Diagnostic significance of serum angiotensin-converting enzyme activity in biochemical tests with special reference of chronic liver diseases.
To assess the degree of the differential ability of serum angiotensin-converting enzyme (ACE) activity as compared with 13 conventional biochemical tests, we studied 76 healthy subjects and 107 patients with chronic liver diseases. It was found that the mean values of serum ACE activity were significantly different between the healthy group and groups with liver disease. According to discriminant function analysis, the diagnostic accuracy reached 82.2% in 14 tests. In order to analyze the extent of contribution of each test to the entire diagnostic accuracy, we made an indicator of the relative decrease rate expressed as a percentage, which is 100-100 x (13-test diagnostic accuracy less one test/14-test diagnostic accuracy). The relative decrease rate of serum ACE activity was 11.4%, the largest in value. In conclusion, serum ACE activity may be one of the best discriminators to characterize chronic liver disease.


Erosive osteoarthritis during treatment with bevacizumab and paclitaxel in a patient with recurrent papillary serous carcinoma of the ovary.
Bevacizumab (BVC) is currently used in recurrent ovarian cancer and as part of the initial treatment for ovarian cancer. The most serious toxicities associated with BVC include gastrointestinal perforations, delayed wound healing, and hemorrhage. Arthritis had never been addressed in patients who received BVC treatment. This is the first case report of arthritis emergence linked to BVC administration. A 59-year-old female with recurrent ovarian cancer received multiple hormonal and cytotoxic regimens for 5 years and then developed erosive osteoarthritis of the hands secondary to BVC and paclitaxel. This effect was confirmed by a significant improvement in her symptoms and signs, after treatment was discontinued.


High case fatality cholera outbreak in Western Kenya, August 2010.
Cholera is a disease caused by the bacterium Vibrio cholera and has been an important public health problem since its first pandemic in 1817. Kenya has had numerous outbreaks of cholera ever since it was first detected there during 1971. In August 2010 an outbreak of cholera occurred in Kuria West District spreading to the neighboring Migori District. We conducted an investigation in order to determine the magnitude of the problem and institute control measures. In order to update the line lists we reviewed records in Migori and Kuria district hospitals and conducted active case search in the community between 30th August and 6th September 2010. Data was analyzed using Epi-Info 3.5.2. A total of 114 cases and with 10 deaths (Case Fatality Rate = 9%) were documented. The index case was an 80 years old woman from Mabera Division who had hosted a cultural marriage ceremony a day before the outbreak. The mean age of case patients was 34.5 years (Standard Deviation=23.4) with a range 5 to 80 years. Females accounted for 61.4% of cases; people aged 10-39 years accounted 46.9%, those 40-69 years accounted for 29.2% and those above 70 years accounted for 9.7% of the cases. Sixty percent of deaths occurred among patients aged 50 years and over, case fatality rate was highest in this age group (16.7%) followed by those aged 40-49 years (12.5%), 20-29 years (10%) and 10-19 years (4.8%). The outbreak was confirmed within 2 weeks of onset after one (16.7%) of the six samples taken tested positive for V. cholera (serotype Inaba). High case fatality rate and late laboratory confirmation was noted in this outbreak. There was urgent need to capacity build the districts on cholera case management, outbreak management, and equip the Migori District Hospital laboratory to allow prompt confirmation.


Crocetin inhibits the proliferation, migration and TGF-β2-induced epithelial-mesenchymal transition of retinal pigment epithelial cells.
Retinal pigment epithelial (RPE) cells, the major cell type in the fibrotic membrane of proliferative vitreoretinopathy, display enhanced proliferative and migratory capacities and epithelial-mesenchymal transition (EMT). In this study, we investigated the potential impact of crocetin on the proliferation, migration and EMT of cultured ARPE-19 cells. The cells were treated with crocetin alone or in combination with transforming growth factor-β2 (TGF-β2). Cell proliferation was examined using the CCK-8 assay. Cell cycle distribution was analyzed by flow cytometry after propidium iodide staining. The expression levels of proliferating cell nuclear antigen (PCNA), p21 and p53 were examined by Western blot analysis. Cell migration was assessed by in vitro scratch and Transwell assays. Real-time PCR, Western blotting and immunofluorescence were used to assess EMT features. Treatment of ARPE-19 cells with crocetin (50-200μM) significantly inhibited their proliferation and migration in a concentration- and time-dependent manner. Crocetin induced G1 arrest, reduced PCNA protein expression and increased the p21 and p53 accumulation in ARPE-19 cells. Crocetin inhibited TGF-β2-induced EMT in ARPE-19 cells by maintaining the expression of E-cadherin and ZO-1 and by reducing the expression of vimentin and α-SMA through the suppression of phosphorylation of p38. These results indicate that crocetin is an effective inhibitor of the proliferation, migration and TGF-β2-mediated EMT of ARPE-19 cells.


RNA viruses and the mitogenic Raf/MEK/ERK signal transduction cascade.
The Raf/MEK/ERK signal transduction cascade belongs to the mitogen-activated protein kinase (MAPK) cascades. Raf/MEK/ERK signaling leads to stimulus-specific changes in gene expression, alterations in cell metabolism or induction of programmed cell death (apoptosis), and thus controls cell differentiation and proliferation. It is induced by extracellular agents, including pathogens such as RNA viruses. Many DNA viruses are known to induce cellular signaling via this pathway. As these pathogens partly use the DNA synthesis machinery for their replication, they aim to drive cells into a proliferative state. In contrast, the consequences of RNA virus-induced Raf/MEK/ERK signaling were less clear for a long time, but since the turn of the century the number of publications on this topic has rapidly increased. Research on this virus/host-interaction will broaden our understanding of its relevance in viral replication. This important control center of cellular responses is differently employed to support the replication of several important human pathogenic RNA viruses including influenza, Ebola, hepatitis C and SARS corona viruses.


Thrombogenicity of mechanical aortic valves in an animal model: site specific testing is crucial.
We evaluated a new trileaflet prosthesis and a control bileaflet prosthesis in the mitral and aortic positions in 27 calves. The prototype trileaflet valve (TV1) functioned satisfactorily in the mitral position (TV1m, n = 7) but later yielded thrombogenic complications in the aortic position (TV1a, n = 4). The valve was redesigned (TV2) and retested in the mitral (TV2m n = 4) and aortic (TV2a, n = 5) positions, along with control valves (Cm, n = 4; Ca, n = 3). At necropsy, the valves were graded on a scale of 0 (no visible thrombi) to 4 (thrombi greater than 5 mm and/or obstructed leaflets). The TV1m, TV2m, and Cm animals, respectively, had implant durations of 215+/-112, 140+/-63, and 159+/-89 days and thrombus grades of 0.71+/-0.76, 0.33+/-0.58, and 1.50+/-0.58. The TV1a, TV2a, and Ca animals had implant durations of 18+/-12, 159+/-61, and 108+/-62 days and thrombus grades of 2.75+/-1.00, 0.50+/-0.58, and 0.67+/-0.58 (p < .005; TV2a vs. TV1a). Three TV1a calves died early of valve related complications. A design irregularity, undetected in the mitral position but revealed in the aortic position, caused a high early mortality in the TV1a animals. Redesigning the prosthesis eliminated valve related mortality and significantly reduced the thrombus grade. Because satisfactory performance in the mitral position does not guarantee safety or efficacy in the aortic position, site specific preclinical testing is crucial for mechanical heart valves.


Geo-engineering experiments in two urban ponds to control eutrophication.
Many urban ponds experience detrimental algal blooms as the result of eutrophication. During a two year field experiment, the efficacy of five in situ treatments to mitigate eutrophication effects in urban ponds was studied. The treatments targeted the sediment phosphorus release and were intended to switch the ponds from a turbid phytoplankton-dominated state to a clear-water state with a low phytoplankton biomass. Two eutrophic urban ponds were each divided into six compartments (300-400 m(2); 210-700 m(3)). In each pond the following treatments were tested: dredging in combination with biomanipulation (involving fish biomass control and the introduction of macrophytes) with and without the addition of the flocculant polyaluminiumchloride, interception and reduction of sediment phosphorus release with lanthanum-modified bentonite (Phoslock(®)) in combination with biomanipulation with and without polyaluminiumchloride; biomanipulation alone; and a control. Trial results support the hypothesis that the combination of biomanipulation and measures targeting the sediment phosphorus release can be effective in reducing the phytoplankton biomass and establishing and maintaining a clear-water state, provided the external phosphorus loading is limited. During the experimental period dredging combined with biomanipulation showed mean chlorophyll-a concentrations of 5.3 and 6.2 μg L(-1), compared to 268.9 and 52.4 μg L(-1) in the control compartments. Lanthanum-modified bentonite can be an effective alternative to dredging and in combination with biomanipulation it showed mean chlorophyll-a concentrations of 5.9 and 7.6 μg L(-1). Biomanipulation alone did not establish a clear-water state or only during a limited period. As the two experimental sites differed in their reaction to the treatments, it is important to choose the most promising treatment depending on site specific characteristics. In recovering the water quality status of urban ponds, continuing attention is required to the concurrent reduction of external phosphorus loading and to maintaining an appropriate fish community.


Spatio-Temporal Differences in Dystrophin Dynamics at mRNA and Protein Levels Revealed by a Novel FlipTrap Line.
Dystrophin (Dmd) is a structural protein that links the extracellular matrix to actin filaments in muscle fibers and is required for the maintenance of muscles integrity. Mutations in Dmd lead to muscular dystrophies in humans and other vertebrates. Here, we report the characterization of a zebrafish gene trap line that fluorescently labels the endogenous Dmd protein (Dmd-citrine, Gt(dmd-citrine) ct90a). We show that the Dmd-citrine line recapitulates endogenous dmd transcript expression and Dmd protein localization. Using this Dmd-citrine line, we follow Dmd localization to the myosepta in real-time using time-lapse microscopy, and find that the accumulation of Dmd protein at the transverse myosepta coincides with the onset of myotome formation, a critical stage in muscle maturation. We observed that Dmd protein localizes specifically to the myosepta prior to dmd mRNA localization. Additionally, we demonstrate that the Dmd-citrine line can be used to assess muscular dystrophy following both genetic and physical disruptions of the muscle.


Bile acids induce eosinophil degranulation by two different mechanisms.
Eosinophil infiltration and activation occur in the vicinity of the bile ducts in immune cholangiopathies. When cholangiocytes are injured, bile acids may cross the damaged biliary epithelia and affect periductal immune cells. Although immunomodulatory actions of bile acids have been well explored, their effects on eosinophils have never been examined. In this study, we tested the hypothesis that bile acids directly activate eosinophils and induce their effector functions. We found that a hydrophobic bile acid, taurine-con- jugated chenodeoxycholic acid (TCDCA), induces eosinophil degranulation in vitro via 2 different mechanisms depending on its concentration. Degranulation induced by 100 to 500 micromol/L TCDCA was an active and regulated release because it was completely abolished by a tyrosine kinase inhibitor (genistein), by a microfilament inhibitor (cytochalasin B), and by incubation at 4 degrees C. Furthermore, eosinophils stimulated with 10 to 250 micromol/L TCDCA vigorously produced superoxide and interleukin-8 (IL-8). In contrast, at higher concentrations (e.g., > or = 1,000 micromol/L), TCDCA induced granule protein release without concomitant superoxide production and IL-8 production. Further genistein and cytochalasin B failed to inhibit eosinophil degranulation induced by 2,500 micromol/L TCDCA, suggesting that TCDCA at this concentration induced passive degranulation via cytolysis. The analyses of cell morphology and functional viability also supported the presence of 2 mechanisms for TCDCA-induced eosinophil degranulation. Taurine-conjugated ursodeoxycholic acid, a hydrophilic bile acid, similarly activated human eosinophils at relatively low concentrations, although the potency was always lower compared with that of TCDCA. In conclusion, we have shown that bile acids are capable of directly activating eosinophils.


Diagnosis and Outcome of Biopsies of Indeterminate Lesions of the Cavernous Sinus and Meckel's Cave: A Retrospective Case Series in 85 Patients.
When clinical presentation, laboratory studies, or imaging cannot diagnose cavernous sinus (CS) and/or Meckel's cave (MC) lesions, biopsy may be necessary. To review our institutional series of biopsies of indeterminate CS and MC lesions. Records from January 1994 to June 2016 were searched for biopsied indeterminate CS and MC lesions. We defined indeterminate as having an atypical imaging appearance or a broad differential and the need for tissue for definitive diagnosis. We defined primary tumors as originating from cells inherent or near the CS and MC. Eighty-five patients were included (median age 59 [2-85] yr); 22 (28%) had a cancer history. Approaches included frontotemporal craniotomy (n = 48, 56%), endoscopic endonasal (n = 20, 24%), percutaneous transforamen ovale (n = 12, 14%), or retrosigmoid craniotomy (n = 5, 6%). Final diagnosis was metastatic in 27 (32%), primary in 21 (25%), inflammatory in 13 (15%), hematologic in 11 (13%), fungal in 5 (5%), and nondefinitive or nondiagnostic in 8 (10%) patients. Thirteen (59%) patients with a cancer history (n = 22) had a diagnosis consistent with their prior cancer; the remaining had a second pathology (n = 6, 27%) or nondiagnostic biopsy (n = 3, 14%). Two patients had surgical complications resulting in death. In this patient cohort, metastatic tumors were the most likely pathology. The biopsy threshold should be lower in patients with a cancer history if clinical or radiographic diagnosis is uncertain as 27% had a second disease. However, we consider biopsy as a last resort because the risk of major morbidity/mortality, while low, is not zero.


Assessment of quality of cancer-related follow-up care from the cancer survivor's perspective.
We assessed cancer survivors' perceptions of the quality of their follow-up care. We surveyed a population-based cohort of leukemia, bladder, and colorectal cancer survivors diagnosed 2 to 5 years previously in northern California (N = 623; participation rate, 69.2%; overall response rate, 49.2%). Data were collected between April 2003 and November 2004. Ten scales assessed survivors' perceptions of different aspects of care in the last 12 months, and an eleventh scale measured their overall ratings of care. On nine of the 11 scales, mean scores ranged from 88 to 97 on a 0 to 100 response format, indicating very positive experiences. The two areas where quality perceptions were lower were discussions about health promotion and the physician's knowledge of the whole patient. In adjusted analyses, those without private health insurance (P = .02) and Hispanic and Asian survivors compared with whites (P < .001) reported worse timeliness of care. Survivors who had multiple comorbidities reported better scores on timeliness of care (P < .01) and physicians' knowledge (P = .05) than survivors without any comorbidity. Length of the patient-physician relationship was the variable most consistently found to be significantly associated with survivors' quality assessments. Physicians' information exchange had the strongest relationship with overall ratings of care, followed by physicians' affective behavior, their knowledge of the survivor, and survivors' perceptions of coordination of care (P < .001 for all). Delivery of quality follow-up care to cancer survivors may require efforts to improve patient-centered communication and coordination. Special emphasis may need to be placed on health promotion discussions and adoption of a whole-person orientation.


Expression profiles of nestin and synemin in reactive astrocytes and Müller cells following retinal injury: a comparison with glial fibrillar acidic protein and vimentin.
To examine the expression patterns of the intermediate filament (IF) proteins nestin and synemin following retinal injury. Wide-scale retinal injuries were created by experimental retinal detachment of 1, 3, 7, or 30 days' duration. Injuries were induced in the right eyes of Long Evans rats, while the left eyes served as internal controls. Vibratome sections of control and injured retinas were labeled with fluorescent probes using a combination of anti-glial fibrillary acidic protein, -vimentin, -nestin, -synemin, -bromodeoxyuridine, and the lectin probe, isolectin B4. Additionally, antibody specificity, as well as protein and mRNA levels of nestin and synemin were determined and quantified using standard western blotting and real time polymerase chain reaction (RT-PCR) techniques. Immunocytochemistry showed increased Müller cell labeling at 1, 3, and 7 days post injury for all four IFs, although the relative levels of nestin expression varied dramatically between individual Müller cells. Nestin was consistently observed in the foremost processes of those Müller cells that grew into the subretinal space, forming glial scars. Elevated levels of nestin expression were also observed in bromodeoxyuridine-labeled Müller cells following retinal insult. Quantitative polymerase chain reaction (qPCR) showed a twofold increase in nestin mRNA 1 day after injury, a level maintained at 3 and 7 days. Western blotting using anti-nestin showed a single band at 220 kDa and the intensity of this band increased following injury. Anti-synemin labeling of control retinas revealed faint labeling of astrocytes; this increased after injury, demonstrating an association with blood vessels. Additionally, there was an upregulation of synemin in Müller cells. qPCR and western blotting with anti-synemin showed a continuous increase in both gene and protein expression over time. Retinal injury induces an upregulation of a complement of four intermediate filament proteins, including synemin and nestin, in Müller cells. The latter provides suggestive support for the concept that these cells may revert to a more developmentally immature state, since these two IF proteins are developmentally regulated and expressed, and thus may serve as cell cycle reentry markers. Nestin and its differential expression patterns with glial fibrillary acidic protein and vimentin networks, as well as its association with proliferating Müller cells and those extending into the subretinal space, suggest a significant role of this protein in glial scar formation and perhaps gliogenesis. Synemin immunopositive astrocytes demonstrate a close relationship to the retinal vasculature, and illustrate a remarkable ability to reorganize their morphology in response to injury. Further examination of the changes in the cytoskeletal signatures of both of these glial cell types may lead to a more comprehensive understanding of mechanisms underway following retinal and other central nervous system injuries.


[Oral tolerance in the treatment of rheumatoid arthritis and other autoimmune diseases].
Oral administration of antigen has been recognized as a form of inducing antigen-specific unresponsiveness. Studies in animal models of autoimmune diseases have shown the effectiveness of such an approach. Recently, three clinical trials have suggested that oral tolerance can be useful in human disease. In this review, we address the mechanisms underlying this system and the role of oral tolerance in the treatment of human autoimmune disease.


Bilateral putaminal necrosis associated with the mitochondrial DNA A8344G myoclonus epilepsy with ragged red fibers (MERRF) mutation: an infantile case.
Myoclonus epilepsy with ragged red fibers (MERRF) is one of the major mitochondrial encephalomyopathies. Its main clinical features are myoclonus epilepsy, ataxia, and myopathy with ragged red fibers. Whereas there is a close correlation between MERRF syndrome and the A8344G mutation of mitochondrial DNA, the reverse is not true. In fact, this mutation is also responsible for various other syndromes, such as Leigh syndrome, spinocerebellar degeneration, atypical Charcot-Marie-Tooth disease, and multiple truncal lipomas. We describe a child with the A8344G mutation of mitochondrial DNA and an unusual clinical, neuroradiologic, and biochemical phenotype, characterized by early-onset, nonprogressive cerebellar ataxia, and subclinical myoclonias in association with bilateral putaminal necrosis on magnetic resonance imaging and a reduction in complex V activity. Our case confirms the existence of a relationship between alteration in adenosine triphosphatase activity and basal ganglia involvement. We recommend that the possibility of a mitochondrial pathology should always be taken into consideration in the presence of bilateral symmetric lesions of the basal ganglia, even when the typical clinical picture is lacking. (J Child Neurol 2006;21:79-82).


Regulating artificial-intelligence applications to achieve the sustainable development goals.
Artificial intelligence is producing a revolution with increasing impacts on the people, planet, and prosperity. This perspective illustrates some of the AI applications that can accelerate the achievement of the United Nations Sustainable Development Goals (SDGs) and highlights some of the considerations that could hinder the efforts towards them. In this context, we strongly support the development of an 18thSDG on digital technologies. This emphasizes the importance of establishing standard AI guidelines and regulations for the beneficial applications of AI. Such regulations should focus on concrete applications of AI, rather than generally on AI technology, to facilitate both AI development and enforceability of legal implications.


Structure Activity Relationship Studies around DB18, a Potent and Selective Inhibitor of CLK Kinases.
Three series of our lead CLK1 inhibitor DB18 have been designed, synthetized and tested against CLKs and DYRK1A kinases. Their cytotoxicity was subsequently measured on seven representative cancer cell lines. Guided by docking experiments, we focused on the less constrained part of the scaffold, and showed that drastically different substituents can be tolerated here. This work ended with the discovery of another promising derivative 12g, with IC50 = 0.004 µM in the inhibition of HsCLK1 and IC50 = 3.94 µM for the inhibition of HsDYRK1A. The SAR results are discussed in the light of extensive molecular modeling analyses. Finally, a kinome scan (463 human kinases) confirmed the outstanding selectivity of our lead compound DB18, suggesting that this scaffold is of prominent interest for selective CLK inhibitors. Altogether, these results pave the way for the development of inhibitors with novel selectivities in this family of kinases.


A multiplicative reinforcement learning model capturing learning dynamics and interindividual variability in mice.
Both in humans and in animals, different individuals may learn the same task with strikingly different speeds; however, the sources of this variability remain elusive. In standard learning models, interindividual variability is often explained by variations of the learning rate, a parameter indicating how much synapses are updated on each learning event. Here, we theoretically show that the initial connectivity between the neurons involved in learning a task is also a strong determinant of how quickly the task is learned, provided that connections are updated in a multiplicative manner. To experimentally test this idea, we trained mice to perform an auditory Go/NoGo discrimination task followed by a reversal to compare learning speed when starting from naive or already trained synaptic connections. All mice learned the initial task, but often displayed sigmoid-like learning curves, with a variable delay period followed by a steep increase in performance, as often observed in operant conditioning. For all mice, learning was much faster in the subsequent reversal training. An accurate fit of all learning curves could be obtained with a reinforcement learning model endowed with a multiplicative learning rule, but not with an additive rule. Surprisingly, the multiplicative model could explain a large fraction of the interindividual variability by variations in the initial synaptic weights. Altogether, these results demonstrate the power of multiplicative learning rules to account for the full dynamics of biological learning and suggest an important role of initial wiring in the brain for predispositions to different tasks.


Tarsal degenerative joint disease in cattle: blood and synovial fluid changes.
Tarsal degenerative joint disease (DJD) in 27 cattle was classified as primary or secondary based on age, joint conformation defects, faulty hindlimb alignment, or history of trauma to the affected joint(s). Results of blood and synovial fluid analysis for cattle affected with primary or secondary tarsal DJD were grouped in compilation of data. Cattle with tarsal DJD had significantly (P smaller than 0.01) reduced hemoglobin (Hb) content in comparison to that in control cattle. There was highly significant (P smaller than 0.001) reduction in packed cell volume (PCV). A significant difference was not determined for mean corpuscular hemoglobin concentration (MCHC) values of the 2 groups of cattle. Total white blood cell (WBC) counts closely paralleled each other, although mean proportion of neutrophils was significantly (P smaller than 0.05) greater in cattle affected with tarsal DJD, as were mean proportion of lymphocytes (P smaller than 0.02). Synovial fluid samples were analyzed for physical, biochemical, and cytologic properties. Statistical comparisons were made between values determined for arthritic cattle and control cattle. All samples from cattle with tarsal DJD were transudative. Opacity and flocculation were attributed to the presence of cartilaginous fragments and fibrils. There was significant correlation between increased relative viscosity (RV) and higher grades of mucinous precipitate quality (MPQ; r = +0.294, P smaller than 0.05) for all cattle. Mean alkaline phosphatase (ALP) activity for arthritic cattle was significantly (P smaller than 0.001) reduced, as was the mean activity for lactic dehydrogenase (LDH; P smaller than 0.05). The mean aldolase (ALD) activity for arthritic cattle was increased, whereas mean activity values for glutamic oxalacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT) were reduced. Samples from arthritic cattle had reduced total leukocyte counts and significantly (P smaller than 0.05) increased proportion of macrophages in comparison to the values in control cattle.


Investigating implementation of school health policies through a health equity lens: A measures development study protocol.
School-based policies that ensure provision of nutrition, physical activity, and other health-promoting resources and opportunities are essential in mitigating health disparities among underserved populations. Measuring the implementation of such policies is imperative to bridge the gap between policy and practice. Unfortunately, limited practical, psychometrically strong measures of school policy implementation exist. Few available explicitly focus on the issues of equity and social justice as a key component of implementation, which may result in underassessment of the equity implications of policy implementation. The purpose of this study is to develop equity-focused measures in collaboration with practitioners, researchers, and other key implementation partners that will facilitate evaluation of policy implementation determinants (i.e., barriers and facilitators), processes, and outcomes. We will actively seek engagement from practitioners, researchers, and advocacy partners (i.e., stakeholders) who have expertise in school health policy throughout each phase of this project. We propose a multi-phase, 1-year project comprising the following steps: (1) selection of relevant constructs from guiding frameworks related to health equity and implementation science; (2) initial measure development, including expert feedback on draft items; (3) pilot cognitive testing with representatives from key target populations (i.e., school administrators, teachers, food service staff, and students and parents/guardians); and (4) measure refinement based on testing and assessment of pragmatic properties. These steps will allow us to establish initial face and content validity of a set of instruments that can undergo psychometric testing in future studies to assess their reliability and validity. Completion of this project will result in several school policy implementation measurement tools which can be readily used by practitioners and researchers to evaluate policy implementation through a health equity lens. This will provide opportunities for better assessment and accountability of policies that aim to advance health equity among school-aged children and their families. Open Science Framework Registration doi: 10.17605/OSF.IO/736ZU.


[Structural organization of nephrons in the kideny and proximal reabsorption in representatives of different vertebrate classes (according to microdissection and micropuncture studies)].
By microdissection method, single nephrons have been isolated from the river lamprey Lampetra fluviatilis, teleost fish Myoxocephalus scorpius (White sea), frog Rana temporaria, lizard Agama caucasica, hen Gallus domesticus and albino rat Rattus norvegicus (Wistar strain). Tubular reabsorptive capacity was measured in kidneys of lampreys and rats by the split oil droplet method. In the animals studied, each of the nephrons consists of the glomerulus, proximal, thin and distal segments. Relative length of the proximal segment does not depend on phylogenetic position of a species. Transtubular isotonic water reabsorption from the proximal tubule in rats is significantly higher than in lampreys. The level of proximal reabsorption is not related to the length of the proximal tubule in the Verterbrates studied but depends on the intensity of tubular transport. The structure which is similar to Henle's loop is present already in Cyclostomes [12]. Further stage of the progressive development of the uriniferous tubules is presented by uneven localization of nephron populations within the kideney in Reptiles. These data suggest that the effective system of osmotic concentration appeared in evolution not as the result of Henle's loop formation, but on the basis of the development of the medullar substance formed mainly by intercortical and juxtamedullar nephron populations.


Elastography in prostate gland imaging and prostate cancer detection.
Transrectal prostate biopsies under ultrasonography guidance remain the gold standard for the detection of prostate cancer (PCa). Transrectal ultrasonography (TRUS), however, has a limited sensitivity in PCa detection. Prostate elastography (TRES) increases the sensitivity of a TRUS examination. Therefore, the aim of this review is to discuss the usefulness of TRES in prostate gland imaging for the diagnosis and management of prostate cancer based on published literature. The advantages of transrectal elastography were analysed in the context of better diagnostic performance provided by this method. TRES provides additional information for the detection and biopsy guidance concerning prostate cancer, enabling a significant reduction in the number of biopsies.


Central sympathoinhibitory action of ketanserin in rats.
The effect of ketanserin on sympathetic efferent nerve activity which was recorded from the postganglionic renal nerve, inferior cardiac nerve and preganglionic adrenal nerve was studied in buffer nerve-intact rats. Intravenous administration of ketanserin (0.05-5.0 mg/kg) produced bradycardia and a reduction of mean arterial pressure dose-dependently. Renal nerve activity and inferior cardiac nerve activity also were reduced by ketanserin. After i.v. administration, baroreceptor afferent nerve activity did not increase, but actually decrease. Moreover, i.v. and i.c.v. administration of ketanserin caused a decrease in preganglionic adrenal nerve activity accompanied with hypotension and bradycardia. Ketanserin (0.5 mg/kg i.v.) and clonidine (3 micrograms/kg i.v.) produced equihypotension and bradycardia. On the other hand, the ketanserin-induced reduction of renal nerve activity was milder than that induced by clonidine. The present findings confirmed that ketanserin has a central sympathoinhibitory action. This central action of ketanserin may play an important role in ketanserin-induced bradycardia and may be partially responsible for ketanserin-induced hypotension.


The offspring of gestational diabetes.
Gestational diabetes mellitus (GDM) usually develops in the second half of pregnancy and, in order to address the impact of GDM on the conceptus, several issues must be raised: what are the immediate implications for the fetus and the neonate and why do they happen? What are the consequences for the offspring? What can be done? In a theoretical model the whole pathogenesis and spectrum of fetal and neonatal mortality and morbidity could primarily be attributed to the excessive transferal of glucose from mother of fetus, inducing fetal hyperglycemia, leading to fetal pancreatic islet hypertrophy and beta-cell hyperplasia with a consequent rise in insulin secretion. However, besides, and in addition to glucose, it is quite possible that other metabolic fuels, from amino acids to lipids, may also cross the placenta further contributing to the adverse intrauterine environment. Depending upon the time of gestation during critical developmental stages, the same metabolic fuels would have different effects upon the fetus, the neonate and quite possibly, upon the long-term outcome from neurological and psychosocial impairment to the adult development of metabolic and cardiovascular disorders. Based on clinical and experimental evidence that poor maternal homeostasis is at the core of the problem, it is of paramount importance to identify women at risk of GDM and to keep a tight metabolic control in order to avoid immediate and long-term consequences for their offspring.


Effect of Shaft Diameter on the Hydrodynamic Torque of Butterfly Valve Disk.
In this study, computational fluid dynamics (cfd) software and detached eddy simulation turbulence model were used to simulate butterfly valves with different designs. The effects of shaft diameters on the value and the fluctuation of valve disk torque were studied, and the physical reason was discussed. The simulation results were verified by comparing with the experimental data. The findings revealed that with the closing of the valve, the hydraulic torque of the valve disk first increases and then decreases. Meanwhile, the torque decreases gradually with the increase of the shaft diameter. The variation of torque is caused by the change of pressure on both sides of the valve disk. The result also indicates that the fluctuation of torque is induced by the flow separation phenomenon occurs on the valve disk. The fluctuation is significant for the valve opening from 20% to 60%. The strength of the torque fluctuation is greater for the smaller shaft diameter. This study provides a theoretical basis for the design and optimization of butterfly valves.


An immunoconjugate of anti-CD24 and Pseudomonas exotoxin selectively kills human colorectal tumors in mice.
Effective and selective treatment options are needed for patients with colorectal cancer (CRC). The CD24 mucin-like glycoprotein is overexpressed in CRCs; monoclonal antibodies (mAbs) against CD24 inhibit tumor cell growth in vitro and in vivo. Based on the tumor-specific expression of CD24, we investigated the potential of anti-CD24 SWA11 mAb, to deliver a cytotoxic agent into CRC cells. We conjugated SWA11 to a Pseudomonas exotoxin derivative (PE38) via an Fc-binding ZZ domain from Staphylococcal protein A (which binds the Fc domain of mouse IgG2a immunoglobulins) to generate the immunotoxin SWA11-ZZ-PE38; IgG-ZZ-PE38 was used as control. Human HT-29 and COLO320 (CD24-positive) and HCT116 (CD24-negative) CRC cell lines were assayed for immunotoxin binding, cytotoxicity, viability, and apoptosis. Toxicity and antitumor efficacy were tested in mice. The immunotoxin preserved the affinity and specificity of SWA11, bound and selectively killed CD24-expressing CRC cells via apoptosis. IC(50) values ranged from 20 to 50 ng/mL-several orders of magnitude lower than that of the mAb alone. The immunotoxins were not toxic to mice at the maximum dose of 0.75 mg/kg. Growth of HT-29 xenograft tumors was significantly reduced in mice given SWA11-ZZ-PE38 (by 78%) compared to untreated mice. Anti-CD24 SWA11 mAb can deliver a PE exotoxin derivative to CRC cells and cause them to undergo apoptosis, without toxicity to normal tissues. This immunotoxin might be developed as a therapeutic treatment for patients with CRC.


Glomerular expression of endothelial nitric oxide synthase in deoxycorticosterone acetate-salt-treated rats.
1. In the present study, we investigated the relationship between chronic volume loading and glomerular endothelial nitric oxide synthase (eNOS) expression. Immunohistochemical expression of eNOS in glomeruli was semiquantified by graded scores of staining intensity. Each glomerulus was isolated by microdissection and mRNA expression was detected by reverse transcription-polymerase chain reaction (RT-PCR) in desoxycorticosterone acetate (DOCA)-salt-treated rats. 2. Glomerular expansion and dilatation of tubules were the main histological findings and glomerular and vascular injury scores were significantly higher in the DOCA-salt-treated group than in the control group. Endothelial NOS staining in glomeruli in DOCA-salt-treated animals was 81.4% lower than in control animals. Endothelial NOS mRNA was also detected at a very low rate in the kidney of treated rats compared with control rats (22/80 vs 74/80 glomeruli, respectively). 3. These results suggest that eNOS protein and mRNA expression in glomeruli was reduced by DOCA-salt loading. Chronic volume loading may damage the glomerulus and this may be mediated, at least in part, by disruption of eNOS.


Fluoxetine and thioridazine inhibit efflux and attenuate crystalline biofilm formation by Proteus mirabilis.
Proteus mirabilis forms extensive crystalline biofilms on indwelling urethral catheters that block urine flow and lead to serious clinical complications. The Bcr/CflA efflux system has previously been identified as important for development of P. mirabilis crystalline biofilms, highlighting the potential for efflux pump inhibitors (EPIs) to control catheter blockage. Here we evaluate the potential for drugs already used in human medicine (fluoxetine and thioridazine) to act as EPIs in P. mirabilis, and control crystalline biofilm formation. Both fluoxetine and thioridazine inhibited efflux in P. mirabilis, and molecular modelling predicted both drugs interact strongly with the biofilm-associated Bcr/CflA efflux system. Both EPIs were also found to significantly reduce the rate of P. mirabilis crystalline biofilm formation on catheters, and increase the time taken for catheters to block. Swimming and swarming motilies in P. mirabilis were also significantly reduced by both EPIs. The impact of these drugs on catheter biofilm formation by other uropathogens (Escherichia coli, Pseudomonas aeruginosa) was also explored, and thioridazine was shown to also inhibit biofilm formation in these species. Therefore, repurposing of existing drugs with EPI activity could be a promising approach to control catheter blockage, or biofilm formation on other medical devices.


A pilot project of residual-insecticide spraying to control malaria transmitted by the Anopheles punctulatus group in Netherlands New Guinea.
The authors report on preliminary observations carried out in three experimental houses in Netherlands New Guinea, the object of which was to determine whether residual spraying with insecticides might be expected to give good results in the control of malaria transmitted by mosquitos of the Anopheles punctulatus group and by A. karwari. One house was sprayed with DDT, another with dieldrin, and the third was left unsprayed. From the kills recorded of mosquitos entering these houses at night it is apparent that good results can be anticipated with both insecticides, although dieldrin is the more effective.Observations made at the same time on the behaviour of these mosquitos indicate that they have greater contact with the inside walls of houses than was previously thought.


MINI-INVASIVE TREATMENT METHODS OF SPIDER VEINS: SCLEROTHERAPY AND RADIOFREQUENCY THERMOCOAGULATION.
The aim: This study was conducted to compare the results of spider vein: sclerotherapy or radiofrequency thermocoagulation. Materials and methods: The study included 52 patients with spider veins, who were randomized into two treatment groups: sclerotherapy or radiofrequency thermocoagulation. Treatment outcomes were assessed using: a self-assessed questionnaire, CIVIQ 20 questionnaire, computer evaluation of images, registration relapses complications, negative manifestations, and intensity of the pain syndrome. Results: Both methods showed a statistically significant difference in the quality of life indicators before and one month after treatment (p<0.001 for both groups). Radiofrequency thermocoagulation showed a greater impact on the patient's quality of life (p = 0.003). The average length of spider veins in the treatment area decreased the most with radiofrequency thermocoagulation (by 92.1%), slightly less after sclerotherapy (by 73.4%) (p < 0,01). Conclusions: Both treatments have shown good results for spider veins and were reasonably safe with few negative manifestations. Radiofrequency coagulation better eliminates small veins, less than 0.3 mm.


Scaffold structure and fabrication method affect proinflammatory milieu in three-dimensional-cultured chondrocytes.
Cartilage tissue engineering has emerged as an attractive therapeutic option for repairing damaged cartilage tissue in the arthritic joint. High levels of proinflammatory cytokines present at arthritic joints can cause cartilage destruction and instability of the engineered cartilage tissue, and thus it is critical to engineer strong and stable cartilage that is resistant to the inflammatory environment. In this study, we demonstrate that scaffolding materials with different pore sizes and fabrication methods influence the microenvironment of chondrocytes and the response of these cells to proinflammatory cytokines, interleukin-1beta, and tumor necrosis factor alpha. Silk scaffolds prepared using the organic solvent hexafluoroisopropanol as compared to an aqueous-based method, as well as those with larger pore sizes, supported the deposition of higher cartilage matrix levels and lower expression of cartilage matrix degradation-related genes, as well as lower expression of endogenous proinflammatory cytokines IL-1β in articular chondrocytes. These biochemical properties could be related to the physical properties of the scaffolds such as the water uptake and the tendency to leach or adsorb proinflammatory cytokines. Thus, scaffold structure may influence the behavior of chondrocytes by influencing the microenvironment under inflammatory conditions, and should be considered as an important component for bioengineering stable cartilage tissues.


Ketogenic propensity is differentially related to lipid-induced hepatic and peripheral insulin resistance.
Determine the ketogenic response (β-hydroxybutyrate, a surrogate of hepatic ketogenesis) to a controlled lipid overload in humans. In total, nineteen young, healthy adults (age: 28.4 ± 1.7 years; BMI: 22.7 ± 0.3 kg/m2 ) received either a 12 h overnight lipid infusion or saline in a randomized, crossover design. Plasma ketones and inflammatory markers were quantified by colorimetric and multiplex assays. Hepatic and peripheral insulin sensitivity was assessed by the hyperinsulinemic-euglycemic clamp. Skeletal muscle biopsies were obtained to quantify gene expression related to ketone body metabolism and inflammation. By design, the lipid overload-induced hepatic (50%, p < 0.001) and peripheral insulin resistance (73%, p < 0.01) in healthy adults. Ketones increased with hyperlipidemia and were subsequently reduced with hyperinsulinemia during the clamp procedure (Saline: Basal = 0.22 mM, Insulin = 0.07 mM; Lipid: Basal = 0.78 mM, Insulin = 0.51 mM; 2-way ANOVA: Lipid p < 0.001, Insulin p < 0.001, Interaction p = 0.07). In the saline control condition, ketones did not correlate with hepatic or peripheral insulin sensitivity. Conversely, in the lipid condition, ketones were positively correlated with hepatic insulin sensitivity (r = 0.59, p < 0.01), but inversely related to peripheral insulin sensitivity (r = -0.64, p < 0.01). Hyperlipidemia increased plasma inflammatory markers, but did not impact skeletal muscle inflammatory gene expression. Gene expression related to ketone and fatty acid metabolism in skeletal muscle increased in response to hyperlipidemia. This work provides important insight into the role of ketones in human health and suggests that ketone body metabolism is altered at the onset of lipid-induced insulin resistance.


UV-B radiation induced exchange of the D1 reaction centre subunits produced from the psbA2 and psbA3 genes in the Cyanobacterium synechocystis sp. PCC 6803.
UV-B irradiation of Synechocystis 6803 cells inhibits photosystem II activity, which can be restored via de novo synthesis of the D1 (and D2) reaction center subunits. Recently we have shown that of the two psbA genes that encode identical D1 proteins in Synechocystis 6803, UV-B preferentially enhances the transcription of psbA3 compared to that of psbA2 [Máté, Z., Sass, L., Szekeres, M., Vass, I. and Nagy, F. (1998) J. Biol. Chem. 273, 17439-17444]. Here we studied the effect of UV-B on the synthesis of the D1 protein from the psbA2 and psbA3 genes in the P7 mutant of Synechocystis 6803. In this mutant, psbA2 carries the Ala251-->Val point mutation, which confers resistance to the photosystem II electron transport inhibitor metribuzin, but psbA3 is the same as in the wild-type. By applying variable chlorophyll fluorescence measurements to distinguish between metribuzin-sensitive and metribuzin-resistant photosystem II centers we quantified the amount of the D1 protein produced from each of the psbA3 and psbA2 genes. When the cells were exposed to UV-B light, the fraction of D1 protein produced from the psbA3 gene was increased from 15-20 to 32-40% of the total D1. This effect was reversible by transferring the cells to visible light. The rate of D1 production from psbA3 increased with increasing UV-B intensities, and was a transient phenomenon at low UV-B levels (0.1 microE x m-2 x s-1). It is concluded that the enhancement of psbA3 gene transcription by UV-B light leads to enhanced D1 protein synthesis from this gene. Our findings demonstrate that the main role of psbA3 transcription activated by UV-B is to increase the size of the psbA mRNA pool available for translation when a rapid repair of the D1 protein is needed under UV-B stress.


Regulatory Dynamics of Cell Differentiation Revealed by True Time Series From Multinucleate Single Cells.
Dynamics of cell fate decisions are commonly investigated by inferring temporal sequences of gene expression states by assembling snapshots of individual cells where each cell is measured once. Ordering cells according to minimal differences in expression patterns and assuming that differentiation occurs by a sequence of irreversible steps, yields unidirectional, eventually branching Markov chains with a single source node. In an alternative approach, we used multi-nucleate cells to follow gene expression taking true time series. Assembling state machines, each made from single-cell trajectories, gives a network of highly structured Markov chains of states with different source and sink nodes including cycles, revealing essential information on the dynamics of regulatory events. We argue that the obtained networks depict aspects of the Waddington landscape of cell differentiation and characterize them as reachability graphs that provide the basis for the reconstruction of the underlying gene regulatory network.


Neck kinematics in rear-end impacts.
The purpose of this study was to document the kinematics of the neck during low-speed rear-end impacts. In a series of experiments reported by Deng et al (2000), a pneumatically driven mini-sled was used to study cervical spine motion using six cadavers instrumented with metallic markers at each cervical level, a 9-accelerometer mount on the head, and a tri-axial accelerometers on the thorax. A 250-Hz x-ray system was used to record marker motion while acceleration data were digitized at 10,000 Hz. Results show that, in the global coordinate system, the head and all cervical vertebrae were primarily in extension during the entire period of x-ray data collection. In local coordinate systems, upper cervical segments were initially in relative flexion while lower segments were in extension. Facet joint capsular stretch ranged from 17 to 97%. In the vertical direction, the head and T1 accelerated upward almost instantaneously after impact initiation while there was delay for the head in the horizontal direction. This combination was the result of a force vector which was pointed in the forward and upward direction to generate an extension moment. Upward ramping of the torso was larger in tests with a 20-deg seatback angle. The study concluded that the kinematics of the neck is rather complicated and greatly influenced by the large rotations of the thoracic spine. Significant posterior shear deformation was found, as evidenced by the large facet capsular stretch. Although the neck forms a "mild" S-shaped curve during whiplash, using its shape as an injury mechanism can be misleading because the source of pain is likely to be located in the facet capsules.


Multifocality and multicentricity in breast cancer and survival outcomes.
The clinicopathological characteristics and the prognostic significance of multifocal (MF) and multicentric (MC) breast cancers are not well established. MF and MC were defined as more than one lesion in the same quadrant or in separate quadrants, respectively. The Kaplan-Meier product limit was used to calculate recurrence-free survival (RFS), breast cancer-specific survival (BCSS), and overall survival (OS). Cox proportional hazards models were fit to determine independent associations of MF/MC disease with survival outcomes. Of 3924 patients, 942 (24%) had MF (n = 695) or MC (n = 247) disease. MF/MC disease was associated with higher T stages (T2: 26% versus 21.6%; T3: 7.4% versus 2.3%, P < 0.001), grade 3 disease (44% versus 38.2%, P < 0.001), lymphovascular invasion (26.2% versus 19.3%, P < 0.001), and lymph node metastases (43.1% versus 27.3%, P < 0.001). MC, but not MF, breast cancers were associated with a worse 5-year RFS (90% versus 95%, P = 0.02) and BCSS (95% versus 97%, P = 0.01). Multivariate analysis shows that MF or MC did not have an independent impact on RFS, BCSS, or OS. MF/MC breast cancers were associated with poor prognostic factors, but were not independent predictors of worse survival outcomes. Our findings support the current TNM staging system of using the diameter of the largest lesion to assign T stage.


Binuclear platinum-iridium complexes: synthesis, reactivity and luminescence.
The chemistry of the heterobinuclear platinum-iridium complex [PtIr(CO)3(μ-dppm)2][PF6], 1, dppm = Ph2PCH2PPh2, is described. The reaction of a hydride with 1 gave [HPtIr(CO)2(μ-dppm)2], by displacement of the carbonyl ligand from platinum, while reaction of 1 with dihydrogen, hydrogen chloride or Ph2MeSiH gave the fluxional complex [PtIrH4(CO)(μ-dppm)2][PF6], [PtIrH2Cl2(CO)(μ-dppm)2][PF6], or [PtIrH(SiMePh2)(CO)2(μ-dppm)2][PF6], respectively, by oxidative addition at iridium. Complex 1 reacted, often regioselectively, with several alkynes to give the μ-η(1),η(1) bridging alkyne complexes [PtIr(μ-RCCR')(CO)2(μ-dppm)2][PF6], R = H, R' = Ph, 4-C6H4Me, CO2Me; R = Ph, R' = CO2Me; R = R' = CO2Me. The complex [PtIr(μ-HCC-4-C6H4Me)(CO)2(μ-dppm)2][PF6] reacted reversibly with CO to give [PtIr(μ-HCC-4-C6H4Me)(CO)3(μ-dppm)2][PF6] and [PtIr(CO)3(μ-dppm)2][PF6], 1. With HCl, [PtIr(μ-HCC-4-C6H4Me)(CO)2(μ-dppm)2][PF6] reacted to give [PtIrHCl(μ-HCC-4-C6H4Me)(CO)2(μ-dppm)2][PF6], by oxidative addition at iridium, and then the alkenylplatinum derivative [PtIrCl{HC=CH(4-C6H4Me)}(CO)2(μ-dppm)2][PF6]. [PtIr(μ-HCC-4-C6H4Me)(CO)2(μ-dppm)2][PF6] reacted slowly with dihydrogen to give 4-MeC6H4CH=CH2 and [PtIrH4(CO)(μ-dppm)2][PF6]. The complex [PtIr(μ-HCCPh)(CO)2(μ-dppm)2][PF6] is intensely luminescent in solution at room temperature, with features characteristic of a d(8)-d(8) face-to-face complex.


Effectiveness of palliative care consultation service on caregiver burden over time between terminally ill cancer and non-cancer family caregivers.
The responsibility of taking care of terminal patients is accepted as a role of family members in Taiwan. Only a few studies have focused on the effect of palliative care consultation service (PCCS) on caregiver burden between terminal cancer family caregivers (CFCs) and non-cancer family caregivers (NCFCs). Therefore, the purpose of this study is to address the effect of PCCS on caregiver burden between CFC and NCFC over time. A prospective longitudinal study was conducted in a medical center in northern Taiwan from July to November 2017. The participants were both terminally ill cancer and non-cancer patients who were prepared to receive PCCS, as well as their family caregivers. Characteristics including family caregivers and terminal patients and Family Caregiver Burden Scale (FCBS) were recorded pre-, 7, and 14 days following PCCS. A generalized estimating equation model was used to analyze the change in the level of family caregiver burden (FCB) between CFC and NCFC. The study revealed that there were no statistically significant differences in FCB between CFC and NCFC 7 days and 14 days after PCCS (p > 0.05). However, FCB significantly decreased in both CFC and NCFC from pre-PCCS to 14 days after PCCS (β = - 12.67, p = 0.013). PPI of patients was the key predictor of FCB over time following PCCS (β = 1.14, p = 0.013). This study showed that PCCS can improve FCB in not only CFC but also NCFC. We suggest that PCCS should be used more widely in supporting family caregivers of terminally ill patients to reduce caregiver burden.


A Phylogeographic Approach to the Drosophila suzukii (Diptera: Drosophilidae) Invasion in Brazil.
Biological invasions have reached large parts of the globe, due to human actions across the planet. Drosophila suzukii (Matsumura, 1931) is a globally invasive species, always associated with enormous and costly damage to agricultural crops. Native to Southeast Asia, D. suzukii recently (i.e., 2013) invaded and is dispersing through South America. Here, we used a phylogeographic approach based on the cytochrome c oxidase subunit I gene fragment to explore the invasion dynamics of D. suzukii populations in Brazil. We identified five haplotypes and moderate genetic diversity in Brazilian populations, which are undergoing demographic and spatial expansion. The analyses of molecular variance indicated a high genetic structure among the populations, which is partially explained by their morphoclimatic origin and invasion history. Drosophila suzukii expanded from southern to southeastern Brazil, aided by human-mediated transport of fruits from region to region. The sharing of haplotypes among Brazilian and other invaded regions of the world suggests a single invasion event of D. suzukii in Brazil, originating from previously invaded areas (e.g., North America and Europe). The rapid geographic dispersal and wide variety of fruits attacked by of D. suzukii require immediate implementation of control strategies (legal and phytosanitary) to manage this pest in Brazil.


Lucky gene 5-HTTLPR and postpartum depression: A systematic review.
Postpartum depression (PPD) should be given more attention for its increasing incidences, severe complications and complex pathogenesis. Previous studies of PPD have mainly been focused on the social contributions to its etiology such as age, marriage and economic status, whilst less attention has been given to inner biological factors. Currently, emerging researches have endeavored to explore 5-HTT related pathogenesis of PPD. This report was aimed at proffering updates on some research advancements in the field of PPD through the reviewing published papers concerning postpartum depression, with prime focus on the role of 5-HTT. This review report dug into articles containing both PPD and 5-HTTLPR. Web of Science, Pubmed and CNKI (National Knowledge Infrastructure) were employed for searching relevant publications. There was a strong association between 5-HTTLPR polymorphism and the pathogenesis of PPD, with established evidence showing that L allele (Long allele) in 5-HTTLPR was associated with reduced susceptibility to PPD. All things considered, sufficient clinical experiments are needed to ascertain the feasibility of our theoretical statements. In addition, relevant articles are comparatively scarce presently.


Interventional endosonography.
Endoscopic ultrasound (EUS) has become the most accurate imaging modality for locoregional cancer staging of the gastrointestinal (GI) tract. Fine-needle aspiration (FNA) capabilities have added a whole new level of accuracy in nodal staging with reported numbers in the 90% range for luminal and pancreaticobiliary disease. In addition, new non-GI applications are being evaluated like the role of EUS-FNA for non-small cell lung carcinoma and exploration of the posterior mediastinum. Furthermore, the same capabilities that allow for safe tissue sampling are being explored for interventional applications like EUS-guided celiac plexus neurolysis and fine-needle injection. The following review describes the current clinical status of EUS in GI oncology as well as future and novel indications and therapeutic strategies for this technology.


Micromolar 4-aminopyridine enhances invasion of a vertebrate neurosecretory terminal arborization: optical recording of action potential propagation using an ultrafast photodiode-MOSFET camera and a photodiode array.
Modulation of the amount of neuropeptide released from a neurosecretory tissue may be achieved by different means. These include alterations in the quantity secreted from each active nerve terminal or in the actual number of terminals activated. From the vertebrate hypothalamus, magnocellular neurons project their axons as bundles of fibers through the median eminence and infundibular stalk to arborize extensively and terminate in the neurohypophysis, where the neurohypophysial peptides and proteins are released into the circulation by a Ca-dependent mechanism. Elevating [Ca2+]o increases the magnitude of an intrinsic optical change in the neurohypophysial terminals that is intimately related to the quantity of neuropeptide released. Similarly, the addition of micromolar concentrations of 4-aminopyridine to the bathing solution enhances this change in large angle light scattering. However, we show here that, while these effects are superficially similar, they reflect different mechanisms of action. Evidence from intrinsic optical signals (light scattering) and extrinsic (potentiometric dye) absorption changes suggests that calcium increases the amount of neuropeptide released from each active terminal in the classical manner, while 4-aminopyridine exerts its secretagogue action by enhancing the invasion of action potentials into the magno-cellular neuron's terminal arborization, increasing the actual number of terminals activated. Physiologically, electrical invasion of the complex terminal arborization in the neurohypophysis may represent an extremely sensitive control point for modulation of peptide secretion. This would be especially effective in a neurohaemal organ like the posterior pituitary, where, in contrast with a collection of presynaptic terminals, the precise location of release is less important than the quantity released.


Controlled Dendrimersome Nanoreactor System for Localized Hypochlorite-Induced Killing of Bacteria.
Antibiotic resistance is a serious global health problem necessitating new bactericidal approaches such as nanomedicines. Dendrimersomes (DSs) have recently become a valuable alternative nanocarrier to polymersomes and liposomes due to their molecular definition and synthetic versatility. Despite this, their biomedical application is still in its infancy. Inspired by the localized antimicrobial function of neutrophil phagosomes and the versatility of DSs, a simple three-component DS-based nanoreactor with broad-spectrum bactericidal activity is presented. This was achieved by encapsulation of glucose oxidase (GOX) and myeloperoxidase (MPO) within DSs (GOX-MPO-DSs), self-assembled from an amphiphilic Janus dendrimer, that possesses a semipermeable membrane. By external addition of glucose to GOX-MPO-DS, the production of hypochlorite (-OCl), a highly potent antimicrobial, by the enzymatic cascade was demonstrated. This cascade nanoreactor yielded a potent bactericidal effect against two important multidrug resistant pathogens, Staphylococcus aureus (S. aureus) and Pseudomonas aeruginosa (P. aeruginosa), not observed for H2O2 producing nanoreactors, GOX-DS. The production of highly reactive species such as -OCl represents a harsh bactericidal approach that could also be cytotoxic to mammalian cells. This necessitates the development of strategies for activating -OCl production in a localized manner in response to a bacterial stimulus. One option of locally releasing sufficient amounts of substrate using a bacterial trigger (released toxins) was demonstrated with lipidic glucose-loaded giant unilamellar vesicles (GUVs), envisioning, e.g., implant surface modification with nanoreactors and GUVs for localized production of bactericidal agents in the presence of bacterial growth.


Changes in the Solid-, Liquid-, and Epithelium-Associated Bacterial Communities in the Rumen of Hu Lambs in Response to Dietary Urea Supplementation.
The rumen bacteria in the solid, liquid, and epithelial fractions are distinct and play important roles in the degradation of urea nitrogen. However, the effects of urea on rumen bacteria from the three fractions remain unclear. In this study, 42 Hu lambs were fed a total mixed ration based on concentrate and roughage (55:45, dry matter basis) and randomly assigned to one of three experimental diets: a basal diet with no urea (UC, 0 g/kg), a basal diet supplemented with low urea levels (LU, 10 g/kg DM), and a basal diet supplemented with high urea levels (HU, 30 g/kg DM). After an 11-week feeding trial, six animals from each treatment were harvested. Rumen metabolites levels were measured, and bacteria of the rumen solid, liquid, and epithelial fractions were examined based on 16S rRNA gene sequencing. Under urea supplementation, the concentrations of ammonia and butyrate in the rumen increased, whereas the concentration of propionate decreased. The population of total protozoa was the highest in the LU treatment. Prevotella 1 was the most abundant genus in all samples. The unclassified Muribaculaceae, bacteria within the families Lachnospiraceae and Ruminococcaceae, and Christensenellaceae R7 were abundant in the solid and liquid fractions. Butyrivibrio 2 and Treponema 2 were the abundant bacteria in the epithelial fraction. Principal coordinate analysis showed separation of the solid, liquid and epithelial bacteria regardless of diet, suggesting that rumen fraction had stronger influences on the bacterial community than did urea supplementation. However, the influences on the bacterial community differed among the three fractions. In the solid and liquid fractions, Succinivibrionaceae UCG 001 and Prevotella 1 showed decreased abundance with dietary urea supplementation, whereas the abundance of Oscillospira spp. was increased. Howardella spp. and Desulfobulbus spp. were higher in the epithelial fraction of the UC and LU treatments relative to HU treatment. Comparisons of predictive function in the rumen solid, liquid, and epithelial fractions among the three treatments also revealed differences. Collectively, these results reveal the change of the rumen bacterial community to dietary urea supplementation.


Obstructive Sleep Apnea and Circulating Biomarkers of Oxidative Stress: A Cross-Sectional Study.
Oxidative stress (OS) drives cardiometabolic diseases. Intermittent hypoxia consistently increases oxidative stress markers. Obstructive sleep apnea (OSA) patients experience intermittent hypoxia and an increased rate of cardiovascular disease, however, the impact of OSA on OS markers is not clear. The objective was to assess relationships between OSA severity and biomarker levels. Patients with suspected OSA referred for a polysomnogram (PSG) provided fasting blood sample. Plasma levels of 8-isoprostane, 8-hydroxydeoxyguanosine (8-OHdG), and superoxide dismutase (SOD) were measured. The relationship between OSA and OS was assessed both before and after controlling for confounders (age, sex, smoking history, history of cardiovascular disease, ethnicity, diabetes, statin usage, body mass index (BMI)). 402 patients were studied (68% male, mean age ± SD = 50.8 ± 11.8 years, apnea-hypopnea index (AHI) = 22.2 ± 21.6 events/hour, BMI = 31.62 ± 6.49 kg/m2). In a multivariable regression, the AHI significantly predicted 8-isoprostane levels (p = 0.0008) together with age and statin usage; AHI was not a predictor of 8-OHdG or SOD. Female sex (p < 0.0001) and no previous history of cardiovascular disease (p = 0.002) were associated with increased antioxidant capacity. Circulating 8-isoprostane levels may be a promising biomarker of the severity of oxidative stress in OSA patients. Prospective studies are needed to determine whether this biomarker is associated with long-term cardiometabolic complications in OSA.


Flow increase is decisive to initiate angiogenesis in veins exposed to altered hemodynamics.
Exposing a vein to altered hemodynamics by creating an arteriovenous (AV) shunt evokes considerable vessel formation that may be of therapeutic potential. However, it is unclear whether the introduction of oscillatory flow and/or flow increase is decisive. To distinguish between these mechanical stimuli we grafted a femoral vein into the arterial flow pathway of the contralateral limb in rats creating an arterioarterial (AA) loop (n = 7). Alternatively, we connected the femoral artery and vein using the vein graft, whereby we created an AV-loop (n = 27). Vessel loops were embedded in a fibrin filled chamber and blood flow was measured by means of flow probes immediately after surgery (day 0) and 15 days after loop creation. On day 15, animals were sacrificed and angiogenesis was evaluated using μCT and histological analysis. Mean flow increased from 0.5 to 2.4 mL/min and was elevated throughout the cardiac cycle at day 0 in AV-loops whereas, as expected, it remained unchanged in AA-loops. Flow in AV-loops decreased with time, and was at day 15 not different from untreated femoral vessels or AA-loop grafts. Pulsatile flow oscillations were similar in AV-and AA-loops at day 0. The flow amplitude amounted to ~1.3 mL/min which was comparable to values in untreated arteries. Flow amplitude remained constant in AA-loops, whereas it decreased in AV-loops (day 15: 0.4 mL/min). A large number of newly formed vessels were present in AV-loops at day 15 arising from the grafted vein. In marked contrast, angiogenesis originating from the grafted vein was absent in AA-loops. We conclude that exposure to substantially increased flow is required to initiate angiogenesis in grafted veins, whereas selective enhancement of pulsatile flow is unable to do so. This suggests that indeed flow and most likely wall shear stress is decisive to initiate formation of vessels in this hemodynamically driven angiogenesis model.


Structural basis for the inhibition of bacterial multidrug exporters.
The multidrug efflux transporter AcrB and its homologues are important in the multidrug resistance of Gram-negative pathogens. However, despite efforts to develop efflux inhibitors, clinically useful inhibitors are not available at present. Pyridopyrimidine derivatives are AcrB- and MexB-specific inhibitors that do not inhibit MexY; MexB and MexY are principal multidrug exporters in Pseudomonas aeruginosa. We have previously determined the crystal structure of AcrB in the absence and presence of antibiotics. Drugs were shown to be exported by a functionally rotating mechanism through tandem proximal and distal multisite drug-binding pockets. Here we describe the first inhibitor-bound structures of AcrB and MexB, in which these proteins are bound by a pyridopyrimidine derivative. The pyridopyrimidine derivative binds tightly to a narrow pit composed of a phenylalanine cluster located in the distal pocket and sterically hinders the functional rotation. This pit is a hydrophobic trap that branches off from the substrate-translocation channel. Phe 178 is located at the edge of this trap in AcrB and MexB and contributes to the tight binding of the inhibitor molecule through a π-π interaction with the pyridopyrimidine ring. The voluminous side chain of Trp 177 located at the corresponding position in MexY prevents inhibitor binding. The structure of the hydrophobic trap described in this study will contribute to the development of universal inhibitors of MexB and MexY in P. aeruginosa.


State-to-state dynamics of high-n Rydberg H-atom scattering with H2: inelastic scattering and reactive scattering.
The state-to-state dynamics of high-n Rydberg H-atom scattering with para-H2 at the collision energies of 0.45 and 1.07 eV have been studied using the H-atom Rydberg tagging time-of-flight technique. Both the inelastic scattering and reactive scattering are observed in the experimental time-of-flight spectra. The products H2(v', j' = odd) come only from reactive scattering and present clearly forward-backward asymmetric angular distributions, which differ from those of the corresponding ion-molecule reaction. The products H2(v', j' = even), however, come from both reactive scattering and inelastic scattering. Simulating the rotational distribution from reactive scattering, we found that most of the H2(v', j' = even) products come from inelastic scattering. The angular distributions of the product H2(v', j' = even) are consistent with what is predicted by the conventional textbook mechanism of inelastic scattering, and are a little different from those of the corresponding ion-molecule inelastic scattering. These results suggest that the effect of Rydberg electron could not be neglected in describing the differential cross sections of H* + para-H2 scattering. From the simulation, the branching ratios of the inelastic scattering channel were determined to be 66% and 79% at the collision energies of 0.45 and 1.07 eV, respectively.


[The microflora associated with anatomical embalming as a harmful factor of a working process].
The paper describes the first attempt to isolate and identify the microbiocenosis associated with the objects of a morphological laboratory that uses formalin. The study identified the following microorganisms: the bacteria Bacillus sp., Providencia alcalifaciens, and Staphylococcus aureus, the micromycetes Scopulariopsis brevicaulis, Aspergillus sp., Hormodendron sp., and the mites Dermatophagoides pterronissimus. There is experimental evidence that these organisms are resistant to formalin. The representatives of this cenosis can negatively affect the health of the workers, which requires the development of the optimal technologies of biomaterial fixation.


Seeing minds, matter, and meaning: The CEEing model of pre-reflective subjective construal.
Although subjective construal (i.e., our personal understanding of situations and the people and objects within them) has been an enduring topic in social psychology, its underlying mechanisms have never been fully explored. This review presents subjective construals as a kind of seeing (i.e., pre-reflective processes associated with effortless meaning-making). Three distinct forms of "seeing" (visual, semantic, and psychological) are discussed to highlight the breadth of these construals. The CEEing model characterizes these distinct domains of pre-reflective construals as all being Coherent Effortless Experiences associated with lateral posterior parietal cortex, lateral posterior temporal cortex, tempororoparietal junction, and ventral temporal cortex in an area dubbed gestalt cortex. The link between subjective construals and gestalt cortex is further strengthened by evidence showing that when people have similar subjective construals (i.e., they see things similarly) they show greater neural synchrony (i.e., correlated neural fluctuations over time) with each other in gestalt cortex. The fact that the act of CEEing tends to inhibit alternative construals is discussed as one of the multiple reasons why we fail to appreciate the idiosyncratic nature of our pre-reflective construals, leading to naïve realism and other conflict-inducing outcomes. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Colon cancer screening.
Figure 10 on page 351 of the Research Article "Constitutive and conditional suppression of exogenous and endogenous genes by anti-sense RNA" by J. G. Izant and H. Weintraub (26 July, p. 345) was reproduced erroneously, so that the green stain (NBD-phallacidin) of the actin filaments was not chromatically resolved. The micrographs are intended to document the specific disruption of the actin microfilament distribution, while the RNA and DNA staining pattern (orange-red) was unaffected. The correct figure and legend appear below.


The gynecological Pap test.
The gynecologic pap test is one of the most successful tests ever developed for reducing the incidence of cancer of the uterine cervix. Despite this undisputed fact, cervical cancer is still present in unacceptably high numbers in the United States. A review of the gynecologic Pap test is presented. Data show that the high incidence of cervical cancer in the US is attributed mostly to failure on the part of the client, with smaller but significant failures on the parts of the healthcare provider and medical laboratory. The only way to reduce the incidence of cervical cancer is to increase the screening rate of patients at risk.


Exploring complex fitness surfaces: multiple ornamentation and polymorphism in male guppies.
The sexual ornamentation used by male guppies to attract females comprises many components, each of which varies considerably among males. Although natural and sexual selection have been shown to contribute to divergence among populations in male sexual ornaments, the role of sexual selection in maintaining polymorphism within populations is less clear. We used both parametric quadratic regression and nonparametric projection pursuit regression techniques to reveal the major axes of non-linear sexual selection on male ornaments. We visualized the fitness surfaces defined by these axes using thin-plate splines to allow a direct comparison of the two methodologies. Identification of the major axes of selection and their visualization was critical in determining the form and strength of nonlinear selection. Both types of analysis revealed fitness surfaces comprising three peaks, suggesting that there is more than one way to make an attractive guppy. Disruptive selection may be an important process underlying the presence of multiple sexual ornaments and may contribute to the maintenance of the high levels of polymorphism in male sexual ornaments found in guppy populations.


Narcissism and Devaluing Others: An Exploration of Impaired Control Over Drinking as a Mediating Mechanism of Alcohol-Related Problems.
Devaluing or diminishing the worth of others is how many individuals destroy their relationships, such as by drinking beyond limits at inappropriate times and letting others down. Impaired control over drinking (IC) reflects consuming alcohol beyond predetermined limits. This investigation sought to determine whether facets of vulnerable narcissism (e.g., entitlement-rage, hiding-the-self, contingent-self-esteem, and devaluing) or narcissistic grandiosity (e.g. grandiose-fantasy, self-sacrificing-for-self-enhancement, and exploitativeness) were directly related to IC and indirectly related to drinking outcomes. We examined a path model of 759 university student drinkers. Our results show that while grandiose-fantasy (i.e., desire for special recognition) was negatively linked to IC, devaluing was positively linked to IC. In addition, men scored higher on exploitativeness (i.e., interpersonally manipulative for personal gain) than women. We conducted mediational analysis with asymmetric confidence intervals and a bias-corrected bootstrap technique. Mediational tests showed that higher levels of grandiose-fantasy were indirectly related to fewer alcohol-related problems through less IC and less heavy-episodic drinking. In contrast, higher levels of devaluing were indirectly related to more alcohol-related problems through more IC and heavy-episodic-drinking. Our results suggest that targeting thought processes in which people with Alcohol Use Disorders (AUDs) are actively devaluing others may be a good target for therapeutic intervention.


Retention Rate of Four Different Sealant Materials after Four Years.
To test the hypotheses: 1) cumulative survival rates of fully and partially retained high-viscosity glass-ionomer (HVGIC) ART sealants with heat application and glass-carbomer sealants on occlusal and free-smooth surfaces are both higher than that of resin sealants; 2) cumulative survival rate of fully and partially retained high-viscosity glass-ionomer ART sealant with heat application on occlusal and free-smooth surfaces is higher than that of comparable ART sealants without heat application. The block-randomised clinical trial covered 405 eight-year-old children. The HVGIC was Ketac Molar Easymix, the glass carbomer was GlassCarbomer and the resin sealant was Clinpro. Retention rates of sealants on occlusal and free-smooth surfaces using conventional and modified categorisation (fully and partially retained sealants vs those completely lost [at least one-third of surface re-exposed]) were the dependent variables. The Kaplan-Meier survival method was used. The cumulative survival rate of completely and partially retained resin sealants on occlusal (81.2%) and free-smooth (81%) surfaces after 4 years was statistically significantly higher, and that of glass-carbomer sealants (10.8% and 21.1%, respectively) was statistically significantly lower than those of the other sealant groups. There was no statistically significant difference in survival rates of completely and partially retained high-viscosity glass-ionomer ART sealants with (56% for both surfaces) or without heat application (56%) on occlusal and free-smooth surfaces (55.7% and 59.1%, respectively). Resin sealants had the highest and glass-carbomer sealants the lowest retention rate after 4 years. Application of heat to high-viscosity glass-ionomer ART sealants did not result in a significantly higher sealant retention rate. Use of the modified categorisation for determining sealant retention is advocated.


Optimum coupling and multimode excitation of traveling-waves in a whole-body 9.4T scanner.
Given the absence of a body coil, the radio frequency screen of a whole-body 9.4T magnetic resonance imaging scanner can be used as a circular waveguide. In the unloaded case, the screen allows propagation of the dominant TE11- as well as the TM01-mode. In the first part of this study, the optimum coupling of a circular polarized TE11-mode was determined empirically for excitation and reception with a rectangular patch antenna. Employing full-wave simulations, two simulation models and two phantoms, different patch positions were tested to find the optimum position with respect to coupled power and homogenous excitation field. The best simulation results were validated with measurements. The second part of this study describes the design and measurements of a multimode excitation device. Using the parallel transmit system of the MR scanner, all propagable traveling wave modes could be excited and detected independently. The performance of the multimode device related to field of view, B1+-efficiency and radio frequency shimming was assessed by phantom measurements. Initial results show that three modes are sufficient to homogeneously excite regions of interest at 9.4 T.


[Anorexia nervosa and the perinatal period].
As a complex pathology, anorexia nervosa interacts with the psychological challenges of pregnancy, and raises questions about how to support the women concerned. As part of a multidisciplinary approach, support groups are particularly important, offering both individual and social support. Child-parent drop-in centers can also provide a supportive space for the psychological work of parenting.


Cucurbit[8]uril directed stimuli-responsive supramolecular polymer brushes for dynamic surface engineering.
In situ modification of surfaces with thin layers of polymers is of growing interest as adjustment of surface properties can be made on demand. We present herein a supramolecular 'grafting to' polymer brush via the recognition of surface-bound cucurbit[8]uril (CB[8]) rotaxanes towards end-functionalised polyethylene glycol (PEG). This dynamic supramolecular method represents advantages over traditional approaches, which employ covalent bond formation in the 'grafting to' process. Brush properties can be easily modified post-preparation by exchanging the polymers with small molecules in a controlled, reversible manner. Including both redox- and light-responsive guests in a single rotaxane entity, the CB[8]-mediated preparation of the polymer brush offers unique opportunities to switch the brush composition efficiently. While the PEG brushes are well hydrated in a good solvent (water) and stretch away from the surface, they collapse in a poor solvent (toluene), leading to the formation of a dense layer on the surface. This collapsed conformation protects the heteroternary complexes of CB[8]-rotaxane from dissociation and maintains the attachment of polymers on the surface.


Diabetes primes neutrophils to undergo NETosis, which impairs wound healing.
Wound healing is impaired in diabetes, resulting in significant morbidity and mortality. Neutrophils are the main leukocytes involved in the early phase of healing. As part of their anti-microbial defense, neutrophils form extracellular traps (NETs) by releasing decondensed chromatin lined with cytotoxic proteins. NETs, however, can also induce tissue damage. Here we show that neutrophils isolated from type 1 and type 2 diabetic humans and mice were primed to produce NETs (a process termed NETosis). Expression of peptidylarginine deiminase 4 (PAD4, encoded by Padi4 in mice), an enzyme important in chromatin decondensation, was elevated in neutrophils from individuals with diabetes. When subjected to excisional skin wounds, wild-type (WT) mice produced large quantities of NETs in wounds, but this was not observed in Padi4(-/-) mice. In diabetic mice, higher levels of citrullinated histone H3 (H3Cit, a NET marker) were found in their wounds than in normoglycemic mice and healing was delayed. Wound healing was accelerated in Padi4(-/-) mice as compared to WT mice, and it was not compromised by diabetes. DNase 1, which disrupts NETs, accelerated wound healing in diabetic and normoglycemic WT mice. Thus, NETs impair wound healing, particularly in diabetes, in which neutrophils are more susceptible to NETosis. Inhibiting NETosis or cleaving NETs may improve wound healing and reduce NET-driven chronic inflammation in diabetes.


Extracellular vesicles for personalized medicine: The input of physically triggered production, loading and theranostic properties.
Emerging advances in extracellular vesicle (EV) research brings along new promises for tailoring clinical treatments in order to meet specific disease features of each patient in a personalized medicine concept. EVs may act as regenerative effectors conveying endogenous therapeutic factors from parent cells or constitute a bio-camouflaged delivery system for exogenous therapeutic agents. Physical stimulation may be an important tool in the field of EVs for personalized therapy by powering EV production, loading and therapeutic properties. Physically-triggered EV production is inspired by naturally occurring EV release by shear stress in blood vessels. Bioinspired physically-triggered EV production technologies may bring along high yield advantages combined to scalability assets. Physical stimulation may also provide new prospects for high-efficient EV loading. Additionally, physically-triggered EV theranostic properties brings new hopes for spatio-temporal controlled therapy combined to tracking. Technological considerations related to EV-based personalized medicine and the input of physical stimulation on EV production, loading and theranostic properties will be overviewed herein.


[Epileptic signs of metabolic origin].
It is very difficult to identify metabolic causes of epileptic crises. This is partly because metabolic disorders are not fully understood and partly because the complementary tests required for their identification can be undertaken only in a few laboratories. We describe the characteristics of the metabolic disorders which may most frequently lead to epileptic crises occurring during the neonatal period, the first year of life, between the ages of one and six years and between six and fifteen years of age. We also emphasize the findings which may help in orientation towards diagnosis of these metabolic disorders, and the complementary tests required for confirmation.


Functional characterization of a mammalian Sac1 and mutants exhibiting substrate-specific defects in phosphoinositide phosphatase activity.
The Saccharomyces cerevisiae SAC1 gene was identified via independent analyses of mutations that modulate yeast actin function and alleviate the essential requirement for phosphatidylinositol transfer protein (Sec14p) activity in Golgi secretory function. The SAC1 gene product (Sac1p) is an integral membrane protein of the endoplasmic reticulum and the Golgi complex. Sac1p shares primary sequence homology with a subfamily of cytosolic/peripheral membrane phosphoinositide phosphatases, the synaptojanins, and these Sac1 domains define novel phosphoinositide phosphatase modules. We now report the characterization of a rat counterpart of Sac1p. Rat Sac1 is a ubiquitously expressed 65-kDa integral membrane protein of the endoplasmic reticulum that is found at particularly high levels in cerebellar Purkinje cells. Like Sac1p, rat Sac1 exhibits intrinsic phosphoinositide phosphatase activity directed toward phosphatidylinositol 3-phosphate, phosphatidylinositol 4-phosphate, and phosphatidylinositol 3,5-bisphosphate substrates, and we identify mutant rat sac1 alleles that evoke substrate-specific defects in this enzymatic activity. Finally, rat Sac1 expression in Deltasac1 yeast strains complements a wide phenotypes associated with Sac1p insufficiency. Biochemical and in vivo data indicate that rat Sac1 phosphatidylinositol-4-phosphate phosphatase activity, but not its phosphatidylinositol-3-phosphate or phosphatidylinositol-3, 5-bisphosphate phosphatase activities, is essential for the heterologous complementation of Sac1p defects in vivo. Thus, yeast Sac1p and rat Sac1 are integral membrane lipid phosphatases that play evolutionary conserved roles in eukaryotic cell physiology.


VDL-Surrogate: A View-Dependent Latent-based Model for Parameter Space Exploration of Ensemble Simulations.
We propose VDL-Surrogate, a view-dependent neural-network-latent-based surrogate model for parameter space exploration of ensemble simulations that allows high-resolution visualizations and user-specified visual mappings. Surrogate-enabled parameter space exploration allows domain scientists to preview simulation results without having to run a large number of computationally costly simulations. Limited by computational resources, however, existing surrogate models may not produce previews with sufficient resolution for visualization and analysis. To improve the efficient use of computational resources and support high-resolution exploration, we perform ray casting from different viewpoints to collect samples and produce compact latent representations. This latent encoding process reduces the cost of surrogate model training while maintaining the output quality. In the model training stage, we select viewpoints to cover the whole viewing sphere and train corresponding VDL-Surrogate models for the selected viewpoints. In the model inference stage, we predict the latent representations at previously selected viewpoints and decode the latent representations to data space. For any given viewpoint, we make interpolations over decoded data at selected viewpoints and generate visualizations with user-specified visual mappings. We show the effectiveness and efficiency of VDL-Surrogate in cosmological and ocean simulations with quantitative and qualitative evaluations. Source code is publicly available at https://github.com/trainsn/VDL-Surrogate.


Development and validation of a GEANT4 radiation transport code for CT dosimetry.
The authors have created a radiation transport code using the GEANT4 Monte Carlo toolkit to simulate pediatric patients undergoing CT examinations. The focus of this paper is to validate their simulation with real-world physical dosimetry measurements using two independent techniques. Exposure measurements were made with a standard 100-mm CT pencil ionization chamber, and absorbed doses were also measured using optically stimulated luminescent (OSL) dosimeters. Measurements were made in air with a standard 16-cm acrylic head phantom and with a standard 32-cm acrylic body phantom. Physical dose measurements determined from the ionization chamber in air for 100 and 120 kVp beam energies were used to derive photon-fluence calibration factors. Both ion chamber and OSL measurement results provide useful comparisons in the validation of the Monte Carlo simulations. It was found that simulated and measured CTDI values were within an overall average of 6% of each other.


Diversity of hepatitis B virus X gene-related transcripts in hepatocellular carcinoma: a novel polyadenylation site on viral DNA.
RNA was isolated from tissue of two patients with hepatocellular carcinoma developed on the background of a chronic hepatitis B virus infection. For identification and characterization of 3' ends of X gene open reading frame (ORF)-related transcripts, RNA was reverse transcribed into cDNA and subjected to polymerase chain reaction. Cloned amplification products from tumor tissue of one patient represented an approximately even distribution of transcripts terminating at the established poly(A) signal (standard transcripts) and of truncated transcripts terminating at a CATAAA poly(A) signal within the 3' end region of X gene ORF (truncated transcripts). Amplified cDNA from tumor tissue of the second patient could be attributed mainly to the standard type of transcripts, whereas cDNA from the nontumor tissue of the same patient could be assigned to four groups of transcripts: (i) standard transcripts, (ii) transcripts with internal deletions affecting the 3' end of the X gene, (iii) truncated transcripts, and (iv) hybrid transcripts displaying 5' sequences from the X gene ORF fused to cellular sequences.


The RB-E2F1 pathway regulates autophagy.
Autophagy is a protective mechanism that renders cells viable in stressful conditions. Emerging evidence suggests that this cellular process is also a tumor suppressor pathway. Previous studies showed that cyclin-dependent kinase inhibitors (CDKI) induce autophagy. Whether retinoblastoma protein (RB), a key tumor suppressor and downstream target of CDKIs, induces autophagy is not clear. Here, we show that RB triggers autophagy and that the RB activators p16INK4a and p27/kip1 induce autophagy in an RB-dependent manner. RB binding to E2 transcription factor (E2F) is required for autophagy induction and E2F1 antagonizes RB-induced autophagy, leading to apoptosis. Downregulation of E2F1 in cells results in high levels of autophagy. Our findings indicate that RB induces autophagy by repressing E2F1 activity. We speculate that this newly discovered aspect of RB function is relevant to cancer development and therapy.


Identifying factors associated with experiences of coronary heart disease patients receiving structured chronic care and counselling in European primary care.
Primary care for chronic illness varies across European healthcare systems. In patients suffering from coronary heart disease (CHD), factors associated with patients' experiences of receiving structured chronic care and counselling at the patient and practice level were investigated. In an observational study comprising 140 general practices from five European countries (Austria, Germany, the Netherlands, Switzerland and the United Kingdom), 30 patients with Coronary Heart Disease (CHD) per practice were chosen at random to partake in this research. Patients were provided with a questionnaire and the Patient Assessment of Chronic Illness Care (PACIC-5A) - instrument. Practice characteristics were assessed through a practice questionnaire and face to face interviews. Data were aggregated to obtain two practice scores representing quality management and CHD care, respectively. A hierarchical multilevel analysis was performed to examine the impact of patient and practice characteristics on PACIC scores. The final sample included 1745 CHD-patients from 131 general practices with a mean age of 67.8 (SD 9.9) years. The overall PACIC score was 2.84 (95%CI: 2.79; 2.89) and the 5A score reflecting structured lifestyle counselling was 2.75 (95% CI: 2.69; 2.79). At the patient level, male gender, more frequent practice contact and fewer related or unrelated conditions were associated with higher PACIC scores. At the practice level, performance scores reflecting quality management (p = 0.013) and CHD care (p = 0.009) were associated with improved assessment of the structured chronic care and counselling received. Patients' perceived quality of care varies. However, good practice management and organisation of care were positively reflected in patients' assessments of receiving structured chronic illness care. This highlights the importance of integrating patient experiences into quality measurements to provide feedback to health care professionals.


Method to Convert Stem Cells into Cancer Stem Cells.
The cancer stem cell (CSC) hypothesis suggests that tumors are sustained exclusively by a small population of the cells with stem cell properties. CSCs have been identified in most tumors and are responsible for the initiation, recurrence, and resistance of different cancers. In vitro CSC models will be of great help in revisiting the mechanism of cancer development, as well as the tumor microenvironment and the heterogeneity of cancer and metastasis. Our group recently described the generation of CSCs from induced pluripotent stem cells (iPSCs), which were reprogrammed from normal cells, and/or embryonic stem cells (ESCs). This procedure will improve the understanding of the essential niche involved in cancer initiation. The composition of this cancer-inducing niche, if identified, will let us know how normal cells convert to malignant in the body and how, in turn, cancer prevention could be achieved. Further, once developed, CSCs demonstrate the ability to differentiate into endothelial cells, cancer-associated fibroblasts, and other phenotypes establishing the CSC niche. These will be good materials for developing novel cancer treatments. In this protocol, we describe how to handle mouse iPSCs/ESCs and how to choose the critical time for starting the conversion into CSCs. This CSC generation protocol is essential for understanding the role of CSC in cancer initiation and progress.


Two microRNA signatures for malignancy and immune infiltration predict overall survival in advanced epithelial ovarian cancer.
MicroRNAs have been established as key regulators of tumor gene expression and as prime biomarker candidates for clinical phenotypes in epithelial ovarian cancer (EOC). We analyzed the coexpression and regulatory structure of microRNAs and their co-localized gene targets in primary tumor tissue of 20 patients with advanced EOC in order to construct a regulatory signature for clinical prognosis. We performed an integrative analysis to identify two prognostic microRNA/mRNA coexpression modules, each enriched for consistent biological functions. One module, enriched for malignancy-related functions, was found to be upregulated in malignant versus benign samples. The second module, enriched for immune-related functions, was strongly correlated with imputed intratumoral immune infiltrates of T cells, natural killer cells, cytotoxic lymphocytes, and macrophages. We validated the prognostic relevance of the immunological module microRNAs in the publicly available The Cancer Genome Atlas data set. These findings provide novel functional roles for microRNAs in the progression of advanced EOC and possible prognostic signatures for survival.