Synthesis of [11C]HG-10-102-01 as a new potential PET agent for imaging of LRRK2 enzyme in Parkinson’s disease

The reference standard (4-((5-chloro-4-(methylamino)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (HG-10-102-01) and its precursor (4-((5-chloro-4-(methylamino)pyrimidin-2-yl)amino)-3-hydroxyphenyl)(morpholino)methanone (desmethyl-HG-10-102-01) were synthesized from 2,4,5-trichloropyrimide and 3-methoxy-4-nitrobenzoic acid with overall chemical yield 49% in four steps and 14% in five steps, respectively. The target tracer (4-((5-chloro-4-(methylamino)pyrimidin-2-yl)amino)-3-[11C]methoxyphenyl)(morpholino)methanone ([11C]HG-10-102-01) was prepared from the precursor desmethyl-HG-10-102-01 with [11C]CH3OTf through O-[11C]methylation and isolated by HPLC combined with SPE in 45–55% radiochemical yield, based on [11C]CO2 and decay corrected to end of bombardment (EOB). The radiochemical purity was >99%, and the specific activity (SA) at EOB was 370–1110 GBq/μmol with a total synthesis time of ∼40-min from EOB

Synthesis of a PET tau tracer [11C]PBB3 for imaging of Alzheimer’s disease

The authentic standard PBB3 and its precursor N-desmethyl-PBB3 as well as TBS-protected N-desmethyl-PBB3 precursor for radiolabeling were synthesized from 5-bromo-2-nitropyridine, acrolein diethyl acetal, 6-methoxy-2-methylbenzothiazole, and diethylchlorophosphate with overall chemical yield 1% in six steps, 2% in five steps, and 1% in six steps, respectively. [11C]PBB3 was prepared from either desmethyl-PBB3 or TBS-protected desmethyl-PBB3 with [11C]CH3OTf through N-[11C]methylation and isolated by HPLC combined with SPE in 20–25% and 15–20% radiochemical yield, respectively, based on [11C]CO2 and decay corrected to end of bombardment (EOB). The radiochemical purity was >99%, and the specific activity at EOB was 370–1110 GBq/μmol with a total synthesis time of ∼40-min from EOB

PR-Set7 is Degraded in a Conditional Cul4A Transgenic Mouse Model of Lung Cancer.

BackgroundMaintenance of genomic integrity is essential to ensure normal organismal development and to prevent diseases such as cancer. PR-Set7 (also known as Set8) is a cell cycle regulated enzyme that catalyses monomethylation of histone 4 at Lys20 (H4K20me1) to promote chromosome condensation and prevent DNA damage. Recent studies show that CRL4CDT2-mediated ubiquitylation of PR-Set7 leads to its degradation during S phase and after DNA damage. This might occur to ensure appropriate changes in chromosome structure during the cell cycle or to preserve genome integrity after DNA damage.MethodsWe developed a new model of lung tumor development in mice harboring a conditionally expressed allele of Cul4A. We have therefore used a mouse model to demonstrate for the first time that Cul4A is oncogenic in vivo. With this model, staining of PR-Set7 in the preneoplastic and tumor lesions in AdenoCre-induced mouse lungs was performed. Meanwhile we identified higher protein level changes of γ-tubulin and pericentrin by IHC.ResultsThe level of PR-Set7 down-regulated in the preneoplastic and adenocarcinomous lesions following over-expression of Cul4A. We also identified higher levels of the proteins pericentrin and γ-tubulin in Cul4A mouse lungs induced by AdenoCre.ConclusionsPR-Set7 is a direct target of Cul4A for degradation and involved in the formation of lung tumors in the conditional Cul4A transgenic mouse model

Improving Detection in Aerial Images by Capturing Inter-Object Relationships

In many image domains, the spatial distribution of objects in a scene exhibits meaningful patterns governed by their semantic relationships. In most modern detection pipelines, however, the detection proposals are processed independently, overlooking the underlying relationships between objects. In this work, we introduce a transformer-based approach to capture these inter-object relationships to refine classification and regression outcomes for detected objects. Building on two-stage detectors, we tokenize the region of interest (RoI) proposals to be processed by a transformer encoder. Specific spatial and geometric relations are incorporated into the attention weights and adaptively modulated and regularized. Experimental results demonstrate that the proposed method achieves consistent performance improvement on three benchmarks including DOTA-v1.0, DOTA-v1.5, and HRSC 2016, especially ranking first on both DOTA-v1.5 and HRSC 2016. Specifically, our new method has an increase of 1.59 mAP on DOTA-v1.0, 4.88 mAP on DOTA-v1.5, and 2.1 mAP on HRSC 2016, respectively, compared to the baselines

Dynamic characteristics of vehicle-wheel/rail nonlinear contact-foundation system

To study the dynamic characteristics of the vehicle-wheel/rail-foundation system of high-speed trains with consideration of nonlinear wheel/rail contact relationship and effects of nonlinear wheel/rail contact behavior on the railway rail, foundation structure and vehicle, a three-dimensional finite element model of vehicle-wheel/rail nonlinear contact-foundation system is established by using ANSYS software in which, the special contact element is used to simulate wheel/rail nonlinear contact and instantaneous separation. The vertical vibration of the whole system and its spread parts due to the track irregularities are calculated. At the same time, the relationships between the vibration of the wheel/rail system and the train speed, foundation stiffness are analyzed. The numerical results show that the appropriate foundation stiffness is conducive to weaken the vertical acceleration of the vehicle and wheel/rail system, and the vertical displacement and wheel/rail contact stress on the rail top increase with the growth of the train speed. The procedure and results from this paper can provide reference for the design of vehicle-wheel/rail system

Feedback RoI Features Improve Aerial Object Detection

Neuroscience studies have shown that the human visual system utilizes high-level feedback information to guide lower-level perception, enabling adaptation to signals of different characteristics. In light of this, we propose Feedback multi-Level feature Extractor (Flex) to incorporate a similar mechanism for object detection. Flex refines feature selection based on image-wise and instance-level feedback information in response to image quality variation and classification uncertainty. Experimental results show that Flex offers consistent improvement to a range of existing SOTA methods on the challenging aerial object detection datasets including DOTA-v1.0, DOTA-v1.5, and HRSC2016. Although the design originates in aerial image detection, further experiments on MS COCO also reveal our module's efficacy in general detection models. Quantitative and qualitative analyses indicate that the improvements are closely related to image qualities, which match our motivation

Synthesis of [11C]CX-6258 as a new PET tracer for imaging of Pim kinases in cancer

The reference standard CX-6258 {(E)-5-chloro-3-((5-(3-(4-methyl-1,4-diazepane-1-carbonyl)phenyl)furan-2-yl)methylene)indolin-2-one, 4a} and its desmethylated precursor N-desmethyl-CX-6258 {(E)-3-((5-(3-(1,4-diazepane-1-carbonyl)phenyl)furan-2-yl)methylene)-5-chloroindolin-2-one, 5} for radiolabeling were synthesized from 5-bromo-2-furaldehyde and 3-carboxybenzeneboronic acid in 3 and 4 steps with 29–49% and 24–32% overall chemical yield, respectively. The target tracer [11C]CX-6258 {(E)-5-chloro-3-((5-(3-(4-[11C]methyl-1,4-diazepane-1-carbonyl)phenyl)furan-2-yl)methylene)indolin-2-one, [11C]4a} was prepared from N-desmethyl-CX-6258 (5) with [11C]CH3OTf under basic condition (2 N NaOH) through N-[11C]methylation and isolated by HPLC combined with solid-phase extraction (SPE) in 40–50% radiochemical yield based on [11C]CO2 and decay corrected to end of bombardment (EOB) with 370–1110 GBq/μmol specific activity at EOB