Essential Role of the Anterior Piriform Cortex in Mediating Social Novelty Output via a Top-Down Circuit.

Social novelty is indispensable for a wide range of social behaviors. The medial prefrontal cortex (mPFC), along with other social information hubs, composes the foundational circuitry of social novelty. However, the precise circuit mechanisms that govern social novelty processing remain elusive.

Development of a generator for percussive ultrasonic drills used in asteroid exploration based on impedance characteristics analysis.

Percussive ultrasonic drills participate in asteroid exploration missions. Since space environments are complex and working loads vary dramatically, it is necessary to design a drive that better matches the percussive ultrasonic drill to make it achieve high-speed drilling with low power consumption. Impedance characteristics under different load conditions and the load varying in one drilling cycle are investigated based on analyzing the working principle of the percussive ultrasonic drill.

Magnetically actuated gearbox for the wireless control of millimeter-scale robots.

The limited force or torque outputs of miniature magnetic actuators constrain the locomotion performances and functionalities of magnetic millimeter-scale robots. Here, we present a magnetically actuated gearbox with a maximum size of 3 millimeters for driving wireless millirobots. The gearbox is assembled using microgears that have reference diameters down to 270 micrometers and are made of aluminum-filled epoxy resins through casting.

Discovery of SARS-CoV-2 main protease covalent inhibitors from a DNA-encoded library selection.

Covalent inhibitors targeting the main protease (M, or 3CLpro) of SARS-CoV-2 have shown promise in preclinical investigations. Herein, we report the discovery of two new series of molecules that irreversibly bind to SARS-CoV-2 M. These acrylamide containing molecules were discovered using our covalent DNA-encoded library (DEL) screening platform.

Dielectric Characterization and Multistage Separation of Various Cells via Dielectrophoresis in a Bipolar Electrode Arrayed Device.

Isolation of microalgal cells is as an indispensable part of producing biofuels for energy security and detecting toxic contaminants for marine routine monitoring. Microalgae live together with various microalgae naturally, and abundant samples need to be tackled in practical applications. Therefore, effective separation technologies need to be developed urgently to achieve high-throughput separation of various microalgae.

Ga-FAPI-04 vs. F-FDG in a longitudinal preclinical PET imaging of metastatic breast cancer.

Purpose: This longitudinal study aims to evaluate the performance of  Ga-FAPI-04 and F-FDG and to profile the dynamic process of tumor metastasis in a preclinical 4T1 breast cancer model. Although both of these two radioligands are wildly used in clinic, no study was reported on their performance in the longitudinal monitoring of tumor metastasis. Also, no correlation between the expression level of fibroblast activation protein (FAP) and the development of tumor metastasis has been elucidated previously.

Dielectrophoresis Response of Water-in-Oil-in-Water Double Emulsion Droplets with Singular or Dual Cores.

Microfluidic technologies have enabled generation of exquisite multiple emulsion droplets, which have been used in many fields, including single-cell assays, micro-sized chemical reactions, and material syntheses. Electrical controlling is an important technique for droplet manipulation in microfluidic systems, but the dielectrophoretic behaviors of multiple emulsion droplets in electrical fields are rarely studied. Here, we report on the dielectrophoresis response of double emulsion droplets in AC electric fields in microfluidic channel.

The optimization of a novel selective antagonist for human M muscarinic acetylcholine receptor.

Muscarinic acetylcholine receptors (mAChRs) comprise five distinct subtypes denoted M to M. The antagonism of M subtype could increase the release of acetylcholine from vesicles into the synaptic cleft and improve postsynaptic functions in the hippocampus via M receptor activation, displaying therapeutic potentials for Alzheimer's disease. However, drug development for M antagonists is still challenged among different receptor subtypes.

GluN2A-selective positive allosteric modulator-nalmefene-flumazenil reverses ketamine-fentanyl-dexmedetomidine-induced anesthesia and analgesia in rats.

Anesthetics are used to produce hypnosis and analgesic effects during surgery, but anesthesia for a long time after the operation is not conducive to the recovery of animals or patients. Therefore, finding appropriate treatments to counter the effects of anesthetics could enhance postoperative recovery. In the current study, we discovered the novel role of a GluN2A-selective positive allosteric modulator (PAM) in ketamine-induced anesthesia and investigated the effects of the PAM combined with nalmefene and flumazenil (PNF) in reversing the actions of an anesthetic combination (ketamine-fentanyl-dexmedetomidine, KFD).

An Experimental Study of 3D Electrode-Facilitated Particle Traffic Flow-Focusing Driven by Induced-Charge Electroosmosis.

In this paper we present a novel microfluidic approach for continuous, rapid and switchable particle concentration, using induced-charge electroosmosis (ICEO) in 3D electrode layouts. Field-effect control on non-linear electroosmosis in the transverse direction greatly facilitates a selective concentration of biological yeast cells from a straight main microchannel into one of the three downstream branch channels in our microfluidic device. For the geometry configuration of 3D driving electrode plates on sidewalls and a 2D planar gate electrode strip on the channel bottom surface, we briefly describe the underlying physics of an ICEO-based particle flow-focusing method, and provide relevant simulation results to show how gate voltage amplitude can be used to guide the motion trajectory of the concentrated particle stream.

Preclinical Evaluation of a Novel TSPO PET Ligand 2-(7-Butyl-2-(4-(2-[F]Fluoroethoxy)phenyl)-5-Methylpyrazolo[1,5-a]Pyrimidin-3-yl)-N,N-Diethylacetamide (F-VUIIS1018A) to Image Glioma.

Purpose: There is an urgent need for the development of novel positron emission tomography (PET) tracers for glioma imaging. In this study, we developed a novel PET probe ([F]VUIIS1018A) by targeting translocator protein (TSPO), an imaging biomarker for glioma. The purpose of this preclinical study was to evaluate this novel TSPO probe for glioma imaging.

Evaluation of the novel TSPO radiotracer 2-(7-butyl-2-(4-(2-([F]fluoroethoxy)phenyl)-5-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N,N-diethylacetamide in a preclinical model of neuroinflammation.

Translocator Protein (18 kDa, TSPO) is regarded as a useful biomarker for neuroinflammation imaging. TSPO PET imaging could be used to understand the role of neuroinflammation in brain diseases and as a tool for evaluating novel therapeutic effects. As a promising TSPO probe, [F]DPA-714 is highly specific and offers reliable quantification of TSPO in vivo.

Evaluation of TSPO PET Ligands [F]VUIIS1009A and [F]VUIIS1009B: Tracers for Cancer Imaging.

Purpose: Positron emission tomography (PET) ligands targeting translocator protein (TSPO) are potential imaging diagnostics of cancer. In this study, we report two novel, high-affinity TSPO PET ligands that are 5,7 regioisomers, [F]VUIIS1009A ([F]3A) and [F]VUIIS1009B ([F]3B), and their initial in vitro and in vivo evaluation in healthy mice and glioma-bearing rats.

Procedures: VUIIS1009A/B was synthesized and confirmed by X-ray crystallography.

Facile synthesis of SSR180575 and discovery of 7-chloro-N,N,5-trimethyl-4-oxo-3(6-[(18)F]fluoropyridin-2-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide, a potent pyridazinoindole ligand for PET imaging of TSPO in cancer.

A novel synthesis of the translocator protein (TSPO) ligand 7-chloro-N,N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide (SSR180575, 3) was achieved in four steps from commercially available starting materials. Focused structure-activity relationship development about the pyridazinoindole ring at the N3 position led to the discovery of 7-chloro-N,N,5-trimethyl-4-oxo-3(6-fluoropyridin-2-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide (14), a novel ligand of comparable affinity. Radiolabeling with fluorine-18 ((18)F) yielded 7-chloro-N,N,5-trimethyl-4-oxo-3(6-[(18)F]fluoropyridin-2-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide ([(18)F]-14) in high radiochemical yield and specific activity.

Preclinical imaging evaluation of novel TSPO-PET ligand 2-(5,7-Diethyl-2-(4-(2-[(18)F]fluoroethoxy)phenyl)pyrazolo[1,5-a]pyrimidin-3-yl)-N,N-diethylacetamide ([ (18)F]VUIIS1008) in glioma.

Purpose: Translocator protein (TSPO) concentrations are elevated in glioma, suggesting a role for TSPO positron emission tomography (PET) imaging in this setting. In preclinical PET studies, we evaluated a novel, high-affinity TSPO PET ligand, [(18)F]VUIIS1008, in healthy mice and glioma-bearing rats.

Procedures: Dynamic PET data were acquired simultaneously with [(18)F]VUIIS1008 injection, with binding reversibility and specificity evaluated in vivo by non-radioactive ligand displacement or blocking.

A peptide-based positron emission tomography probe for in vivo detection of caspase activity in apoptotic cells.

Purpose: Apoptosis, or programmed cell death, can be leveraged as a surrogate measure of response to therapeutic interventions in medicine. Cysteine aspartic acid-specific proteases, or caspases, are essential determinants of apoptosis signaling cascades and represent promising targets for molecular imaging. Here, we report development and in vivo validation of [(18)F]4-fluorobenzylcarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone ([(18)F]FB-VAD-FMK), a novel peptide-based molecular probe suitable for quantification of caspase activity in vivo using positron emission tomography (PET).

Microwave-assisted, one-pot reaction of 7-azaindoles and aldehydes: a facile route to novel di-7-azaindolylmethanes.

A novel and highly efficient synthetic method leveraging microwave-assisted organic synthesis (MAOS) to yield di-7-azaindolylmethanes (DAIMs) is reported. Under MAOS conditions, reaction of 7-azaindole with aldehydes resulted predominantly in DAIMs, as opposed to the expected 7-azaindole addition products that form at ambient temperature. Based upon studies of different indoles and azaindoles with various aromatic and aliphatic aldehydes, we herein propose a mechanism where rapid and efficient microwave heating promotes nucleophilicity of 7-azaindoles towards the corresponding alkylidene-azaindolene intermediate to form the DAIM.

Synthesis and structure-activity relationships of 5,6,7-substituted pyrazolopyrimidines: discovery of a novel TSPO PET ligand for cancer imaging.

Focused library synthesis and structure-activity relationship development of 5,6,7-substituted pyrazolopyrimidines led to the discovery of 2-(5,7-diethyl-2-(4-(2-fluoroethoxy)phenyl)pyrazolo[1,5-a]pyrimidin-3-yl)-N,N-diethylacetamide (6b), a novel translocator protein (TSPO) ligand exhibiting a 36-fold enhancement in affinity compared to another pyrazolopyrimidine-based TSPO ligand, 6a (DPA-714). Radiolabeling with fluorine-18 ((18)F) facilitated production of 2-(5,7-diethyl-2-(4-(2-[(18)F]fluoroethoxy)phenyl)pyrazolo[1,5-a]pyrimidin-3-yl)-N,N-diethylacetamide ((18)F-6b) in high radiochemical yield and specific activity. In vivo studies of (18)F-6b were performed which illuminated this agent as an improved probe for molecular imaging of TSPO-expressing cancers.

Quantitative preclinical imaging of TSPO expression in glioma using N,N-diethyl-2-(2-(4-(2-18F-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide.

Unlabelled: There is a critical need to develop and rigorously validate molecular imaging biomarkers to aid diagnosis and characterization of primary brain tumors. Elevated expression of translocator protein (TSPO) has been shown to predict disease progression and aggressive, invasive behavior in a variety of solid tumors. Thus, noninvasive molecular imaging of TSPO expression could form the basis of a novel, predictive cancer imaging biomarker.

Quantitative, preclinical PET of translocator protein expression in glioma using 18F-N-fluoroacetyl-N-(2,5-dimethoxybenzyl)-2-phenoxyaniline.

Unlabelled: Translocator protein (TSPO), also referred to as peripheral benzodiazepine receptor (PBR), is a crucial 18-kDa outer mitochondrial membrane protein involved in numerous cellular functions, including the regulation of cholesterol metabolism, steroidogenesis, and apoptosis. Elevated expression of TSPO in oncology correlates with disease progression and poor survival, suggesting that molecular probes capable of assaying TSPO levels may have potential as cancer imaging biomarkers. In preclinical PET studies, we characterized a high-affinity aryloxyanilide-based TSPO imaging ligand, 18F-N-fluoroacetyl-N-(2,5-dimethoxybenzyl)-2-phenoxyaniline (18F-PBR06), as a candidate probe for the quantitative assessment of TSPO expression in glioma.

Microwave-assisted Organic Synthesis of a High-affinity Pyrazolo-pyrimidinyl TSPO Ligand.

We herein report a dramatically improved total synthesis of the high-affinity translocator protein (TSPO) ligand DPA-714, featuring microwave-assisted organic synthesis (MAOS). Compared with previously described approaches, our novel MAOS method dramatically reduces overall reaction time without adversely effecting reaction yields. We envision that the described MAOS protocol may be suitably applied to high-throughput, diversity-oriented synthesis of novel compounds based on the pyrazolo-pyrimidinyl scaffold.

Preparation, crystallization and preliminary X-ray analysis of threonine synthase from Streptococcus mutans.

The thrC gene of Streptococcus mutans encodes threonine synthase, which is a potential target for drug design. To study the structure and function of the enzyme, the thrC gene was amplified from Streptococcus mutans genomic DNA and cloned into the expression vector pET28alpha. The protein was expressed in Escherichia coli in soluble form and purified to homogeneity.

Crystallization and preliminary crystallographic analysis of D-alanine-D-alanine ligase from Streptococcus mutans.

D-Alanine-D-alanine ligase is encoded by the gene ddl (SMU_599) in Streptococcus mutans. This ligase plays a very important role in cell-wall biosynthesis and may be a potential target for drug design. To study the structure and function of this ligase, the gene ddl was amplified from S.