Slit2N and Robo4 regulate lymphangiogenesis through the VEGF-C/VEGFR-3 pathway

Background: Signaling through vascular endothelial growth factor C (VEGF–C) and VEGF receptor 3 (VEGFR-3) plays a central role in lymphangiogenesis and the metastasis of several cancers via the lymphatics. Recently, the Slit2/Robo4 pathway has been recognized as a modulator of vascular permeability and integrity. Signaling via the Robo receptor inhibits VEGF-mediated effects; however, its effects on lymphatic endothelial cell function have not been well characterized. Results: We found that pretreatment with Slit2N, an active fragment of Slit2, inhibited VEGF-C-mediated lung-derived lymphatic endothelial cell (L-LEC) proliferation, migration, and in vitro tube formation. Slit2N induced the internalization of VEGFR-3, which blocked its activation, and inhibited the activation of the PI3K/Akt pathway by VEGF-C in L-LECs. Moreover, we found that inhibition of VEGF-C-induced effects by Slit2N was Robo4-dependent. Conclusion: These results indicate that Slit2N/Robo4 modulates several key cellular functions, which contribute to lymphangiogenesis, and identify this ligand-receptor pair as a potential therapeutic target to inhibit lymphatic metastasis of VEGF-C-overexpressing cancers and manage lymphatic dysfunctions characterized by VEGF-C/VEGFR-3 activation

Atomic-layer molybdenum sulfide optical modulator for visible coherent light

Coherent light sources in the visible range are playing important roles in our daily life and modern technology, since about 50% of the capability of the our human brains is devoted to processing visual information. Visible lasers can be achieved by nonlinear optical process of infrared lasers and direct lasing of gain materials, and the latter has advantages in the aspects of compactness, efficiency, simplicity, etc. However, due to lack of visible optical modulators, the directly generated visible lasers with only a gain material are constrained in continuous-wave operation. Here, we demonstrated the fabrication of a visible optical modulator and pulsed visible lasers based on atomic-layer molybdenum sulfide (MoS 2), a ultrathin two-dimensional material with about 9-10 layers. By employing the nonlinear absorption of the modulator, the pulsed orange, red and deep red lasers were directly generated. Besides, the present atomic-layer MoS 2 optical modulator has broadband modulating properties and advantages in the simple preparation process. The present results experimentally verify the theoretical prediction for the low-dimensional optoelectronic modulating devices in the visible wavelength region and may open an attractive avenue for removing a stumbling block for the further development of pulsed visible lasers

Nonlinear optical response of Au nanorods for broadband pulse modulation in bulk visible lasers

Due to the lack of suitable optical modulators, directly generated Pr3+- and Dy3+-doped bulk visible lasers are limited in the continuous-wave operation; yet, pulsed visible lasers are only sparingly reported recently. It has been theoretically predicated that Au nanorods could modulate the visible light operation, based on the nonlinear optical response of surface plasmon resonance. Here, we demonstrate the saturable absorption properties of Au nanorods in the visible region and experimentally realized the pulsed visible lasers over the spectral range of orange (605nm), red (639nm), and deep red (721nm) with Au nanorods as the optical modulator. We show that Au nanorods have a broad nonlinear optical response and can serve as a type of broadband, low-cost, and eco-friendly candidate for optical switchers in the visible region. Our work also advocates the promise of plasmonic nanostructures for the development of pulsed lasers and other plasmonic devices

Digital breast tomosynthesis-based peritumoral radiomics approaches in the differentiation of benign and malignant breast lesions

PURPOSEWe aimed to evaluate digital breast tomosynthesis (DBT)-based radiomics in the differentiation of benign and malignant breast lesions in women.METHODSA total of 185 patients who underwent DBT scans were enrolled between December 2017 and June 2019. The features of handcrafted and deep learning-based radiomics were extracted from the tumoral and peritumoral regions with different radial dilation distances outside the tumor. A 3-step method was used to select discriminative features and develop the radiomics signature. Discriminative clinical factors were identified by univariate logistic regression. The clinical fac- tors with P < .05 were used to build a clinical model with multivariate logistic regression. The radiomics nomogram was developed by integrating the radiomics signature and discriminative clinical factors. Discriminative performance of the radiomics signature, clinical model, nomo- gram, and breast imaging reporting and data system assessment were evaluated and compared with the receiver operating characteristic and decision curves analysis (DCA).RESULTSA total of 2 handcrafted and 2 deep features were identified as the most discriminative features from the peritumoral regions with 2 mm dilation distances and used to develop the radiomics signature. The nomogram incorporating the radiomics signature, age, and menstruation status showed the best discriminative performance with area under the curve (AUC) values of 0.980 (95% CI, 0.960 to 1.000; sensitivity =0.970, specificity =0.946) in the training cohort and 0.985 (95% CI, 0.960 to 1.000; sensitivity = 0.909, specificity = 0.966) in the validation cohort. DCA con- firmed the potential clinical usefulness of our nomogram.CONCLUSIONOur results illustrate that the radiomics nomogram integrating the DBT imaging features and clinical factors (age and menstruation status) can be considered as a useful tool in aiding the clinical diagnosis of breast cancer

Analysis of gut microbiota and immune-related genes during sea cucumber (<em>Apostichopus japonicus</em>) response to dietary supplementation with <em>Codonopsis pilosula</em>

The gut microbiota composition of sea cucumber (Apostichopus japonicas) was investigated using high-throughput sequencing techniques. The mRNA expression of complement component 3 and lysozyme genes was evaluated using quantitative fluorescence PCR. Sea cucumbers were fed with a basal diet (control group) and an experimental diet supplemented with Codonopsis pilosula (experimental group) for 30 days. The results showed that the alpha diversity of the gut microbiota was changed in different indices, including Chao1, the abundance-based coverage estimator, the Shannon index, and Good's coverage. Dietary C. pilosula promoted the proliferation of the Flavobacteriaceae family of the Proteobacteria phylum and reduced the relative abundance of the Verrucomicrobiaceae family of the Verrucomicrobia phylum. We concluded that dietary C. pilosula supplementation could alter the network interactions among different microbial functional groups by changing the ecological network's microbial community composition and biological evolution. A positive effect on A. japonicus immune responses in the gut was seen via increasing the mRNA expression of the complement component 3 and lysozyme genes. It seems to happen via modulating the balance in gut microbiota

Association of thrombocytopenia with immune checkpoint inhibitors: a large-scale pharmacovigilance analysis based on the data from FDA adverse event reporting system database

Introduction: An increasing number of immune-related adverse events (irAEs) induced by immune checkpoint inhibitors (ICIs) have been reported during clinical treatment. We aimed to explore the clinical characteristics of patients with ICIs-induced ITP under different therapeutic strategies based on the FAERS database and explore the potential biological mechanisms in combination with TCGA pan-cancer data.Methods: Data from FAERS were collected for ICIs adverse reactions between January 2012 and December 2022. Disproportionality analysis identified ICIs-induced ITP in the FAERS database using the reporting odds ratio (ROR), proportional reporting ratio (PRP), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinker algorithms (MGPS). The potential biological mechanisms underlying ITP induced by ICIs were examined using TCGA transcriptome data on cancers.Results: In the FAERS, 345 ICIs-induced ITP reports were retrieved, wherein 290 (84.06%) and 55 (15.94%) were reported as monotherapy and combination therapy, respectively. The median age of the reported patients with ICIs-induced ITP was 69 years (IQR 60-76), of which 62 (18%) died and 47 (13.6%) had a life-threatening outcome. The majority of reported indications were lung, skin, and bladder cancers, and the median time to ITP after dosing was 42 days (IQR 17-135), with 64 patients (43.5%) experiencing ITP within 30 days of dosing and 88 patients experiencing ITP in less than 2 months (59.9%). The occurrence of ICIs-induced ITP may be associated with ICIs-induced dysregulation of the mTORC1 signaling pathway and megakaryocyte dysfunction.Conclusion: There were significant reporting signals for ITP with nivolumab, pembrolizumab, cemiplimab, atezolizumab, avelumab, durvalumab, ipilimumab, nivolumab/ipilimumab, and pembrolizumab/ipilimumab. Patients treated with anti-PD-1 in combination with anti-CTLA-4 are more likely to have an increased risk of ICIs-induced ITP. Patients with melanoma are at a higher risk of developing ITP when treated with ICI and should be closely monitored for this risk within 60 days of treatment. The potential biological mechanism of ICIs-induced ITP may be related to the dysfunction of megakaryocyte autophagy through the overactivation of the mTOR-related signaling pathway. This study provides a comprehensive understanding of ICIs-induced ITP. Clinicians should pay attention to this potentially fatal adverse reaction

The Perturbation of Infant Gut Microbiota Caused by Cesarean Delivery Is Partially Restored by Exclusive Breastfeeding

Early establishment of the infant gut microbiome has been attributed to various environmental factors that may influence long-term health. The aim of this study was to determine the single and combined impacts of the delivery mode, feeding pattern and postnatal antibiotic exposure on the initial establishment of infant gut microbiome at 6 weeks postpartum. A cross-sectional study was conducted at a single center in China. Fecal samples were collected from 120 infants at 6 weeks postpartum. The V3-V4 regions of 16S rRNA gene were analyzed by Illumina sequencing, and clinical information was obtained from medical records and questionnaire survey. Compared with vaginally delivered infants, the gut microbial community structure of cesarean delivered infants were significantly different (P = 0.044), in parallel with the decreased relative abundance of Bifidobacterium (P = 0.028), which contrasts with the normal gut microbial establishment. Using the vaginally delivered and exclusively breastfed (VB) infants as a reference, the comparative analysis of cesarean delivered and exclusively breastfed (CB) infants with cesarean delivered and mixed-fed (CM) infants showed that both within- and between-group UniFrac distance were significantly smaller in CB infants (P &lt; 0.001, P &lt; 0.001). LEfSe analysis showed that the relative abundances of Enterococcus, Veillonella, and Faecalibacterium were significantly different between CB and CM infants, whereas the relative abundances of those genera in VB infants were close to those of CB infants, and distinct from those of CM infants. Additionally, no significant difference of microbial composition, alpha diversity, or community structure was observed between postnatal antibiotics exposed infants and unexposed infants. In summary, delivery mode had a significant impact on the infant gut microbial community structure and composition, and the gut microbiota was disturbed in infants delivered by cesarean section. However, our study showed that this disturbance of gut microbiota in cesarean delivered infants was partially restored by exclusive breastfeeding in comparison with mixed feeding. No distinct impact of postnatal antibiotic exposure on infant gut microbiome was found at 6 weeks of age

miR-182 Regulates Metabolic Homeostasis by Modulating Glucose Utilization in Muscle

SummaryUnderstanding the fiber-type specification and metabolic switch in skeletal muscle provides insights into energy metabolism in physiology and diseases. Here, we show that miR-182 is highly expressed in fast-twitch muscle and negatively correlates with blood glucose level. miR-182 knockout mice display muscle loss, fast-to-slow fiber-type switching, and impaired glucose metabolism. Mechanistic studies reveal that miR-182 modulates glucose utilization in muscle by targeting FoxO1 and PDK4, which control fuel selection via the pyruvate dehydrogenase complex (PDHC). Short-term high-fat diet (HFD) feeding reduces muscle miR-182 levels by tumor necrosis factor α (TNFα), which contributes to the upregulation of FoxO1/PDK4. Restoration of miR-182 expression in HFD-fed mice induces a faster muscle phenotype, decreases muscle FoxO1/PDK4 levels, and improves glucose metabolism. Together, our work establishes miR-182 as a critical regulator that confers robust and precise controls on fuel usage and glucose homeostasis. Our study suggests that a metabolic shift toward a faster and more glycolytic phenotype is beneficial for glucose control

GraphScope Flex: LEGO-like Graph Computing Stack

Graph computing has become increasingly crucial in processing large-scale graph data, with numerous systems developed for this purpose. Two years ago, we introduced GraphScope as a system addressing a wide array of graph computing needs, including graph traversal, analytics, and learning in one system. Since its inception, GraphScope has achieved significant technological advancements and gained widespread adoption across various industries. However, one key lesson from this journey has been understanding the limitations of a "one-size-fits-all" approach, especially when dealing with the diversity of programming interfaces, applications, and data storage formats in graph computing. In response to these challenges, we present GraphScope Flex, the next iteration of GraphScope. GraphScope Flex is designed to be both resource-efficient and cost-effective, while also providing flexibility and user-friendliness through its LEGO-like modularity. This paper explores the architectural innovations and fundamental design principles of GraphScope Flex, all of which are direct outcomes of the lessons learned during our ongoing development process. We validate the adaptability and efficiency of GraphScope Flex with extensive evaluations on synthetic and real-world datasets. The results show that GraphScope Flex achieves 2.4X throughput and up to 55.7X speedup over other systems on the LDBC Social Network and Graphalytics benchmarks, respectively. Furthermore, GraphScope Flex accomplishes up to a 2,400X performance gain in real-world applications, demonstrating its proficiency across a wide range of graph computing scenarios with increased effectiveness

The Chinese Open Science Network (COSN): Building an Open Science Community From Scratch

Open Science is becoming a mainstream scientific ideology in psychology and related fields. However, researchers, especially early-career researchers (ECRs) in developing countries, are facing significant hurdles in engaging in Open Science and moving it forward. In China, various societal and cultural factors discourage ECRs from participating in Open Science, such as the lack of dedicated communication channels and the norm of modesty. To make the voice of Open Science heard by Chinese-speaking ECRs and scholars at large, the Chinese Open Science Network (COSN) was initiated in 2016. With its core values being grassroots-oriented, diversity, and inclusivity, COSN has grown from a small Open Science interest group to a recognized network both in the Chinese-speaking research community and the international Open Science community. So far, COSN has organized three in-person workshops, 12 tutorials, 48 talks, and 55 journal club sessions and translated 15 Open Science-related articles and blogs from English to Chinese. Currently, the main social media account of COSN (i.e., the WeChat Official Account) has more than 23,000 subscribers, and more than 1,000 researchers/students actively participate in the discussions on Open Science. In this article, we share our experience in building such a network to encourage ECRs in developing countries to start their own Open Science initiatives and engage in the global Open Science movement. We foresee great collaborative efforts of COSN together with all other local and international networks to further accelerate the Open Science movement