary structures as the root cause but also ratifies the Principle of Chirality Hierarchy, in which the chirality of a higher hierarchy dictates that of lower ones. Possible applications of this work to asymmetric synthesis and macromolecular assembly are discussed.Efficient energy transfer is particularly important for multiexcitonic processes like singlet fission and photon upconversion. Observation of the transition from short-range tunneling to long-range hopping during triplet exciton transfer from CdSe nanocrystals to anthracene is reported here. This is firmly supported by steady-state photon upconversion measurements, a direct proxy for the efficiency of triplet energy transfer (TET), as well as transient absorption measurements. When phenylene bridges are initially inserted between a CdSe nanocrystal donor and anthracene acceptor, the rate of TET decreases exponentially, commensurate with a decrease in the photon upconversion quantum efficiency from 11.6% to 4.51% to 0.284%, as expected from a tunneling mechanism. However, as the rigid bridge is increased in length to 4 and 5 phenylene units, photon upconversion quantum efficiencies increase again to 0.468% and 0.413%, 1.5-1.6 fold higher than that with 3 phenylene units (using the convention where the maximum upconversion quantum efficiency is 100%). This suggests a transition from exciton tunneling to hopping, resulting in relatively efficient and distance-independent TET beyond the traditional 1 nm Dexter distance. Transient absorption spectroscopy is used to confirm triplet energy transfer from CdSe to transmitter, and the formation of a bridge triplet state as an intermediate for the hopping mechanism. This first observation of the tunneling-to-hopping transition for long-range triplet energy transfer between nanocrystal light absorbers and molecular acceptors suggests that these hybrid materials should further be explored in the context of artificial photosynthesis.The chronic bee paralysis virus (CBPV), extracted from sick or dead bees, was studied by mobility measurements via electrospray charge reduction with a differential mobility analyzer (DMA) of unusually high resolution. Three different particles are observed. The most abundant one contributes a mobility peak at 38.3 nm, approximately as expected for CBPV. The peak is very sharp in spite of the nonisometric nature of CBPV. We also observe a previously unreported weaker well-resolved shoulder 4.8% more mobile, perhaps due to empty (genome-free) particles. Another sharp peak appearing at approximately 17.51 nm is likely associated with the known icosahedral CBPV satellite (CBPVS). The 17.51 and 38.3 nm peaks offer size and mobility standards much narrower than previously reported at any size above 5 nm, with relative full peak width at half-maximum (FWHM) in mobility approaching 2% (∼1% in diameter). Slight but clear imperfections in the DMA response and the electrospraying process suggest that the real width of the viral mobility distribution is less than 2%.Bacterial deposition is the first step in the formation of microbial biofilms in environmental technology, and there is high interest in controlling such deposition. Earlier work indicated that direct current (DC) electric fields could influence bacterial deposition in percolation columns. Here, a time-resolved quartz crystal microbalance with dissipation monitoring (QCM-D) and microscopy-based cell counting were used to quantify DC field effects on the deposition of bacterial strains Pseudomonas putida KT2440 and Pseudomonas fluorescens LP6a at varying electrolyte concentrations and weak electric field strengths (0-2 V cm-1). DC-induced frequency shifts (Δf), dissipation energy (ΔD), and ratios thereof (Δf/ΔD) proved as good indicators of the rigidity of cell attachment. We interpreted QCM-D signals using a theoretical approach by calculating the attractive DLVO-force and the shear and drag forces acting on a bacterium near collector surfaces in a DC electric field. We found that changes in DC-induced deposition of bacteria depended on the relative strengths of electrophoretic drag and electro-osmotic shear forces. This could enable the prediction and electrokinetic control of microbial deposition on surfaces in natural and manmade ecosystems.Extending upon our previous publication [Drummond, M.; J. Chem. Inf. Model. 2019, 59, 1634-1644], two additional computational methods are presented to model PROTAC-mediated ternary complex structures, which are then used to predict the efficacy of any accompanying protein degradation. Method 4B, an extension to one of our previous approaches, incorporates a clustering procedure uniquely suited for considering ternary complexes. Method 4B yields the highest proportion to date of crystal-like poses in modeled ternary complex ensembles, nearing 100% in two cases and always giving a hit rate of at least 10%. Techniques to further improve this performance for particularly troublesome cases are suggested and validated. This demonstrated ability to reliably reproduce known crystallographic ternary complex structures is further established through modeling of a newly released crystal structure. Moreover, for the far more common scenario where the structure of the ternary complex intermediate is unknown, the methods detailed in this work nonetheless consistently yield results that reliably follow experimental protein degradation trends, as established through seven retrospective case studies. These various case studies cover challenging yet common modeling situations, such as when the precise orientation of the PROTAC binding moiety in one (or both) of the protein pockets has not been experimentally established. Successful results are presented for one PROTAC targeting many proteins, for different PROTACs targeting the same protein, and even for degradation effected by an E3 ligase that has not been structurally characterized in a ternary complex. Overall, the computational modeling approaches detailed in this work should greatly facilitate PROTAC screening and design efforts, so that the many advantages of a PROTAC-based degradation approach can be effectively utilized both rapidly and at reduced cost.A series of multifunctional ratiometric near-infrared fluorescent probes ( CYOH-3 , CYOH-4 , CYOH-5 , and CYOH-6 ) for esterase detection are designed by gradually changing the deflection of the plane twist in the molecule. These probes are composed of different ring-structure trigger groups (from three-membered ring to six-membered ring) and the same luminescent group CYOH. These probes show maximum absorption at ∼585 nm and a fluorescence emission peak at ∼655 ± 5 nm. In the presence of esterase, the probes were hydrolyzed to expose the fluorophore CYOH (λabs = 690 nm, λem = 710 ± 5 nm), thus exhibiting ratiometric near-infrared fluorescence. mTOR inhibitor The probe CYOH-6 has lower plane deflection angle and better ratiometric (R = I710±5nm/I657±4nm) fluorescence properties than probes CYOH-3 , CYOH-4 , and CYOH-5 . CYOH-6 (six-membered ring) has been successfully used to target esterase in mitochondria and distinguish between dead cells (esterase inactivation) and live cells. In addition, CYOH-6 has been well used for monitoring of esterase activity in zebrafish and mice, which proves that these probes have good prospects for clinical biomedical applications.Male infertility is a multifactorial condition. Unexplained male infertility is often caused by spermatogenesis dysfunction. Knockout of Pin1, an important regulator of cell proliferation and differentiation, produces male infertility phenotypes such as testicular immaturity and azoospermia with spermatogonia depletion and blood-testis barrier (BTB) dysfunction. Gene therapy has been clinically considered for the treatment of male infertility, but it is not preferred because of the risks of adverse effects in germ cells. Direct intracellular protein delivery using nanoparticles is considered an effective alternative to gene therapy; however, in vivo testicular protein delivery remains a pressing challenge. Here, we investigated the direct intracellular protein delivery strategy using a fibroin nanoparticle-encapsulated cationic lipid complex (Fibroplex) to restore intratesticular PIN1. Local intratesticular delivery of PIN1 via Fibroplex in Pin1 knockout testes produced fertile mice, achieving recovery from the infertile phenotypes. Mechanistically, PIN1-loaded Fibroplex was successfully delivered into testicular cells, including spermatogonial cells and Sertoli cells, and the sustained release of PIN1 restored the gene expression required for the proliferation of spermatogonial cells and BTB integrity in Pin1 knockout testes. Collectively, testicular PIN1 protein delivery using Fibroplex might be an effective strategy for treating male infertility.A correlation between oxygen site distributions and ionic conductivity has been established in the recently discovered family of oxide-ion conductors Ba3M2O8.5±δ (M = Nb, V, Mo, W). We rationalize this observation on the basis of structural insights gained from the first single-crystal neutron diffraction data collected for a member of this family, Ba3NbWO8.5, and theoretical considerations of bonding and O site energies.The D3 dopamine receptor (D3R) has been suggested as a drug target for the treatment of a number of neuropsychiatric disorders, including substance use disorders (SUD). Many D3R-selective antagonists are bivalent in nature in that they engage two distinct sites on the receptor-a primary pharmacophore binds to the orthosteric site, where dopamine binds, whereas a secondary pharmacophore interacts with a unique secondary binding pocket (SBP). When engagement of the secondary pocket exerts allosteric activity, the compound is said to be bitopic. We recently reported the synthesis and characterization of two bitopic antagonists of the D3R, (±)-VK04-87 and (±)-VK05-95, which incorporated a racemic trans-cyclopropylmethyl linking chain. To gain a better understanding of the role of chirality in determining the pharmacology of such compounds, we resolved the enantiomers of (±)-VK04-87. We found that the (+)-isomer displays higher affinity for the D3R and exhibits greater selectivity versus the D2R than the (-)-isomer. Strikingly, using functional assays, we found that (+)-VK04-87 inhibits the D3R in a noncompetitive manner, while (-)-VK04-87 behaves as a purely competitive antagonist, indicating that the apparent allosteric activity of the racemate is due to the (+)-isomer. Molecular dynamic simulations of (+)-VK04-87 and (-)-VK04-87 binding to the D3R suggest that the (+)-isomer is able to interact with the SBP of the receptor whereas the (-)-isomer bends away from this pocket, thus potentially explaining their differing pharmacology. These results emphasize the importance of the linker, and its isomeric conformations, within extended-length molecules for their positioning and engagement within GPCR binding pockets.