Many-Body Resonances in the Avalanche Instability of Many-Body Localization.

Many-body localized (MBL) systems fail to reach thermal equilibrium under their own dynamics, even though they are interacting, nonintegrable, and in an extensively excited state. One instability toward thermalization of MBL systems is the so-called "avalanche," where a locally thermalizing rare region is able to spread thermalization through the full system. The spreading of the avalanche may be modeled and numerically studied in finite one-dimensional MBL systems by weakly coupling an infinite-temperature bath to one end of the system. We find that the avalanche spreads primarily via strong many-body resonances between rare near-resonant eigenstates of the closed system. Thus we find and explore a detailed connection between many-body resonances and avalanches in MBL systems.

Recent Advances in the Development of Antidepressants Targeting the Purinergic P2X7 Receptor.

The purinergic P2X7 receptor (P2X7R) is an adenosine triphosphate (ATP)- gated cation channel protein. Although extracellular ATP (eATP) is maintained at the nanomolar concentration range under normal conditions, it is elevated to micromolar levels in response to cell stress or damage, resulting in activation of P2X7R in the brain. The binding of eATP to P2X7R in glial cells in the brain activates the NLRP3 inflammasome and releases pro-inflammatory cytokines, such as IL-1ß, IL-6, IL-18, and TNFα. Depression has been demonstrated to be strongly associated with neuroinflammation activated by P2X7R. Therefore, P2X7R is an attractive therapeutic target for depression. Multinational pharmaceutical companies, including AstraZeneca, GlaxoSmithKline, Janssen, Lundbeck, and Pfizer, have developed CNS-penetrating P2RX7 antagonists. Several of these have been evaluated in clinical trials. This review summarizes the recent development of P2X7R antagonists as novel antidepressant agents in terms of structural optimization, as well as in vitro/in vivo evaluation and physicochemical properties of representative compounds.

A High-Affinity 64Cu-Labeled Ligand for PET Imaging of Hepsin: Design, Synthesis, and Characterization.

Hepsin, a cell surface serine protease, is a potential biomarker for the detection of prostate cancer due to its high expression in prostate cancer but not in normal prostate. This study aimed to develop a radioligand for positron emission tomography (PET) imaging of hepsin. Six leucine-arginine (Leu-Arg) dipeptide derivatives (two diastereomers for each of three ligands) were synthesized and evaluated for their binding affinities and selectivity for hepsin. Based on the binding assay, a natCu-1,4,7,10-tetraazacyclododecane-N,N',N″,N‴-tetraacetic acid (DOTA)-conjugated ligand (3B) was selected for the development of a PET radioligand. [64Cu]3B was synthesized by labeling the DOTA-conjugated compound 11B with [64Cu]CuCl2 at 80 °C for 20 min. The radioligand was evaluated for prostate cancer cell binding and PET imaging in a prostate tumor mouse model. The results demonstrated that [64Cu]3B exhibited high binding to LNCaP cells, intermediate binding to 22Rv1 cells, and low binding to PC3 cells. PET studies of [64Cu]3B in mice, implanted with 22Rv1 and PC3 cells on each flank, revealed that the radioligand uptake was high and persistent in the 22Rv1 tumors over time, whereas it was low in PC3 tumors. The results of this study suggest that [64Cu]3B is a promising PET radioligand for hepsin imaging.

A self-triggered radioligand therapy agent for fluorescence imaging of the treatment response in prostate cancer.

PURPOSE: Radioligand therapy (RLT) targeting prostate-specific membrane antigen (PSMA) is emerging as an effective treatment option for metastatic castration-resistant prostate cancer (mCRPC). An imaging-based method to quantify early treatment responses can help to understand and optimize RLT. METHODS: We developed a self-triggered probe 2 targeting the colocalization of PSMA and caspase-3 for fluorescence imaging of RLT-induced apoptosis. RESULTS: The probe binds to PSMA potently with a Ki of 4.12 nM, and its fluorescence can be effectively switched on by caspase-3 with a Km of 67.62 µM. Cellular and in vivo studies demonstrated its specificity for imaging radiation-induced caspase-3 upregulation in prostate cancer. To identify the detection limit of our method, we showed that probe 2 could achieve 1.79 times fluorescence enhancement in response to 177Lu-RLT in a medium PSMA-expressing 22Rv1 xenograft model. CONCLUSION: Probe 2 can potently bind to PSMA, and the fluorescence signal can be sensitively switched on by caspase-3 both in vitro and in vivo. This method may provide an effective tool to investigate and optimize PSMA-RLT.

TNP and its analogs: Modulation of IP6K and CYP3A4 inhibition.

Inositol hexakisphosphate kinase (IP6K) is an important mammalian enzyme involved in various biological processes such as insulin signalling and blood clotting. Recent analyses on drug metabolism and pharmacokinetic properties on TNP (N2-(m-trifluorobenzyl), N6-(p-nitrobenzyl)purine), a pan-IP6K inhibitor, have suggested that it may inhibit cytochrome P450 (CYP450) enzymes and induce unwanted drug-drug interactions in the liver. In this study, we confirmed that TNP inhibits CYP3A4 in type I binding mode more selectively than the other CYP450 isoforms. In an effort to find novel purine-based IP6K inhibitors with minimal CYP3A4 inhibition, we designed and synthesised 15 TNP analogs. Structure-activity relationship and biochemical studies, including ADP-Glo kinase assay and quantification of cell-based IP7 production, showed that compound 9 dramatically reduced CYP3A4 inhibition while retaining IP6K-inhibitory activity. Compound 9 can be a tool molecule for structural optimisation of purine-based IP6K inhibitors.

Colossal angular magnetoresistance in ferrimagnetic nodal-line semiconductors.

Efficient magnetic control of electronic conduction is at the heart of spintronic functionality for memory and logic applications1,2. Magnets with topological band crossings serve as a good material platform for such control, because their topological band degeneracy can be readily tuned by spin configurations, dramatically modulating electronic conduction3-10. Here we propose that the topological nodal-line degeneracy of spin-polarized bands in magnetic semiconductors induces an extremely large angular response of magnetotransport. Taking a layered ferrimagnet, Mn3Si2Te6, and its derived compounds as a model system, we show that the topological band degeneracy, driven by chiral molecular orbital states, is lifted depending on spin orientation, which leads to a metal-insulator transition in the same ferrimagnetic phase. The resulting variation of angular magnetoresistance with rotating magnetization exceeds a trillion per cent per radian, which we call colossal angular magnetoresistance. Our findings demonstrate that magnetic nodal-line semiconductors are a promising platform for realizing extremely sensitive spin- and orbital-dependent functionalities.

Inhibitors of prostate-specific membrane antigen in the diagnosis and therapy of metastatic prostate cancer - a review of patent literature.

INTRODUCTION: Prostate-specific membrane antigen (PSMA), also known as glutamate carboxypeptidase II, is a potential target protein for imaging and treatment of patients with prostate cancer because of its overexpression during metastasis. Various PSMA-targeted imaging and therapeutic probes have been designed and synthesized based on the Lys-urea-Glu motif. Structural modifications have been made exclusively in the linker region, while maintaining the Lys-urea-Glu structure that interacts with S1 and S1' pockets. AREA COVERED: This review includes WIPO-listed patents (from January 2017 to June 2020) reporting PSMA-targeted probes based on the Lys-urea-Glu or Glu-urea-Glu structure. EXPERT OPINION: : PSMA-targeted imaging agents labeled with radionuclides such as fluorine-18, copper-64, gallium-68, and technetium-99m have been successfully translated into clinical phase for the early diagnosis of metastatic prostate cancer. Recently, PSMA-targeted therapeutic agents labeled with iodine-131, lutetium-177, astatine-211, and lead-212 have also been developed with notable progress. Most PSMA-targeted agents are based on the Lys-urea-Glu or Glu-urea-Glu structure, demonstrate strong PSMA-binding affinity in nanomolar range, and achieve diverse structural modifications in the non-pharmacophore pocket. By exploiting the S1 accessory pocket or the tunnel region of the PSMA active site, the in vivo efficacy and pharmacokinetic profiles of the PMSA-targeted agents can be effectively modulated.

Structure-activity relationship studies of dipeptide-based hepsin inhibitors with Arg bioisosteres.

Hepsin is a type II transmembrane serine protease (TTSP) associated with cell proliferation and overexpressed in several types of cancer including prostate cancer (PCa). Because of its significant role in cancer progression and metastasis, hepsin is an attractive protein as a potential therapeutic and diagnostic biomarker for PCa. Based on the reported Leu-Arg dipeptide-based hepsin inhibitors, we performed structural modification and determined in vitro hepsin- and matriptase-inhibitory activities. Comprehensive structure-activity relationship studies identified that the p-guanidinophenylalanine-based dipeptide analog 22a exhibited a strong hepsin-inhibitory activity (Ki = 50.5 nM) and 22-fold hepsin selectivity over matriptase. Compound 22a could be a prototype molecule for structural optimization of dipeptide-based hepsin inhibitors.

Structure-activity relationship studies of prostate-specific membrane antigen (PSMA) inhibitors derived from α-amino acid with (S)- or (R)-configuration at P1' region.

Prostate-specific membrane antigen (PSMA), a type II membrane glycoprotein, is considered an excellent target for the diagnosis or treatment of prostate cancer. We previously investigated the effect of ß- and γ-amino acids with (S)- or (R)-configuration in the S1 pocket on the binding affinity for PSMA. However, comprehensive studies on the effect of α-amino acid with (R)-configuration in the S1' pocket has not been reported yet. We selected ZJ-43 (1) and DCIBzL (5) as templates and synthesized their analogues with (S)- or (R)-configuration in the P1 and P1' regions. The PSMA-inhibitory activities of compounds with altered chirality in the P1' region were dropped dramatically, with their IC50 values changing from nM to µM ranges. The compounds with (S)-configuration at both P1 and P1' regions were more potent than the others. The findings of this study may provide insights regarding the structural modification of PSMA inhibitor in the S1' binding pocket.

Novel ß- and γ-Amino Acid-Derived Inhibitors of Prostate-Specific Membrane Antigen.

Prostate-specific membrane antigen (PSMA) is an excellent biomarker for the early diagnosis of prostate cancer progression and metastasis. The most promising PSMA-targeted agents in the clinical phase are based on the Lys-urea-Glu motif, in which Lys and Glu are α-(l)-amino acids. In this study, we aimed to determine the effect of ß- and γ-amino acids in the S1 pocket on the binding affinity for PSMA. We synthesized and evaluated the ß- and γ-amino acid analogues with (S)- or (R)-configuration with keeping α-(l)-Glu as the S1'-binding pharmacophore. The structure-activity relationship studies identified that compound 13c, a ß-amino acid analogue with (R)-configuration, exhibited the most potent PSMA inhibitory activity with an IC50 value of 3.97 nM. The X-ray crystal structure of PSMA in complex with 13c provided a mechanistic basis for the stereochemical preference of PSMA, which can guide the development of future PSMA inhibitors.

Design and synthesis of a novel BODIPY-labeled PSMA inhibitor.

Prostate-specific membrane antigen (PSMA) is a zinc-bound metalloprotease which is highly expressed in metastatic prostate cancer. It has been considered an excellent target protein for prostate cancer imaging and targeted therapy because it is a membrane protein and its active site is located in the extracellular region. We successfully synthesized and evaluated a novel PSMA ligand conjugated with BODIPY650/665. Compound 1 showed strong PSMA-inhibitory activity and selective uptake into PSMA-expressing tumors. Compound 1 has the potential to be utilized as a near infrared (NIR) optical imaging probe targeting PSMA-expressing cancers.

A 769 µW Battery-Powered Single-Chip SoC With BLE for Multi-Modal Vital Sign Monitoring Health Patches.

An all-in-one battery powered low-power SoC for measuring multiple vital signs with wearables is proposed. All functionality needed in a typical wearable use case scenario, including dedicated readouts, power management circuitry, digital signal processing and wireless communication (BLE) is integrated in a single die. This high level of integration allows an unprecedented level of miniaturization leading to smaller component count which reduces cost and improves comfort and signal integrity. The SoC includes an ECG, Bio-Impedance and a fully differential PPG readout and can interface with external sensors (like an IMU). In a typical application scenario where all sensor readouts are enabled and key features (like heart rate) are calculated on the chip and streamed over the radio, the SoC consumes only 769 µW from the regulated 1.2 V supply.

A 665 µW Silicon Photomultiplier-Based NIRS/EEG/EIT Monitoring ASIC for Wearable Functional Brain Imaging.

This paper presents a sub-mW ASIC for multimodal brain monitoring. The ASIC is co-integrated with electrode(s) and optodes (i.e., optical source and detector) as an active sensor to measure electroencephalography (EEG), bio-impedance (BioZ), and near-infrared spectroscopy (NIRS) on scalp. The target is to build a wearable EEG-NIRS headset for low-cost functional brain imaging. The proposed NIRS readout utilizes the near-infrared light to measure the pulse oximetry and blood oxygen saturation (SpO2). While traditional photodiodes are supported, the readout also allows the use of silicon photomultipliers (SiPMs) as optical detectors. The SiPM improves optical sensitivity while significantly reducing the average power of two LEDs to 150 µW. On circuit level, a SAR-based calibration compensates maximum 40 µA current from ambient light, while digital DC-servo loops reduces the baseline static SiPM current up to 400 µA, leading to an overall dynamic range of 87 dB. The EEG readout exhibits 720 MΩ input impedance at 50 Hz. The BioZ readout has 3 mΩ/√(Hz) impedance sensitivity by employing dynamic circuit techniques. When EEG, BioZ, and NIRS are enabled at the same time, one ASIC consumes 665 µW including the power of LEDs.

A 36 µW 1.1 mm2 Reconfigurable Analog Front-End for Cardiovascular and Respiratory Signals Recording.

This paper presents a 1.2 V 36 µW reconfigurable analog front-end (R-AFE) as a general-purpose low-cost IC for multiple-mode biomedical signals acquisition. The R-AFE efficiently reuses a reconfigurable preamplifier, a current generator (CG), and a mixed signal processing unit, having an area of 1.1 mm2 per R-AFE while supporting five acquisition modes to record different forms of cardiovascular and respiratory signals. The R-AFE can interface with voltage-, current-, impedance-, and light-sensors and hence can measure electrocardiography (ECG), bio-impedance (BioZ), photoplethysmogram (PPG), galvanic skin response (GSR), and general-purpose analog signals. Thanks to the chopper preamplifier and the low-noise CG utilizing dynamic element matching, the R-AFE mitigates ${\text{1}}\text{/}f$ noise from both the preamplifier and the CG for improved measurement sensitivity. The IC achieves competitive performance compared to the state-of-the-art dedicated readout ICs of ECG, BioZ, GSR, and PPG, but with approximately 1.4×-5.3× smaller chip area per channel.

A highly sensitive, direct and label-free technique for Hg(2+) detection using Kelvin probe force microscopy.

For several decades, various nanomaterials have been used in a wide range of industrial fields, research areas, and commercial products. Among many nanomaterials, nano-sized mercury materials are one of the most widely used nanomaterials in real life. However, due to the high toxicity of Hg(2+), it is imperative to develop an effective and practical detection method for Hg(2+) to protect human health and environment. In this study, a highly sensitive, label-free method of detecting Hg(2+) that requires only a single drop of solution was developed. The detection mechanism is based on the different surface potential arising from Hg(2+) binding to mismatched thymine-thymine sequences, creating a very stable base pair. The surface potential is measured with Kelvin probe force microscopy (KPFM) to a molecular resolution. The developed method is capable of detecting 2 fmol of Hg(2+), which is 500 times more sensitive than previously reported techniques. Moreover, our method can selectively detect Hg(2+) and can also be applied to tap water and river water. This KPFM-based Hg(2+) detection method can be used as an early detection technique for practical applications.