Desymmetrization of Cyclohexadienones through Phase-Transfer-Catalyzed Stereoselective Intramolecular Aza-Michael Addition with Chiral Sulfinamide Nucleophiles.

This paper reports the desymmetrization of cyclohexadienones through stereoselective intramolecular aza-Michael addition with a tethered chiral sulfinamide nucleophile. The reaction was facilitated by phase-transfer catalysis and produced various nitrogen-containing bicyclic compounds with a yield of up to 93% and a diastereomeric ratio of up to >20:1.

Machine learning for cryosection pathology predicts the 2021 WHO classification of glioma.

BACKGROUND: Timely and accurate intraoperative cryosection evaluations remain the gold standard for guiding surgical treatments for gliomas. However, the tissue-freezing process often generates artifacts that make histologic interpretation difficult. In addition, the 2021 WHO Classification of Tumors of the Central Nervous System incorporates molecular profiles in the diagnostic categories, so standard visual evaluation of cryosections alone cannot completely inform diagnoses based on the new classification system. METHODS: To address these challenges, we develop the context-aware Cryosection Histopathology Assessment and Review Machine (CHARM) using samples from 1,524 glioma patients from three different patient populations to systematically analyze cryosection slides. FINDINGS: Our CHARM models successfully identified malignant cells (AUROC = 0.98 ± 0.01 in the independent validation cohort), distinguished isocitrate dehydrogenase (IDH)-mutant tumors from wild type (AUROC = 0.79-0.82), classified three major types of molecularly defined gliomas (AUROC = 0.88-0.93), and identified the most prevalent subtypes of IDH-mutant tumors (AUROC = 0.89-0.97). CHARM further predicts clinically important genetic alterations in low-grade glioma, including ATRX, TP53, and CIC mutations, CDKN2A/B homozygous deletion, and 1p/19q codeletion via cryosection images. CONCLUSIONS: Our approaches accommodate the evolving diagnostic criteria informed by molecular studies, provide real-time clinical decision support, and will democratize accurate cryosection diagnoses. FUNDING: Supported in part by the National Institute of General Medical Sciences grant R35GM142879, the Google Research Scholar Award, the Blavatnik Center for Computational Biomedicine Award, the Partners' Innovation Discovery Grant, and the Schlager Family Award for Early Stage Digital Health Innovations.

A deep learning model using chest X-ray for identifying TB and NTM-LD patients: a cross-sectional study.

BACKGROUND: Timely differentiating between pulmonary tuberculosis (TB) and nontuberculous mycobacterial lung disease (NTM-LD), which are radiographically similar, is important because infectiousness and treatment differ. This study aimed to evaluate whether artificial intelligence could distinguish between TB or NTM-LD patients by chest X-rays (CXRs) from suspects of mycobacterial lung disease. METHODS: A total of 1500 CXRs, including 500 each from patients with pulmonary TB, NTM-LD, and patients with clinical suspicion but negative mycobacterial culture (Imitator) from two hospitals, were retrospectively collected and evaluated in this study. We developed a deep neural network (DNN) and evaluated model performance using the area under the receiver operating characteristic curves (AUC) in both internal and external test sets. Furthermore, we conducted a reader study and tested our model under three scenarios of different mycobacteria prevalence. RESULTS: Among the internal and external test sets, the AUCs of our DNN model were 0.83 ± 0.005 and 0.76 ± 0.006 for pulmonary TB, 0.86 ± 0.006 and 0.64 ± 0.017 for NTM-LD, and 0.77 ± 0.007 and 0.74 ± 0.005 for Imitator. The DNN model showed higher performance on the internal test set in classification accuracy (66.5 ± 2.5%) than senior (50.8 ± 3.0%, p < 0.001) and junior pulmonologists (47.5 ± 2.8%, p < 0.001). Among different prevalence scenarios, the DNN model has stable performance in terms of AUC to detect TB and mycobacterial lung disease. CONCLUSION: DNN model had satisfactory performance and a higher accuracy than pulmonologists on classifying patients with presumptive mycobacterial lung diseases. DNN model could be a complementary first-line screening tool.

Synergistic Palladium/Chiral Phosphoric Acid-Catalyzed Kinetic Resolution via Stereoselective Intramolecular Substitution of Unactivated Allylic Alcohols.

This paper reports the kinetic resolution of racemic secondary alcohols (O-nucleophiles) via stereoselective intramolecular allylic substitution. The reaction was enabled by synergistic palladium and chiral phosphoric acid catalysis and produced chiral cis-1,3-disubstituted 1,3-dihydroisobenzofurans with a selective factor of up to 60.9 and a diastereomeric ratio of up to 7.8:1. Asymmetric synthesis of a compound with antihistaminic activity was demonstrated as the application of this methodology.

Insight into Stereocontrol in the Asymmetric Intramolecular Allylation with a tert-Butylsulfinamide Nucleophile: Application in the Synthesis of Chiral Isoindoline-1-Carboxylic Acid Esters.

The asymmetric induction afforded by a chiral sulfinyl group in a palladium/Brønsted-acid-catalyzed intramolecular allylic amination was investigated. Predictions of the diastereoselectivity for various substrates under assumed total thermodynamic control were obtained from density functional theory (DFT), and the correlation with experimental data demonstrates abrupt changes to kinetic control across the substrate scope. The resulting heterocyclic product was readily converted to valuable isoindoline-1-carboxylic acid esters by a two-step oxidation sequence, providing asymmetric access to a key unnatural α-amino acid scaffold.

A 1.9-V all-organic battery-supercapacitor hybrid device with high rate capability and wide temperature tolerance in a metal-free water-in-saltelectrolyte.

Developing battery-supercapacitor hybrid devices (BSHs) is viewed as an efficient route to shorten the gap between supercapacitors and batteries. In this study, a composite hydrogel consisting of perylene tetracarboxylic diimide (PTCDI) and reduced graphene oxide (rGO) is tested as the anode for BSHs in the electrolyte of ammonium acetate (NH4Ac) with a record concentration of 32 molality (m). This water-in-salt electrolyte exhibits a wide electrochemical stability window of 2.13 V and high conductivity of 23.3 mS cm-1 even at -12 °C. Molecular dynamics calculations and spectroscopic measurements reveal that a favorable water-acetate interaction occurs in a high concentration NH4Ac electrolyte. On the other hand, the study of electrode kinetics in 32 m NH4Ac demonstrates a high capacitive contribution to charge storage in PTCDI-rGO although an electrode redox reaction involves reversible enolization of carbonyl groups in PTCDI. This result suggests fast NH4+-ion intercalation kinetics in charge-discharge processes. Furthermore, the electrode performance is improved by optimizing the loading amount of rGO in composites. The best-performing composite electrode delivers the maximum capacity of 165 mAh g-1 at 0.5 A g-1 and sustains a great capacity retention of 66% at 8 A g-1. Finally, an all-organic BSH device is tested in a broad temperature window from -20 to 50 °C and is well operated at 1.9 V regardless of operating temperatures. Due to the synergetic effect of splendid electrolyte properties and high anode capacities, BSH devices possess the maximum energy density of 12.9 Wh kg-1 at the power density of 827 W kg-1 and retain 74 % of the initial capacity after 3000 cycles at 1 A g-1. Our study paves a novel route towards designing inexpensive and environmentally friendly BSH devices with high performances.

Palladium/Brønsted-Acid-Catalyzed Diastereoselective Cyclization with Chiral Sulfinamides as Nucleophiles.

This article reports diastereoselective cyclization with chiral sulfinamides as nucleophiles in two reaction pathways: (1) intramolecular allylic substitution and (2) sequential aerobic oxidation with aza-Michael addition. These reactions were enabled by synergistic palladium and Brønsted acid catalysis and produced chiral isoindolines with good yields of 55-92% and high diastereoselectivities of 10:1 to >20:1 dr.

Recalibration of deep learning models for abnormality detection in smartphone-captured chest radiograph.

Image-based teleconsultation using smartphones has become increasingly popular. In parallel, deep learning algorithms have been developed to detect radiological findings in chest X-rays (CXRs). However, the feasibility of using smartphones to automate this process has yet to be evaluated. This study developed a recalibration method to build deep learning models to detect radiological findings on CXR photographs. Two publicly available databases (MIMIC-CXR and CheXpert) were used to build the models, and four derivative datasets containing 6453 CXR photographs were collected to evaluate model performance. After recalibration, the model achieved areas under the receiver operating characteristic curve of 0.80 (95% confidence interval: 0.78-0.82), 0.88 (0.86-0.90), 0.81 (0.79-0.84), 0.79 (0.77-0.81), 0.84 (0.80-0.88), and 0.90 (0.88-0.92), respectively, for detecting cardiomegaly, edema, consolidation, atelectasis, pneumothorax, and pleural effusion. The recalibration strategy, respectively, recovered 84.9%, 83.5%, 53.2%, 57.8%, 69.9%, and 83.0% of performance losses of the uncalibrated model. We conclude that the recalibration method can transfer models from digital CXRs to CXR photographs, which is expected to help physicians' clinical works.

Enantioselective Intramolecular Allylic Substitution via Synergistic Palladium/Chiral Phosphoric Acid Catalysis: Insight into Stereoinduction through Statistical Modeling.

The mode of asymmetric induction in an enantioselective intramolecular allylic substitution reaction catalyzed by a combination of palladium and a chiral phosphoric acid was investigated by a combined experimental and statistical modeling approach. Experiments to probe nonlinear effects, the reactivity of deuterium-labeled substrates, and control experiments revealed that nucleophilic attack to the π-allylpalladium intermediate is the enantio-determining step, in which the chiral phosphate anion is involved in stereoinduction. Using multivariable linear regression analysis, we determined that multiple noncovalent interactions with the chiral environment of the phosphate anion are integral to enantiocontrol in the transition state. The synthetic protocol to form chiral pyrrolidines was further applied to the asymmetric construction of C-O bonds at fully substituted carbon centers in the synthesis of chiral 2,2-disubstituted benzomorpholines.

Harnessing Noncovalent Interactions in Dual-Catalytic Enantioselective Heck-Matsuda Arylation.

The use of more than one catalyst in one-pot reaction conditions has become a rapidly evolving protocol in the development of asymmetric catalysis. The lack of molecular insights on the mechanism and enantioselectivity in dual-catalytic reactions motivated the present study focusing on an important catalytic asymmetric Heck-Matsuda cross-coupling. A comprehensive density functional theory (M06 and B3LYP-D3) investigation of the coupling between a spirocyclic cyclopentene and 4-fluorophenyl diazonium species under a dual-catalytic condition involving Pd2(dba)3 (dba = trans, trans-dibenzylideneacetone) and chiral 2,2'-binaphthyl diamine (BINAM)-derived phosphoric acids (BDPA, 2,2'-binaphthyl diamine-derived phosphoric acids) is presented. Among various mechanistic possibilities examined, the pathway with explicit inclusion of the base (in situ generated sodium bicarbonate/sodium biphosphate) is found to be energetically more preferred over the analogous base-free routes. The chiral phosphate generated by the action of sodium carbonate on BDPA is found to remain associated with the reaction site as a counterion. The initial oxidative addition of Pd(0) to the aryl diazonium bond gives rise to a Pd-aryl intermediate, which then goes through the enantiocontrolling migratory insertion to the cyclic alkene, leading to an arylated cycloalkene intermediate. Insights on how a series of noncovalent interactions, such as C-H···O, C-H···N, C-H···F, C-H···π, lp···π, O-H···π, and C-F···π, in the enantiocontrolling transition state (TS) render the migration of the Pd-aryl to the si prochiral face of the cyclic alkene more preferred over that to the re face are utilized for modulating the enantioselectivity. Aided by molecular insights on the enantiocontrolling transition states, we predicted improved enantioselectivity from 37% to 89% by changes in the N-aryl substituents of the catalyst. Subsequent experiments in our laboratory offered very good agreement with the predicted enantioselectivities.

Enantiodivergent Steglich rearrangement of O-carboxylazlactones catalyzed by a chirality switchable helicene containing a 4-aminopyridine unit.

A pseudo-enantiomeric pair of optically switchable helicenes containing a catalytic 4-N-methylaminopyridine (MAP) bottom unit and a C2-symmetric, (10R,11R)-dimethoxymethyl-dibenzosuberane top template was synthesized. They underwent complementary photoswitching at 290 nm (P/M', <1/>99) and 340 nm (P/M', 91/9) and unidirectional thermo-rotation at 130 °C (P/M', >99/<1). They were utilized to catalyze enantiodivergent Steglich rearrangement of O- to C-carboxylazlactones, with formation of either enantiomer with up to 91% ee (R) and 94% ee (S), respectively.

Preparation of Furo[3,2-c]coumarins from 3-Cinnamoyl-4-hydroxy-2H-chromen-2-ones and Acyl Chlorides: A Bu3P-Mediated C-Acylation/Cyclization Sequence.

A Bu3P-mediated cyclization reaction of 3-cinnamoyl-4-hydroxy-2H-chromen-2-ones though electrophilic addition of acyl chlorides towards the synthesis of highly functionalized furo[3,2-c]coumarins bearing a phosphorus ylide moiety is described. These unprecedented cyclization reaction proceeds under mild reaction conditions within short reaction times (1 min to 1 h), and can be further applied in the synthesis of alkenyl-substituted furo[3,2-c]coumarins by the treatment with carbonyl electrophiles under basic conditions.

Aspirin and nonsteroidal anti-inflammatory drugs after but not before diagnosis are associated with improved breast cancer survival: a meta-analysis.

PURPOSE: The association between nonsteroidal anti-inflammatory drugs (NSAIDs) and breast cancer survival is still controversial. The aim of our meta-analysis was to assess the survival benefit of NSAIDs. METHODS: A literature search was conducted in PubMed and EMBASE (to September 2014). A meta-analysis was performed with hazard ratios (HRs) and 95% confidence intervals (CIs) as the effect measures. Subgroup analyses were based on time of NSAID use (before and after diagnosis), medication type (aspirin and other nonaspirin NSAIDs), and study design (cohort and case-control studies). RESULTS: There were 16 eligible studies. Use of NSAIDs after diagnosis was significantly inversely associated with relapse/metastasis (HR 0.69, 95% CI 0.59-0.80) and tended toward potentially protective effects on all-cause mortality, although significance was not reached (HR 0.79, 95% CI 0.61-1.02). In cohort studies, the association between post-diagnostic use of NSAIDs and breast cancer survival was stronger with reduced heterogeneity (breast-cancer-specific mortality: HR 0.65, 95% CI 0.48-0.89, I(2) = 65.3%; all-cause mortality: HR 0.73, 95% CI 0.57-0.92, I(2) = 83.2%; relapse/metastasis: HR 0.73, 95% CI 0.61-0.86, I(2) = 48.3%). Aspirin use after diagnosis was significantly associated with breast-cancer-specific mortality (HR 0.69, 95% CI 0.50-0.96) and relapse/metastasis (HR 0.75, 95% CI 0.56-1.00), and tended toward a protective effect on all-cause mortality, although significance was not reached (HR 0.79, 95% CI 0.60-1.03). Including cohort studies only, we obtained similar results and post-diagnostic use of aspirin was significantly associated with all-cause mortality (HR 0.72, 95% CI 0.56-0.93). CONCLUSIONS: NSAIDs and aspirin after but not before diagnosis were associated with improved breast cancer survival, including breast-cancer-specific mortality, all-cause mortality, and relapse/metastasis.

Direct ß-acylation of 2-arylidene-1,3-indandiones with acyl chlorides catalyzed by organophosphanes.

We have developed an organophosphane-catalyzed direct ß-acylation of a series of conjugated systems bearing ketone, amide and ester functionalities using acyl chlorides as trapping reagents. A wide variety of highly functional ketone derivatives were generated efficiently under very mild conditions with high yields according to our protocol. Our adducts can even be utilized as important building blocks for the synthesis of functional tri/tetracyclic pyridazine derivatives.

Fabrication of high-power piezoelectric transformers using lead-free ceramics for application in electronic ballasts.

CuO is doped into (Na(0.5)K(0.5))NbO(3) (NKN) ceramics to improve the piezoelectric properties and thus obtain a piezoelectric transformer (PT) with high output power. In X-ray diffraction patterns, the diffraction angles of the CuO-doped NKN ceramics shift to lower values because of an expansion of the lattice volume, thus inducing oxygen vacancies and enhancing the mechanical quality factor. A homogeneous microstructure is obtained when NKN is subjected to CuO doping, leading to improved electrical properties. PTs with different electrode areas are fabricated using the CuO-doped NKN ceramics. Considering the efficiency, voltage gain, and temperature rise of PTs at a load resistance of 1 kΩ, PTs with an electrode with an inner diameter of 15 mm are combined with the circuit design for driving a 13-W T5 fluorescent lamp. A temperature rise of 6°C and a total efficiency of 82.4% (PT and circuit) are obtained using the present PTs.

Intra- and intermolecular hydrogen bonds enhance the fluoride-responsiveness of functionalized glycolipid-based gelators.

We propose a facile approach toward enhancing the efficiency of fluoride-responsive gels through the positioning of functionalized receptor units, allowing tunable intra- and intermolecular hydrogen bonding, in the gelator molecules. We prepared the new glycolipid-based gelator 2 and its hydroxy and methoxy derivatives 2a and 2b, respectively, to study the effects of three types modes of supramolecular assembly: solely intermolecular hydrogen bonding in 2, solely intramolecular hydrogen bonding in 2b, and both inter- and intramolecular hydrogen bonding in 2a. 1H NMR spectra confirmed the self-assembly interactions of these glycolipid-based gelators. We measured the minimum gel concentrations and sol-gel transitions and recorded X-ray diffraction patterns and electron micrographs to characterize the gelation behavior and structural organization of each of these supramolecular gels. Among these three gelators, only 2 and 2a could form organogels in the test solvents, indicating that intermolecular hydrogen bonding plays a determinant role in the supramolecular assemblies leading to gelation. The self-assembly of 2 resulted in a bilayer-packed lamellar structure within ribbon-like fibers, whereas that of 2a resulted in hexagonally packed cylindrical micelles within tree-like fibers. A minimum amount of 0.3 equivalent of F- was required for complete disruption of the gel formed from 2a, which was approximately four times lower than that required for the gel formed from 2. Thus, the incorporation of a ß-hydroxy motif-the only difference in the chemical structures of 2 and 2a-led to interesting variations in the resulting gel morphologies and enhanced the gel's fluoride-responsiveness.

Effects of improved process for CuO-doped NKN lead-free ceramics on high-power piezoelectric transformers.

In this paper, the effects of the electrical proper- ties of CuO-doped (Na(0.5)K(0.5))NbO(3) (NKN) ceramics prepared separately using the B-site oxide precursor method (BO method) and conventional mixed-oxide method (MO method) on high-power piezoelectric transformers (PTs) were investigated. The performances of PTs made with these two substrates were compared. Experimental results showed that the output power and temperature stability of PTs could be enhanced because of the lower resonant impedance of the ceramics prepared using the BO method. In addition, the output power of PTs was more affected by the resonant impedance than by the mechanical quality factor (Q(m)) of the ceramics. The PTs fabricated with ceramics prepared using the BO method showed a high efficiency of more than 94% and a maximum output power of 8.98 W (power density: 18.3 W/cm(3)) with temperature increase of 3°C under the optimum load resistance (5 kΩ) and an input voltage of 150 V(pp). This output power of the lead-free disk-type PTs is the best reported so far.

Doping effects of CuO additives on the properties of low-temperature-sintered PMnN-PZT-based piezoelectric ceramics and their applications on surface acoustic wave devices.

To develop the anisotropic ceramic substrate with low sintering temperature for surface acoustic wave (SAW) applications, the low cost and feasible material with moderate piezoelectric properties, good dielectric properties, and higher Curie temperature were explored. The piezoelectric ceramics with compositions of Pb[(Mn(1/3)Nb(2/3))(0.06-) (Zr(0.52)Ti(0.48))0.94] O(3) (PMnN-PZT) + 0.5 wt.% PbO + x wt.% CuO (0.05 = x = 0.3) had been prepared by the conventional mixed-oxides method. CuO dopants were used as the sintering aid to improve the bulk density under low sintering temperature (i.e., 980-1040 degrees C). The phase structures, microstructures, frequency behavior of dielectric properties (up to 50 MHz), piezoelectric properties, ferroelectric properties, and temperature stability with the amount of CuO additive were systematically investigated. Experimental results showed that the sintering temperature could be lowered down to 1020 degrees C and still keep reasonably good piezoelectric activity (i.e., high electromechanical coupling factor (k(p)), (k(t)) and dielectric and ferroelectric properties. The preferable composition, obtained at x = 0.1, presented the values of the electromechanical coupling factor (k(p)) (k(t)), mechanical quality factor (Q(m)), piezoelectric charge constant (d(33)), dielectric constant, dielectric loss, temperature coefficient of resonant frequency (TCF(B)), and Curie point (T(c)) of 0.54, 0.48, 850, 238 pc/N, 1450, 0.0023, 1.1 kV/mm, 26 coul/cm(2), -150 ppm/ degrees C, and 348 degrees C. Using this developed low-temperature-sintered material to make the piezoelectric substrate, the SAW filter was fabricated and its properties were measured. Results showed that this device possessed very high value of k(2)(7.13%) with a good TCF (-40.15 ppm/ degrees C), and a surface wave velocity (V(P)) of 2196 m/s.

The improvement of dynamic characteristics of ultrasonic therapeutic transducers using fine-grain PZT-based piezoceramics.

Optimizing the dynamic resonant characteristics of ultrasonic therapeutic transducers depends most importantly on fine-grain piezoceramics with good resonant properties. In this paper, we prepare and compare modified Pb(0.99)Sr(0.01)[0.03(Mn(1/3)Nb(2/3))-0.97(Zr(0.51)Ti(0.49))]O(3) piezoceramics with 0.1 wt% CaCO(3) and 0.8 wt% PbO additives (PMZT3) synthesized by B-oxides precursor (BO) and conventional ceramic mixed-oxide methods (MO). Our experimental results show that the BO-type piezoceramics have better grain microstructure and better material properties [e.g., d(33)= 340 pc/N, k(t)= 0.52, Q(m)= 1250, temperature coefficient of change rate of resonant frequency (TCF) = 0.01%/degrees C, and temperature coefficient of change rate of clamped capacitance (TCC) = 0.18%/degrees C]. We construct 1-MHz transducers using our BO and MO types of piezoceramics and examine their dynamic resonant characteristics as the transducers are driven by a power driver with open-loop control. Results show that the transducers with the BO-type piezoceramics have better dynamic characteristics, such as time stability (e.g., aging rate of resonant frequency at thickness mode = 0.26%/decade cycle, and aging rate of clamped capacitance = 0.55%/decade cycle) and temperature stability as BO-type piezoceramics. Furthermore, we observe that the clamped capacitance variation has more influence on the transducer dynamic characteristics than the resonant frequency variation, and we verify the observation from the partial derivative ratio of the transfer function derived by a simulated ultrasonic equivalent circuit system. It is concluded that the BO-type piezoceramics are better candidates than the MO-type samples for obtaining optimum dynamic resonant characteristics in ultrasonic therapeutic transducers.