Methotrexate and sulfasalazine promote adenosine release by a mechanism that requires ecto-5'-nucleotidase-mediated conversion of adenine nucleotides.
We and others have shown that an increased extracellular concentration of adenosine mediates the antiinflammatory effects of methotrexate and sulfasalazine both in vitro and in vivo, but the mechanism by which these drugs increase extracellular adenosine remains unclear. The results of the experiments reported here provide three distinct lines of evidence that adenosine results from the ecto-5'-nucleotidase- mediated conversion of adenine nucleotides to adenosine. First, pretreatment of a human microvascular endothelial cell line (HMEC-1) with methotrexate increases extracellular adenosine after exposure of the pretreated cells to activated neutrophils; the ecto-5'-nucleotidase inhibitor alpha, beta-methylene adenosine-5'-diphosphate (APCP) abrogates completely the increase in extracellular adenosine. Second, there is no methotrexate-mediated increase in extracellular adenosine concentration in the supernate of cells deficient in ecto-5'-nucleotidase, but there is a marked increase in extracellular adenosine concentration in the supernates of these cells after transfection and surface expression of the enzyme. Finally, as we have shown previously, adenosine mediates the antiinflammatory effects of methotrexate and sulfasalazine in the murine air pouch model of inflammation, and injection of APCP, the ecto-5'-nucleotidase inhibitor, abrogates completely the increase in adenosine and the decrement in inflammation in this in vivo model. These results not only show that ecto-5'-nucleotidase activity is a critical mediator of methotrexate- and sulfasalazine-induced antiinflammatory activity in vitro and in vivo but also indicate that adenine nucleotides, released from cells, are the source of extracellular adenosine.


Information and power: Women of color's experiences interacting with health care providers in pregnancy and birth.
Preterm birth and other poor birth outcomes disproportionately affect women of color. Emerging evidence suggests that socially-driven issues such as disrespect, abuse, and discrimination within the health care system influence how people of color experience care during pregnancy, birth, and postpartum, which contributes to poorer outcomes for the mother and baby. As recommended by community partners, we explored how interactions with providers were perceived and understood in the context of seeking care for pregnancy and birth. For this constructivist grounded theory study, we recruited 22 self-identified women of color 18 years of age or older and who were between six weeks and one year postpartum. Women participated in interviews exploring their experiences, which were audiorecorded and transcribed. Data were analyzed using dimensional analysis and situational analysis methods. The concepts of information and power surfaced in analysis, in which providers have control over the information they share and "package" information to exert power over women's ability to participate in decision-making. An established relationship with providers and acknowledged levels of privilege or marginalization influenced how information was shared. Contextual factors included provider bias and judgment towards their patients, health care system structural issues, and the overall power dynamic between patient and provider. Women of color's experiences during pregnancy and birth were influenced by how they were treated by providers, particularly in how information was shared and withheld. The providers' control over information led to a power dynamic that diminished women's ability to maintain autonomy and make health care decisions for themselves and their children. This study provides insight and impetus for change in how providers share information, utilize informed consent, and provide respectful care to women of color during pregnancy and birth care.


Prognostic significance of elevated endothelin-1 levels in patients with colorectal cancer.
Prognostic factors from clinical, laboratory and pathological data of patients with colorectal cancer are essential to identify high-risk groups to whom beneficial adjuvant therapy could be given. Endothelin-1, a growth factor, has been associated with the development and spread of solid tumours. This prospective study was performed to determine whether preoperative plasma big ET-1 levels might be useful as a prognostic indicator in patients with colorectal carcinoma. Sixty-five consecutive patients with colorectal cancer confirmed by biopsy were included prospectively into this study over a 12-month period. Plasma samples from a peripheral vein were obtained prior to surgery. Univariate analysis of survival using age (< or > 70 years), sex, Dukes' stage (A&B versus C), tumour size (< or > 50 mm), vascular invasion and plasma big ET-1 levels was performed and significant factors were then analysed with the Cox regression model. Three variables, age, Dukes' tumour stage and plasma big ET-1 levels, were found to have prognostic significance (p<0.05). Factors associated with a poorer prognosis were age >70 years (p=0.02), Dukes' C tumours (p=0.04) and plasma big ET-1 levels >4.2 pg/mL (p=0.02). The Cox regression model identified the same three variables as having independent prognostic value for overall survival. Preoperative plasma big ET-1 levels may be useful in predicting overall survival in patients with colorectal cancer. Plasma big ET-1 levels may be useful in the selection of high-risk lymph node-negative patients with colorectal cancer for adjuvant therapy.


New urinary biomarkers for diabetic kidney disease.
Diabetic kidney disease is the leading cause of end-stage renal disease in developed and developing countries. Microalbuminuria is the gold standard for detection and prediction of diabetic kidney disease and cardiovascular risk disease in clinical practice. However, microalbuminuria has several limitations, such as lower sensitive, larger variability. It is urgent to explore higher sensitivity and specificity for earlier detection of diabetic kidney disease and more accurate prediction of the progression to end stage renal disease. We reviewed some new and important urinary biomarkers, such as: transferrin, immunoglobulin G, immunoglobulin M, Cystanic C, podocytes, type IV collagen, 8-oxo-7, 8-dihydro-2'-deoxyguanosine, ceruloplasmin, monocyte chemoattractant protein-1 and so on. We need good quality, long-term, large longitudinal trials to validate published biomarkers and find new biomarkers, considering biomarkers reviewed here are from small cross-sectional studies.


A well-balanced flow equation for noise removal and edge detection.
In this paper, an anisotropic nonlinear diffusion equation for image restoration is presented. The model has two terms: the diffusion and the forcing term. The balance between these terms is made in a selective way, in which boundary points and interior points of the objects that make up the image are treated differently. The optimal smoothing time concept, which allows for finding the ideal stop time for the evolution of the partial differential equation is also proposed. Numerical results show the proposed model's high performance.


Astronomy. Galactic encounters.
Studies of the Local Group of galaxies to which the Milky Way belongs are shedding light on some of the processes by which galaxies formed and evolved. In her Perspective, Wyse reviews recent studies of collisions between the Milky Way and smaller satellite galaxies. There is evidence for minor collisions with satellites such as the Sagittarius dwarf galaxy. But the Milky Way does not seem to have suffered any major collisions over the past 10,000 million years, making our galaxy unusual according to galaxy-formation models. Andromeda, another large galaxy in the Local Group, conforms better with expectation, showing evidence for significant recent accretion and/or disruption events.


The triune brain in antiquity: Plato, Aristotle, Erasistratus.
Tripartite neuropsychologies have featured through two and half millennia of Western thought. They received a modern airing in Paul MacLean's well-known text The Triune Brain. This paper examines the origin of these triune psychophysiologies. It is argued that the first such psychophysiology was developed in the fifth century BCE in the Republic and its Pythagorean sequel, the Timaeus. Aristotle, Plato's pupil and colleague, developed a somewhat similar theory, though this time based on his exhaustive biological researches. Finally, a generation later, Herophilus and Erasistratus at the Alexandrian Museum put together a more anatomically informed tripartite theory that, somewhat modified by Galen in the second century AD, remained the prevailing orthodoxy for nearly fifteen hundred years until it was overturned by the great figures of the Renaissance. Nonetheless, as already mentioned, the notion that human neuropsychology is somehow best thought of as having a tripartite structure has remained remarkably resilient and has reappeared time and again in modern and early modern times. This paper investigates its origins and suggests that it is perhaps now time to move on.


Sudden sensorineural hearing loss: results of intratympanic steroids as salvage treatment.
The aim of the present study was to verify the efficacy and the safety of intratympanic dexamethasone to treat sudden sensorineural hearing loss as salvage therapy. A prospective study was conducted on patients affected by idiopathic sudden hearing loss who were treated before with some systemic therapy, but without recovery of the hearing The patients able to undergo the study, but who refused salvage treatment were considered as control group. A solution of Dexamethasone 4 mg/ml was then injected through the posterior-inferior quadrant filling completely the middle ear. The follow-up in the following 6 months included an audiogram every month. The number of patients treated with salvage therapy was 36. The patients who refused treatment were further 10. The salvage treatment was done with a mean delay of 24.3 days from the onset of symptoms. Mean hearing threshold after the onset of sudden hearing loss at PTA was 66.5 dB. After the failed treatment the mean PTA was 59.6 dB. The mean PTA after the intratympanic steroid administration was 46.8 dB, with a mean improvement of 12.8 dB. No hearing change was noted in the 10 patients who refused salvage therapy. The patients that assumed systemic steroid as first therapy showed a better PTA threshold after the salvage intratympanic treatment (p<0.01). A significant difference (p<0.05) of hearing recovery was evidenced between non-smoker patients and those with smoking habit. Our data showed that a salvage treatment with intratympanic dexamethasone should be suggested to all patients who failed the first systemic treatment. The systemic steroid therapy done before the salvage treatment seems to exert a protective role for the inner ear, as shown by our series. On the contrary the smoke habit is a negative prognostic factor in the hearing recovery.


[Reinterpretation of the potentiality of Critical-emancipative Workshops].
This qualitative study aims to discuss the potential of Critical-emancipative Workshops utilizing the Tree of Knowledge as a facilitator strategy. The theoretical basis that constitutes this workshop was: the critical-emancipative education and empowerment; emotions as constructors of knowledge; the dialectical approach to transform reality and awareness; participation and shared responsibility. The study was conducted with 95 professionals working in 12 Family Health Staff in a city in the province of São Paulo, Brazil. The results indicate that the potential of the Critical-emancipatory Workshops relate directly to theoretical basis. The dynamics Tree of Knowledge used in the evaluation was powerful to reveal them. Thus, the workshops constitute an important tool for nursing in terms of their educational dimension, particularly, to face gender-based violence against women.


The tragedy of the emeritus and the fates of anatomical collections: Alfred Benninghoff's memoir of Ferdinand Count Spee.
Retirement can be a significant period in modern academic careers, and emeritus professors have shaped the fates of collections in departments and disciplines. This is evidenced by reconstructing the meanings of Alfred Benninghoff's remarkable memoir of Ferdinand Count Spee, sometime director of the anatomical institute in the University of Kiel. Thematizing the 'tragedy' of the emeritus, Benninghoff's 1944 article recalls his predecessor's possessive interactions with his collections as these approached assorted endings. With nostalgia and humour, it places the old aristocrat physically, intellectually and emotionally in a building that bombing would soon destroy. Benninghoff's Spee retained control over the microscope slides with which he engaged colleagues in conversations about research in embryology and physiological anatomy. He lost authority over the teaching charts and wet preparations, but still said a long farewell to these things; he tried, like a conductor alone after a concert, to recapture an experience he had once shared. The elegy is interpreted as apologetic about anatomy under National Socialism, and as offering a model of collegiality. It illustrates how collections have mediated relations between scientific generations at the end of a career.


Integration of text- and data-mining using ontologies successfully selects disease gene candidates.
Genome-wide techniques such as microarray analysis, Serial Analysis of Gene Expression (SAGE), Massively Parallel Signature Sequencing (MPSS), linkage analysis and association studies are used extensively in the search for genes that cause diseases, and often identify many hundreds of candidate disease genes. Selection of the most probable of these candidate disease genes for further empirical analysis is a significant challenge. Additionally, identifying the genes that cause complex diseases is problematic due to low penetrance of multiple contributing genes. Here, we describe a novel bioinformatic approach that selects candidate disease genes according to their expression profiles. We use the eVOC anatomical ontology to integrate text-mining of biomedical literature and data-mining of available human gene expression data. To demonstrate that our method is successful and widely applicable, we apply it to a database of 417 candidate genes containing 17 known disease genes. We successfully select the known disease gene for 15 out of 17 diseases and reduce the candidate gene set to 63.3% (+/-18.8%) of its original size. This approach facilitates direct association between genomic data describing gene expression and information from biomedical texts describing disease phenotype, and successfully prioritizes candidate genes according to their expression in disease-affected tissues.


Linking microbiome and stress hormone responses in wild tropical treefrogs across continuous and fragmented forests.
The amphibian skin microbiome is an important component of anti-pathogen defense, but the impact of environmental change on the link between microbiome composition and host stress remains unclear. In this study, we used radiotelemetry and host translocation to track microbiome composition and function, pathogen infection, and host stress over time across natural movement paths for the forest-associated treefrog, Boana faber. We found a negative correlation between cortisol levels and putative microbiome function for frogs translocated to forest fragments, indicating strong integration of host stress response and anti-pathogen potential of the microbiome. Additionally, we observed a capacity for resilience (resistance to structural change and functional loss) in the amphibian skin microbiome, with maintenance of putative pathogen-inhibitory function despite major temporal shifts in microbiome composition. Although microbiome community composition did not return to baseline during the study period, the rate of microbiome change indicated that forest fragmentation had more pronounced effects on microbiome composition than translocation alone. Our findings reveal associations between stress hormones and host microbiome defenses, with implications for resilience of amphibians and their associated microbes facing accelerated tropical deforestation.


Anesthetic and convulsant barbiturates alter gamma-aminobutyric acid-stimulated chloride flux across brain membranes.
gamma-Aminobutyric acid (GABA), the major inhibitory neurotransmitter in the mammalian brain, increases membrane chloride conductance. Previously, the authors reported that GABA increases 36Cl- uptake by membrane vesicles (microsacs) prepared from mouse brain. In the present study, we examined the actions of barbiturates on basal and GABA-stimulated chloride influx by brain vesicles. The anesthetic barbiturates pentobarbital, phenobarbital, mephobarbital, amobarbital, hexobarbital and R-(-)-1-methyl-5-phenyl-5-propyl barbiturate enhanced GABA-dependent chloride flux. Barbiturate enhancement of GABA action was seen at concentrations that are subanesthetic in vivo (e.g., 10 microM pentobarbital was effective). Pentobarbital was about 10 times more potent than pentobarbital, suggesting that chloride flux is related to the sedative rather than anticonvulsant actions of barbiturates. Pentobarbital (1 mM) prevented the antagonism of GABA-stimulated 36Cl- produced by picrotoxinin. The barbiturates generally produced no change in GABA-independent flux, although large concentrations of pentobarbital or hexobarbital produced a slight enhancement of chloride flux in the absence of GABA. The convulsant barbiturate S-(+)-1-methyl-5-phenyl-5-propyl barbiturate inhibited GABA-stimulated chloride flux, an action opposite to that of its anesthetic enantiomer. These experiments provide evidence for a functional coupling among GABA and barbiturate receptors and the chloride ionophore and suggest that the GABA-activated chloride channel is a site of action for intoxicant-anesthetic and convulsant barbiturates.


Targeting MYCN-expressing triple-negative breast cancer with BET and MEK inhibitors.
Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer that does not respond to endocrine therapy or human epidermal growth factor receptor 2 (HER2)-targeted therapies. Individuals with TNBC experience higher rates of relapse and shorter overall survival compared to patients with receptor-positive breast cancer subtypes. Preclinical discoveries are needed to identify, develop, and advance new drug targets to improve outcomes for patients with TNBC. Here, we report that MYCN, an oncogene typically overexpressed in tumors of the nervous system or with neuroendocrine features, is heterogeneously expressed within a substantial fraction of primary and recurrent TNBC and is expressed in an even higher fraction of TNBCs that do not display a pathological complete response after neoadjuvant chemotherapy. We performed high-throughput chemical screens on TNBC cell lines with varying amounts of MYCN expression and determined that cells with higher expression of MYCN were more sensitive to bromodomain and extraterminal motif (BET) inhibitors. Combined BET and MEK inhibition resulted in a synergistic decrease in viability, both in vitro and in vivo, using cell lines and patient-derived xenograft (PDX) models. Our preclinical data provide a rationale to advance a combination of BET and MEK inhibitors to clinical investigation for patients with advanced MYCN-expressing TNBC.


End-of-life care in Toronto neonatal intensive care units: challenges for physician trainees.
Physician trainees in neonatology can find it extremely challenging to care for patients from diverse linguistic and multicultural backgrounds. This challenge is particularly highlighted when difficult and ethically challenging end-of-life (EOL) decision-making with parents is required. While these interactions are an opportunity for growth and learning, they also have the potential to lead to misunderstanding and uncertainty and can add to trainees' insecurity, unpreparedness and stress when participating in such interactions. To explore the challenges for trainees when EOL decisions are undertaken and to encourage them to reflect on how they might influence such decision-making. An in-depth, semi-structured interview guide was developed: the interview questions address trainees' beliefs, attitudes, preferences and expectations regarding discussions of EOL neonatal care. Twelve interviews were completed and the audio records transcribed verbatim, after removal of identifying personal information. Participants identified six domains of challenge in EOL care: withdrawal of life-sustaining treatment based on poor outcome, explaining 'no resuscitation options' to parents, clarifying 'do not resuscitate (DNR)' orders, empowering families with knowledge and shared decision-making, dealing with different cultures and managing personal internal conflict. Participants experienced the most difficulty during the initial stages of training and eventually reported good knowledge of the EOL care process. They had a sense of security and confidence working within a multidisciplinary care team, which includes experienced nursing staff as well as bereavement and palliative care coordinator within the neonatal intensive care unit. The challenges experienced by physician trainees when providing EOL care can serve as focal points for improving EOL educational programmes for neonatal fellowship training.


Phase II randomized trial of weekly paclitaxel with or without estramustine phosphate in progressive, metastatic, hormone-refractory prostate cancer.
This study was conducted to determine the similarity of response rates and safety produced by weekly paclitaxel with or without oral estramustine in patients with metastatic hormone-refractory prostate cancer. Between December 1998 and December 1999, 163 patients were randomized to receive 28-day cycles of paclitaxel 100 mg/m2 on days 2, 9, and 16 plus estramustine 280 mg orally 3 times a day on days 1-3, 8-10, and 15-17, or to receive paclitaxel 100 mg/m2 alone on days 1, 8, and 15. Objective response was defined as a > oe = 50% decrease in prostate-specific antigen (PSA) maintained for 4 weeks with stable or improved performance status. Response rates included 37 partial responses for paclitaxel/estramustine (47%) and 22 partial responses for paclitaxel (27%; P < 0.01). Median duration of response was 15.1 months for paclitaxel/estramustine and 15.5 months for paclitaxel; median survival was 16.1 months and 13.1 months, respectively (P = 0.049). Common toxicities for both treatments included neutropenia, gastrointestinal events, neuropathy, and asthenia. Thromboembolic events were more frequent in the paclitaxel/estramustine arm (no prophylactic anticoagulants). The rate of PSA decline for paclitaxel/estramustine was almost 2 times that of paclitaxel (47% vs. 27%), with acceptable toxicity. Multivariate analysis of prognostic factors affecting survival was not significant for treatment arm (P = 0.08). Although the incidence of thromboembolic events appeared to be increased in the paclitaxel/ estramustine arm, the addition of estramustine was responsible for a 20% increase in the rate of PSA decline. Neither treatment arm had significant impact on quality of life as measured by the Functional Assessment of Cancer Therapy-Prostate quality of life questionnaire. This study produced encouraging data; further studies of paclitaxel/ estramustine are recommended.


The effect of immobilization devices and left-foot adapter on brake-response time.
The ability to perform an emergency stop is essential for safe driving and can be represented by total brake-response time, reaction time, and braking time. Immobilization of the lower extremities is routinely performed for a variety of musculoskeletal conditions. This study sought to investigate the effect of immobilization with a left-foot driving adapter, a controlled-ankle-motion device, and a short leg cast on braking times. Our hypothesis was that there would be a significant difference in braking-time values between individuals utilizing a left-foot driving adapter or immobilization device and control individuals wearing normal footwear. A prospective, observational study was conducted to assess the effect of the immobilization devices on braking times. A driving simulator was used to assess total brake-response time, reaction time, and braking time in thirty-five volunteers. Volunteers were assessed while (1) wearing normal footwear (control group), (2) wearing a controlled-ankle-motion boot, (3) wearing a removable short leg cast, and (4) employing a left-foot driving adapter. The mean total brake-response time was significantly increased as compared with that of the control group in all three study groups. The mean reaction time was significantly increased for the short leg cast and controlled-ankle-motion groups as compared with reaction time in the control group. The mean braking time was significantly increased in the controlled-ankle-motion and left-foot driving-adapter groups as compared with braking time in the control group. Total brake-response time while wearing a controlled-ankle-motion boot or a short leg cast or while utilizing a left-foot driving adapter is significantly increased, or worsened, as compared with the response time while wearing normal footwear. This information may prove valuable to physicians when counseling patients on when it may be safe to return to driving.


Metabolic Syndrome and its Correlates among Hypertensive Patients in Abuja, North Central Nigeria.
Metabolic syndrome is a constellation of abnormalities which includes central obesity, dyslipidaemia, elevated blood pressure and hyperglycemia. Hypertension, (which is a very common component of metabolic syndrome), and diabetes mellitus, are independently associated. Also, studies examining metabolic syndrome inAbuja, a city with affluence-driven lifestyle, are not available. This study aimed to investigate the prevalence of metabolic syndrome among hypertensive patients in Abuja, Nigeria, as well as to examine the associations between metabolic syndrome and certain factors in that cohort of hypertensive patients. This was a retrospective study that used data from hypertensive patients who attended clinic over a period of five years. Eight hundred and fifty-eight, (858-combined), case files of pre-treated, (previously known hypertensive patients) and newly diagnosed hypertensive participants were used for the study. The student t-tests were used to compare continuous variables, while Chi-square (χ2) tests were used for relationship between qualitative variables. The likelihood ratio test was employed to further confirm the statistical significance of certain independent variables relating with metabolic syndrome. A P-value of < 0.05 was considered statistically significant. The mean ages were 48.70±12.18, 49.19±11.06 and 48.2±13.3 years for combined group, the pre-treated and the newly-diagnosed groups respectively. The pre-treated, group consists of those previously known hypertensive patients, while the new group consists of those who were newly diagnosed hypertensive patients and were treatment naïve. The prevalence of metabolic syndrome in this study was 45.5% in the combined group, 47.23% in the pre-treated group and 37.3% in the newly diagnosed group. The commonest component of metabolic syndrome was reduced high density lipoprotein cholesterol, HDL-C. Metabolic syndrome is prevalent among hypertensive patients in Abuja, Nigeria. Some correlates of metabolic syndrome include; elevated BMI, truncal obesity, elevated total cholesterol, the use of thiazide diuretics and beta blockers as antihypertensives.


Isolation of Smenopyrone, a Bis-γ-Pyrone Polypropionate from the Caribbean Sponge Smenospongia aurea.
The organic extract of the Caribbean sponge Smenospongia aurea has been shown to contain an array of novel chlorinated secondary metabolites derived from a mixed PKS-NRPS biogenetic route such as the smenamides. In this paper, we report the presence of a biogenetically different compound known as smenopyrone, which is a polypropionate containing two γ-pyrone rings. The structure of smenopyrone including its relative and absolute stereochemistry was determined by spectroscopic analysis (NMR, MS, ECD) and supported by a comparison with model compounds from research studies. Pyrone polypropionates are unprecedented in marine sponges but are commonly found in marine mollusks where their biosynthesis by symbiotic bacteria has been hypothesized and at least in one case demonstrated. Since pyrones have recently been recognized as bacterial signaling molecules, we speculate that smenopyrone could mediate inter-kingdom chemical communication between S. aurea and its symbiotic bacteria.


Reciprocal expression of integration host factor and HU in the developmental cycle and infectivity of Legionella pneumophila.
Legionella pneumophila is an intracellular parasite of protozoa that differentiates late in infection into metabolically dormant cysts that are highly infectious. Regulation of this process is poorly understood. Here we report that the small DNA binding regulatory proteins integration host factor (IHF) and HU are reciprocally expressed over the developmental cycle, with HU expressed during exponential phase and IHF expressed postexponentially. To assess the role of these regulatory proteins in development, chromosomal deletions were constructed. Single (ihfA or ihfB) and double deletion (Deltaihf) IHF mutants failed to grow in Acanthamoeba castellanii unless complemented in trans when expressed temporally from the ihfA promoter but not under P(tac) (isopropyl-beta-d-thiogalactopyranoside). In contrast, IHF mutants were infectious for HeLa cells, though electron microscopic examination revealed defects in late-stage cyst morphogenesis (thickened cell wall, intracytoplasmic membranes, and inclusions of poly-beta-hydroxybutyrate), and were depressed for the developmental marker MagA. Green fluorescent protein promoter fusion assays indicated that IHF and the stationary-phase sigma factor RpoS were required for full postexponential expression of magA. Finally, defects in cyst morphogenesis noted for Deltaihf mutants in HeLa cells correlated with a loss of both detergent resistance and hyperinfectivity compared with results for wild-type cysts. These studies establish IHF and HU as markers of developmental stages and show that IHF function is required for both differentiation and full virulence of L. pneumophila in natural amoebic hosts.


A Rare Case of Sinonasal Pleomorphic Adenoma.
Pleomorphic adenoma (PA) is the most prevalent benign tumor of the salivary glands, characterized by both epithelial and mesenchymal differentiation. It primarily originates within the parotid and submandibular glands, with only rare occurrences in the minor salivary glands. PA in the sinonasal area is extremely rare. Herein, we present a case of a 61-year-old female with a large soft tissue mass in the paranasal sinus and nasal cavity, as evidenced by computed tomography imaging. The patient suffered from repeated nasal congestion for more than 6 months. Eventually, the mass was completely resected using an endoscopic endonasal prelacrimal approach under general anesthesia. Postoperative pathological examination revealed the presence of PA in the nasal sinus.


Altered Long Noncoding RNA and Messenger RNA Expression in Experimental Intracerebral Hemorrhage - a Preliminary Study.
Functional recovery in the chronic phase is a difficult problem in intracerebral hemorrhage (ICH) treatment. Long noncoding RNAs (lncRNAs) are demonstrated to be involved in central nervous system (CNS) disorders. However, the roles of lncRNAs in post-ICH injury and repair are poorly understood, especially those that may be attributed to long-term neurological deficit. The present study depicted the lncRNA and messenger RNA (mRNA) profile by microarray at late stage after an experimental ICH. LncRNA and mRNA microarray was used to first identify differentially expressed genes. Gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to determine bio-functions and signaling pathways, with which differentially expressed genes are most closely related. Quantitative real-time polymerase chain reaction (PCR) was used to validate the results of microarray. Finally, the lncRNA-mRNA co-expression network was constructed to find the interaction of genes. A total of 625 differentially expressed lncRNAs and 826 expressed mRNAs were identified. Altered genes were enriched in mitochon-drial matrix, G-protein coupled receptor signaling pathway, and olfactory transduction, which may be associated with ICH-induced pathophysiologic changes in the long term. A co-expression network profile based on 5 validated differentially expressed lncRNAs and 205 interacted mRNAs was composed of 210 nodes and 298 connections. Mitochondrial matrix, reduced G-protein coupled receptor activity, and impaired olfactory transduction may be involved in the sequelae following ICH. Further, these dysregulated lncRNAs and mRNAs may be the promising therapeutic targets to overcome obstacles in functional recovery following ICH.


Knockdown of Oligosaccharyltransferase Subunit Ribophorin 1 Induces Endoplasmic-Reticulum-Stress-Dependent Cell Apoptosis in Breast Cancer.
Ribophorin 1 (RPN1) is a major part of Oligosaccharyltransferase (OST) complex, which is vital for the N-linked glycosylation. Though it has been verified that the abnormal glycosylation is closely related to the development of breast cancer, the detail role of RPN1 in breast cancer remains unknown. In this study, we explored the public databases to investigate the relationship between the expression levels of OST subunits and the prognosis of breast cancer. Then, we focused on the function of RPN1 in breast cancer and its potential mechanisms. Our study showed that the expression of several OST subunits including RPN1, RPN2, STT3A STT3B, and DDOST were upregulated in breast cancer samples. The protein expression level of RPN1 was also upregulated in breast cancer. Higher expression of RPN1 was correlated with worse clinical features and poorer prognosis. Furthermore, knockdown of RPN1 suppressed the proliferation and invasion of breast cancer cells in vitro and induced cell apoptosis triggered by endoplasmic reticulum stress. Our results identified the oncogenic function of RPN1 in breast cancer, implying that RPN1 might be a potential biomarker and therapeutic target for breast cancer.


Adult Parasitoids of Honeydew-Producing Insects Prefer Honeydew Sugars to Cover their Energetic Needs.
To meet their carbohydrate requirements, adult parasitoids exploit a broad range of sugar resources, including floral and extrafloral nectar and honeydew. Although honeydew might be the predominant sugar source, especially in agricultural systems, it often is nutritionally inferior to sugar sources like nectar. Given its broad availability, it may be expected that sugar-feeding insects have evolved specialized adaptations to deal with this typically inferior sugar source. This would apply especially to organisms that have a close association with honeydew producers. Here, we hypothesized that parasitoids of honeydew-producing insects should show a pronounced response to sugars, such as fructose, sucrose, melezitose, and trehalose, and to a lesser extent glucose. To test this hypothesis, we investigated sugar consumption, feeding behavior and survival of the aphid parasitoid Aphidius ervi on several sugars (equiweight solutions). Our results show that A. ervi adults consumed typical honeydew sugars (sucrose, fructose, trehalose, and melezitose) the most, while consuming considerably less glucose or melibiose. Rhamnose, which does not occur in aphid honeydew, was not, or was only marginally, consumed. When different sugars were provided at the same time, A. ervi adults preferred sucrose or fructose over glucose or melezitose. Furthermore, pre-exposure to sucrose or fructose significantly reduced subsequent intake of glucose, suggesting an acquired distaste for glucose after being previously exposed to highly preferred sugars such as sucrose and fructose. Altogether, this study shows that A. ervi adults prefer sugars (fructose, melezitose, trehalose, and sucrose) that are overrepresented in aphid honeydew and show a lower preference to one (glucose) that is underrepresented in honeydew.


Exploration of the Drosophila acetylcholinesterase substrate activation site using a reversible inhibitor (Triton X-100) and mutated enzymes.
Cholinesterases are activated at low substrate concentration, and this is followed by inhibition as the level of substrate increases. However, one of these two components is sometimes lacking. In Drosophila acetylcholinesterase, the two phases are present, allowing both phenomena to be studied. Several kinetic schemes can explain this complex kinetic behavior. Among them, one model assumes that activation results from the binding of a substrate molecule to a non-productive site affecting the entrance of a substrate molecule into the active site. To test this hypothesis, we looked for an inhibitor competitive for activation and we found Triton X-100. Using organophosphates or carbamates as hemisubstrates, we showed that Triton X-100 inhibits or increases phosphorylation or carbamoylation of the enzyme. In vitro mutagenesis of the residues lining the active site gorge allowed us to locate the Triton X-100 binding site at the rim of the gorge with glutamate 107 playing the major role. These results led to the hypothesis that substrate binding at this site affects the entrance of another substrate molecule into the active site cleft.


Reward-Based Learning as a Function of Severity of Substance Abuse Risk in Drug-Naïve Youth with ADHD.
Attention-deficit/hyperactivity disorder (ADHD) is associated with elevated risk for later development of substance use disorders (SUD), specifically because youth with ADHD, similar to individuals with SUD, exhibit deficits in learning abilities and reward processing. Another known risk factor for SUD is familial history of substance dependence. Youth with familial SUD history show reward processing deficits, higher prevalence of externalizing disorders, and higher impulsivity scores. Thus, the main objective of this proof-of-concept study is to investigate whether risk loading (ADHD and parental substance use) for developing SUD in drug-naïve youth impacts reward-related learning. Forty-one drug-naïve youth, stratified into three groups: Healthy Controls (HC, n = 13; neither ADHD nor parental SUD), Low Risk (LR, n = 13; ADHD only), and High Risk (HR, n = 15; ADHD and parental SUD), performed a novel Anticipation, Conflict, and Reward (ACR) task. In addition to conventional reaction time (RT) and accuracy analyses, we analyzed computational variables including learning rates and assessed the influence of learned predictions of reward probability and stimulus congruency on RT. The multivariate ANOVA on learning rate, congruence, and prediction revealed a significant main Group effect across these variables [F(3, 37) = 3.79, p = 0.018]. There were significant linear effects for learning rate (Contrast Estimate = 0.181, p = 0.038) and the influence of stimulus congruency on RTs (Contrast Estimate = 1.16, p = 0.017). Post hoc comparisons revealed that HR youth showed the most significant deficits in accuracy and learning rates, while stimulus congruency had a lower impact on RTs in this group. LR youth showed scores between those of the HC and HR youth. These preliminary results suggest that deficits in learning and in adjusting to task difficulty are a function of increasing risk loading for SUD in drug-naïve youth. These results also highlight the importance of developing and applying computational models to study intricate details in behavior that typical analytic methodology may not be sensitive to.


[Diagnostic capabilities of ultrasound biomicroscopy in phaco surgery].
Capabilities of ultrasound biomicroscopy (UBM) as a diagnostic method for surgical planning and outcome analysis in nonstandard situations in phaco surgery have been investigated. The study enrolled 270 patients (278 eyes) with pseudophakia and 26 patients (33 eyes) with aphakia. The scanning was done on OTI HF 35-50 Ultrasound System biomicroscope (UBM) - OTI, Canada. An original method of intraocular lens (IOL) position evaluation by means of UBM, providing precise information on relative position of the IOL and ocular axes, planes, and anatomical structures, has been developed. The proposed technique has been applied to determine both whether the position of the IOL is correct (46 eyes) and, if not, which of three types of its dislocation is present (232 eyes). Clinical and functional features of each of the dislocation types have been analyzed. Detailed analysis of UBM scans of 47 patients (47 eyes) showed that secondary glaucoma development was triggered by loss of proper endocapsular fixation of the IOL with consequent traumatic contact between IOL haptics and uveal tract. This contact, on the one hand, leads to excessive wash-out of pigment and obstruction of outflow routes. On the other hand, it causes subacute reactive uveitis which aggravates preexisting ocular hypertension and glaucoma course. It has been demonstrated that UBM performed prior to IOL implantation enables adequate assessment of the implant bed, accounting for lens capsule integrity, ciliary sulcus configuration and parameters, as well as the extent of structural changes in the globe, which may result from trauma, uveitis or improper evacuation of lens matter during cataract removal. Authors recommend to include UBM into assessment of aphakic patients planned for secondary IOL implantation and to decide on IOL model and its fixation type depending on the UBM results.


Immobilization of Candida antarctica lipase B on Polystyrene Nanoparticles.
Polystyrene (PS) nanoparticles were prepared via a nanoprecipitation process. The influence of the pH of the buffer solution used during the immobilization process on the loading of Candida antarctica lipase B (Cal-B) and on the hydrolytic activity (hydrolysis of p-nitrophenyl acetate) of the immobilized Cal-B was studied. The pH of the buffer solution has no influence on enzyme loading, while immobilized enzyme activity is very dependent on the pH of adsorption. Cal-B immobilized on PS nanoparticles in buffer solution pH 6.8 performed higher hydrolytic activity than crude enzyme powder and Novozyme 435.


Multiple uses of forest plots in presenting analysis results in health research: A Tutorial.
Forest plots are an important graphical method in meta-analyses used to show results from individual studies and pooled analyses. Forest plots are easy and straightforward to understand because they provide tabular and graphical information about estimates of comparisons or associations, corresponding precision, and statistical significance. This visual representation also makes it easier to see variations between individual study results. Forest plots are widely used in not only systematic reviews and meta-analyses but also observational studies and clinical trials. In this study, we aimed to show readers the various uses of forest plots in displaying analysis results. We used a tutorial type to show multiple uses of forest plots in meta-analyses, clinical trials, and observational studies according to the PICO (Population or Subgroup, Intervention or Exposure, Control, and Outcome) framework. We introduced forest plots' structure, application, current practice, and research advances in health research. We provided some examples from the literature to show the various uses of forest plot-type graphics in health research including meta-analyses, clinical trials, and observational studies. It is expected that our discussion of the current multiple uses of forest plots in meta-analyses, clinical trials, and observational studies provides a glimpse about their potential in displaying results in a way that makes comparisons between items easier.


[Pharyngo-laryngeal spindle cell carcinoma].
Spindle cell carcinoma, a relatively uncommon neoplasia in the otorhinolaryngologic field has a benign polypoid appearance, and often results in diagnostic and therapeutic difficulties. A review of the published literature, and of all of the eight cases we have had in our department has been made, with special attention-being pad to anatomopathologic diagnosis, treatment and prognosis. To sum up, it represents a malignant neoplasia epithelial in origin and of a difficult clinical and pathological diagnosis, which would be more adequately treated by surgical exeresis. It has a worse prognosis than epidermoid carcinoma which is common in this part of the throat.


Hypnotherapy for Irritable Bowel Syndrome-Type Symptoms in Patients with Quiescent Inflammatory Bowel Disease: A Randomized, Controlled Trial.
Many inflammatory bowel disease [IBD] patients in remission have persisting symptoms, compatible with irritable bowel syndrome [IBS-type symptoms]. We aimed to compare the effectiveness of gut-directed hypnotherapy vs standard medical treatment [SMT] for IBS-type symptoms in IBD patients. In this multicentre, randomized, controlled, open-label trial, patients aged 12-65 years with IBD in clinical remission [global assessment] and biochemical remission [faecal calprotectin ≤100 µg/g, or ≤200 µg/g without inflammation at endoscopy] with IBS according to Rome III criteria were randomized to hypnotherapy or SMT. Primary outcome was the proportion with ≥50% reduction on a visual analog scale for symptom severity, as measured with the Irritable Bowel Syndrome Severity Scoring System [IBS-SSS] at week 40 [i.e. 6 months after finishing the intervention], compared to baseline. Secondary outcomes included total IBS-SSS score, quality of life, adequate relief, IBS-related cognitions, and depression and anxiety scores. Eighty patients were included, of whom 70 received at least one session of the allocated treatment and were included in the modified intention-to-treat-population. Seven patients were excluded because of missing baseline data required for the primary outcome. The primary outcome was met in nine [27%] of 33 patients randomized to SMT and nine [30%] of 30 patients randomized to hypnotherapy [p = 0.81]. Adequate relief was reported in 60% and 40% of subjects, respectively. Exploratory analyses of secondary outcomes revealed no apparent differences between the two treatment groups. Hypnotherapy was not superior to SMT in the treatment of IBS-type symptoms in IBD patients. Both treatment strategies are reasonable options from a clinical perspective.


Assessing for prenatal risk factors associated with infant neurologic morbidity using a multivariate analysis.
To characterize the biochemical and demographic profiles of pregnant people with maternal immune activation (MIA) and identify the prenatal characteristics associated with neurologic morbidity in offspring. This was a retrospective cohort study of 602 mother-infant dyads with births between 2009 and 2010 in California. Multivariable logistic regression was used to build a MIA vulnerability profile including mid-pregnancy biochemical markers and maternal demographic characteristics, and its relationship with infant neurologic morbidity was examined. Of the 602 mother-infant dyads, 80 mothers and 61 infants had diagnoses suggestive of MIA and neurologic morbidity, respectively. Our model, including two demographic and seven biochemical characteristics, identified mothers with MIA with good performance (AUC:0.814; 95% CI:0.7-0.8). Three demographic and five inflammatory markers together identified 80% of infants with neurological morbidity (AUC:0.802, 95% CI:0.7-0.8). Inflammatory environment in mothers with pre-existing risk factors like obesity, poverty, and prematurity renders offspring more susceptible to neurologic morbidities.


A multi-criteria decision framework for circular wastewater systems in emerging megacities of the Global South.
Lima faces increasing water stress due to demographic growth, climate change and outdated water management infrastructure. Moreover, its highly centralized wastewater management system is currently unable to recover water or other resources. Hence, the primary aim of this study is to identify suitable wastewater treatment alternatives for both eutrophication mitigation and indirect potable reuse (IPR). For eutrophication mitigation, we examined MLE, Bardenpho, Step-feed, HF-MBR, and FS-MBR. For IPR, we considered secondary treatment+UF + RO + AOP or MBR + RO + AOP. These alternatives form part of a WWTP network at a district level, aiding Lima's pursuit of a circular economy approach. This perspective allows reducing environmental impacts through resource recovery, making the system more resilient to disasters and future water shortages. The methods used to assess these scenarios were Life Cycle Assessment for the environmental dimension; Life Cycle Costing for the economic perspective; and Multi-Criteria Decision Analysis to integrate both the quantitative tools aforementioned and qualitative criteria for social and techno-operational dimensions, which combined, strengthen the decision-making process. The decision-making steered towards Bardenpho for eutrophication abatement when environmental and economic criteria were prioritized or when the four criteria were equally weighted, while HF-MBR was the preferred option when techno-operational and social aspects were emphasized. In this scenario, global warming (GW) impacts ranged from 0.23 to 0.27 kg CO2eq, eutrophication mitigation varied from 6.44 to 7.29 g PO4- equivalent, and costs ranged between 0.12 and 0.17 €/m3. Conversely, HF-MBR + RO + AOP showed the best performance when IPR was sought from the outset. In the IPR scenario, GW impacts were significantly higher, at 0.46-0.51 kg CO2eq, eutrophication abatement was above 98 % and costs increased to ca. 0.44 €/m3.


[Prevalence of urinary disorders and their relation to sexuality in women--point of view of gynecologist].
The cross-sectional study of a random sample (population of patients and healthy subjects) was performed. Questionnaire survey of 970 women aged 18 years and older in Vladimir using an Urination Disorder Questionnaire was performed. The prevalence of violations of lower urinary tract function according to incidence of outpatient visits from 03/29/11 to 01/04/11 was evaluated. According to the data of examination, urination disorders were detected in 61% of women aged 45 years and older, in 23% of respondents aged 40-45 years and in 16%--up to 40 years old. Urine collection disorders were found in 94% of women, disorders of urinary bladder emptying--in 83%, disorders after urinary bladder emptying--in 36% of patients. The most common disorders of urination were urinary incontinence--in 27% of women, and nocturia--in 19% of women. The frequency of urinary incontinence (27%) was significantly higher than the overall prevalence of overactive bladder (9%). Among women, 21% said that they have sexual problems, but 70% does not solve this problem.


Reverse Engineering Provides Insights on the Evolution of Subgroups A to E Avian Sarcoma and Leukosis Virus Receptor Specificity.
The initial step of retrovirus entry-the interaction between the virus envelope glycoprotein trimer and a cellular receptor-is complex, involving multiple, noncontiguous determinants in both proteins that specify receptor choice, binding affinity and the ability to trigger conformational changes in the viral glycoproteins. Despite the complexity of this interaction, retroviruses have the ability to evolve the structure of their envelope glycoproteins to use a different cellular protein as receptors. The highly homologous subgroup A to E Avian Sarcoma and Leukosis Virus (ASLV) glycoproteins belong to the group of class 1 viral fusion proteins with a two-step triggering mechanism that allows experimental access to intermediate structures during the fusion process. We and others have taken advantage of replication-competent ASLVs and exploited genetic selection strategies to force the ASLVs to naturally evolve and acquire envelope glycoprotein mutations to escape the pressure on virus entry and still yield a functional replicating virus. This approach allows for the simultaneous selection of multiple mutations in multiple functional domains of the envelope glycoprotein that may be required to yield a functional virus. Here, we review the ASLV family and experimental system and the reverse engineering approaches used to understand the evolution of ASLV receptor usage.


Medication usage and the risk of neoplasia in patients with Barrett's esophagus.
Experimental evidence indicates that proton pump inhibitors (PPIs), nonsteroidal anti-inflammatory drugs (NSAIDs)/aspirin, and statins can protect patients with Barrett's esophagus (BE) from developing neoplasias. However, only limited data are available on chemoprevention in patients with BE. A retrospective observational study was performed using data from patients with documented BE. Prescription information was collected from pharmacy records. Cox regression analyses were performed to examine the association between prescriptions for PPIs, NSAIDs/aspirin, or statins and the risk of developing esophageal dysplasia or adenocarcinoma during follow-up (from 1982 to 2005). We examined 344 patients diagnosed with BE (mean age 61 years, 90.4% Caucasian, 94.2% male). After BE diagnosis, 67.2% of the patients were prescribed PPIs for a mean duration of 5.1 years; 49.1% were prescribed NSAIDs for a mean duration of 3.6 years, and 25.3% were prescribed statins for a mean duration of 2.8 years. During 2620 patient-years, high grade dysplasia or esophageal adenocarcinoma developed in 33 patients. PPI treatment after BE diagnosis was associated with a reduced risk of high grade dysplasia or cancer; this association persisted after adjustment for gender, age, and the length of BE. NSAID and/or aspirin therapy were associated with a nonsignificant trend toward lower incidence of high grade dysplasia or esophageal cancer. PPI therapy reduces the risk of neoplasms in patients with BE. NSAIDs/aspirin appear to reduce cancer risk whereas statin use is not significantly associated with the risk of neoplasia in patients with BE.


Sterols in the central nervous system.
Aberrations in cerebral cholesterol homeostasis can lead to severe neurological diseases and have been linked to Alzheimer's disease. Many proteins involved in peripheral cholesterol metabolism are also present in the brain. Yet, brain cholesterol metabolism is very different from that in the remainder of the body. This review reports on present insights into the regulation of cerebral cholesterol homeostasis, focusing on cholesterol trafficking between astrocytes and neurons. Astrocytes are a major site of cholesterol synthesis. They secrete cholesterol in the form of apolipoprotein E-containing HDL-like particles. After birth, neurons are thought to reduce their cholesterol synthesis and rely predominantly on astrocytes for their cholesterol supply. How exactly neurons regulate their cholesterol supply is largely unknown. A role for the brain-specific cholesterol metabolite, 24(S)-hydroxycholesterol, in this process was recently proposed. Recent findings strengthen the link between brain cholesterol metabolism and factors involved in synaptic plasticity, a process essential for learning and memory functions, as well as regeneration, which are affected in Alzheimer's disease. Insight into the regulation of cerebral cholesterol homeostasis will provide possibilities to modulate the key steps involved and may lead to the development of therapies for the prevention as well as treatment of neurodegenerative diseases such as Alzheimer's disease.


The anchoring effect on the spin transport properties and I-V characteristics of pentacene molecular devices suspended between nickel electrodes.
Spin-polarized transport properties are determined for pentacene sandwiched between Ni surface electrodes with various anchoring ligands. These calculations are carried out using spin density functional theory in tandem with a non-equilibrium Green's function technique. The presence of a Se atom at the edge of the pentacene molecule significantly modifies the transport properties of the device because Se has a different electronegativity than S. Our theoretical results clearly show a larger current for spin-up electrons than for spin-down electrons in the molecular junction that is attached asymmetrically across the Se linker at one side of the Ni electrodes (in an APL magnetic orientation). Moreover, this molecular junction exhibits pronounced NDR as the bias voltage is increased from 0.8 to 1.0 V. However, this novel NDR behavior is only detected in this promising pentacene molecular device. The NDR in the current-voltage (I-V) curve results from the narrowness of the density of states for the molecular states. The feasibility of controlling the TMR is also predicted in these molecular device nanostructures. Spin-dependent transmission calculations show that the sign and strength of the current-bias voltage characteristics and the TMR could be tailored for the organic molecule devices. These molecular junctions are joined symmetrically and asymmetrically between Ni metallic probes across the S and Se atoms (at the ends of the edges of the pentacene molecule). Our theoretical findings show that spin-valve phenomena can occur in these prototypical molecular junctions. The TMR and NDR results show that nanoscale junctions with spin valves could play a vital role in the production of novel functional molecular devices.


RNAseq of diverse spring wheat cultivars released during last 110 years.
Here, we performed RNA-seq based expression analysis of root and leaf tissues of a set of 24 historical spring wheat cultivars representing 110 years of temporal genetic variations. This huge 130 tissues RNAseq dataset was initially used to study expression pattern of 97 genes regulating root growth and development in wheat. Root system architecture (RSA) is an important target for breeding stress-resilient and high-yielding wheat cultivars under climatic fluctuations. However, root transcriptome analysis is usually obscured due to challenges in root research due to their below ground presence. We also validated the dataset by performing correlation analysis between expression of RSA related genes in roots and leaves with 25 root traits analyzed under varying moisture conditions and 10 yield-related traits. The Pearson's correlation coefficients between root phenotypes and expression of root-specific genes varied from -0.72 to 0.78, and strong correlations with genes such as DRO1, TaMOR, ARF4, PIN1 was observed. The presented datasets have multiple uses such as a) studying the change in expression pattern of genes during time, b) differential expression of genes in two very important tissues of wheat i.e., leaf and roots, and c) studying customized expression of genes associated with important phenotypes in diverse wheat cultivars. The initial findings presented here provided key insights into understanding the transcriptomic basis of phenotypic variability of RSA in wheat cultivars.


Effects of peptides derived from terminal modifications of the aβ central hydrophobic core on aβ fibrillization.
Considerable research effort has focused on the discovery of mitigators that block the toxicity of the β-amyloid peptide (Aβ) by targeting a specific step involved in Aβ fibrillogenesis and subsequent aggregation. Given that aggregation intermediates are hypothesized to be responsible for Aβ toxicity, such compounds could likely prevent or mitigate aggregation, or alternatively cause further association of toxic oligomers into larger nontoxic aggregates. Herein we investigate the effect of modifications of the KLVFF hydrophobic core of Aβ by replacing N- and C-terminal groups with various polar moieties. Several of these terminal modifications were found to disrupt the formation of amyloid fibrils and in some cases induced the disassembly of preformed fibrils. Significantly, mitigators that incorporate MiniPEG polar groups were found to be effective against Aβ(1-40) fibrilligonesis. Previously, we have shown that mitigators incorporating alpha,alpha-disubstituted amino acids (ααAAs) were effective in disrupting fibril formation as well as inducing fibril disassembly. In this work, we further disclose that the number of polar residues (six) and ααAAs (three) in the original mitigator can be reduced without dramatically changing the ability to disrupt Aβ(1-40) fibrillization in vitro.


Acupuncture with specific mode electro-stimulation effectively and transiently opens the BBB through Shh signaling pathway.
To explore a new method that patients with brain diseases such as stroke sequelae are hindered by blood-brain barrier (BBB) in clinical treatment. Research preliminarily found that acupuncture with specific mode electro-stimulation (EA) to open BBB-assisted drug delivery may be is an effective means to improve the clinical efficacy of brain disease patients. So here we further explore the features and mechanism. Middle cerebral artery occlusion/R recovery rats were employed as the animal model. Laser Doppler monitoring cerebral blood flow decreased to 45 ± 10% of the baseline value as modeling criteria and TTC staining observed infarcted areas of brain tissue. The permeability of FITC-Dextran and EB in the frontal lobe of rats was observed by microscope. After that, Western blot and Immunofluorescence staining for the detection of the shh and Gli1 signal molecule, Claudin-5 Occludin ZO-1 tight junction (TJ) proteins. EA can open the BBB stably and effectively, and has the characteristics of starting to close soon after the end of EA; EA inhibits the Shh-Gli1 signaling pathway, and downregulates Occludin ZO-1 TJ proteins. These results suggest that EA is safe and reversible in opening the BBB, and its mechanism is related to the inhibition of Shh signaling pathway to down-regulate the expression of TJ proteins.


Primary DNA sequence determines sites of maintenance and de novo methylation by mammalian DNA methyltransferases.
Analysis of the enzymatic methylation of oligodeoxynucleotides containing multiple C-G groups showed that hemimethylated sites in duplex oligomers are not significantly methylated by human or murine DNA methyltransferase unless those sites are capable of being methylated de novo in the single- or double-stranded oligomers. Thus, the primary sequence of the target strand, rather than the methylation pattern of the complementary strand, determines maintenance methylation. This suggests that de novo and maintenance methylation are the same process catalyzed by the same enzyme. In addition, the study revealed that complementary strands of oligodeoxynucleotides are methylated at different rates and in different patterns. Both primary DNA sequence and the spacing between C-G groups seem important since in one case studied, maximal methylation required a specific spacing of 13 to 17 nucleotides between C-G pairs.


Growth of cell lines and clinical specimens of human non-small cell lung cancer in a serum-free defined medium.
We tested the ability of serum-free media to support the in vitro growth of human non-small cell lung carcinoma. A medium containing insulin, transferrin, sodium selenite, hydrocortisone, epidermal growth factor, and bovine serum albumin (1 mg/ml) with serum precoating of culture dishes (modified LA medium) supported three previously established cell lines of non-small cell lung cancer and prevented fibroblast proliferation in fresh tumor specimens but did not support long term tumor cell growth from fresh specimens. We added triiodothyronine, sodium pyruvate, and additional glutamine, insulin, and epidermal growth factor to modified LA medium, precoated with fibronectin and collagen instead of serum, and deleted bovine serum albumin, defining a new medium called ACL-3. ACL-3 medium alone supported the short term growth of 10 of 12 cell lines and the soft agarose cloning of 9 of 12 cell lines tested, and ACL-3 supplemented by an optimal concentration of bovine serum albumin (5 mg/ml) supported the long term growth of 10 of 12 cell lines tested. Moreover, we have grown tumor cells for more than 6 months from 11 of 33 (33%) consecutive fresh clinical specimens of human lung adenocarcinoma in ACL-3 with bovine serum albumin. ACL-3 medium provides a defined environment for the study of growth factor requirements of human non-small cell lung cancer and enhances our ability to grow human lung cancer, particularly adenocarcinoma, in vitro.


Genes involved in centrosome-independent mitotic spindle assembly in Drosophila S2 cells.
Animal mitotic spindle assembly relies on centrosome-dependent and centrosome-independent mechanisms, but their relative contributions remain unknown. Here, we investigated the molecular basis of the centrosome-independent spindle assembly pathway by performing a whole-genome RNAi screen in Drosophila S2 cells lacking functional centrosomes. This screen identified 197 genes involved in acentrosomal spindle assembly, eight of which had no previously described mitotic phenotypes and produced defective and/or short spindles. All 197 genes also produced RNAi phenotypes when centrosomes were present, indicating that none were entirely selective for the acentrosomal pathway. However, a subset of genes produced a selective defect in pole focusing when centrosomes were absent, suggesting that centrosomes compensate for this shape defect. Another subset of genes was specifically associated with the formation of multipolar spindles only when centrosomes were present. We further show that the chromosomal passenger complex orchestrates multiple centrosome-independent processes required for mitotic spindle assembly/maintenance. On the other hand, despite the formation of a chromosome-enriched RanGTP gradient, S2 cells depleted of RCC1, the guanine-nucleotide exchange factor for Ran on chromosomes, established functional bipolar spindles. Finally, we show that cells without functional centrosomes have a delay in chromosome congression and anaphase onset, which can be explained by the lack of polar ejection forces. Overall, these findings establish the constitutive nature of a centrosome-independent spindle assembly program and how this program is adapted to the presence/absence of centrosomes in animal somatic cells.


Predictors and Moderators of Treatment Outcomes for Anxious Children Randomized to Computer-Assisted Cognitive Behavioral Therapy or Standard Community Care.
Introduction: Computer-assisted cognitive behavioral therapy (CCBT) for childhood anxiety disorders may aid the dissemination of CBT, while maintaining treatment fidelity. Although CCBT is an effective intervention, not everyone benefits equally from treatment. Identifying patient characteristics that predict who will benefit from treatment and to what extent can help with matching patients to suitable interventions, and allow researchers and clinicians to modify, and individualize, their treatment formats more effectively. Such predictors and moderators have not yet been examined for CCBT outcomes in anxious children and studies of more traditional treatment formats have yielded inconsistent results. Methods: Using data from a randomized clinical trial evaluating CCBT for children with anxiety disorders, this study examined predictors and moderators of treatment outcomes in a sample of 100 children (age: mean [M] = 9.82, standard deviation [SD] = 1.82), randomized to either CCBT (n = 49) or standard community care (n = 51). Potential predictors and moderators were identified from the literature and examined in stepwise multiple linear regression models, using posttreatment anxiety severity and global impairment as outcomes. Results: Parent-rated internalizing symptoms predicted posttreatment anxiety severity for both treatment groups. High pretreatment levels of anxiety severity predicted higher global impairment at posttreatment for the group receiving community care, but not for the CCBT group. Conclusion: Further research is needed to clarify which patient characteristics are associated with CCBT outcomes in a consistent way. ClinicalTrials.gov identifier: NCT01416805.


Multidisciplinary personalized approach in the management of vulvar cancer - the Vul.Can Team experience.
Multidisciplinary treatment strategy involving adjuvant radiotherapy for advanced vulvar cancer could be useful in offering the best personalized clinical approach. In 2013, the VULvar CANcer Multi-Disciplinary Team (Vul.Can MDT) was set up in our institution, in order to share knowledge and expertise, high-quality diagnosis, and evidence-based decision making in the context of personalized medicine. The aim of this observational study was to report on our series of vulvar cancer patients managed postoperatively with radiotherapy within the framework of a formal multidisciplinary tumor board. Coupling surgical and oncological international guidelines with "case-by-case" discussions, a multi-specialist consensus was progressively reached and internal recommendations were developed and introduced in the daily routine. Data from vulvar cancer patients who underwent primary surgery and adjuvant radiotherapy throughout a 5-year period were retrospectively collected. Actuarial local control was the primary endpoint, while secondary end-points were acute and late toxicities, disease-free survival, and overall survival. Toxicity was evaluated according to the Common Toxicity Criteria Adverse Event v 4.0 scale. The analysis included 35 patients with squamous vulvar cancer treated with adjuvant radiotherapy±chemotherapy, from April 2013 to September 2017. Median age was 70 years (range 18-87), all patients underwent surgery followed by concomitant chemoradiation (45.7%) or radiotherapy alone (54.3%). The median prophylactic dose on lymphatic drainage was 45 Gy, while positive nodes and perineal area received 51.2 Gy and 52.6 Gy, respectively. Chemotherapy involved the cisplatin-based regimen (45.7%)±5-fluorouracil (37.1%). Median follow-up was 32 months (range 6-72): the 24-months local control, disease-free survival, and actuarial overall survival rates were 88.6%, 82.0%, and 91.0%, respectively. Low rates of severe acute (12%) and late (3%) toxicities occurred. The outcomes of this series support the benefit of a multidisciplinary personalized approach in the management of vulvar cancer.


Factors associated with severe malaria among children below ten years in Mutasa and Nyanga districts, Zimbabwe, 2014-2015.
Severe malaria is a rare life threatening illness. Only a small proportion of patients with clinical malaria progress to this medical emergency. On reviewing 61 malaria death investigation forms submitted to the provincial office in 2014, 22(36%) were children below ten years who succumbed to severe malaria. Mutasa and Nyanga Districts reported 73% of these deaths. This study was conducted to determine factors associated with severe malaria so as to come up with evidence based interventions to prevent severe malaria and associated mortality. A 1:2 unmatched case control study was conducted. A case was defined as a child 10 years and below, who was admitted at Hauna (Mutasa) or Nyanga District Hospitals between September 2014 and May 2015 with a primary diagnosis of severe malaria. Controls were children of similar age with uncomplicated malaria. Permission to conduct the study was sought and granted by the Medical Research Council of Zimbabwe (Approval number B/874), Joint Research Ethics Committee, Health Studies Office and the Manicaland Directorate Institutional Review Board. Written informed consent was sought from all caregivers of enrolled children. Interviewer administered questionnaires were used to ascertain exposures. A total of 52 cases and 104 controls were enrolled into the study. The median age of cases was 4 years (Q1=3, Q3=9) and 6 years for controls (Q1=3, Q3=8). The Case Fatality Rate among cases was 28.8%. The independent risk factors for severe malaria were; distance >10km to the nearest health facility [Adjusted Odds Ratio (aOR)=14.35, 95% CI=1.30, 158.81], duration of symptoms before seeking medical care >2 days [aOR=9.03, 95% CI=2.21, 36.93], having comorbidities [aOR=5.38, 95% CI=1.90, 15.19], staying in a house under construction [aOR=4.51, 95%CI=1.80, 11.32] and duration of illness before receiving antimalarial medicines >24 hours [aOR=3.82, 95% CI=1.44, 10.12]. Owning at least one ITN in the household [aOR=0.32, 95% CI=0.11, 0.95] and having a mother as a caregiver [aOR=0.23, 95% CI=0.09, 0.76] were independently protective of severe malaria. Being undernourished [Odds Ratio (OR)=10.13, 95% CI=1.04, 98.49] and being female [OR=0.27, 95% CI=0.08, 0.96] were associated with mortality owing to severe malaria. Factors associated with severe malaria and mortality owing to severe malaria identified in this study are consistent with other studies. Caregiver healthcare seeking behaviours, patient related factors and health system related factors are important determinants of severe malaria among children. There is need for regular health education campaigns emphasizing on malaria prevention, signs and symptoms and benefits of seeking medical care immediately for sick children.


Multifunctional Flexible Sensor Based on Laser-Induced Graphene.
The paper presents the design and fabrication of a low-cost and easy-to-fabricate laser-induced graphene sensor together with its implementation for multi-sensing applications. Laser-irradiation of commercial polymer film was applied for photo-thermal generation of graphene. The graphene patterned in an interdigitated shape was transferred onto Kapton sticky tape to form the electrodes of a capacitive sensor. The functionality of the sensor was validated by employing them in electrochemical and strain-sensing scenarios. Impedance spectroscopy was applied to investigate the response of the sensor. For the electrochemical sensing, different concentrations of sodium sulfate were prepared, and the fabricated sensor was used to detect the concentration differences. For the strain sensing, the sensor was deployed for monitoring of human joint movements and tactile sensing. The promising sensing results validating the applicability of the fabricated sensor for multiple sensing purposes are presented.


Aromatase inhibitors affect vaginal proliferation and steroid hormone receptors.
Women with breast cancer who are treated with aromatase inhibitors often experience vaginal atrophy symptoms and sexual dysfunction. This work aims to study proliferation and the presence and distribution of steroid hormone receptors in vaginal biopsies in relation to vaginal atrophy and vaginal pH in women with breast cancer who are on adjuvant endocrine treatment and in healthy postmenopausal women. This is a cross-sectional study that compares postmenopausal aromatase inhibitor-treated women with breast cancer (n = 15) with tamoxifen-treated women with breast cancer (n = 16) and age-matched postmenopausal women without treatment (n = 19) or with vaginal estrogen therapy (n = 16). Immunohistochemistry was used to study proliferation and steroid hormone receptor staining intensity. Data was correlated with estrogen and androgen levels, vaginal atrophy scores, and vaginal pH. Aromatase inhibitor-treated women had a lower grade of proliferation, weaker progesterone receptor staining, and stronger androgen receptor staining, which correlated with plasma estrone levels, vaginal atrophy scores, and vaginal pH. Women with aromatase inhibitor-treated breast cancer exhibit reduced proliferation and altered steroid hormone receptor staining intensity in the vagina, which are related to clinical signs of vaginal atrophy. Although these effects are most probably attributable to estrogen suppression, a possible local inhibition of aromatase cannot be ruled out.


Species richness and occupancy estimation in communities subject to temporary emigration.
Species richness is the most common biodiversity metric, although typically some species remain unobserved. Therefore, estimates of species richness and related quantities should account for imperfect detectability. Community dynamics can often be represented as superposition of species-specific phenologies (e.g., in taxa with well-defined flight [insects], activity [rodents], or vegetation periods [plants]). We develop a model for such predictably open communities wherein species richness is expressed as the sum over observed and unobserved species of estimated species-specific and site-specific occurrence indicators and where seasonal occurrence is modeled as a species-specific function of time. Our model is a multispecies extension of a multistate model with one unobservable state and represents a parsimonious way of dealing with a widespread form of "temporary emigration." For illustration we use Swiss butterfly monitoring data collected under a robust design (RD); species were recorded on 13 transects during two secondary periods within < or = 7 primary sampling periods. We compare estimates with those under a variation of the model applied to standard data, where secondary samples are pooled. The latter model yielded unrealistically high estimates of total community size of 274 species. In contrast, estimates were similar under models applied to RD data with constant (122) or seasonally varying (126) detectability for each species, but the former was more parsimonious and therefore used for inference. Per transect, 6-44 (mean 21.1) species were detected. Species richness estimates averaged 29.3; therefore only 71% (range 32-92%) of all species present were ever detected. In any primary period, 0.4-5.6 species present were overlooked. Detectability varied by species and averaged 0.88 per primary sampling period. Our modeling framework is extremely flexible; extensions such as covariates for the occurrence or detectability of individual species are easy. It should be useful for communities with a predictable form of temporary emigration where rigorous estimation of community metrics has proved challenging so far.


Biologic variability of cardiac troponin I in healthy dogs and dogs with different stages of myxomatous mitral valve disease using standard and high-sensitivity immunoassays.
Biologic variability (BV) is one aspect of interpreting changes in biomarker concentrations known to be clinically important in people with cardiac disease, but it has not been adequately addressed in dogs so far. The purpose of the study was to determine BV of cardiac troponin I (cTnI) in healthy dogs and dogs with 3 stages of myxomatous mitral valve disease (MMVD). Healthy dogs and dogs with 3 stages of MMVD were prospectively assigned to groups based on comprehensive clinical evaluation using current guidelines. Concentrations of cTnI were measured hourly, daily, and weekly using standard and high-sensitivity immunoassays. Within- (CVI ) and between-subject (CVG ) coefficients of variability, percent reference change value (RCV), and index of individuality (IoI) were calculated. All 10 healthy dogs and 76/112 (68%) of samples from 28 MMVD dogs had cTnI concentrations below the limit of detection (LOD) using a standard sensitivity immunoassay. Only 49/160 (31%) of healthy dog samples and no MMVD samples had cTnI below the high-sensitivity immunoassay LOD. Data analysis for the high-sensitivity immunoassay revealed CVI of 48.1%, CVG of 60.1%, RCV of 134.0%, and IoI of 0.804 in healthy dogs. In MMVD dogs, CVI was 39.6%, CVG was 80.7%, RCV was 110%, and IoI was 0.494. Of all MMVD dogs, those with Stage B2 had the lowest RCV of 91%. Biologic variability affects cTnI concentrations in healthy dogs and dogs with MMVD. Consideration of BV may be clinically relevant when monitoring individual changes in cTnI values, using high-sensitivity immunoassays.


Overuse in volleyball training/practice: A review on shoulder and spine-related injuries.
Overuse injuries are predominant in sports involving the repetition of similar movements patterns, such as in volleyball or beach volleyball, and they may represent as much a problem as do acute injuries. This review discusses the prevalence of two of the most common overuse-related injuries in volleyball: shoulder and back/spine injuries. Risk factors and the aetiology of these injuries are illustrated in order to make possible to initiate preventive programme or post-injuries solutions. Data collected from literature showed a moderately higher injury rate for overuse shoulder injuries compared to the back/spine (19.0 ± 11.2% and 16.8 ± 9.7%, respectively). These data could be underestimated, and future epidemiological studies should consider overuse injuries separately from the others, with new methodological approaches. In addition to age, biomechanical and anatomical features of a volleyball technique utilised in game and the amount of hours played are considered as the main risk factors for overuse upper limb injuries, both for professional and recreational athletes. Together with post-injuries solutions, great importance has to be placed on preventive programmes, such as preventive rehabilitation, stretching, adequate warm up, strength-power exercises, etc. Furthermore, it is particularly suggested that coaches and players work together in order to develop new game/training techniques that minimise stresses and range of motion of the principal anatomical structures involved, while maintaining athletes performance.


Microbial Contamination of Bedding Material: One Health in Poultry Production.
In poultry farms, the mixture of bedding material, chicken excrement, and feathers seems to play an important role in pathogen development which may contribute to a potential risk of zoonosis, spreading the disease through the food chain. The purpose of this study was to analyze microbial contamination in bedding material and other matrices as well as potential antimicrobial resistances in chicken production facilities, and also to identify the sampling techniques and assays used. This study evidences the available data published, following the PRISMA methodology. Among the environmental samples, surface swabs were frequently used as a passive sampling technique. Morphological identification was performed in all studies. From all the matrices, the bedding material was the most contaminated. Most studies focused on bacterial contamination, with Salmonella sp. and Campylobacter sp. being commonly reported and three studies evidenced fungal contamination, being Penicillium sp.- and Aspergillus sp.-dominant. Mycotoxin assessment was only performed in one study, being identified in all bedding samples. The screening for bacteria resistance evidenced bacteria multidrug resistance; however, fungal susceptibility to azoles was not assessed in any of the analyzed studies. Briefly, this review evidences the microbial contamination in poultry facilities, emphasizing animals' bedding as a potential source of contamination. Additionally, this study contributes to a sampling and analysis protocol proposal to assess the microbial contamination in this setting. Additionally, the knowledge gaps identified highlight the need of further research regarding microbial contamination and toxicological potential on animals' bedding in order to mitigate the exposure in poultry pavilions.


Anti-Müllerian Hormone and Testicular Function in Prepubertal Boys With Cryptorchidism.
The functional capacity of the testes in prepubertal boys with cryptorchidism before treatment has received very little attention. The assessment of testicular function at diagnosis could be helpful in the understanding of the pathophysiology of cryptorchidism and in the evaluation of the effect of treatment. Anti-Müllerian hormone is a well-accepted Sertoli cell biomarker to evaluate testicular function during childhood without the need for stimulation tests. The aim of the study was to assess testicular function in prepubertal children with cryptorchidism before orchiopexy, by determining serum anti-Müllerian hormone (AMH). We also evaluated serum gonadotropins and testosterone and looked for associations between testicular function and the clinical characteristics of cryptorchidism. We performed a retrospective, cross-sectional, analytical study at a tertiary pediatric public hospital. All clinical charts of patients admitted at the outpatient clinic, and recorded in our database with the diagnosis of cryptorchidism, were eligible. The main outcome measure of the study was the serum concentration of AMH. Secondary outcome measures were serum LH, FSH, and testosterone. For comparison, serum hormone levels from a normal population of 179 apparently normal prepubertal boys were used. Out of 1,557 patients eligible in our database, 186 with bilateral and 124 with unilateral cryptorchidism were selected using a randomization software. Median AMH standard deviation score was below 0 in both the bilaterally and the unilaterally cryptorchid groups, indicating that testicular function was overall decreased in patients with cryptorchidism. Serum AMH was significantly lower in boys with bilateral cryptorchidism as compared with controls and unilaterally cryptorchid patients between 6 months and 1.9 years and between 2 and 8.9 years of age. Serum AMH below the normal range reflected testicular dysfunction in 9.5-36.5% of patients according to the age group in bilaterally cryptorchid boys and 6.3-16.7% in unilaterally cryptorchid boys. FSH was elevated in 8.1% and LH in 9.1% of boys with bilateral cryptorchidism, most of whom were anorchid. In patients with present testes, gonadotropins were only mildly elevated in less than 5% of the cases. Basal testosterone was mildly decreased in patients younger than 6 months old, and uninformative during childhood. Prepubertal boys with cryptorchidism, especially those with bilaterally undescended gonads, have decreased AMH production. Although serum AMH may fall within the normal range, there is a considerable prevalence of testicular dysfunction during childhood in this frequent condition.


Combining Laser-Induced Breakdown Spectroscopy (LIBS) and Visible Near-Infrared Spectroscopy (Vis-NIRS) for Soil Phosphorus Determination.
Conventional wet chemical methods for the determination of soil phosphorus (P) pools, relevant for environmental and agronomic purposes, are labor-intensive. Therefore, alternative techniques are needed, and a combination of the spectroscopic techniques-in this case, laser-induced breakdown spectroscopy (LIBS)-and visible near-infrared spectroscopy (vis-NIRS) could be relevant. We aimed at exploring LIBS, vis-NIRS and their combination for soil P estimation. We analyzed 147 Danish agricultural soils with LIBS and vis-NIRS. As reference measurements, we analyzed water-extractable P (Pwater), Olsen P (Polsen), oxalate-extractable P (Pox) and total P (TP) by conventional wet chemical protocols, as proxies for respectively leachable, plant-available, adsorbed inorganic P, and TP in soil. Partial least squares regression (PLSR) models combined with interval partial least squares (iPLS) and competitive adaptive reweighted sampling (CARS) variable selection methods were tested, and the relevant wavelengths for soil P determination were identified. LIBS exhibited better results compared to vis-NIRS for all P models, except for Pwater, for which results were comparable. Model performance for both the LIBS and vis-NIRS techniques as well as the combined LIBS-vis-NIR approach was significantly improved when variable selection was applied. CARS performed better than iPLS in almost all cases. Combined LIBS and vis-NIRS models with variable selection showed the best results for all four P pools, except for Pox where the results were comparable to using the LIBS model with CARS. Merging LIBS and vis-NIRS with variable selection showed potential for improving soil P determinations, but larger and independent validation datasets should be tested in future studies.


Ultrastructure of an indigotin-producing dome mutant of Schizophyllum commune.
Electron microscopic observations of an indigotin-producing dome mutant of Schizophyllum commune Fr. have shown that large wall ingrowths occur within the hyphae. These ingrowths are coupled with morphological abnormalities produced by the dome mutation. The pigment indigotin appears to be produced by progressive condensation within vacuoles and to a lesser extent within the wall ingrowths. Cytochemical techniques have shown that the wall ingrowths are similar in structure to the hyphal walls. there was no evidence for the passage of condensed indigotin into the medium; the pigment granules found in the medium must therefore form outside the hyphae.


Hand of FATe: lipid metabolism in hematopoietic stem cells.
Hematopoietic stem cells (HSCs) reside in the bone marrow and are important in replenishing all cells in the blood through a process termed hematopoiesis. One of the defining characteristics of HSCs is that they must be able to balance their self-renewal capacity with their differentiation into committed blood cells in various blood lineages. For these events to occur, HSCs must be tightly regulated in the bone marrow by intrinsic and extrinsic factors to maintain steady hematopoiesis. Recently, the effect on how metabolism regulates HSC function has received a great amount of attention. In particular, lipids have been found to participate in mitochondrial activity to maintain HSCs, a role previously overlooked due to HSCs being thought of as mostly glycolytic. Moreover, there has been a re-emergence of how adipocytes in the bone marrow can regulate HSCs. As these areas evolve, more studies are required to determine the exact contribution of lipids toward HSC maintenance. These studies will allow newer therapeutic targets to help reduce abnormal hematopoiesis such as myelopoiesis, which contributes to many metabolic diseases.


ARGONAUTE10 and ARGONAUTE1 regulate the termination of floral stem cells through two microRNAs in Arabidopsis.
Stem cells are crucial in morphogenesis in plants and animals. Much is known about the mechanisms that maintain stem cell fates or trigger their terminal differentiation. However, little is known about how developmental time impacts stem cell fates. Using Arabidopsis floral stem cells as a model, we show that stem cells can undergo precise temporal regulation governed by mechanisms that are distinct from, but integrated with, those that specify cell fates. We show that two microRNAs, miR172 and miR165/166, through targeting APETALA2 and type III homeodomain-leucine zipper (HD-Zip) genes, respectively, regulate the temporal program of floral stem cells. In particular, we reveal a role of the type III HD-Zip genes, previously known to specify lateral organ polarity, in stem cell termination. Both reduction in HD-Zip expression by over-expression of miR165/166 and mis-expression of HD-Zip genes by rendering them resistant to miR165/166 lead to prolonged floral stem cell activity, indicating that the expression of HD-Zip genes needs to be precisely controlled to achieve floral stem cell termination. We also show that both the ubiquitously expressed ARGONAUTE1 (AGO1) gene and its homolog AGO10, which exhibits highly restricted spatial expression patterns, are required to maintain the correct temporal program of floral stem cells. We provide evidence that AGO10, like AGO1, associates with miR172 and miR165/166 in vivo and exhibits "slicer" activity in vitro. Despite the common biological functions and similar biochemical activities, AGO1 and AGO10 exert different effects on miR165/166 in vivo. This work establishes a network of microRNAs and transcription factors governing the temporal program of floral stem cells and sheds light on the relationships among different AGO genes, which tend to exist in gene families in multicellular organisms.


Resilience and Equity in a Time of Crises: Investing in Public Urban Greenspace Is Now More Essential Than Ever in the US and Beyond.
The intersecting negative effects of structural racism, COVID-19, climate change, and chronic diseases disproportionately affect racial and ethnic minorities in the US and around the world. Urban populations of color are concentrated in historically redlined, segregated, disinvested, and marginalized neighborhoods with inadequate quality housing and limited access to resources, including quality greenspaces designed to support natural ecosystems and healthy outdoor activities while mitigating urban environmental challenges such as air pollution, heat island effects, combined sewer overflows and poor water quality. Disinvested urban environments thus contribute to health inequity via physical and social environmental exposures, resulting in disparities across numerous health outcomes, including COVID-19 and chronic diseases such as cancer and cardiovascular diseases (CVD). In this paper, we build off an existing conceptual framework and propose another conceptual framework for the role of greenspace in contributing to resilience and health equity in the US and beyond. We argue that strategic investments in public greenspaces in urban neighborhoods impacted by long term economic disinvestment are critically needed to adapt and build resilience in communities of color, with urgency due to immediate health threats of climate change, COVID-19, and endemic disparities in chronic diseases. We suggest that equity-focused investments in public urban greenspaces are needed to reduce social inequalities, expand economic opportunities with diversity in workforce initiatives, build resilient urban ecosystems, and improve health equity. We recommend key strategies and considerations to guide this investment, drawing upon a robust compilation of scientific literature along with decades of community-based work, using strategic partnerships from multiple efforts in Milwaukee Wisconsin as examples of success.


Ligand Tuning of Localized Surface Plasmon Resonances in Antimony-Doped Tin Oxide Nanocrystals.
Aliovalent-doped metal oxide nanocrystals exhibiting localized surface plasmons (LSPRs) are applied in systems that require reflection/scattering/absorption in infrared and optical transparency in visible. Indium tin oxide (ITO) is currently leading the field, but indium resources are known to be very restricted. Antimony-doped tin oxide (ATO) is a cheap candidate to substitute the ITO, but it exhibits less advantageous electronic properties and limited control of the LSPRs. To date, LSPR tuning in ATO NCs has been achieved electrochemically and by aliovalent doping, with a significant decrease in doping efficiency with an increasing doping level. Here, we synthesize plasmonic ATO nanocrystals (NCs) via a solvothermal route and demonstrate ligand exchange to tune the LSPR energies. Attachment of ligands acting as Lewis acids and bases results in LSPR peak shifts with a doping efficiency overcoming those by aliovalent doping. Thus, this strategy is of potential interest for plasmon implementations, which are of potential interest for infrared upconversion, smart glazing, heat absorbers, or thermal barriers.


[Duodenal eosinophilia in functional dyspepsia in a Colombian sample: a case-control study].
Functional dyspepsia (FD) is a complex symptom. Currently there are multiple therapeutic options that are used for the management of these patients; however, FD therapies are based on symptomatic control and do not address the pathophysiological pathways involved in its development. The duodenum has been proposed as a key site to understand the complex pathophysiology involved in FD. The aim of the study is to determine duodenal eosinophilia in patients with FD and establish the clinical-pathological correlation with the cardinal symptoms of dyspepsia. Case-control study. Patients older than 18 years with dyspepsia according to the Rome IV criteria, and upper gastrointestinal endoscopy normal (FD group).Patients with iron deficiency anemia and chronic diarrhea (control group). Biopsies were taken in the stomach, duodenal bulb and second portion of duodenum. A sample size of 140 patients (70 patients in the FD group and 70 patients in the control group) was calculated. The collected information was described and analyzed by conventional statistical techniques. 243 patients were recruited. 84 patients were included in the FD group and 84 patients in the control group. 135 patients were women (80.3%). The mean age was 53.6 years (SD 14.9). Duodenal eosinophilia was found with significant difference in patients with early satiety (p=0.01). There was no difference in patients with postprandial fullness (p=0.63), epigastric pain or burning (p=0.26), gastroesophageal reflux symptoms (p=0.13), allergy and food intolerance (p=0.42) and smoking (p=0.28). There was no relationship between duodenal mastocytosis and early satiety (p=0.98), postprandial fullness (p=0.78), and epigastric pain or burning (p=0.82). Duodenal eosinophilia was similar in FD and controls. In subgroup analysis, duodenal eosinophilia occurs in patients with early satiety.


Electronic discharge summaries--are they being done and do they have the required information?
A retrospective audit was conducted to evaluate the completeness of the available electronic discharge summaries. Forty-five randomly selected patients had their respective electronic discharge summaries reviewed including criteria such as length of stay; discharge summary availability; documentation of discharge medications; medication changes; medical co-morbidities and follow-up arrangements. There were electronic discharge summaries available for thirty-six (80%) of the included patients of which; thirty-three (91.7%) had the medication list available; twenty-six (72.2%) had clear documentation of medication changes; thirty-five (97.2%) had clear documentation of the patients' co-morbidities; and thirty (83.3%) had clear follow-up plans documented. The readmission rate was found to be high when compared to published numbers with a quarter of the discharged patients being readmitted within 28 days. The recommendations resulting from this audit include the need for improved education on the requirements of the electronic dischange summary, appropriate documentation and possible implementation of out-of-hour discharge summary availability.