The Causal Relationships Between Gut Microbiota, Brain Volume, and Intelligence: A Two-Step Mendelian Randomization Analysis.

BACKGROUND: Growing evidence indicates that dynamic changes in gut microbiome can affect intelligence; however, whether these relationships are causal remains elusive. We aimed to disentangle the poorly understood causal relationship between gut microbiota and intelligence. METHODS: We performed a 2-sample Mendelian randomization (MR) analysis using genetic variants from the largest available genome-wide association studies of gut microbiota (N = 18,340) and intelligence (N = 269,867). The inverse-variance weighted method was used to conduct the MR analyses complemented by a range of sensitivity analyses to validate the robustness of the results. Considering the close relationship between brain volume and intelligence, we applied 2-step MR to evaluate whether the identified effect was mediated by regulating brain volume (N = 47,316). RESULTS: We found a risk effect of the genus Oxalobacter on intelligence (odds ratio = 0.968 change in intelligence per standard deviation increase in taxa; 95% CI, 0.952-0.985; p = 1.88 × 10-4) and a protective effect of the genus Fusicatenibacter on intelligence (odds ratio = 1.053; 95% CI, 1.024-1.082; p = 3.03 × 10-4). The 2-step MR analysis further showed that the effect of genus Fusicatenibacter on intelligence was partially mediated by regulating brain volume, with a mediated proportion of 33.6% (95% CI, 6.8%-60.4%; p = .014). CONCLUSIONS: Our results provide causal evidence indicating the role of the microbiome in intelligence. Our findings may help reshape our understanding of the microbiota-gut-brain axis and development of novel intervention approaches for preventing cognitive impairment.

Multi-tissue transcriptome-wide association study reveals susceptibility genes and drug targets for insulin resistance-relevant phenotypes.

AIM: Genome-wide association studies (GWAS) have identified multiple susceptibility loci associated with insulin resistance (IR)-relevant phenotypes. However, the genes responsible for these associations remain largely unknown. We aim to identify susceptibility genes for IR-relevant phenotypes via a transcriptome-wide association study. MATERIALS AND METHODS: We conducted a large-scale multi-tissue transcriptome-wide association study for IR (Insulin Sensitivity Index, homeostasis model assessment-IR, fasting insulin) and lipid-relevant traits (high-density lipoprotein cholesterol, triglycerides, low-density lipoprotein cholesterol and total cholesterol) using the largest GWAS summary statistics and precomputed gene expression weights of 49 human tissues. Conditional and joint analyses were implemented to identify significantly independent genes. Furthermore, we estimated the causal effects of independent genes by Mendelian randomization causal inference analysis. RESULTS: We identified 1190 susceptibility genes causally associated with IR-relevant phenotypes, including 58 genes that were not implicated in the original GWAS. Among them, 11 genes were further supported in differential expression analyses or a gene knockout mice database, such as KRIT1 showed both significantly differential expression and IR-related phenotypic effects in knockout mice. Meanwhile, seven proteins encoded by susceptibility genes were targeted by clinically approved drugs, and three of these genes (H6PD, CACNB2 and DRD2) have been served as drug targets for IR-related diseases/traits. Moreover, drug repurposing analysis identified four compounds with profiles opposing the expression of genes associated with IR risk. CONCLUSIONS: Our study provided new insights into IR aetiology and avenues for therapeutic development.

High-throughput functional dissection of noncoding SNPs with biased allelic enhancer activity for insulin resistance-relevant phenotypes.

Most of the single-nucleotide polymorphisms (SNPs) associated with insulin resistance (IR)-relevant phenotypes by genome-wide association studies (GWASs) are located in noncoding regions, complicating their functional interpretation. Here, we utilized an adapted STARR-seq to evaluate the regulatory activities of 5,987 noncoding SNPs associated with IR-relevant phenotypes. We identified 876 SNPs with biased allelic enhancer activity effects (baaSNPs) across 133 loci in three IR-relevant cell lines (HepG2, preadipocyte, and A673), which showed pervasive cell specificity and significant enrichment for cell-specific open chromatin regions or enhancer-indicative markers (H3K4me1, H3K27ac). Further functional characterization suggested several transcription factors (TFs) with preferential allelic binding to baaSNPs. We also incorporated multi-omics data to prioritize 102 candidate regulatory target genes for baaSNPs and revealed prevalent long-range regulatory effects and cell-specific IR-relevant biological functional enrichment on them. Specifically, we experimentally verified the distal regulatory mechanism at IRS1 locus, in which rs952227-A reinforces IRS1 expression by long-range chromatin interaction and preferential binding to the transcription factor HOXC6 to augment the enhancer activity. Finally, based on our STARR-seq screening data, we predicted the enhancer activity of 227,343 noncoding SNPs associated with IR-relevant phenotypes (fasting insulin adjusted for BMI, HDL cholesterol, and triglycerides) from the largest available GWAS summary statistics. We further provided an open resource (http://www.bigc.online/fnSNP-IR) for better understanding genetic regulatory mechanisms of IR-relevant phenotypes.

Laxative effect of Wenyang Yiqi Decoction on loperamide-induced astriction model mice.

Background: Although a common disease, astriction is difficult to treat and severely affects quality of life. Wenyang Yiqi Decoction (WYD) is a kind of traditional Chinese medicine (TCM) that is used to treat astriction; however, the mechanism remains unclear. Therefore, this work assessed the laxative effect of WYD on loperamide-induced astriction (LIA) model mice. Methods: We replicated a constipation model in mice and detected changes in fecal parameters such as feces quantity and water content, intestinal transit function, and histopathological changes in the constipated mice. After five days of WYD intervention, mouse tissues were taken out for detection. We also measured the levels of gastrin (Gas), substance P (SP), acetylcholinesterase (AChE), and vasoactive intestinal peptide (VIP) in the mice's serum. Additionally, we used quantitative real-time polymerase chain reaction (qRT-PCR) and Western Blot to detect c-Kit and stem cell factor (SCF), and examined the effects of WYD on the tight junction (TJ) proteins occludin (Ocln), zonula occludens-1 (ZO-1), and claudin-1 (Cldn-1) in the mice's intestines. Results: Through histopathological changes, we observed less destruction of epithelial cells and greater integrity of goblet and epithelial cells in WYD-treated mice than in mice in the loperamide group. qRT-PCR and western blot analysis of c-Kit and SCF showed that WYD could boost the levels of c-Kit and SCF. The qRT-PCR and immunohistochemical (IHC) analyses of enteral tight occludin (Ocln), occludenas-1 (ZO-1), and cldin-1 (Cldn-1) showed that WYD could boost the level of ZO-1 and decrease the level of Cldn-1. The study also investigated the effect of WYD treatment on the enteral barrier function of astriction model mice and found that the TJ proteins (ZO-1, Cldn-1) in the colon of the astriction model mice had significant changes compared to the normal group, and WYD intervention was found to increase the expression of ZO-1, and decrease the expression of Cldn-1. Conclusions: WYD alleviates LIA by regulating enteral hormones, boosting the number of interstitial cells of Cajal (ICCs), or adjusting enteral block action.

Strong Reliable Electrostatic Actuation Based on Self-Clearing Using a Thin Conductive Layer.

Electrostatic adhesion, as a promising actuation technique for soft robotics, severely suffers from the failure caused by the unpredictable electrical breakdown. This study proposes a novel self-clearing mechanism for electrostatic actuators, particularly for electrostatic adhesion. By simply employing an enough thin conductive layer (e.g., <7 µm for copper), this method can spontaneously clear the conductor around the breakdown sites effectively once breakdowns onset and survive the actuator shortly after the electrical damage. Compared with previous self-clearing methods, which typically rely on new specific materials, this mechanism is easy to operate and compatible with various materials and fabrication processes. In our tests, it can improve the maximum available voltage by 260% and the maximum electrostatic adhesive force by 276%. In addition, the robustness and repeatability of the self-clearing mechanism are validated by surviving consecutive breakdowns and self-clearing of 173 times during 65 min. This method is also demonstrated to be capable of recovering the electrostatic pad from severe physical damages such as punctures, penetrations, and cuttings successfully and enabling stable and reliable operation of the electrostatic clutch, or gripping, for example, even after the short-circuit takes place for hundreds of times. Therefore, the proposed self-clearing method sheds new light on high performance and more extensive practical applications of electrostatic actuators in the future.

Origami-Inspired Soft Twisting Actuator.

Soft actuators have shown great advantages in compliance and morphology matched for manipulation of delicate objects and inspection in a confined space. There is an unmet need for a soft actuator that can provide torsional motion to, for example, enlarge working space and increase degrees of freedom. Toward this goal, we present origami-inspired soft pneumatic actuators (OSPAs) made from silicone. The prototype can output a rotation of more than one revolution (up to 435°), more significant than its counterparts. Its rotation ratio ( = rotation angle/aspect ratio) is more than 136°, about twice the largest one in other literature. We describe the design and fabrication method, build the analytical model and simulation model, and analyze and optimize the parameters. Finally, we demonstrate the potentially extensive utility of the OSPAs through their integration into a gripper capable of simultaneously grasping and lifting fragile or flat objects, a versatile robot arm capable of picking and placing items at the right angle with the twisting actuators, and a soft snake robot capable of changing attitude and directions by torsion of the twisting actuators.

CircKIF4A Is a Prognostic Factor and Modulator of Natural Killer/T-Cell Lymphoma Progression.

Background: Natural killer/T-cell lymphoma (NKTL) is difficult to treat. Circular RNAs (circ RNAs) have been implicated in tumorigenesis. However, the function of circKIF4A in NKTL has not been investigated. Methods: QPCR analysis was used to compare circKIF4A levels in NKTL cell lines versus normal cell lines. Kaplan-Meier survival analysis was used to assess the effect of circKIF4A on the prognosis of NKTL. The correlation between clinicopathological features and circKIF4A expression was examined using cox regression analysis. Luciferase reporter, RNA immunoprecipitation and immunohistochemistry assays were also used to investigate the mechanisms of circKIF4A in NKTL. Results: Our analyses revealed that circKIF4A is significantly upregulated in NKTL cell lines and that its upregulation correlates with the poor prognosis of NKTL. The silencing of circKIF4A significantly suppressed glucose uptake and lactate production in NKTL cells. Moreover, we showed that circKIF4A, PDK1, and BCL11A bind miR-1231 and that circKIF4A regulates PDK1 and BCL11A expressions by sponging miR-1231. Conclusions: During NKTL progression, circKIF4A regulated PDK1 and BCL11A levels by sponging miR-1231. Our data indicated that circKIF4A is oncogenic in NKTL and that it is a predictor of poor prognosis of NKTL.

Miniature Mobile Robot Using Only One Tilted Vibration Motor.

In miniature mobile robots, reducing the number of actuators can effectively reduce the size and weight of the robot. However, it is challenging to design a robot with as few actuators as possible without losing good motion performance. This work presented a simple-structured low-cost miniature mobile robot. It is driven by only a single tilted motor and yet is fully capable of being controlled to move forward and turn left or right on the ground. Based on the stick-slip mechanism, the robot's motion is achieved by interplaying between the centrifugal force generated by the vibration motor tilted on the robot and the friction force of the robot. The robot's speed can be controlled by regulating the magnitude and the period of the applied voltage. Finally, the robot can translate and rotate on the ground and follow various arbitrary paths. The prototype weighs only 11.15 g, costs $6.35, and is 20 mm in diameter and 25 mm in height. The proposed system is experimentally verified and demonstrates the controllability of the robot by the movement along a straight line, a circle, and more arbitrary paths.

Self-shrinking soft demoulding for complex high-aspect-ratio microchannels.

Microchannels are the essential elements in animals, plants, and various artificial devices such as soft robotics, wearable sensors, and organs-on-a-chip. However, three-dimensional (3D) microchannels with complex geometry and a high aspect ratio remain challenging to generate by conventional methods such as soft lithography, template dissolution, and matrix swollen processes, although they are widespread in nature. Here, we propose a simple and solvent-free fabrication method capable of producing monolithic microchannels with complex 3D structures, long length, and small diameter. A soft template and a peeling-dominant template removal process are introduced to the demoulding process, which is referred to as soft demoulding here. In combination with thermal drawing technology, microchannels with a small diameter (10 µm), a high aspect ratio (6000, length-to-diameter), and intricate 3D geometries are generated. We demonstrate the vast applicability and significant impact of this technology in multiple scenarios, including soft robotics, wearable sensors, soft antennas, and artificial vessels.

Flexible Metal Electrodes by Femtosecond Laser-Activated Deposition for Human-Machine Interfaces.

Flexible metal electrodes are essential for flexible electronics, where the main challenge is to obtain mask-free patterned metals directly on substrates such as poly(dimethylsiloxane) (PDMS) at low cost. This work highlights a feasible strategy named femtosecond laser-activated metal deposition for electroless deposition of metals (Cu, Ni, Ag, and Au) on PDMS, which is suitable for maskless and low-cost fabrication of metal layers on PDMS and even on other materials of different natures including polyethylene terephthalate, paper, Si, and glass. The electrical conductivity of the PDMS/Cu electrode is comparable to that of bulk Cu. Moreover, robust bonding at the PDMS/Cu interface is evidenced by a scotch tape test and bending test of more than 20,000 cycles. Compared with previous studies using a nanosecond laser, the restriction on absorbing sensitizers could be alleviated, and catalysts could originate from precursors without polymer substrates under a femtosecond laser, which may be attributed to nonlinear absorption and ultrashort heating time with the femtosecond laser. Implementing a human-machine interface task is demonstrated by recognizing hand gestures via a multichannel electrode array with high fidelity to control a robot hand.

CircMMP1 promotes colorectal cancer growth and metastasis by sponging miR-1238 and upregulating MMP family expression.

BACKGROUND: Circular RNAs (circRNAs) are a type of non-coding RNA which play an important role in the regulation of biological processes of various malignant tumors. However, the potential molecular mechanisms and roles of circRNAs in colorectal cancer (CRC) remain unelucidated. METHODS: In the current study, we analyzed the data of high-throughput microarray sequencing to screen differentially expressed circRNAs in CRC. Cell counting kit-8 (CCK-8), colony-formation, transwell, mouse xenograft models and immunohistochemistry assays were used to explore the function of circRNAs. TargetScan database, quantitative real-time polymerase chain reaction (qRT-PCR), double luciferase and RNA immunoprecipitation (RIP) were used to explore the molecular mechanism. RESULTS: We identified circMMP1 (hsa_circ_0024109) as a frequently upregulated circRNA in both CRC tissues and cells. Both in vitro and in vivo experiments demonstrated that circMMP1 knockdown significantly inhibited the proliferation and metastasis of CRC. The results demonstrated that circMMP1 promoted the growth and metastasis of CRC by sponging miR-1238 and upregulating the expression of matrix metalloproteinase 1 (MMP1), MMP2, and MMP9 expression. CONCLUSIONS: In conclusion, our study identified the biological role of the circMMP1-miR-1238-MMP1/MMP2/MMP9 axis in the growth and metastasis of CRC, which is crucial for the monitoring and treatment of CRC. Further research on circMMP1 may provide a theoretical basis for diagnostic biomarkers of early CRC screening.

Upregulated circRAD18 promotes tumor progression by reprogramming glucose metabolism in papillary thyroid cancer.

BACKGROUND: By regulating complex functional processes, circRNAs are crucial in the development of different cancers. Nevertheless, most circRNAs in papillary thyroid cancer metabolic reprogramming remain unknown. METHODS: The expression of circRNA was assessed by qRT-PCR in papillary thyroid cancer tissues and cell lines. Cell proliferation and glucose intake experiments were performed by certain kit. Transwell assays and wound healing assays were performed to investigate the function of circRNA in metastasis. In addition, a serious of molecular experiments were conducted to determine the exact mechanism of circRAD18. Luciferase reporter and RNA immunoprecipitation assay were conducted to determine the molecular interaction between circRNA and miRNA. RESULTS: We characterized circRAD18 as a significantly upregulated circRNA in papillary thyroid tissues and cell lines and found its downregulation could inhibit the growth and metastasis ability of papillary thyroid cancer. Interestingly, we found that circRAD18 was involved in glucose metabolism reprogramming of papillary thyroid cancer, and its silence could remarkably inhibit cell glucose uptake and lactate production in papillary thyroid cancer cells. Inhibition of circRAD18 could decrease the expression level of PDK1 protein by sponging miR-516b. CONCLUSIONS: This study verified the novel function of the circRAD18-miR-516b-PDK1 axis in papillary thyroid cancer metabolic reprogramming progression, which has potential to be a novel therapeutic target.

MALAT1 Promotes Tumorigenesis and Increases Cellular Sensitivity to Herceptin in HER2-positive Breast Cancer.

BACKGROUND: The function of MALAT1, a long non-coding RNAs (lncRNA), in HER2- positive breast cancer remains largely unexplored. OBJECTIVES: This study aimed to investigate the effect of MALAT1 on tumor development in HER2-positive breast cancer. METHODS: We detected MALAT1 expression in HER2-positive breast cancer cells and tissues, and analyzed the effects of MALAT1 on cell proliferation in HER2-positive breast cancer cells lines (BT-474 and SKBR3). A mouse xenograft model was established for detecting the function of MALAT1 in HER2-positive breast cancer. RESULTS AND DISCUSSION: As a result, MALAT1 was remarkably up-regulated in HER2-positive breast cancer both in cells and tissues. In addition, the silencing of MALAT1 inhibited the proliferation of HER2-positive breast cancer cells both in vitro and in vivo. Furthermore, knockdown of MALAT1 by shRNA down-regulated DNMT1, DNMT3a, and DNMT3b, while up-regulated BRCA1 and PTEN in HER2-positive breast cancer both in cell lines and mouse xenograft models. CONCLUSION: In short, MALAT1 might be a potential biomarker and therapeutic target for HER2- positive breast cancer therapy.

Modeling and Optimization of Electrostatic Film Actuators Based on the Method of Moments.

Electrostatic film actuators represent a promising new approach to drive a soft robot, but they lack a comprehensive model to link the design parameters and actuation performance, making actuator design and parameter optimization challenging. To solve this problem, we build a mathematical model based on the method of moments by assuming that each electrode consists of a large number of line charges. This model can directly deduce fluctuation in thrust and adhesive forces during actuator movement, as well as the distribution of electric potential and field strength, for analysis and optimization. It consumes shorter computing time and fewer computing resources, but with comparable accuracy, in comparison with previous indirect means. It is validated by results from both previous studies and on-site experiments. Based on this model, we generate numerous values of actuator output force for different structural parameters. By analyzing the tendency, we summarize a parameter optimization workflow and write an open-sourced program as an example to facilitate the parameter selection for actuator design starting from scratch.

Construction of an immune-related genes nomogram for the preoperative prediction of axillary lymph node metastasis in triple-negative breast cancer.

Immune system disorder is associated with metastasis of triple-negative breast cancers (TNBCs). A robust, individualized immune-related genes (IRGs)-based classifier was aimed to develop and validate in our study to precisely estimate the axillary lymph node (ALN) status preoperatively in patients with early-stage TNBC. We first analyzed RNA sequencing profiles in TNBC patients from The Cancer Genome Atlas database by using bioinformatics approaches, and screened 23 differentially expressed IRGs. A 9-gene panel was generated with an area under the curve (AUC) of 0.77 [95% confidence interval (95% CI), 0.68-0.87]. We detected the 9 ALN-status-related IRGs in the training set (n = 133) and developed a reduced and optimized five-IRGs signature, which effectively distinguished TNBC patients with ALN metastasis (AUC, 0.80; 95% CI, 0.65-0.86), and was superior to preoperative ultrasound-based ALN status (AUC, 0.73; 95% CI, 0.53-0.93). Predictive efficiency (AUC, 0.77; 95% CI 0.61-0.93) of this five-IRGs signature was validated in the validation set (n = 81). Furthermore, IRGs nomogram incorporated IRGs signature with US-based ALN status showed higher ALN status prediction efficacy than US-based ALN status and five-IRGs signature alone in both training and validation sets. IRGs nomogram may aid in identifying patients who can be exempted from axillary surgery.Novelty and impact: An immune-related genes (IRGs) nomogram was first developed and externally validated in our study, which incorporated the IRGs signature with ultrasound (US)-based axillary lymph nodes (ALN) status. IRGs nomogram is superior to IRGs signature alone for preoperative estimation of ALN metastasis in patients with triple-negative breast cancer (TNBC). It is a favourable biomarker for preoperatively predicting ALN metastasis risk and may aid in clinical decision-making in early-stage TNBCs.

Helical edge states of topological photonic crystals with line defects.

Topologically protected edge states of honeycomb photonic crystals (PCs) have been extensively studied in recent years. Here we propose several optimized two-dimensional PC configurations with distinct line defects introduced by breaking the C6 symmetry of each topological lattice along the interfaces between two different topologies. The spin-flipping nature of the defect modes of these PC configurations is measured, which is expected to offer a novel realization mechanism of quantum spin Hall effect. The line defects can be treated as unidirectional air waveguides due to the characteristic topological properties. We manipulate the coupling effect of two helical edge states with tunable waveguide widths. It shows that the air waveguide has possibility for practical applications because of its suppression of backward scattering and considerable transmission efficiency.

LINC00703 Acts as a Tumor Suppressor via Regulating miR-181a/KLF6 Axis in Gastric Cancer.

PURPOSE: Long noncoding RNA 00703 (LINC00703) was found originating from a region downstream of Kruppel-like factor 6 (KLF6) gene, having 2 binding sites for miR-181a. Since KLF6 has been reported as a target of miR-181a in gastric cancer (GC), this study aims to investigate whether LINC00703 regulates the miR-181a/KLF6 axis and plays a functional role in GC pathogenesis. MATERIALS AND METHODS: GC tissues, cell lines, and nude mice were included in this study. RNA binding protein immunoprecipitation (RIP) and pull-down assays were used to evaluate interaction between LINC00703 and miR-181a. Quantitative real-time polymerase chain reaction and western blot were applied for analysis of gene expression at the transcriptional and protein levels. A nude xenograft mouse model was used to determine LINC00703 function in vivo. RESULTS: We revealed that LINC00703 competitively interacts with miR-181a to regulate KLF6. Overexpression of LINC00703 inhibited cell proliferation, migration/invasion, but promoted apoptosis in vitro, and arrested tumor growth in vivo. LINC00703 expression was found to be decreased in GC tissues, which was positively correlated with KLF6, but negatively with the miR-181a levels. CONCLUSIONS: LINC00703 may have an anti-cancer function via modulation of the miR-181a/KLF6 axis. This study also provides a new potential diagnostic marker and therapeutic target for GC treatment.