Discovery of a brain penetrant small molecule antagonist targeting LPA1 receptors to reduce neuroinflammation and promote remyelination in multiple sclerosis.

Multiple sclerosis (MS) is a chronic neurological disease characterized by inflammatory demyelination that disrupts neuronal transmission resulting in neurodegeneration progressive disability. While current treatments focus on immunosuppression to limit inflammation and further myelin loss, no approved therapies effectively promote remyelination to mitigate the progressive disability associated with chronic demyelination. Lysophosphatidic acid (LPA) is a pro-inflammatory lipid that is upregulated in MS patient plasma and cerebrospinal fluid (CSF). LPA activates the LPA1 receptor, resulting in elevated CNS cytokine and chemokine levels, infiltration of immune cells, and microglial/astrocyte activation. This results in a neuroinflammatory response leading to demyelination and suppressed remyelination. A medicinal chemistry effort identified PIPE-791, an oral, brain-penetrant, LPA1 antagonist. PIPE-791 was characterized in vitro and in vivo and was found to be a potent, selective LPA1 antagonist with slow receptor off-rate kinetics. In vitro, PIPE-791 induced OPC differentiation and promoted remyelination following a demyelinating insult. PIPE-791 further mitigated the macrophage-mediated inhibition of OPC differentiation and inhibited microglial and fibroblast activation. In vivo, the compound readily crossed the blood-brain barrier and blocked LPA1 in the CNS after oral dosing. Direct dosing of PIPE-791 in vivo increased oligodendrocyte number, and in the mouse experimental autoimmune encephalomyelitis (EAE) model of MS, we observed that PIPE-791 promoted myelination, reduced neuroinflammation, and restored visual evoked potential latencies (VEP). These findings support targeting LPA1 for remyelination and encourage development of PIPE-791 for treating MS patients with advantages not seen with current immunosuppressive disease modifying therapies.

Characterizing dysregulations via cell-cell communications in Alzheimer's brains using single-cell transcriptomes.

BACKGROUND: Alzheimer's disease (AD) is a devastating neurodegenerative disorder affecting 44 million people worldwide, leading to cognitive decline, memory loss, and significant impairment in daily functioning. The recent single-cell sequencing technology has revolutionized genetic and genomic resolution by enabling scientists to explore the diversity of gene expression patterns at the finest resolution. Most existing studies have solely focused on molecular perturbations within each cell, but cells live in microenvironments rather than in isolated entities. Here, we leveraged the large-scale and publicly available single-nucleus RNA sequencing in the human prefrontal cortex to investigate cell-to-cell communication in healthy brains and their perturbations in AD. We uniformly processed the snRNA-seq with strict QCs and labeled canonical cell types consistent with the definitions from the BRAIN Initiative Cell Census Network. From ligand and receptor gene expression, we built a high-confidence cell-to-cell communication network to investigate signaling differences between AD and healthy brains. RESULTS: Specifically, we first performed broad communication pattern analyses to highlight that biologically related cell types in normal brains rely on largely overlapping signaling networks and that the AD brain exhibits the irregular inter-mixing of cell types and signaling pathways. Secondly, we performed a more focused cell-type-centric analysis and found that excitatory neurons in AD have significantly increased their communications to inhibitory neurons, while inhibitory neurons and other non-neuronal cells globally decreased theirs to all cells. Then, we delved deeper with a signaling-centric view, showing that canonical signaling pathways CSF, TGFß, and CX3C are significantly dysregulated in their signaling to the cell type microglia/PVM and from endothelial to neuronal cells for the WNT pathway. Finally, after extracting 23 known AD risk genes, our intracellular communication analysis revealed a strong connection of extracellular ligand genes APP, APOE, and PSEN1 to intracellular AD risk genes TREM2, ABCA1, and APP in the communication from astrocytes and microglia to neurons. CONCLUSIONS: In summary, with the novel advances in single-cell sequencing technologies, we show that cellular signaling is regulated in a cell-type-specific manner and that improper regulation of extracellular signaling genes is linked to intracellular risk genes, giving the mechanistic intra- and inter-cellular picture of AD.

Frequency-encoded eye tracking smart contact lens for human-machine interaction.

Eye tracking techniques enable high-efficient, natural, and effortless human-machine interaction by detecting users' eye movements and decoding their attention and intentions. Here, a miniature, imperceptible, and biocompatible smart contact lens is proposed for in situ eye tracking and wireless eye-machine interaction. Employing the frequency encoding strategy, the chip-free and battery-free lens successes in detecting eye movement and closure. Using a time-sequential eye tracking algorithm, the lens has a great angular accuracy of <0.5°, which is even less than the vision range of central fovea. Multiple eye-machine interaction applications, such as eye-drawing, Gluttonous Snake game, web interaction, pan-tilt-zoom camera control, and robot vehicle control, are demonstrated on the eye movement model and in vivo rabbit. Furthermore, comprehensive biocompatibility tests are implemented, demonstrating low cytotoxicity and low eye irritation. Thus, the contact lens is expected to enrich approaches of eye tracking techniques and promote the development of human-machine interaction technology.

Identification and In Vivo Evaluation of Myelination Agent PIPE-3297, a Selective Kappa Opioid Receptor Agonist Devoid of ß-Arrestin-2 Recruitment Efficacy.

Structure-activity relationship studies led to the discovery of PIPE-3297, a fully efficacious and selective kappa opioid receptor (KOR) agonist. PIPE-3297, a potent activator of G-protein signaling (GTPγS EC50 = 1.1 nM, 91% Emax), did not elicit a ß-arrestin-2 recruitment functional response (Emax < 10%). Receptor occupancy experiments performed with the novel KOR radiotracer [3H]-PIPE-3113 revealed that subcutaneous (s.c.) administration of PIPE-3297 at 30 mg/kg in mice achieved 90% occupancy of the KOR in the CNS 1 h post dose. A single subcutaneous dose of PIPE-3297 in healthy mice produced a statistically significant increase of mature oligodendrocytes (P < 0.0001) in the KOR-enriched striatum, an effect that was not observed in animals predosed with the selective KOR antagonist norbinaltorphimine. An equivalent dose given to mice in an open-field activity-monitoring system revealed a small KOR-independent decrease in total locomotor activity versus vehicle measured between 60 and 75 min post dose. Daily doses of PIPE-3297 at both 3 and 30 mg/kg s.c. reduced the disease score in the mouse experimental autoimmune encephalomyelitis (EAE) model. Visually evoked potential (VEP) N1 latencies were also significantly improved versus vehicle in both dose groups, and latencies matched those of untreated animals. Taken together, these findings highlight the potential therapeutic value of functionally selective G-protein KOR agonists in demyelinating disease, which may avoid the sedating side effects typically associated with classical nonbiased KOR agonists.

Single-short-cavity dual-comb fiber laser with over 120†kHz repetition rate difference based on polarization multiplexing.

An all-fiber single-short-cavity dual-comb laser with a high repetition rate of up to 500 MHz and a high repetition rate difference of over 120 kHz was demonstrated. The laser setup exploits high birefringence of a polarization-maintaining gain fiber to generate asynchronous combs based on the polarization-multiplexing method. By adopting short-linear-cavity and all-birefringent configuration, a repetition rate difference several orders of magnitude larger than that of a previous work was achieved. The soliton dual-comb showed good mutual coherence and stability, which reveals the potential to enhance the acquisition rate and accuracy of dual-comb measurement systems.

Metasurface around the side surface of an optical fiber for light focusing.

Optical fibers integrated with metasurfaces have drawn tremendous interest in recent years due to the great potential for revolutionizing and functionalizing traditional optics. However, in most cases, metasurfaces have been placed on the fiber end-facet where the area is quite limited. Here, by dressing a series of identical dielectric rings around the side surface of the microfiber and adjusting their positions along the microfiber axis, we extracted guided waves into free-space radiation with continuously controllable phase shift and achieved circular-arc-shaped line focusing. We demonstrated that the off-fiber foci could be rotated around the fiber axis by tuning the polarization of the guided waves. In addition, we demonstrated that the shape of the focus could be further tuned by introducing symmetry breaking into the dielectric rings. Our study provides a new dimension for the design of optical fiber devices decorated with metasurfaces.

Twisted black phosphorus-based van der Waals stacks for fiber-integrated polarimeters.

The real-time, in-line analysis of light polarization is critical in optical networks, currently suffering from complex systems with numerous bulky opto-electro-mechanical elements tandemly arranged along the optical path. Here, we design and fabricate a fiber-integrated polarimeter by vertically stacking three photodetection units based on six-layer van der Waals materials, including one bismuth selenide (Bi2Se3) layer for power calibration, two twisted black phosphorus (BP) layers for polarization detection, and three hexagonal boron nitride (hBN) layers for encapsulation. The self-power-calibrated, self-driven, and unambiguous detection of both linearly polarized (LP) and circularly polarized (CP) light is realized by the broken symmetry-induced linear photogalvanic effects (LPGEs) and circular photogalvanic effects (CPGEs) in the two BP units. Moreover, the device enables single-pixel polarimetric imaging to acquire spatial polarization information. The ultracompact device structure, free from external optical and mechanical modules, may inspire the development of miniaturized optical and optoelectronic systems.

Compact fiber-integrated scattering device based on mixed-phase TiO2 for speckle spectrometer.

A universal, repeatable, and controllable integration of single-mode optical fiber and mixed-phase TiO2 is used to manufacture a compact fiber-integrated scattering device. Based on the device, we achieve a high-performance and compact fiber-based speckle spectrometer, which has a resolution of 20 pm over a bandwidth of 15 nm, in the 1550 nm range. We test the capability of our proposed spectrometer to reconstruct narrow linewidth and broadband optical spectrums, and compare the performance with that of a traditional optical spectrum analyzer.

Optical fiber tip integrated photoelectrochemical sensors.

In this work, we design and fabricate a compact photoelectrochemical (PEC) sensor by integrating a graphene-MoS2 heterostructure on an optical fiber tip. The graphene serves as a transparent carrier transport layer, and the MoS2 presents a photoelectrical transducer that generates photocarriers and interacts with ascorbic acid (AA) in solution. This device is used to demonstrate a self-powered detection of AA with a concentration range between 1 mM and 50 mM, and a time response of ∼ 6 ms. The device downsizes traditional PEC systems to the micrometer scale, benefiting the real-time monitoring of biochemical changes in small areas and opening the pathway for miniaturized PEC sensing applications.

Expression patterns of long non-coding RNAs in peripheral blood mononuclear cells of non-segmental vitiligo.

OBJECTIVE: We explored the patterns of long non-coding RNA (lncRNA) expression in peripheral blood mononuclear cells (PBMCs) from patients with non-segmental vitiligo. METHODS: We used high-throughput RNA sequencing technology to generate sequence data from five patients with non-segmental vitiligo alongside five normal healthy individuals, and then performed bioinformatics analyses to detect the differential expression of lncRNA in PBMCs. Gene Ontology (GO) and pathway analyses were performed for functional annotation, and quantitative real-time polymerase chain reaction (qRT-PCR) was used to verify gene expression. Target miRNAs and mRNAs of differentially expressed lncRNAs were predicted using bioinformatics analysis. RESULTS: A total of 292 lncRNAs were differentially expressed in non-segmental vitiligo (fold change ≥ 2.0, P < .05), of which 171 were upregulated and 121 were downregulated. Six differentially expressed lncRNAs were selected, namely ENST00000460164.1, ENST00000393264.2, NR-046211.1, NR-135491.1, NR-135320.1, and ENST00000381108.3, for validation by qRT-PCR. The results showed that ENST00000460164.1 and NR-046211.1 were highly expressed in PBMCs of non-segmental vitiligo. An lncRNA-miRNA-mRNA network containing two lncRNAs, 17 miRNAs, and 223 mRNAs was constructed. CONCLUSION: Our results revealed patterns of differentially expressed lncRNAs in the PBMCs of non-segmental vitiligo individuals. ENST00000460164.1, and NR-046211.1 may be potential biomarkers and drug targets for the treatment of non-segmental vitiligo.

Silica optical fiber integrated with two-dimensional materials: towards opto-electro-mechanical technology.

In recent years, the integration of graphene and related two-dimensional (2D) materials in optical fibers have stimulated significant advances in all-fiber photonics and optoelectronics. The conventional passive silica fiber devices with 2D materials are empowered for enhancing light-matter interactions and are applied for manipulating light beams in respect of their polarization, phase, intensity and frequency, and even realizing the active photo-electric conversion and electro-optic modulation, which paves a new route to the integrated multifunctional all-fiber optoelectronic system. This article reviews the fast-progress field of hybrid 2D-materials-optical-fiber for the opto-electro-mechanical devices. The challenges and opportunities in this field for future development are discussed.

Discovery of PIPE-359, a Brain-Penetrant, Selective M1 Receptor Antagonist with Robust Efficacy in Murine MOG-EAE.

The discovery of PIPE-359, a brain-penetrant and selective antagonist of the muscarinic acetylcholine receptor subtype 1 is described. Starting from a literature-reported M1 antagonist, linker replacement and structure-activity relationship investigations of the eastern 1-(pyridinyl)piperazine led to the identification of a novel, potent, and selective antagonist with good MDCKII-MDR1 permeability. Continued semi-iterative positional scanning facilitated improvements in the metabolic and hERG profiles, which ultimately delivered PIPE-359. This advanced drug candidate exhibited robust efficacy in mouse myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalitis (EAE), a preclinical model for multiple sclerosis.

Clinical Characteristics, Surgical Outcomes, and Prognostic Factors of Intracranial Primary Central Nervous System Lymphoma.

BACKGROUND: Intracranial primary central nervous system lymphoma (PCNSL) is a rare aggressive malignant tumor with poor prognosis. The effect of surgical resection on intracranial PCNSL is still controversial. This study investigates the efficacy and safety of surgical resection, as well as to analyze the clinical characteristics and prognostic factors of intracranial PCNSL. METHODS: The clinical materials of 89 consecutive patients with intracranial PCNSL were analyzed retrospectively. Outcome in survival was assessed by progression-free survival (PFS) and overall survival (OS). Univariate and multivariate analyses were performed for various potential prognostic factors to identify independent prognostic factors of intracranial PCNSL. RESULTS: Among the 89 patients, gross total resection (GTR) was achieved in 57 patients (64.0%), subtotal resection (STR) in 14 patients (15.8%), and biopsy in 18 patients (20.2%).The PFS and OS at 2 years were estimated at 32.3% and 74.1%, respectively. The median PFS was 20 months (95% confidence interval, 16-23) and the median OS was 32 months (95% confidence interval, 25-38). Patients with surgical resection (GTR and STR) had better PFS than those with biopsy, and the difference of PFS was statistically significant (P = 0.007). However, the difference of OS was not statistically significant (P = 0.062). Multivariate analysis showed that invasion of deep structure was the only independent risk factor for intracranial PCNSL. Eleven patients (12.4%) had surgical complications, mainly including limb weakness and visual field defect. CONCLUSIONS: For intracranial PCNSL, surgical excision can improve PFS but not OS. Invasion of deep structure was the only independent risk factor for intracranial PCNSL.

Expression profile and bioinformatics analyses of circular RNAs in keloid and normal dermal fibroblasts.

Increasing evidence indicates that circular RNAs (circRNAs) play a crucial regulatory role in the pathogenesis of multiple diseases. However, no study has examined the potential biological function and expression profile of circRNAs in keloid dermal fibroblasts (KDFs). Therefore, the aim of this study to investigate the expression profile of circRNAs and analyze their role in KDFs. Bioinformatic analyses and high-throughput RNA sequencing technology were applied to explore the expression profile of circRNAs in 3 human KDFs and normal dermal fibroblasts (NDFs). The differentially expressed circRNAs were verified by reverse transcription PCR (RT-PCR), quantitative real-time-PCR (qRT-PCR) and Sanger sequencing. A circRNA-microRNA (miRNA)-mRNA interaction network was created using bioinformatics tools. Hsa_circ_0008259, was selected to confirm its function by qRT-PCR and Western blot. Collectively, 411 circRNAs, of which 206 were upregulated and 205 decreased, were found to be differentially expressed in KDFs and could bind to 2532 miRNA response elements (MREs). GO and KEGG pathways enrichment analyses showed that differentially expressed circRNAs were mainly involved in apoptosis, focal adhesion, PI3K-Akt and metabolic pathway, and may regulate the pathogenesis and development of keloid. Two candidate circRNAs (hsa_circRNA_0008259, hsa_circRNA_0005480) were verified to be significantly reduced in KDFs, and one candidate circRNA (hsa_circRNA_0002198) was significantly elevated in accordance with RNA-Seq data analysis. Overexpression of hsa_circRNA_0008259 inhibited type I and Ⅲ collagen expression. Taken together, our study demonstrates for the first time that circRNAs exhibits differential expression in KDFs, and may be key players in the pathogenesis of keloid, or act as biomarkers of keloid.

Ultrahigh Responsivity Photodetectors of 2D Covalent Organic Frameworks Integrated on Graphene.

2D materials exhibit superior properties in electronic and optoelectronic fields. The wide demand for high-performance optoelectronic devices promotes the exploration of diversified 2D materials. Recently, 2D covalent organic frameworks (COFs) have emerged as next-generation layered materials with predesigned π-electronic skeletons and highly ordered topological structures, which are promising for tailoring their optoelectronic properties. However, COFs are usually produced as solid powders due to anisotropic growth, making them unreliable to integrate into devices. Here, by selecting tetraphenylethylene monomers with photoelectric activity, elaborately designed photosensitive 2D-COFs with highly ordered donor-acceptor topologies are in situ synthesized on graphene, ultimately forming COF-graphene heterostructures. Ultrasensitive photodetectors are successfully fabricated with the COFETBC-TAPT -graphene heterostructure and exhibited an excellent overall performance with a photoresponsivity of ≈3.2 × 107 A W-1 at 473 nm and a time response of ≈1.14 ms. Moreover, due to the high surface area and the polarity selectivity of COFs, the photosensing properties of the photodetectors can be reversibly regulated by specific target molecules. The research provides new strategies for building advanced functional devices with programmable material structures and diversified regulation methods, paving the way for a generation of high-performance applications in optoelectronics and many other fields.

Downregulation of miR­186 promotes the proliferation and drug resistance of glioblastoma cells by targeting Twist1.

Temozolomide (TMZ) is widely used as a chemotherapeutic agent in the treatment of glioma; however, the development of drug resistance remains a major obstacle in the effective treatment of glioblastoma. Increasing evidence has indicated that microRNAs (miRs) are involved in the drug resistance of glioma; however, the role of miR­186­5p in the TMZ resistance of glioblastoma remains unknown. In the present study, the role of miR­186­5p in the resistance of glioblastoma to TMZ was investigated. mRNA and protein expression levels were detected via reverse transcription­quantitative PCR and western blot analysis, respectively. It was determined that miR­186­5p was significantly downregulated in glioblastoma tissues and cell lines. Additionally, the expression of miR­186­5p was decreased, whereas that of Twist1 was upregulated during the development of drug resistance in glioma cells. The introduction of miR­186 into glioblastoma cells via transfection decreased the proliferation and TMZ resistance of glioblastoma cells, as determined via 5­ethynyl­2'­deoxyuridine and Cell Counting Kit­8 assays, whereas the inhibition of miR­186­5p induced opposing effects. Furthermore, luciferase reporter and expression rescue assays revealed that miR­186­5p bound to the 3'­untranslated region of Twist­related protein 1 (Twist1). In conclusion, the present study demonstrated that downregulation of miR­186­5p may contribute to the proliferation and drug resistance of glioblastoma cells via the regulation of Twist1 expression. These results suggested that miR­186­5p may be a novel therapeutic target in the treatment of glioblastoma.

Thermo⁻Mechanical Behavior and Constitutive Modeling of In Situ TiB2/7050 Al Metal Matrix Composites Over Wide Temperature and Strain Rate Ranges.

The thermo-mechanical behavior of in situ TiB2/7050 Al metal matrix composites is investigated by quasi-static and Split Hopkinson Pressure Bar compression tests over a wide range of temperature (20~30 °C) and strain rate (0.001~5000 s-1). Johnson-Cook and Khan-Liu constitutive models determined from curve fitting and constrained optimization are used to predict the flow stress during deformation. In addition, another Johnson-Cook model calculated from an orthogonal cutting experiment and finite element simulation is also compared in this study. The prediction capability of these models is compared in terms of correlation coefficient and average absolute error. Due to the assumptions in orthogonal cutting theory, the determined Johnson-Cook model from cutting cannot describe the material deformation behavior accurately. The results also show that the Khan-Liu model has better performance in characterizing the material's thermo-mechanical behavior.

A Flexible Wireless Dielectric Sensor for Noninvasive Fluid Monitoring.

A flexible wireless dielectric sensor is presented here for noninvasively monitoring the permittivity and conductivity of fluids, based on resistor-inductor-capacitor (RLC) resonant circuit and capacitively coupled contactless conductivity detection (C4D) technique. The RLC sensor consists of one single-turn inductor and one interdigital capacitor. The resonant frequency of the device is sensitive to the surrounding environment, thanks to the electric field leaked out between the interdigital capacitor electrodes. Through the high-frequency structure simulator (HFSS) simulation, and experiments on ethanol/water solutions and NaCl solutions, it was confirmed that a fluid's permittivity and conductivity could be detected by the return loss curve (S11). With great repeatability and stability, the proposed sensor has potential for broad applications, especially in wearable low-cost smart devices.

Evaluations of the effect of HuangQi against heart failure based on comprehensive echocardiography index and metabonomics.

BACKGROUND: HuangQi (HQ) is a major medicinal herb commonly used as an ingredient of traditional Chinese medicine (TCM) formulas. It has been proved to be effective against heart failure (HF). However, its holistic therapeutic mechanism is not yet well explored. PURPOSE: The present study was designed to investigate the inhibitory effects and action mechanism of HQ in adriamycin (ADR)-induced HF rats. METHODS: An integrative approach combining comprehensive echocardiography index (CEI) and metabonomics was conducted to assess the integral efficacy of HQ against HF. CEI was constructed to comprehensively evaluate the protection of HQ through principal component analysis of eight echocardiography parameters. Meanwhile, NMR-based untargeted metabolomic studies were performed to investigate the regulative effects of HQ coupled with correlation analysis. RESULTS: HQ showed significant regulatory effects on four echocardiography parameters (left ventricular diastolic diameter, left ventricular systolic wall thickness, ejection fraction and fractional shortening). The effect on comprehensive CEI also demonstrated the efficacy of HQ against HF, especially on the first principal component (PC1). HQ could exert marked metabolic regulations on five key metabolites related to HF (NAG, 3-hydroxybutyrate, glutamine, succinate and acetoacetate), which were mainly involved into alterations of energy metabolism, oxidative stress, hypertrophy, as well as inflammatory. Their correlation analysis revealed the relationship between the metabolic profiles and cardiac function, which further authenticated the systemic regulation of HQ against HF. CONCLUSION: Current evidences revealed that HQ was effective in control of HF from cardiac dysfunction and metabolic alterations. This study provided a useful approach for evaluating the efficacy of TCMs against HF.

Evaluation of Residual Stress Distribution and Relaxation on In Situ TiB2/7050 Al Composites.

Interior residual stresses induced by quenching may cause distortion during subsequent machining processes. Hence, various strategies have been employed to relieve the interior residual stress, such as stretching, post treatment, and other techniques. In this study, the stress distribution inside TiB2/7050 Al composite extrusions was investigated and the effects of different methods on relieving the quenching-induced stress were compared. Firstly, three TiB2/7050 Al composite extrusions were treated by stretching, stretching and heat treatment, and stretching and cold treatment processes, respectively. Then, the multiple-cut contour method was employed to assess the residual stresses in the three workpieces. Experimental results indicate that the interior stress of TiB2/7050 Al composite extrusions after stretching ranges from −89 MPa to +55 MPa, which is larger than that in 7050 aluminum alloy, which ranges from −25 Pa to +25 MPa. The heat treatment performs better than the cold treatment to reduce the post-stretching residual stress, with a reduction of 23.2⁻46.4% compared to 11.3⁻40.8%, respectively. From the stress map, it is found that the stress distribution after the heat treatment is more uniform compared with that after the cold treatment.