Structure and mechanogating of the mammalian tactile channel PIEZO2.

PIEZO2 is a mechanosensitive cation channel that has a key role in sensing touch, tactile pain, breathing and blood pressure. Here we describe the cryo-electron microscopy structure of mouse PIEZO2, which is a three-bladed, propeller-like trimer that comprises 114 transmembrane helices (38 per protomer). Transmembrane helices 1-36 (TM1-36) are folded into nine tandem units of four transmembrane helices each to form the unusual non-planar blades. The three blades are collectively curved into a nano-dome of 28-nm diameter and 10-nm depth, with an extracellular cap-like structure embedded in the centre and a 9-nm-long intracellular beam connecting to the central pore. TM38 and the C-terminal domain are surrounded by the anchor domain and TM37, and enclose the central pore with both transmembrane and cytoplasmic constriction sites. Structural comparison between PIEZO2 and its homologue PIEZO1 reveals that the transmembrane constriction site might act as a transmembrane gate that is controlled by the cap domain. Together, our studies provide insights into the structure and mechanogating mechanism of Piezo channels.

Organic-Hydrochloride-Modified ZnO Electron Transport Layer for Efficient Defect Passivation and Stress Release in Rigid and Flexible all Inorganic Perovskite Solar Cells.

All inorganic CsPbI2Br perovskite (AIP) has attracted great attention due to its excellent resistance against thermal stress as well as the remarkable capability to deliver high-voltage output. However, CsPbI2Br perovskite solar cells (PeSCs) still encounter critical challenges in attaining both high efficiency and mechanical stability for commercial applications. In this work, formamidine disulfide dihydrochloride (FADD) modified ZnO electron transport layer (ETL) has been developed for fabricating inverted devices on either rigid or flexible substrate. It is found that the FADD modification leads to efficient defects passivation, thereby significantly reducing charge recombination at the AIP/ETL interface. As a result, rigid PeSCs (r-PeSCs) deliver an enhanced efficiency of 16.05% and improved long-term thermal stability. Moreover, the introduced FADD can regulate the Young's modulus (or Derjaguin-Muller-Toporov (DMT) modilus) of ZnO ETL and dissipate stress concentration at the AIP/ETL interface, effectively restraining the crack generation and improving the mechanical stability of PeSCs. The flexible PeSCs (f-PeSCs) exhibit one of the best performances so far reported with excellent stability against 6000 bending cycles at a curvature radius of 5 mm. This work thus provides an effective strategy to simultaneously improve the photovoltaic performance and mechanical stability.

Visible Light-Activated Ultralong-Lived Triplet Excitons of Carbon Dots for White-Light Manipulated Anti-Counterfeiting.

Room temperature phosphorescence (RTP) has emerged as an interesting but rare phenomenon with multiple potential applications in anti-counterfeiting, optoelectronic devices, and biosensing. Nevertheless, the pursuit of ultralong lifetimes of RTP under visible light excitation presents a significant challenge. Here, new phosphorescent materials that can be excited by visible light with record-long lifetimes are demonstrated, realized through embedding nitrogen doped carbon dots (N-CDs) into a poly(vinyl alcohol) (PVA) film. The RTP lifetime of the N-CDs@PVA film is remarkably extended to 2.1 s excited by 420 nm, representing the highest recorded value for visible light-excited phosphorescent materials. Theoretical and experimental studies reveal that the robust hydrogen bonding interactions can effectively reduce the non-radiative decay rate and radiative transition rate of triplet excitons, thus dramatically prolong the phosphorescence lifetime. Notably, the RTP emission of N-CDs@PVA film can also be activated by easily accessible low-power white-light-emitting diode. More significantly, the practical applications of the N-CDs@PVA film in state-of-the-art anti-counterfeiting security and optical information storage domains are further demonstrated. This research offers exciting opportunities for utilizing visible light-activated ultralong-lived RTP systems in a wide range of promising applications.

Macrophage and fibroblast trajectory inference and crosstalk analysis during myocardial infarction using integrated single-cell transcriptomic datasets.

BACKGROUND: Cardiac fibrosis after myocardial infarction (MI) has been considered an important part of cardiac pathological remodeling. Immune cells, especially macrophages, are thought to be involved in the process of fibrosis and constitute a niche with fibroblasts to promote fibrosis. However, the diversity and variability of fibroblasts and macrophages make it difficult to accurately depict interconnections. METHODS: We collected and reanalyzed scRNA-seq and snRNA-seq datasets from 12 different studies. Differentiation trajectories of these subpopulations after MI injury were analyzed by using scVelo, PAGA and Slingshot. We used CellphoneDB and NicheNet to infer fibroblast-macrophage interactions. Tissue immunofluorescence staining and in vitro experiments were used to validate our findings. RESULTS: We discovered two subsets of ECM-producing fibroblasts, reparative cardiac fibroblasts (RCFs) and matrifibrocytes, which appeared at different times after MI and exhibited different transcriptional profiles. We also observed that CTHRC1+ fibroblasts represent an activated fibroblast in chronic disease states. We identified a macrophage subset expressing the genes signature of SAMs conserved in both human and mouse hearts. Meanwhile, the SPP1hi macrophages were predominantly found in the early stages after MI, and cell communication analysis indicated that SPP1hi macrophage-RCFs interactions are mainly involved in collagen deposition and scar formation. CONCLUSIONS: Overall, this study comprehensively analyzed the dynamics of fibroblast and macrophage subsets after MI and identified specific subsets of fibroblasts and macrophages involved in scar formation and collagen deposition.

Two-dimensionally high AR performance beam scanning utilizing randomly-rotated single-PIN-diode elements for circularly-polarized programmable metasurface.

In this paper, we introduce a novel technique that utilizes randomly rotated elements (RREs) for the cross-polarization and axial ratio (AR) control of a circularly polarized programmable metasurface (CPPMS). We evaluate the CPPMS performance by comparing RREs layout with uniform elements (UEs) layout, and analyze far-field radiation parameters for 50 groups of CPPMS with different RREs layouts. Simulation results demonstrate consistent and improved performance across various RREs layouts, showcasing reduced cross-polarization and enhanced AR beamwidth. To validate these findings, we design a 1-bit CPPMS in Ku-band comprising 20 × 20 elements with the optimal RREs layout, and conduct measurements in an anechoic chamber. The CPPMS prototype achieves high gain (22.34 dBi), low cross-polarization (-20.5 dB), and a narrow 3 dB AR beamwidth (8.93°). Notably, it offers wide-angle beam scanning capabilities of up to ±60°. The gain bandwidth at -3 dB ranges from 14.54 to 16.65 GHz, with a relative bandwidth of 7.3%, while the 3 dB AR bandwidth extends from 14.24 to 16.07 GHz. Consequently, the proposed 1-bit CPPMS exhibits high-performance two-dimensional AR beam scanning, presenting promising applications in satellite communications.

3D parallel pulsed chaos LiDAR system.

We propose and experimentally demonstrate a parallel pulsed chaos light detection and ranging (LiDAR) system with a high peak power, parallelism, and anti-interference. The system generates chaotic microcombs based on a chip-scale Si3N4 microresonator. After passing through an acousto-optic modulator, the continuous-wave chaotic microcomb can be transformed into a pulsed chaotic microcomb, in which each comb line provides pulsed chaos. Thus, a parallel pulsed chaos signal is generated. Using the parallel pulsed chaos as the transmission signal of LiDAR, we successfully realize a 4-m three-dimensional imaging experiment using a microelectromechanical mirror for laser scanning. The experimental results indicate that the parallel pulsed chaos LiDAR can detect twice as many pixels as direct detection continuous wave parallel chaos LiDAR under a transmission power of -6 dBm, a duty cycle of 25%, and a pulse repetition frequency of 100 kHz. By further increasing the transmission power to 10 dBm, we acquire an 11 cm × 10 cm image of a target scene with a resolution of 30 × 50 pixels. Finally, the anti-jamming ability of the system is evaluated, and the results show that the system can withstand interferences of at least 15 dB.

40 Gb/s multimode all-optical regenerator based on the low-loss silicon-based nanowaveguide.

With the increasing demand for communication capacity, all-optical regeneration of multimode signals is a helpful technology of network nodes and optical signal processors. However, the difficulty of regenerating signal in higher-order modes hinders the practical application of multimode all-optical regenerators. In this study, we experimentally demonstrate the 40 Gb/s all-optical regeneration of NRZ-OOK signal in TE0 and TE1 modes via four-wave mixing (FWM) in the low-loss silicon-based nanowaveguide. By optimizing the parameters of waveguide section to enhance FWM conversion efficiency of two modes, and introducing Euler bending to reduce crosstalk between modes, the transmission loss of the silicon waveguide is 0.3 dB/cm, and the FWM conversion efficiency of the multimode regenerator is as high as -9.6 dB (TE0) and -13.0 dB (TE1). Both modes achieve extinction ratio enhancement of about 6 dB after regeneration. This silicon-based all-optical regenerator has great application potential in all-optical signal processing systems.

A phase 1 trial of the MEK inhibitor selumetinib in combination with pembrolizumab for advanced or metastatic solid tumors.

MEK inhibitors have immunomodulatory activity and potential for synergistic activity when combined with PD-1 inhibitors. We evaluated selumetinib (inhibitor of MEK1/2) plus pembrolizumab (anti‒PD-1 antibody) in patients with advanced/metastatic solid tumors. In this phase 1b study, adults with previously treated advanced/metastatic solid tumors received pembrolizumab 200 mg intravenously every 3 weeks plus selumetinib on days 1‒14 per 3-week cycle (2 weeks on/1 week off); selumetinib dosing began at 50 mg orally twice daily with escalation in 25 mg increments for ≤ 35 cycles. Primary endpoints were dose-limiting toxicities (DLTs), adverse events (AEs), and treatment discontinuations due to AEs. Thirty-two patients were enrolled. Dose escalation was completed up to selumetinib 125 mg twice daily. The target DLT rate of 30% was not reached at any dose level. In the selumetinib 100 mg group, 2/11 patients (18.2%) experienced DLTs (n = 1 grade 3 diarrhea, n = 1 grade 3 fatigue). In the selumetinib 125 mg group, 3/14 (21.4%) experienced DLTs (n = 1 grade 2 retinal detachment, n = 1 grade 3 retinopathy, n = 1 grade 3 stomatitis). Dose-related changes in pharmacokinetic exposures were observed for selumetinib and N-desmethyl selumetinib up to 100 mg (saturation at 125 mg). Two patients achieved partial responses (1 each with selumetinib 75 mg and 125 mg) for an objective response rate of 6%. The study was stopped early because of insufficient efficacy. Although the target DLT rate was not reached at any dose level and no new safety signals were identified, selumetinib plus pembrolizumab had limited antitumor activity in this population. Trial registration: ClinicalTrials.gov , NCT03833427.

Optimizing auxiliary laser heating for Kerr soliton microcomb generation.

Auxiliary laser heating has become a widely adopted method for Kerr soliton frequency comb generation in optical microcavities, thanks to its reliable and easy-to-achieve merits for solving the thermal instability during the formation of dissipative Kerr solitons. Here, we conduct optimization of auxiliary laser heating by leveraging the distinct loss and absorption characteristics of different longitudinal and polarization cavity modes. We show that even if the auxiliary and pump lasers enter orthogonal polarization modes, their mutual photothermal balance can be efficient enough to maintain a cavity thermal equilibrium as the pump laser enters the red-detuning soliton regime, and by choosing the most suitable resonance for the auxiliary and pump lasers, the auxiliary laser power can be reduced to 20% of the pump laser and still be capable of warranting soliton generation. Moreover, we demonstrate soliton comb generation using integrated laser modules with a few milliwatt on-chip pump and auxiliary powers, showcasing the potential for further chip integration of the auxiliary laser heating method.

System-wide identification of novel de-ubiquitination targets for USP10 in gastric cancer metastasis through multi-omics screening.

OBJECTIVE: Ubiquitin-specific peptidase 10 (USP10), a typical de-ubiquitinase, has been found to play a double-edged role in human cancers. Previously, we reported that the expression of USP10 was negatively correlated with the depth of gastric wall invasion, lymph node metastasis, and prognosis in gastric cancer (GC) patients. However, it remains unclear whether USP10 can regulate the metastasis of GC cells through its de-ubiquitination function. METHODS: In this study, proteome, ubiquitinome, and transcriptome analyses were conducted to comprehensively identify novel de-ubiquitination targets for USP10 in GC cells. Subsequently, a series of validation experiments, including in vitro cell culture studies, in vivo metastatic tumor models, and clinical sample analyses, were performed to elucidate the regulatory mechanism of USP10 and its de-ubiquitination targets in GC metastasis. RESULTS: After overexpression of USP10 in GC cells, 146 proteins, 489 ubiquitin sites, and 61 mRNAs exhibited differential expression. By integrating the results of multi-omics, we ultimately screened 9 potential substrates of USP10, including TNFRSF10B, SLC2A3, CD44, CSTF2, RPS27, TPD52, GPS1, RNF185, and MED16. Among them, TNFRSF10B was further verified as a direct de-ubiquitination target for USP10 by Co-IP and protein stabilization assays. The dysregulation of USP10 or TNFRSF10B affected the migration and invasion of GC cells in vitro and in vivo models. Molecular mechanism studies showed that USP10 inhibited the epithelial-mesenchymal transition (EMT) process by increasing the stability of TNFRSF10B protein, thereby regulating the migration and invasion of GC cells. Finally, the retrospective clinical sample studies demonstrated that the downregulation of TNFRSF10B expression was associated with poor survival among 4 of 7 GC cohorts, and the expression of TNFRSF10B protein was significantly negatively correlated with the incidence of distant metastasis, diffuse type, and poorly cohesive carcinoma. CONCLUSIONS: Our study established a high-throughput strategy for screening de-ubiquitination targets for USP10 and further confirmed that inhibiting the ubiquitination of TNFRSF10B might be a promising therapeutic strategy for GC metastasis.

Multitask Deep Learning-Based Whole-Process System for Automatic Diagnosis of Breast Lesions and Axillary Lymph Node Metastasis Discrimination from Dynamic Contrast-Enhanced-MRI: A Multicenter Study.

BACKGROUND: Accurate diagnosis of breast lesions and discrimination of axillary lymph node (ALN) metastases largely depend on radiologist experience. PURPOSE: To develop a deep learning-based whole-process system (DLWPS) for segmentation and diagnosis of breast lesions and discrimination of ALN metastasis. STUDY TYPE: Retrospective. POPULATION: 1760 breast patients, who were divided into training and validation sets (1110 patients), internal (476 patients), and external (174 patients) test sets. FIELD STRENGTH/SEQUENCE: 3.0T/dynamic contrast-enhanced (DCE)-MRI sequence. ASSESSMENT: DLWPS was developed using segmentation and classification models. The DLWPS-based segmentation model was developed by the U-Net framework, which combined the attention module and the edge feature extraction module. The average score of the output scores of three networks was used as the result of the DLWPS-based classification model. Moreover, the radiologists' diagnosis without and with the DLWPS-assistance was explored. To reveal the underlying biological basis of DLWPS, genetic analysis was performed based on RNA-sequencing data. STATISTICAL TESTS: Dice similarity coefficient (DI), area under receiver operating characteristic curve (AUC), accuracy, sensitivity, specificity, and kappa value. RESULTS: The segmentation model reached a DI of 0.828 and 0.813 in the internal and external test sets, respectively. Within the breast lesions diagnosis, the DLWPS achieved AUCs of 0.973 in internal test set and 0.936 in external test set. For ALN metastasis discrimination, the DLWPS achieved AUCs of 0.927 in internal test set and 0.917 in external test set. The agreement of radiologists improved with the DLWPS-assistance from 0.547 to 0.794, and from 0.848 to 0.892 in breast lesions diagnosis and ALN metastasis discrimination, respectively. Additionally, 10 breast cancers with ALN metastasis were associated with pathways of aerobic electron transport chain and cytoplasmic translation. DATA CONCLUSION: The performance of DLWPS indicates that it can promote radiologists in the judgment of breast lesions and ALN metastasis and nonmetastasis. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY STAGE: 3.

Eco-Friendly Production of Boron Nitride Nanosheets via Deep Eutectic Solvents and Their Application in Enhancing Thermal Conductivity of PVDF Composites.

Boron nitride nanosheets (BNNS) are expected to be ideal fillers because of their high thermal conductivity and excellent electrical insulation. However, it is still an open challenge to produce BNNS on a large scale using ecofriendly solvents. Here, first, we demonstrate an effective liquid exfoliation method for producing BNNS via utilizing deep eutectic solvents (DES) composed of D,L-menthol and various acids with the assistance of ultrasonication. The results show that the BNNSs with sizes of 1-2 µm in width and 6-8 nm in thickness were successfully exfoliated with a DES formulation of D,L-menthol and decanoic acid. Second, the obtained BNNSs were used for fabricating 1,6-hexanediol diacrylate@polydopamine functionalized BNNS (HDDA@BNNSs-PDA) core-shell microspheres via a Pickering emulsion method. Furthermore, these microspheres were incorporated into a polyvinylidene fluoride (PVDF) matrix to construct 3D thermally conductive networks, leading to a substantial enhancement in the thermal conductivity of the resulting composites. Impressively, the composites with only 25 wt % of BNNS loading reach a high thermal conductivity of 3.20 W/m K, which is a 1500% increase over the pure polymer matrix. This work not only provides a significant way for producing BNNSs ecofriendly but also demonstrates a tactic for constructing 3D thermally conductive networks.

Prevalence of homologous recombination biomarkers in multiple tumor types: an observational study.

Aim: To determine the prevalence of deleterious mutations in BRCA1 and BRCA2 and in 13 genes involved in homologous recombination repair (HRR), the prevalence of genomic loss of heterozygosity and the allelic and hereditary status of BRCA1, BRCA2 and other HRR gene mutations in multiple solid tumor types. Patients & methods: This was a retrospective observational study of patients with an advanced/metastatic diagnosis in one of 15 solid tumor types, who were identified in a real-world clinico-genomic database. Results: Tumor tissue samples from 9457 patients were analyzed, among which 4.7% had known or suspected deleterious BRCA1/2 mutations. The prevalence (range) of mutations in HRR genes was 13.6% (2.4%-26.0%) and genomic loss of heterozygosity ≥16% was 20.6% (2.6-34.4%) across all tumor types. Conclusion: The prevalence of mutations varied significantly depending on the type of tumor.

The integrity of the human genome is maintained via multiple pathways of DNA repair, one of the most important of which is homologous recombination repair (HRR), which uses a sister chromatid as a template for high-fidelity restoration of altered DNA sequences. This study aimed to determine the prevalence of deleterious mutations, i.e., changes in the genetic code that interfere with proper cellular function, in the breast cancer genes BRCA1 and BRCA2 and in 13 other genes involved in HRR in various types of solid tumors in patients with advanced or metastatic cancer. The researchers found that 4.7% of tumor samples had BRCA1/2 mutations, 13.6% had mutations in any of the HRR genes and 20.6% had genomic loss of heterozygosity (gLOH) of at least 16% i.e., loss of sections of chromosomes affecting 16% or more of the genome. BRCA1/2 mutations were most common in ovarian cancer (13.1%), prostate cancer (9.3%), breast cancer (8.2%) and pancreatic cancer (4.9%). Prevalence for mutations in HRR genes ranges from 2.4 to 26.0% and gLOH ≥16% ranged from 2.6 to 34.4% depending on the tumor type. In conclusion, the prevalence of mutations in the BRCA1/2 genes, HRR genes and gLOH ≥16% varied widely across 15 tumor types.

The usefulness of contrast echocardiography in the evaluation of cardiac masses: a multicenter study.

BACKGROUND: Cardiac masses can encompass a variety of conditions, such as tumors, thrombi, vegetations, calcific lesions, and other rare diseases. Treatment and management of these types of cardiac masses differ considerably. Thus, accurately distinguishing among thrombi, benign tumors, and malignant tumors in the heart is of great importance. Contrast echocardiography (CE) has emerged as a promising technology. Although published guidelines suggest that CE can enhance image quality and assist in differentiating between benign and malignant lesions, most studies on CE diagnosis of cardiac masses are limited to case reports or retrospective/small-sample-sized prospective cohorts. This study aims to evaluate the diagnostic accuracy of CE in patients with suspected cardiac masses and address the insufficient evidence for differential diagnosis using CE. METHODS: Between April 2018 and July 2022, a prospective multicenter study was conducted, which included 145 consecutive patients suspected to have cardiac masses based on transthoracic echocardiography. All patients underwent CE examinations. The echocardiographic diagnosis relied on qualitative factors such as echogenicity, boundary, morphology of the base, mass perfusion, pericardial effusion, and motility as well as quantitative factors such as the area of the masses and the peak intensity ratio of the masses to adjacent myocardium (A1/A2). RESULTS: The final confirmed diagnoses were as follows: 2 patients had no cardiac mass, 4 patients had pseudomass, 43 patients had thrombus, 66 patients had benign tumors, and 30 patients had malignant tumors. The receiver operating characteristic (ROC) analysis indicated that an optimal A1/A2 cutoff value of 0.499 distinguished a cardiac tumor from a thrombus, with AUC, sensitivity, specificity, PPV, and NPV of 0.977, 97.9%, 90.7%, 95.9%, and 95.1%, respectively. The optimal A1/A2 cutoff value of 1.583 distinguished a cardiac tumor from a thrombus, with AUC, sensitivity, specificity, PPV, and NPV of 0.950, 93.3%, 93.9%, 87.5%, and 96.9%, respectively. CONCLUSIONS: Combined with qualitative and quantitative analyses, CE has the potential to accurately differentiate among different types of cardiac masses.

Author Correction: Structure and mechanogating mechanism of the Piezo1 channel.

In Extended Data Fig. 9a of this Article, the bottom micrographs of mPiezo1-ΔL3-4-IRES-GFP and mPiezo1-ΔL7-8-IRES-GFP (labelled 'permeabilized') are inadvertently the same images. The corrected figure panels are shown in the accompanying Amendment.

Structure and mechanogating mechanism of the Piezo1 channel.

The mechanosensitive Piezo channels function as key eukaryotic mechanotransducers. However, their structures and mechanogating mechanisms remain unknown. Here we determine the three-bladed, propeller-like electron cryo-microscopy structure of mouse Piezo1 and functionally reveal its mechanotransduction components. Despite the lack of sequence repetition, we identify nine repetitive units consisting of four transmembrane helices each-which we term transmembrane helical units (THUs)-which assemble into a highly curved blade-like structure. The last transmembrane helix encloses a hydrophobic pore, followed by three intracellular fenestration sites and side portals that contain pore-property-determining residues. The central region forms a 90 Å-long intracellular beam-like structure, which undergoes a lever-like motion to connect THUs to the pore via the interfaces of the C-terminal domain, the anchor-resembling domain and the outer helix. Deleting extracellular loops in the distal THUs or mutating single residues in the beam impairs the mechanical activation of Piezo1. Overall, Piezo1 possesses a unique 38-transmembrane-helix topology and designated mechanotransduction components, which enable a lever-like mechanogating mechanism.

Macrod1 suppresses diabetic cardiomyopathy via regulating PARP1-NAD+-SIRT3 pathway.

Diabetic cardiomyopathy (DCM), one of the most serious long-term consequences of diabetes, is closely associated with oxidative stress, inflammation and apoptosis in the heart. MACRO domain containing 1 (Macrod1) is an ADP-ribosylhydrolase 1 that is highly enriched in mitochondria, participating in the pathogenesis of cardiovascular diseases. In this study, we investigated the role of Macrod1 in DCM. A mice model was established by feeding a high-fat diet (HFD) and intraperitoneal injection of streptozotocin (STZ). We showed that Macrod1 expression levels were significantly downregulated in cardiac tissue of DCM mice. Reduced expression of Macrod1 was also observed in neonatal rat cardiomyocytes (NRCMs) treated with palmitic acid (PA, 400 µM) in vitro. Knockout of Macrod1 in DCM mice not only worsened glycemic control, but also aggravated cardiac remodeling, mitochondrial dysfunction, NAD+ consumption and oxidative stress, whereas cardiac-specific overexpression of Macrod1 partially reversed these pathological processes. In PA-treated NRCMs, overexpression of Macrod1 significantly inhibited PARP1 expression and restored NAD+ levels, activating SIRT3 to resist oxidative stress. Supplementation with the NAD+ precursor Niacin (50 µM) alleviated oxidative stress in PA-stimulated cardiomyocytes. We revealed that Macrod1 reduced NAD+ consumption by inhibiting PARP1 expression, thereby activating SIRT3 and anti-oxidative stress signaling. This study identifies Macrod1 as a novel target for DCM treatment. Targeting the PARP1-NAD+-SIRT3 axis may open a novel avenue to development of new intervention strategies in DCM. Schematic illustration of macrod1 ameliorating diabetic cardiomyopathy oxidative stress via PARP1-NAD+-SIRT3 axis.

Statistical and practical considerations in planning and conduct of dose-optimization trials.

The U.S. Food and Drug Administration launched Project Optimus with the aim of shifting the paradigm of dose-finding and selection toward identifying the optimal biological dose that offers the best balance between benefit and risk, rather than the maximum tolerated dose. However, achieving dose optimization is a challenging task that involves a variety of factors and is considerably more complicated than identifying the maximum tolerated dose, both in terms of design and implementation. This article provides a comprehensive review of various design strategies for dose-optimization trials, including phase 1/2 and 2/3 designs, and highlights their respective advantages and disadvantages. In addition, practical considerations for selecting an appropriate design and planning and executing the trial are discussed. The article also presents freely available software tools that can be utilized for designing and implementing dose-optimization trials. The approaches and their implementation are illustrated through real-world examples.

Repair spinal cord injury with a versatile anti-oxidant and neural regenerative nanoplatform.

Spinal cord injury (SCI) often results in motor and sensory deficits, or even paralysis. Due to the role of the cascade reaction, the effect of excessive reactive oxygen species (ROS) in the early and middle stages of SCI severely damage neurons, and most antioxidants cannot consistently eliminate ROS at non-toxic doses, which leads to a huge compromise in antioxidant treatment of SCI. Selenium nanoparticles (SeNPs) have excellent ROS scavenging bioactivity, but the toxicity control problem limits the therapeutic window. Here, we propose a synergistic therapeutic strategy of SeNPs encapsulated by ZIF-8 (SeNPs@ZIF-8) to obtain synergistic ROS scavenging activity. Three different spatial structures of SeNPs@ZIF-8 were synthesized and coated with ferrostatin-1, a ferroptosis inhibitor (FSZ NPs), to achieve enhanced anti-oxidant and anti-ferroptosis activity without toxicity. FSZ NPs promoted the maintenance of mitochondrial homeostasis, thereby regulating the expression of inflammatory factors and promoting the polarization of macrophages into M2 phenotype. In addition, the FSZ NPs presented strong abilities to promote neuronal maturation and axon growth through activating the WNT4-dependent pathways, while prevented glial scar formation. The current study demonstrates the powerful and versatile bioactive functions of FSZ NPs for SCI treatment and offers inspiration for other neural injury diseases.

Enhancing clinical awareness: retrospective analysis of neurosyphilis cases and diagnostic predictors for early recognition and treatment.

OBJECTIVE: This is a retrospective analysis of clinical data from individuals diagnosed with neurosyphilis, aiming to enhance healthcare professionals' understanding of the disease and expedite early diagnosis and intervention. METHODS: A retrospective analysis was conducted on the clinical records of 50 patients who received a diagnosis of symptomatic neurosyphilis and were admitted to the Neurology Department during the period spanning January 2012 to December 2022. RESULTS: Clinical manifestations encompassed diverse phenotypes, with syphilitic meningitis accounting for 16% of cases, characterized by symptoms such as headache, blepharoptosis, paralysis, blurred vision, and tinnitus. Meningovascular syphilis presented in 36% of cases, exhibiting episodic loss of consciousness, limb numbness, and limb convulsion. Paralytic dementia manifested in 36% of cases, featuring symptoms such as memory loss, sluggish response, and slow movement. Tabes dorsalis was observed in 12% of cases, presenting with weakness, numbness, and staggering. Routine cerebrospinal fluid (CSF) analysis indicated abnormal white blood cell counts in 60% of patients, while biochemical testing revealed abnormal protein content in 52% of patients. Notably, statistically significant differences were observed between patients with interstitial and parenchymatous neurosyphilis (Z = 2.023, P = 0.044) in terms of CSF protein content. Electroencephalogram (EEG) results were abnormal in six patients, and imaging studies unveiled diverse findings in 46 patients. CONCLUSION: The study highlights the importance of neurological and/or ocular symptoms in diagnosing symptomatic neurosyphilis. Individuals with hypomnesia should be closely monitored for potential neurosyphilis. Integrating clinical manifestations, laboratory tests, EEG, and imaging can reduce misdiagnosis. This comprehensive approach shows promise in improving early identification and management of neurosyphilis.