Ultrasensitive Protein Aggregate Quantification Assays for Neurodegenerative Diseases on the Simoa Platform.

Nanoscale aggregates play a key role in the pathogenesis of neurodegenerative disorders such as Alzheimer's and Parkinson's disease. However, quantifying these aggregates in complex biological samples, such as biofluids and postmortem brain tissue, has been challenging due to their low concentration and small size, necessitating the development of methods with high sensitivity and specificity. Here, we have developed ultrasensitive assays utilizing the Quanterix Simoa platform to detect α-synuclein, β-amyloid and tau aggregates, including those with common posttranslational modifications such as truncation of α-synuclein and AT8 phosphorylation of tau aggregates.

Mapping and visualization of global research progress on deubiquitinases in ovarian cancer: a bibliometric analysis.

Background: Ovarian cancer is a highly aggressive malignancy with limited therapeutic options and a poor prognosis. Deubiquitinating enzymes (DUBs) have emerged as critical regulators of protein ubiquitination and proteasomal degradation, influencing various cellular processes relevant to cancer pathogenesis. In this study, the research progress between ovarian cancer and DUBs was mapped and visualized using bibliometrics, and the expression patterns and biological roles of DUBs in ovarian cancer were summarized.

Pore Classification and Structural Characteristics of Oligocene-Pliocene Shale Reservoirs in the Western Qaidam Depression.

Oligocene-Pliocene shale reservoirs in the Western Qaidam Depression represent typical mixed shale deposits characterized by moderate organic matter (OM) abundance and sufficient OM maturity, indicating substantial shale-oil resource potential. Here, a comprehensive study was conducted to analyze the reservoir characteristics of different shale types, including the Upper Xiaganchaigou (late Oligocene), Shangganchaigou (Miocene), and Xiayoushashan (early Pliocene) Formations in the Western Qaidam Depression. Our analysis focused on the pore structural characteristics of shale reservoirs, employing X-ray diffraction, casting thin sections, scanning electron microscopy, low-temperature nitrogen adsorption, and nuclear magnetic resonance (NMR) as investigative techniques.

Cerebral organoids with chromosome 21 trisomy secrete Alzheimer's disease-related soluble aggregates detectable by single-molecule-fluorescence and super-resolution microscopy.

Understanding the role of small, soluble aggregates of beta-amyloid (Aβ) and tau in Alzheimer's disease (AD) is of great importance for the rational design of preventative therapies. Here we report a set of methods for the detection, quantification, and characterisation of soluble aggregates in conditioned media of cerebral organoids derived from human iPSCs with trisomy 21, thus containing an extra copy of the amyloid precursor protein (APP) gene. We detected soluble beta-amyloid (Aβ) and tau aggregates secreted by cerebral organoids from both control and the isogenic trisomy 21 (T21) genotype.

A computational suite for the structural and functional characterization of amyloid aggregates.

We developed the aggregate characterization toolkit (ACT), a fully automated computational suite based on existing and widely used core algorithms to measure the number, size, and permeabilizing activity of recombinant and human-derived aggregates imaged with diffraction-limited and super-resolution microscopy methods at high throughput. We have validated ACT on simulated ground-truth images of aggregates mimicking those from diffraction-limited and super-resolution microscopies and showcased its use in characterizing protein aggregates from Alzheimer's disease. ACT is developed for high-throughput batch processing of images collected from multiple samples and is available as an open-source code.

Characterization of full-length p53 aggregates and their kinetics of formation.

Mutations in the TP53 gene are common in cancer with the R248Q missense mutation conferring an increased propensity to aggregate. Previous p53 aggregation studies showed that, at micromolar concentrations, protein unfolding to produce aggregation-prone species is the rate-determining step. Here we show that, at physiological concentrations, aggregation kinetics of insect cell-derived full-length wild-type p53 and p53R248Q are determined by a nucleation-growth model, rather than formation of aggregation-prone monomeric species.

Constructing a cost-efficient, high-throughput and high-quality single-molecule localization microscope for super-resolution imaging.

Single-molecule localization microscopy (SMLM) leverages the power of modern optics to unleash ultra-precise structural nanoscopy of complex biological machines in their native environments as well as ultra-sensitive and high-throughput medical diagnostics with the sensitivity of a single molecule. To achieve this remarkable speed and resolution, SMLM setups are either built by research laboratories with strong expertise in optical engineering or commercially sold at a hefty price tag. The inaccessibility of SMLM to life scientists for technical or financial reasons is detrimental to the progress of biological and biomedical discoveries reliant on super-resolution imaging.

Parthenolide reveals an allosteric mode to inhibit the deISGylation activity of SARS-CoV‑2 papain-like protease.

The coronavirus papain-like protease (PLpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for viral polypeptide cleavage and the deISGylation of interferon-stimulated gene 15 (ISG15), which enable it to participate in virus replication and host innate immune pathways. Therefore, PLpro is considered an attractive antiviral drug target. Here, we show that parthenolide, a germacrane sesquiterpene lactone, has SARS-CoV-2 PLpro inhibitory activity.

IKZF1 selectively enhances homologous recombination repair by interacting with CtIP and USP7 in multiple myeloma.

In multiple myeloma (MM), the activities of non-homologous end joining (NHEJ) and homologous recombination repair (HR) are increased compared with healthy controls. Whether and how IKZF1 as an enhancer of MM participates in the DNA repair pathway of tumor cells remains elusive. We used an endonuclease AsiSI-based system and quantitative chromatin immunoprecipitation assay (qChIP) analysis to test whether IKZF1 is involved in DNA repair.

An economic, square-shaped flat-field illumination module for TIRF-based super-resolution microscopy.

Super-resolution microscopy allows complex biological assemblies to be observed with remarkable resolution. However, the presence of uneven Gaussian-shaped illumination hinders its use in quantitative imaging or high-throughput assays. Methods developed to circumvent this problem are often expensive, hard to implement, or not applicable to total internal reflection fluorescence imaging.

ZCL-082, a boron-containing compound, induces apoptosis of non-Hodgkin's lymphoma via targeting p90 ribosomal S6 kinase 1/NF-κB signaling pathway.

Introduction: Despite the rapid progress in the diagnosis and treatment, the prognosis of some types of non-Hodgkin's lymphoma (NHL), especially those with double-hit or double-expressor genotypes, remains poor. Novel targets and compounds are needed to improve the prognosis of NHL.

Methods: We investigated the effect of ZCL-082, a novel boron-containing compound with anti-proliferating activity against ovarian cancer cells, on NHL cells and human peripheral blood mononuclear cells by CCK-8 assay, Annexin V/PI double staining assay, RH123/PI double staining, Western blot, and immunohistochemistry.

Hsp90/C terminal Hsc70-interacting protein regulates the stability of Ikaros in acute myeloid leukemia cells.

The stability of Ikaros family zinc finger protein 1 (Ikaros), a critical hematopoietic transcription factor, can be regulated by cereblon (CRBN) ubiquitin ligase stimulated by immunomodulatory drugs in multiple myeloma. However, other stabilization mechanisms of Ikaros have yet to be elucidated. In this study, we show that the pharmacologic inhibition or knockdown of Hsp90 downregulates Ikaros in acute myeloid leukemia (AML) cells.

Targeting USP47 overcomes tyrosine kinase inhibitor resistance and eradicates leukemia stem/progenitor cells in chronic myelogenous leukemia.

Identifying novel drug targets to overcome resistance to tyrosine kinase inhibitors (TKIs) and eradicating leukemia stem/progenitor cells are required for the treatment of chronic myelogenous leukemia (CML). Here, we show that ubiquitin-specific peptidase 47 (USP47) is a potential target to overcome TKI resistance. Functional analysis shows that USP47 knockdown represses proliferation of CML cells sensitive or resistant to imatinib in vitro and in vivo.

Wu-5, a novel USP10 inhibitor, enhances crenolanib-induced FLT3-ITD-positive AML cell death via inhibiting FLT3 and AMPK pathways.

The kinase FLT3 internal tandem duplication (FLT3-ITD) is related to poor clinical outcomes of acute myeloid leukemia (AML). FLT3 inhibitors have provided novel strategies for the treatment of FLT3-ITD-positive AML. But they are limited by rapid development of acquired resistance and refractory in monotherapy.

Intelligent classification of platelet aggregates by agonist type.

Platelets are anucleate cells in blood whose principal function is to stop bleeding by forming aggregates for hemostatic reactions. In addition to their participation in physiological hemostasis, platelet aggregates are also involved in pathological thrombosis and play an important role in inflammation, atherosclerosis, and cancer metastasis. The aggregation of platelets is elicited by various agonists, but these platelet aggregates have long been considered indistinguishable and impossible to classify.

Intelligent frequency-shifted optofluidic time-stretch quantitative phase imaging.

Optofluidic time-stretch quantitative phase imaging (OTS-QPI) is a powerful tool as it enables high-throughput (>10,000 cell/s) QPI of single live cells. OTS-QPI is based on decoding temporally stretched spectral interferograms that carry the spatial profiles of cells flowing on a microfluidic chip. However, the utility of OTS-QPI is troubled by difficulties in phase retrieval from the high-frequency region of the temporal interferograms, such as phase-unwrapping errors, high instrumentation cost, and large data volume.

Fused tetraphenylethylene-triphenylamine as an efficient hole transporting material in perovskite solar cells.

A fused tetraphenylethylene-based hole transporting material shows higher power conversion efficiency and better stability compared with its non-fused counterpart, and the former molecule even outperforms the conventional spiro-OMeTAD.

A novel "mosaic-type" nanoparticle for selective drug release targeting hypoxic cancer cells.

The surface potential of particles is a double-edged sword for nanomedicine. The negative charge can protect nanoparticles from clearance before they reach the tumor tissue; however, it is difficult to phagocytose the negative particles by target cells due to the negative potential of the cytomembrane. Preparing techniques to efficiently release the encapsulated drug from negative nanoparticles into target cells is a formidable challenge facing advanced drug delivery studies.

Characterization of naturally occurring pentacyclic triterpenes as novel inhibitors of deubiquitinating protease USP7 with anticancer activity in vitro.

Deubiquitinating protease USP7 is a promising therapeutic target for cancer treatment, and interest in developing USP7 inhibitors has greatly increased. In the present study, we reported a series of natural pentacyclic triterpenes with USP7 inhibitory activity in vitro. Among them, both the ursane triterpenes and oleanane triterpenes were more active than the lupine triterpenes, whereas ursolic acid was the most potent with IC of 7.

CDDO-Me reveals USP7 as a novel target in ovarian cancer cells.

Deubiquitinating enzyme USP7 has been involved in the pathogenesis and progression of several cancers. Targeting USP7 is becoming an attractive strategy for cancer therapy. In this study, we identified synthetic triterpenoid C-28 methyl ester of 2-cyano-3, 12-dioxoolen-1, 9-dien-28-oic acid (CDDO-Me) as a novel inhibitor of USP7 but not of other cysteine proteases such as cathepsin B and cathepsin D.

Modeling the reflectance of the lunar regolith by a new method combining Monte Carlo Ray tracing and Hapke's model with application to Chang'E-1 IIM data.

In this paper, we model the reflectance of the lunar regolith by a new method combining Monte Carlo ray tracing and Hapke's model. The existing modeling methods exploit either a radiative transfer model or a geometric optical model. However, the measured data from an Interference Imaging spectrometer (IIM) on an orbiter were affected not only by the composition of minerals but also by the environmental factors.