Alzheimer's disease remains without a disease-modifying therapy that improves symptoms after therapy withdrawal. Because no investigational agents have demonstrated disease-modifying effects ...clinically, we tested whether the Fyn inhibitor, saracatinib, provides persistent improvement in a transgenic model. Aged APPswe/PS1ΔE9 mice were treated with saracatinib or memantine for 4 weeks and spatial memory improved to control levels. After drug washout, there was sustained rescue of both memory function and synapse density by saracatinib, but a loss of benefit from memantine. These data demonstrate a disease-modifying persistent benefit for saracatinib in a preclinincal Alzheimer's model, and distinguish its action from that of memantine.
•Disease-modifying effects of saracatinib or memantine were assessed in vivo.•Saracatinib but not memantine exhibited persistent rescue of synapses and memory.•Saracatinib benefit was observed at least one month after therapy discontinuation.•Withdrawal study design can differentiate disease-modifying and symptomatic agents.
Glycosyl phosphates are shown to be activated to stereospecific nucleophilic substitution reactions by precisely tailored bis-thiourea catalysts. Enhanced reactivity and scope is observed with ...phosphate relative to chloride leaving groups. Stronger binding (Km) to the H-bond donor and enhanced reactivity of the complex (kcat) enables efficient catalysis with broad functional group compatibility under mild, neutral conditions.
The Ni-catalyzed carboacylation of alkynes with amide electrophiles and triarylboroxines is presented. The reaction generates all-carbon tetrasubstituted alkene products in up to 62% yield. ...NiCl2·glyme is used as an inexpensive precatalyst in the absence of any external reductant or exogenous ligand. Design of Experiment (DoE) was used to achieve the best combination of yield and stereoselectivity in this acylative carbodifunctionalization of alkynes to generate highly substituted enones.
Herein, we report Ni-catalyzed intramolecular carboacylation of imides containing a tethered alkene and tetraarylborate nucleophiles. Using a nickel-phosphine catalyst system, α-substituted, γ-amino ...ketones are generated in up to 92% yield with site selectivity. Deprotection and cyclization of the γ-amino ketone product afforded a cyclic imine in 71% yield, and a stereoselective reduction formed the β-substituted, δ-amino alcohol in 66% yield with 2.3:1 d.r. and 94% ee (major diastereomer).
The precision of stereopsis and vergence are ultimately limited by internal binocular disparity noise. Here we propose an equivalent noise model with both global and local internal disparity noises ...to provide a unified explanation of both absolute and relative disparity thresholds. To test this model, we developed a psychophysical procedure to measure the equivalent internal disparity noise by adding external disparity noise to random-Gabor-patch stereograms. We used the method of constant stimuli to measure the minimum and maximum disparity thresholds (Dmin and Dmax) for both absolute and relative disparity. Consistent with previous studies, we found that Dmin thresholds are substantially worse for absolute disparity than for relative disparity. We tested three relative disparity mechanisms: (1) the difference between the monocular separations of targets projecting to the two eyes; (2) the direct measurement of relative disparity; and (3) the difference of absolute disparities of targets. Computing the difference of absolute disparities when detecting relative disparity, Mechanism 3 cancels global noise, resulting in a much lower relative Dmin threshold, and provides a reasonable fit to the experimental data. We also found that the presence of as much as 2400 arcsec of external disparity noise does not appear to affect the Dmax threshold. This observation suggests that Dmax is implicated in a mechanism that disregards the disparity variance of individual items, relying instead on the average disparity across all items, supporting the depth model proposed in our previous study (Ding & Levi, 2021), which posits distinct mechanisms governing Dmin and Dmax thresholds.
The PI3K-AKT-mTOR signaling pathway is frequently activated in glioblastoma and offers several druggable targets. However, clinical efficacy of PI3K/mTOR inhibitors in glioblastoma has not yet been ...demonstrated. Insufficient drug delivery may limit the efficacy of PI3K/mTOR inhibitors against glioblastoma. The presence of the efflux transporters ABCB1/Abcb1 (P-glycoprotein, MDR1) and ABCG2/Abcg2 (BCRP) at the blood-brain barrier (BBB) restricts the brain penetration of many drugs.
We used
drug transport assays and performed pharmacokinetic/pharmacodynamic studies in wild-type and ABC-transporter knockout mice. The efficacy of PI3K-mTOR inhibition was established using orthotopic allograft and genetically engineered spontaneous glioblastoma mouse models.
The mTOR inhibitors rapamycin and AZD8055 are substrates of ABCB1, whereas the dual PI3K/mTOR inhibitor NVP-BEZ235 and the PI3K inhibitor ZSTK474 are not. Moreover, ABCG2 transports NVP-BEZ235 and AZD8055, but not ZSTK474 or rapamycin. Concordantly,
mice revealed increased brain penetration of rapamycin (13-fold), AZD8055 (7.7-fold), and NVP-BEZ235 (4.5-fold), but not ZSTK474 relative to WT mice. Importantly, ABC transporters limited rapamycin brain penetration to subtherapeutic levels, while the reduction in NVP-BEZ235 brain penetration did not prevent target inhibition. NVP-BEZ235 and ZSTK474 demonstrated antitumor efficacy with improved survival against U87 orthotopic gliomas, although the effect of ZSTK474 was more pronounced. Finally, ZSTK474 prolonged overall survival in Cre-LoxP conditional transgenic
mice, mainly by delaying tumor onset.
PI3K/mTOR inhibitors with weak affinities for ABC transporters can achieve target inhibition in brain (tumors), but have modest single-agent efficacy and combinations with (BBB penetrable) inhibitors of other activated pathways may be required.
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Port-a-caths are implanted intravascular chest ports that enable venous access. With more port placements performed by interventional radiologists, it is important to discern differences in infection ...and complication rates between double- and single-lumen ports.
We retrospectively reviewed 1,385 port placements over 2 years at the University of Miami. Patients were grouped by single- or double-lumen ports. Data on duration of catheter stay, bloodstream infections, malfunctions, and other complications (fibrin sheath, thrombosis, catheter malposition) were collected. Multivariate Cox regression was performed to identify variables predicting port infection.
The mean patient age was 58.8 years; the mean BMI was 26.9 kg/m
; and 61.5% of these patients were female. Our search revealed 791 double-lumen ports (57.1%) and 594 single-lumen ports (42.9%). The median follow-up was 668 days (range, 2-1,297). Double-lumen ports were associated with significantly higher rates of bacteremia (2.78% vs 0.84%;
= .02), port malfunction (8.3% vs 2.0%;
< .001), fibrin sheath formation (2.2% vs 0.5%;
< .02), catheter tip malposition (1.0% vs 0;
= .01), and catheter-associated thrombosis (1.4% vs 0;
= .003). Multivariate Cox regression analysis, after adjusting for other variables, showed that double-lumen chest ports had 2.98 times (95% confidence interval, 1.12-7.94) the hazard rate of single-lumen ports for developing bloodstream infection (
= .029).
Double-lumen chest ports are associated with increased risk for bloodstream infection, malfunction, fibrin sheath formation, catheter tip malposition, and catheter-associated thrombosis. Interventional radiologists may consider placing single-lumen ports if clinically feasible; however, future studies are needed to determine clinical significance. The study limitations included the retrospective study design and the potential loss of patient follow-up.
This article presents a hybrid five-level converter (H5LC) with cascaded full-bridge submodules (FBSMs) for high voltage direct current (HVdc) transmission. A five-level converter operates at a ...fundamental switching frequency to generate symmetric five-level square wave output voltages which are shaped into smooth sinusoidal voltages by the ac-side FBSMs. Using a proposed third-order harmonic voltage injection scheme, the FBSMs' total blocking voltage is limited to one-eighth of the dc-side voltage, reducing the H5LC's losses, footprint, and capital costs. dc pole-to-pole fault blocking is enabled using a bypass branch consisting of bidirectional thyristor valves and fast mechanical switches to suppress the ac-side fault contribution within half a fundamental cycle. Full-scale HVdc simulation studies show the H5LC's ability to control real and reactive powers and additionally, its dc fault resilience. A lab-scale hardware implementation of an H5LC with 30 FBSMs is presented to verify its operating principle. In contrast to the half-bridge submodule based modular multilevel converter, the H5LC has improved efficiency, fewer semiconductor devices, and significantly reduced energy storage requirements.
The most important adverse effect of antithrombotic treatment is the occurrence of bleeding. In the case of severe bleeding in a patient who uses anticoagulant agents or when a patient on ...anticoagulants needs to undergo an urgent invasive procedure, it may be useful to reverse anticoagulant treatment. Conventional anticoagulants such as vitamin K antagonists may be neutralized by administration of vitamin K or prothrombin complex concentrates, whereas heparin and heparin derivatives can be counteracted by protamine sulphate. The anti‐hemostatic effect of aspirin and other antiplatelet strategies can be corrected by the administration of platelet concentrate and/or desmopressin, if needed. Recently, a new generation of anticoagulants with a greater specificity towards activated coagulation factors as well as new antiplatelet agents have been introduced and these drugs show promising results in clinical studies. A limitation of these new agents may be the lack of an appropriate strategy to reverse the effect if a bleeding event occurs, although experimental studies show hopeful results for some of these agents.
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