Melanoma secretion of transforming growth factor-ß2 leads to loss of epidermal AMBRA1 threatening epidermal integrity and facilitating tumour ulceration.

BACKGROUND: For patients with early American Joint Committee on Cancer (AJCC)-stage melanoma the combined loss of the autophagy regulatory protein AMBRA1 and the terminal differentiation marker loricrin in the peritumoral epidermis is associated with a significantly increased risk of metastasis. OBJECTIVES: The aim of the present study was to evaluate the potential contribution of melanoma paracrine transforming growth factor (TGF)-ß signalling to the loss of AMBRA1 in the epidermis overlying the primary tumour and disruption of epidermal integrity. METHODS: Immunohistochemistry was used to analyse AMBRA1 and TGF-ß2 in a cohort of 109 AJCC all-stage melanomas, and TGF-ß2 and claudin-1 in a cohort of 30 or 42 AJCC stage I melanomas, respectively, with known AMBRA1 and loricrin (AMLo) expression. Evidence of pre-ulceration was analysed in a cohort of 42 melanomas, with TGF-ß2 signalling evaluated in primary keratinocytes. RESULTS: Increased tumoral TGF-ß2 was significantly associated with loss of peritumoral AMBRA1 (P < 0·05), ulceration (P < 0·001), AMLo high-risk status (P < 0·05) and metastasis (P < 0·01). TGF-ß2 treatment of keratinocytes resulted in downregulation of AMBRA1, loricrin and claudin-1, while knockdown of AMBRA1 was associated with decreased expression of claudin-1 and increased proliferation of keratinocytes (P < 0·05). Importantly, we show loss of AMBRA1 in the peritumoral epidermis was associated with decreased claudin-1 expression (P < 0·05), parakeratosis (P < 0·01) and cleft formation in the dermoepidermal junction (P < 0·05). CONCLUSIONS: Collectively, these data suggest a paracrine mechanism whereby TGF-ß2 causes loss of AMBRA1 overlying high-risk AJCC early-stage melanomas and reduced epidermal integrity, thereby facilitating erosion of the epidermis and tumour ulceration.

Strategic directions in the what and how of learning and teaching innovation-a fifty-year synopsis.

Student learning experiences at university are constantly evolving; new disciplinary discoveries, new knowledge, interdisciplinary synergies and new exigencies make learning a dynamic experience for students, teachers and researchers alike; and that is just the what of learning. Add to this, changes in the how of learning, new pedagogies and new technologies, new partners in the provision of learning, as well as new configurations of where learning takes place, such as on campus, at home, in the workplace and online; and it is not hard to make the case that learning experiences of students enrolled in a degree are relatively more complex today than they were even 20 years ago. Much of this change has been captured over the last five decades in the journal Higher Education. The ongoing challenge of these changes is the complexity that accompanies them. How do we improve the student experience of learning in a complex context? What should the outcomes of a higher education degree be? What learning processes are likely to lead better outcomes? How do you assess the quality of learning that may occur in small groups on campus or online, or in large groups in both places, or in laboratories or the workplace? What is the role of material objects in these experiences and do they contribute to outcomes? This manuscript will consider such questions and where the journal is pointing researchers towards new avenues that are developing in learning and teaching internationally.

Observational constraints on particle acidity using measurements and modelling of particles and gases.

In many parts of the world, the implementation of air quality regulations has led to significant decreases in SO2 emissions with minimal impact on NH3 emissions. In Canada and the United States, the molar ratio of NH3 : SO2 emissions has increased dramatically between 1990 and 2014. In many regions of North America, this will lead the molar ratio of NHx : SO4, where NHx is the sum of particle phase NH4+ and gas phase NH3, and SO4 is the sum of particle phase HSO4- and SO42-, to exceed 2. A thermodynamic model (E-AIM model II) is used to investigate the sensitivity of particle pH, and the gas-particle partitioning of NHx and inorganic nitrate, to the atmospheric NHx : SO4 ratio. Steep increases in pH and the gas fraction of NHx are found as NHx : SO4 varies from below 1 to above 2. The sensitivity of the gas fraction of nitrate also depends strongly on temperature. The results show that if NHx : SO4 exceeds 2, and the gas and particle phase NHx are in equilibrium, the particle pH will be above 2. Observations of the composition of particulate matter and gas phase NH3 from two field campaigns in southern Canada in 2007 and 2012 have median NHx : SO4 ratios of 3.8 and 25, respectively. These campaigns exhibited similar amounts of NH3, but very different particle phase loadings. Under these conditions, the pH values calculated using the observations as input to the E-AIM model were in the range of 1-4. The pH values were typically higher at night because the higher relative humidity increased the particle water content, diluting the acidity. The assumption of equilibration between the gas and particle phase NHx was evaluated by comparing the observed and modelled gas fraction of NHx. In general, E-AIM was able to reproduce the partitioning well, suggesting that the dominant constituents contributing to particle acidity were measured, and that the estimated pH values were realistic. These results suggest that regions of the world where the ratio of NH3 : SO2 emissions is beginning to exceed 2 on a molar basis may be experiencing rapid increases in aerosol pH of 1-3 pH units. This could have important consequences for the rates of condensed phase reactions that are acid-catalyzed.

A simple vacuum suitcase for enabling plasma facing component characterization in fusion devices.

We have demonstrated a vacuum suitcase to transport samples in vacuo to a surface analysis station for characterization of tokamak plasma facing components (PFCs). This technique enables surface analysis at powerful, dedicated stations that are not encumbered by design constraints imposed on them by a tokamak. The vacuum suitcase is an alternative solution to characterizing PFCs using diagnostics that are designed and built around a tokamak. The vacuum suitcase, called the Sample Exposure Probe (SEP), features mobile ultra-high vacuum pumping. Active pumping under high vacuum enables sample transfer between the Lithium Tokamak eXperiment-ß (LTX-ß) and a high resolution X-ray Photoelectron Spectroscopy (XPS) system that is situated close by. A thermocouple inserted in the back of the sample head measures heat flux from the plasma during exposure, and together with a button heater, allows the sample to match the LTX-ß PFCs in high temperature operations. As vacuum conditions are better during transfer and analysis than in the tokamak, less contamination is introduced to the samples. XPS scans on a dedicated analysis station enable peak identification due to higher resolution and signal to noise ratio. A similar probe could be implemented for other fusion devices. The SEP is the first vacuum suitcase implementation for fusion applications that incorporates active pumping.

Cytodifferentiation during spermiogenesis in Lumbricus terrestris.

The structural changes during spermiogenesis were studied on developing spermatids in seminal vesicles and receptacles of Lumbricus terrestris fixed in glutaraldehyde-osmium tetroxide and embedded in Epon-Araldite. The centriole plays a prominent role in the morphogenesis and organization of the microtubules of the manchette and flagellum. Microtubules arising from the centriole extend anteriorly to encase the developing middle piece, the nucleus, and the acrosome. The manchette not only provides a supporting framework for the cell during elongation, but also may provide the motive force for the elimination of both nucleoplasm and cytoplasm. The manchette participates in segregation and elimination of the nuclear vesicle that contains the nonchromatin nucleoplasm. Compartmentalization and conservation may also be a function of the manchette since those elements which remain within the framework of microtubules are retained, while all the cytoplasm outside the manchette is discarded. At maturation, the endoplasmic reticulum plays a key role in dismantling the manchette and reducing the cytoplasm external to it. During the early stages of middle-piece formation, six ovoid mitochondria aggregate at the posterior pole of the spermatid nucleus. Concurrent with manchette formation, the mitochondria are compressed laterally into elongate wedge-shaped components, and their outer limiting membranes fuse to form an hexagonal framework that surrounds the dense intramitochondrial matrices. Dense glycogen granules are arranged linearly between the peripheral flagellar tubules and the outer membrane of the mature sperm tail.

The development of surface specialization in the secretory epithelium of the avian salt gland in response to osmotic stress.

Cell surface specialization, a characteristic common to most ion-transporting epithelia, was studied in the salt (nasal) gland of the domestic duck in relation to osmotic stress. Three days after hatching, experimental ducklings were given 1% NaCl to drink for 12 hr and freshwater for the remainder of each day. Control ducklings were maintained exclusively on freshwater. The fine structure of the secretory epithelium was examined on various days of the regimen. The nasal gland epithelium of the secretory lobule is composed of several types of cells. Peripheral cells, lying at the blind ends of the branched secretory tubules, are similar in both control and experimental animals at all stages of glandular development. These generative cells contain few mitochondria and have nearly smooth cell surfaces. Partially specialized secretory cells predominate in the secretory tubules of control animals and appear as transitional cells in the tubular epithelium of salt-stressed animals. These cells contain few mitochondria and bear short folds along their lateral cell surfaces. Fully specialized cells dominate the secretory epithelium of osmotically stressed ducklings. The lateral and basal surfaces of these cells are deeply folded, forming complex intra- and extracellular compartments. This vast increase in absorptive surface area is paralleled by an increase in the number of mitochondria that pack the basal compartments. The development of this fully specialized cell is correlated with the marked increase in (Na(+)-K(+))-ATPase activity in the glands of osmotically stressed birds.

The fine structure of cockroach campaniform sensilla.

Campaniform sensilla on cockroach legs provide a good model system for the study of mechanoreceptive sensory transduction. This paper describes the structure of campaniform sensilla on the cockroach tibia as revealed by light- and electron-microscopy. Campaniform sensilla are proprioceptive mechanoreceptors associated with the exoskeleton. The function of each sensillum centers around a single primary sense cell, a large bipolar neuron whose 40 micro-wide cell body is available for electrophysiological investigation with intracellular microelectrodes. Its axon travels to the central nervous system; its dendrite gives rise to a modified cilium which is associated with the cuticle. The tip of the 20 micro-long dendrite contains a basal body, from which arises a 9 + 0 connecting cilium. This cilium passes through a canal in the cuticle, and expands in diameter to become the sensory process, a membrane-limited bundle of 350-1000 parallel microtubules. The tip of the sensory process is firmly attached to a thin cap of exocuticle; mechanical depression of this cap, which probably occurs during walking movements, effectively stimulates the sensillum. The hypothesis is presented that the microtubules of the sensory process play an important role in mechanoelectric transduction in cockroach campaniform sensilla.

Clinical responses to oxprenolol in the elderly.

Data from 6 controlled clinical trials of oxprenolol carried out in the United States were reviewed to determine the efficacy and tolerability of oxprenolol in patients aged greater than or equal to 55 years. All study designs but 1 called for dosage to be increased to a maximum of 480 mg/day. In a 10-week trial of oxprenolol versus placebo given twice daily, oxprenolol reduced diastolic pressure by 8 mm Hg, while placebo reduced it by 3 mm Hg. A comparison of once-daily with twice-daily dosing showed similar results for both groups: -12/-6 mm Hg for once-daily and -9/-8 mm Hg for twice-daily. There were 2 short-term studies comparing oxprenolol and placebo, both given in addition to hydrochlorothiazide. In the first, the change in blood pressure with oxprenolol was -18/-14 mm Hg and with placebo was +6/-3 mm Hg; only 3 of 14 patients receiving oxprenolol received a maximal dosage. In the follow-up study, most of the dosages were titrated to maximum; reductions were -9/-9 mm Hg with oxprenolol treatment and 0/-12 mm Hg with placebo. Two long-term studies compared oxprenolol and propranolol, also as combination therapy with hydrochlorothiazide. In the 14-week study, the reduction in blood pressure was slightly better with oxprenolol: -15/-15 versus -12/-11 mm Hg. In the 27-week study, almost half of the patients in the oxprenolol group received the maximal dosage. Blood pressure was reduced 2 or 3 mm Hg less with oxprenolol than with propranolol. Oxprenolol was well tolerated in the elderly; it produced a low incidence of typical beta-blocker side effects even when given in a once-daily regimen.

Quantification of dynamic velopharyngeal port excursion following sphincter pharyngoplasty.

The sphincter pharyngoplasty is a surgical procedure designed to correct velopharyngeal dysfunction. Its advocates cite the theoretical advantage of its induction of dynamic activity of the neovelopharyngeal port, but this dynamic activity has yet to be quantitatively demonstrated in the literature. The purpose of this study was to quantify postoperative velopharyngeal dynamism and to document the results of intervention outcome on sphincteric excursion measurements from minimal-to-maximal orifice closure. We conducted a 7-year retrospective review of speech videofluoroscopy evaluations in patients who had undergone sphincter pharyngoplasty in our center. Between 1989 and 1994, there were 58 patients so treated for postpalatoplasty velopharyngeal dysfunction by two surgeons using the same operative technique. Patients for whom sphincter pharyngoplasty was recommended fulfilled both of the following criteria: (1) velopharyngeal dysfunction caused by an anatomic, myoneural, or combined deficiency of the velopharyngeal sphincter that would not be expected to be managed by speech therapy alone, and (2) preoperative videonasendoscopy and speech videofluoroscopic studies that demonstrated large-gap coronal, circular, or bow-tie closure patterns or velopharyngeal hypodynamism. Of the original 58 patients, 24 underwent postoperative speech videofluoroscopic evaluations with basal views. Of these, 20 of the evaluations (83 percent) were of adequate quality to be included in a research study. Still images showing maximum and minimum excursion of the sphincter in basal view were obtained. To test for observer reliability, the speech videofluoroscopic studies were randomized and presented for measurement to the same individual on two occasions, each session separated by a 1-month time interval. Topographic imaging software was used to obtain maximum and minimum measurements to within 0.1 mm. Partitioning the variance of the data showed that measurement variability was a very small portion of the total, and that difference between the minimum and maximum values was the largest source of variability. Of the total variability in the data, 64.0 percent originated in the minimum/maximum difference, 34.3 percent came from patient variability, and only 1.7 percent resulted from original or repeat measurements. The patient variability may be exaggerated because of variability in the scale of measurement. Results of this study indicate a quantifiable and statistically significant difference in maximum-to-minimum excursion of sphincteric closure. Sphincter pharyngoplasty appears to be dynamic in the majority of cases.

Performance improvement: the organization's quest.

In today's health care marketplace, quality has become an expectation. Stakeholders are demanding quality clinical outcomes, and accrediting bodies are requiring clinical performance data. The Roosevelt Institute's quest was to define and quantify quality outcomes, develop an organizational culture of performance improvement, and ensure customer satisfaction. Several of the organization's leaders volunteered to work as a team to develop a specific performance improvement approach tailored to the organization. To date, over 200 employees have received an orientation to the model and its philosophy and nine problem action and process improvement teams have been formed.

Development time, oviposition activity and onset of diapause in Culex tarsalis, Culex restuans and Culiseta inornata in southern Manitoba.

Development times and survival of immatures and reproductive diapause of adult females of Culex tarsalis, Cx. restuans and Culiseta inornata were investigated from hatching to adult emergence at 15, 20 and 25 degrees C in the laboratory and at natural temperatures and photoperiods in southern Manitoba. Based on patterns of oviposition in artificial pools operated from mid-April to the end of September and development time of the immature stages, 3 generations of Cx. tarsalis, Cx. restuans and Cs. inornata were possible in 1980 and 1981. In 1981, 70% of field-reared Cx. tarsalis females emerging in mid-August were in diapause. Field-reared Cx. restuans and Cs. inornata entered reproductive diapause 2-3 weeks later than Cx. tarsalis.

Nailing down a diagnosis.

Nails can act as a barometer of an individual's health, offer clues to nutritional disturbances and serve as windows through which to view capillary changes associated with constitutional disease. Understanding growth and development of normal nails is essential to the identification and interpretation of nail pathology. Causes of onychopathology include genetic disease, trauma, tumors, dermatologic disease, miscellaneous acquired disorders and generalized systemic disease. Diagnosis is aided by the realization that the nails have a limited number of reaction patterns when disturbed by disease. Any of these reactions may manifest a host of disorders. Clinicians should remember to include the nails in patient assessment. The nails are interesting anatomical and physiological areas that can help make a diagnosis.

Materials analysis and particle probe: a compact diagnostic system for in situ analysis of plasma-facing components (invited).

The objective of the materials analysis particle probe (MAPP) in NSTX is to enable prompt and direct analysis of plasma-facing components exposed to plasma discharges. MAPP allows multiple samples to be introduced to the level of the plasma-facing surface without breaking vacuum and analyzed using X-ray photoelectron spectroscopy (XPS), ion-scattering and direct recoil spectroscopy, and thermal desorption spectroscopy (TDS) immediately following the plasma discharge. MAPP is designed to operate as a diagnostic within the ∼12 min NSTX minimum between-shot time window to reveal fundamental plasma-surface interactions. Initial calibration demonstrates MAPP's XPS and TDS capabilities.