Vertically Integrated Monolithic Neuromorphic Nanowire Device for Physiological Information Processing.

This study demonstrates the conceptual design and fabrication of a vertically integrated monolithic (VIM) neuromorphic device. The device comprises an n-type SnO2 nanowire bottom channel connected by a shared gate to a p-type P3HT nanowire top channel. This architecture establishes two distinct neural pathways with different response behaviors. The device generates excitatory and inhibitory postsynaptic currents, mimicking the corelease mechanism of bilingual synapses. To enhance the signal processing efficiency, we employed a bipolar spike encoding strategy to convert fluctuating sensory signals to spike trains containing positive and negative pulses. Utilizing the neuromorphic platform for synaptic processing, physiological signals featuring bidirectional fluctuations, including electrocardiogram and breathing signals, can be classified with an accuracy of over 90%. The VIM device holds considerable promise as a solution for developing highly integrated neuromorphic hardware for healthcare and edge intelligence applications.

Choriocapillaris flow features in children with myopic anisometropia.

AIMS: To examine differences between the eyes in choriocapillaris perfusion and choroidal thickness in children with myopic anisometropia. METHODS: In this observational and prospective study, 46 children with myopic anisometropia were enrolled. Choriocapillaris perfusion parameters, including the percentage of flow voids, the total number of flow voids and the average flow void area were obtained by optical coherence tomography angiography (OCTA). The OCTA image was divided into a 1 mm-diameter central circle (C1) and a 2.5 mm-diameter annulus (without the inner central 1 mm circle, C1-2.5). Both C1 and C1-2.5 are centred on the foveola. The C1-2.5 was divided into nasal (N1-2.5), temporal (T1-2.5), inferior (I1-2.5) and superior (S1-2.5) areas. Differences in these parameters in different regions between eyes were analysed. RESULTS: There were no significant differences in the percentage of flow voids and the average flow void area between the fellow eyes. The total number of signal voids was significantly higher in the less myopic eyes in C1-2.5 (p=0.032), S1-2.5 (p=0.008) and N1-2.5 (p=0.019). Changes in spherical equivalent refraction and axial length were both correlated with the changes in the total number of flow voids in N1-2.5 (R=-0.431, p=0.03; R=-0.297, p=0.047). CONCLUSIONS: The choroid in the macular region becomes thinner and the total number of flow voids in the nasal macular region decreased with the amplitude of myopia. This suggests that a decrease in total number of flow voids may indicate an early change in myopia.

Comprehensive analysis reveals the prognostic and immunogenic characteristics of DNA methylation regulators in lung adenocarcinoma.

DNA methylation regulators (DMRs) play a key role in DNA methylation, thus mediating tumor occurrence, metastasis, and immunomodulation. However, the effects of DMRs on clinical outcomes and immunotherapy response remain unexplored in lung adenocarcinoma (LUAD). In this study, eight LUAD cohorts and one immunotherapeutic cohort of lung cancer were utilized. We constructed a DNA methylation regulators-related signature (DMRRS) using univariate and multivariate COX regression analysis. The DMRRS-defined low-risk group was preferentially associated with favorable prognosis, tumor-inhibiting microenvironment, more sensitivity to several targeted therapy drugs, and better immune response. Afterward, the prognostic value and predictive potential in immunotherapy response were validated. Collectively, our findings uncovered that the DMRRS was closely associated with the tumor immune microenvironment and could effectively predict the clinical outcome and immune response of LUAD patients.

Genetic Insights into the causal relationship between cannabis use and diabetic phenotypes: A genetic correlation and Mendelian randomization study.

BACKGROUND: Previous studies have highlighted the association between cannabis use and diabetes and its complications; however, the causality remains ambiguous. METHODS: Univariate Mendelian randomization (MR), multivariate MR, mediation MR, and linkage disequilibrium score (LDSC) analysis to assess the causal relationship between cannabis use and 12 diabetic phenotypes. Summary statistics for lifetime cannabis use (N = 184,765) and cannabis use disorder (CUD) (N = 374,287) from genome-wide association studies. The primary method used was inverse-variance-weighted (IVW). A range of sensitivity analyses ensured the robustness of the results. RESULTS: LDSC analysis revealed a significant genetic correlation between CUD and T2DM, as well as between lifetime cannabis use and four diabetic phenotypes (P < 0.05). After correction by false discovery rate (FDR), the primary IVW analysis indicates that the genetically predicted CUD is positively associated with the risk of diabetic hypoglycemia (OR = 1.11, 95% CI 1.04-1.20, P = 0.003, PFDR = 0.04) and proliferative diabetic retinopathy (PDR) (OR = 1.12, 95% CI 1.04-1.19, P = 4.89×10-4, PFDR =0.01). Additionally, suggestive evidence links CUD with increased risks of diabetic nephropathy, type 1 diabetes mellitus (T1DM), diabetic retinopathy, and T1DM associated with diabetic ketoacidosis (P < 0.05 & PFDR > 0.05). No causal relationship was detected between lifetime cannabis use and diabetic phenotypes (P > 0.05 & PFDR > 0.05). Multivariable and mediation MR analyses revealed that glycated hemoglobin A1c partially mediates the causal effect of CUD on PDR and diabetic hypoglycemia. CONCLUSION: This MR study suggests that CUD may have a causal role in several diabetic disease phenotypes.

CTRP6 protects against ferroptosis to drive lung cancer progression and metastasis by destabilizing SOCS2 and augmenting the xCT/GPX4 pathway.

Lung cancer is a highly heterogeneous malignancy, and despite the rapid development of chemotherapy and radiotherapy, acquired drug resistance and tumor progression still occur. Thus, it is urgent to identify novel therapeutic targets. Our research aims to screen novel biomarkers associated with the prognosis of lung carcinoma patients and explore the potential regulatory mechanisms. We obtained RNA sequencing (RNA-seq) data of lung cancer patients from public databases. Clinical signature analysis, weighted gene coexpression network analysis (WGCNA) and the random forest algorithm showed that C1q/tumor necrosis factor-related protein-6 (CTRP6) is a core gene related to lung cancer prognosis, and it was determined to promote tumor proliferation and metastasis both in vivo and in vitro. Mechanistically, silencing CTRP6 was determined to promote xCT/GPX4-involved ferroptosis through functional assays related to lipid peroxidation, Fe2+ concentration and mitochondrial ultrastructure. By performing interactive proteomics analyses in lung tumor cells, we identified the interaction between CTRP6 and suppressor of cytokine signaling 2 (SOCS2) leading to SOCS2 ubiquitination degradation, subsequently enhancing the downstream xCT/GPX4 signaling pathway. Moreover, significant correlations between CTRP6-mediated SOCS2 and ferroptosis were revealed in mouse models and clinical specimens of lung cancer. As inducing ferroptosis has been gradually regarded as an alternative strategy to treat tumors, targeting CTRP6-mediated ferroptosis could be a potential strategy for lung cancer therapy.

Scleral remodeling in early adulthood: the role of FGF-2.

Emmetropization, a natural process of ocular elongation, is closely associated with scleral remodeling. The Fibroblast growth factor-2 (FGF-2) was reported involved in scleral remodeling in myopia models. Herein, we aimed to investigate the role of scleral fibroblast-to-myofibroblast differentiation and FGF-2 in scleral remodeling during maturation. Our findings revealed that the posterior scleral fibroblasts (SFs) from mature guinea pigs exhibit increased stiffness compared to those from young guinea pigs. Moreover, mature SFs displayed decreased cell proliferation but increased levels of α-SMA, matrix metalloproteinase 2 (MMP2), and collagen 1, when compared to young SFs. Additionally, the mRNA expression of scleral Fgf-2, Fgf receptor 1 (Fgfr1), Fgfr2, Fgfr3, and Fgfr4 was increased in mature SFs. Notably, exogenous FGF-2 showed increased cell proliferation and led to decreased expression of α-SMA, MMP2, and collagen 1 in mature SFs. Overall, our findings highlight the influence of maturation on SFs from posterior scleral shells, resulting in increased stiffness and the manifestation of fibroblast-to-myofibroblast differentiation during development. Exogenous FGF-2 increased cell proliferation and reversed the age-related fibroblast-to-myofibroblast differentiation, suggesting a potential role of FGF-2 in regulating scleral remodeling.

Mixed-Dimensional Nanoparticle-Nanowire Channels for Flexible Optoelectronic Artificial Synapse with Enhanced Photoelectric Response and Asymmetric Bidirectional Plasticity.

A mixed-dimensional dual-channel synaptic transistor composed of inorganic nanoparticles and organic nanowires was fabricated to expand the photoelectric gain range. The device can actualize the sensitization features of the nociceptor and shows improved responsiveness to visible light. Under electrical pulses with different polarities, the apparatus exhibits reconfigurable asymmetric bidirectional plasticity. Moreover, the devices demonstrate good operational tolerance and mechanical stability, retaining more than 60% of their maximum responsiveness after 100 consecutive/bidirectional and 1000 flex/flat operations. The improved photoelectric response of the device endows a high image recognition accuracy of greater than 80%. Asymmetric bidirectional plasticity is used as punishment/reward in a psychological experiment to emulate the improvement of learning motivation and enables real-time forward and backward deflection (+7 and -25°) of artificial muscle. The mixed-dimensional optoelectronic artificial synapses with switchable behavior and electron/hole transport type have important prospects for neuromorphic processing and artificial somatosensory nerves.

Minichromosome maintenance protein family member 6 mediates hepatocellular carcinoma progression by recruiting UBE3A to induce P53 ubiquitination.

With limited therapeutic options for hepatocellular carcinoma (HCC), it is of great significance to investigate the underlying mechanisms and identifying tumor drivers. MCM6, a member of minichromosome maintenance proteins (MCMs), was significantly elevated in HCC progression and associated with poor prognosis. Knockdown of MCM6 significantly inhibited the proliferation and migration of HCC cells with the increased apoptosis ratio and cell cycle arrest, whereas overexpression of MCM6 induced adverse effects. Mechanistically, MCM6 could decrease the P53 activity by inducing the degradation of P53 protein. In addition, MCM6 enhanced the ubiquitination of P53 by recruiting UBE3A to form a triple complex. Furthermore, overexpression of UBE3A significantly rescued the P53 activation and suppression of malignant behaviors mediated by MCM6 inhibition. In conclusion, MCM6 facilitated aggressive phenotypes of HCC cells by UBE3A/P53 signaling, providing potential biomarkers and targets for HCC.

Effect of red-light therapy on retinal and choroidal blood perfusion in myopic children.

OBJECTIVE: To investigate the effect of repeated low-level red-light therapy (RLRLT) on retinal and choroidal blood perfusion in myopic children. METHODS: Forty-seven myopic children (mean spherical equivalent refractive error [SE]: -2.31 ± 1.26 D; age range: 8.0-11.0 years) were enrolled and received RLRLT (power 2 mW, wavelength 650 nm) for 3 min twice a day, while 20 myopic children (SE: -2.75 ± 0.84 D; age range: 7.0-10.0 years) were included as a control group. All participants wore single-vision distance glasses. Refractive error, axial length (AL) and other biometric parameters were measured at baseline and during follow-up visits in the first, second and fourth weeks after initiation of treatment. Retinal thickness, subfoveal choroidal thickness (SFCT), total choroidal area (TCA), luminal area (LA), stromal area (SA) and choroidal vascularity index (CVI) were obtained using optical coherence tomography (OCT). The percentage retinal vascular density (VD%) and choriocapillaris flow voids (FV%) were measured using en-face OCT angiography. RESULTS: After 4 weeks of treatment, a significant increase in SFCT was observed in the RLRLT group, with an average increase of 14.5 µm (95% confidence interval [CI]: 9.6-19.5 µm), compared with a decrease of -1.7 µm (95% CI: -9.1 to 5.7 µm) in the control group (p < 0.0001). However, no significant changes in retinal thickness or VD% were observed in either group (all p > 0.05). In the OCT images from the RLRLT group, no abnormal retinal morphology related to photodamage was observed. The horizontal scans revealed an increase in TCA, LA and CVI over time (all p < 0.05), while SA and FV% remained unchanged (both p > 0.05). CONCLUSIONS: These findings indicate that RLRLT can enhance choroidal blood perfusion in myopic children, demonstrating a cumulative effect over time.

Mammalian-brain-inspired neuromorphic motion-cognition nerve achieves cross-modal perceptual enhancement.

Perceptual enhancement of neural and behavioral response due to combinations of multisensory stimuli are found in many animal species across different sensory modalities. By mimicking the multisensory integration of ocular-vestibular cues for enhanced spatial perception in macaques, a bioinspired motion-cognition nerve based on a flexible multisensory neuromorphic device is demonstrated. A fast, scalable and solution-processed fabrication strategy is developed to prepare a nanoparticle-doped two-dimensional (2D)-nanoflake thin film, exhibiting superior electrostatic gating capability and charge-carrier mobility. The multi-input neuromorphic device fabricated using this thin film shows history-dependent plasticity, stable linear modulation, and spatiotemporal integration capability. These characteristics ensure parallel, efficient processing of bimodal motion signals encoded as spikes and assigned with different perceptual weights. Motion-cognition function is realized by classifying the motion types using mean firing rates of encoded spikes and postsynaptic current of the device. Demonstrations of recognition of human activity types and drone flight modes reveal that the motion-cognition performance match the bio-plausible principles of perceptual enhancement by multisensory integration. Our system can be potentially applied in sensory robotics and smart wearables.

CRISPR/Cas9-mediated genome editing in vancomycin-producing strain Amycolatopsis keratiniphila.

Amycolatopsis is an important source of diverse valuable bioactive natural products. The CRISPR/Cas-mediated gene editing tool has been established in some Amycolatopsis species and has accomplished the deletion of single gene or two genes. The goal of this study was to develop a high-efficient CRISPR/Cas9-mediated genome editing system in vancomycin-producing strain A. keratiniphila HCCB10007 and enhance the production of vancomycin by deleting the large fragments of ECO-0501 BGC. By adopting the promoters of gapdhp and ermE*p which drove the expressions of scocas9 and sgRNA, respectively, the all-in-one editing plasmid by homology-directed repair (HDR) precisely deleted the single gene gtfD and inserted the gene eGFP with the efficiency of 100%. Furthermore, The CRISPR/Cas9-mediated editing system successfully deleted the large fragments of cds13-17 (7.7 kb), cds23 (12.7 kb) and cds22-23 (21.2 kb) in ECO-0501 biosynthetic gene cluster (BGC) with high efficiencies of 81%-97% by selecting the sgRNAs with a suitable PAM sequence. Finally, a larger fragment of cds4-27 (87.5 kb) in ECO-0501 BGC was deleted by a dual-sgRNA strategy. The deletion of the ECO-0501 BGCs revealed a noticeable improvement of vancomycin production, and the mutants, which were deleted the ECO-0501 BGCs of cds13-17, cds22-23 and cds4-27, all achieved a 30%-40% increase in vancomycin yield. Therefore, the successful construction of the CRISPR/Cas9-mediated genome editing system and its application in large fragment deletion in A. keratiniphila HCCB10007 might provide a powerful tool for other Amycolatopsis species.

Gene expression profile analyses to identify potential biomarkers for myopia.

PURPOSE: Increasing evidence suggests myopia is not a simple refractive error, many other factors might also be involved. Here, we assessed myopic and normal corneas' gene expression profiles to identify possible diagnostic and therapeutic biomarkers for myopia. MATERIALS AND METHODS: We obtained the expression profile of ten patients and seven normal control samples from the GSE112155 and GSE151631 datasets based on the Gene Expression Omnibus (GEO) database. We used the "limma" R package to determine the differentially expressed genes (DEGs) between myopic and normal corneas. Weighted gene co-expression network analysis (WGCNA) was used to identify critical co-expressed modules related to myopia, and enrichment analyses were used to annotate the function of genes encompassed in the compulsory module. We also validated these findings in two external datasets (GSE24641 and GSE136701). RESULTS: We identified that the DEGs were significantly enriched in ultraviolet (UV) response, TNF-α signaling via NFκB, Angiogenesis, Myogenesis pathways, etc. We used 2095 genes to construct the co-expression gene modules and found five interesting modules because the eigengene expression of these modules was significantly differentially expressed between myopic and normal corneas. Notably, the enrichment analysis found that the genes encompassed in lightgreen module were significantly enriched in immune-related pathways. These findings were proved by subsequent analysis based on Xcell software. We found the component of B cells, CD4+ memory T cells, CD8+ central memory T cells, plasmacytoid dendritic cells, T helper 2 (Th2) cells, regulatory T cells (Tregs), etc. were significantly increased in myopic corneas, while CD8+ T cells, CD4+ T central memory cells, natural killer T (NKT) cells, and T helper 1 (Th1) cells were significantly decreased. CONCLUSION: Our findings identified some markers that might detect diagnosis and treatment for myopia from cornea aspect. Future studies are warranted to verify the functional role of immune-related pathways in cornea during the pathogenesis or progression of myopia.

The effect of antioxidant dietary supplements and diet-derived circulating antioxidants on vitiligo outcome: evidence from genetic association and comprehensive Mendelian randomization.

Background: Previous studies have indicated that antioxidant diets may have a positive impact on vitiligo by interfering with oxidative stress mechanisms. However, there has been a lack of research utilizing the Mendelian randomization (MR) method to analyze the relationship between antioxidant diet intake and vitiligo. Methods: In this study, we employed both univariate Mendelian randomization (UVMR) and multivariate Mendelian randomization (MVMR) approaches. The specific antioxidant dietary supplements (such as coffee intake, green tea intake, herbal tea intake, standard tea intake, and average weekly red wine intake) as well as diet-derived circulating antioxidants, including Vit. C (ascorbate), Vit. E (α-tocopherol), Vit. E (γ-tocopherol), Carotene, Vit. A (retinol), Zinc, and Selenium (N = 2,603-428,860) were significantly associated with independent single-nucleotide polymorphisms (SNPs). We obtained pooled statistics on vitiligo from a meta-analysis of three genome-wide association studies (GWASs) of European ancestry, including 4,680 cases and 39,586 controls. Inverse variance weighted (IVW) was employed as the primary analytical method, and sensitivity analysis was conducted to assess the robustness of the main findings. Results: Genetically, coffee intake [odds ratio (OR) = 0.17, 95% confidence interval (CI) 0.07-0.37, p = 1.57 × 10-5], average weekly red wine intake (OR = 0.28, 95% CI 0.08-1.00, p = 0.049), and standard tea intake (OR = 0.99, 95% CI 0.98-0.99, p = 5.66 × 10-7) were identified as protective factors against vitiligo. However, no causal effect between the intake of other antioxidant diets and vitiligo was found. Moreover, no instances of pleiotropy or heterogeneity were observed in this study. Conclusion: Our study indicates that coffee, standard tea, and red wine consumption can potentially reduce the risk of vitiligo. However, there is insufficient evidence to support that other antioxidant diets have a significant effect on vitiligo.

Advances on myeloid-derived suppressor cells in hepatitis B virus infection / 中华临床感染病杂志

Myeloid-derived suppressor cells (MDSCs) are a group of immature and heterogeneous cells that can inhibit T cell function. In pathological conditions such as tumors, infections, and chronic inflammation, the large expansion of MDSCs is involved in processes of immune escape, immune tolerance and inflammatory reactions. MDSCs are also crucial in the pathophysiology of hepatitis B virus (HBV) infection, however, their activation, differentiation, and function during HBV infection are still unclear. This article reviews the general characteristics and roles of MDSCs in HBV infection, as well as related drug therapies, in order to provide information for further research on the related mechanism and potential targeted treatment.

A High-Strength Neuromuscular System That Implements Reflexes as Controlled by a Multiquadrant Artificial Efferent Nerve.

We demonstrate an artificial efferent nerve that distinguishes environment-responsive conditioned and unconditioned reflexes, i.e., hand-retraction reflex and muscle memory, respectively. These reflex modes are immediately switchable by altering the polarity of charge carriers in a parallel-channeled artificial synapse; this ability emulates multiplexed neurotransmission of different neurotransmitters to form glutamine-induced short-term plasticity and acetylcholine-induced long-term plasticity. This is the successful control of high-strength artificial muscle fibers by using an artificial efferent nerve to form a neuromuscular system that can realize curvature and force simultaneously and in which all these aspects far surpass currently available neuromuscular systems. Furthermore, the special four-quadrant information-processing mechanism of our artificial efferent nerve allows complex application extensions, i.e., relative-position tracking of sound sources, immediate switchable learning modes between fast information processing and long-term memory, and high-accuracy pattern cognition. This work is a step toward development of human-compatible artificial neuromuscular systems.