Convergence of coronary artery disease genes onto endothelial cell programs.

Linking variants from genome-wide association studies (GWAS) to underlying mechanisms of disease remains a challenge1-3. For some diseases, a successful strategy has been to look for cases in which multiple GWAS loci contain genes that act in the same biological pathway1-6. However, our knowledge of which genes act in which pathways is incomplete, particularly for cell-type-specific pathways or understudied genes. Here we introduce a method to connect GWAS variants to functions. This method links variants to genes using epigenomics data, links genes to pathways de novo using Perturb-seq and integrates these data to identify convergence of GWAS loci onto pathways. We apply this approach to study the role of endothelial cells in genetic risk for coronary artery disease (CAD), and discover 43 CAD GWAS signals that converge on the cerebral cavernous malformation (CCM) signalling pathway. Two regulators of this pathway, CCM2 and TLNRD1, are each linked to a CAD risk variant, regulate other CAD risk genes and affect atheroprotective processes in endothelial cells. These results suggest a model whereby CAD risk is driven in part by the convergence of causal genes onto a particular transcriptional pathway in endothelial cells. They highlight shared genes between common and rare vascular diseases (CAD and CCM), and identify TLNRD1 as a new, previously uncharacterized member of the CCM signalling pathway. This approach will be widely useful for linking variants to functions for other common polygenic diseases.

Multiomic Analysis and CRISPR Perturbation Screens Identify Endothelial Cell Programs and Novel Therapeutic Targets for Coronary Artery Disease.

Endothelial cells (EC) are an important mediator of atherosclerosis and vascular disease. Their exposure to atherogenic risk factors such as hypertension and serum cholesterol leads to endothelial dysfunction and many disease-associated processes. Identifying which of these multiple EC functions is causally related to disease risk has been challenging. There is evidence from in vivo models and human sequencing studies that dysregulation of nitric oxide production directly affects risk of coronary artery disease. Human genetics can help prioritize the other EC functions with causal relationships because germline mutations are acquired at birth and serve as a randomized test of which pathways affect disease risk. Though several coronary artery disease risk variants have been linked to EC function, this process has been slow and laborious. Unbiased analyses of EC dysfunction using multiomic approaches promise to identify the causal genetic mechanisms responsible for vascular disease. Here, we review the data from genomic, epigenomic, and transcriptomic studies that prioritize EC-specific causal pathways. New methods that CRISPR (clustered regularly interspaced short palindromic repeats) perturbation technology with genomic, epigenomic, and transcriptomic analysis promise to speed up the characterization of disease-associated genetic variation. We summarize several recent studies in ECs which use high-throughput genetic perturbation to identify disease-relevant pathways and novel mechanisms of disease. These genetically validated pathways can accelerate the identification of drug targets for the prevention and treatment of atherosclerosis.

Computer-assisted image analysis of preexisting histological patterns of the cephalic vein to predict wrist arteriovenous fistula non-maturation.

BACKGROUND: We used computer-assisted image analysis to determine whether preexisting histological features of the cephalic vein influence the risk of non-maturation of wrist fistulas. METHODS: This study focused on patients aged 20-80 years who underwent their first wrist fistula creation. A total of 206 patients participated, and vein samples for Masson's trichrome staining were collected from 134 patients. From these, 94 patients provided a complete girth of the venous specimen for automatic image analysis. Maturation was assessed using ultrasound within 90 days after surgery. RESULTS: The collagen to muscle ratio in the target vein, measured by computer-assisted imaging, was a strong predictor of non-maturation in wrist fistulas. Receiver operating characteristic analysis revealed an area under the curve of 0.864 (95% confidence interval of 0.782-0.946, p < 0.001). The optimal cut-off value for the ratio was 1.138, as determined by the Youden index maximum method, with a sensitivity of 89.0% and specificity of 71.4%. For easy application, we used a cutoff value of 1.0; the non-maturation rates for patients with ratios >1 and ≤ 1 were 51.7% (15 out of 29 patients) and 9.2% (6 out of 65 patients), respectively. Chi-square testing revealed significantly different non-maturation rates between the two groups (X2 (1, N = 94) = 20.9, p < 0.01). CONCLUSION: Computer-assisted image interpretation can help to quantify the preexisting histological patterns of the cephalic vein, while the collagen-to-muscle ratio can predict non-maturation of wrist fistula development at an early stage.

Role of the Peroxisome Proliferator Activated Receptors in Hypertension.

Nuclear receptors represent a large family of ligand-activated transcription factors which sense the physiological environment and make long-term adaptations by mediating changes in gene expression. In this review, we will first discuss the fundamental mechanisms by which nuclear receptors mediate their transcriptional responses. We will focus on the PPAR (peroxisome proliferator-activated receptor) family of adopted orphan receptors paying special attention to PPARγ, the isoform with the most compelling evidence as an important regulator of arterial blood pressure. We will review genetic data showing that rare mutations in PPARγ cause severe hypertension and clinical trial data which show that PPARγ activators have beneficial effects on blood pressure. We will detail the tissue- and cell-specific molecular mechanisms by which PPARs in the brain, kidney, vasculature, and immune system modulate blood pressure and related phenotypes, such as endothelial function. Finally, we will discuss the role of placental PPARs in preeclampsia, a life threatening form of hypertension during pregnancy. We will close with a viewpoint on future research directions and implications for developing novel therapies.

Dietary Folate, Vitamin B6, and Vitamin B12 and Risk of Cardiovascular Diseases among Individuals with Type 2 Diabetes: A Case-Control Study.

BACKGROUND: Emerging evidence suggests that dietary one-carbon metabolism-related B-vitamins are associated with the reduced risk of cardiovascular disease (CVD) in the general population. However, only a few studies have assessed their associations in patients with type 2 diabetes (T2D). OBJECTIVE: This study aimed to assess the associations between the intake of three one-carbon metabolism-related B-vitamins (folate, vitamin B6, and vitamin B12) and CVD risk in Chinese patients with T2D. METHODS: A hospital-based case-control study of 419 patients with T2D and newly diagnosed CVD and 419 age- (±5 years) and sex-matched T2D-only controls was carried out in China. A validated 79-item semi-quantitative food-frequency questionnaire administered in face-to-face interviews was used to measure dietary B-vitamin intake. Conditional logistic regression was used to assess associations, which were tested by estimating odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: Compared with the lowest quartile, the multivariable-adjusted ORs and 95% CIs for highest quartile were 0.32 (95% CI: 0.20, 0.52; p trend <0.001) for folate, 0.47 (95% CI: 0.30, 0.76; p trend = 0.002) for vitamin B6, and 1.02 (95% CI: 0.67, 1.55; p trend = 0.841) for vitamin B12. Consistent inverse associations were found for folate intake from eggs, vegetables, fruits, soy, and other foods but not for folate intake from grains. CONCLUSIONS: Findings suggest that the high consumption of folate and vitamin B6, but not that of vitamin B12, might be associated with the low risk of CVD in patients with T2D. This study suggests that dietary folate and vitamin B6 protect against CVD in patients with T2D.

Viable Allogeneic Mitochondria Transplantation Improves Gas Exchange and Alveolar-Capillary Permeability in Rats with Endotoxin-Induced Acute Lung Injuries.

Background: Acute lung injuries (ALI) cause disruption of the alveolar-capillary barrier and is the leading cause of death in critically ill patients. This study tested the hypothesis that the administration of freshly isolated viable allogeneic mitochondria can prevent alveolar-capillary barrier injuries at the endothelial level, as mitochondrial dysfunction of the pulmonary endothelium is a critical aspect of ALI progression. Methods: ALI was induced by intratracheal lipopolysaccharide instillation (LPS, 1mg/kg) in anesthetized rats. Mitochondria (100 µg) were isolated from the freshly harvested soleus muscles of naïve rats and stained with a green fluorescence MitoTracker™ dyne. A mitochondria or placebo solution was randomly administered into the jugular veins of the rats at 2 h and 4 h after ALI induction. An arterial blood gas analysis was done 20 h later. The animals were then sacrificed and lung tissues were harvested for analysis. Results: An IVIS Spectrum imaging system was used to obtain ex vivo heart-lung block images and track the enhancement of MitoTracker™ fluorescence in the lungs. Mitochondria transplantation significantly improved arterial oxygen contents (PaO2 and SaO2) and reduced CO2 tension in rats with ALI. Animals with mitochondrial transplants had significantly higher ATP concentrations in their lung tissues. Allogeneic mitochondria transplantation preserved alveolar-capillary barrier function, as shown by a reduction in protein levels in the bronchoalveolar lavage fluid and decreased extravasated Evans blue dyne and hemoglobin content in lung tissues. In addition, relaxation responses to acetylcholine and eNOS expression were potentiated in injured pulmonary arteries and inflammatory cells infiltration into lung tissue was reduced following mitochondrial transplantation. Conclusions: Transplantation of viable mitochondria protects the integrity of endothelial lining of the alveolar-capillary barrier, thereby improving gas exchange during the acute stages of endotoxin-induced ALI. However, the long-term effects of mitochondrial transplantation on pulmonary function recovery after ALI requires further investigation.

A diet rich in fruit and whole grains is associated with a low risk of type 2 diabetes mellitus: findings from a case-control study in South China.

OBJECTIVE: Various foods are associated with or protect against type 2 diabetes mellitus (T2DM). This study was to examine the associations of foods and food patterns with the risk of T2DM in South China. DESIGN: Case-control study. SETTING: The dietary patterns were identified by a principal components factor analysis. Univariable and multivariable conditional logistic regression analyses were used to analyse the associations between food groups and dietary patterns and the risk of T2DM. PARTICIPANTS: A total of 384 patients with T2DM and 768 controls. RESULTS: After adjustment for total energy intake, the standard intake of grains (228·3 ± 71·9 v. 238·8 ± 73·1 g/d, P = 0·025) and fruits (109 ± 90 v. 145 ± 108 g/d, P < 0·001) were lower in T2DM than in controls. Four dietary patterns were identified: (1) high light-coloured vegetables and low grains, (2) high fruits, (3) high red meat and low grains and (4) high dark-coloured vegetable. After adjustment for covariables, multivariable conditional logistic regression analyses showed significant dose-dependent inverse associations between total fruit intake, whole grains intake and the score of the high-fruit dietary pattern (all Pfor trend < 0·001) and the risk of T2DM. The adjusted OR (95 % CI) for T2DM comparing the extreme quartiles were 0·46 (0·29, 0·76) for total fruits, 0·48(0·31, 0·77) for whole grains and 0·42 (0·26, 0·68) for the high-fruit dietary pattern, respectively. Similar associations were observed for all subgroups of fruits (dark-colour and light-colour). CONCLUSION: In South China, a diet rich in fruit and whole grains is associated with lower risk of T2DM.

Pt/AlGaN Nanoarchitecture: Toward High Responsivity, Self-Powered Ultraviolet-Sensitive Photodetection.

Energy-saving photodetectors are the key components in future photonic systems. Particularly, self-powered photoelectrochemical-type photodetectors (PEC-PDs), which depart completely from the classical solid-state junction device, have lately intrigued intensive interest to meet next-generation power-independent and environment-sensitive photodetection. Herein, we construct, for the first time, solar-blind PEC PDs based on self-assembled AlGaN nanostructures on silicon. Importantly, with the proper surface platinum (Pt) decoration, a significant boost of photon responsivity by more than an order of magnitude was achieved in the newly built Pt/AlGaN nanoarchitectures, demonstrating strikingly high responsivity of 45 mA/W and record fast response/recovery time of 47/20 ms without external power source. Such high solar-blind photodetection originates from the unparalleled material quality, fast interfacial kinetics, as well as high carrier separation efficiency which suggests that embracement of defect-free wide-bandgap semiconductor nanostructures with appropriate surface decoration offers an unprecedented opportunity for designing future energy-efficient and large-scale optoelectronic systems on a silicon platform.

Enhanced light extraction of the deep-ultraviolet micro-LED via rational design of chip sidewall.

In this Letter, we perform a comprehensive investigation on the optical characterization of micro-sized deep-ultraviolet (DUV) LEDs (micro-LEDs) emitting below 280 nm, highlighting the light extraction behavior in relation to the design of chip sidewall angle. We found that the micro-LEDs with a smaller inclined chip sidewall angle (∼33∘) have improved external quantum efficiency (EQE) performance 19% more than that of the micro-LEDs with a larger angle (∼75∘). Most importantly, the EQE improvement by adopting an inclined sidewall can be more outstanding as the diameter of the LED chip reduces from 40 to 20 µm. The enhanced EQE of the micro-LEDs with smaller inclined chip sidewall angles can be attributed to the stronger reflection of the inclined sidewall, leading to enhanced light extraction efficiency (LEE). In the end, the numerical optical modeling further reveals and verifies the impact of the sidewall angles on the LEE of the micro-LEDs, corroborating our experiment results. This Letter provides a fundamental understanding of the light extraction behavior with optimized chip geometry to design and fabricate highly efficient micro-LEDs in a DUV spectrum of the future.

Development of highly efficient ultraviolet LEDs on hybrid patterned sapphire substrates.

A hybrid patterned sapphire substrate (HPSS) aiming to achieve high-quality Al(Ga)N epilayers for the development of GaN-based ultraviolet light-emitting diodes (UV LEDs) has been prepared. The high-resolution X-ray diffraction measurements reveal that the Al(Ga)N epilayers grown on a HPSS and conventional patterned sapphire substrate (CPSS) have similar structural quality. More importantly, benefiting from the larger refractive index contrast between the patterned silica array and sapphire, the photons can escape from the hybrid substrate with an improved transmittance in the UV band. As a result, in comparison with the UV LEDs grown on the CPSS, the LEDs grown on the HPSS exhibit a significantly enhanced light output power by 14.5% and more than 22.9% higher peak external quantum efficiency, owing to the boost of the light extraction efficiency from the adoption of the HPSS which can be used as a promising substrate to realize high-efficiency and high-power UV LEDs of the future.

Cation-Exchange Induced Precise Regulation of Single Copper Site Triggers Room-Temperature Oxidation of Benzene.

The controllable synthesis of stable single-metal site catalysts with an expected coordination environment for high catalytic activity and selectivity is still challenging. Here, we propose a cation-exchange strategy for precise production of an edge-rich sulfur (S) and nitrogen (N) dual-decorated single-metal (M) site catalysts (M = Cu, Pt, Pd, etc.) library. Our strategy relies on the anionic frameworks of sulfides and N-rich polymer shell to generate abundant S and N defects during high-temperature annealing, further facilitating the stabilization of exchanged metal species with atomic dispersion and excellent accessibility. This process was traced by in situ transmission electron microscopy, during which no metal aggregates were observed. Both experiments and theoretical results reveal the precisely obtained S, N dual-decorated Cu sites exhibit a high activity and low reaction energy barrier in catalytic hydroxylation of benzene at room temperature. These findings provide a route to controllably produce stable single-metal site catalysts and an engineering approach for regulating the central metal to improve catalytic performance.

PPARγ and RhoBTB1 in hypertension.

PURPOSE OF REVIEW: This review provides an up-to-date understanding of how peroxisome proliferator activated receptor γ (PPARγ) exerts its cardioprotective effect in the vasculature through its activation of novel PPARγ target genes in endothelium and vascular smooth muscle. RECENT FINDINGS: In vascular endothelial cells, PPARγ plays a protective role by increasing nitric oxide bioavailability and preventing oxidative stress. RBP7 is a PPARγ target gene enriched in vascular endothelial cells, which is likely to form a positive feedback loop with PPARγ. In vascular smooth muscle cells, PPARγ antagonizes the renin-angiotensin system, maintains vascular integrity, suppresses vasoconstriction, and promotes vasodilation through distinct pathways. Rho-related BTB domain containing protein 1 (RhoBTB1) is a novel PPARγ gene target in vascular smooth muscle cells that mediates the protective effect of PPARγ by serving as a substrate adaptor between the Cullin-3 RING ubiquitin ligase and phosphodiesterase 5, thus restraining its activity through ubiquitination and proteasomal degradation. SUMMARY: In the vasculature, PPARγ exerts its cardioprotective effect through its transcriptional activity in endothelium and vascular smooth muscle. From the understanding of PPARγ's transcription targets in those pathways, novel hypertension therapy target(s) will emerge.

Repression of microRNA-21 inhibits retinal vascular endothelial cell growth and angiogenesis via PTEN dependent-PI3K/Akt/VEGF signaling pathway in diabetic retinopathy.

Diabetic retinopathy (DR) is a microvascular complication of diabetes and one of the most common causes of blindness in active stage. This study is performed to explore the effects of microRNA-21 (miR-21) on retinal vascular endothelial cell (RVEC) viability and angiogenesis in rats with DR via the phosphatidylinositiol 3-kinase/protein kinase B (PI3K/Akt)/vascular endothelial growth factor (VEGF) signaling pathway by binding to phosphatase and tensin homolog (PTEN). Sprague Dawley (SD) rats were used for establishment of DR models. Target relationship between miR-21 and PTEN was assessed by bioinformatics prediction in combination with dual-luciferase reporter gene assay. Identification of expression of miR-21, PTEN and PI3K/Akt/VEGF signaling pathway-related genes in the retinal tissues was then conducted. In order to assess the contributory role of miR-21 in DR, the RVECs were transfected with mimic or inhibitor of miR-21, or siRNA-PTEN, followed by the detection of expression of PTEN and PI3K/Akt/VEGF-related genes, as well as the measurement of cell viability, cell cycle and apoptosis. Increased expression of miR-21 and PI3K/Akt/VEGF related genes, along with a reduced expression of PTEN was observed in the retinal tissues of DR rats. PTEN was targeted and negatively regulated by miR-21, while the PI3K/Akt/VEGF signaling pathway was activated by miR-21. RVECs transfected with miR-21 inhibitor exhibited promoted viability and angiogenesis, and inhibited apoptosis. To conclude, our results indicated that miR-21 overexpression could potentially stimulate RVEC viability and angiogenesis in rats with DR through activation of the PI3K/Akt/VEGF signaling pathway via repressing PTEN expression, highlighting the potential of miR-21 as a target for DR treatment.

Anti-inflammatory diterpenes from the fruits of Vitex trifolia L. var. simplicifolia Cham.

Two new labdane-type diterpenes, named viterotulin C (1) and vitexilactone D (2), together with five known diterpenes (3-7), were isolated from the fruits of Vitex trifolia L. var. simplicifolia Cham. Their structures were elucidated by detailed analysis of spectroscopic data. All the compounds were evaluated for their inhibitory effects on nuclear factor-kappa B (NF-κB) pathway in HEK 293 cell line. These compounds presented inhibition on TNF-α-induced NF-κB activation, with inhibition rates ranging from 42.52 ± 10.69% to 68.86 ± 10.76% at the concentration of 50 µM.

A Beta/ZSM-22 Zeolites-Based-Mixed Matrix Solid-Phase Dispersion Method for the Simultaneous Extraction and Determination of Eight Compounds with Different Polarities in Viticis Fructus by High-Performance Liquid Chromatography.

Viticis Fructus (VF) was named Manjingzi as a commonly used traditional Chinese medicine (TCM) targeting various pains and inflammation for more than 2000 years. To guarantee the quality of Viticis Fructus, a simple, quick and eco-friendly Beta/ZSM-22 zeolites-based-mixed matrix solid-phase dispersion method (B/Z-MMSPD) was established for simultaneous extraction and determination of eight compounds (two phenolic acids, two iridoid glycosides, vanillin and three flavonoids) with different polarities from Viticis Fructus by high performance liquid chromatography coupled with a diode array detector (HPLC-DAD). Beta and ZSM-22 were mixed as the sorbent. Water, tetrahydrofuran and methanol were blended with certain ratio as the eluent. Several parameters including types of sorbents, mass ratio of Beta to ZSM-22, mass ratio of matrix to sorbent, grinding time, types, concentration and volume of eluent were optimized. The recoveries of eight analytes were within the range of 95.0%-105% (RSDs ≤ 4.13%). The limits of detection and limits of quantitation ranged from 0.5 to 5.5 µg/g and from 1.5 to 16 µg/g, respectively. Compared to the traditional extract methods, it was a simple, rapid, efficient and green method. The results demonstrated that a simple, rapid, efficient and green B/Z-MMSPD was developed for the simultaneous extraction and determination of eight target analytes with different polarities for quality control of Viticis Fructus.

A Supported Nickel Catalyst Stabilized by a Surface Digging Effect for Efficient Methane Oxidation.

A surface digging effect of supported Ni NPs on an amorphous N-doped carbon is described, during which the surface-loaded Ni NPs would etch and sink into the underneath carbon support to prevent sintering. This process is driven by the strong coordination interaction between the surface Ni atoms and N-rich defects. In the aim of activation of C-H bonds for methane oxidation, those sinking Ni NPs could be further transformed into thermodynamically stable and active metal-defect sites within the as-generated surface holes by simply elevating the temperature. In situ transmission electron microscopy images reveal the sunk Ni NPs dig themselves adaptive surface holes, which would largely prevent the migration of Ni NPs without weakening their accessibility. The reported two-step strategy opens up a new route to manufacture sintering-resistant supported metal catalysts without degrading their catalytic efficiency.

LPS promotes the expression of PD-L1 in gastric cancer cells through NF-κB activation.

Gastric cancers are a group of highly aggressive malignancies with a huge disease burden worldwide. Gastric infections, such as helicobacter pylori, can induce the occurrence of gastric cancers. However, the role of gastric infection in gastric cancer development is unclear. Programmed death-ligand 1 (PD-L1, B7-H1) is a member of the B7 family of cell surface ligands, which binds the PD-1 transmembrane receptor and inhibits T-cell activation within cancer tissues. It has been reported that the expression of PD-L1 is inversely related to the prognosis of patients with gastric cancers. Therefore, the regulation of PD-L1 expression in gastric cancers needs to be studied. In the current study, we explored the possible effects of lipopolysaccharide (LPS) on PD-L1 expression in gastric cancer cells. We observed that LPS stimulation could markedly increase PD-L1 expression in gastric cancer cells. Furthermore, we found that nuclear factor-κB (NF-κB) activation was involved in PD-L1 expression in gastric cancer cells exposed to LPS stimulation through p65-binding to the PD-L1 promoter. Taken together, these data indicate that gastric infection might promote the development of gastric cancers thought the LPS-NF-κB-PD-L1 axis.

Distribution patterns of microcalcifications in suspected thyroid carcinoma: a classification method helpful for diagnosis.

PURPOSE: The aim of this study was to compare the distribution patterns of microcalcifications in thyroid cancers with benign cases. METHODS: In total, 358 patients having microcalcifications on ultrasonography were analysed. Microcalcifications were categorised according to the distribution patterns: (I) microcalcifications inside one (a) or more (b) suspected nodules, (II) microcalcifications not only inside but also surrounding a suspected single (a) or multiple (b) nodules, and (III) focal (a) or diffuse (b) microcalcifications in the absence of any suspected nodule. Differences in distribution patterns of microcalcifications in benign and malignant thyroid lesions were compared. RESULTS: We found that the distribution patterns of microcalcifications differed between malignant (n = 325) and benign lesions (n = 117) (X 2 = 9.926, p < 0.01). Benign lesions were classified as type Ia (66.7%), type Ib (29.1%) or type IIIa (4.3%). The specificity of type II and type IIIb in diagnosing malignant cases was 100%. Among malignant lesions, 172 locations were classified as type Ia, 106 as type Ib, 12 as type IIa, 7 as IIb, 7 as type IIIa and 19 as type IIIb. Accompanying Hashimoto thyroiditis was most frequent in type III (51.6%). CONCLUSIONS: Types II and IIIb are highly specific for cancer detection. Microcalcifications outside a nodule and those detected in the absence of any nodule should therefore be reviewed carefully in clinical practice. KEY POINTS: • A method to classify distribution patterns of thyroid microcalcifications is presented. • Distribution features of microcalcifications are useful for diagnosing thyroid cancers. • Microcalcifications outside a suspicious nodule are highly specific for thyroid cancers. • Microcalcifications without suspicious nodules should also alert the physician to thyroid cancers.

Discovery of Alternative Producers of the Enediyne Antitumor Antibiotic C-1027 with High Titers.

The potent cytotoxicity and unique mode of action make the enediyne antitumor antibiotic C-1027 an exquisite drug candidate for anticancer chemotherapy. However, clinical development of C-1027 has been hampered by its low titer from the original producer Streptomyces globisporus C-1027. Here we report three new C-1027 alternative producers, Streptomyces sp. CB00657, CB02329, and CB03608, from The Scripps Research Institute actinomycetes strain collection. Together with the previously disclosed Streptomyces sp. CB02366 strain, four C-1027 alternative producers with C-1027 titers of up to 11-fold higher than the original producer have been discovered. The five C-1027 producers, isolated from distant geographic locations, are distinct Streptomyces strains based on morphology and taxonomy. Pulsed-field gel electrophoresis and Southern analysis of the five C-1027 producers reveal that their C-1027 biosynthetic gene clusters (BGCs) are all located on giant plasmids of varying sizes. The high nucleotide sequence similarity among the five C-1027 BGCs implies that they most likely have evolved from a common ancestor.

Association between the sonographer's experience and diagnostic performance of IOTA simple rules.

BACKGROUND: To validate the clinical value of simple rules in distinguishing malignant adnexal masses from benign ones and to explore the effect of simple rules for experienced and less-experienced sonographers. METHODS: Patients with persistent adnexal masses were enrolled between November 2013 and December 2015. All masses were proven through histological examinations. Five sets of diagnoses were made and compared with one another. Diagnosis 1 was made, according to the simple rules, by a trainee with little clinical diagnostic experience. Diagnoses 2 and 3 were made by experienced and less-experienced sonographers, respectively, according to their clinical experiences. With diagnosis 1 as a reference, the two sonographers were asked to provide a second diagnosis, which were diagnoses 4 and 5. The efficiency of the five sets of diagnoses was compared using ROC curves. RESULTS: In total, 75 malignant (37.7%) and 124 benign lesions (62.3%) were enrolled in this study. The mean diameter of the benign masses was obviously smaller than that of the malignant ones (6.8 ± 3.4 cm vs. 9.3 ± 4.9 cm, p < 0.01). The malignant ratio in postmenopausal women was much higher (66.1%) than that in the premenopausal population (25.7%) (p < 0.0001). Totally, 156 of the 199 cases (79.4%) resulted in conclusive diagnoses. Sensitivity and specificity were 98.4% and 73.9%, respectively, among the conclusive cases. The area under the ROC curve (Az) for the simple rule diagnosis was significantly lower than that for the experienced sonographer diagnosis (0.85 vs. 0.96, p < 0.0001); compared with the less-experienced sonographer, this difference was not significant (0.85 vs. 0.86, p = 0.9776). No significant difference was found in the comparison between the diagnoses made by the experienced sonographer before and after referencing the simple rule diagnosis (Az, 0.96 vs. 0.97, p = 0.2055). Using diagnosis 1 as a reference, the diagnostic performance of the less-experienced sonographer increased (from 0.86 to 0.92, p = 0.012); however, it was still lower than that of the experienced sonographer (Az, 96% vs. 92%, p = 0.0241). CONCLUSIONS: The simple rules was an appealing method for discriminating malignant masses from benign ones, particularly for a less-experienced sonographer.