Tuning strained alkyne reactivity
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organic synthesis has evolved into a burgeoning field of study largely focused on cyclooctyne, wherein physical organic chemistry helps guide rational molecular ...design to produce molecules with intriguing properties. Concurrent research in the field of carbon nanomaterials has produced new types of strained alkyne macrocycles, such as cycloparaphenyleneacetylenes, that possess uniquely curved aromatic π systems but hover on the edge of stability. In 2018, we introduced a strained alkyne scaffold that marries the synthetic accessibility and stability of cyclooctyne with the curved π system of carbon nanomaterials. These molecules are strained alkyne-containing cycloparaphenylenes (or
n
+1CPPs
), which have been shown to possess size-dependent reactivity as well as the classic characteristics of the unfunctionalized parent CPP, such as a tunable HOMO-LUMO gap and bright fluorescence for large sizes. Herein, we elaborate further on this scaffold, introducing two modifications to the original design and fully characterizing the kinetics of the strain-promoted azide-alkyne cycloaddition (SPAAC) for each
n
+1CPP
with a model azide. Additionally, we explain how electronic (the incorporation of fluorine atoms) and strain (a
meta
linkage which heightens local strain at the alkyne) modulations affect SPAAC reactivity
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the distortion-interaction computational model. Altogether, these results indicate that through a modular synthesis and rational chemical design, we have developed a new family of tunable and inherently fluorescent strained alkyne carbon nanomaterials.
Strained alkyne-containing cycloparaphenylenes unite curved carbon nanomaterials with tunable reactivity
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physical organic chemistry. Herein we describe the rational design and synthesis of new derivatives with heightened SPAAC reactivity.
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IJS, KILJ, NUK, UL, UM, UPUK
Storing solar energy is a vital component of using renewable energy sources to meet the growing demands of the global energy economy. Molecular solar thermal (MOST) energy storage is a promising ...means to store solar energy with on-demand energy release. The light-induced isomerization reaction of norbornadiene (NBD) to quadricyclane (QC) is of great interest because of the generally high energy storage density (0.97 MJ kg–1) and long thermal reversion lifetime (t 1/2,300K = 8346 years). However, the mechanistic details of the ultrafast excited-state 2 + 2-cycloaddition are largely unknown due to the limitations of experimental techniques in resolving accurate excited-state molecular structures. We now present a full computational study on the excited-state deactivation mechanism of NBD and its dimethyl dicyano derivative (DMDCNBD) in the gas phase. Our multiconfigurational calculations and nonadiabatic molecular dynamics simulations have enumerated the possible pathways with 557 S2 trajectories of NBD for 500 fs and 492 S1 trajectories of DMDCNBD for 800 fs. The simulations predicted the S2 and S1 lifetimes of NBD (62 and 221 fs, respectively) and the S1 lifetime of DMDCNBD (190 fs). The predicted quantum yields of QC and DCQC are 10 and 43%, respectively. Our simulations also show the mechanisms of forming other possible reaction products and their quantum yields.
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IJS, KILJ, NUK, PNG, UL, UM
The mechanism by which cells decide to skip mitosis to become polyploid is largely undefined. Here we used a high-content image-based screen to identify small-molecule probes that induce ...polyploidization of megakaryocytic leukemia cells and serve as perturbagens to help understand this process. Our study implicates five networks of kinases that regulate the switch to polyploidy. Moreover, we find that dimethylfasudil (diMF, H-1152P) selectively increased polyploidization, mature cell-surface marker expression, and apoptosis of malignant megakaryocytes. An integrated target identification approach employing proteomic and shRNA screening revealed that a major target of diMF is Aurora kinase A (AURKA). We further find that MLN8237 (Alisertib), a selective inhibitor of AURKA, induced polyploidization and expression of mature megakaryocyte markers in acute megakaryocytic leukemia (AMKL) blasts and displayed potent anti-AMKL activity in vivo. Our findings provide a rationale to support clinical trials of MLN8237 and other inducers of polyploidization and differentiation in AMKL.
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► Screen identifies > 200 compounds regulating megakaryocyte polyploidization ► Integrated target identification approach suggests regulatory kinase networks ► Aurora kinase A activity mediates megakaryocyte polyploidization and differentiation ► Induction of polyploidization provides a therapeutic strategy for AMKL
Megakaryocytes undergo a modified form of the cell cycle termed endomitosis, in which cells skip the late stages of mitosis to become polyploid. Using a chemical screening approach, Wen et al. now provide insight into the protein kinase networks that regulate endomitosis and reveal a differentiation therapy strategy for the treatment of acute megakaryocytic leukemia.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The effect of short-range order and dispersivity on charge-transport for organic crystalline semiconductors are important and unresolved questions. This exploration is the first to discern the role ...of short-range order on charge-transport for crystalline organic semiconductors. A multimode computational approach (including Molecular Dynamics and kinetic Monte Carlo simulations) is employed to understand the hole mobility dispersivity of crystalline organic semiconductors. Crystalline organic solids feature a mesoscale region where dispersive charge-transport dominates; our calculations show a clear transition of charge-mobility from non-dispersive to dispersive. An empirical relationship between the dispersive and non-dispersive transport transition region and ideal simulation box thickness is put forth. The dispersive to non-dispersive transition region occurs when energetic disorder approaches 72 meV. Non-dispersive transport is observed for simulation box sizes greater than 3.7 nm, which corresponds to approximately 12 π-stacked layers in typical π-stacked organic solids. A qualitative relationship is deduced between the variability of measured dispersive hole and variability of computed dispersive hole mobilities and system size. This relationship will guide future charge-transport investigations of condensed-phase organic systems.
It is unclear what mechanisms govern latent HIV infection in vivo or in primary cell models. To investigate these questions, we compared the HIV and cellular transcription profile in three primary ...cell models and peripheral CD4+ T cells from HIV-infected ART-suppressed individuals using RT-ddPCR and RNA-seq. All primary cell models recapitulated the block to HIV multiple splicing seen in cells from ART-suppressed individuals, suggesting that this may be a key feature of HIV latency in primary CD4+ T cells. Blocks to HIV transcriptional initiation and elongation were observed more variably among models. A common set of 234 cellular genes, including members of the minor spliceosome pathway, was differentially expressed between unstimulated and activated cells from primary cell models and ART-suppressed individuals, suggesting these genes may play a role in the blocks to HIV transcription and splicing underlying latent infection. These genes may represent new targets for therapies designed to reactivate or silence latently-infected cells.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In order to understand the conformational behavior of organic components in organic electronic devices, we have computed the torsional potentials for a library of thiophene-based heterodimers. The ...accuracy and efficiencies of computational methods for these organic materials were benchmarked for 11 common density functionals with three Pople basis sets against a Focal Point Analysis (FPA) on a model oligothiophene 2,5-bis(3-tetradecylthiophen-2-yl)thieno3,2-b-thiophene (BTTT) system. This study establishes a set of general trends in regards to conformational preferences, as well as planarization and rotational barriers for a library comprised of common fragments found in organic materials. These gas phase structures are compared to experimental crystal structures to determine the effect of crystal packing on geometry. Finally, we analyze the structure of hole-transporting material DERDTS-TBDT and design a new oligomer likely to be planar in the solid state.
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IJS, KILJ, NUK, PNG, UL, UM
In 2002 it was discovered that a lightning discharge can rise out of the top of tropical thunderstorms and branch out spectacularly to the base of the ionosphere at 90 km altitude. Several dozens of ...such gigantic jets have been recorded or photographed since, but eluded capture by high-speed video cameras. Here we report on 4 gigantic jets recorded in Colombia at a temporal resolution of 200 µs to 1 ms. During the rising stage, one or more luminous steps are revealed at 32-40 km, before a continuous final jump of negative streamers to the ionosphere, starting in a bidirectional (bipolar) fashion. The subsequent trailing jet extends upward from the jump onset, with a current density well below that of lightning leaders. Magnetic field signals tracking the charge transfer and optical Geostationary Lightning Mapper data are now matched unambiguously to the precisely timed final jump process in a gigantic jet.
The reactivities and torquoselectivities of electrocyclic ring opening reactions of fluoromethyl-substituted cyclobutenes and oxetenes were studied with M06-2X density functional theory. The ...torquoselectivities of a series of mono-, di-, and trifluoromethylcyclobutenes and oxetenes result from the interplay of favorable orbital interactions and closed-shell repulsions. When the substituent rotates inward, there can be a favorable interaction between the breaking σCO bond and the σCF* orbital (σCO → σCF*) of the fluoromethyl group in fluoromethyloxetenes. The preference for rotation of a fluoromethyl group is decreased in trifluoromethyloxetenes because closed-shell repulsions between the breaking σCO bond and trifluoromethyl substituent orbitals compete with the σCO → σCF* interaction.
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ABSTRACT
Introduction
An objective of the Military Health System is to deliver an improved health care experience. Patient satisfaction affects the patient experience, health outcomes, and treatment ...compliance. The purpose of this study is to identify indicators of high and low patient satisfaction within a military dental setting.
Materials and Methods
De-identified data from 248,342 responses to the DoD Dental Patient Satisfaction Survey conducted from October 2014 to March 2016 were used. The overall satisfaction and other related outcomes were analyzed by age, sex, beneficiary status, current rank, current Service, type of dental treatment, clinic location, and clinic size. Unpaired t-tests and logistic regression modeling were used to ascertain relationships between various aspects of patient satisfaction and variables of interest.
Results
Overall, 96% of patients attending military dental clinics were satisfied, whereas 72% of patients were satisfied with the number of days waited for an appointment. Air Force patients were the most satisfied compared to their Army, Navy, and Marine Corps counterparts. Patients treated in small dental clinics (less than 5 dentists) were 74% more satisfied than patients treated at large dental clinics (more than 12 dentists). Patients seeking routine dental treatment were significantly more satisfied with the number of days waiting for an appointment (odds ratio = 8.03; 95% CI: 7.64–8.43) compared to patients waiting for an emergency dental appointment.
Conclusions
There were important differences in patient satisfaction by military Service and clinic size, suggesting that improvement in satisfaction may need to be Service specific. These differences warrant further research that could inform policy changes directed at improving service members’ dental care and readiness.
Dysregulation of iron metabolism in cancer is well documented and it has been suggested that there is interdependence between excess iron and increased cancer incidence and progression. In an effort ...to better understand the linkages between iron metabolism and breast cancer, a predictive mathematical model of an expanded iron homeostasis pathway was constructed that includes species involved in iron utilization, oxidative stress response and oncogenic pathways. The model leads to three predictions. The first is that overexpression of iron regulatory protein 2 (IRP2) recapitulates many aspects of the alterations in free iron and iron-related proteins in cancer cells without affecting the oxidative stress response or the oncogenic pathways included in the model. This prediction was validated by experimentation. The second prediction is that iron-related proteins are dramatically affected by mitochondrial ferritin overexpression. This prediction was validated by results in the pertinent literature not used for model construction. The third prediction is that oncogenic Ras pathways contribute to altered iron homeostasis in cancer cells. This prediction was validated by a combination of simulation experiments of Ras overexpression and catalase knockout in conjunction with the literature. The model successfully captures key aspects of iron metabolism in breast cancer cells and provides a framework upon which more detailed models can be built.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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