Advanced Process Combinatorics (United States)

Vesicle Amine Transport-1 (VAT1) is a protein that is overexpressed in many cancers, including breast cancer, glioblastoma, and angiosarcoma. High VAT1 expression correlates with poor overall survival, and genetic knockout models of VAT1 indicate potent antimigratory activity, suggesting that VAT1 is a promising antimetastasis target. Recently, the natural product neocarzilin A (NCA) from Streptomyces carzinostaticus was reported to be the first validated small-molecule inhibitor of VAT1, having strong activity in metastasis models of angiosarcoma and breast cancer. While knockdown of VAT1 has no effect on cell viability, NCA has significant cytotoxicity, suggesting that NCA is not selective for VAT1. Additionally, NCA has poor aqueous solubility, making in vivo administration of NCA challenging and thus limiting its therapeutic potential. Here, we report the design, synthesis, bioactivity, and pharmacokinetics of novel NCA derivatives with improved drug-like properties. Specifically, we have developed derivatives with altered warheads, replacing chlorines on the trichloroketone with fluorines. Using a modified synthetic route, we accessed NCA derivatives with greater than 25-fold improvements in solubility and 30-fold improvements in the antimigratory to antiproliferative bioactivity ratio. The two best derivatives, along with the parent, were analyzed for oral bioavailability, with the two more soluble derivatives showing greatly improved bioavailability. Overall, these studies have resulted in the development of VAT1 inhibitors with improved properties, which will enable further study of the pharmacological inhibition of VAT1 as an antimetastatic strategy. Additionally, these studies provide insights into novel trihalomethyl ketone warheads and identify chlorodifluoroketone as a potent and selective new warhead.

Availability of diabetes prevention programs is largely limited to urban (U) areas, posing a challenge to diabetes prevention in rural (R) areas. Virta Health provides carbohydrate-restricted nutrition therapy (CRNT) through continuous remote care (CRC) and has been implemented nationwide to prevent progression of prediabetes (preD). In this retrospective analysis, we aim to assess the 1-year effect of the program on cardiometabolic markers in individuals with preD from both R and U counties. A random sample of individuals with preD who remained in the program at least 1y was selected (250 from R areas and 250 from U areas). Changes in metabolic markers from enrollment (E) to 1y were assessed in a linear mixed effect model. Characteristics at E were consistent between the R and U cohorts (age=50.9 (9.4)y, BMI= 36.7 (7.7)kg/m2, HbA1c=5.8(0.3)%). HbA1c [-0.2% from E:5.7±0.0 (R), -0.2% from E: 5.8±0.0 (U); ps<0.001], weight [-9.2% from E:231.3±1.3 (R), -9.2% from E: 231.4±1.3 (U); ps<0.001], HDL-C [13.3% from E:49.5±0.6 (R), 13.1% from E:50.2±0.6 (U); ps<0.001], TG [-24.3% from E:152.2±4.2 (R), -26.9% from E:137.4±4.2 (U); ps<0.001] improved, with no differences between R and U areas. Liver enzymes [ALT at E: 28.4±0.9(R), 27.6±0.9(U) U/L; ALP at E: 79.4±1.3(R), 76.5±1.3(U) U/L ] were within normal limits and significantly decreased [ALT:-11.2% (R), -11.5%(U); ALP: -5.7% (R), -5.8% (U); ps<0.001]. Total cholesterol, LDL-cholesterol, and AST were unchanged. Individuals with preD in both R and U settings showed similar improvements in weight, HbA1c, and cardiometabolic markers. These findings demonstrate the effectiveness of this care model in improving cardiometabolic risk markers in people with preD living in both R and U areas. Disclosure S.J. Athinarayanan: Employee; Virta Health Corp. R.N. Adams: Employee; Virta Health Corp. Stock/Shareholder; Virta Health Corp. B.M. Volk: Employee; Virta Health Corp. Stock/Shareholder; Virta Health Corp. C.G.P. Roberts: Other Relationship; Virta Health Corp. A. Zoller: Employee; Virta Health Corp. Stock/Shareholder; Virta Health Corp. A.L. McKenzie: Employee; Virta Health Corp. Stock/Shareholder; Virta Health Corp. Employee; Abbott.

As feiras livres da cidade de São Paulo, enquanto paisagem cotidiana que envolve o sujeito situado, se transformam em patrimônio para os sujeitos que ela compõe, a partir de sua fruição. Nesse contexto, a presente pesquisa teve o objetivo de apresentar, baseado no ponto de vista do sujeito, o feirante, argumentação teórica sobre a construção das feiras livres enquanto patrimônio e, mais à fundo, patrimônio-territorial. A pesquisa orientou-se em uma abordagem qualitativa por meio de entrevistas com feirantes das Zonas Sul, Norte, Leste, Oeste e Central da cidade de São Paulo. Buscou-se, por meio dessas entrevistas, dar base a argumentação sobre a maneira como essas feiras se mostram para os sujeitos viventes enquanto patrimônio-territorial, conceito proposto por Costa (2016; 2017; 2018; e 2022), que no contexto da América Latina, continente assentado pelo discurso colonialista, aponta um respiro utopista, uma epistemologia situada, que aproxima o patrimônio de um ponto de vista existencial e propositivo. Por meio desse conceito foi possível concluir que as feiras livres da cidade de São Paulo se mostram dentro do circuito inferior da economia de maneira atípica, pelas relações sociais e econômicas, criadas através da junção entre o modelo do capital e as relações sociais bucólicas. E que no auge dos seus mais de 100 anos de história na grande metrópole, se mantém renovada e atuante, muito além de sua função no abastecimento da população local. Portando, conclui-se, também, que sua fruição é o que a transforma em patrimônio-territorial do sujeito sitiado.

Increasing the level of autonomy in both small aircraft and autos has the potential to generate greater efficiency and utility in multimodal regional transportation systems.In previous research, the PI and collaborators developed a computational analysis framework to assess the impact of aircraft technology advancement in electric propulsion and autonomy on the future of ondemand, regional air transportation system.A sensitivity analysis revealed increasing level of autonomy and an improved ridesharing model (on the ground and in the air) could lead to significant increase in the total number of individuals who could afford this new mode of transportation.Activities in this CCAT project a) explored and then generated a model for for the autonomous automobile option to enhance the impact of autonomy at a multi-modal level b) explored options for a connectivity metrics that could well-capture the efficacy of different multi-modal architectures.Outcome models, analysis, and metrics were successfully developed and used to inform a larger research effort developing a computational model for a project under NASA sponsorship (in which the NASA Technical Monitor served as government partner on this CCAT project).17.

The flash pyrolysis of trans 3-pentenenitrile (3-PN, CH3-CH[double bond, length as m-dash]CH-CH2-CN) was studied by combining the results of VUV photoionization mass spectra with broadband microwave spectra recorded as a function of the temperature of the pyrolysis tube. The two separated functional groups (vinyl and nitrile) open up isomerization as an initial step in competition with unimolecular dissociation. Primary products were detected by keeping the 3-PN concentration low and limiting reaction times to the traversal time of the gas in the pyrolysis tube (∼100 μs). The reaction is quenched and products are cooled by expansion into vacuum before interrogation over the 8-18 GHz region using chirped-pulse broadband methods. 118 nm VUV photoionization of the same reaction mixture provides a means of detecting all products with ionization potentials below 10.5 eV with minimal fragmentation. These results are combined with a detailed computational investigation of the C5H7N and related potential energy surfaces, leading to a consistent picture of the unimolecular decomposition of 3-PN. Loss of two H-atoms to form a 79 amu product is proven from its microwave transitions to contain trans-Z-2,4-pentadienenitrile, while no pyridine is observed. Methyl loss, HCN loss, and breaking the central C(2)-C(3) bond all occur following isomerization of the position of the double bond, thereby opening up low-energy pathways to these decomposition channels.

Structural mechanical metamaterials, with their mass-efficient architectures and unprecedented mechanical properties, are in critical demand for high-performance applications. However, finding the optimal 3D geometries towards a particular property, such as reaching the stiffness upper bound, usually demands high volume of calculations or numerical optimizations. Here we generate structured mechanical metamaterials by imitating the natural occupation of periodic volume by inflated soap films. Our strategy of occupying volume between two periodic constant mean curvature (CMC) surfaces generates a series of mechanical metamaterials of varied relative densities ranging from 0 to 1. The mechanically isotropic ISO-CMC structures exhibit bulk moduli over 94% of the theoretical limit. Using finite element models, we reveal the fundamental mechanical behaviors of the structures that lead to ideal performances. These phenomena are found to be in close relation to the curvature-driven design of our metamaterial structures. These structures are compared to other reported mechanical metamaterials, such as closed-cell plate structures and triply periodic minimal surface (TPMS) structures. The unique curvature-driven thickening strategy of our method renders structures that outperform their peers in terms of bulk moduli and relative density coverage. The CMC structures present a new class of easily 3D printable, permeable and stiff mechanical metamaterials. The design methodology also could serve in future development of novel mechanical metamaterials powered by advanced computational tools.

Aqueous-phase reactions within microporous Brønsted acids occur at active centers comprised of water-reactant-clustered hydronium ions, solvated within extended hydrogen-bonded water networks that tend to stabilize reactive intermediates and transition states differently. The effects of these diverse clustered and networked structures were disentangled here by measuring turnover rates of gas-phase ethanol dehydration to diethyl ether (DEE) on H-form zeolites as water pressure was increased to the point of intrapore condensation, causing protons to become solvated in larger clusters that subsequently become solvated by extended hydrogen-bonded water networks, according to in situ IR spectra. Measured first-order rate constants in ethanol quantify the stability of SN2 transition states that eliminate DEE relative to (C2H5OH)(H+)(H2O) n clusters of increasing molecularity, whose structures were respectively determined using metadynamics and ab initio molecular dynamics simulations. At low water pressures (2-10 kPa H2O), rate inhibition by water (-1 reaction order) reflects the need to displace one water by ethanol in the cluster en route to the DEE-formation transition state, which resides at the periphery of water-ethanol clusters. At higher water pressures (10-75 kPa H2O), water-ethanol clusters reach their maximum stable size ((C2H5OH)(H+)(H2O)4-5), and water begins to form extended hydrogen-bonded networks; concomitantly, rate inhibition by water (up to -3 reaction order) becomes stronger than expected from the molecularity of the reaction, reflecting the more extensive disruption of hydrogen bonds at DEE-formation transition states that contain an additional solvated non-polar ethyl group compared to the relevant reactant cluster, as described by non-ideal thermodynamic formalisms of reaction rates. Microporous voids of different hydrophilic binding site density (Beta; varying H+ and Si-OH density) and different size and shape (Beta, MFI, TON, CHA, AEI, FAU), influence the relative extents to which intermediates and transition states disrupt their confined water networks, which manifest as different kinetic orders of inhibition at high water pressures. The confinement of water within sub-nanometer spaces influences the structures and dynamics of the complexes and extended networks formed, and in turn their ability to accommodate the evolution in polarity and hydrogen-bonding capacity as reactive intermediates become transition states in Brønsted acid-catalyzed reactions.

In recent years, dynamic, 'click' hydrogels have been applied in numerous biomedical applications. Owing to the mild, cytocompatible, and highly specific reaction kinetics, a multitude of orthogonal handles have been developed for fabricating dynamic hydrogels to facilitate '4D' cell culture. The high degree of tunability in crosslinking reactions of orthogonal 'click' chemistry has enabled a bottom-up approach to install specific biomimicry in an artificial extracellular matrix. In addition to click chemistry, highly specific enzymatic reactions are also increasingly used for network crosslinking and for spatiotemporal control of hydrogel properties. On the other hand, covalent adaptable chemistry has been used to recapitulate the viscoelastic component of biological tissues and for formulating self-healing and shear-thinning hydrogels. The common feature of these three classes of chemistry (i.e., orthogonal click chemistry, enzymatic reactions, and covalent adaptable chemistry) is that they can be carried out under ambient and aqueous conditions, a prerequisite for maintaining cell viability for in situ cell encapsulation and post-gelation modification of network properties. Due to their orthogonality, different chemistries can also be applied sequentially to provide additional biochemical and mechanical control to guide cell behavior. Herein, we review recent advances in the use of orthogonal click chemistry, enzymatic reactions, and covalent adaptable chemistry for the development of dynamically tunable and biomimetic hydrogels.

Electronic structure, collision-induced dissociation (CID) and bond properties of closo-[B6X6]2- (X = Cl-I) are investigated in direct comparison with their closo-[B12X12]2- analogues. Photoelectron spectroscopy (PES) and theoretical investigations reveal that [B6X6]2- dianions are electronically significantly less stable than the corresponding [B12X12]2- species. Although [B6Cl6]2- is slightly electronically unstable, [B6Br6]2- and [B6I6]2- are intrinsically stable dianions. Consistent with the trend in the electron detachment energy, loss of an electron (e- loss) is observed in CID of [B6X6]2- (X = Cl, Br) but not for [B6I6]2-. Halogenide loss (X- loss) is common for [B6X6]2- (X = Br, I) and [B12X12]2- (X = Cl, Br, I). Meanwhile, X˙ loss is only observed for [B12X12]2- (X = Br, I) species. The calculated reaction enthalpies of the three competing dissociation pathways (e-, X- and X˙ loss) indicated a strong influence of kinetic factors on the observed fragmentation patterns. The repulsive Coulomb barrier (RCB) determines the transition state for the e- and X- losses. A significantly lower RCB for X- loss than for e- loss was found in both experimental and theoretical investigations and can be rationalized by the recently introduced concept of electrophilic anions. The positive reaction enthalpies for X- losses are significantly lower for [B6X6]2- than for [B12X12]2-, while enthalpies for X˙ losses are higher. These observations are consistent with a difference in bond character of the B-X bonds in [B6X6]2- and [B12X12]2-. A complementary bonding analysis using QTAIM, NPA and ELI-D based methods suggests that B-X bonds in [B12X12]2- have a stronger covalent character than in [B6X6]2-, in which X has a stronger halide character.

Flunixin, a potent nonsteroidal anti-inflammatory drug widely used in veterinary medicine, was found to exist in at least two crystal forms, in contrast to clonixin which exists in four solvent-free forms and multiple solvates.