Single-cell transcriptome analysis profiling lymphatic invasion-related TME in colorectal cancer.

Lymphatic invasion (LI) is extremely aggressive and induces worse prognosis among patients with colorectal cancer (CRC). Thus, it is critical to characterize the cellular and molecular mechanisms underlying LI in order to establish novel and efficacious therapeutic targets that enhance the prognosis of CRC patients. RNA-seq data, clinical and survival information of colon adenocarcinoma (COAD) patients were obtained from the TCGA database. In addition, three scRNA-seq datasets of CRC patients were acquired from the GEO database. Data analyses were conducted with the R packages. We assessed the tumor microenvironment (TME) differences between LI+ and LI- based scRNA-seq data, LI+ cells exhibited augmented abundance of immunosuppression and invasive subset. Marked extracellular matrix network activation was also observed in LI+ cells within SPP1+ macrophages. We revealed that an immunosuppressive and pro-angiogenic TME strongly enhanced LI, as was evidenced by the CD4+ Tregs, CD8+ GZMK+, SPP1+ macrophages, e-myCAFs, and w-myCAFs subcluster infiltrations. Furthermore, we identified potential LI targets that influenced tumor development, metastasis, and immunotherapeutic response. Finally, a novel LIRS model was established based on the expression of 14 LI-related signatures, and in the two testing cohorts, LIRS was also proved to have accurate prognostic predictive ability. In this report, we provided a valuable resource and extensive insights into the LI of CRC. Our conclusions can potentially benefit the establishment of highly efficacious therapeutic targets as well as diagnostic biomarkers that improve patient outcomes.

Heterozygous variants of NOD2, IL10RA, PLA2G6 and COL7A1 correlate with Crohn's disease.

To identify candidate pathogenic genes of early-stage Crohn's disease (CD) and predict potential roles of genetic factors in CD, we performed whole exome sequencing on a child with early-stage Crohn's disease (CD) and her parents (core family), found that the patient carried heterozygous variants of 4 genes: NOD2 c. 2257 C > T, IL10RA c. 301 C > T, PLA2G6 c. 2029 C > T, COL7A1 c. 3190 G > A. Heterozygous variants of NOD2, IL10RA, PLA2G6 and COL7A1, intestinal inflammatory response is triggered, normal intestinal wall tissue damage, leading to CD phenotype.

SoxC transcription factors shape the epigenetic landscape to establish competence for sensory differentiation in the mammalian organ of Corti.

The auditory organ of Corti is comprised of only two major cell types-the mechanosensory hair cells and their associated supporting cells-both specified from a single pool of prosensory progenitors in the cochlear duct. Here, we show that competence to respond to Atoh1, a transcriptional master regulator necessary and sufficient for induction of mechanosensory hair cells, is established in the prosensory progenitors between E12.0 and 13.5. The transition to the competent state is rapid and is associated with extensive remodeling of the epigenetic landscape controlled by the SoxC group of transcription factors. Conditional loss of Sox4 and Sox11-the two homologous family members transiently expressed in the inner ear at the time of competence establishment-blocks the ability of prosensory progenitors to differentiate as hair cells. Mechanistically, we show that Sox4 binds to and establishes accessibility of early sensory lineage-specific regulatory elements, including ones associated with Atoh1 and its direct downstream targets. Consistent with these observations, overexpression of Sox4 or Sox11 prior to developmental establishment of competence precociously induces hair cell differentiation in the cochlear progenitors. Further, reintroducing Sox4 or Sox11 expression restores the ability of postnatal supporting cells to differentiate as hair cells in vitro and in vivo. Our findings demonstrate the pivotal role of SoxC family members as agents of epigenetic and transcriptional changes necessary for establishing competence for sensory receptor differentiation in the inner ear.

DoTA: Unsupervised Detection of Traffic Anomaly in Driving Videos.

Video anomaly detection (VAD) has been extensively studied for static cameras but is much more challenging in egocentric driving videos where the scenes are extremely dynamic. This paper proposes an unsupervised method for traffic VAD based on future object localization. The idea is to predict future locations of traffic participants over a short horizon, and then monitor the accuracy and consistency of these predictions as evidence of an anomaly. Inconsistent predictions tend to indicate an anomaly has occurred or is about to occur. To evaluate our method, we introduce a new large-scale benchmark dataset called Detection of Traffic Anomaly (DoTA)containing 4,677 videos with temporal, spatial, and categorical annotations. We also propose a new VAD evaluation metric, called spatial-temporal area under curve (STAUC), and show that it captures how well a model detects both temporal and spatial locations of anomalies unlike existing metrics that focus only on temporal localization. Experimental results show our method outperforms state-of-the-art methods on DoTA in terms of both metrics. We offer rich categorical annotations in DoTA to benchmark video action detection and online action detection methods. The DoTA dataset has been made available at: https://github.com/MoonBlvd/Detection-of-Traffic-Anomaly.

Theoretical basis and experimental verification for evaluating the distribution of engineered nanoparticles in water-oil system.

The distribution of nanoparticles between aqueous and organic phases is universally considered as the starting point in predicting the fate and bioavailability of engineered nanoparticles in the environment. However, the theoretical basis for determining the distribution of nanoparticles in the immiscible water-oil system remains unclear. Here, for the first time, theoretical calculations were conducted to illustrate the underlying mechanism. It was suggested that the distribution of nanoparticles was largely controlled by the surface charge, particle size and surface hydrophobicity, and the water-oil interface was not the favorable phase for nanoparticles until a size threshold (10 nm) was met and the particle surface became amphiphilic. The theoretical results were verified by the experimental approaches of different nanoparticles distributed in the water-octanol mixture. The neutralization of a charged surface led to enhanced distribution into octanol for hydrophobic nanoparticles (e.g., aqueous C60), yet it had little effect on hydrophilic nanoparticles (e.g., fullerol). More nanoparticles were trapped at the water-oil interface when size grew larger (e.g., Ag-CIT and Au-CIT with citrate) and the surface rendered amphiphilic by polymeric coatings (e.g., Ag-PVP with polyvinylpyrrolidone), though larger hydrophobic nanoparticles like aqu-nC60 tended to stay in the octanol. The surface charge and hydrophobicity may have an important impact on the path-dependent distribution of nanoparticles in water- octanol system. The mechanistic insights based on theoretical calculations and experimental approaches will facilitate the accurate prediction of the distribution of engineered nanoparticles in biological and environmental systems.

Progressive hemifacial atrophy in a Chinese patient: A case report.

BACKGROUND: Progressive hemifacial atrophy (PHA) is a rare and progressive condition of unknown etiology that is characterized by chronic progressive atrophy of the skin, subcutaneous tissue, muscle, and bone on 1 side of the face. However, its precise pathogenesis remains poorly understood. CASE PRESENTATION: Here, we report a case of PHA, which manifested as left-sided facial atrophy. Whole-exome sequencing of peripheral blood samples from the patient and his parents, together with bioinformatics analyses, led to the identification of mutations in ARHGAP4 and CFAP47. CONCLUSION: This report is the first to describe ARHGAP4 and CFAP47 mutations in a patient with PHA. These mutations may be related to the occurrence of hemifacial atrophy, although further studies are needed to clarify the role of ARHGAP4 and CFAP47 in the context of PHA pathogenesis.

Non-synonymous alterations in AKR7A3 and ABCA6 correlate with bleeding in aged patients treated with rivaroxaban.

Rivaroxaban is an oral anticoagulant that inhibits thrombin and blocks coagulation cascade through directly inactivating factors Xa. Despite rivaroxaban is widely used for prevention and treatment of venous thrombosis, and its common adverse reactions have been reported, including abnormal coagulation, mucosal hemorrhage, hematuria, and intracranial hemorrhage. To explore potential drivers of individual differences in adverse reactions induced by rivaroxaban, we performed whole-exome sequencing and found that AKR7A3 rs1738023/rs1738025 and ABCA6 rs7212506 are susceptible sites for rivaroxaban-related bleeding in aged patients treated with rivaroxaban. Gene functional annotation and signaling pathway enrichment indicated that homozygous mutations in AKR7A3 and ABCA6 might alter normal rivaroxaban transport and metabolism, and lead to continuous accumulation of activated drugs and toxic substances in vivo. Our results suggested that interindividual differences in bleeding events induced by rivaroxaban may be potentially driven by genetic alterations related to abnormal metabolism and transport of rivaroxaban.

POU4F3 pioneer activity enables ATOH1 to drive diverse mechanoreceptor differentiation through a feed-forward epigenetic mechanism.

During embryonic development, hierarchical cascades of transcription factors interact with lineage-specific chromatin structures to control the sequential steps in the differentiation of specialized cell types. While examples of transcription factor cascades have been well documented, the mechanisms underlying developmental changes in accessibility of cell type-specific enhancers remain poorly understood. Here, we show that the transcriptional "master regulator" ATOH1-which is necessary for the differentiation of two distinct mechanoreceptor cell types, hair cells in the inner ear and Merkel cells of the epidermis-is unable to access much of its target enhancer network in the progenitor populations of either cell type when it first appears, imposing a block to further differentiation. This block is overcome by a feed-forward mechanism in which ATOH1 first stimulates expression of POU4F3, which subsequently acts as a pioneer factor to provide access to closed ATOH1 enhancers, allowing hair cell and Merkel cell differentiation to proceed. Our analysis also indicates the presence of both shared and divergent ATOH1/POU4F3-dependent enhancer networks in hair cells and Merkel cells. These cells share a deep developmental lineage relationship, deriving from their common epidermal origin, and suggesting that this feed-forward mechanism preceded the evolutionary divergence of these very different mechanoreceptive cell types.

Mesenchymal stem cell-derived exosomes protect trabecular meshwork from oxidative stress.

This study aims to investigate the beneficial effects of exosomes derived from bone marrow mesenchymal stem cells (BMSCs) on trabecular meshwork cells under oxidative stress and predict candidate genes associated with this process. Trabecular meshwork cells were pretreated with BMSC-derived exosomes for 24 h, and exposed to 0.1 mM H2O2 for 6 h. Survival rate of trabecular meshwork cells was measured with CCK-8 assay. Production of intracellular reactive oxygen species (iROS) was measured using a flow cytometer. RT-PCR and ELISA were used to detect mRNA and protein levels of inflammatory cytokines and matrix metalloproteinases (MMPs). Sequencing of RNA and miRNA for trabecular meshwork cells from Exo and control groups was performed on BGISEQ500 platform. Phenotypically, pretreatment of BMSC-derived exosomes improves survival rate of trabecular meshwork cells exposed to H2O2, reduces production of iROS, and inhibits expression of inflammatory cytokines, whereas increases expression of MMPs. There were 23 miRNAs, 307 lncRNAs, and 367 mRNAs differentially expressed between Exo and control groups. Exosomes derived from BMSCs may protect trabecular meshwork cells from oxidative stress. Candidate genes responsible for beneficial effects, such as DIO2 and HMOX1, were predicted.

Targeted capture sequencing identifies genetic variations of GRK4 and RDH8 in Han Chinese with essential hypertension in Xinjiang.

Essential hypertension is a common cardiovascular disease with complex etiology, closely related to genetic and environmental factors. The pathogenesis of hypertension involves alteration in vascular resistance caused by sympathetic nervous system (SNS) and renin angiotensin system (RAS). Susceptibility factors of hypertension vary with regions and ethnicities. In this study, we conducted target capture sequencing on 54 genes related to SNS and RAS derived from a collection of Han nationality, consisting of 151 hypertension patients and 65 normal subjects in Xinjiang, China. Six non-synonymous mutations related to hypertension were identified, including GRK4 rs1644731 and RDH8 rs1801058, Mutations are predicted to affect 3D conformation, force field, transmembrane domain and RNA secondary structure of corresponding genes. Based on protein interaction network and pathway enrichment, GRK4 is predicted to participate in hypertension by acting on dopaminergic synapse, together with interacting components. RDH8 is involved in vitamin A (retinol) metabolism and consequent biological processes related to hypertension. Thus, GRK4 and RDH8 may serve as susceptibility genes for hypertension. This finding provides new genetic evidence for elucidating risk factors of hypertension in Han nationality in Xinjiang, which in turn, enriches genetic resource bank of hypertension susceptibility genes.

Enhancer decommissioning imposes an epigenetic barrier to sensory hair cell regeneration.

Adult mammalian tissues such as heart, brain, retina, and the sensory structures of the inner ear do not effectively regenerate, although a latent capacity for regeneration exists at embryonic and perinatal times. We explored the epigenetic basis for this latent regenerative potential in the mouse inner ear and its rapid loss during maturation. In perinatal supporting cells, whose fate is maintained by Notch-mediated lateral inhibition, the hair cell enhancer network is epigenetically primed (H3K4me1) but silenced (active H3K27 de-acetylation and trimethylation). Blocking Notch signaling during the perinatal period of plasticity rapidly eliminates epigenetic silencing and allows supporting cells to transdifferentiate into hair cells. Importantly, H3K4me1 priming of the hair cell enhancers in supporting cells is removed during the first post-natal week, coinciding with the loss of transdifferentiation potential. We hypothesize that enhancer decommissioning during cochlear maturation contributes to the failure of hair cell regeneration in the mature organ of Corti.

Effects of Elevated CO2 and Heat on Wheat Grain Quality.

Wheat is one of the most important staple foods in temperate regions and is in increasing demand in urbanizing and industrializing countries such as China. Enhancing yield potential to meet the population explosion around the world and maintaining grain quality in wheat plants under climate change are crucial for food security and human nutrition. Global warming resulting from greenhouse effect has led to more frequent occurrence of extreme climatic events. Elevated atmospheric CO2 concentration (eCO2) along with rising temperature has a huge impact on ecosystems, agriculture and human health. There are numerous studies investigating the eCO2 and heatwaves effects on wheat growth and productivity, and the mechanisms behind. This review outlines the state-of-the-art knowledge regarding the effects of eCO2 and heat stress, individually and combined, on grain yield and grain quality in wheat crop. Strategies to enhance the resilience of wheat to future warmer and CO2-enriched environment are discussed.

Simultaneous sulfamethoxazole degradation with electricity generation by microbial fuel cells using Ni-MOF-74 as cathode catalysts and quantification of antibiotic resistance genes.

Antibiotic wastewater presents serious challenges in water treatment. Metal-organic frameworks (MOFs) have received significant attention as promising precursors and sacrificial templates in the preparation of porous carbon-supported catalysts. Herein, we investigated the sulfamethoxazole (SMX) degradation and electrochemical performance of microbial fuel cells (MFCs) that applied as-prepared Ni-MOF-74 and Ni-N-C (Ni-MOF-74 underwent pyrolysis treatment at different temperatures) as air-cathode catalyst. Firstly, the electrocatalytic activity towards oxygen reduction reaction (ORR) of the catalyst was investigated by rotating disk electrode. The results showed that electron transfer number for Ni-MOF-74 was 2.12, while that of 800Ni-N-C was 3.44, which was close to four-electron reduction. Applying Ni-MOF-74 in MFCs, a maximum power density of 446 mW/m2 was obtained, which was close to that of 800Ni-N-C. Besides, using Ni-MOF-74 as cathode catalyst, a chemical oxygen demand removal rate of about 84% was obtained, and the degradation rate of 10 mg/L SMX was 61%. The degradation rate decreased with increasing antibiotic concentration, but the average degradation efficiency increased stepwise. Additionally, the relative abundance of resistant gene sul1 in the reactors of the new catalytic material was about 62% lower than that of sul1 in the control (Pt/C) reactors, and the relative abundance of sul2 was about 73% lower. Moreover, cost assessments related to the catalyst performance are presented. The findings of this study demonstrated that Ni-MOF-74 could be considered as a two-electron transfer ORR catalyst, and offers a promising technique for preparation of Ni-N-C for use as four-electron transfer ORR catalysts. In comparison, Ni-MOF-74 could be a promising ORR catalyst of MFCs for antibiotic degradation.

Ultrathin and Robust Micro-Nano Composite Coating for Implantable Pressure Sensor Encapsulation.

Implantable pressure sensors enable more accurate disease diagnosis and real-time monitoring. Their widescale usage is dependent on a reliable encapsulation to protect them from corrosion of body fluids, yet not increasing their sizes or impairing their sensing functions during their lifespans. To realize the above requirements, an ultrathin, flexible, waterproof while robust micro-nano composite coating for encapsulation of an implantable pressure sensor is designed. The composite coating is composed of a nanolayer of silane-coupled molecules and a microlayer of parylene polymers. The mechanism and principle of the composite encapsulation coating with high adhesion are elucidated. Experimental results show that the error of the sensors after encapsulation is less than 2 mmHg, after working continuously for equivalently over 434 days in a simulated body fluid environment. The effects of the coating thickness on the waterproof time and the error of the sensor are also studied. The encapsulated sensor is implanted in an isolated porcine eye and a living rabbit eye, exhibiting excellent performances. Therefore, the micro-nano composite encapsulation coating would have an appealing application in micro-nano-device protections, especially for implantable biomedical devices.

Generation of inner ear hair cells by direct lineage conversion of primary somatic cells.

The mechanoreceptive sensory hair cells in the inner ear are selectively vulnerable to numerous genetic and environmental insults. In mammals, hair cells lack regenerative capacity, and their death leads to permanent hearing loss and vestibular dysfunction. Their paucity and inaccessibility has limited the search for otoprotective and regenerative strategies. Growing hair cells in vitro would provide a route to overcome this experimental bottleneck. We report a combination of four transcription factors (Six1, Atoh1, Pou4f3, and Gfi1) that can convert mouse embryonic fibroblasts, adult tail-tip fibroblasts and postnatal supporting cells into induced hair cell-like cells (iHCs). iHCs exhibit hair cell-like morphology, transcriptomic and epigenetic profiles, electrophysiological properties, mechanosensory channel expression, and vulnerability to ototoxin in a high-content phenotypic screening system. Thus, direct reprogramming provides a platform to identify causes and treatments for hair cell loss, and may help identify future gene therapy approaches for restoring hearing.

Worldwide, hearing loss is the most common loss of sensation. Most cases of hearing loss are due to the death of specialized hair cells found deep inside the ear. These hair cells convert sounds into nerve impulses which can be understood by the brain. Hair cells naturally degrade as part of aging and can be damaged by other factors including loud noises, and otherwise therapeutic drugs, such as those used in chemotherapy for cancer. In humans and other mammals, once hair cells are lost they cannot be replaced. Hair cells have often been studied using mice, but the small number of hair cells in their ears, and their location deep inside the skull, makes it particularly difficult to study them in this way. Scientists are seeking ways to grow hair cells in the laboratory to make it easier to understand how they work and the factors that contribute to their damage and loss. Different cell types in the body are formed in response to specific combinations of biological signals. Currently, scientists do not have an efficient way to grow hair cells in the laboratory, because the correct signals needed to create them are not known. Menendez et al. have now identified four proteins which, when activated, convert fibroblasts, a common type of cell, into hair cells similar to those in the ear. These proteins are called Six1, Atoh1, Pou4f3 and Gfi1. Menendez et al. termed the resulting cells induced hair cells, or iHCs for short, and analyzed these cells to identify those characteristics that are similar to normal hair cells, as well as their differences. Importantly, the iHCs were found to be damaged by the same chemicals that specifically harm normal hair cells, suggesting they are useful test subjects. The ability to create hair cells in the laboratory using more easily available cells has many uses. These cells can help to understand the normal function of hair cells and how they become damaged. They can also be used to test new drugs to assess their success in preventing or reversing hearing loss. These findings may also lead to genetic solutions to curing hearing loss.

Organ of Corti size is governed by Yap/Tead-mediated progenitor self-renewal.

Precise control of organ growth and patterning is executed through a balanced regulation of progenitor self-renewal and differentiation. In the auditory sensory epithelium-the organ of Corti-progenitor cells exit the cell cycle in a coordinated wave between E12.5 and E14.5 before the initiation of sensory receptor cell differentiation, making it a unique system for studying the molecular mechanisms controlling the switch between proliferation and differentiation. Here we identify the Yap/Tead complex as a key regulator of the self-renewal gene network in organ of Corti progenitor cells. We show that Tead transcription factors bind directly to the putative regulatory elements of many stemness- and cell cycle-related genes. We also show that the Tead coactivator protein, Yap, is degraded specifically in the Sox2-positive domain of the cochlear duct, resulting in down-regulation of Tead gene targets. Further, conditional loss of the Yap gene in the inner ear results in the formation of significantly smaller auditory and vestibular sensory epithelia, while conditional overexpression of a constitutively active version of Yap, Yap5SA, is sufficient to prevent cell cycle exit and to prolong sensory tissue growth. We also show that viral gene delivery of Yap5SA in the postnatal inner ear sensory epithelia in vivo drives cell cycle reentry after hair cell loss. Taken together, these data highlight the key role of the Yap/Tead transcription factor complex in maintaining inner ear progenitors during development, and suggest new strategies to induce sensory cell regeneration.

A Simple, Low-Cost Micro-Coating Method for Accuracy Improvement and Its Application in Pressure Sensors.

The demand for high-accuracy pressure sensors has increased with the advancement of technology in a wide variety of applications. However, it is generally difficult and expensive to improve the accuracy of the pressure sensor because it usually depends on the sensing principle and the internal physical structure of the pressure sensor, varying with its material and production process. Thus, a simple, low-cost, and generally applied post-processing method is proposed to improve the accuracy of pressure sensors. In this method, a micro-coating is cladded on the surface of the sensor, which effectively isolates the adverse effect of the external environment, similar to applying a "micro-protective clothing" on the pressure sensor. Experiments on seven pressure sensors are conducted, in which the micron-thin parylene polymer is utilized as the surface-deposited coating layer to demonstrate the improvement of accuracy. Results show that the accuracy was improved, with an average increase of approximately 62.54% than before cladding, while the sensitivity was almost unchanged. The principle of improving the accuracy of this method was also analyzed. The proposed simple, efficient, and low-cost method of cladding micro-coating for enhancing the accuracy of sensors can be widely applied in various fields of industrial automatic control.

Genome-wide haplotype association study identifies risk genes for non-small cell lung cancer.

Lung cancer is the leading cause of cancer-related death worldwide. Most lung cancer is non-small cell lung cancer (NSCLC), in which malignant cells form in the lung epithelium. Mutations in multiple genes and environmental factors both contribute to NSCLC, and although some NSCLC susceptibility genes have been characterized, the pathogenesis of this disease remains unclear. To identify genes conferring NSCLC risk and determine their associated pathological mechanism, we combined genome-wide haplotype associated analysis with gene prioritization using 224,677 SNPs in 37 NSCLC cell lines and 116 unrelated European individuals. Five candidate genes were identified: ESR1, TGFBR1, INSR, CDH3, and MAP3K5. All of these have previously been implicated in NSCLC, with the exception of CDH3, which can therefore be considered a novel indicator of NSCLC risk. Functional annotation confirmed the relationship between these five genes and NSCLC. Our findings are indicative of the underlying pathological mechanisms of NSCLC and provide information to support future directions in diagnosing and treating NSCLC.

A Transmembrane Polymorphism of Fcγ Receptor IIb Is Associated with Kidney Deficiency Syndrome in Rheumatoid Arthritis.

Objective. The purpose is to investigate the role of kidney deficiency and the association between kidney deficiency and a polymorphism FcγRIIb 695T>C coding for nonsynonymous substitution IIe232Thr (I232T) in rheumatoid arthritis (RA). Methods. Clinical parameters and autoantibodies were analyzed and genotyping was performed in 159 kidney deficiency and 161 non-kidney-deficiency RA patients. Results. The age of disease onset and disease duration exhibited significant differences between two groups (P < 0.01). Patients with kidney deficiency tend to have higher activity of disease (P < 0.05). Anti-cyclic citrullinated peptides antibodies (ACPA) levels of patients with kidney deficiency were higher than the controls (P = 0.039). 125 (78.6%) kidney deficiency and 114 (70.8%) non-kidney-deficiency patients had both ACPA-positive and RF-positive (P = 0.04, OR = 3.29). FcγRIIb I232TT homozygotes were identified in 10 of 159 (6.3%) kidney deficiency subjects and 1 of 161 (0.6%) controls (P = 0.000, OR = 16.45). Furthermore, in pooled genotype analysis, I232IT and I232TT homozygotes were significantly enriched in kidney deficiency individuals compared with the controls (P = 0.000, OR = 3.79). Frequency of T allele was associated with kidney deficiency RA population (P = 0.000, OR = 3.18). Conclusion. This study confirmed that kidney deficiency was closely associated with disease activity and autoimmune disorder in RA. Kidney deficiency in RA is first to reveal a strong genetic link to FcγRIIb variants.