Advanced theoretical design of light-driven molecular rotary motors: enhancing thermal helix inversion and visible-light activation.

In this study, we have advanced the field of light-driven molecular rotary motors (LDMRMs) by achieving two pivotal goals: lowering the thermal helix inversion (THI) barrier and extending the absorption wavelength into the visible spectrum. This study involves the structural reengineering of a second-generation visible LDMRM, resulting in the synthesis of a novel class, specifically, 2-((2S)-5-methoxy-2-methyl-2,3-dihydro-1H-cyclopenta[a]naphthalen-1-yl)-3-oxo-2,3-dihydro-1H-dibenzo[e,g]indole-6,9-dicarbonitrile. This redesigned motor stands out with its two photoisomerization stages and two thermal helix inversions, featuring exceptionally low THI barriers (4.00 and 2.05 kcal mol-1 at the OM2/MRCI level for the EM → EP and ZM → ZP processes, respectively). Moreover, it displays absorption wavelengths in the visible light range (482.98 and 465.76 nm for the EP and ZP isomers, respectively, at the TD-PBE0-D3/6-31G(d,p) level), surpassing its predecessors in efficiency, as indicated by the narrow HOMO-LUMO energy gap. Ultrafast photoisomerization kinetics (approximately 0.8-1.6 ps) and high quantum yields (around 0.3-0.6) were observed through trajectory surface hopping simulations. Additionally, the simulated time-resolved fluorescence emission spectrum indicates a significantly reduced "dark state" duration (0.09-0.26 ps) in these newly designed LDMRMs compared to the original ones, marking a substantial leap forward in the design and efficiency of LDMRMs.

Three-Component Ring-Expansion Reaction of Indoles Leading to Synthesis of Pyrrolo[2,3-c]quinolines.

Herein, we have developed an atom- and step-economic three-component cascade reaction that enables a modular platform for the synthesis of pyrrolo[2,3-c]quinoline compounds through ring-expansion/cyclization by way of novel N1-C2 cleavage of indoles. The metal-free catalytic system exhibits a broad functional group tolerance.

Sacrificial scaffold-assisted direct ink writing of engineered aortic valve prostheses.

Heart valve disease has become a serious global health problem, which calls for numerous implantable prosthetic valves to fulfill the broader needs of patients. Although current three-dimensional (3D) bioprinting approaches can be used to manufacture customized valve prostheses, they still have some complications, such as limited biocompatibility, constrained structural complexity, and difficulty to make heterogeneous constructs, to name a few. To overcome these challenges, a sacrificial scaffold-assisted direct ink writing approach has been explored and proposed in this work, in which a sacrificial scaffold is printed to temporarily support sinus wall and overhanging leaflets of an aortic valve prosthesis that can be removed easily and mildly without causing any potential damages to the valve prosthesis. The bioinks, composed of alginate, gelatin, and nanoclay, used to print heterogenous valve prostheses have been designed in terms of rheological/mechanical properties and filament formability. The sacrificial ink made from Pluronic F127 has been developed by evaluating rheological behavior and gel temperature. After investigating the effects of operating conditions, complex 3D structures and homogenous/heterogenous aortic valve prostheses have been successfully printed. Lastly, numerical simulation and cycling experiments have been performed to validate the function of the printed valve prostheses as one-way valves.

Mode-specific dynamics in multichannel reaction NH+ + H2.

The vibrational- and rotational-mode specificity of the multichannel NH+ + H2 reaction is studied on a recently constructed ab initio-based global potential energy surface using an initial state selected quasi-classical trajectory method, and the trajectories are analyzed using an isometric feature mapping and k-means approach. All excitation modes promote two reactions (R1: NH'+ + H2 → NH+ + HH' and R4: NH'+ + H2 → NH2+ + H') where both NH and HH bonds are broken, but reduce the reactivity of the proton-transfer reaction R2 (NH'+ + H2 → N + H'H2+) at low collision energies. For the hydrogen-transfer reaction R3 (NH'+ + H2 → HNH'+ + H), the rotational excitation of NH+ enhances the reactivity remarkably, while its vibrational excitation has an inhibiting effect on the reaction. The trajectory analyses show that the vibrational and rotational excitations of NH+ make R3 tend to go over a submerged saddle point instead of extracting hydrogen atoms directly. On the other hand, the motions of the H2 reactant facilitate the enhancement of the reactivity but they do not affect the mechanism of R3. In addition, the results suggest that the coupling of the isometric feature mapping and the k-means approach in the trajectory analysis is an appropriate tool for reaction-dynamics studies.

A Radical-Initiated Fragmentary Rearrangement Cascade of Ene-Ynamides to [1,2]-Annulated Indoles via Site-Selective Cyclization.

Straightforward access to [1,2]-annulated indoles, key substructures in natural products, is highly desirable yet challenging. Herein, a radical triggered fragmentary cyclization cascade reaction of ene-ynamides is presented, providing a rapid access into [1,2]-annulated indoles by an intermolecular radical addition, intramolecular cyclization, desulfonylative aryl migration, and site-selective C(sp2)-N cyclization sequence. DFT calculations support oxidation of N-centered radical species to cations prior to the C-N bond formation, followed by an unusual aza-Nazarov cyclization.

A multi-dimensional non-uniform corrosion model for bioabsorbable metallic vascular stents.

Bioabsorbable metallic vascular stents (BMVSs) are an innovative technological advancement in the medical engineering field of vascular implants. BMVSs have great potential to revolutionize vascular intervention, but the lack of understanding of the construction material's natural corrosion within the body inhibits the use in clinical medicine. In this study, a corrosion function concept for in vivo implants was created to develop a multi-dimensional, non-uniform corrosion model with a larger goal of simulating the mechanical integrity of BMVSs. This proposed corrosion model simulates the corrosion rate and its effects on magnesium (Mg) alloy AZ31 based on continuum damage mechanics. The model was calibrated using three degradation experiments on Mg alloy specimens. These experiments focused on multi-dimensional corrosion, mass loss rate, and mechanical integrity during the corrosion process. Lastly, to verify the applicability of the proposed model, the resulting corrosion behaviors and mechanical characteristics of the BMVSs were implemented into a finite element framework to produce an overarching simulation of the BMVS's degradation in vivo. The results of the experiments and simulations revealed a proportional link between the corrosion of BMVSs and the number of exposed surfaces. A non-linear decline in mechanical integrity with increasing mass loss was also discovered through experimentation and modeling. Furthermore, the model and simulation can provide some details about changes in morphology and mechanics during BMVS corrosion. This work gives new insights into accurately modeling for BMVS degradation and can be used to optimize product development of BMVSs. STATEMENT OF SIGNIFICANCE: Bioabsorbable metallic vascular stents (BMVSs) are an innovative technological advancement in the medical engineering field of vascular implants. Despite BMVSs have great potential to revolutionize vascular intervention, the lack of understanding of the construction material's natural corrosion within the body inhibits their use in clinical medicine. In this study, a novel multi-dimensional non-uniform corrosion model was proposed to unveil the mechanisms during the in vivo degradation of bioabsorbable metallic implants, which can accurately capture the overlooked changes in morphology and mechanics during BMVS corrosion. This work provides a technical solution to enhance the modeling accuracy in BMVS degradation and can be further used to optimize the design of BMVSs in the future.

Study on the bending behavior of biodegradable metal cerebral vascular stents using finite element analysis.

Excellent bending behavior is evaluated as the primary factor during the design of biodegradable metal cerebral vascular stents (BMCVSs), which enables vascular stents to be successfully delivered to the targeted location and avoids unnecessary damage to blood vessels. Unfortunately, this bending behavior has been barely investigated which limits the design of BMCVSs with optimal structures. Herein, six BMCVSs were designed and their bending process were simulated using finite element analysis (FEA). Then, the effects of the stent bridge connection type and structure on the bending behavior were systematically analyzed and an universal mathematical model was further established, in which the influence of the structure parameters of the stent bridge on the flexibility of stents was considered. After that, the bending mechanism of the high-stress zone of the bridge was investigated. Finally, the causes and effects of the self-contacting phenomenon as well as the inner-stent protrusion phenomenon in the bending state were analyzed theoretically, and corresponding solutions were proposed to optimize the design of stents. The numerical results show that the stents with the dislocation-line W-shaped unit have better flexibility than the other stents. The flexibility is positively correlated to the cube of the length of linear part and to the square of the curvature of curved part. The self-contacting phenomenon of the bridge during bending can constrain the formation of inner-stent protrusion, which can eliminate the negative effects of the implanted stents on the hemodynamics in blood vessels. This study is expected to provide practical guidance for the structural design of BMCVSs for clinical applications.

Quasi-classical trajectory analysis with isometric feature mapping and locally linear embedding: deep insights into the multichannel reaction on an NH3+(4A) potential energy surface.

From the perspective of data analysis, finding and determining reaction paths from the quasi-classical trajectories of a polyatomic reaction system are equivalent to finding low-dimensional manifolds embedded in a high-dimensional space. Two manifold learning methods, isometric feature mapping and locally linear embedding, are applied to the analysis of reaction trajectories, which are calculated by the quasi-classical trajectory approach on a newly developed accurate quartet state NH3+(4A) potential energy surface for a multichannel reaction NH+ + H2→ N + H3+/NH2+ + H. The results show that isometric feature mapping can clearly identify different reaction paths from the reactive trajectories, and the locally linear embedding is better for the classification of non-reactive trajectories, and both of them facilitate quantitative analysis. With the help of trajectory analysis, the competition between the two H-atom abstraction reactions can be attributed to two different capture paths.

DYNAMO: A Phase II Study of Duvelisib (IPI-145) in Patients With Refractory Indolent Non-Hodgkin Lymphoma.

PURPOSE: Indolent non-Hodgkin lymphoma (iNHL) remains largely incurable and often requires multiple lines of treatment after becoming refractory to standard therapies. Duvelisib was approved by the Food and Drug Administration for relapsed or refractory (RR) chronic lymphocytic leukemia or small lymphocytic lymphoma (SLL) and RR follicular lymphoma (FL) after two or more prior systemic therapies. On the basis of the activity of duvelisib, a first-in-class oral dual inhibitor of phosphoinositide 3-kinase-δ,-γ, in RR iNHL in a phase I study, the safety and efficacy of duvelisib monotherapy was evaluated in iNHL refractory to rituximab and either chemotherapy or radioimmunotherapy. PATIENTS AND METHODS: Eligible patients had measurable iNHL (FL, SLL, or marginal zone B-cell lymphoma) double refractory to rituximab (monotherapy or in combination) and to either chemotherapy or radioimmunotherapy. All were treated with duvelisib 25 mg orally twice daily in 28-day cycles until progression, unacceptable toxicity, or death. The primary end point was overall response rate (ORR) using the revised International Working Group criteria for malignant lymphoma. RESULTS: This open-label, global phase II trial enrolled 129 patients (median age, 65 years; median of three prior lines of therapy) with an ORR of 47.3% (SLL, 67.9%; FL, 42.2%; MZL, 38.9%). The estimated median duration of response was 10 months, and the estimated median progression-free survival was 9.5 months. The most frequent any-grade treatment-emergent adverse events (TEAEs) were diarrhea (48.8%), nausea (29.5%), neutropenia (28.7%), fatigue (27.9%), and cough (27.1%). Among the 88.4% of patients with at least one grade 3 or greater TEAE, the most common TEAEs were neutropenia (24.8%), diarrhea (14.7%), anemia (14.7%), and thrombocytopenia (11.6%). CONCLUSION: In the DYNAMO study, oral duvelisib monotherapy demonstrated clinically meaningful activity and a manageable safety profile in heavily pretreated, double-refractory iNHL, consistent with previous observations. Duvelisib may provide a new oral treatment option for this patient population of which many are elderly and in need of additional therapies.

A magnetoelectric flux gate: new approach for weak DC magnetic field detection.

The magnetic flux gate sensors based on Faraday's Law of Induction are widely used for DC or extremely low frequency magnetic field detection. Recently, as the fast development of multiferroics and magnetoelectric (ME) composite materials, a new technology based on ME coupling effect is emerging for potential devices application. Here, we report a magnetoelectric flux gate sensor (MEFGS) for weak DC magnetic field detection for the first time, which works on a similar magnetic flux gate principle, but based on ME coupling effect. The proposed MEFGS has a shuttle-shaped configuration made of amorphous FeBSi alloy (Metglas) serving as both magnetic and magnetostrictive cores for producing a closed-loop high-frequency magnetic flux and also a longitudinal vibration, and one pair of embedded piezoelectric PMN-PT fibers ([011]-oriented Pb(Mg,Nb)O3-PbTiO3 single crystal) serving as ME flux gate in a differential mode for detecting magnetic anomaly. In this way, the relative change in output signal of the MEFGS under an applied DC magnetic anomaly of 1 nT was greatly enhanced by a factor of 4 to 5 in comparison with the previous reports. The proposed ME flux gate shows a great potential for magnetic anomaly detections, such as magnetic navigation, magnetic based medical diagnosis, etc.

A micromachined piezoelectric microgripper for manipulation of micro/nanomaterials.

Micro/nanomaterials and devices have attracted great interest in recent years because of their extensive application prospects in almost all kinds of fields. However, the manipulations of the material at the micro/nanoscale, such as the separation or transfer of a micro/nano-object in the process of assembling micro/nanodevices, are quite difficult. In this paper, we present a micromachined micro-gripper made of photoresist material (SU-8) and driven by piezoelectric Pb(Mg,Nb)O3-PbTiO3 single crystal pieces. In order to keep two grasping jaws of the micro-gripper operating in the same plane at the micro/nanometer scale, a fine circular flexure hinge was fabricated for elastically connecting them together. After introducing the interface effect, the relationship between the opening stroke of two jaws and the applied voltage was developed and then confirmed by finite element simulation. The micro-gripper was finally installed on a six degree of freedom stage for performing a pick-up, release, and transfer manipulation of a 2 µm ZnO micro-fiber. The presented piezoelectric micro-gripper shows a great potential for the precise manipulation of a single piece of micro/nanomaterial for micro/nanodevices' assembling.

Enhanced Resonance Magnetoelectric Coupling in (1-1) Connectivity Composites.

Bulk-magnetoelectric (ME) composites consisting of various piezoelectric and piezomagnetic materials with (3-0), (3-1), (2-2), and (2-1) connectivity are proposed in a bid to realize strong ME coupling for next-generation electronic-device applications. Here, 1D (1-1) connectivity ME composites consisting of a [011]-oriented Pb(Mg,Nb)O3 -PbTiO3 (PMN-PT) single-crystal fiber laminated with laser-treated amorphous FeBSi alloy (Metglas) and operating in L-T mode (longitudinally magnetized and transversely poled) are reported, which exhibit an enhanced resonant ME coupling coefficient of ≈7000 V cm-1  Oe-1 , which is nearly seven times higher than the best result published previously, and also a superhigh magnetic sensitivity of 1.35 × 10-13 T (directly detected) at resonance at room temperature, representing a significant advance in bulk magnetoelectric materials. The theoretical analyses based on magnetic-circuit and equivalent-circuit methods show that the enhancement in ME coupling can be attributed to the reduction in resonance loss of laser-treated Metglas alloy due to nanocrystallization and the strong magnetic-flux-concentration effect in (1-1) configuration composites.

Efficacy, safety, pharmacokinetics and pharmacodynamics of SAR245409 (voxtalisib, XL765), an orally administered phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor: a phase 1 expansion cohort in patients with relapsed or refractory lymphoma.

The maximum tolerated dose of SAR245409 (voxtalisib), a pan-class I phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor, was determined in a phase 1 dose-escalation study in advanced solid tumors. We report safety, pharmacokinetics (PK), pharmacodynamics and preliminary efficacy of SAR245409 capsules 50 mg twice daily in an expansion cohort of 16 patients with relapsed/refractory lymphoma. The most common treatment-related adverse events (AEs) were nausea (31.3%) and diarrhea (25.0%). The most common grade 3/4 treatment-related AE was increased alanine aminotransferase (12.5%). PK results were consistent with solid tumors, confirming a relatively short steady-state half-life (mean 4.61 h). Among 12 evaluable patients, one complete response and two partial responses were achieved in patients with and without PI3K/mTOR pathway alterations. In a patient with mantle cell lymphoma achieving PR, SAR245409 was associated with significant inhibition of PI3K/mTOR and extracellular signal-related kinase (ERK) pathways. Preliminary efficacy warrants further evaluation of SAR245409 in lymphoma.

Phase I safety, pharmacokinetic, and pharmacodynamic study of SAR245409 (XL765), a novel, orally administered PI3K/mTOR inhibitor in patients with advanced solid tumors.

PURPOSE: This phase I, first-in-human study evaluated the safety, maximum-tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and preliminary efficacy of SAR245409, an inhibitor of pan-Class I phosphoinositide 3-kinase (PI3K) and mTOR, administered orally once or twice daily in patients with advanced solid tumors. EXPERIMENTAL DESIGN: Eighty-three patients received SAR245409. Doses ranged from 15 to 120 mg twice daily, and 70 to 100 mg once daily. A 3+3 dose-escalation design was used to determine the MTD. Patients were evaluated for adverse events and response. Assessments included pharmacokinetic, pharmacodynamic impact of SAR245409 on PI3K pathway signaling in hair sheath cells, skin and tumor, and characterization of tumor molecular alterations. RESULTS: The MTDs were 50 mg twice daily and 90 mg once daily. The most frequent treatment-related adverse events were nausea (36.1%), diarrhea (21.7%), vomiting (19.3%), and decreased appetite (16.9%). The most frequent treatment-related grade 3/4 adverse events were increases in alanine aminotransferase (6.0%) and aspartate aminotransferase (4.8%). SAR245409 had a relatively short plasma half-life (2.96-7.52 hours). At MTDs, once- and twice-daily regimens yielded similar mean steady-state plasma exposure. A reduction in PI3K and mTORC1/mTORC2 pathway signaling was observed in serial hair sheath cells, skin, and tumor samples. Best response was stable disease in 48% of evaluable patients; seven patients had minor tumor regression. Twelve patients with stable disease were treated for ≥16 weeks. No trend was observed correlating tumor molecular alteration with antitumor activity. CONCLUSION: SAR245409 had a manageable safety profile, demonstrated reduced PI3K and mTORC1/mTORC2 pathway signaling and was associated with clinically relevant stable disease.

The partitioned LASSO-patternsearch algorithm with application to gene expression data.

BACKGROUND: In systems biology, the task of reverse engineering gene pathways from data has been limited not just by the curse of dimensionality (the interaction space is huge) but also by systematic error in the data. The gene expression barcode reduces spurious association driven by batch effects and probe effects. The binary nature of the resulting expression calls lends itself perfectly to modern regularization approaches that thrive in high-dimensional settings. RESULTS: The Partitioned LASSO-Patternsearch algorithm is proposed to identify patterns of multiple dichotomous risk factors for outcomes of interest in genomic studies. A partitioning scheme is used to identify promising patterns by solving many LASSO-Patternsearch subproblems in parallel. All variables that survive this stage proceed to an aggregation stage where the most significant patterns are identified by solving a reduced LASSO-Patternsearch problem in just these variables. This approach was applied to genetic data sets with expression levels dichotomized by gene expression bar code. Most of the genes and second-order interactions thus selected and are known to be related to the outcomes. CONCLUSIONS: We demonstrate with simulations and data analyses that the proposed method not only selects variables and patterns more accurately, but also provides smaller models with better prediction accuracy, in comparison to several alternative methodologies.

LASSO-Patternsearch algorithm with application to ophthalmology and genomic data.

The LASSO-Patternsearch algorithm is proposed to efficiently identify patterns of multiple dichotomous risk factors for outcomes of interest in demographic and genomic studies. The patterns considered are those that arise naturally from the log linear expansion of the multivariate Bernoulli density. The method is designed for the case where there is a possibly very large number of candidate patterns but it is believed that only a relatively small number are important. A LASSO is used to greatly reduce the number of candidate patterns, using a novel computational algorithm that can handle an extremely large number of unknowns simultaneously. The patterns surviving the LASSO are further pruned in the framework of (parametric) generalized linear models. A novel tuning procedure based on the GACV for Bernoulli outcomes, modified to act as a model selector, is used at both steps. We applied the method to myopia data from the population-based Beaver Dam Eye Study, exposing physiologically interesting interacting risk factors. We then applied the the method to data from a generative model of Rheumatoid Arthritis based on Problem 3 from the Genetic Analysis Workshop 15, successfully demonstrating its potential to efficiently recover higher order patterns from attribute vectors of length typical of genomic studies.

Detecting disease-causing genes by LASSO-Patternsearch algorithm.

The Genetic Analysis Workshop 15 Problem 3 simulated rheumatoid arthritis data set provided 100 replicates of simulated single-nucleotide polymorphism (SNP) and covariate data sets for 1500 families with an affected sib pair and 2000 controls, modeled after real rheumatoid arthritis data. The data generation model included nine unobserved trait loci, most of which have one or more of the generated SNPs associated with them. These data sets provide an ideal experimental test bed for evaluating new and old algorithms for selecting SNPs and covariates that can separate cases from controls, because the cases and controls are known as well as the identities of the trait loci. LASSO-Patternsearch is a new multi-step algorithm with a LASSO-type penalized likelihood method at its core specifically designed to detect and model interactions between important predictor variables. In this article the original LASSO-Patternsearch algorithm is modified to handle the large number of SNPs plus covariates. We start with a screen step within the framework of parametric logistic regression. The patterns that survived the screen step were further selected by a penalized logistic regression with the LASSO penalty. And finally, a parametric logistic regression model were built on the patterns that survived the LASSO step. In our analysis of Genetic Analysis Workshop 15 Problem 3 data we have identified most of the associated SNPs and relevant covariates. Upon using the model as a classifier, very competitive error rates were obtained.