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Camellia oleifera Abel., a small evergreen tree or shrub, is mainly distributed in central and southern China with a larger scale of 4.5 × 106 hectares (Zhu 2020). In May 2021, severe leaf spots were observed in plantation located in Shuangfeng County (27°41'36" N, 111°56'60" E), Hunan Province, China. More than 60 C. oleifera plants were surveyed with over 80% disease incidence. The symptoms on leaves were initially small brown lesions from leaf margins or tips, developing to suborbicular or irregular-shaped dark brown lesions, leading to leaves withered. A total of 60 symptomatic samples were randomly collected. Lesion margins were surface sterilized in 2% sodium hypochlorite for 1 min, rinsed with sterile distilled water for three times, dried, placed on potato dextrose agar (PDA), and incubated at 25°C in the dark for 3 days. Hyphal sections from colony edges were transferred to new PDA plates. Three isolates of Botryosphaeria dothidea were obtained. Colonies of B. dothidea were initially white gradually turning dark-gray with dense aerial mycelium after 6 days. To induce sporulation, colonies of YCB17 were transferred to synthetic nutrient-poor agar (SNA) with sterilized leaves of C. oleifera. Cultures were initially incubated at 25°C in the dark for 3 days, then alternatively exposed to 12-hours near-UV light and 12-hours white light (CHU et al. 2021). After 5 days, conidia formed on leaves were examined microscopically. The conidia were unicellular, aseptate, hyaline, and fusoid, 20.9-25.5×4.7-6.4 µm (n = 50). Morphological characteristics of the isolates matched the description of B. dothidea (Slippers et al. 2014). DNA sequence was amplified using primer pairs ITS1/ITS4 (Tang et al. 2022), EF1-728F/986R (Slippers et al. 2004), and βt2a/2b (GlassDonaldson. 1995) respectively. The sequences of three isolates (YCB2, YCB3, YCB17) were deposited in GenBank with accession numbers ON714603, MZ613350, MZ613349 (ITS), OM328342, OM328343, OM328344 (TEF-1α), and OM328345, OM328346, OM328347 (TUB2). A blast search of sequences showed the ITS, TEF-1α, and TUB2 sequences had99% identity with homologue sequences from B. dothidea isolates IRNHM-KZ49 (MG198191.1), CAP288 (EF638732.1) and Mu1 (MK423987.1), respectively. For pathogenicity testing, healthy leaves of 2-year-old C. oleifera plants in the greenhouse were spray-inoculated with conidial suspension (2×106 conidia/mL) from YCB17. Ten surface-sterilized and wounded leaves per plant were sprayed with 30 µL suspension. The other ten wounded leaves sprayed with sterile distilled water served as control. All plants were kept in the greenhouse with temperature at 26 ± 2°C and 50% relative humidity. After 12 days, initial symptoms were observed on more than 80% leaves inoculated with conidial suspension, whereas no symptoms were observed on the control leaves. The test was repeated three times with similar results. It was found that B. dothidea could cause leaf spot of C. oleifera. The infected leaves showed same symptom as samples. Re-isolated fungi from infected leaves were morphologically identical to B. dothidea. Botryosphaeria dothidea has been reported causing leaf spot in a wide range of hosts, but has not previously been reported causing disease on C. oleifera. To our knowledge, this is the first report of B. dothidea causing leaf spot of Camellia oleifera in China. The information on identification of this fungus may be helpful to the control and prevention of the disease. References: 1. Chu Rui-Tian, et al. 2021. Mycosystema 40(3): 473. 2. Glass, N. L., and Donaldson, G. C. 1995. Appl. Environ. Microbiol. 61: 1323. 3. Slippers, B., et al. 2004. Mycologia 96:83. 4. Slippers, B., et al. 2014. Persoonia 33:155. 5. Tang, Y., et al. 2022. Plant Dis. 106: 765. 6. Zhu P.X. People's Daily. 2020.11.09. http://gz.people.com.cn/n2/2020/1119/c194844-34425098.html. *Indicates the corresponding author. Kaifa Guo, E-mail: andygkf@126.com.

Background: HIF pathway is quickly activated during myocardial ischemia after myocardial infarction(MI), and cardiac microvascular leakage contributes to heart tissue damage. HIF2α isprofoundly expressed in cardiac endothelial cells (ECs) and the embryonic deletion of HIF2Aresults in increased vascular permeability and aberrant ECs behavior. However, the direct roleof endothelial cell-specific HIF2α (ecHIF2α) in ischemic heart disease is not known. Wehypothesized that ecHIF2α expression in response to myocardial infarction (MI) is protectiveagainst heart failure through the reduction of cardiac ECs apoptosis and inflammation. Methods and Results: To address our hypothesis, we generated EC-specific inducible-HIF2α knockout mice (ecHIF2α -/- ) by crossing Hif2a flox/flox mice with Cre ERT2 mice. To assess the functional role of HIF2α inischemic heart injury, we ligated the proximal left anterior descending coronary artery to induceMI using the same age and gender-matched ecHIF2α -/- and control ( Hif2a flox/flox ) mice. Cardiacfunction was determined by echocardiography after two and four weeks of ligation. Analysis ofechocardiography revealed worsened heart function, and Masson’s Trichrome stain displayedincreased fibrosis in ecHIF2α -/- mice. In vitro , ECIS analysis of isolated cardiac microvascularendothelial cells showed decreased endothelial barrier function in ecHIF2α -/- cells. In addition,hypoxic stimulation reduces the tube formation capacity in ecHIF2α-/- cells and is sensitive tohypoxia-induced early-stage apoptosis. Deletion of HIF2α, as well as its binding partner ARNT,increased the expression of several inflammatory genes, including IL-6. Interestingly,overexpression of ARNT alone abolishes the HIF2α deletion-induced inflammatory geneexpression. IL-6 protein levels in HIF2α deleted human aortic endothelial cells (HAoEC) show asignificant reduction (n=3-5, p Conclusion: Collectively our data revealed an essential role of endothelial HIF2α/ARNT in maintaining cardiacfunctions by increasing endothelial barrier function and decreasing inflammation. Therefore,HIF2A/ARNT could provide a potential therapeutic target for the treatment of ischemic heartdisease.

Introduction: Cardiovascular dysfunction is a major complication of severe sepsis. Microvascular leakage and mitochondrial dysfunction during sepsis are critically involved in heart failure. However, the underlying mechanisms between cardiac microvascular barrier function and sepsis-induced heart failure are not well studied. Kinin B1 receptor (B1R) regulates inflammation and induces capillary leakage. Previous findings from our lab also revealed an increase in B1R serum level in both septic patients and animal models within 24 hours. Hypothesis: We hypothesized that treatment with B1R antagonist protects against sepsis-induced microvascular leakage and mitochondrial dysfunction. Methods and Results: To address the hypothesis, we pre-treated WT male mice with either vehicle (control) or a specific B1R antagonist B6929 via subcutaneous injection, then subjected them to 40% cecal ligation and puncture (CLP) to induce polymicrobial sepsis. Echocardiographic analysis revealed an early cardioprotective effect of B1R inhibition, as evidenced by the improvement of EF%, FS%, and cardiac output in mice pre-treated with B1R antagonist (n=6-8, p2 O 2 measurement of the freshly isolated cardiac mitochondria from CLP-induced septic mice also showed that B1R inhibition partially abolished the production of H 2 O 2 . The opening of mPTP was also reduced with B1R antagonist treatment. In vivo cardiac vascular permeability assessed using the Miles assay further demonstrated that B1R inhibition prevented sepsis-induced cardiac microvascular leakage and edema. Similar improvements were also observed in the liver and kidney. Interestingly,B1R antagonist treatment abolished CLP-induced serum level of IL-6 by 70%. In in-vitro study, B1R antagonist treatment inhibited LPS-induced IL-6 expressions in human cardiac microvacuolar endothelial cells (HCMECs). Finally, ECIS based analysis demonstrated that IL-6 deletion using either siRNA or B1R antagonist treatment rescued LPS-induced endothelial barrier leakage. Conclusions: Our findings suggest that targeting B1R via IL-6 may be a novel therapeutic approach for the treatment of sepsis-associated cardiovascular disease.

Background While many interventions to reduce hospital admissions and emergency department (ED) visits for patients with cardiovascular disease have been developed, identifying ambulatory cardiac patients at high risk for admission can be challenging. Hypothesis A computational model based on readily accessible clinical data can identify patients at risk for admission. Methods Electronic health record (EHR) data from a tertiary referral center were used to generate decision tree and logistic regression models. International Classification of Disease (ICD) codes, labs, admissions, medications, vital signs, and socioenvironmental variables were used to model risk for ED presentation or hospital admission within 90 days following a cardiology clinic visit. Model training and testing were performed with a 70:30 data split. The final model was then prospectively validated. Results A total of 9326 patients and 46 465 clinic visits were analyzed. A decision tree model using 75 patient characteristics achieved an area under the curve (AUC) of 0.75 and a logistic regression model achieved an AUC of 0.73. A simplified 9‐feature model based on logistic regression odds ratios achieved an AUC of 0.72. A further simplified numerical score assigning 1 or 2 points to each variable achieved an AUC of 0.66, specificity of 0.75, and sensitivity of 0.58. Prospectively, this final model maintained its predictive performance (AUC 0.63–0.60). Conclusion Nine patient characteristics from routine EHR data can be used to inform a highly specific model for hospital admission or ED presentation in cardiac patients. This model can be simplified to a risk score that is easily calculated and retains predictive performance.

Recently, indoor positioning becomes a popular issue because of its corresponding location-aware applications. Owing to the limits of the sheltered signal of satellites in indoor environments, one of the alternative scheme is Bluetooth Low Energy (BLE) technology. BLE device broadcasts Received Signal Strength Indicator (RSSI) for distance estimation and further positioning. However, in the complex indoor environment, the reflection, fading, and multipath effect of BLE make the variable RSSI and may lead to poor quality of RSSI. In this study, the concept called Differential Distance Correction (DDC) is similar to the Differential Global Navigation Satellite System (DGNSS). This method can eliminate some residuals and further improve the results with the corrected distance. On the other hand, Pedestrian Dead Reckoning (PDR) is another common indoor positioning method. PDR can propagate the next position from the current position by the implemented of inertial sensors. Despite that, the error of inertial sensors would accumulate with time and walking distance, which position update is required for restraining the drift. Accordingly, the two indoor positioning methods have their strong and weak point. BLE-based positioning is absolute positioning, while PDR is relative positioning. This study proposes a concept that combines the two methods. The pedestrian receives the RSSI and records the information from inertial sensors simultaneously. Through the complementary of two methods, the positioning results would be improved from 29% to 66% according to different travelled distance.

Background The transvaginal natural orifice specimen extraction (NOSE) approach for right-side colon surgery has been proven to exhibit favorable short-term outcomes. However, thus far, no study has reported the advantages of transrectal NOSE for right-side colon surgery. The aim of this study was to compare the technical feasibility, safety, and short-term outcomes of minimally invasive right hemicolectomy using the transrectal NOSE method and those of conventional mini-laparotomy specimen extraction. Methods A study was conducted on consecutive patients who had minimally invasive right hemicolectomy either for malignancy or benign disease at Chang Gung Memorial Hospital, Linkou, Taiwan, between January 2017 and December 2018. The patients were divided into two groups: conventional surgery with specimen extraction using mini-laparotomy and NOSE surgery. Surgical outcomes, including complications, postoperative short-term recovery, and pain intensity, were analyzed. Results We enrolled 297 patients (151 males, mean age 64.9 ± 12.8 years) who had minimally invasive right hemicolectomy. Of these 297 patients, 272 patients had conventional surgery with specimen extraction through mini-laparotomy and 25 patients had NOSE surgery (23 transrectal, 2 transvaginal). The diagnosis of colon disease did not differ significantly between the conventional and NOSE groups. Postoperative morbidity and mortality rates were comparable. The postoperative hospital stay was significantly (p = 0.004) shorter in the NOSE group (median 5 days, range 3–17 days) than in the conventional group (median 7 days, range 3–45 days). Postoperative pain was significantly (p = 0.026 on postoperative day 1 and p = 0.002 on postoperative day 2) greater in the conventional group than in the NOSE group. Conclusions NOSE was associated with acceptable short-term surgical outcomes that were comparable to those of conventional surgery. NOSE results in less postoperative wound pain and a shorter hospital stay than conventional surgery. Larger studies are needed

INTRODUCTION: Pathological cardiac fibrosis, through excessive extracellular matrix protein deposition from fibroblasts and pro-fibrotic immune responses and vascular stiffening is associated with most forms of cardiovascular disease. Pathological cardiac fibrosis and stiffening can lead to heart failure and arrythmias and vascular stiffening may lead to hypertension. ROCK, a serine/threonine kinase downstream of the Rho-family of GTPases, may regulate many pro-fibrotic and pro-stiffening signaling pathways in numerous cell types. AREAS COVERED: This article outlines the molecular mechanisms by which ROCK in fibroblasts, T helper cells, endothelial cells, vascular smooth muscle cells, and macrophages mediate fibrosis and stiffening. We speculate on how ROCK could be targeted to inhibit cardiovascular fibrosis and stiffening. EXPERT OPINION: Critical gaps in knowledge must be addressed if ROCK inhibitors are to be used in the clinic. Numerous studies indicate that each ROCK isoform may play differential roles in regulating fibrosis and may have opposing roles in specific tissues. Future work needs to highlight the isoform- and tissue-specific contributions of ROCK in fibrosis, and how isoform-specific ROCK inhibitors in murine models and in clinical trials affect the pathophysiology of cardiac fibrosis and stiffening. This could progress knowledge regarding new treatments for heart failure, arrythmias and hypertension and the repair processes after myocardial infarction.

Second- and third-generation BCR-ABL1 tyrosine kinase inhibitors (TKIs) are associated with cardiovascular adverse events (CVAEs) in patients with Philadelphia chromosome-positive (Ph+) leukemia.We hypothesized that second- and third-generation BCR-ABL1 TKIs may cause CVAEs through the activation of Rho-associated coiled-coil containing kinase (ROCK).Peripheral blood mononuclear cells from 53 Ph+ patients on TKIs and 15 control patients without Ph+ leukemia were assessed for ROCK activity through capillary electrophoresis (median follow-up = 26 months [Q1-Q3: 5-37 months]). We also investigated the effects of TKIs and ROCK on endothelial dysfunction in vitro, which could contribute to CVAEs.Patients receiving second- and third-generation TKIs had 1.6-fold greater ROCK activity compared with patients receiving imatinib and control patients. Elevated ROCK activity was associated with an increased incidence of CVAEs in Ph+ leukemia patients. In endothelial cells in vitro, we found that dasatinib and ponatinib treatment led to changes in actin intensity and endothelial permeability, which can be reversed by pharmacologic inhibition of ROCK. Ponatinib led to decreased cell proliferation, but this was not accompanied by senescence. Dasatinib and ponatinib treatment led to phosphor-inhibition of endothelial nitric oxide synthase and decreased nitric oxide production. ROCK inhibition reversed endothelial permeability and endothelial nitric oxide synthase-related endothelial dysfunction. Imatinib and nilotinib induce phosphorylation of p190RhoGAP.Our findings suggest ROCK activity may be a prognostic indicator of CVAEs in patients receiving BCR-ABL1 TKIs. With further study, ROCK inhibition may be a promising approach to reduce the incidence of CVAEs associated with second- and third-generation BCR-ABL1 TKIs.

Background The pathogenesis of vascular stiffening and hypertension is marked by non‐compliance of vessel wall because of deposition of collagen fibers, loss of elastin fibers, and increased vascular thickening. Rho/Rho‐associated coiled‐coil containing kinases 1 and 2 (ROCK1 and ROCK2) have been shown to regulate cellular contraction and vascular remodeling. However, the role of ROCK isoforms in mediating pathogenesis of vascular stiffening and hypertension is not known. Methods and Results Hemizygous Rock mice ( Rock1 +/− and Rock2 +/− ) were used to determine the role of ROCK1 and ROCK2 in age‐related vascular dysfunction. Both ROCK activity and aortic stiffness increased to a greater extent with age in wild‐type mice compared with that of Rock1 +/− and Rock2 +/− mice. As a model for age‐related vascular stiffening, we administered angiotensin II (500 ng/kg per minute) combined with nitric oxide synthase inhibitor, L‐N ω ‐nitroarginine methyl ester (0.5 g/L) for 4 weeks to 12‐week‐old male Rock1 +/− and Rock2 +/− mice. Similar to advancing age, angiotensin II/L‐N ω ‐nitroarginine methyl ester caused increased blood pressure, aortic stiffening, and vascular remodeling, which were attenuated in Rock2 +/− , and to a lesser extent, Rock1 +/− mice. The reduction of aortic stiffening in Rock2 +/− mice was accompanied by decreased collagen deposition, relatively preserved elastin content, and less aortic wall hypertrophy. Indeed, the upregulation of collagen I by transforming growth factor‐β1 or angiotensin II was greatly attenuated in Rock2 −/− mouse embryonic fibroblasts. Conclusions These findings indicate that ROCK1 and ROCK2 mediate both age‐related and pharmacologically induced aortic stiffening, and suggest that inhibition of ROCK2, and to a lesser extent ROCK1, may have therapeutic benefits in preventing age‐related vascular stiffening.

Durable and temporary mechanical circulatory support (MCS) use is growing for a range of cardiovascular indications. Kidney dysfunction is common in people evaluated for or receiving durable or temporary MCS and portends worse outcomes. This kidney dysfunction can be due to preexisting kidney chronic kidney disease (CKD), acute kidney injury (AKI) related to acute cardiovascular disease necessitating MCS, AKI due to cardiac procedures, and acute and chronic MCS effects and complications. Durable MCS, with implantable continuous flow pumps, is used for long-term support in advanced heart failure refractory to guideline-directed medical and device therapy, either permanently or as a bridge to heart transplantation. Temporary MCS—encompassing in this review intra-aortic balloon pumps (IABP), axial flow pumps, centrifugal flow pumps, and venoarterial ECMO—is used for diverse situations: high-risk percutaneous coronary interventions (PCI), acute decompensated heart failure, cardiogenic shock, and resuscitation after cardiac arrest. The wide adoption of MCS makes it imperative to improve understanding of the effects of MCS on kidney health/function and of kidney health/function on MCS outcomes. The complex structure and functions of the kidney, and the complex health states of individuals receiving MCS, makes investigations in this area challenging, and current knowledge is limited. Fortunately, the increasing nephrology toolbox of noninvasive kidney health/function assessments may enable development and testing of individualized management strategies and therapeutics in the future. We review technology, epidemiology, pathophysiology, clinical considerations, and future directions in MCS and nephrology.

Hypoxia-inducible factors (HIFs) are the master regulators of angiogenesis, a process that is impaired in patients with diabetes mellitus (DM). The transcription factor aryl hydrocarbon receptor nuclear translocator (ARNT, also known as HIF1β) has been implicated in the development and progression of diabetes. Angiogenesis is driven primarily by endothelial cells (ECs), but both global and EC-specific loss of ARNT-cause are associated with embryonic lethality. Thus, we conducted experiments in a line of mice carrying an inducible, EC-specific ARNT-knockout mutation (ArntΔEC, ERT2) to determine whether aberrations in ARNT expression might contribute to the vascular deficiencies associated with diabetes. Mice were first fed with a high-fat diet to induce diabetes. ArntΔEC, ERT2 mice were then adminstrated with oral tamoxifen to disrupt Arnt and peripheral angiogenesis was evaluated by using laser-Doppler perfusion imaging to monitor blood flow after hindlimb ischemia. The ArntΔEC, ERT2 mice had impaired blood flow recovery under both non-diabetic and diabetic conditions, but the degree of impairment was greater in diabetic animals. In addition, siRNA-mediated knockdown of ARNT activity reduced measurements of tube formation, and cell viability in human umbilical vein endothelial cells (HUVECs) cultured under high-glucose conditions. The ArntΔEC, ERT2 mutation also reduced measures of cell viability, while increasing the production of reactive oxygen species (ROS) in microvascular endothelial cells (MVECs) isolated from mouse skeletal muscle, and the viability of ArntΔEC, ERT2 MVECs under high-glucose concentrations increased when the cells were treated with an ROS inhibitor. Collectively, these observations suggest that declines in endothelial ARNT expression contribute to the suppressed angiogenic phenotype in diabetic mice, and that the cytoprotective effect of ARNT expression in ECs is at least partially mediated by declines in ROS production.

Cavernous angioma (CA) is a vascular pathology caused by loss of function in one of the 3 CA genes (CCM1, CCM2, and CCM3) that result in rho kinase (ROCK) activation. We investigated a novel ROCK2 selective inhibitor for the ability to reduce brain lesion formation, growth and maturation. We used genetic methods to explore the use of a ROCK2-selective kinase inhibitor to reduce growth and hemorrhage of CAs. The role of ROCK2 in CA was investigated by crossing Rock1 or Rock2 hemizygous mice with Ccm1 or Ccm3 hemizygous mice, and we found reduced lesions in the Rock2 hemizygous mice. A ROCK2-selective inhibitor, BA-1049 was used to investigate efficacy in reducing CA lesions after oral administration to Ccm1(+/−) and Ccm3(+/−) mice that were bred into a mutator background. After assessing the dose range effective to target brain endothelial cells in an ischemic brain model, Ccm1(+/−) and Ccm3(+/−) transgenic mice were treated for three (Ccm3(+/−)) or four months (Ccm1(+/−)), concurrently, randomized to receive one of three doses of BA-1049 in drinking water, or placebo. Lesion volumes were assessed by micro-computed tomography. BA-1049 reduced activation of ROCK2 in Ccm3(+/−)Trp53(−/−) lesions. Ccm1(+/−)Msh2(−/−) (n=68) and Ccm3(+/−)Trp53(−/−) (n=71) mice treated with BA-1049 or placebo showed a significant dose-dependent reduction in lesion volume after treatment with BA-1049, and a reduction in hemorrhage (iron deposition) near lesions at all doses. These translational studies show that BA-1049 is a promising therapeutic agent for treatment of CA, a disease with no current treatment except surgical removal of the brain lesions.

BACKGROUND The purpose of this study was to examine the longitudinal association between rising violent crime and elevated blood pressure (BP). METHODS We analyzed 217,816 BP measurements from 17,783 adults during a temporal surge in violent crime in Chicago (2014–2016). Serial observations were abstracted from the electronic health record at an academic medical center and paired to the City of Chicago Police Data Portal. The violent crime rate (VCR) was calculated as the number of violent crimes per 1,000 population per year for each census tract. Longitudinal multilevel regression models were implemented to assess elevated BP (systolic BP ≥ 140 mm Hg or diastolic BP ≥ 90 mm Hg) as a function of the VCR, adjusting for patient characteristics, neighborhood characteristics, and time effects. Secondary dependent measures included elevated heart rate, obesity, missed outpatient appointments, all-cause hospital admissions, and cardiovascular hospital admissions. RESULTS At baseline, the median VCR was 41.3 (interquartile range: 15.2–66.8), with a maximum rise in VCR of 59.1 over the 3-year surge period. A 20-unit rise in the VCR was associated with 3% higher adjusted odds of having elevated BP (95% confidence interval [CI]: 1.01–1.06), 8% higher adjusted odds of missing an outpatient appointment (95% CI: 1.03–1.13), and 6% higher adjusted odds of having a cardiovascular-related hospital admission (95% CI: 1.01–1.12); associations were not significant for elevated heart rate and obesity. CONCLUSION Rising violent crime was associated with increased BP during a temporal crime surge.

We worked on a FePt granular film with a columnar structure, for the purpose of ultrahigh density perpendicular magnetic recording media. In experiments, a Fe53Pt47-SiO230%-C25% (10 nm) film was deposited on a silicon substrate with a MgO (12 nm) interlayer at 510 °C. The perpendicular coercivity of the film is 29 kOe, with a squareness of 1. Bright-field TEM images show that the FePt granular film has small and uniform grains of 8.3 ± 1.9 nm with a columnar structure. More work of high-resolution TEM imaging shows excellent L10 ordering inside the FePt grains. The measurement of remnant coercivity proves that it has an energy barrier of 290kBT at room temperature, meaning excellent thermal stability. We demonstrate FePt granular film to be a qualified candidate for high-density perpendicular magnetic recording media, and both SiO2 and C addition helps form columnar structure.

Indoor positioning has attracted much attention in recent years due to the trend of Internet of Things (IoT), which is capable of providing numerous applications such as personal tracking, vehicle locator, and Location-Based Service (LBS). To put LBS into practice, positioning and navigation are one of the necessary techniques. Using the smartphone to process indoor positioning also become more and more usual. The most common algorithm in the inertial navigation system is Pedestrian Dead Reckoning (PDR), utilizing sensors built-in the smartphones to conquer the strait of GNSS-denied environment. However, for the purpose of eliminating the error accumulated with time, PDR combining with other algorithms, for instance, updating some geospatial information steadily is a better way to solve this problem. Therefore, this research proposes the imaged based aided algorithm. Moreover, in this study, a novel Artificial Neural Networks (ANN) embedded the system is proposed. The self-designed georeferenced markers and the indoor floor plan will be produced by an Indoor Mobile Mapping System (IMMS) in advance. This research proposed using Cascade-Correlation neural Network (CCN) to estimate the distance between the marker and the smartphone camera. The accuracy using this method can achieve to 0.27 meter. As if at least three coordinates and the distance can be obtained simultaneously, the position of the user can be calculated by the trilateration method. From the experiment, the accuracy of the positioning is about 0.5 meter. This way seems to have the high potential to bring into play on the real-time indoor positioning.

Background and Purpose— Previously, murine models Krit1 +/− Msh2 −/ − and Ccm2 +/ − Trp53 −/ − showed a reduction or no effect on cerebral cavernous malformation (CCM) burden and favorable effects on lesional hemorrhage by the robust Rock (Rho-associated protein kinase) inhibitor fasudil and by simvastatin (a weak pleiotropic inhibitor of Rock). Herein, we concurrently investigated treatment of the more aggressive Pdcd10/Ccm3 model with fasudil, simvastatin, and higher dose atorvastatin to determined effectiveness of Rock inhibition. Methods— The murine models, Pdcd10 +/ − Trp53 −/ − and Pdcd10 +/ − Msh2 −/ − , were contemporaneously treated from weaning to 5 months of age with fasudil (100 mg/kg per day in drinking water, n=9), simvastatin (40 mg/kg per day in chow, n=11), atorvastatin (80 mg/kg per day in chow, n=10), or with placebo (n=16). We assessed CCM volume in mouse brains by microcomputed tomography. Lesion burden was calculated as lesion volume normalized to total brain volume. We analyzed chronic hemorrhage in CCM lesions by quantitative intensity of Perls staining in brain sections. Results— The Pdcd10 +/ − Trp53 −/ − /Msh2 −/ − models showed a mean CCM lesion burden per mouse reduction from 0.0091 in placebos to 0.0042 ( P =0.027) by fasudil, and to 0.0047 ( P =0.025) by atorvastatin treatment, but was not changed significantly by simvastatin. Hemorrhage intensity per brain was commensurately decreased by Rock inhibition. Conclusions— These results support the exploration of proof of concept effect of high-dose atorvastatin on human CCM disease for potential therapeutic testing.

Charles Darwin viewed eyes as the epitome of evolution by natural selection, describing them as organs of extreme perfection and complication. The visual system is therefore fertile ground for teaching fundamental concepts in optics and biology, subjects with scant representation during the rise and spread of immersive technologies in K-12 education. The visual system is an ideal topic for three-dimensional (3D) virtual reality learning environments (VRLEs), and here we describe a 3D VRLE that simulates the vision of a tarsier, a nocturnal primate that lives in southeast Asia. Tarsiers are an enduring source of fascination for having enormous eyes, both in absolute size and in proportion to the size of the animal. Our motivation for developing a tarsier-inspired VRLE, or Tarsier Goggles, is to demonstrate the optical and selective advantages of hyperenlarged eyes for nocturnal visual predation. In addition to greater visual sensitivity, users also experience reductions in visual acuity and color vision. On a philosophical level, we can never know the visual world of another organism, but advances in 3D VRLEs allow us to try in the service of experiential learning and educational outreach.

Statins, 3-hydroxy-methylglutaryl coenzyme A reductase inhibitors, have been used for decades for the prevention of coronary artery disease and stroke. They act primarily by lowering serum cholesterol through the inhibition of cholesterol synthesis in the liver, which results in the upregulation of low-density lipoprotein receptors in the liver. This results in the removal of low-density lipoproteincholesterol. Studies have suggested that statins may demonstrate additional effects that are independent of their effects on low-density lipoprotein-cholesterol. These have been termed “pleiotropic” effects. Pleiotropic effects may be due to the inhibition of isoprenoid intermediates by statins. Isoprenoid inhibition has effects on the small guanosine triphosphate binding proteins Rac and Rho which in turn effects nicotinamide adenine dinucleotide phosphate oxidases. Therefore, there are changes in endothelial nitric oxide synthase expression, atherosclerotic plaque stability, pro-inflammatory cytokines and reactive oxygen species production, platelet reactivity, and cardiac fibrosis and hypetrophy development. Recently, statins have been compared to the ezetimibe and the recently published outcomes data on the proprotein convertase subtilisin kexin type 9 inhibitors has allowed for a reexamination of statin pleiotropy. As a result of these diverse effects, it has been suggested that statins also have anti-arrhythmic effects. This review focuses on the mechanisms of statin pleiotropy and discusses evidence from the statin clinical trials as well as examining the possible anti-arrhythmic effects atrial fibrillation and ventricular tachyarrhythmias.

ObjectiveUltraviolet B (UVB) is an important trigger of skin inflammation and lupus with leukocyte recruitment to inflamed skin. We recently reported the involvement of neutrophil NETosis in UVB-induced skin inflammation, and that NETotic nuclear envelope rupture is driven by PKCα-mediated nuclear lamin B disassembly. To address the role of Actin cytoskeleton in NETosis, we investigated the effects of Rho kinase (ROCK) and its downstream actomyosin cytoskeletal networks on PKCα nuclear translocation and NET formation, as well as their involvement in UVB-induced skin inflammation.MethodsWe studied the dynamic changes of ROCK and actomyosin cytoskeletal networks during NETosis induction and their involvement in PKCα nuclear translocation. Using mice with hematopoietic-specific ROCK1 deficiency, we investigated the effects of ROCK1 deficiency on NETosis, and its involvement in UVB-induced skin inflammation.ResultsOur time course studies demonstrated the dynamic changes of actin polymerization and ROCK activation, support the role of actin cytoskeleton in nuclear translocation of cytosolic PKCα in early stage of NETosis induction. Inhibition of actin polymerization or key molecules of the ROCK/MLCK/myosin pathway decreased PKCα nuclear translocation and NET formation. Genetic deficiency of ROCK1, inhibited NETosis ex vivo and in vivo, decreased extracellular display of NET-associated IL-17A, TNFα, IFNγ, and IFNα in inflamed skin, which were correlated with the ameliorated skin inflammation in UVB-irradiated mice with hematopoietic-specific ROCK1 deficiency.ConclusionsROCK regulated NETosis through modulation of PKCα nuclear translocation via actomyosin cytoskeletal networks in neutrophils. ROCK1 deficiency ameliorated UVB- induced skin inflammation by attenuation of NETosis and NET-associated cytokines.

Over the past four decades, no class of drugs has had more impact on cardiovascular health than the 3-hydroxy-methylglutaryl coenzyme A reductase inhibitors or statins. Developed as potent lipid-lowering agents, statins were later shown to reduce morbidity and mortality of patients who are at risk for cardiovascular disease. However, retrospective analyses of some of these clinical trials have uncovered some aspects of their clinical benefits that may be additional to their lipid-lowering effects. Such ‘pleiotropic’ effects of statins garnered intense interest and debate over its contribution to cardiovascular risk reduction. This review will provide a brief background of statin pleiotropy, assess the available clinical evidence for and against their non-lipid-lowering benefits, and propose future research directions in this field.

Background. The blood-brain barrier (BBB) regulates the exchange of molecules between the brain and peripheral blood and is composed primarily of microvascular endothelial cells (BMVECs), which form the lining of cerebral blood vessels and are linked via tight junctions (TJs). The BBB is regulated by components of the extracellular matrix (ECM), and matrix metalloproteinase 3 (MMP3) remodels the ECM’s basal lamina, which forms part of the BBB. Oxidative stress is implicated in activation of MMPs and impaired BBB. Thus, we investigated whether MMP3 modulates BBB permeability. Methods. Experiments included in vivo assessments of isoflurane anesthesia and dye extravasation from brain in wild-type (WT) and MMP3-deficient (MMP3-KO) mice, as well as in vitro assessments of the integrity of monolayers of WT and MMP3-KO BMVECs and the expression of junction proteins. Results. Compared to WT mice, measurements of isoflurane usage and anesthesia induction time were higher in MMP3-KO mice and lower in WT that had been treated with MMP3 (WT+MMP3), while anesthesia emergence times were shorter in MMP3-KO mice and longer in WT+MMP3 mice than in WT. Extravasation of systemically administered dyes was also lower in MMP3-KO mouse brains and higher in WT+MMP3 mouse brains, than in the brains of WT mice. The results from both TEER and Transwell assays indicated that MMP3 deficiency (or inhibition) increased, while MMP3 upregulation reduced barrier integrity in either BMVEC or the coculture. MMP3 deficiency also increased the abundance of TJs and VE-cadherin proteins in BMVECs, and the protein abundance declined when MMP3 activity was upregulated in BMVECs, but not when the cells were treated with an inhibitor of extracellular signal related-kinase (ERK). Conclusion. MMP3 increases BBB permeability following the administration of isoflurane by upregulating the ERK signaling pathway, which subsequently reduces TJ and VE-cadherin proteins in BMVECs.

Significance: Label-free quantitative phase imaging is a promising technique for the automatic detection of abnormal red blood cells (RBCs) in real time. Although deep-learning techniques can accurately detect abnormal RBCs from quantitative phase images efficiently, their applications in diagnostic testing are limited by the lack of transparency. More interpretable results such as morphological and biochemical characteristics of individual RBCs are highly desirable. Aim: An end-to-end deep-learning model was developed to efficiently discriminate thalassemic RBCs (tRBCs) from healthy RBCs (hRBCs) in quantitative phase images and segment RBCs for single-cell characterization. Approach: Two-dimensional quantitative phase images of hRBCs and tRBCs were acquired using digital holographic microscopy. A mask region-based convolutional neural network (Mask R-CNN) model was trained to discriminate tRBCs and segment individual RBCs. Characterization of tRBCs was achieved utilizing SHapley Additive exPlanation analysis and canonical correlation analysis on automatically segmented RBC phase images. Results: The implemented model achieved 97.8% accuracy in detecting tRBCs. Phase-shift statistics showed the highest influence on the correct classification of tRBCs. Associations between the phase-shift features and three-dimensional morphological features were revealed. Conclusions: The implemented Mask R-CNN model accurately identified tRBCs and segmented RBCs to provide single-RBC characterization, which has the potential to aid clinical decision-making.

Background and introduction The difference in cardiovascular disease risk between age-matched women and men narrows as transition through menopause in observational studies. Estrogen exerts complex physiological effects via its non-nuclear and nuclear actions. Experimental studies have shown that endothelial estrogen receptors mediate vasoprotection via endothelial nitric oxide production, reendothelialization, and atherosclerosis. Prior studies in vitro addressed estrogen's effects on endothelial cells and vascular smooth muscle cells, leading to vasoprotection. However, the in vivo evidences are lacking for beneficial effects of endothelium non-nuclear ERα signaling on vascular remodelling in response to injury. Purpose This study aims to clarify the impact of endothelial ERα non-nuclear signaling in the vasoprotection, using a novel mouse model lacking tissue-specific ERα non-nuclear signaling. Methods We identified the amino acids of ERα which were responsible for its binding to p85α subunit of phosphatidylinositol 3-kinase in vitro. We generated a novel mouse model in which non-nuclear signaling of ERα was ablated in endothelial cells by crossing Tie2-Cre transgenic mice with floxed ERα mutants (RR259/260AA) in which p85α and ERα interaction was disrupted. Results In endothelial cells isolated from ERαKI/KITie2 cre/+ animals, E2 failed to induce phosphorylation of Akt, confirming the absence of ERα non-nuclear signaling. Baseline characteristics at 8 to 12 weeks of age were undistinguishable between the genotypes, including body weight, systolic blood pressure, uterine weight and echocardiographic fractional shortening. We then assessed how vascular remodelling process was impacted in a carotid artery wire injury model. Histological analyses with Elastica van Gieson staining two weeks after injury revealed that estrogen dependent suppression of remodelling response (intima to medial ratio) was abolished in ERαki/kiTie2cre/+mice (P=0.0004). Masson's Trichrome staining showed that in the presence of E2 fibrosis was significantly higher in ERαki/kiTie2cre/+ mice than ERαki/kiTie2cre/− mice (P=0.0015). Conclusions We generated a novel mouse model for tissue-specific ablation of ERα non-nuclear signaling by interfering ERα-PI3K interaction. Our results demonstrate that the pivotal role for ERα non-nuclear signaling of endothelial cells in carotid arterial protection following injury with its minimal impact on baseline cardiovascular phenotype. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Japan Heart Foundation Research Grant, SENSHIN Medical Research Foundation

Background The blood–brain barrier (BBB) regulates the exchange of molecules between the brain and peripheral blood and is composed primarily of microvascular endothelial cells (BMVECs), which form the lining of cerebral blood vessels and are linked via tight junctions (TJs). The BBB is regulated by components of the extracellular matrix (ECM), and matrix metalloproteinase 3 (MMP3) remodels the basal lamina of the ECM, which forms part of the BBB. Thus, we investigated whether MMP3 modulates BBB permeability. Methods Experiments included in-vivo assessments of isoflurane anesthesia and dye extravasation from brain in wild-type (WT) and MMP3-deficient (MMP3-KO) mice, as well as in-vitro assessments of the integrity of monolayers of WT and MMP3-KO BMVECs (via measurements of transendothelial electrical resistance [TEER] and transwell assays in a co-culture of BMVECs with astrocytes and the expression of junction proteins. Results Compared to assessments in WT mice, measurements of isoflurane usage and anesthesia induction time were higher in MMP3-KO mice and lower in WT mice that had been treated with MMP3 (WT + MMP3), while anesthesia emergence times were shorter in MMP3-KO mice and longer in WT + MMP3 mice than in WT mice. Extravasation of systemically administered dyes was also lower in MMP3-KO mouse brains, and higher in WT + MMP3 mouse brains, than in the brains of WT mice, and the results from both TEER and transwell assays indicated that MMP3 deficiency (or inhibition) increased, while MMP3 upregulation reduced, barrier integrity in either BMVEC monolayers or the co-culture. MMP3 deficiency also increased the abundance of TJ and VE-cadherin proteins in BMVECs, and the protein abundance declined when MMP3 activity was upregulated in BMVECs, but not when the cells were treated with an inhibitor of extracellular signal related kinase (ERK). Conclusion MMP3 increases BBB permeability by upregulating the ERK signaling pathway, which subsequently reduces TJ and VE-cadherin proteins abundance in BMVECs. Collectively, these observations suggest that MMP3 could be therapeutically targeted to manipulate BBB permeability and treat neurological disease.