Selective Inversion Research Articles

Mapping Electrophile Chemoselectivity in DalPhos/Nickel N-Arylation Catalysis: The Unusual Influence of Remote Sterics.

We disclose herein our evaluation of competitive (hetero)aryl-X (X: Br>Cl>OTf) reactivity preferences in bisphosphine/Ni-catalyzed C-N cross-coupling catalysis, using furfurylamine as a prototypical nucleophile, and employing DalPhos and DPPF as representative ancillary ligands with established efficacy. Beyond this general (pseudo)halide ranking, other intriguing structure-reactivity trends were noted experimentally, including the unexpected observation that bulky alkyl (e. g., R=tBu) substitution in para-R-aryl-X electrophiles strongly discourages (pseudo)halide reactivity relative to smaller substituents (e. g., nBu, Et, Me), despite being both remote from, and having a similar electronic influence on, the reacting C-X bond; such effects on nickel oxidative addition have not been documented previously and were not observed in our comparator reactions presented herein involving palladium. Density functional theory modeling of such PhPAd-DalPhos/Ni-catalyzed C-N cross-couplings revealed the origins of competitive turnover of C-Br over C-Cl, and possible ways in which bulky para-alkyl substitution might discourage net electrophile uptake/turnover, leading to inversion of halide selectivity.

Watershed regions are more susceptible to tissue microstructural injury in multiple sclerosis.

Histopathologic studies report higher concentrations of multiple sclerosis white matter lesions in watershed areas of the brain, suggesting that areas with relatively lower oxygen levels may be more vulnerable to disease. However, it is unknown at what point in the disease course lesion predilection for watershed territories begins. Accordingly, we studied a cohort of people with newly diagnosed disease and asked whether (1) white matter lesions disproportionally localize to watershed-regions and (2) the degree of microstructural injury in watershed-lesions is more severe. Fifty-four participants, i.e. 38 newly diagnosed people with multiple sclerosis, clinically isolated syndrome or radiologically isolated syndrome, and 16 age- and sex-matched healthy controls underwent brain magnetic resonance imaging. T1-weighted and T2-weighted fluid-attenuated inversion recovery sequences, selective inversion recovery quantitative magnetisation transfer images, and the multi-compartment diffusion imaging with the spherical mean technique were acquired. We computed the macromolecular-to-free pool size ratio, and the apparent axonal volume fraction maps to indirectly estimate myelin and axonal integrity, respectively. We produced a flow territory atlas in each subject's native T2-weighted fluid-attenuated inversion recovery images using a T1-weighted magnetic resonance imaging template in the Montreal Neurological Institute 152 space. Lesion location relative to the watershed, non-watershed and mixed brain vascular territories was annotated. The same process was performed on the T2-weighted fluid-attenuated inversion recovery images of the healthy controls using 294 regions of interest. Generalized linear mixed models for continuous outcomes were used to assess differences in size, pool size ratio and axonal volume fraction between lesions/regions of interests (in healthy controls) situated in different vascular territories. In patients, we assessed 758 T2-lesions and 356 chronic black holes (cBHs). The watershed-territories had higher relative and absolute concentrations of T2-lesions (P≤0.041) and cBHs (P≤0.036) compared to either non-watershed- or mixed-zones. T2-lesions in watershed-areas also had lower pool size ratio relative to T2-lesions in either non-watershed- or mixed-zones (P = 0.039). These results retained significance in the sub-cohort of people without vascular comorbidities and when accounting for periventricular lesions. In healthy controls, axonal volume fraction was higher only in mixed-areas regions of interest compared to non-watershed-ones (P = 0.008). No differences in pool size ratio were seen. We provide in vivo evidence that there is an association between arterial vascularisation of the brain and multiple sclerosis-induced tissue injury as early as the time of disease diagnosis. Our findings underline the importance of oxygen delivery and healthy arterial vascularisation to prevent lesion formation and foster a better outcome in multiple sclerosis.

Pitfalls in measurements of R1 relaxation rates of protein backbone 15N nuclei.

The dynamics of the backbone and side-chains of protein are routinely studied by interpreting experimentally determined 15N spin relaxation rates. R1(15N), the longitudinal relaxation rate, reports on fast motions and encodes, together with the transverse relaxation R2, structural information about the shape of the molecule and the orientation of the amide bond vectors in the internal diffusion frame. Determining error-free 15N longitudinal relaxation rates remains a challenge for small, disordered, and medium-sized proteins. Here, we show that mono-exponential fitting is sufficient, with no statistical preference for bi-exponential fitting up to 800MHz. A detailed comparison of the TROSY and HSQC techniques at medium and high fields showed no statistically significant differences. The least error-prone DD/CSA interference removal technique is the selective inversion of amide signals while avoiding water resonance. The exchange of amide with solvent deuterons appears to affect the rate R1 of solvent-exposed amides in all fields tested and in each DD/CSA interference removal technique in a statistically significant manner. In summary, the most accurate R1(15N) rates in proteins are achieved by selective amide inversion, without the addition of D2O. Importantly, at high magnetic fields stronger than 800MHz, when non-mono-exponential decay is involved, it is advisable to consider elimination of the shortest delays (typically up to 0.32s) or bi-exponential fitting.

Characteristic reflection wavefield-based wave equation traveltime inversion

Introducing a high-precision deep-depth velocity model is essential for accurately imaging seismic data in complex areas such as deepwater and deep depth in oil and gas exploration. Conventional methods, such as reflection full-waveform inversion (RFWI), face challenges, notably the cycle-skipping issue, especially when the initial velocity model is far away from the true model. To address this, we develop a novel wave equation traveltime inversion (WETI) using the characteristic reflection wavefield (CRW) to update the low-wavenumber components of the velocity model. The CRWs are primary reflections in seismic data that contribute significantly to velocity model updates. We implement a multistep approach, including migration, characteristic reflector structure (CRS) picking, and demigration to extract the CRW. This extraction, constrained by CRS, ensures accurate matching between the observed and the simulated CRWs, even with an inaccurate initial velocity model, thus enabling an accurate traveltime shift estimation during inversion. Unlike conventional methods that use all reflection data simultaneously, CRW-WETI strategically selects fewer CRWs, enhancing inversion convexity and avoiding local minima from the cycle-skipping problem. This selective inversion begins with a limited number of CRWs to ensure stability and progressively incorporates more as the WETI process advances, eventually transitioning into conventional RFWI. Moreover, with the CRS constraint, CRW can be selected based on the target region. The target-oriented velocity inversion can also be implemented easily to update a local anomalous velocity model. Numerical examples of synthetic and field data demonstrate the effectiveness and validity of our method.

Evaluating cerebrovascular reactivity measured by velocity selective inversion arterial spin labeling with different post-labeling delays: The effect of fast flow.

Velocity selective arterial spin labeling (VSASL) quantification assumes that the labeled bolus continuously moves into the imaging voxel during the post-labeling delay (PLD). Faster blood flow could lead to a bolus duration shorter than the applied PLD of VSASL and cause underestimation of cerebral blood flow (CBF). This study aims to evaluate the performance of velocity-selective inversion (VSI) prepared arterial spin labeling (ASL) with different PLDs and pseudo-continuous ASL (PCASL) for quantification of hypercapnia-induced cerebrovascular reactivity (CVR), using phase-contrast (PC) MRI as a global reference. We compared CVR obtained by VSI-ASL with PLD of 1520 ms (VSASL-1520), 1000 ms (VSASL-1000), and 500 ms (VSASL-500), PCASL with PLD of 1800 ms (PCASL-1800), and PC MRI on eight healthy volunteers at two sessions. Compared with PC MRI, VSASL-1520 produced significantly lower global CVR values, while PCASL-1800, VSASL-1000, and VSASL-500 yielded more consistent results. The reduced CVR in VSASL-1520 was more pronounced in carotid territories including frontal and temporal lobes than in vertebral territories such as the occipital lobe. This is largely caused by the underestimated perfusion during hypercapnia due to the reduced bolus duration being less than the PLD. Although VSASL offers certain advantages over spatially selective ASL due to its reduced susceptibility to delayed ATT, this technique is prone to biases when the ATT is excessively short. Therefore, a short PLD should be employed for reliable perfusion and CVR quantification in populations or conditions with fast flow.

Nelotanserin, a selective 5-HT2A receptor inverse agonist, attenuates aspects of nicotine withdrawal but not reward in mice

Nicotine smoking contributes to many preventable disabilities, diseases and deaths. Targeting nicotine reward and withdrawal is a basis for the majority of smoking cessation pharmacotherapies. Due to the emergence of interest in 5-HT2A receptor modulators for numerous psychiatric disorders, we investigated the effect of nelotanserin, a 5-HT2A receptor inverse agonist, on nicotine reward and withdrawal in ICR mice. In nicotine-dependent mice, nelotanserin dose-dependently reduced somatic signs of nicotine withdrawal and thermal hyperalgesia as measured in the hot plate test. However, nelotanserin had no effect on anxiety-like behavior and failed to reduce nicotine reward as measured in the conditioned place preference test. Our results suggest that inverse agonism of the 5-HT2A receptor may be a feasible novel mechanism for smoking cessation by reducing both physical withdrawal and thermal hyperalgesia associated with nicotine abstinence but may require complementary pharmacotherapies targeting affective and reward-associated decrements to improve cessation outcomes.

A mathematical model for velocity-selective arterial spin labeling.

To present a theoretical framework that rigorously defines and analyzes key concepts and quantities for velocity selective arterial spin labeling (VSASL). An expression for the VSASL arterial delivery function is derived based on (1) labeling and saturation profiles as a function of velocity and (2) physiologically plausible approximations of changes in acceleration and velocity across the vascular system. The dependence of labeling efficiency on the amplitude and effective bolus width of the arterial delivery function is defined. Factors that affect the effective bolus width are examined, and timing requirements to minimize quantitation errors are derived. The model predicts that a flow-dependent negative bias in the effective bolus width can occur when velocity selective inversion (VSI) is used for the labeling module and velocity selective saturation (VSS) is used for the vascular crushing module. The bias can be minimized by choosing a nominal labeling cutoff velocity that is lower than the nominal cutoff velocity of the vascular crushing module. The elements of the model are specified in a general fashion such that future advances can be readily integrated. The model can facilitate further efforts to understand and characterize the performance of VSASL and provide critical theoretical insights that can be used to design future experiments and develop novel VSASL approaches.

Stereoselective Shi-type epoxidation with 3-oxo-4,6-O-benzylidene pyranoside catalysts: unveiling the role of carbohydrate skeletons.

Asymmetric epoxidation represents a hot topic in organic synthesis. In recent years, organocatalysts based on sugar skeletons have been exploited in asymmetric epoxidation to achieve enantiomeric pure epoxides. In this work, two different endocyclic ketones derived from glucose and galactose protected with a 4,6-O-benzylidene group have been prepared and exploited for Shi-type epoxidation. The two carbohydrates show an opposite preferential stereoselective epoxidation on various olefins, affording the epoxides in high conversions and modest enantioselectivities. DFT calculations disclosed the reasons behind the inversion of selectivity achieved by the two catalysts, showing that a delicate balance between the catalyst conformation, its protecting groups, and the secondary interactions with the substrate govern the final observed results.

Converging evidence that left extrastriate body area supports visual sensitivity to social interactions

Navigating our complex social world requires processing the interactions we observe. Recent psychophysical and neuroimaging studies provide parallel evidence that the human visual system may be attuned to efficiently perceive dyadic interactions. This work implies, but has not yet demonstrated, that activity in body-selective cortical regions causally supports efficient visual perception of interactions. We adopt a multi-method approach to close this important gap. First, using a large fMRI dataset (n= 92), we found that the left hemisphere extrastriate body area (EBA) responds more to face-to-face than non-facing dyads. Second, we replicated a behavioral marker of visual sensitivity to interactions: categorization of facing dyads is more impaired by inversion than non-facing dyads. Third, in a pre-registered experiment, we used fMRI-guided transcranial magnetic stimulation to show that online stimulation of the left EBA, but not a nearby control region, abolishes this selective inversion effect. Activity in left EBA, thus, causally supports the efficient perception of social interactions.

Sequential rearrangement and stereochemical reorganization to design an antimicrobial peptide with enhanced stability

Antimicrobial peptides (AMPs) are natural molecules that function within the innate immune system to counteract pathogenic invasion and minimize the detrimental consequences of infection. However, utilizing these molecules for medical applications has been challenging. In this study, we selected a model AMP with poor stability, Tilapia Piscidin 4 (TP4), and modified its sequence and chirality (TP4-γ) to improve its potential for clinical application. The strategy of chirality inversion was inspired by the cereulide peptide, which has a DDLL enantiomer pattern and exhibits exceptional stability. Sequential substitution of key residues and selective chirality inversion yielded a less toxic peptide with enhanced stability and notable antimicrobial activity. In addition to its superior stability profile and antimicrobial activity, TP4-γ treatment reduced the level of LPS-induced nitric oxide (NO) release in a macrophage cell line. This reduction in NO release may reflect anti-inflammatory properties, as NO is widely known to promote inflammatory processes. Hence, our heterochiral peptide construct shows a more suitable pharmacokinetic profile than its parental compound, and further studies are warranted to develop the molecule for potential clinical application.

Steering CO2 Electroreduction Selectivity U-Turn to Ethylene by Cu-Si Bonded Interface.

Copper (Cu), with the advantage of producing a deep reduction product, is a unique catalyst for the electrochemical reduction of CO2 (CO2RR). Designing a Cu-based catalyst to trigger CO2RR to a multicarbon product and understanding the accurate structure-activity relationship for elucidating reaction mechanisms still remain a challenge. Herein, we demonstrate a rational design of a core-shell structured silica-copper catalyst (p-Cu@m-SiO2) through Cu-Si direct bonding for efficient and selective CO2RR. The Cu-Si interface fulfills the inversion in CO2RR product selectivity. The product ratio of C2H4/CH4 changes from 0.6 to 14.4 after silica modification, and the current density reaches a high of up to 450 mA cm-2. The kinetic isotopic effect, in situ attenuated total reflection Fourier-transform infrared spectra, and density functional theory were applied to elucidate the reaction mechanism. The SiO2 shell stabilizes the *H intermediate by forming Si-O-H and inhibits the hydrogen evolution reaction effectively. Moreover, the direct-bonded Cu-Si interface makes bare Cu sites with larger charge density. Such bare Cu sites and Si-O-H sites stabilized the *CHO and activated the *CO, promoting the coupling of *CHO and *CO intermediates to form C2H4. This work provides a promising strategy for designing Cu-based catalysts with high C2H4 catalytic activity.

Selective inversion of rift basins in lithospheric-scale analogue experiments

Abstract. Basin inversion is commonly attributed to the reverse reactivation of basin-bounding normal faults. This association implies that basin uplift and inversion-related structures are mainly controlled by the frictional behaviour of pre-existing faults and associated damage zones. In this study, we use lithospheric-scale analogue experiments of orthogonal extension followed by shortening to explore how the flow behaviour of ductile layers underneath rift basins promote or suppress basin inversion. Our experiments show that the rheology of the ductile lower crust and lithospheric mantle, modulated by the imposed bulk strain rate, determine (1) basin distribution in a wide rift setting and (2) strain accommodation by fault reactivation and basin uplift during subsequent shortening. When the ductile layers deform uniformly during extension (i.e. stretching) and shortening (i.e. thickening), all of the basins are inverted. When deformation in the ductile layers is localised during extension (i.e. necking) and shortening (i.e. folding), only some basins – which are evenly spaced apart – are inverted. We interpret the latter as selective basin inversion, which may be related to the superposition of crustal-scale and lithospheric-scale boudinage during the previous basin-forming extensional phase and/or folding of the ductile layers during shortening.

Load-independent multi-objective sensor placement method for localization and reconstruction of external excitations under interval uncertainties

The direct measurement of external excitations under operation conditions remains challenging in many engineering applications. This study proposes a method of optimal sensor placement for the best localization and reconstruction of external excitations when considering multi-source uncertainties. The excitation inversion is achieved in the framework of minimizing the discrepancy between the forward and inversed modal loads. To accurately obtain the modal force in the time-domain excitation reconstruction algorithm, three combined indicators of the interested modal matrix are defined, which integrate measures of effectiveness, stability, orthogonality, and robustness of inverse modal transformation. The optimal sensor placement is determined by multi-objective particle swarm optimization and Pareto optimal solution. In addition, to alleviate the computational burden of loading localization, a surrogate model based on an interval kriging interpolation model and sequential sampling strategies is established for the forward modal forces. And a time-dependent interval error of modal forces inspired by the theory of second-order narrow bounds in system reliability is developed to guide the inversion process. Notably, the developed sensor selection and excitation inversion methods are independent of the type, location, and time evolution of external excitations. Eventually, two numerical examples and an experimental case are discussed to demonstrate the validity and feasibility of the developed approach.

Microbial Transformation of Pimavanserin by Cunninghamella blakesleeana AS 3.970

Pimavanserin is an approved selective 5-HT2A receptor inverse agonist for treating Parkinson’s disease psychosis. However, few studies on its metabolism in vitro have been investigated. In this research, eight strains of fungi are used to study the pimavanserin metabolism profiles in vitro and six of them demonstrated positive transformation results. Factors influencing the transformation rate, like substrate concentration, culture time, initial media pH value, culture temperature, and shaking speed, were evaluated and optimized. Cunninghamella blakesleeana AS3.970 provided the best transformation rate of 30.31%, and 10 unreported metabolites were screened by LC-MS/MS. Among these metabolites, M1 is the major one and identified as 1-(4-fluorobenzyl)-3-(4-(2-hydroxy-2-methylpropoxy)benzyl)-1-(1-methylpiperidin-4-yl)urea, which is a hydroxylation product of the pimavanserin. A preliminary molecular docking simulation was performed, which indicated that M1 exhibits similar binding properties with pimavanserin and may become a potential candidate for Parkinson’s disease treatment.

Kinetic and Product Study of the S‐oxidation vs HAT Chemoselectivity in Reactions Promoted by Nonheme Iron(IV)‐oxo Complex/NHPI Mediator System

AbstractThe chemoselectivity between S‐oxidation and hydrogen atom transfer (HAT) from C−H bonds has been investigated in the oxidations of a series of aryl sulfides, alkyl aromatic compounds and benzylic alcohols promoted by the iron(IV)‐oxo complex [(N4Py)FeIV(O)]2+ (N4Py: N,N‐bis(2‐pyridylmethyl)‐N‐bis(2‐pyridyl)‐methylamine) either alone or in the presence of the N‐hydroxyphthalimide (NHPI) mediator via kinetic and product studies. Kinetic analyses indicate a generally higher reactivity of [(N4Py)FeIV(O)]2+ for S‐oxidation process while HAT is favored in the reactions promoted by phthalimide‐N‐oxyl radical (PINO) deriving from NHPI oxidation. Product analysis in intermolecular competitive oxidations confirms the kinetic results with sulfoxides obtained as major products in the oxidation promoted by [(N4Py)FeIV(O)]2+. Conversely, when NHPI is employed as a mediator, significant differences in terms of chemoselectivity are observed, and HAT‐derived products are obtained in higher yields which translate into an inversion of selectivity in the case of the substrates containing activated C−H bonds like diphenylmethane, triphenylmethane and benzylic alcohols. A similar change of chemoselectivity is also observed in the oxidation of aromatic substrates containing both a sulfur atom and α to OH benzylic C−H bonds, with the sulfoxide product more abundant in the absence of NHPI and carbonyl products prevailing with the [(N4Py)FeIV(O)]2+/NHPI system.

Impact of mechanical stratigraphy on deformation style and distribution of seismicity in the central External Dinarides: a 2D forward kinematic modelling study

The External Dinarides fold-thrust belt formed during Mid-Eocene–Oligocene times by SW-propagating thrusting from the Internal Dinarides towards the Adriatic foreland. Although previously considered as structurally quite uniform, recent work reported along-strike contrasting deformation styles in two structural domains within this fold-thrust belt. The two areas with very contrasting deformation styles are separated by the N–S-striking dextral Split-Karlovac Fault, a 250 km long, transpressive transfer fault. The southeastern domain is characterized by a thin-skinned SW-vergent nappe stack in contrast to the northwestern domain, where a set of blind, thick-skinned top-SW thrust duplexes prevail underneath the passive NE-vergent backthrusts. To better understand why the External Dinarides underwent such contrasting along-strike deformation, we reconsidered a temporal and spatial along- and across-strike distribution of Paleo-Mesozoic lithofacies to both sides of the Split-Karlovac Fault and estimated the role of mechanical stratigraphy on deformation styles in this part of the fold-thrust belt. Therefore, we constructed a new 2D kinematic forward model in the western backthrust-dominated domain. Our best-fit forward-modelled balanced cross section across the central Velebit Mtn. portrays a 75 km wide triangle zone. This zone took up at least 47 km of shortening during Eo-Oligocene times. It comprises a set of thin-skinned NE-vergent backthrusts detached in the upper Paleozoic atop a SW-vergent thick-skinned antiformal stack detached in the lower Paleozoic Adriatic basement. The NE-vergent backthrusts likely nucleated at lateral facies boundaries related to extensional half grabens that locally formed during Middle Triassic and Late Jurassic passive margin extension. During the Eo-Oligocene folding and thrusting, the selective inversion of inherited Mesozoic half grabens boundary faults into the NE-vergent backthrusts in the northwestern domain led to the observed along-strike changes in the deformation style of the External Dinarides. A seismotectonic analysis of instrumentally recorded earthquakes suggests contrasting seismic behaviour along the central and southern Velebit transects within the northwestern structural domain. The central Velebit Mtn. triangle structure appears to currently accommodate dominantly strike-slip motion, with reverse faulting being confined to east of the Split-Karlovac Fault. In contrast, seismicity along the southern Velebit cross section appears to be confined to the structurally lowermost parts of the triangle zone and the foreland, while it´s structurally higher parts are less seismically active. Also, a predominance of reverse faulting along this transect suggests ongoing accommodation of shortening in this part. Our results indicate that both the variations in the mechanical stratigraphy and the pre-orogenic structural inheritance obtained during rifting and passive margin stages exert control on contractional structures within the External Dinarides, including the distribution of present-day seismicity.

New framework for land surface temperature and emissivity inversion based on hyperspectral thermal infrared data

ABSTRACT Hyperspectral thermal infrared (HTIR) data offers enormous potential for land surface temperature (LST) and emissivity (LSE) inversion. Methods to fully use a large amount of spectral information, while avoiding data redundancy, is constantly being explored. Therefore, a new framework for LST and LSE inversion using HTIR data is proposed in this study. First, the stepwise iteration method based on information content was used to select channels that were more sensitive to land surface information. Principal component analysis (PCA) and a two-step machine learning method were then used to retrieve the LST and LSE based on the selected channels. The findings demonstrate that the LST and spectra of the LSE can be obtained simultaneously based on the proposed framework. An LST inversion accuracy of 1.5K and an emissivity inversion accuracy of 0.017 can be achieved. However, an increase in the number of channels does not result in superior outcomes. Satisfactory inversion results can be obtained by selecting only 10–35 channels with the highest information content. In conclusion, this framework can be used to guide channel selection and land surface parameters inversion for HTIR sensors.

Safety and efficacy of pitolisant in children aged 6 years or older with narcolepsy with or without cataplexy: a double-blind, randomised, placebo-controlled trial

Narcolepsy is a life-long disorder characterised by excessive daytime sleepiness and cataplexy, often arising in childhood or adolescence. Pitolisant, a selective histamine H3 receptor inverse agonist, has been approved in Europe and USA for adults with narcolepsy with or without cataplexy, with a favourable safety profile. This phase 3 study aimed to assess the safety and efficacy of pitolisant in children with narcolepsy with or without cataplexy. For this double-blind, randomised, placebo-controlled, multisite study, we recruited patients aged 6-17 years with narcolepsy with or without cataplexy in 11 sleep centres in five countries (Italy, France, Netherlands, Russia, and Finland). Participants were required to have a Pediatric Daytime Sleepiness Scale score of 15 or greater and to have not received psychostimulants for at least 14 days before enrolment; participants who needed anticataplectics (including sodium oxybate) were required to have been on a stable dose for at least 1 month. Participants were randomly assigned to treatment with pitolisant or placebo in a 2:1 ratio at the end of screening. Randomisation was stratified by study centre and treatment was allocated using an interactive web response system. After a 4-week screening period including a 2-week baseline period, patients entered in a 4-week individual up-titration scheme from 5 mg a day to a maximum of 40 mg a day of pitolisant or placebo; treatment was administered at a stable dose for 4 weeks, followed by a 1-week placebo period. For the primary analysis, we assessed pitolisant versus placebo using change in the Ullanlinna Narcolepsy Scale (UNS) total score from baseline to the end of double-blind period in the full analysis set, defined as all randomly allocated patients who received at least one dose of treatment and who had at least one baseline UNS value. A decrease in the UNS total score reflects a reduction in both excessive daytime sleepiness and cataplexy. All adverse events were assessed in the safety population, defined as all participants who took at least one dose of study medication. An open-label follow-up is ongoing. This study is registered at ClinicalTrials.gov, NCT02611687. Between June 6, 2016, and April 3, 2021, we screened 115 participants and 110 were randomly assigned (mean age 12·9 [SD 3·0] years, 61 [55%] male, and 90 [82%] with cataplexy; 72 assigned to pitolisant and 38 to placebo); 107 (70 receiving pitolisant and 37 receiving placebo) completed the double-blind period. The mean adjusted difference in UNS total score from baseline to the end of the double-blind period was -6·3 (SE 1·1) in the pitolisant group and -2·6 (1·4) in the placebo group (least squares mean difference -3·7; 95% CI -6·4 to -1·0, p=0·007). Treatment-emergent adverse events were reported in 22 (31%) of 72 patients in the pitolisant group and 13 (34%) of 38 patients in the placebo group. The most frequently reported adverse events (affecting ≥5% of patients) in either group were headache (14 [19%] in the pitolisant group and three [8%] in the placebo group) and insomnia (five [7%] in the pitolisant group and one [3%] in the placebo group). Pitolisant treatment resulted in an improvement in narcolepsy symptoms in children, although the UNS was not validated for use in children with narcolepsy when our study began. The safety profile was similar to that reported in adults but further studies are needed to confirm long-term safety. Bioprojet.

Quantification of cross-relaxation in downfield 1 H MRS at7T in human calf muscle.

The purpose of this study was to characterize the 1 H downfield MR spectrum from 8.0 to 10.0ppm of human skeletal muscle at 7T and determine the T1 and cross-relaxation rates of observed resonances. We performed downfield MRS in the calf muscle of 7 healthy volunteers. Single-voxel downfield MRS was collected using alternately selective or broadband inversion-recovery sequences and spectrally selective 90° E-BURP RF pulse excitation centered at 9.0ppm with bandwidth = 600 Hz (2.0ppm). MRS was collected using TIs of 50-2500 ms. We modeled recovery of the longitudinal magnetization of three observable resonances using two models: (1) a three-parameter model accounting for the apparent T1 recovery and (2) a Solomon model explicitly including cross-relaxation effects. Three resonances were observed in human calf muscle at 7T at 8.0, 8.2, and 8.5ppm. We found broadband (broad) and selective (sel) inversion recovery T1 = mean ± SD (ms): T1-broad,8.0ppm = 2108.2 ± 664.5, T1-sel,8.0ppm = 753.6 ± 141.0 (p = 0.003); T1-broad,8.2ppm = 2033.5 ± 338.4, T1-sel,8.2ppm = 135.3 ± 35.3 (p < 0.0001); and T1-broad,8.5ppm = 1395.4 ± 75.4, T1-sel,8.5ppm = 107.1 ± 40.0 (p < 0.0001). Using the Solomon model, we found T1 = mean ± SD (ms): T1-8.0ppm = 1595.6 ± 491.1, T1-8.2ppm = 1737.2 ± 963.7, and T1-8.5ppm = 849.8 ± 282.0 (p =0.04). Post hoc tests corrected for multiple comparisons showed no significant difference in T1 between peaks. The cross-relaxation rate σAB = mean ± SD (Hz) of each peak was σAB,8.0ppm = 0.76 ± 0.20, σAB,8.2ppm = 5.31 ± 2.27, and σAB,8.5ppm = 7.90 ± 2.74 (p < 0.0001); post hoc t-tests revealed the cross-relaxation rate of the 8.0ppm peak was significantly slower than the peaks at 8.2 ppm (p =0.0018) and 8.5ppm (p =0.0005). We found significant differences in effective T1 and cross-relaxation rates of 1 H resonances between 8.0 and 8.5ppm in the healthy human calf muscle at 7T.

Post-polymerisation diversification of conjugated polymers by an inverse electron demand Diels–Alder reaction

Post-polymerization diversification to tune the optical properties of conjugated polymers was achieved via an effective tetrazine–alkyne inverse electron demand Diels–Alder reaction.