Tiki1 is required for head formation via Wnt cleavage-oxidation and inactivation.

Secreted Wnt morphogens are signaling molecules essential for embryogenesis, pathogenesis, and regeneration and require distinct modifications for secretion, gradient formation, and activity. Whether Wnt proteins can be posttranslationally inactivated during development and homeostasis is unknown. Here we identify, through functional cDNA screening, a transmembrane protein Tiki1 that is expressed specifically in the dorsal Spemann-Mangold Organizer and is required for anterior development during Xenopus embryogenesis. Tiki1 antagonizes Wnt function in embryos and human cells via a TIKI homology domain that is conserved from bacteria to mammals and acts likely as a protease to cleave eight amino-terminal residues of a Wnt protein, resulting in oxidized Wnt oligomers that exhibit normal secretion but minimized receptor-binding capability. Our findings identify a Wnt-specific protease that controls head formation, reveal a mechanism for morphogen inactivation through proteolysis-induced oxidation-oligomerization, and suggest a role of the Wnt amino terminus in evasion of oxidizing inactivation. TIKI proteins may represent potential therapeutic targets.

Identification, structural, and biophysical characterization of a positive modulator of human Kv3.1 channels.

Voltage-gated potassium channels (Kv) are tetrameric membrane proteins that provide a highly selective pathway for potassium ions (K+) to diffuse across a hydrophobic cell membrane. These unique voltage-gated cation channels detect changes in membrane potential and, upon activation, help to return the depolarized cell to a resting state during the repolarization stage of each action potential. The Kv3 family of potassium channels is characterized by a high activation potential and rapid kinetics, which play a crucial role for the fast-spiking neuronal phenotype. Mutations in the Kv3.1 channel have been shown to have implications in various neurological diseases like epilepsy and Alzheimer's disease. Moreover, disruptions in neuronal circuitry involving Kv3.1 have been correlated with negative symptoms of schizophrenia. Here, we report the discovery of a novel positive modulator of Kv3.1, investigate its biophysical properties, and determine the cryo-EM structure of the compound in complex with Kv3.1. Structural analysis reveals the molecular determinants of positive modulation in Kv3.1 channels by this class of compounds and provides additional opportunities for rational drug design for the treatment of associated neurological disorders.

Frizzled receptors facilitate Tiki inhibition of Wnt signaling at the cell surface.

The membrane-tethered protease Tiki antagonizes Wnt3a signaling by cleaving and inactivating Wnt3a in Wnt-producing cells. Tiki also functions in Wnt-receiving cells to antagonize Wnt signaling by an unknown mechanism. Here, we demonstrate that Tiki inhibition of Wnt signaling at the cell surface requires Frizzled (FZD) receptors. Tiki associates with the Wnt-FZD complex and cleaves the N-terminus of Wnt3a or Wnt5a, preventing the Wnt-FZD complex from recruiting and activating the coreceptor LRP6 or ROR1/2 without affecting Wnt-FZD complex stability. Intriguingly, we demonstrate that the N-terminus of Wnt3a is required for Wnt3a binding to LRP6 and activating ß-catenin signaling, while the N-terminus of Wnt5a is dispensable for recruiting and phosphorylating ROR1/2. Both Tiki enzymatic activity and its association with the Wnt-FZD complex contribute to its inhibitory function on Wnt5a. Our study uncovers the mechanism by which Tiki antagonizes Wnt signaling at the cell surface and reveals a negative role of FZDs in Wnt signaling by acting as Tiki cofactors. Our findings also reveal an unexpected role of the Wnt3a N-terminus in the engagement of the coreceptor LRP6.

MaLAdapt Reveals Novel Targets of Adaptive Introgression From Neanderthals and Denisovans in Worldwide Human Populations.

Adaptive introgression (AI) facilitates local adaptation in a wide range of species. Many state-of-the-art methods detect AI with ad-hoc approaches that identify summary statistic outliers or intersect scans for positive selection with scans for introgressed genomic regions. Although widely used, approaches intersecting outliers are vulnerable to a high false-negative rate as the power of different methods varies, especially for complex introgression events. Moreover, population genetic processes unrelated to AI, such as background selection or heterosis, may create similar genomic signals to AI, compromising the reliability of methods that rely on neutral null distributions. In recent years, machine learning (ML) methods have been increasingly applied to population genetic questions. Here, we present a ML-based method called MaLAdapt for identifying AI loci from genome-wide sequencing data. Using an Extra-Trees Classifier algorithm, our method combines information from a large number of biologically meaningful summary statistics to capture a powerful composite signature of AI across the genome. In contrast to existing methods, MaLAdapt is especially well-powered to detect AI with mild beneficial effects, including selection on standing archaic variation, and is robust to non-AI selective sweeps, heterosis from deleterious mutations, and demographic misspecification. Furthermore, MaLAdapt outperforms existing methods for detecting AI based on the analysis of simulated data and the validation of empirical signals through visual inspection of haplotype patterns. We apply MaLAdapt to the 1000 Genomes Project human genomic data and discover novel AI candidate regions in non-African populations, including genes that are enriched in functionally important biological pathways regulating metabolism and immune responses.

MHCRoBERTa: pan-specific peptide-MHC class I binding prediction through transfer learning with label-agnostic protein sequences.

Predicting the binding of peptide and major histocompatibility complex (MHC) plays a vital role in immunotherapy for cancer. The success of Alphafold of applying natural language processing (NLP) algorithms in protein secondary struction prediction has inspired us to explore the possibility of NLP methods in predicting peptide-MHC class I binding. Based on the above motivations, we propose the MHCRoBERTa method, RoBERTa pre-training approach, for predicting the binding affinity between type I MHC and peptides. Analysis of the results on benchmark dataset demonstrates that MHCRoBERTa can outperform other state-of-art prediction methods with an increase of the Spearman rank correlation coefficient (SRCC) value. Notably, our model gave a significant improvement on IC50 value. Our method has achieved SRCC value and AUC value as 0.785 and 0.817, respectively. Our SRCC value is 14.3% higher than NetMHCpan3.0 (the second highest SRCC value on pan-specific) and is 3% higher than MHCflurry (the second highest SRCC value on all methods). The AUC value is also better than any other pan-specific methods. Moreover, we visualize the multi-head self-attention for the token representation across the layers and heads by this method. Through the analysis of the representation of each layer and head, we can show whether the model has learned the syntax and semantics necessary to perform the prediction task well. All these results demonstrate that our model can accurately predict the peptide-MHC class I binding affinity and that MHCRoBERTa is a powerful tool for screening potential neoantigens for cancer immunotherapy. MHCRoBERTa is available as an open source software at github (https://github.com/FuxuWang/MHCRoBERTa).

Combined application of myo-inositol and corn steep liquor enhances seedling growth and cold tolerance in cucumber and tomato.

Low temperatures pose a common challenge in the production of cucumbers and tomatoes, hindering plant growth and, in severe cases, leading to plant death. In our investigation, we observed a substantial improvement in the growth of cucumber and tomato seedlings through the application of corn steep liquor (CSL), myo-inositol (MI), and their combinations. When subjected to low-temperature stress, these treatments resulted in heightened levels of photosynthetic pigments, thereby fostering enhanced photosynthesis in both tomato and cucumber plants. Furthermore, it contributed to a decrease in malondialdehyde (MDA) levels and electrolyte leakage (REP). The effectiveness of the treatment was further validated through the analysis of key gene expressions (CBF1, COR, MIOX4, and MIPS1) in cucumber. Particularly, noteworthy positive outcomes were noted in the treatment involving 0.6 mL L-1 CSL combined with 72 mg L-1 MI. This study provides valuable technical insights into leveraging the synergistic effects of inositol and maize leachate to promote early crop growth and bolster resistance to low temperatures.

Cancer-associated fibroblast-derived circFARP1 modulates non-small cell lung cancer invasion and metastasis through the circFARP1/miR-338-3p/SOX4 axis.

The pleiotropic effect of cancer-associated fibroblasts (CAFs) on tumour progression depends on the environment. circFARP1 is critical for CAFs-induced gemcitabine (GEM) resistance in pancreatic cancer. Its specific role and mechanism in non-small cell lung cancer (NSCLC) have not been reported yet. We prepared a cancer-associated fibroblasts-conditioned medium (CAF-CM) to incubate the A549 cells. Quantitative real-time polymerase chain reaction was used to detect RNA levels. We detected protein expression by immunohistochemistry, immunocytochemistry, western blot and immunofluorescence. We also detected the targeting impact between circFARP1, miR-338-3p and SRY-box transcription factor 4 (SOX4) by using dual-luciferase reporter and RNA pull-down assays. We determined cell proliferation, migration and invasion capabilities through Cell Counting Kit-8 and transwell assays. In addition, we measured tumour volume and weight in vivo by establishing a xenograft tumour model. CircFARP1 levels were remarkably high in the CAFs. The transfection experiments found that circFARP1 downregulation in CAFs caused migration, proliferation and invasion inhibition of CAFs and A549 cells, whereas inhibiting miR-38-3p or overexpressing SOX4 in CAFs could significantly reverse the inhibition. In vivo study in nude mice confirmed that CAFs could promote NSCLC tumour growth and knockdown of circFARP1 could inhibit tumour growth of NSCLC, whereas miR-38-3p downregulation or SOX4 overexpression could significantly reverse the inhibition. circFARP1 promotes NSCLC development by stimulating miR-338-3p/SOX4 signalling axis to regulate CAFs.

Disability level's impact on blood pressure-mortality association in older long-term care adults: evidence from a large Chinese cohort study.

BACKGROUND: Evidence of the optimal blood pressure (BP) target for older adults with disability in long-term care is limited. We aim to analyze the associations of BP with mortality in older adults in long-term care setting with different levels of disability. METHODS: This prospective cohort study was based on the government-led long-term care programme in Chengdu, China, including 41,004 consecutive disabled adults aged ≥ 60 years. BP was measured during the baseline survey by trained medical personnel using electronic sphygmomanometers. Disability profile was assessed using the Barthel index. The association between blood pressure and mortality was analyzed with doubly robust estimation, which combined exposure model by inverse probability weighting and outcome model fitted with Cox regression. The non-linearity was examined by restricted cubic spline. The primary endpoint was all-cause mortality, and the secondary endpoints were cardiovascular and non-cardiovascular mortality. RESULTS: The associations between systolic blood pressure (SBP) and all-cause mortality were close to a U-shaped curve in mild-moderate disability group (Barthel index ≥ 40), and a reversed J-shaped in severe disability group (Barthel index < 40). In mild-moderate disability group, SBP < 135 mmHg was associated with elevated all-cause mortality risks (HR 1.21, 95% CI, 1.10-1.33), compared to SBP between 135 and 150 mmHg. In severe disability group, SBP < 150 mmHg increased all-cause mortality risks (HR 1.21, 95% CI, 1.16-1.27), compared to SBP between 150 and 170 mmHg. The associations were robust in subgroup analyses in terms of age, gender, cardiovascular comorbidity and antihypertensive treatment. Diastolic blood pressure (DBP) < 67 mmHg (HR 1.29, 95% CI, 1.18-1.42) in mild-moderate disability group and < 79 mmHg (HR 1.15, 95% CI, 1.11-1.20) in severe disability group both demonstrated an increased all-cause mortality risk. CONCLUSION: The optimal SBP range was found to be higher in older individuals in long-term care with severe disability (150-170mmHg) compared to those with mild to moderate disability (135-150mmHg). This study provides new evidence that antihypertensive treatment should be administered cautiously in severe disability group in long-term care setting. Additionally, assessment of disability using the Barthel index can serve as a valuable tool in customizing the optimal BP management strategy. TRIAL REGISTRATION: Chinese Clinical Trial Registry (Registration Number: ChiCTR2100049973).

The history and evolution of the Denisovan-EPAS1 haplotype in Tibetans.

Recent studies suggest that admixture with archaic hominins played an important role in facilitating biological adaptations to new environments. For example, interbreeding with Denisovans facilitated the adaptation to high-altitude environments on the Tibetan Plateau. Specifically, the EPAS1 gene, a transcription factor that regulates the response to hypoxia, exhibits strong signatures of both positive selection and introgression from Denisovans in Tibetan individuals. Interestingly, despite being geographically closer to the Denisova Cave, East Asian populations do not harbor as much Denisovan ancestry as populations from Melanesia. Recently, two studies have suggested two independent waves of Denisovan admixture into East Asians, one of which is shared with South Asians and Oceanians. Here, we leverage data from EPAS1 in 78 Tibetan individuals to interrogate which of these two introgression events introduced the EPAS1 beneficial sequence into the ancestral population of Tibetans, and we use the distribution of introgressed segment lengths at this locus to infer the timing of the introgression and selection event. We find that the introgression event unique to East Asians most likely introduced the beneficial haplotype into the ancestral population of Tibetans around 48,700 (16,000-59,500) y ago, and selection started around 9,000 (2,500-42,000) y ago. Our estimates suggest that one of the most convincing examples of adaptive introgression is in fact selection acting on standing archaic variation.

A signature of Neanderthal introgression on molecular mechanisms of environmental responses.

Ancient human migrations led to the settlement of population groups in varied environmental contexts worldwide. The extent to which adaptation to local environments has shaped human genetic diversity is a longstanding question in human evolution. Recent studies have suggested that introgression of archaic alleles in the genome of modern humans may have contributed to adaptation to environmental pressures such as pathogen exposure. Functional genomic studies have demonstrated that variation in gene expression across individuals and in response to environmental perturbations is a main mechanism underlying complex trait variation. We considered gene expression response to in vitro treatments as a molecular phenotype to identify genes and regulatory variants that may have played an important role in adaptations to local environments. We investigated if Neanderthal introgression in the human genome may contribute to the transcriptional response to environmental perturbations. To this end we used eQTLs for genes differentially expressed in a panel of 52 cellular environments, resulting from 5 cell types and 26 treatments, including hormones, vitamins, drugs, and environmental contaminants. We found that SNPs with introgressed Neanderthal alleles (N-SNPs) disrupt binding of transcription factors important for environmental responses, including ionizing radiation and hypoxia, and for glucose metabolism. We identified an enrichment for N-SNPs among eQTLs for genes differentially expressed in response to 8 treatments, including glucocorticoids, caffeine, and vitamin D. Using Massively Parallel Reporter Assays (MPRA) data, we validated the regulatory function of 21 introgressed Neanderthal variants in the human genome, corresponding to 8 eQTLs regulating 15 genes that respond to environmental perturbations. These findings expand the set of environments where archaic introgression may have contributed to adaptations to local environments in modern humans and provide experimental validation for the regulatory function of introgressed variants.

Application of PVC pipes as an adjustable bilateral traction device in lower limb fractures.

OBJECTIVE: To introduce a new type of simple adjustable bilateral bidirectional polyvinyl chloride (PVC) tube traction device and discuss the value of using this device before surgery in patients with lower limb fractures. METHODS: To introduce the manufacturing process of an adjustable bilateral traction device made of PVC pipes. From August 2018 to November 2019, the data of 36 patients with lower limb fractures who were treated with this traction device were retrospectively analysed. The treatment outcomes were analysed, including length of both lower limbs, fracture reduction, lower limb mobility, visual analogue scale (VAS) score, incidence of complications, and patient satisfaction. RESULTS: All patients were able to move the affected limb immediately after using the device. The patient's pain was significantly reduced, they were able to turn over freely during bed rest, and the length of the affected limb was restored to that of the healthy limb. Thirty-four (94.5%) patients were satisfied with the reduction of the fracture end, 2 (5.5%) patients with tibiofibular fractures showed angular displacement of the fractured end and satisfactory reduction after the position of the bone traction needle was adjusted; 7 (19.5%) patients developed deep vein thrombosis of the affected lower limb during traction; there was no decubitus or vascular nerve injury, and the overall complication rate was 25% (9/36). All the patients and their families were satisfied with the results of this treatment. CONCLUSION: The aim of this study is to introduce a new type of traction device. It is advantageous in that it is light weight, low cost, easy to assemble, promotes immediate movement of the affected limb after assembly, improves patient comfort and can be used with a titanium steel needle for MRI examination under traction. In the clinical setting, it has been shown to be suitable for the temporary treatment of patients with lower leg fractures prior to surgery, particularly patients who, for various reasons, require nonsurgical treatment in the short term.

Short term effects of a novel combined approach compared with physical therapy alone among older patients with temporomandibular degenerative joint disease: a prospective cohort study.

BACKGROUND: There is a lack of consensus regarding the best treatment option, including physical exercise, available for temporomandibular degenerative joint disease (DJD) that affect the older patients. Herein, we aimed to study and compare the efficacy of a combined approach using injection and home physical exercise with physical therapy alone as well as explored an optimal treatment strategy for older patients with DJD. METHODS: We included 213 older patients with DJD treated at our medical centre from June 2020 to June 2021, 64 of whom were selected for analysis. Of these 64 patients, 32 received injections combined with home physical exercise, and the other 32 received physical therapy alone. Propensity score matching was used to ensure that the two groups did not differ significantly in categorical and continuous variables. Measurements included pain intensity, maximum mouth opening, joint crepitus, jaw functional limitation scale (JFLS) scores, treatment times, and treatment durations. Improvement in each measurement was compared between the two groups 2, 4, and 12 weeks after the treatment commenced, as were the final treatment times and durations. RESULTS: Pain intensity, maximum mouth opening, and JFLS scores in the two groups improved 2, 4, and 12 weeks after treatment (all p < 0.05). The crepitus ratio improved significantly only in the combined treatment group after 12 weeks. Compared with the physical therapy group, pain while opening the mouth improved after 2, 4, and 12 weeks in the combined treatment group. Furthermore, 2 weeks after treatment, the physical therapy group showed significant improvement in maximal mouth opening compared with the combined treatment group. No significant between-group differences were observed regarding improvement in joint crepitus and JFLS scores at each observation point. The combined treatment group had a significantly lower number of visits than the physical therapy group; however, the treatment duration was longer. CONCLUSION: Compared with physical therapy, pain while opening the mouth is significantly improved by the combined treatment within 12 weeks, and the number of required visits is fewer. Physical therapy improves the patients' mouth-opening capabilities in a short time (2 weeks), and the treatment cycle is short.

An Infusion Containers Detection Method Based on YOLOv4 with Enhanced Image Feature Fusion.

The detection of infusion containers is highly conducive to reducing the workload of medical staff. However, when applied in complex environments, the current detection solutions cannot satisfy the high demands for clinical requirements. In this paper, we address this problem by proposing a novel method for the detection of infusion containers that is based on the conventional method, You Only Look Once version 4 (YOLOv4). First, the coordinate attention module is added after the backbone to improve the perception of direction and location information by the network. Then, we build the cross stage partial-spatial pyramid pooling (CSP-SPP) module to replace the spatial pyramid pooling (SPP) module, which allows the input information features to be reused. In addition, the adaptively spatial feature fusion (ASFF) module is added after the original feature fusion module, path aggregation network (PANet), to facilitate the fusion of feature maps at different scales for more complete feature information. Finally, EIoU is used as a loss function to solve the anchor frame aspect ratio problem, and this improvement allows for more stable and accurate information of the anchor aspect when calculating losses. The experimental results demonstrate the advantages of our method in terms of recall, timeliness, and mean average precision (mAP).

Wide field of view chiral imaging with a liquid crystal planar lens enabled by digitalized nanogratings.

To compensate for the inability for polarization imaging by conventional methods, metasurface optics with compactness and multi-function emerge as an approach to provide images with different linear and circular polarizations. Here, we propose a liquid crystal (LC) geometric phase-based chiral imaging lens (CIL) that simultaneously forms images of objects with opposite helicity. The CIL (Diameter 2.3 cm) was optimized by a spatial multiplexing algorithm and realized using the digital holography technique, where the LC domains were regulated by pixelated nanogratings with varied orientation. We investigated the potential of the patterning technique toward high order LC alignment by balancing the periodicity and depth of the nanogratings. The CIL exhibited a wide field of view of ±20°, which is attributed to the self- assembling effects of LC molecules. The compactness, lightness, and ability to produce chiral images of the LC CIL even at large angles have significant potential for practical polarization imaging.

High-throughput and controllable manufacturing of liquid crystal polymer planar microlens array for compact fingerprint imaging.

The microlens array (MLA) with a small geometric footprint and unique performances, is the key enabler to push the development of photonic devices toward miniaturization, multi-function and large-scale integration. However, the realization of 100% fill-factor (FF) MLAs with high controllability and its mass manufacturing without complex steps has always been a difficult issue. Here, we propose an efficient, highly flexible and low-cost manufacturing approach for MLAs with a high FF via snapshot polarization patterning. The digitalized linear polarization pattern was distributed across the photo-alignment layer with both high efficiency and accuracy, enabling large-area liquid crystal MLA with parameter controllability from element to element. The MLA manufacturing process does not involve developing, etching and deposition steps and is suitable for industry up-scaling. We further proposed a novel compact compound-eye imaging system for biometrics with the obtained MLAs. The 100% FF MLA enables high light utilization efficiency and low background crosstalk, yielding compact biometrics indentation with high recognition accuracy. The realization of such planar optics would lead to a plethora of different miniaturized multiaperture imaging systems in the future.

Frizzled proteins are colonic epithelial receptors for C. difficile toxin B.

Clostridium difficile toxin B (TcdB) is a critical virulence factor that causes diseases associated with C. difficile infection. Here we carried out CRISPR-Cas9-mediated genome-wide screens and identified the members of the Wnt receptor frizzled family (FZDs) as TcdB receptors. TcdB binds to the conserved Wnt-binding site known as the cysteine-rich domain (CRD), with the highest affinity towards FZD1, 2 and 7. TcdB competes with Wnt for binding to FZDs, and its binding blocks Wnt signalling. FZD1/2/7 triple-knockout cells are highly resistant to TcdB, and recombinant FZD2-CRD prevented TcdB binding to the colonic epithelium. Colonic organoids cultured from FZD7-knockout mice, combined with knockdown of FZD1 and 2, showed increased resistance to TcdB. The colonic epithelium in FZD7-knockout mice was less susceptible to TcdB-induced tissue damage in vivo. These findings establish FZDs as physiologically relevant receptors for TcdB in the colonic epithelium.

NMT1 Enhances the Stemness of NSCLC Cells by Activating the PI3K/AKT Pathway.

INTRODUCTION: Abundant studies have disclosed that proteins can function as pivotal tumor promoters or suppressors in cancers' progression. This work was planned to investigate the regulatory function of N-myristoyltransferase-1 (NMT1) on non-small cell lung cancer (NSCLC) and the underlying molecular mechanisms. METHODS: The self-renewal abilities were assessed through a spheroid-formation assay. The tumorigenic abilities were examined through nude mice in vivo assay. The proteins' expression was measured through Western blot. The NMT1 protein expression in tumor tissues was measured through an IHC assay. The cell migration and invasion was confirmed through a transwell assay. The IC50 was verified through a CCK-8 assay. The NMT1 mRNA expression in NSCLC tissues was detected through RT-qPCR. RESULTS: It was demonstrated that NMT1 exhibited higher expression in spheroid cells. Additionally, NMT1 facilitated the stemness in NSCLC. It was also found that NMT1 accelerated NSCLC tumor metastasis and the resistance to cisplatin. Moreover, NMT1 activated the PI3K/AKT pathway to facilitate stemness in NSCLC. NMT1 was also higher in tumor tissues of NSCLC patients and resulted in a poor survival rate. CONCLUSION: NMT1 enhanced the stemness of NSCLC cells by activating the PI3K/AKT pathway. This discovery suggested that NMT1 may be a valid therapeutic biomarker for NSCLC.

PAF makes it EZ(H2) for ß-catenin transactivation.

In this issue of Molecular Cell, Park and colleagues (Jung et al., 2013) show that PAF (PCNA-associated factor) binds to and hyperactivates transcriptional function of ß-catenin in colon cancer cells by recruiting EZH2 to the coactivator complex. PAF-ß-catenin and PAF-PCNA interactions are competitive, raising the question of whether ß-catenin might regulate PCNA-dependent DNA replication and repair.

Network analysis of KLF5 targets showing the potential oncogenic role of SNHG12 in colorectal cancer.

BACKGROUND: KLF5 is a member of the Kruppel-like factor, subfamily of zinc finger proteins that are involved in cancers. KLF5 functions as a transcription factor and regulates the diverse protein-coding genes (PCGs) in colorectal cancer (CRC). However, the long non-coding RNAs (lncRNAs) regulated by KLF5 in CRC are currently unknown. METHODS: In this study, we first designed a computational pipeline to determine the PCG and lncRNA targets of KLF5 in CRC. Then we analyzed the motif pattern of the binding regions for the lncRNA targets. The regulatory co-factors of KLF5 were then searched for through bioinformatics analysis. We also constructed a regulatory network for KLF5 and annotated its functions. Finally, one of the KLF5 lncRNA targets, SNHG12, was selected to further explore its expression pattern and functions in CRC. RESULTS: We were able to identify 19 lncRNA targets of KLF5 and found that the motifs of the lncRNA binding sites were GC-enriched. Next, we pinpointed the transcription factors AR and HSF1 as the regulatory co-factors of KLF5 through bioinformatics analysis. Then, through the analysis of the regulatory network, we found that KLF5 may be involved in DNA replication, DNA repair, and the cell cycle. Furthermore, in the cell cycle module, the SNHG12 up-regulating expression pattern was verified in the CRC cell lines and tissues, associating it to CRC invasion and distal metastasis. This indicates that SNHG12 may play a critical part in CRC tumorigenesis and progression. Additionally, expression of SNHG12 was found to be down-regulated in CRC cell lines when KLF5 expression was knocked-down by siRNA; and a strong correlation was observed between the expression levels of SNHG12 and KLF5, further alluding to their regulatory relationship. CONCLUSIONS: In conclusion, the network analysis of KLF5 targets indicates that SNHG12 may be a significant lncRNA in CRC.

The association of metabolic syndrome components and chronic kidney disease in patients with hypertension.

BACKGROUND: Hypertension is a highly prevalent disease and the leading cause of chronic kidney disease (CKD). Metabolic syndrome could also be the risk factor for CKD. We sought to study the association between metabolic syndrome components and the prevalence of CKD in patients with hypertension. METHODS: We carried out a multi-center cross-sectional study from Apr. 2017- Apr. 2018 in 15 cities in China. RESULTS: A total of 2484 patients with hypertension were enrolled. Among them, 56% were male and the average age was 65.12 ± 12.71 years. The systolic BP/diastolic BP was 142 ± 18/83 ± 12 mmHg. Metabolic syndrome components turned out to be highly prevalent in patients with hypertension, ranging from 40 to 58%. The prevalence of chronic kidney disease reached 22.0%. Multi-variate logistic analysis revealed that elevated triglyceride (TG) (OR = 1.81, 95% CI 1.28-2.57, p < 0.01), elevated fasting blood glucose (FBG) (OR = 1.43, 95% CI 1.00-2.07, p = 0.05) and hypertension grades (OR = 1.20, 95% CI 1.00-1.44, p = 0.05) were associated with the prevalence of CKD. In sub-group analysis, elevated TG remained strongly associated with CKD in both diabetes (OR = 2.10, 95%CI 1.22-3.61, p < 0.01) and non-diabetes (OR = 1.53, 95% CI 1.09-2.16, p = 0.01). In sub-group analysis of hypertension grades, there was also a graded trend between elevated TG and CKD from controlled blood pressure (BP) to hypertension grade 2 (OR = 1.81, 95%CI 1.06-3.11, p = 0.03; OR = 1.85, 95%CI 1.00-3.43, p = 0.05; OR = 2.81, 95% CI 1.09-7.28, p = 0.03, respectively). CONCLUSION: Elevated TG, elevated FBG and hypertension grades were significantly associated with the prevalence of CKD in patients with hypertension. Particularly, elevated TG was strongly associated with CKD, independent of diabetes and hypertension grades.