Simulated total PSA and PSA produced by drug-sensitive and drug-resistant tumor cells in representative subjects.

4A and 4B demonstrate simulated PSA levels in a “responder” Subject A and a “partial responder” Subject B, respectively. Black line represents model predicted total PSA level. Pink and grey solid lines represent model predicted PSA from drug-sensitive and drug-resistant tumor cells, respectively. Red and green vertical dashed lines represent the first and the last recorded date of leuprorelin treatment, respectively. Blue horizontal dotted line represents the lower limit of quantification (LLOQ) of the PSA assay.</p

Parameter estimates of the final PSA kinetics model.

Parameter estimates of the final PSA kinetics model.</p

Profiles of PSA kinetics in representative patients with hormone-sensitive prostate cancer.

Black line represents model-predicted PSA levels. Open circles and solid circles represent observed PSA levels above the lower limit of quantification (LLOQ) and observed PSA levels below the LLOQ, respectively. Red and green vertical dashed lines represent the first and the last recorded date of leuprorelin treatment, respectively. Blue horizontal dotted line represents the LLOQ value of the PSA assay. Black arrows represent the fill dates of leuprolide.</p

Diagnostic plots for the final disease progression model.

From left to right and top to bottom: Observed log PSA concentrations (DV) versus individual log predicted values (IPRED), individual weighted residuals (IWRES) versus the IPRED, IWRES versus time, and expected conditional weighted residuals (ECWRES) versus the expected log predicted values (EPRED). The red line represents the loess regression line.</p

Simulation results for percentages of subjects with PSA progression within one, two, and three years.

3A and 3B show simulated PSA progression in subjects with 5th percentile, median and 95th percentile of hemoglobin level and baseline PSA level, respectively.</p

Summary of baseline demographic data and laboratory values of subjects included in model development.

Summary of baseline demographic data and laboratory values of subjects included in model development.</p

Flexible High-Temperature MoS₂ Field-Effect Transistors and Logic Gates

High-temperature-resistant integrated circuits with excellent flexibility, a high integration level (nanoscale transistors), and low power consumption are highly desired in many fields, including aerospace. Compared with conventional SiC high-temperature transistors, transistors based on two-dimensional (2D) MoS2 have advantages of superb flexibility, atomic scale, and ultralow power consumption. However, MoS2 cannot survive at high temperature and drastically degrades above 200 °C. Here, we report MoS2 field-effect transistors (FETs) with top/bottom hexagonal boron nitride (h-BN) encapsulation and graphene electrodes. With the protection of the h-BN/h-BN structure, the devices can survive at much higher temperature (≥500 °C in air) than those of the MoS2 devices ever reported, which provides us an opportunity to explore the electrical properties and working mechanism of MoS2 devices at high temperature. Unlike the relatively low-temperature situation, the on/off ratio and subthreshold swing of MoS2 FETs show drastic variation at elevated temperature due to the injection of thermal emission carriers. Compared with metal electrode, devices with a graphene electrode demonstrate superior performance at high temperature (∼1-order-larger current on/off ratio, 3–7 times smaller subthreshold swing, and 5–9 times smaller threshold voltage shift). We further realize that the flexible CMOS NOT gate based on the above technique, and demonstrate logic computing at 550 °C. This work may stimulate the fundamental research of properties of 2D materials at high temperature, and also creates conditions for next-generation flexible harsh-environment-resistant integrated circuits

Two-Dimensional Transition Metal Dichalcogenide Tunnel Field-Effect Transistors for Biosensing Applications

Field-effect transistor (FET) biosensors based on two-dimensional (2D) materials have drawn significant attention due to their outstanding sensitivity. However, the Boltzmann distribution of electrons imposes a physical limit on the subthreshold swing (SS), and a 2D-material biosensor with sub-60 mV/dec SS has not been realized, which hinders further increase of the sensitivity of 2D-material FET biosensors. Here, we report tunnel FETs (TFETs) based on a SnSe2/WSe2 heterostructure and observe the tunneling effect of a 2D material in aqueous solution for the first time with an ultralow SS of 29 mV/dec. A bilayer dielectric (Al2O3/HfO2) and graphene contacts, which significantly reduce the leakage current in solution and contact resistance, respectively, are crucial to the realization of the tunneling effect in solution. Then, we propose a novel biosensing method by using tunneling current as the sensing signal. The TFETs show an extremely high pH sensitivity of 895/pH due to ultralow SS, surpassing the sensitivity of FET biosensors based on a single 2D material (WSe2) by 8-fold. Specific detection of glucose is realized, and the biosensors show a superb sensitivity (3158 A/A for 5 mM), wide sensing range (from 10–9 to 10–3 M), low detection limit (10–9 M), and rapid response rate (11 s). The sensors also exhibit the ability of monitoring glucose in complex biofluid (sweat). This work provides a platform for ultrasensitive biosensing. The discovery of the tunneling effect of 2D materials in aqueous solution may stimulate further fundamental research and potential applications

Data_Sheet_1_Evaluation of partial volume correction and analysis of longitudinal [18F]GTP1 tau PET imaging in Alzheimer's disease using linear mixed-effects models.PDF

PurposeWe evaluated the impact of partial volume correction (PVC) methods on the quantification of longitudinal [18F]GTP1 tau positron-emission tomography (PET) in Alzheimer's disease and the suitability of describing the tau pathology burden temporal trajectories using linear mixed-effects models (LMEM).MethodsWe applied van Cittert iterative deconvolution (VC), 2-compartment, and 3-compartment, and the geometric transfer matrix plus region-based voxelwise methods to data acquired in an Alzheimer's disease natural history study over 18 months at a single imaging site. We determined the optimal PVC method by comparing the standardized uptake value ratio change (%ΔSUVR) between diagnostic and tau burden–level groups and the longitudinal repeatability derived from the LMEM. The performance of LMEM analysis for calculating %ΔSUVR was evaluated in a natural history study and in a multisite clinical trial of semorinemab in prodromal to mild Alzheimer's disease by comparing results to traditional per-visit estimates.ResultsThe VC, 2-compartment, and 3-compartment PVC methods had similar performance, whereas region-based voxelwise overcorrected regions with a higher tau burden. The lowest within-subject variability and acceptable group separation scores were observed without PVC. The LMEM-derived %ΔSUVR values were similar to the per-visit estimates with lower variability.ConclusionThe results indicate that the tested PVC methods do not offer a clear advantage or improvement over non-PVC images for the quantification of longitudinal [18F]GTP1 PET data. LMEM offers a robust framework for the longitudinal tau PET quantification with low longitudinal test–retest variability.Clinical trial registrationNCT02640092 and NCT03289143.</p

Table2_Investigation of the Pharmacological Effect and Mechanism of Jinbei Oral Liquid in the Treatment of Idiopathic Pulmonary Fibrosis Using Network Pharmacology and Experimental Validation.XLSX

Overview: Idiopathic pulmonary fibrosis (IPF) is a disease caused by many factors, eventually resulting in lung function failure. Jinbei oral liquid (JBOL) is a traditional Chinese clinical medicine used to treat pulmonary diseases. However, the pharmacological effects and mechanism of the action of JBOL on IPF remain unclear. This study investigated the protective effects and mechanism of the action of JBOL on IPF using network pharmacology analysis, followed by in vivo and in vitro experimental validation.Methods: The components of JBOL and their targets were screened using the TCMSP database. IPF-associated genes were obtained using DisGeNET and Drugbank. The common targets of JBOL and IPF were identified with the STRING database, and a protein–protein interaction (PPI) network was constructed. GO and KEGG analyses were performed. Sprague–Dawley rats were injected with bleomycin (BLM) to establish an IPF model and treated orally with JBOL at doses of 5.4, 10.8, and 21.6 ml/kg. A dose of 54 mg/kg of pirfenidone was used as a control. All rats were treated for 28 successive days. Dynamic pulmonary compliance (Cdyn), minute ventilation volume (MVV), vital capacity (VC), and lung resistance (LR) were used to evaluate the efficacy of JBOL. TGF-β–treated A549 cells were exposed to JBOL, and epithelial-to-mesenchymal transition (EMT) changes were assessed. Western blots were performed.Results: Two hundred seventy-eight compounds and 374 targets were screened, and 103 targets related to IPF were identified. Core targets, including MAPK1 (ERK2), MAPK14 (p38), JUN, IL-6, AKT, and others, were identified by constructing a PPI network. Several pathways were involved, including the MAPK pathway. Experimentally, JBOL increased the levels of the pulmonary function indices (Cdyn, MVV, and VC) in a dose-dependent manner and reduced the RL level in the BLM-treated rats. JBOL increased the epithelial marker E-cadherin and suppressed the mesenchymal marker vimentin expression in the TGF-β–treated A549 cells. The suppression of ERK1/2, JNK, and p38 phosphorylation by JBOL was validated.Conclusion: JBOL had therapeutic effects against IPF by regulating pulmonary function and EMT through a systemic network mechanism, thus supporting the need for future clinical trials of JBOL.</p