Nucleophilic substitution by amide nitrogen in the aromatic rings of [zn − H]˙+ ions; the structures of the [b2 − H − 17]˙+ and [c1 − 17]+ ions

Peptide radical cations that contain an aromatic amino acid residue cleave to give [zn − H]˙+ ions with [b2 − H − 17]˙+ and [c1 − 17]+ ions, the dominant products in the dissociation of [zn − H]˙+, also present in lower abundance in the CID spectra. Isotopic labeling in the aromatic ring of [Yπ˙GG]+ establishes that in the formation of [b2 − H − 17]˙+ ions a hydrogen from the δ-position of the Y residue is lost, indicating that nucleophilic substitution on the aromatic ring has occurred. A preliminary DFT investigation of nine plausible structures for the [c1 − 17]+ ion derived from [Yπ˙GG]+ shows that two structures resulting from attack on the aromatic ring by oxygen and nitrogen atoms from the peptide backbone have significantly better energies than other isomers. A detailed study of [Yπ˙GG]+ using two density functionals, B3LYP and M06-2X, with a 6-31++G(d,p) basis set gives a higher barrier for attack on the aromatic ring of the [zn − H]˙+ ion by nitrogen than by the carbonyl oxygen. However, subsequent rearrangements involving proton transfers are much higher in energy for the oxygen-substituted isomer leading to the conclusion that the [c1 − 17]+ ions are the products of nucleophilic attack by nitrogen, protonated 2,7-dihydroxyquinoline ions. The [b2 − H − 17]˙+ ions are formed by loss of glycine from the same intermediates involved in the formation of the [c1 − 17]+ ions.postprin

A preclinical study on the combination therapy of everolimus and transarterial chemoembolization in hepatocellular carcinoma

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Jointly Active and Passive Beamforming Designs for IRS-Empowered WPCN

This paper studies an intelligent reflecting surface (IRS)-empowered wireless powered communication network (WPCN) in Internet of Things (IoT) networks. In particular, a power station (PS) with multiple antennas uses energy beamforming to enable wireless charging to multiple IoT devices, in the downlink wireless energy transfer (WET) phase; then, during the uplink wireless information transfer (WIT) phase, these IoT devices utilise the harvested energy to concurrently transmit their individual information signal to a multi-antenna access point (AP), which equips with multi-user decomposition (MUD) techniques to reconstruct the IoT devices’ signal. An IRS is deployed to improve the energy collection and information transmission capabilities in the WET and WIT phases, respectively. To examine the performance of the system under study, We maximize the sum throughput with the aim of jointly designing the optimal solutions for the active PS energy beamforming, AP receive beamforming, passive IRS beamforming, and time scheduling. Due to the multiple coupled variables, the resulting formulation is non-convex, and a two-level scheme to solve the problem is proposed. At the outer level, a one-dimensional (1-D) search method is applied to find the optimal time scheduling, while at the inner level, an iterative block coordinate descent (BCD) algorithm is proposed to design the optimal receive beamforming, energy beamforming, and IRS phase shifts. In particular, the receive beamforming part is designed by considering the equivalence between sum rate maximisation and sum mean square error (MSE) minimisation, thereby deriving a closed-form solution. Furthermore, we alternately optimize the energy beamforming and IRS phase shifts using Lagrange dual transformation (LDT), quadratic transformation (QT), and alternating direction method of multipliers (ADMM) methods. Finally, numerical results are presented to showcase the performance of the proposed solution and highlight its advant..

Formation, isomerization and dissociation of ε- and α-carbon-centered tyrosylglycylglycine radical cations

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Laser cooling of a diatomic molecule

It has been roughly three decades since laser cooling techniques produced ultracold atoms, leading to rapid advances in a vast array of fields. Unfortunately laser cooling has not yet been extended to molecules because of their complex internal structure. However, this complexity makes molecules potentially useful for many applications. For example, heteronuclear molecules possess permanent electric dipole moments which lead to long-range, tunable, anisotropic dipole-dipole interactions. The combination of the dipole-dipole interaction and the precise control over molecular degrees of freedom possible at ultracold temperatures make ultracold molecules attractive candidates for use in quantum simulation of condensed matter systems and quantum computation. Also ultracold molecules may provide unique opportunities for studying chemical dynamics and for tests of fundamental symmetries. Here we experimentally demonstrate laser cooling of the molecule strontium monofluoride (SrF). Using an optical cycling scheme requiring only three lasers, we have observed both Sisyphus and Doppler cooling forces which have substantially reduced the transverse temperature of a SrF molecular beam. Currently the only technique for producing ultracold molecules is by binding together ultracold alkali atoms through Feshbach resonance or photoassociation. By contrast, different proposed applications for ultracold molecules require a variety of molecular energy-level structures. Our method provides a new route to ultracold temperatures for molecules. In particular it bridges the gap between ultracold temperatures and the ~1 K temperatures attainable with directly cooled molecules (e.g. cryogenic buffer gas cooling or decelerated supersonic beams). Ultimately our technique should enable the production of large samples of molecules at ultracold temperatures for species that are chemically distinct from bialkalis.Comment: 10 pages, 7 figure

Ipl1/aurora kinase suppresses S-CDK-driven spindle formation during prophase I to ensure chromosome integrity during meiosis

Cells coordinate spindle formation with DNA repair and morphological modifications to chromosomes prior to their segregation to prevent cell division with damaged chromosomes. Here we uncover a novel and unexpected role for Aurora kinase in preventing the formation of spindles by Clb5-CDK (S-CDK) during meiotic prophase I and when the DDR is active in budding yeast. This is critical since S-CDK is essential for replication during premeiotic S-phase as well as double-strand break induction that facilitates meiotic recombination and, ultimately, chromosome segregation. Furthermore, we find that depletion of Cdc5 polo kinase activity delays spindle formation in DDR-arrested cells and that ectopic expression of Cdc5 in prophase I enhances spindle formation, when Ipl1 is depleted. Our findings establish a new paradigm for Aurora kinase function in both negative and positive regulation of spindle dynamics

Baseline Demographics, Comorbidities, Treatment Patterns and Burden of Atopic Dermatitis in Adults and Adolescents from the GLOBOSTAD Long-Term Observational Study

Introduction: Insights into real-world treatment of atopic dermatitis (AD) are relevant to clinical decision making. The aim of this analysis was to characterize patients who receive dupilumab for AD in a real-world setting. Methods: The GLOBOSTAD registry is an ongoing, longitudinal, prospective, observational study of patients with AD who receive dupilumab according to country-specific prescribing information. We report baseline characteristics, comorbidities and treatment patterns for patients enrolled from July 11, 2019 to March 31, 2022. Analyses are descriptive; no formal statistical comparisons were performed. Results: Nine hundred fifty-two adults and adolescents were enrolled in GLOBOSTAD. Patients had a high disease burden before starting dupilumab: (mean [standard deviation]) percent body surface area affected (44.8 [24.42]), Eczema Area and Severity Index total score (24.8 [12.95]), SCORing Atopic Dermatitis total score (60.5 [16.34]), Patient-Oriented Eczema Measure total score (19.7 [6.37]) and Dermatology Life Quality Index total score (13.7 [7.02]). Overall, 741 (77.8%) patients reported ≥ 1 type 2 inflammatory comorbidities, most frequently allergic rhinitis (492 [51.7%]), asthma (323 [33.9%]), food allergy (294 [30.9%]) or another allergy (274 [28.8%]). In the previous 12 months, 310 (32.6%) patients had received systemic non-steroidal immunosuppressants and 169 (17.8%) systemic corticosteroids; 449 (47.2%) had received topical corticosteroids, most commonly potent topical corticosteroids; 141 (14.8%) had received topical calcineurin inhibitors and 32 (3.4%) ultraviolet therapy. Most (713 [74.9%]) patients started dupilumab because of prior treatment failure. Conclusion: Patients enrolled in GLOBOSTAD demonstrated considerable multidimensional burden of disease across AD signs, symptoms and quality of life despite previous use of systemic and non-systemic AD treatments

Characterization of the Psychological, Physiological and EEG Profile of Acute Betel Quid Intoxication in Naïve Subjects

Betel quid use and abuse is wide spread in Asia but the physiological basis of intoxication and addiction are unknown. In subjects naïve to the habit of betel quid intoxication, the psychological and physiological profile of intoxication has never been reported. We compared the effect of chewing gum or chewing betel quid, and subsequent betel quid intoxication, on psychological assessment, prospective time interval estimation, numerical and character digit span, computerized 2 choice tests and mental tasks such as reading and mathematics with concurrent monitoring of ECG, EEG and face temperature in healthy, non-sleep deprived, male subjects naïve to the habit of chewing betel quid. Betel quid intoxication, dose dependently induced tachycardia (max 30 bpm) and elevated face temperature (0.7°C) (P<0.001) above the effects observed in response to chewing gum (max 12 bpm and 0.3°C) in 12 subjects. Gross behavioral indices of working memory such as numerical or character digit span in 8 subjects, or simple visual-motor performance such as reaction speed or accuracy in a two choice scenario in 8 subjects were not affected by betel quid intoxication. Betel quid intoxication strongly influenced the psychological aspects of perception such as slowing of the prospective perception of passage of a 1 minute time interval in 8 subjects (P<0.05) and perceived increased arousal (P<0.01) and perceived decreased ability to think (P<0.05) in 31 subjects. The EEG spectral profile recorded from mental states associated with open and closed eyes, and mental tasks such as reading and eyes closed mental arithmetic were significantly modified (P<0.05) relative to chewing gum by betel quid intoxication in 10 subjects. The prevalence of betel quid consumption across a range of social and work settings warrants greater investigation of this widespread but largely under researched drug

Evaluation of rK39 rapid diagnostic tests for canine visceral leishmaniasis : longitudinal study and meta-analysis

Canine visceral leishmaniasis is a vector-borne disease caused by the intracellular parasite Leishmania infantum. It is an important veterinary disease, and dogs are also the main animal reservoir for human infection. The disease is widespread in the Mediterranean area, and parts of Asia and South and Central America, and is potentially fatal in both dogs and humans unless treated. Diagnosis of canine infections requires serological or molecular tests. Detection of infection in dogs is important prior to treatment, and in epidemiological studies and control programmes, and a sensitive and specific rapid diagnostic test would be very useful. Rapid diagnostic tests (RDTs) have been developed, but their diagnostic performance has been reported to be variable. We evaluated the sensitivity of a RDT based on serological detection of the rK39 antigen in a cohort of naturally infected Brazilian dogs. The sensitivity of the test to detect infection was relatively low, but increased with time since infection and the severity of infection. We then carried out a meta-analysis of published studies of rK39 RDTs, evaluating the sensitivity to detect disease and infection. The results suggest that rK39 RDTs may be useful in a veterinary clinical setting, but the sensitivity to detect infection is too low for operational control programmes

Timed inhibition of CDC7 increases CRISPR-Cas9 mediated templated repair.

Repair of double strand DNA breaks (DSBs) can result in gene disruption or gene modification via homology directed repair (HDR) from donor DNA. Altering cellular responses to DSBs may rebalance editing outcomes towards HDR and away from other repair outcomes. Here, we utilize a pooled CRISPR screen to define host cell involvement in HDR between a Cas9 DSB and a plasmid double stranded donor DNA (dsDonor). We find that the Fanconi Anemia (FA) pathway is required for dsDonor HDR and that other genes act to repress HDR. Small molecule inhibition of one of these repressors, CDC7, by XL413 and other inhibitors increases the efficiency of HDR by up to 3.5 fold in many contexts, including primary T cells. XL413 stimulates HDR during a reversible slowing of S-phase that is unexplored for Cas9-induced HDR. We anticipate that XL413 and other such rationally developed inhibitors will be useful tools for gene modification