Stereodivergent 1,3-difunctionalization of alkenes by charge relocation.

Alkenes are indispensable feedstocks in chemistry. Functionalization at both carbons of the alkene-1,2-difunctionalization-is part of chemistry curricula worldwide1. Although difunctionalization at distal positions has been reported2-4, it typically relies on designer substrates featuring directing groups and/or stabilizing features, all of which determine the ultimate site of bond formation5-7. Here we introduce a method for the direct 1,3-difunctionalization of alkenes, based on a concept termed 'charge relocation', which enables stereodivergent access to 1,3-difunctionalized products of either syn- or anti-configuration from unactivated alkenes, without the need for directing groups or stabilizing features. The usefulness of the approach is demonstrated in the synthesis of the pulmonary toxin 4-ipomeanol and its derivatives.

Isothiouronium-Mediated Conversion of Carboxylic Acids to Cyanomethyl Thioesters.

We report the development of an isothiouronium salt as a reagent for the operationally simple synthesis of cyanomethyl thioesters with high functional group tolerance and avoiding the use of thiols. Additionally, we show that the products can be engaged in amide synthesis in either a two-step or one-pot fashion.

Clinical and echocardiographic predictors of the anterior mitral leaflet repair failure.

BACKGROUND: Anterior mitral leaflet prolapse repair is a highly effective procedure, but despite excellent operative results still has an inferior long-term durability when compared to posterior leaflet repair. METHODS: We analysed mitral repair durability in 74 consecutive patients operated for anterior leaflet prolapse between 2010 and 2021. Their pre- and postoperative clinical, echocardiographic data and repair durability as well, were compared with 74 randomly assigned posterior leaflet prolapse patients who underwent valve repair during the same period. RESULTS: While groups were of similar age, patients with anterior leaflet prolapse had an inferior preoperative status in terms of functional reserve, atrial fibrillation, operative risk, ejection fraction and had more dilated left heart chambers as well. 1, 5, and 10-year freedom from repair failure was 87.1 ± 4.6%, 79.8 ± 6.5% and 50.7 ± 12.5% in the anterior, and 98.5 ± 1.5% respectively in the posterior leaflet group. Atrial fibrilation (hazard ratio [HR] 5.365; 95%; confidence interval [CI] 1.093-26.324 p = .038) and left ventricle end-systolic diameter (HR 1.160 95%; CI 1.037-1.299 p = .010) independently predicted anterior leaflet repair failure. Receiver Operating Curve analysis established left ventricle end-systolic diameter ≤42 mm as a cut-off value associated with improved anterior leaflet repair durability. Accordingly, 10-year repair durability in a subset of patients, with preserved left ventricle end-systolic diameter (≤42 mm) was 86.4 ± 7.8%. CONCLUSION: Better long-term repair durability in patients with anterior mitral leaflet prolapse and preserved sinus rhytm and left-ventricle diameters justifies early reconstructive approach.

Study of local anodic oxidation regimes in MoSe2.

Scanning probe microscopy is widely known not only as a well-established research method but also as a set of techniques enabling precise surface modification. One such technique is local anodic oxidation (LAO). In this study, we investigate the LAO of MoSe2 transferred on an Au/Si substrate, focusing specifically on the dependence of the height and diameter of oxidized dots on the applied voltage and time of exposure at various humidities. Depending on the humidity, two different oxidation regimes were identified. The first, at a relative humidity (RH) of 60%-65%, leads to in-plane isotropic oxidation. For this regime, we analyze the dependence of the size of oxidized dots on the oxidation parameters and modify the classical equation of oxidation kinetics to account for the properties of MoSe2 and its oxide. In this regime, patterns with a maximum spatial resolution of 10 nm were formed on the MoSe2 surface. The second is the in-plane anisotropic oxidation regime that arises at a RH of 40%-50%. In this regime, oxidation leads to the formation of triangles oxidized inside the zigzag edges. Based on the mutual orientation of zigzag and armchair directions in successive oxidized layers, the stacking type and phase of MoSe2 flakes were determined. These results allow LAO to be considered not only as an ultra-high-resolution nanolithography method, but also as a method for investigating the crystal structure of materials with strong intrinsic anisotropy, such as transition metal dichalcogenides.

Effect of crystal structure on the Young's modulus of GaP nanowires.

Young's modulus of tapered mixed composition (zinc-blende with a high density of twins and wurtzite with a high density of stacking faults) gallium phosphide (GaP) nanowires (NWs) was investigated by atomic force microscopy. Experimental measurements were performed by obtaining bending profiles of as-grown inclined GaP NWs deformed by applying a constant force to a series of NW surface locations at various distances from the NW/substrate interface. Numerical modeling of experimental data on bending profiles was done by applying Euler-Bernoulli beam theory. Measurements of the nano-local stiffness at different distances from the NW/substrate interface revealed NWs with a non-ideal mechanical fixation at the NW/substrate interface. Analysis of the NWs with ideally fixed base resulted in experimentally measured Young's modulus of 155 ± 20 GPa for ZB NWs, and 157 ± 20 GPa for WZ NWs, respectively, which are in consistence with a theoretically predicted bulk value of 167 GPa. Thus, impacts of the crystal structure (WZ/ZB) and crystal defects on Young's modulus of GaP NWs were found to be negligible.

Genome-wide association study identifies a novel locus for cannabis dependence.

Despite moderate heritability, only one study has identified genome-wide significant loci for cannabis-related phenotypes. We conducted meta-analyses of genome-wide association study data on 2080 cannabis-dependent cases and 6435 cannabis-exposed controls of European descent. A cluster of correlated single-nucleotide polymorphisms (SNPs) in a novel region on chromosome 10 was genome-wide significant (lowest P=1.3E-8). Among the SNPs, rs1409568 showed enrichment for H3K4me1 and H3K427ac marks, suggesting its role as an enhancer in addiction-relevant brain regions, such as the dorsolateral prefrontal cortex and the angular and cingulate gyri. This SNP is also predicted to modify binding scores for several transcription factors. We found modest evidence for replication for rs1409568 in an independent cohort of African American (896 cases and 1591 controls; P=0.03) but not European American (EA; 781 cases and 1905 controls) participants. The combined meta-analysis (3757 cases and 9931 controls) indicated trend-level significance for rs1409568 (P=2.85E-7). No genome-wide significant loci emerged for cannabis dependence criterion count (n=8050). There was also evidence that the minor allele of rs1409568 was associated with a 2.1% increase in right hippocampal volume in an independent sample of 430 EA college students (fwe-P=0.008). The identification and characterization of genome-wide significant loci for cannabis dependence is among the first steps toward understanding the biological contributions to the etiology of this psychiatric disorder, which appears to be rising in some developed nations.

Synthesis, Structure, and Reactivity of Binaphthyl Supported Dihydro[1,6]diazecines.

A short approach to chiral diaza-olefines from protected 2,2'-diamino-1,1'-binaphthyl is presented. Cis- and trans-olefines can be selectively obtained by twofold N-allylation followed by RCM or by bridging a 2,2'-diamino-1,1'-binaphthyl precursor with trans-1,4-dibromo-2-butene. Deprotection afforded cis- and trans-dihydro[1,6]diazecines 1 in 58 and 64% overall yield. The reactivity of the but-2-ene-1,4-diyl fragment was investigated yielding corresponding epoxides, diols, and mono- and dibromo products. In several cases rearrangements and participation of the proximate N-Boc group was observed. In no case could allylic substitution be accomplished. From 13 compounds X-ray structure analyses could be obtained.

Current Correlations in a Quantum Dot Ring: A Role of Quantum Interference.

We present studies of the electron transport and circular currents induced by the bias voltage and the magnetic flux threading a ring of three quantum dots coupled with two electrodes. Quantum interference of electron waves passing through the states with opposite chirality plays a relevant role in transport, where one can observe Fano resonance with destructive interference. The quantum interference effect is quantitatively described by local bond currents and their correlation functions. Fluctuations of the transport current are characterized by the Lesovik formula for the shot noise, which is a composition of the bond current correlation functions. In the presence of circular currents, the cross-correlation of the bond currents can be very large, but it is negative and compensates for the large positive auto-correlation functions.

Chemoselective Activation of Diethyl Phosphonates: Modular Synthesis of Biologically Relevant Phosphonylated Scaffolds.

Phosphonates have garnered considerable attention for years owing to both their singular biological properties and their synthetic potential. State-of-the-art methods for the preparation of mixed phosphonates, phosphonamidates, phosphonothioates, and phosphinates rely on harsh and poorly selective reaction conditions. We report herein a mild method for the modular preparation of phosphonylated derivatives, several of which exhibit interesting biological activities, that is based on chemoselective activation with triflic anhydride. This procedure enables flexible and even iterative substitution with a broad range of O, S, N, and C nucleophiles.

Evidence of CNIH3 involvement in opioid dependence.

Opioid dependence, a severe addictive disorder and major societal problem, has been demonstrated to be moderately heritable. We conducted a genome-wide association study in Comorbidity and Trauma Study data comparing opioid-dependent daily injectors (N=1167) with opioid misusers who never progressed to daily injection (N=161). The strongest associations, observed for CNIH3 single-nucleotide polymorphisms (SNPs), were confirmed in two independent samples, the Yale-Penn genetic studies of opioid, cocaine and alcohol dependence and the Study of Addiction: Genetics and Environment, which both contain non-dependent opioid misusers and opioid-dependent individuals. Meta-analyses found five genome-wide significant CNIH3 SNPs. The A allele of rs10799590, the most highly associated SNP, was robustly protective (P=4.30E-9; odds ratio 0.64 (95% confidence interval 0.55-0.74)). Epigenetic annotation predicts that this SNP is functional in fetal brain. Neuroimaging data from the Duke Neurogenetics Study (N=312) provide evidence of this SNP's in vivo functionality; rs10799590 A allele carriers displayed significantly greater right amygdala habituation to threat-related facial expressions, a phenotype associated with resilience to psychopathology. Computational genetic analyses of physical dependence on morphine across 23 mouse strains yielded significant correlations for haplotypes in CNIH3 and functionally related genes. These convergent findings support CNIH3 involvement in the pathophysiology of opioid dependence, complementing prior studies implicating the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate system.

Stress-related anhedonia is associated with ventral striatum reactivity to reward and transdiagnostic psychiatric symptomatology.

BACKGROUND: Early life stress (ELS) is consistently associated with increased risk for subsequent psychopathology. Individual differences in neural response to reward may confer vulnerability to stress-related psychopathology. Using data from the ongoing Duke Neurogenetics Study, the present study examined whether reward-related ventral striatum (VS) reactivity moderates the relationship between retrospectively reported ELS and anhedonic symptomatology. We further assessed whether individual differences in reward-related VS reactivity were associated with other depressive symptoms and problematic alcohol use via stress-related anhedonic symptoms and substance use-associated coping. METHOD: Blood oxygen level-dependent functional magnetic resonance imaging (fMRI) was collected while participants (n = 906) completed a card-guessing task, which robustly elicits VS reactivity. ELS, anhedonic symptoms, other depressive symptoms, coping behavior, and alcohol use behavior were assessed with self-report questionnaires. Linear regressions were run to examine whether VS reactivity moderated the relationship between ELS and anhedonic symptoms. Structural equation models examined whether this moderation was indirectly associated with other depression symptoms and problematic alcohol use through its association with anhedonia. RESULTS: Analyses of data from 820 participants passing quality control procedures revealed that the VS × ELS interaction was associated with anhedonic symptoms (p = 0.011). Moreover, structural equation models indirectly linked this interaction to non-anhedonic depression symptoms and problematic alcohol use through anhedonic symptoms and substance-related coping. CONCLUSIONS: These findings suggest that reduced VS reactivity to reward is associated with increased risk for anhedonia in individuals exposed to ELS. Such stress-related anhedonia is further associated with other depressive symptoms and problematic alcohol use through substance-related coping.

Dissociable cortico-striatal connectivity abnormalities in major depression in response to monetary gains and penalties.

BACKGROUND: Individuals with major depressive disorder (MDD) are characterized by maladaptive responses to both positive and negative outcomes, which have been linked to localized abnormal activations in cortical and striatal brain regions. However, the exact neural circuitry implicated in such abnormalities remains largely unexplored. METHOD: In this study 26 unmedicated adults with MDD and 29 matched healthy controls (HCs) completed a monetary incentive delay task during functional magnetic resonance imaging (fMRI). Psychophysiological interaction (PPI) analyses probed group differences in connectivity separately in response to positive and negative outcomes (i.e. monetary gains and penalties). RESULTS: Relative to HCs, MDD subjects displayed decreased connectivity between the caudate and dorsal anterior cingulate cortex (dACC) in response to monetary gains, yet increased connectivity between the caudate and a different, more rostral, dACC subregion in response to monetary penalties. Moreover, exploratory analyses of 14 MDD patients who completed a 12-week, double-blind, placebo-controlled clinical trial after the baseline fMRI scans indicated that a more normative pattern of cortico-striatal connectivity pre-treatment was associated with greater improvement in symptoms 12 weeks later. CONCLUSIONS: These results identify the caudate as a region with dissociable incentive-dependent dACC connectivity abnormalities in MDD, and provide initial evidence that cortico-striatal circuitry may play a role in MDD treatment response. Given the role of cortico-striatal circuitry in encoding action-outcome contingencies, such dysregulated connectivity may relate to the prominent disruptions in goal-directed behavior that characterize MDD.

Functional genetic variants in the vesicular monoamine transporter 1 modulate emotion processing.

Emotional behavior is in part heritable and often disrupted in psychopathology. Identification of specific genetic variants that drive this heritability may provide important new insight into molecular and neurobiological mechanisms involved in emotionality. Our results demonstrate that the presynaptic vesicular monoamine transporter 1 (VMAT1) Thr136Ile (rs1390938) polymorphism is functional in vitro, with the Ile allele leading to increased monoamine transport into presynaptic vesicles. Moreover, we show that the Thr136Ile variant predicts differential responses in emotional brain circuits consistent with its effects in vitro. Lastly, deep sequencing of bipolar disorder (BPD) patients and controls identified several rare novel VMAT1 variants. The variant Phe84Ser was only present in individuals with BPD and leads to marked increase monoamine transport in vitro. Taken together, our data show that VMAT1 polymorphisms influence monoamine signaling, the functional response of emotional brain circuits and risk for psychopathology.

Prevalence and impact on survival of hepatopulmonary syndrome and cirrhotic cardiomyopathy in a cohort of cirrhotic patients.

BACKGROUND & AIMS: Extrahepatic complications of cirrhosis increase the risk for decompensation of the liver disease and death. Previous studies show common pathogenetic mechanisms involved in the development of hepatopulmonary syndrome and cirrhotic cardiomyopathy. We aimed to assess the link between these entities and their effect on disease-related patient morbidity and mortality. METHODS: Seventy-four consecutive cirrhotic patients without prior history of cardiovascular and pulmonary disease were included in a prospective observational study. Routine blood work, arterial blood gas analysis, pulse oximetry measurements, N-terminal pro-brain natriuretic peptide levels and contrast enhanced echocardiography examination with tissue Doppler imaging were performed in all patients. Patients were followed up for a median of 6 months and disease-related adverse events and death were the main outcomes tested. Statistical analysis was conducted according to the presence of hepatopulmonary syndrome or cirrhotic cardiomyopathy. RESULTS: Hepatopulmonary syndrome was diagnosed in 17 patients (23%) and cirrhotic cardiomyopathy in 30 patients (40.5%). There was no association between the presence of cirrhotic cardiomyopathy and the existence of mild or moderate hepatopulmonary syndrome. No echocardiographic parameters were useful in predicting the presence of hepatopulmonary syndrome. N-terminal pro-brain natriuretic peptide levels and length of QT interval did not aid in diagnosis of cirrhotic cardiomyopathy. Neither entity had significant influence on disease-related outcomes in the follow-up period. CONCLUSIONS: Hepatopulmonary syndrome and cirrhotic cardiomyopathy are independent complications arising in cirrhosis and have a limited influence on morbidity and mortality on a pre-liver transplantation population.

A neurogenetics approach to understanding individual differences in brain, behavior, and risk for psychopathology.

Neurogenetics research has begun to advance our understanding of how genetic variation gives rise to individual differences in brain function, which, in turn, shapes behavior and risk for psychopathology. Despite these advancements, neurogenetics research is currently confronted by three major challenges: (1) conducting research on individual variables with small effects, (2) absence of detailed mechanisms, and (3) a need to translate findings toward greater clinical relevance. In this review, we showcase techniques and developments that address these challenges and highlight the benefits of a neurogenetics approach to understanding brain, behavior and psychopathology. To address the challenge of small effects, we explore approaches including incorporating the environment, modeling epistatic relationships and using multilocus profiles. To address the challenge of mechanism, we explore how non-human animal research, epigenetics research and genome-wide association studies can inform our mechanistic understanding of behaviorally relevant brain function. Finally, to address the challenge of clinical relevance, we examine how neurogenetics research can identify novel therapeutic targets and for whom treatments work best. By addressing these challenges, neurogenetics research is poised to exponentially increase our understanding of how genetic variation interacts with the environment to shape the brain, behavior and risk for psychopathology.

Indirect bandgap MoSe2 resonators for light-emitting nanophotonics.

Transition metal dichalcogenides (TMDs) are promising for new generation nanophotonics due to their unique optical properties. However, in contrast to direct bandgap TMD monolayers, bulk samples have an indirect bandgap that restricts their application as light emitters. On the other hand, the high refractive index of these materials allows for effective light trapping and the creation of high-Q resonators. In this work, a method for the nanofabrication of microcavities from indirect TMD multilayer flakes, which makes it possible to achieve pronounced resonant photoluminescence enhancement due to the cavity modes, is proposed. Whispering gallery mode (WGM) resonators are fabricated from bulk indirect MoSe2 using resistless scanning probe lithography. A micro-photoluminescence (µ-PL) investigation revealed the WGM spectra of the resonators with an enhancement factor up to 100. The characteristic features of WGMs are clearly seen from the scattering experiments which are in agreement with the results of numerical simulations. It is shown that the PL spectra in the fabricated microcavities are contributed by two mechanisms demonstrating different temperature dependences. The indirect PL, which is quenched with the temperature decrease, and the direct PL which almost does not depend on the temperature. The results of the work show that the suggested approach has great prospects in nanophotonics.

Photon Drag Currents and Terahertz Generation in α-Sn/Ge Quantum Wells.

We have fabricated α-Sn/Ge quantum well heterostructures by sandwiching nano-films of α-Sn between Ge nanolayers. The samples were grown via e-beam deposition and characterized by Raman spectroscopy, atomic force microscopy, temperature dependence of electrical resistivity and THz time-resolved spectroscopy. We have established the presence of α-Sn phase in the polycrystalline layers together with a high electron mobility µ = 2500 ± 100 cm2 V-1 s-1. Here, the temperature behavior of the resistivity in a magnetic field is distinct from the semiconducting films and three-dimensional Dirac semimetals, which is consistent with the presence of linear two-dimensional electronic dispersion arising from the mutually inverted band structure at the α-Sn/Ge interface. As a result, the α-Sn/Ge interfaces of the quantum wells have topologically non-trivial electronic states. From THz time-resolved spectroscopy, we have discovered unusual photocurrent and THz radiation generation. The mechanisms for this process are significantly different from ambipolar diffusion currents that are responsible for THz generation in semiconducting thin films, e.g., Ge. Moreover, the THz generation in α-Sn/Ge quantum wells is almost an order of magnitude greater than that found in Ge. The substantial strength of the THz radiation emission and its polarization dependence may be explained by the photon drag current. The large amplitude of this current is a clear signature of the formation of conducting channels with high electron mobility, which are topologically protected.

Stable and easily available sulfide surrogates allow a stereoselective activation of alcohols.

Isothiouronium salts are easily accessible and stable compounds. Herein, we report their use as versatile deoxasulfenylating agents enabling a stereoselective, thiol-free protocol for synthesis of thioethers from alcohols. The method is simple, scalable and tolerates a broad range of functional groups otherwise incompatible with other methods. Late-stage modification of several pharmaceuticals provides access to multiple analogues of biologically relevant molecules. Performed experiments give insight into the reaction mechanism.

MoS2 flake as a van der Waals homostructure: luminescence properties and optical anisotropy.

We investigated multilayer plates prepared by exfoliation from a high-quality MoS2 crystal and revealed that they represent a new object - a van der Waals homostructure consisting of a bulk core and a few detached monolayers on its surface. This architecture comprising elements with different electron band structures leads to specific luminescence, when the broad emission band from the core is cut by the absorption peaks of strong exciton resonances in the surface monolayers. The exfoliated flakes exhibit strong optical anisotropy. We have observed linear to circular polarization conversion that reaches 15% for normally incident light in transmission geometry. This background effect is due to the fluctuations of the c axis relative to the normal, whereas the pronounced resonance contribution is explained by the polarization anisotropy of the excitons localized in the stripes of the dissected surface monolayers.

Accuracy of Three-Dimensional (3D) Printed Dental Digital Models Generated with Three Types of Resin Polymers by Extra-Oral Optical Scanning.

Digital impression devices are used alternatively to conventional impression techniques and materials. The aim of this study was to evaluate the precision of extraoral digitalization of three types of photosensitive resin polymers used for 3D printing with the aid of a digital extraoral optical scanner. The alignment of the scans was performed by a standard best-fit alignment. Trueness and precision were used to evaluate the models. The trueness was evaluated by using bias as a measure and the standard deviation was used to evaluate the precision. After assessing the normality of the distributions, an independent Kruskal-Wallis test was used to compare the trueness and precision across the material groups. The Mann-Whitney test was used as a post-hoc test for significant differences. The result of the analysis showed significant differences (U = 66, z = -2.337, p = 0.019) in trueness of mesiodistal distances. Upon visual inspection of the models, defects were noticed on two out of nine of the models printed with a photosensitive polymer. The defects were presented as cavities caused by air bubbles and were also reflected in the scans. Mean precision did not vary too much between these three photosensitive polymer resins, therefore, the selection of 3D printing materials should be based on the trueness and the required precision of the clinical purpose of the model.