Multiple Pathways Control the Reactivation of Telomerase in HTLV-I-Associated Leukemia.
While telomerase (hTERT) activity is absent from normal somatic cells, reactivation of hTERT expression is a hallmark of cancer cells. Telomerase activity is required for avoiding replicative senescence and supports immortalization of cellular proliferation. Only a minority of cancer cells rely on a telomerase-independent process known as alternative lengthening of telomeres, ALT, to sustain cancer cell proliferation. Multiple genetic, epigenetic, and viral mechanisms have been found to de-regulate telomerase gene expression, thereby increasing the risk of cellular transformation. Here, we review the different strategies used by the Human T-cell leukemia virus type 1, HTLV-I, to activate hTERT expression and stimulate its enzymatic activity in virally infected CD4 T cells. The implications of hTERT reactivation in HTLV-I pathogenesis and disease treatment are discussed.


Multivariate fMRI and Eye Tracking Reveal Differential Effects of Visual Interference on Recognition Memory Judgments for Objects and Scenes.
Recent work has demonstrated that the perirhinal cortex (PRC) supports conjunctive object representations that aid object recognition memory following visual object interference. It is unclear, however, how these representations interact with other brain regions implicated in mnemonic retrieval and how congruent and incongruent interference influences the processing of targets and foils during object recognition. To address this, multivariate partial least squares was applied to fMRI data acquired during an interference match-to-sample task, in which participants made object or scene recognition judgments after object or scene interference. This revealed a pattern of activity sensitive to object recognition following congruent (i.e., object) interference that included PRC, prefrontal, and parietal regions. Moreover, functional connectivity analysis revealed a common pattern of PRC connectivity across interference and recognition conditions. Examination of eye movements during the same task in a separate study revealed that participants gazed more at targets than foils during correct object recognition decisions, regardless of interference congruency. By contrast, participants viewed foils more than targets for incorrect object memory judgments, but only after congruent interference. Our findings suggest that congruent interference makes object foils appear familiar and that a network of regions, including PRC, is recruited to overcome the effects of interference.


Stimulation of angiogenesis by adenosine on the chick chorioallantoic membrane.
The effect of adenosine on the vascular density of the chick chorioallantoic membrane was studied. Elvax polymer pellets containing 0.2-3.0 mg of adenosine were placed on the chorioallantoic membrane of 10-day embryos. Control pellets containing mannitol were placed at least 1 cm away. After 4 days the membrane was formalin-fixed and removed. A thin plastic coverslip, inscribed with concentric circles (4-8 mm in diameter), was placed over the pellet. A vascular density index was estimated at 20 X by counting the number of intercepts between vessels and the inscribed circles. Adenosine stimulated a dose-dependent increase (p less than 0.01) in the vascular density index with the 3-mg pellets inducing a 15% increase. Inosine, a major metabolite of adenosine, did not cause a change in the number of intercepts counted. The adenosine-stimulated increase in vascularity was blocked with 110 micrograms of methyl-isobutyl-xanthine injected daily into the albumin. Partial inhibition was observed with 55 micrograms/day. Methyl-isobutyl-xanthine by itself did not affect the vascular density index. Dipyridamole enhanced adenosine's stimulation of vascular growth an additional 52%. Given alone, however, it had no effect on the membrane's vascularity. These data support an angiogenic role for adenosine. The modest, but consistent, increase in the vascular density index stimulated by adenosine, and the fact that it may be released during tissue hypoxia, is consistent with an hypothesis that this nucleoside plays a modulatory role in vessel proliferation accompanying conditions of long-term hypoxia.


Can an herbivore affect where a top predator kills its prey by modifying woody vegetation structure?
In large mammal communities, little is known about modification of interspecific interactions through habitat structure changes. We assessed the effects of African elephants (Loxodonta africana) on features of woody habitat structure that can affect predator-prey interactions. We then explored how this can influence where African lions (Panthera leo) kill their prey. Indeed, lions are stalk-and-ambush predators and habitat structure and concealment opportunities are assumed to influence their hunting success. During 2 years, in Hwange National Park, Zimbabwe, kill sites (n = 167) of GPS-collared lions were characterized (visibility distance for large mammals, distance to a potential ambush site and presence of elephant impacts). We compared characteristics of lion kill sites with characteristics of random sites (1) at a large scale (i.e. in areas intensively used by lions, n = 418) and (2) at the microhabitat scale (i.e. in the direct surrounding available habitat, < 150 m, n = 167). Elephant-impacted sites had a slightly higher visibility and a longer distance to a potential ambush site than non-impacted sites, but these relationships were characterized by a high variability. At large scale, kill sites were characterized by higher levels of elephant impacts compared to random sites. At microhabitat scale, compared to the direct nearby available habitat, kill sites were characterized by a reduced distance to a potential ambush site. We suggest a conceptual framework whereby the relative importance of habitat features and prey abundance could change upon the scale considered.


Long-term natural history of neurofibromatosis Type 2-associated intracranial tumors.
Neurofibromatosis Type 2 (NF2) is a heritable tumor predisposition syndrome that leads to the development of multiple intracranial tumors, including meningiomas and schwannomas. Because the natural history of these tumors has not been determined, their optimal management has not been established. To define the natural history of NF2-associated intracranial tumors and to optimize management strategies, the authors evaluated long-term clinical and radiographic data in patients with NF2. Consecutive NF2 patients with a minimum of 4 years of serial clinical and MRI follow-up were analyzed. Seventeen patients, 9 males and 8 females, were included in this analysis (mean follow-up 9.5±4.8 years, range 4.0-20.7 years). The mean age at initial evaluation was 33.2±15.5 years (range 12.3-57.6 years). Patients harbored 182 intracranial neoplasms, 164 of which were assessable for growth rate analysis (18 vestibular schwannomas [VSs], 11 nonvestibular cranial nerve [CN] schwannomas, and 135 meningiomas) and 152 of which were assessable for growth pattern analysis (15 VSs, 9 nonvestibular CN schwannomas, and 128 meningiomas). New tumors developed in patients over the course of the imaging follow-up: 66 meningiomas, 2 VSs, and 2 nonvestibular CN schwannomas. Overall, 45 tumors (29.6%) exhibited linear growth, 17 tumors (11.2%) exhibited exponential growth, and 90 tumors (59.2%) displayed a saltatory growth pattern characterized by alternating periods of growth and quiescence (mean quiescent period 2.3±2.1 years, range 0.4-11.7 years). Further, the saltatory pattern was the most frequently identified growth pattern for each tumor type: meningiomas 60.9%, VSs 46.7%, and nonvestibular schwannoma 55.6%. A younger age at the onset of NF2-related symptoms (p=0.01) and female sex (p=0.05) were associated with an increased growth rate in meningiomas. The identification of saltatory growth in meningiomas increased with the duration of follow-up (p=0.01). Neurofibromatosis Type 2-associated intracranial tumors most frequently demonstrated a saltatory growth pattern. Because new tumors can develop in NF2 patients over their lifetime and because radiographic progression and symptom formation are unpredictable, resection may be best reserved for symptom-producing tumors. Moreover, establishing the efficacy of nonsurgical therapeutic interventions must be based on long-term follow-up (several years).


Molecular analysis of the notch repressor-complex in Drosophila: characterization of potential hairless binding sites on suppressor of hairless.
The Notch signalling pathway mediates cell-cell communication in a wide variety of organisms. The major components, as well as the basic mechanisms of Notch signal transduction, are remarkably well conserved amongst vertebrates and invertebrates. Notch signalling results in transcriptional activation of Notch target genes, which is mediated by an activator complex composed of the DNA binding protein CSL, the intracellular domain of the Notch receptor, and the transcriptional coactivator Mastermind. In the absence of active signalling, CSL represses transcription from Notch target genes by the recruitment of corepressors. The Notch activator complex is extremely well conserved and has been studied in great detail. However, Notch repressor complexes are far less understood. In Drosophila melanogaster, the CSL protein is termed Suppressor of Hairless [Su(H)]. Su(H) functions as a transcriptional repressor by binding Hairless, the major antagonist of Notch signalling in Drosophila, which in turn recruits two general corepressors--Groucho and C-terminal binding protein CtBP. Recently, we determined that the C-terminal domain (CTD) of Su(H) binds Hairless and identified a single site in Hairless, which is essential for contacting Su(H). Here we present additional biochemical and in vivo studies aimed at mapping the residues in Su(H) that contact Hairless. Focusing on surface exposed residues in the CTD, we identified two sites that affect Hairless binding in biochemical assays. Mutation of these sites neither affects binding to DNA nor to Notch. Subsequently, these Su(H) mutants were found to function normally in cellular and in vivo assays using transgenic flies. However, these experiments rely on Su(H) overexpression, which does not allow for detection of quantitative or subtle differences in activity. We discuss the implications of our results.


Efficient multiframe super-resolution for imagery with lateral shifts.
Trade studies used to design optical imaging systems frequently result in systems being undersampled. The resolution of such systems is limited by the finite size of the detector pixels rather than the cutoff spatial frequency of the optical system. Multiframe super-resolution techniques can be used to combine a number of spatially displaced images from such systems into a single, high-resolution image. Nonlinear optimization techniques have frequently been used to solve this problem. Such techniques define an objective function and use numerical optimization methods to obtain a solution. These numerical methods are often more efficient when derivatives of the objective function with respect to the variables can be calculated analytically rather than numerically. We demonstrate for the simple motion model of pure lateral translation that the derivatives of the objective function with respect to the image lateral shifts can be calculated analytically to speed optimization calculations.


Berry (poly)phenols and cardiovascular health.
Berries are a rich source of (poly)phenols, including anthocyanins, flavan-3-ols, procyanidins, flavonols, ellagitannins, and hydroxycinnamates. Epidemiological evidence indicates that the cardiovascular health benefits of diets rich in berries are related to their (poly)phenol content. These findings are supported by small-scale randomized controlled studies (RCTs) that have shown improvements in several surrogate markers of cardiovascular risk such as blood pressure, endothelial function, arterial stiffness, and blood lipids after acute and short-term consumption of blueberries, strawberries, cranberries, or purified anthocyanin extracts in healthy or diseased individuals. However, firm conclusions regarding the preventive value of berry (poly)phenols cannot be drawn due to the small number of existing studies and limitations that apply to the available data, such as lack of controls or failure to assess the absorption and metabolism of (poly)phenols. Although the current evidence is promising, more long-term RCTs are needed to establish the role of berry (poly)phenols to support cardiovascular health.


Effective treatment of erythema nodosum leprosum with thalidomide is associated with immune stimulation.
The immunomodulatory drug thalidomide is the treatment of choice for erythema nodosum leprosum (ENL), an inflammatory cutaneous and systemic complication of multibacillary leprosy. To elucidate the mechanism of action of thalidomide in this syndrome, we prospectively investigated 20 patients with ENL who were treated with thalidomide for 21 days. All patients responded to treatment, with the majority of them having complete resolution of cutaneous lesions within 7 days. This response was associated with a marked but transient increase in ex vivo mitogen-induced expression of interleukin (IL)-2 and interferon- gamma by CD4(+) and CD8(+) T cells that was observed on treatment day 7, but these returned to pretreatment levels by day 21. Plasma tumor necrosis factor- alpha levels were not high at baseline, and they increased modestly during treatment. Plasma levels of IL-12 increased steadily during thalidomide treatment. Hence, the therapeutic effect of thalidomide in ENL appears to be associated with transient immune stimulation, which suggests that the drug may promote an active immunoregulatory response.


Chronic heart failure beyond city limits.
Chronic heart failure (CHF) develops in frail elderly individuals who have suffered an acute or sustained insult to the structural efficiency of the heart due to the presence of underlying heart disease and/or hypertension. It is also more common in individuals with disproportionately high levels of cardiac disease or its risk factors, for example lower socioeconomic status. As such, this epidemic is particularly significant for older people, males and Aboriginal people; groups who comprise a greater proportion of the population in rural and remote Australia. The aim of this study is to determine if the rates of CHF differ between urban and rural Australia. CHF prevalence rates derived from well validated international CHF prevalence data were applied to the Australian Bureau of Statistics Census data for 2001 and weighted to reflect the proportion of Aboriginal people in each geographical stratum. Australia wide, the estimated prevalence of CHF was 17.87 per 1000, ranging from 13.98/1000 in the Australian Capital Territory to 29.50/1000 in rural Northern Territory. Overall, CHF was more prevalent in rural and remote regions (19.84/1000) and large urban centres (19.01/1000) than in capital cities (16.94/1000) (p<0.001). High prevalence rates were also noted in the idyllic rural locations favoured by retirees. In Victoria, Western Australia, South Australia and the Australian Capital Territory over 70% of the estimated individual cases were located in capital cities. In New South Wales, Queensland, Tasmania and the Northern Territory the highest proportion of cases occurred outside capital cities. The main significance of these findings is that while a majority of heart failure may occur among people living in cities (because that is where most people live), a disproportionate number of cases occur among people living outside these cities (due to age and other socio-demographic risk factors) where services may be fewer and less accessible.


Seroprevalence of antibodies to tick-borne encephalitis virus and Anaplasma phagocytophilum in healthy adults from western Norway.
The aim of this study was to assess the seroprevalence of antibodies to tick-borne encephalitis virus (TBEV) and Anaplasma phagocytophilum in a healthy adult population from Sogn and Fjordane county in western Norway. Sera from 1, 213 blood donors were analysed for IgG-antibodies to TBEV, and a random subgroup of 301 donors for IgG to A. phagocytophilum. In the TBEV ELISA, five (0.4%) sera were positive. These were all interpreted as "false" positives, as four had received vaccines against flaviviruses, and the remaining was negative for neutralizing antibodies to TBEV. Antibodies to A. phagocytophilum were detected by indirect immunofluorescence in 49 (16.2%) subjects (titer range 80-1280). The results indicate that TBE currently is not endemic in this part of western Norway. However, there is serological evidence of the existence of human granulocytic anaplasmosis in the population.


Dishonesty in health care practice: A behavioral experiment on upcoding in neonatology.
Dishonest behavior significantly increases the cost of medical care provision. Upcoding of patients is a common form of fraud to attract higher reimbursements. Imposing audit mechanisms including fines to curtail upcoding is widely discussed among health care policy-makers. How audits and fines affect individual health care providers' behavior is empirically not well understood. To provide new evidence on fraudulent behavior in health care, we analyze the effect of a random audit including fines on individuals' honesty by means of a novel controlled behavioral experiment framed in a neonatal care context. Prevalent dishonest behavior declines significantly when audits and fines are introduced. The effect is driven by a reduction in upcoding when being detectable. Yet upcoding increases when not being detectable as fraudulent. We find evidence that individual characteristics (gender, medical background, and integrity) are related to dishonest behavior. Policy implications are discussed.


Double dissociation of format-dependent and number-specific neurons in human parietal cortex.
Based on neuroimaging methods, it is a commonly held view that numerical representation in the human parietal lobes is format independent. We used a transcranial magnetic stimulation adaptation paradigm to examine the existence of functionally segregated overlapping populations of neurons for different numerical formats and to reveal how numerical information is encoded and represented. Based on 2 experiments, we found that right parietal lobe stimulation showed a dissociation between digits and verbal numbers, whereas the left parietal lobe showed a double dissociation between the different numerical formats. Further analysis and modeling also excluded pre- or postrepresentational components as the source of the current effects. These results demonstrate that both parietal lobes are equipped with format-dependent neurons that encode quantity.


Immunization of guinea pigs with novel hepatitis B antigen as nanoparticle aggregate powders administered by the pulmonary route.
Novel nanoparticle-aggregate formulations containing recombinant hepatitis B surface antigen (rHBsAg) were administered to the lungs of guinea pigs and antibodies generated to this antigen evaluated. Preparations of dry powders of: (a) rHBsAg encapsulated within poly(lactic-co-glycolic acid) (PLGA)/polyethylene glycol (PEG) nanoparticles (antigen nanoparticles, AgN(SD)), (b) rHBsAg in a physical mixture with blank PLGA/PEG nanoparticles (antigen nanoparticle admixture (AgNA(SD)), and (c) rHBsAg encapsulated in PLGA/PEG nanoparticles plus free rHBsAg (antigen nanoparticles and free antigen), were generated by spray drying with leucine. Control groups consisted of alum with adsorbed rHBsAg (AlumAg); reconstituted suspensions of spray-dried rHBsAg-loaded PLGA/PEG nanoparticles with leucine; and rHBsAg-loaded PLGA/PEG nanoparticles (AgN). Control preparations were administered by intramuscular injection; AgN was also spray instilled into the lungs. The IgG titers were measured in the serum for 24 weeks after the initial immunization; IgA titers were measured in the bronchio-alveolar lavage fluid. While the highest titer of serum IgG antibody was observed in guinea pigs immunized with AlumAg administered by the IM route, animals immunized with powder formulations via the pulmonary route exhibited high IgA titers. In addition, guinea pigs immunized with AgNA(SD) via the pulmonary route exhibited IgG titers above 1,000 mIU/ml in the serum (IgG titers above 10 mIU/ml is considered protective). Thus, the disadvantages observed with the existing hepatitis B vaccine administered by the parenteral route may be overcome by administering them as novel dry powders to the lungs. In addition, these powders have the advantage of eliciting a high mucosal immune response in the lungs without traditional adjuvants.


Injectable calcium phosphate hydraulic cement (CPHC) used for periodontal tissue regeneration: A study of a dog model.
Injectable calcium phosphate hydraulic cement (CPHC) is a new bone substitute family. This study aimed to evaluate the use of CPHC in surgical periodontitis-simulating defects in a dog model. CPHC was obtained by adding powder mixtures of different calcium phosphates with different solubility. Alveolar bone was removed by drilling over the mesial and distal roots of the 2nd mandibular premolar in six dogs. The defects were randomly selected, three were untreated and six treated. The defects had a depth of 6 mm and a width of 3 mm. The animals were sacrificed after 9 months and samples prepared, with no decalcification, for histological evaluation. Seventy-nine percent of the root was covered by bone in the experimental defects, compared to 41% of the root for the control defects. Bone height was significantly higher for the experimental defects (4.9 +/- 0.9 mm) than for the control defects (1.4 +/- 0.5 mm). After 9 months, 97 +/- 6% of the CPHC was degradated and replaced by bone. This study proves the interest of this cement because of the particularly high level of periodontal bone regeneration. The ability of the cement to be easily injected and shaped in bone defects and the immediate immobilization of the teeth after hardening is notable. (Journal of Applied Biomaterials & Biomechanics 2003; 1: 186-93).


The effects of oral iron supplementation on cognition in older children and adults: a systematic review and meta-analysis.
In observational studies anaemia and iron deficiency are associated with cognitive deficits, suggesting that iron supplementation may improve cognitive function. However, due to the potential for confounding by socio-economic status in observational studies, this needs to be verified in data from randomised controlled trials (RCTs). To assess whether iron supplementation improved cognitive domains: concentration, intelligence, memory, psychomotor skills and scholastic achievement. Searches included MEDLINE, EMBASE, PsychINFO, Cochrane CENTRAL and bibliographies (to November 2008). Inclusion, data extraction and validity assessment were duplicated, and the meta-analysis used the standardised mean difference (SMD). Subgrouping, sensitivity analysis, assessment of publication bias and heterogeneity were employed. Fourteen RCTs of children aged 6+, adolescents and women were included; no RCTs in men or older people were found. Iron supplementation improved attention and concentration irrespective of baseline iron status (SMD 0.59, 95% CI 0.29 to 0.90) without heterogeneity. In anaemic groups supplementation improved intelligence quotient (IQ) by 2.5 points (95% CI 1.24 to 3.76), but had no effect on non-anaemic participants, or on memory, psychomotor skills or scholastic achievement. However, the funnel plot suggested modest publication bias. The limited number of included studies were generally small, short and methodologically weak. There was some evidence that iron supplementation improved attention, concentration and IQ, but this requires confirmation with well-powered, blinded, independently funded RCTs of at least one year's duration in different age groups including children, adolescents, adults and older people, and across all levels of baseline iron status.


Food preference and foraging activity of ants: recommendations for field applications of low-toxicity baits.
Control of ants using baits of low toxicity cannot be effective without knowledge of bait distribution patterns and bait station densities, which are determined by ants' foraging activities. Furthermore, the success of toxic baits also depends upon attractiveness of bait carriers. Here, we assessed ground and vine foraging activity and food preferences for the three ant species ( Linepithema humile (Mayr) (Hymenoptera: Formicidae), Anoplolepis custodiens (F. Smith) and Crematogaster peringueyi Emery) under field conditions. We found that L. humile's vineyard foraging activity was high and that movement of ant bait by C. peringueyi and A. custodiens in the vineyard was relatively low. Consequently, more bait stations need to be dispensed for more effective control of C. peringueyi and A. custodiens than for L. humile. Different bait densities are discussed for the various ant species. Food preference trials indicated that vineyard foraging ants preferred wet bait attractants over dry ones, making liquids the most ideal carriers for baiting these ants. Linepithema humile was attracted to 25% sugar water, while C. peringueyi was attracted to both 25% sugar water and honey. Anoplolepis custodiens was attracted to tuna but was also attracted to 25% sugar water. Thus, future bait formulations should be tailor made to suit these specific food requirements if baits are to be successful in ant pest management.


Elevated adiponectin and sTNFRII serum levels can predict progression to hepatocellular carcinoma in patients with compensated HCV1 cirrhosis.
An obesity-related altered adipose tissue secretion is suggested as a risk factor for hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV) cirrhosis. However, no prospective study has yet examined the predictive value of circulating adipokines and immuno-inflammatory biomarkers regarding this risk. This was a case-control study nested in a prospective French national cohort of HCV-infected patients with biopsy-proven compensated cirrhosis. We selected 56 HCV1-infected patients who subsequently developed HCC (cases), and 96 controls matched for age, gender and diabetes, not developing HCC after a similar period. Adipokines and immuno-inflammatory biomarkers were determined on baseline frozen serum samples. Their influence on the occurrence of HCC was assessed using a mixed logistic regression model under univariate analysis and a backward stepwise procedure under multivariate analysis. The patients were mostly male (62.5%) with active HCV replication (83%) and had been followed for a median duration of 6.3 years during which 44.4% achieved a sustained viral response. Higher adiponectinemia levels were found in cases than in controls (P = 0.01). Levels of the immuno-inflammatory markers were similar in both groups except sTNFRII >5,000 pg/mL (52% cases versus 24% controls; P = 0.001). No marker was associated with histological steatosis. Under multivariate analysis, baseline adiponectin and sTNFRII levels were independently associated with the occurrence of HCC, alongside previous excessive alcohol intake and HCV viral load. High baseline circulating adiponectin and sTNFRII levels were associated with an increased risk of HCC in patients with HCV1 cirrhosis, independently of their HCV replication status.


A new urease inhibitor from Viola betonicifolia.
Urease has attracted much attention, as it is directly involved in the formation of infection stones and contributes to the pathogenesis of urolithiasis, pyelonephritis, ammonia and hepatic encephalopathy, hepatic coma and urinary catheter encrustation. Moreover, urease is the major cause of pathologies induced by H. pylori, such as gastritis and peptic ulcer. In the present work, the new natural compound, 3-methoxydalbergione, was isolated from Viola betonicifolia. A mechanistic study of this compound as a natural urease inhibitor was performed by using enzyme kinetics and docking studies. 3-Methoxydalbergione could be considered as a lead molecule for drugs useful in the urease associated diseases.


First Report of Stem Rot of Guiana Chestnut (Pachira aquatica) Caused by Pythium splendens.
Guiana chestnut is a perennial tropical plant that has recently become popular as a potted ornamental in Japan. In October 2001, severe stem rot occurred on Guiana chestnut plants grown in a greenhouse in Mie Prefecture, Japan. Water-soaked lesions appeared initially at the base of the stems and enlarged gradually toward the tops of plants. The affected tissues were softened and turned dark brown. Rotting was observed in the vascular bundles with advanced disease development. Globose hyphal swellings were numerous on diseased stems. Sections from diseased stems were cleaned by washing with running tap-water, placed on water agar, and incubated at 25°C. A species of Pythium was identified on the basis of morphological and cultural characteristics (1) and isolated consistently from the rotted stems of diseased plants. All isolates produced abundant hyphal swellings that were globose, smooth, 12 to 39 μm in diameter, mostly terminal, dark colored, and with dense granulated contents. Zoospores were absent. All isolates were of the compatibility '+ type' with production of sexual organs when paired with cultures of the '- type' tester isolate of Pythium splendens Braun (CBS462.48). Oogonia produced by crossings between Guiana chestnut isolates and isolate CBS462.48 were terminal or intercalary, globose, smooth-walled, and 32 to 38 μm in diameter. Antheridia were terminal, one to three per oogonium, sac-like, and diclinous. Oospores were single, aplerotic, globose, and 28 to 32 μm in diameter. The thickness of the oospore wall ranged from 1 to 2 μm. The internal transcribed spacer rDNA sequences of representative isolate OPU591 from Guiana chestnut matched those of CBS462.48 (similarity 99.2%) and have been deposited in GenBank under the Accession No. AY375242. Pathogenicity tests were conducted on potted Guiana chestnut plants (30 cm high and 7 to 10 cm in diameter at base of the stem) using isolate OPU591. A mycelial suspension from one culture, grown at 25°C for 7 days on water agar, was inoculated onto a single plant. Prior to inoculation, a wound (10 mm deep and 30 mm long) was made on the surface at the stem base on five plants. The mycelial suspension was poured onto the base of the stems of five wounded and five nonwounded plants. In addition, five wounded and five nonwounded, noninoculated plants were used as controls. Plants were maintained in a greenhouse for 8 weeks after inoculation. The temperature and relative humidity in the greenhouse ranged from 25 to 30°C and 65 to 75%, respectively. Dark-brown rotting developed on the stems of all wounded, inoculated plants by 20 days after inoculation. P. splendens was isolated from diseased tissues and found to be morphologically identical to the original isolate. This confirmed P. splendens as the causal agent of the disease. Disease did not develop on nonwounded inoculated plants or noninoculated plants. To our knowledge, this is the first report of P. splendens on Guiana chestnut. Potted plants of Guiana chestnut are often injured by frequent transplanting and transferring. Such injuries may have predisposed the plant to infection by P. splendens. Reference: (1) A. J. van der Plaats-Niterink. Page 1 in: Monograph of the Genus Pythium. Studies in Mycology Vol. 21, Centraalbureau Voor Schimmelcultures, Baarn, the Netherlands, 1981.


Target-specific membrane potential dynamics of neocortical projection neurons during goal-directed behavior.
Goal-directed behavior involves distributed neuronal circuits in the mammalian brain, including diverse regions of neocortex. However, the cellular basis of long-range cortico-cortical signaling during goal-directed behavior is poorly understood. Here, we recorded membrane potential of excitatory layer 2/3 pyramidal neurons in primary somatosensory barrel cortex (S1) projecting to either primary motor cortex (M1) or secondary somatosensory cortex (S2) during a whisker detection task, in which thirsty mice learn to lick for water reward in response to a whisker deflection. Whisker stimulation in 'Good performer' mice, but not 'Naive' mice, evoked long-lasting biphasic depolarization correlated with task performance in S2-projecting (S2-p) neurons, but not M1-projecting (M1-p) neurons. Furthermore, S2-p neurons, but not M1-p neurons, became excited during spontaneous unrewarded licking in 'Good performer' mice, but not in 'Naive' mice. Thus, a learning-induced, projection-specific signal from S1 to S2 may contribute to goal-directed sensorimotor transformation of whisker sensation into licking motor output.


Measurement of Scleral Thickness in Humans Using Anterior Segment Optical Coherent Tomography.
Anterior segment optical coherent tomography (AS-OCT, Visante; Zeiss) is used to examine meridional variation in anterior scleral thickness (AST) and its association with refractive error, ethnicity and gender. Scleral cross-sections of 74 individuals (28 males; 46 females; aged between 18-40 years (27.7±5.3)) were sampled twice in random order in 8 meridians: [superior (S), inferior (I), nasal (N), temporal (T), superior-temporal (ST), superior-nasal (SN), inferior-temporal (IT) and inferior-nasal (IN)]. AST was measured in 1mm anterior-to-posterior increments (designated the A-P distance) from the scleral spur (SS) over a 6mm distance. Axial length and refractive error were measured with a Zeiss IOLMaster biometer and an open-view binocular Shin-Nippon autorefractor. Intra- and inter-observer variability of AST was assessed for each of the 8 meridians. Mixed repeated measures ANOVAs tested meridional and A-P distance differences in AST with refractive error, gender and ethnicity. Only right eye data were analysed. AST (mean±SD) across all meridians and A-P distances was 725±46 μm. Meridian SN was the thinnest (662±57 μm) and I the thickest (806±60 μm). Significant differences were found between all meridians (p<0.001), except S:ST, IT:IN, IT:N and IN:N. Significant differences between A-P distances were found except between SS and 6 mm and between 2 and 4 mm. AST measurements at 1mm (682±48 μm) were the thinnest and at 6mm (818±49 μm) the thickest (p<0.001); a significant interaction occurred between meridians and A-P distances (p<0.001). AST was significantly greater (p<0.001) in male subjects but no significant differences were found between refractive error or ethnicity. Significant variations in AST occur with regard to meridian and distance from the SS and may have utility in selecting optimum sites for pharmaceutical or surgical intervention.


Regulation of Caenorhabditis elegans lifespan by a proteasomal E3 ligase complex.
The proteasome maintains cellular homeostasis by degrading oxidized and damaged proteins, a function known to be impaired during aging. The proteasome also acts in a regulatory capacity through E3 ligases to mediate the spatially and temporally controlled breakdown of specific proteins that impact biological processes. We have identified components of a Skp1-Cul1-F-Box E3 ligase complex that are required for the extended lifespan of Caenorhabditis elegans insulin/insulin-like growth factor-1-signaling (IIS) mutants. The CUL-1 complex functions in postmitotic, adult somatic tissues of IIS mutants to enhance longevity. Reducing IIS function leads to the nuclear accumulation of the DAF-16/FOXO transcription factor, which extends lifespan by regulating downstream longevity genes. These CUL-1 complex genes act, at least in part, by promoting the transcriptional activity of DAF-16/FOXO. Together, our findings describe a role for an important cellular pathway, the proteasomal pathway, in the genetic determination of lifespan.


Pretransplant anti-HLA-Cw and anti-HLA-DP antibodies in sensitized patients.
We investigated the prevalence and the strength of anti-HLA-Cw and DP antibodies and clinical outcomes in kidney transplant recipients with isolated donor-specific anti-HLA-Cw antibodies. Patients on the waiting list were screened by Luminex single antigen beads (One Lambda). The strength of antibodies was determined by mean fluorescence intensity (MFI) values of the beads. Of the 1069 patients on the waiting list, 251 (24%) were sensitized with calculated panel reactive antibody >0%. The frequency and the median MFI values of anti-HLA antibodies to Cw (56%, 4955) and DP (35%, 2945) were lower than anti-HLA-A (79%, 10,194), B (86%, 11,235), DR (66%, 7866) and DQ (69%, 8283) (p<0.01). Among three major sensitizing events, only previous transplant was associated with development of all anti-HLA antibodies and history of pregnancy was associated only with development of anti-HLA-A antibodies. Eight patients with donor-specific anti-HLA-Cw antibodies received transplantation. During a median 6 months of follow-up (range 3-24 months), patient and graft survival was 100% without any acute rejection. In summary, the prevalence and the strength of anti-HLA-Cw and HLA-DP were lower compared to anti-HLA-A, B, DR, and DQ antibodies and previous organ transplantation was the main sensitizing event in our cohort of patients.


Early and Persistent Dendritic Hypertrophy in the Basolateral Amygdala following Experimental Diffuse Traumatic Brain Injury.
In the pathophysiology of traumatic brain injury (TBI), the amygdala remains understudied, despite involvement in processing emotional and stressful stimuli associated with anxiety disorders, such as post-traumatic stress disorder (PTSD). Because the basolateral amygdala (BLA) integrates inputs from sensory and other limbic structures coordinating emotional learning and memory, injury-induced changes in circuitry may contribute to psychiatric sequelae of TBI. This study quantified temporal changes in dendritic complexity of BLA neurons after experimental diffuse TBI, modeled by midline fluid percussion injury. At post-injury days (PIDs) 1, 7, and 28, brain tissue from sham and brain-injured adult, male rats was processed for Golgi, glial fibrillary acidic protein (GFAP), or silver stain and analyzed to quantify BLA dendritic branch intersections, activated astrocytes, and regional neuropathology, respectively. Compared to sham, brain-injured rats at all PIDs showed enhanced dendritic branch intersections in both pyramidal and stellate BLA neuronal types, as evidenced by Sholl analysis. GFAP staining in the BLA was significantly increased at PID1 and 7 in comparison to sham. However, the BLA was relatively spared from neuropathology, demonstrated by an absence of argyrophilic accumulation over time, in contrast to other brain regions. These data suggest an early and persistent enhancement of dendritic complexity within the BLA after a single diffuse TBI. Increased dendritic complexity would alter information processing into and through the amygdala, contributing to emotional symptoms post-TBI, including PTSD.


The 2019 Revised Version of Association Research Circulation Osseous Staging System of Osteonecrosis of the Femoral Head.
The Association Research Circulation Osseous (ARCO) presents the 2019 revised staging system of osteonecrosis of the femoral head (ONFH) based on the 1994 ARCO classification. In October 2018, ARCO established a task force to revise the staging system of ONFH. The task force involved 29 experts who used a web-based survey for international collaboration. Content validity ratios for each answer were calculated to identify the levels of agreement. For the rating queries, a consensus was defined when more than 70% of the panel members scored a 4 or 5 rating on a 5-point scale. Response rates were 93.1%-100%, and through the 4-round Delphi study, the 1994 ARCO classification for ONFH was successfully revised. The final consensus resulted in the following 4-staged system: stage I-X-ray is normal, but either magnetic resonance imaging or bone scan is positive; stage II-X-ray is abnormal (subtle signs of osteosclerosis, focal osteoporosis, or cystic change in the femoral head) but without any evidence of subchondral fracture, fracture in the necrotic portion, or flattening of the femoral head; stage III-fracture in the subchondral or necrotic zone as seen on X-ray or computed tomography scans. This stage is further divided into stage IIIA (early, femoral head depression ≤2 mm) and stage IIIB (late, femoral head depression >2 mm); and stage IV-X-ray evidence of osteoarthritis with accompanying joint space narrowing, acetabular changes, and/or joint destruction. This revised staging system does not incorporate the previous subclassification or quantitation parameters, but the panels agreed on the future development of a separate grading system for predicting disease progression. A staging system has been developed to revise the 1994 ARCO classification for ONFH by an expert panel-based Delphi survey. ARCO approved and recommends this revised system as a universal staging of ONFH.


Uro-oncology in times of COVID-19: The available evidence and recommendations in the Indian scenario.
The Corona Virus Disease-2019 (COVID-19), one of the most devastating pandemics ever, has left thousands of cancer patients to their fate. The future course of this pandemic is still an enigma, but health care services are expected to resume soon in a phased manner. This might be a long drawn process and we need to have policies in place, to be able to fight both, the SARS-CoV-2 virus and cancer, simultaneously, and emerge triumphant. An extensive literature search for impact of delay in management of various urological malignancies was carried out. Expert opinions were sought wherever there was paucity of evidence, in order to reach a consensus and come up with recommendations for directing uro-oncology services in the times of COVID-19. The panel recommends deferring treatment of patients with renal cell carcinoma by 3 to 6 months, except for those with ongoing hematuria and/or inferior vena cava thrombus, which warrant immediate surgery. Metastatic renal cell cancers should be started on targeted therapy. Low grade non-muscle invasive bladder cancers can be kept on active surveillance while high risk non-muscle invasive bladder cancers and muscle invasive bladder cancers should be treated within 3 months. Neoadjuvant chemotherapy should be avoided. Management of low and intermediate risk prostate cancer can be deferred for 3 to 6months while high risk prostate cancer patients can be initiated on neoadjuvant androgen deprivation therapy. Patients with testicular tumors should undergo high inguinal orchiectomy and be treated according to stage without delay, with stage I patients being offered surveillance. Penile cancers should undergo penectomy, while clinically negative groins can be kept on surveillance. Neoadjuvant chemotherapy should be avoided and adjuvant therapy should be deferred. We need to tailor our treatment strategies to the prevailing present conditions, so as to fight and defeat both, the SARS-CoV-2 virus and cancer. Protection of health care workers, judicious use of available resources, and a rational and balanced outlook towards different malignancies is the need of the hour.


Are omega-3 fatty acids options for prevention and treatment of cognitive decline and dementia?
To report recent data on the potential role of omega-3 fatty acids (n-3 FA) found in oily fish, especially docosahexaenoic acid (DHA), to prevent and treat cognitive decline and Alzheimer's disease. Observational studies still provide conflicting results, in which the majority indicate beneficial effects on cognition, both when assessed as a continuous variable or as incident dementia, mainly Alzheimer's disease. Experimental studies have demonstrated potentially ameliorating effects of eicosapentaenoic acid (EPA) and DHA on amyloid fragment formation, signal transduction including upregulation of the apolipoprotein receptor SorLA, as well as on angiogenesis. The role of EPA and DHA metabolites on Alzheimer's disease pathology is under investigation. Recently, three randomized intervention studies, with duration up to 6 months have been reported. In contrast to a small study from Taiwan, no positive overall effects were reported from the Swedish OmegAD Study or from a Dutch study, although post hoc analyses indicate that selected individuals with mild forms of Alzheimer's disease or cognitive decline may respond to treatment. No firm conclusions can be drawn. Based on epidemiological data, fish including oily fish could be advised as part of a balanced diet for public health purpose, although the evidence for better cognition is only fairly consistent. It is unlikely that n-3 FA will emerge as a treatment option in general for improving cognitive function in patients with Alzheimer's disease. n-3 FA, especially DHA, may turn out as an adjuvant therapy in selected cases. Further long-term intervention studies on individuals with mild cognitive reductions are awaited.


Repeat Two-Stage Exchange Arthroplasty for Periprosthetic Knee Infection Is Dependent on Host Grade.
Two-stage exchange arthroplasty after a previous, failed 2-stage exchange procedure is fraught with difficulties, and there are no clear guidelines for treatment or prognosis given the heterogeneous group of patients in whom this procedure has been performed. The Musculoskeletal Infection Society (MSIS) staging system was developed in an attempt to stratify patients according to infection type, host status, and local soft-tissue status. The purpose of this study was to report the results of 2-stage exchange arthroplasty following a previous, failed 2-stage exchange protocol for periprosthetic knee infection as well as to identify risk factors for failure. We retrospectively identified 45 patients who had undergone 2 or more 2-stage exchange arthroplasties for periprosthetic knee infection from 2000 to 2013. Patients were stratified according to the MSIS system, and risk factors for failure were analyzed. The minimum follow-up was 2 years (mean, 6 years; range, 24 to 132 months). At the time of follow-up, twenty-two (49%) of the patients had undergone another revision due to infection and 28 (62%) had undergone another revision for any reason. The infection recurred in 6 (75%) of 8 substantially immunocompromised hosts (MSIS type C) and in 3 (30%) of 10 uncompromised hosts (type A) following the second 2-stage exchange arthroplasty (p = 0.06). The infection recurred in 4 (80%) of 5 patients with compromise of the extremity (MSIS type 3) and 3 (33%) of 9 patients with an uncompromised extremity (type 1) (p = 0.27). Both extremely compromised hosts with an extremely compromised extremity (type C3) had recurrence of the infection whereas 3 (30%) of the 10 uncompromised patients with no or less compromise of the extremity (type A1 or A2) did. Five patients in the failure group underwent a third 2-stage exchange arthroplasty following reinfection, and 3 of them were infection-free at the time of the latest follow-up. Uncompromised hosts (MSIS type A) with an acceptable wound (MSIS type 1 or 2) had a 70% rate of success (7 of 10) after a repeat 2-stage exchange arthroplasty, whereas type-B2 hosts had a 50% success rate (10 of 20). The repeat 2-stage exchange procedure failed in both type-C3 hosts; thus, alternative salvage procedures should be considered for such patients. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.


Quantitative phosphoproteomic analysis of T cell receptor signaling in diabetes prone and resistant mice.
Type 1 diabetes, in human patients and NOD mice, results from an immune attack on insulin-producing beta-cells of the pancreas by autoreactive T lymphocytes. In NOD mice, genetically controlled perturbations in the signaling pathways downstream of the antigen-specific T cell receptor (TCR) may be instrumental in the altered responses of T cells, manifest as inefficient induction of apoptosis after recognition of self-antigens in the thymus or as perturbed reactivity of mature T cells in peripheral organs. To map this signaling difference(s), we have used mass spectrometry-based quantitative phosphoproteomics to compare the activation of primary CD4(+) T cells of diabetes-prone NOD and -resistant B6.H2g7 mice. Immunoprecipitation and IMAC purification of tyrosine-phosphorylated peptides, combined with a stable-isotope iTRAQ labeling, enabled us to identify and quantify over 77 phosphorylation events in 54 different proteins downstream of TCR stimulation of primary CD4(+) T cells. This analysis showed a generally higher level of phosphotyrosine in activated NOD cells, as well as several phosphorylation sites that appeared to be differentially regulated in these two strains (involving TXK, CD5, PAG1, and ZAP-70). These data highlight the differences in signaling between CD4(+) T cell compartments of NOD and B6g7 mice and may underlie the dysregulation of T cells in NOD mice.


New Horizons for Perovskite Solar Cells Employing DNA-CTMA as the Hole-Transporting Material.
We investigate solution-processed low-temperature lead-halide perovskite solar cells employing deoxyribose nucleic acid (DNA)-hexadecyl trimethyl ammonium chloride (CTMA) as the hole-transport layer and (6,6)-phenyl C61 -butyric acid methyl ester (PCBM) as electron-acceptor layer in an inverted p-i-n device configuration. The perovskite solar cells utilizing a bio-based charge-transport layer demonstrate power conversion efficiency values of 15.86 %, with short-circuit current density of 20.85 mA cm(-2) , open circuit voltage of 1.04 V, and fill factor of 73.15 %, and improved lifetime. DNA-based devices maintained above 85 % of the initial efficiency after 50 days in air.


Integrated and sequence-ordered BAC- and YAC-based physical maps for the rat genome.
As part of the effort to sequence the genome of Rattus norvegicus, we constructed a physical map comprised of fingerprinted bacterial artificial chromosome (BAC) clones from the CHORI-230 BAC library. These BAC clones provide approximately 13-fold redundant coverage of the genome and have been assembled into 376 fingerprint contigs. A yeast artificial chromosome (YAC) map was also constructed and aligned with the BAC map via fingerprinted BAC and P1 artificial chromosome clones (PACs) sharing interspersed repetitive sequence markers with the YAC-based physical map. We have annotated 95% of the fingerprint map clones in contigs with coordinates on the version 3.1 rat genome sequence assembly, using BAC-end sequences and in silico mapping methods. These coordinates have allowed anchoring 358 of the 376 fingerprint map contigs onto the sequence assembly. Of these, 324 contigs are anchored to rat genome sequences localized to chromosomes, and 34 contigs are anchored to unlocalized portions of the rat sequence assembly. The remaining 18 contigs, containing 54 clones, still require placement. The fingerprint map is a high-resolution integrative data resource that provides genome-ordered associations among BAC, YAC, and PAC clones and the assembled sequence of the rat genome.


Partial regeneration of the human hip via autologous bone marrow nucleated cell transfer: A case study.
This is a case report of a 64-year-old white male with a 20 year history of unilateral hip pain that had become debilitating over the last several years. On intake, Harris hip score was rated as: Pain subscale = 10, Function subscale = 32, Deformity subscale = 4, Motions subscale = 4.775 with a total score of 50.8 out of 100. MRI of the affected hip showed severe degeneration with spurring, decrease in joint space, and several large subchondral cysts. The patient had been evaluated by an orthopedic surgeon and told he was a candidate for bipolar hip replacement. Two autologous nucleated cell collections were performed from bone marrow with subsequent isolation and transfers into the intra-articular hip using a hyaluronic acid and thrombin activated platelet rich plasma scaffold. Marrow samples were processed by centrifugation and lysis techniques to isolate nucleated cells. This report describes partial by articular surface regeneration 8 weeks after intraarticular bone marrow transfer. Post-op 3.0T FGRE MRI showed neocortex formation when compared to immediate pre-op MRI and objective improvements were noted that coincided with subjective reports of improvement.


Comparison of chromosome aberrations in peripheral blood lymphocytes from people occupationally exposed to ionizing and radiofrequency radiation.
The genotoxic effects of occupational exposure to ionizing and non-ionizing radiation were investigated in 25 physicians and nurses working in hospitals and in 20 individuals working at radio-relay stations. Examination was conducted by chromosome aberration analysis of peripheral blood lymphocytes. The data showed that total number of chromosome aberrations in people exposed to ionizing and radio-frequency radiation (4.08 +/- 0.37 and 4.35 +/- 0.5 on 200 scored metaphases, respectively) were almost equally higher than those of non-irradiated subjects. The increase was in proportion to the number of individuals having more that 5-aberration/200 metaphases. Acentric fragments comprised the most frequently seen type of aberration. The average numbers in examined groups (11.8 x 10(-3) and 14.8 x 10(-3) per cell, respectively), were significantly higher than 4.2 x 10(-3), which was observed in controls, unexposed individuals. Dicentric fragments were also frequent (4.8 x 10(-3) and 6.25 x 10(-3), respectively, vs. 0.52 x 10(-3) in control). In contrast, the frequency of chromatid breaks increased only after ionizing radiation (3.8 x 10(-3) vs. 0.26 x 10(-3) in control). A positive correlation between the total number of chromosome aberrations and cumulative 6-years dosage was also found. The data emphasized the dangerous effects of prolonged exposure to both types of radiation and indicated that chromosomal aberration analysis should be obligatory for individuals working at radio-relay stations.


Dynamic selection of models for a ventilator-management advisor.
A ventilator-management advisor (VMA) is a computer program that monitors patients who are treated with a mechanical ventilator. A VMA implements a patient-specific physiologic model to interpret patient data and to predict the effects of alternative control settings for the ventilator. Because a VMA evaluates its physiologic model repeatedly during each cycle of data interpretation, highly complex models may require more computation time than is available in this time-critical application. On the other hand, less complex models may be inaccurate if they are unable to represent a patient's physiologic abnormalities. For each patient, a VMA should select a model that balances the tradeoff of prediction accuracy and computation-time complexity. I present a method to select models that are at an appropriate level of detail for time-constrained decision tasks. The method is based on a local search in a graph of models (GoM) for a model that maximizes the tradeoff of computation-time complexity and prediction accuracy. For each model under consideration, a belief network computes a probability of model adequacy given the qualitative prior information, and the goodness of fit of the model to the data provides a measure of the conditional probability of adequacy given the quantitative observations. I apply this method to the problem of model selection for a VMA. I describe an implementation of a graph of physiologic models that range in complexity from VentPlan, a simple model with 3 compartments, to VentSim, a multicompartment model with detailed airway, circulation and mechanical ventilator components.(ABSTRACT TRUNCATED AT 250 WORDS)


Doppler ultrasound in the estimation of the severity of pulmonary infundibular stenosis in infants and children.
Pressure gradients estimated by Doppler echocardiography were compared with values obtained at cardiac catheterisation in 31 children (aged seven days to 16 years, mean 2 years 7 months) with pulmonary infundibular stenosis including 16 with tetralogy of Fallot. Various parasternal and subcostal positions were explored to obtain the maximum velocity of blood flow and the obstructive gradient was calculated from the modified Bernoulli formula. The gradient across the obstruction could be measured directly at the time of catheterisation in only 21 patients. The correlation coefficient for the Doppler and total measured gradients was r = 0.90 for catheter entry and r = 0.77 for catheter withdrawal. Doppler ultrasound, by measuring the total gradient from the right ventricle to the pulmonary artery, provides a non-invasive assessment of the severity of pulmonary stenosis, and in those with infundibular obstruction allowance need not be made for possible energy losses caused by the elongated obstruction or the presence of narrowing at more than one level.


Common mode noise rejection properties of amplitude and phase noise in a heterodyne interferometer.
High precision metrology systems based on heterodyne interferometry can measure the position and attitude of objects to accuracies of picometer and nanorad, respectively. A frequently found feature of the general system design is the subtraction of a reference phase from the phase of the position interferometer, which suppresses low frequency common mode amplitude and phase fluctuations occurring in volatile optical path sections shared by both the position and reference interferometer. Spectral components of the noise at frequencies around or higher than the heterodyne frequency, however, are generally transmitted into the measurement band and may limit the measurement accuracy. Detailed analytical calculations complemented with Monte Carlo simulations show that high frequency noise components may also be entirely suppressed, depending on the relative difference of measurement and reference phase, which may be exploited by corresponding design provisions. While these results are applicable to any heterodyne interferometer with certain design characteristics, specific calculations and related discussions are given for the example of the optical metrology system of the LISA Pathfinder mission to space.


Fus1p interacts with components of the Hog1p mitogen-activated protein kinase and Cdc42p morphogenesis signaling pathways to control cell fusion during yeast mating.
Cell fusion in the budding yeast Saccharomyces cerevisiae is a temporally and spatially regulated process that involves degradation of the septum, which is composed of cell wall material, and occurs between conjugating cells within a prezygote, followed by plasma membrane fusion. The plasma membrane protein Fus1p is known to be required for septum degradation during cell fusion, yet its role at the molecular level is not understood. We identified Sho1p, an osmosensor for the HOG MAPK pathway, as a binding partner for Fus1 in a two-hybrid screen. The Sho1p-Fus1p interaction occurs directly and is mediated through the Sho1p-SH3 domain and a proline-rich peptide ligand on the Fus1p COOH-terminal cytoplasmic region. The cell fusion defect associated with fus1Delta mutants is suppressed by a sho1Delta deletion allele, suggesting that Fus1p negatively regulates Sho1p signaling to ensure efficient cell fusion. A two-hybrid matrix containing fusion proteins and pheromone response pathway signaling molecules reveals that Fus1p may participate in a complex network of interactions. In particular, the Fus1p cytoplasmic domain interacts with Chs5p, a protein required for secretion of specialized Chs3p-containing vesicles during bud development, and chs5Delta mutants were defective in cell surface localization of Fus1p. The Fus1p cytoplasmic domain also interacts with the activated GTP-bound form of Cdc42p and the Fus1p-SH3 domain interacts with Bni1p, a yeast formin that participates in cell fusion and controls the assembly of actin cables to polarize secretion in response to Cdc42p signaling. Taken together, our results suggest that Fus1p acts as a scaffold for the assembly of a cell surface complex involved in polarized secretion of septum-degrading enzymes and inhibition of HOG pathway signaling to promote cell fusion.


Spalt-Like Transcription Factor 1 (SALL1) Gene Expression Inhibits Cell Proliferation and Cell Migration of Human Glioma Cells Through the Wnt/β-Catenin Signaling Pathway.
BACKGROUND The spalt-like transcription factor 1 (SALL1) gene is a member of the Krüppel-associated box-containing zinc finger proteins (KRAB-ZFPs) and has been shown to modulate the onset and progression of human tumors. This study aimed to investigate the regulatory effects and mechanisms of SALL1 gene expression in human glioblastoma and glioma cells and tissue samples from patients with cerebral glioma. MATERIAL AND METHODS The human glioblastoma cell lines, LN229, U87-MG, U-251, U343, and the Hs683 glioma cell line were studied. The cell counting kit-8 (CCK-8) assay, cell cycle assay, wound-healing assay, transwell assay, Western blot, and quantitative real-time polymerase chain reaction (qRT-PCR) were used to evaluate cell proliferation, cell migration, and the cell cycle and expression of SALL1. Expression of SALL1 mRNA in 120 samples of cerebral glioma and 20 samples of normal brain were studied. Overall survival data from patients with cerebral glioma were analyzed. RESULTS SALL1 expression was down-regulated in human glioblastoma and glioma cells and in cerebral glioma tissues. Down-regulation of SALL1 expression was associated with reduced overall survival. Overexpression of SALL1 was associated with inhibition of cell proliferation associated with cell cycle arrest at the G0/G1 phase. SALL1 inhibited cell migration by preventing epithelial-mesenchymal transition (EMT) and down-regulating the expression of stem cell markers. Reduced levels of ß-catenin and downregulation of c-Myc and cyclin D1 and upregulation of p21and p27 expression were associated with SALL1 expression. CONCLUSIONS In human glioblastoma cells and cerebral glioma tissues, SALL1 acted as a tumor suppressor gene by inhibiting Wnt/ß-catenin signaling.


Antioxidant treatment for amyotrophic lateral sclerosis / motor neuron disease.
Free radical accumulation and oxidative stress have been proposed as contributing to the progression of amyotrophic lateral sclerosis (or motor neuron disease). A range of antioxidant medications are available, and have been studied. To examine the effects of antioxidant medication in the treatment of people with amyotrophic lateral sclerosis. We searched the Cochrane Neuromuscular Disease Group trials register (July 2003), MEDLINE (from January 1966 to July 2003), EMBASE (from January 1980 to July 2003) and other sources. All randomized or quasi-randomized controlled trials of antioxidant treatment for amyotrophic lateral sclerosis. The reviewers independently applied the selection criteria, assessed study quality and two reviewers performed independent data extraction. The search identified 21 studies for consideration but only eight studies met the inclusion criteria. Only two studies used our predetermined primary outcome measure, (survival at 12 months treatment). Sufficient data were available from three studies to allow analysis of the primary outcome measure, and a meta-analysis was performed. In the individual studies no significant effect was observed of vitamin E 500 mg twice daily; acetylcysteine 50 mg/kg daily subcutaneous infusion; or a combination of L-methionine 2 g, vitamin E 400 International Units, and selenium 3 x 10-5g three times daily (Alsemet). No significant effect on the primary outcome measure was observed in a meta-analysis of antioxidants in general when combining the results. No significant differences were demonstrated in secondary outcome measures. There is insufficient evidence of efficacy of individual antioxidants, or antioxidants in general, in the treatment of people with amyotrophic lateral sclerosis. One study reported a mild positive effect, but this was not supported by the analysis we used. Generally the studies were poorly designed, and underpowered, with low numbers of participants and of short duration. Further well-designed trials of medications such as vitamin C and E are unlikely to be performed. If future trials of antioxidant medications are performed, careful attention should be given to sample size, outcome measures, and duration of the trial. The high tolerance and safety, and relatively low cost of vitamins C and E, and other considerations related to the lack of other effective treatments for amyotrophic lateral sclerosis, explain the continuing use of these vitamins by physicians and patients. While there is no substantial clinical trial evidence to support their clinical use, there is no clear contraindication.


Hydroperoxide-induced increases in intracellular calcium due to annexin VI translocation and inactivation of plasma membrane Ca2+-ATPase.
Oxidative stress can cause changes in intracellular free calcium concentration ([Ca2+]i) that resemble those occurring under normal cell signaling. In the alveolar macrophage, hydroperoxide-induced elevation of [Ca2+]i modulates the respiratory burst and other important physiologic functions. The source of Ca2+ released by hydroperoxide is intracellular but separate from the endoplasmic reticulum pool released by receptor-mediated stimuli (Hoyal, C. R., Gozal, E., Zhou, H., Foldenauer, K., and Forman, H. J. (1996) Arch. Biochem. Biophys. 326, 166-171). Previous studies in other cells have suggested that mitochondria are a potential source of oxidant-induced [Ca2+]i elevation. In this study we have identified another potential source of hydroperoxide-releasable intracellular calcium, that bound to annexin VI on the inner surface of the plasma membrane. Translocation of annexin VI from the membrane during exposure to t-butyl hydroperoxide matched elevation of [Ca2+]i as a function of time and t-butyl hydroperoxide concentration. The translocation was possibly due to a combination of ATP depletion and oxidative modification of membrane lipids and proteins. A sustained increase in [Ca2+]i occurring > 50 pmol/10(6) cells (50 microM under these conditions) appeared to be a consequence of membrane Ca2+-ATPase dysfunction. These results suggest that exposure to oxidative stress results in early alterations to the plasma membrane and concomitant release of Ca2+ into the cytosol. In addition it suggests a mechanism for participation of annexin VI translocation that may underlie the alterations in macrophage function by oxidative stress.


Thromboembolic risk in 16 274 atrial fibrillation patients undergoing direct current cardioversion with and without oral anticoagulant therapy.
To study the risk of thromboembolism in a nationwide cohort of atrial fibrillation patients undergoing direct current (DC) cardioversion with or without oral anticoagulant coverage. A retrospective study of 16 274 patients in Denmark discharged from hospital after a first-time DC cardioversion for atrial fibrillation between 2000 and 2008. Use of oral anticoagulant therapy within 90 days prior and 360 days after DC cardioversion was obtained from the Danish Register of Medicinal Product Statistics. The risk of thromboembolism was estimated by calculating incidence rates and by multivariable adjusted Cox proportional-hazard models. During the initial 30 days following discharge, the thromboembolic incidence rate was 10.33 per 100 patient-years for the no prior oral anticoagulant therapy group [n = 5084 (31.2%)], as compared with 4.00 per 100 patient-years for the prior oral anticoagulant therapy group [n = 11 190 (68.8%)], [hazard ratio associated with no prior oral anticoagulant therapy was 2.25; 95% confidence interval (CI), 1.43-3.53]. Thromboembolic risk stratification by the CHADS2 and CHA2DS2-VASc scores did not change the results. Hazard ratio with no oral anticoagulant therapy was 2.21; 95% CI, 0.79-6.77 and 2.40; 95% CI, 1.46-3.95 with CHA2DS2-VASc score 0-1 and CHA2DS2-VASc score 2 or more, respectively. Direct current cardioversion for atrial fibrillation without oral anticoagulation is associated with a high risk of thromboembolism. Notably, the risk is high in the initial period after cardioversion, indicating a hazardous association between DC cardioversion without anticoagulation and thromboembolism.


Run, hide, or fight: anti-predation strategies in endangered red-nosed cuxiú (Chiropotes albinasus, Pitheciidae) in southeastern Amazonia.
Although primate predation is rarely observed, a series of primate anti-predation strategies have been described. Energetic costs of such strategies can vary from high-cost mobbing, via less costly alarm calling, to low-cost furtive concealment. Here we report the anti-predation strategies of red-nosed cuxiú, Chiropotes albinasus, based on direct observations from four study sites in southeastern Brazilian Amazonia. Over a collective period of 1255 fieldwork hours, we observed nine direct interactions between raptors (all potential predators) and red-nosed cuxiús. Of these, one (11%) resulted in predation. Raptors involved were: Harpia harpyja (four events), Leucopternis sp. (two events), Spizaëtus tyrannus (one event), and unidentified large raptors (two events). Predation attempts occurred in flooded-forest and terra firme rainforest, were directed at both adult and non-adult cuxiús, and involved both adult and juvenile raptors. Anti-predation strategies adopted by the cuxiús included: (1) group defence and mobbing behaviour (two occasions), (2) dropping into dense sub-canopy (seven occasions), (3) alarm calling (eight occasions), and (4) fleeing to, and hiding in, dense vegetation (eight occasions). During each encounter at least two of these behaviours were recorded. These are the first published records of predation, predation attempts, and anti-predator behaviour involving red-nosed cuxiú.


Prevalence and risk of thrombophilia defects in vascular patients.
This paper reviews the available data on the prevalence of thrombophilia defects in patients with peripheral vascular disease (PVD) and attempts to delineate the risk of failure of vascular intervention in these patients. The prevalence of thrombophilia in stable claudicants is 25% and increases to 40% in those requiring revascularisation, compared to only 11% in the control group. The overall prevalence of thrombophilia defects in patients with premature atherosclerosis appears to be between 15 and 30%. The prevalence in the typical cohort of patients with PVD appears to be similar. All these studies have recruited patients with symptoms significant enough to warrant intervention. The overall prevalence of thrombophilia calculated from these trials, therefore, may not be truly indicative of the general vascular population who may not even present primary or secondary healthcare. The risk of thrombotic occlusion following arterial revascularisation in patients with an identified thrombophilia defect appears to be almost three times that of patients with no evidence of a thrombophilia defect. The best management of these patients has not been determined and needs to be evaluated by prospective randomized trials.


Symptom-specific differential motor network modulation by deep brain stimulation in Parkinson's disease.
Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an established neurosurgical treatment for the motor symptoms of Parkinson's disease (PD). While often highly effective, DBS does not always yield optimal therapeutic outcomes, and stimulation-induced adverse effects, including paresthesia, muscle contractions, and nausea/lightheadedness, commonly occur and can limit the efficacy of stimulation. Currently, objective metrics do not exist for monitoring neural changes associated with stimulation-induced therapeutic and adverse effects. In the present study, the authors combined intraoperative functional MRI (fMRI) with STN DBS in 20 patients with PD to test the hypothesis that stimulation-induced blood oxygen level-dependent signals contained predictive information concerning the therapeutic and adverse effects of stimulation. As expected, DBS resulted in blood oxygen level-dependent activation in myriad motor regions, including the primary motor cortex, caudate, putamen, thalamus, midbrain, and cerebellum. Across the patients, DBS-induced improvements in contralateral Unified Parkinson's Disease Rating Scale tremor subscores correlated with activation of thalamic, brainstem, and cerebellar regions. In addition, improvements in rigidity and bradykinesia subscores correlated with activation of the primary motor cortex. Finally, activation of specific sensorimotor-related subregions correlated with the presence of DBS-induced adverse effects, including paresthesia and nausea (cerebellar cortex, sensorimotor cortex) and unwanted muscle contractions (caudate and putamen). These results suggest that DBS-induced activation patterns revealed by fMRI contain predictive information with respect to the therapeutic and adverse effects of DBS. The use of fMRI in combination with DBS therefore may hold translational potential to guide and improve clinical stimulator optimization in patients.


Acousto-optic modulation of a point-scatterer array.
Acoustic modulation of light scattering from a linear centrosymmetric array is analyzed by considering far-field contributions due to optoelastic (OE) effect and acoustically induced translation of the array elements. The modulated light intensity is shown to vary sinusoidally at the acoustic frequency when the physical constants representative of the above effects are within ranges of their physical limits. The OE and translation components of the acousto-optic (AO) signal are shown to be in phase quadrature, each exhibiting a double-sided maxima when expressed as a function of the detector angle.


Effects of exercise on cardiovascular risk factors following stroke or transient ischemic attack: a systematic review and meta-analysis.
This review aimed to investigate the effects of exercise-based interventions on cardiovascular risk factors in individuals with stroke or transient ischemic attack. MEDLINE, EMBASE, PsycINFO, and CINAHL were searched from inceptions to 28 December 2016. Randomized controlled trials were included that involved exercise with or without other interventions, included participants of any age, with diagnosis of transient ischemic attack or stroke, at any stage of severity or time period following the event, and reported cardiovascular risk factor outcomes. Review Manager (version 5.3) was used to aggregate data from all studies and from those involving only exercise interventions. This review included 18 randomized controlled trials (930 participants) in the qualitative synthesis, 14 of which were included in the quantitative analysis (720 participants; ranging from 84 to 438 participants within individual meta-analyses). All interventions were effective in reducing resting systolic blood pressure (mean difference (MD): -5.32 mmHg, 95% confidence interval (CI): -9.46 to -1.18, P = 0.01), fasting glucose (MD: -0.11 mmol/L, 95% CI: -0.17 to -0.06, P < 0.0001), and fasting insulin (MD: -17.14 pmol/L, 95% CI: -32.90 to -1.38, P = 0.03), and increasing high-density lipoprotein cholesterol (MD: 0.10 mmol/L, 95% CI: 0.03-0.18, P = 0.008). Effects were maintained following meta-analysis of only exercise interventions. Findings suggest that exercise-based interventions are effective in reducing systolic blood pressure, fasting glucose, and fasting insulin, and increasing high-density lipoprotein cholesterol after stroke or transient ischemic attack, providing evidence for their implementation as a strategy for secondary prevention.


Diagnostic dilemmas of high-grade transformation (Richter's syndrome) of chronic lymphocytic leukaemia: results of the phase II National Cancer Research Institute CHOP-OR clinical trial specialist haemato-pathology central review.
Richter's syndrome (RS) refers to high-grade transformation of B-cell chronic lymphocytic leukaemia (CLL), usually to diffuse large B-cell lymphoma, as assessed according to strict World Health Organization (WHO)-defined histological criteria. Although this is a relatively evidence-poor area, the recommended clinical management of high-grade transformation differs considerably from that of relapsed CLL. The 'CHOP-OR' trial was a single-arm, multicentre, non-randomized phase II National Cancer Research Institute trial in patients with newly diagnosed RS, recruited from across the UK from April 2011 to December 2014. Forty-three patients were enrolled, of whom 37 were ultimately evaluable for response. The aim was to verify the presence of RS in the trial patients and identify pitfalls in the diagnosis of RS. Two independent, specialist haematopathologists reviewed histological material from 40 available cases enrolled in the CHOP-OR trial to determine whether the submitted diagnosis of RS was correct. Three cases were unavailable for central review. This series represents the largest central review of RS within a prospective trial in the literature to date. Thirty-three of the 40 (82.5%) submitted cases showed features consistent with WHO-defined RS. Reasons for diagnostic uncertainty in discrepant cases included large proliferation centres, variably confluent and serpiginous proliferation centres, and an apparently high proliferation index, sometimes attributable to a thick section or associated normal bone marrow proliferation. We discuss the importance of high-quality histological and immunohistochemical sections and strict adherence to WHO criteria in the diagnosis of RS. This study further reinforces the importance of centralized review of cases of haematological malignancy.


Efficient 1856 nm emission from Tm,Mg:LiNbO3 laser.
Efficient continuous-wave laser emission at 1856 nm from a Tm,Mg:LiNbO(3) crystal slab with high Tm(3+) doping concentration is reported. A maximum output power of 2.62 W is realized with a slope efficiency of 19.6% and the beam quality factor M(2) of 1.7 at room temperature. We believe that this is the first demonstration of watt-level laser operation in Tm,Mg:LiNbO(3) crystal and the output power is four orders of magnitude higher than that reported previously in Tm-doped LiNbO(3) crystal. Performance degradation due to the photorefractive effect under high intensity 1856 nm laser is not observed thanks to the co-doping of magnesium ions. Quantitative analysis about the long-term photorefractive effect is also provided. Multi-wavelength laser operation is realized by using different narrow-band output couplers. This demonstration opens up a viable pathway towards 2-μm integrated optic devices for achieving laser oscillation, electro-optic and nonlinear optical effects within just one sample simultaneously.


Cilengitide: the first anti-angiogenic small molecule drug candidate design, synthesis and clinical evaluation.
Cilengitide, a cyclic RGD pentapeptide, is currently in clinical phase III for treatment of glioblastomas and in phase II for several other tumors. This drug is the first anti-angiogenic small molecule targeting the integrins αvβ3, αvβ5 and αvβ1. It was developed by us in the early 90s by a novel procedure, the spatial screening. This strategy resulted in c(RGDfV), the first superactive αvβ3 inhibitor (100 to 1000 times increased activity over the linear reference peptides), which in addition exhibited high selectivity against the platelet receptor αIIbβ3. This cyclic peptide was later modified by N-methylation of one peptide bond to yield an even greater antagonistic activity in c(RGDf(NMe)V). This peptide was then dubbed Cilengitide and is currently developed as drug by the company Merck-Serono (Germany). This article describes the chemical development of Cilengitide, the biochemical background of its activity and a short review about the present clinical trials. The positive anti-angiogenic effects in cancer treatment can be further increased by combination with "classical" anti-cancer therapies. Several clinical trials in this direction are under investigation.


Transcranial magnetic stimulation of primary motor cortex affects mental rotation.
Neuroimaging studies have shown that motor structures are activated not only during overt motor behavior but also during tasks that require no overt motor behavior, such as motor imagery and mental rotation. We tested the hypothesis that activation of the primary motor cortex is needed for mental rotation by using single- pulse transcranial magnetic stimulation (TMS). Single-pulse TMS was delivered to the representation of the hand in left primary motor cortex while participants performed mental rotation of pictures of hands and feet. Relative to a peripheral magnetic stimulation control condition, response times (RTs) were slower when TMS was delivered at 650 ms but not at 400 ms after stimulus onset. The magnetic stimulation effect at 650 ms was larger for hands than for feet. These findings demonstrate that (i) activation of the left primary motor cortex has a causal role in the mental rotation of pictures of hands; (ii) this role is stimulus-specific because disruption of neural activity in the hand area slowed RTs for pictures of hands more than feet; and (iii) left primary motor cortex is involved relatively late in the mental rotation process.


Evidence for a number sense.
Numerosity is inherently confounded by related stimulus attributes such as density and area, and many studies have reported interactions of various strengths between area, density, and numerosity. However, direct measurements of sensitivity within the area-density-numerosity space show that numerosity emerges as the most spontaneous and sensitive dimension, strongly supporting the existence of a dedicated number sense.


Graphene and carbon nanodots in mesoporous materials: an interactive platform for functional applications.
The present review is focused on a specific class of nanocomposites obtained through integration of graphene or carbon-based nanomaterials (such as carbon nanodots) with mesoporous inorganic or hybrid materials, obtained via template assisted self-assembly. The task of integrating graphene and carbon nanodots with a self-assembly process is still very challenging and this review shows some of the solutions which have been envisaged so far. These nanocomposite materials are an ideal interactive platform for developing innovative functional applications; they have a high capability of undergoing integration into advanced devices, which well exploits the advantage of tuning the wide properties and flexibility of the soft-chemistry route. A wide range of applications have been developed so far which span from sensing to electronics up to optics and biomedicine. Even though a large number of proof-of-concepts have been reported to date, an even greater expansion of applications in the field is expected to happen in the near future.


Carbon monoxide: from toxin to endogenous modulator of cardiovascular functions.
Carbon monoxide (CO) is a pollutant commonly recognized for its toxicological attributes, including CNS and cardiovascular effects. But CO is also formed endogenously in mammalian tissues. Endogenously formed CO normally arises from heme degradation in a reaction catalyzed by heme oxygenase. While inhibitors of endogenous CO production can raise arterial pressure, heme loading can enhance CO production and lead to vasodepression. Both central and peripheral tissues possess heme oxygenases and generate CO from heme, but the inability of heme substrate to cross the blood brain barrier suggests the CNS heme-heme oxygenase-CO system may be independent of the periphery. In the CNS, CO apparently acts in the nucleus tractus solitarii (NTS) promoting changes in glutamatergic neurotransmission and lowering blood pressure. At the periphery, the heme-heme oxygenase-CO system can affect cardiovascular functions in a two-fold manner; specifically: 1) heme-derived CO generated within vascular smooth muscle (VSM) can promote vasodilation, but 2) its actions on the endothelium apparently can promote vasoconstriction. Thus, it seems reasonable that the CNS-, VSM- and endothelial-dependent actions of the heme-heme oxygenase-CO system may all affect cardiac output and vascular resistance, and subsequently blood pressure.


Effects of encapsulated propolis on blood glycemic control, lipid metabolism, and insulin resistance in type 2 diabetes mellitus rats.
The present study investigates the encapsulated propolis on blood glycemic control, lipid metabolism, and insulin resistance in type 2 diabetes mellitus (T2DM) rats. The animal characteristics and biological assays of body weight, fasting blood glucose (FBG), fasting serum insulin (FINS), insulin act index (IAI), triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were measured and euglycemic hyperinsulinemic glucose clamp technique were used to determine these effects. Our findings show that oral administration of encapsulated propolis can significantly inhibit the increasing of FBG and TG in T2DM rats and can improve IAI and M value in euglycemic hyperinsulinemic clamp experiment. There was no significant effects on body weight, TC, HDL-C, and LDL-C in T2DM rats treated with encapsulated propolis. In conclusion, the results indicate that encapsulated propolis can control blood glucose, modulate lipid metabolism, and improve the insulin sensitivity in T2DM rats.


Actions Targeting the Double Burden of Malnutrition: A Scoping Review.
In many developing countries, nutritional and epidemiological transitions are contributing to continuous undernutrition and escalating overnutrition, resulting in coexisting forms of malnutrition often referred as the "double burden of malnutrition" (DBM). This complex phenomenon constitutes an unprecedented challenge to global public health and has been prioritized by international health organizations, prompting governments to swift action. Specifically, five years ago the World Health Organization proposed a roadmap to tackle the DBM though so-called "double-duty actions". The objective of this review was to synthesize the literature on interventions which address the DBM. We developed a scoping review to identify interventions addressing the DBM. We searched PUBMED for papers reporting interventions until December 2019. Articles examining interventions, government policies, or tools at the individual, household, or community level to address the double burden of malnutrition were included. Seven articles met the inclusion criteria. Three were from sub-Saharan Africa, one was from Southeast Asia, and one was from Central America. Two were modelling studies, with one covering 24 low-income countries and the other focusing on Ghana. Notwithstanding the pressing issue of the DBM, there is a paucity of studies examining double-duty actions despite the attention that it has garnered within the global nutrition community. Whilst nutrient deficiencies may be curbed by poverty reduction measures, for obesity prevention nutrition, education and promotion of physical activity, along with the encouragement of local food production, may be instrumental.


Complex iron smelting and prehistoric culture in Tanzania.
Western scientists and students of history have long explaind th iron bloomery process by evidence available from European archeology. Ethnographic, technological, and archeological research into the technological life of the Haya of northwestern Tanzania show that these people and their forebears 1500 to 2000 years ago practiced a highly advanced iron smelting technology based on preheating principles and, as a result, produced carbon steel. This sophisticated technology may have evolved as an adaptation to overexploited forest resources. These discoveries are significant for the history of Africa and the history of metallurgy.


In vivo electrical conductivity of hepatic tumours.
Knowledge of electrical tissue conductivity is necessary to determine deposition of electromagnetic energy and can further be used to diagnostically differentiate between normal and neoplastic tissue. We measured 17 rats with a total of 24 tumours of the K12/TRb rat colon cancer cell line. In each animal we measured in vivo hepatic tumour and normal tissue conductivity at seven frequencies from 10 Hz to 1 MHz, at different tumour stages between 6 and 12 weeks after induction. Conductivity of normal liver tissue was 1.26 +/- 0.15 mS cm(-1) at 10 Hz, and 4.61 +/- 0.42 mS cm(-1) at 1 MHz. Conductivity of tumour was 2.69 +/- 0.91 mS cm(-1) at 10 Hz, and 5.23 +/- 0.82 mS cm(-1) at 1 MHz. Conductivity was significantly different between normal and tumour tissue (p < 0.05). We determined the percentage of necrosis and fibrosis at the measurement site. We fitted the conductivity data to the Cole-Cole model. For the tumour data we determined Spearman's correlation coefficients between the Cole-Cole parameters and age, necrosis, fibrosis and tumour volume and found significant correlation between necrosis and the Cole-Cole parameters (p < 0.05). We conclude that necrosis within the tumour and the associated membrane breakdown is likely responsible for the observed change in conductivity.


High glucose-induced proteome alterations in retinal pigmented epithelium cells and its possible relevance to diabetic retinopathy.
Diabetic retinopathy can cause poor vision and blindness. Previous research has shown that high blood glucose weakens retinal capillaries and induces glycoxidation. However, the detailed molecular mechanisms underlying the effects of high blood glucose on development of diabetic retinopathy have yet to be elucidated. In this study, we cultured a retinal pigmented epithelium cell line (ARPE-19) in mannitol-balanced 5.5 mM, 25 mM, and 100 mM d-glucose media, and evaluated protein expression and redox-regulation. We identified 56 proteins that showed significant changes in protein expression, and 33 proteins showing significant changes in thiol reactivity, in response to high glucose concentration. Several proteins that are involved in signal transduction, gene regulation, and transport showed significant changes in expression, whereas proteins involved in metabolism, transport, and cell survival displayed changes in thiol reactivity. Further analyses of clinical plasma specimens confirmed that the proteins lamin B2, PUMA, WTAP, ASGR1, and prohibitin 2 showed type 2 diabetic retinopathy-dependent alterations. In summary, in this study, we used a comprehensive retinal cell-based proteomic approach for the identification of changes in protein expression and redox-associated retinal markers induced by high glucose concentration. Some of the identified proteins have been validated with clinical samples and provide potential targets for the prognosis and diagnosis of diabetic retinopathy.


Bisphosphonate use in chronic kidney disease: association with adynamic bone disease in a bone histology series.
Dual X-ray absorptiometry is the standard diagnostic modality for identification of low bone mineral density, a finding which is in the general population usually indicative of osteopenia or osteoporosis. However, chronic kidney disease (CKD) patients diagnosed with osteopenia or osteoporosis may in actual fact have renal osteodystrophy with high or low bone turnover. While bisphosphonates are currently prescribed for the prevention of fractures in osteoporosis and high-risk osteopenic patients, the clinical utility of bisphosphonate therapy in CKD has not been established. Furthermore, bisphosphonates accumulate in bone, inhibit osteoclasts, and may cause or exacerbate low-turnover (adynamic) bone disease - particularly in patients presenting with low parathyroid hormone (PTH) levels or receiving treatment for secondary hyperparathyroidism. Bone biopsy with non-decalcified histopathology remains the gold standard for the identification and evaluation of bone disorders, including osteoporosis and renal osteodystrophy. Thirteen CKD patients (stage II-IV), referred to our clinic over a 12-month period, were identified as having taken bisphosphonates from 4 to >60 months after a diagnosis of osteopenia or osteoporosis. All patients underwent biopsies of trabecular bone from the iliac crest following oral administration of time-separated doses of doxycycline and tetracycline. Bone pathology was assessed after processing for mineralized histology. For all patients, clinical data collection included assessment of likely causes of kidney disease, MDRD glomerular filtration rate, calcium-phosphate product, intact PTH level, alkaline phosphatase, and bisphosphonate exposure. All 13 patients were diagnosed with adynamic bone on biopsy evaluation. Eleven biopsies revealed decreased cancellous bone mass; 8 showed decreased osteoid surface; 8 disclosed decreased osteoid thickness, and all 13 demonstrated low or low-normal osteoclast/osteoblast interface. Assessment of dynamic bone formation demonstrated decreased or absent single- or double-labeled osteoid in all 13 bone specimens. Based on these observations, the use of bisphosphonates in CKD cannot be recommended.


Macrophage Anti-inflammatory Behaviour in a Multiphase Model of Atherosclerotic Plaque Development.
Atherosclerosis is an inflammatory disease characterised by the formation of plaques, which are deposits of lipids and cholesterol-laden macrophages that form in the artery wall. The inflammation is often non-resolving, due in large part to changes in normal macrophage anti-inflammatory behaviour that are induced by the toxic plaque microenvironment. These changes include higher death rates, defective efferocytic uptake of dead cells, and reduced rates of emigration. We develop a free boundary multiphase model for early atherosclerotic plaques, and we use it to investigate the effects of impaired macrophage anti-inflammatory behaviour on plaque structure and growth. We find that high rates of cell death relative to efferocytic uptake results in a plaque populated mostly by dead cells. We also find that emigration can potentially slow or halt plaque growth by allowing material to exit the plaque, but this is contingent on the availability of live macrophage foam cells in the deep plaque. Finally, we introduce an additional bead species to model macrophage tagging via microspheres, and we use the extended model to explore how high rates of cell death and low rates of efferocytosis and emigration prevent the clearance of macrophages from the plaque.


Efficient team structures in an open-ended cooperative creativity experiment.
Creativity is progressively acknowledged as the main driver for progress in all sectors of humankind's activities: arts, science, technology, business, and social policies. Nowadays, many creative processes rely on many actors collectively contributing to an outcome. The same is true when groups of people collaborate in the solution of a complex problem. Despite the critical importance of collective actions in human endeavors, few works have tackled this topic extensively and quantitatively. Here we report about an experimental setting to single out some of the key determinants of efficient teams committed to an open-ended creative task. In this experiment, dynamically forming teams were challenged to create several artworks using LEGO bricks. The growth rate of the artworks, the dynamical network of social interactions, and the interaction patterns between the participants and the artworks were monitored in parallel. The experiment revealed that larger working teams are building at faster rates and that higher commitment leads to higher growth rates. Even more importantly, there exists an optimal number of weak ties in the social network of creators that maximizes the growth rate. Finally, the presence of influencers within the working team dramatically enhances the building efficiency. The generality of the approach makes it suitable for application in very different settings, both physical and online, whenever a creative collective outcome is required.


The effect of Bt crops on soil invertebrates: a systematic review and quantitative meta-analysis.
The ongoing debate about the ecological effects of Bt-crops calls for thorough reviews about the impact on soil biodiversity and their ecosystem services. Transgenic Bt-crops have been genetically modified by inserting a Bacillus thuriengensis gene so the plant expresses a Cry toxin aimed for insect crop pests. Non-target soil invertebrates are particularly recognized for their contribution to plant nutrient availability and turnover of organic matter and it is therefore relevant to protect these invertebrate taxa. A number of studies have compared the population abundance and biomass of soil invertebrates in agricultural fields planted with genetically modified Bt crops and their conventional counterparts. Here, were review and analyze a selection of studies on Protista, nematodes, Collembola, mites, enchytraeids, and earthworms systematically to empower the evidence for asking the question whether population abundances and biomasses of soil invertebrates are changed by Bt crops compared to conventional crops. 6110 titles were captured, of which 38 studies passed our inclusion criteria, and a final number of 22 publications were subject to data extraction. A database with 2046 records was compiled covering 36 locations and the Bt types Cry1Ab, Cry1Ac, Cry3Bb1 and Cry3Aa. Comparative effect sizes in terms of Hedges' g were calculated irrespectively of statistical significance of effects of the source studies. Cry effects on populations were compared across the studies in a meta-analysis employing a hierarchical Bayesian approach of weighted data according to the level of replication. The temporal development of effect sizes was modelled, thereby taking into account the variable duration of the field experiments. There was considerable variation among soil invertebrate orders, but the sample size was insufficient and the sample heterogeneity too large to draw any credible conclusions on the effect of Cry at the order level. However, across orders there was no significant effect of Cry on soil invertebrates.