Observation of universal Hall response in strongly interacting Fermions.

The Hall effect, which originates from the motion of charged particles in magnetic fields, has deep consequences for the description of materials, extending far beyond condensed matter. Understanding such an effect in interacting systems represents a fundamental challenge, even for small magnetic fields. In this work, we used an atomic quantum simulator in which we tracked the motion of ultracold fermions in two-leg ribbons threaded by artificial magnetic fields. Through controllable quench dynamics, we measured the Hall response for a range of synthetic tunneling and atomic interaction strengths. We unveil a universal interaction-independent behavior above an interaction threshold, in agreement with theoretical analyses. The ability to reach hard-to-compute regimes demonstrates the power of quantum simulation to describe strongly correlated topological states of matter.

CDK12 promotes tumorigenesis but induces vulnerability to therapies inhibiting folate one-carbon metabolism in breast cancer.

Cyclin-dependent kinase 12 (CDK12) overexpression is implicated in breast cancer, but whether it has a primary or only a cooperative tumorigenic role is unclear. Here, we show that transgenic CDK12 overexpression in the mouse mammary gland per se is sufficient to drive the emergence of multiple and multifocal tumors, while, in cooperation with known oncogenes, it promotes earlier tumor onset and metastasis. Integrative transcriptomic, metabolomic and functional data reveal that hyperactivation of the serine-glycine-one-carbon network is a metabolic hallmark inherent to CDK12-induced tumorigenesis. Consistently, in retrospective patient cohort studies and in patient-derived xenografts, CDK12-overexpressing breast tumors show positive response to methotrexate-based chemotherapy targeting CDK12-induced metabolic alterations, while being intrinsically refractory to other types of chemotherapy. In a retrospective analysis of hormone receptor-negative and lymph node-positive breast cancer patients randomized in an adjuvant phase III trial to 1-year low-dose metronomic methotrexate-based chemotherapy or no maintenance chemotherapy, a high CDK12 status predicts a dramatic reduction in distant metastasis rate in the chemotherapy-treated vs. not-treated arm. Thus, by coupling tumor progression with metabolic reprogramming, CDK12 creates an actionable vulnerability for breast cancer therapy and might represent a suitable companion biomarker for targeted antimetabolite therapies in human breast cancers.

Genetic diversity among viruses associated with sugarcane mosaic disease in Tucumán, Argentina.

Sugarcane leaves with mosaic symptoms were collected in 2006--07 in Tucumán (Argentina) and analyzed by reverse-transcriptase polymerase chain reaction (RT-PCR) restriction fragment length polymorphism (RFLP) and sequencing of a fragment of the Sugarcane mosaic virus (SCMV) and Sorghum mosaic virus (SrMV) coat protein (CP) genes. SCMV was detected in 96.6% of samples, with 41% showing the RFLP profile consistent with strain E. The remaining samples produced eight different profiles that did not match other known strains. SCMV distribution seemed to be more related to sugarcane genotype than to geographical origin, and sequence analyses of CP genes showed a greater genetic diversity compared with other studies. SrMV was detected in 63.2% of samples and most of these were also infected by SCMV, indicating that, unlike other countries and other Argentinean provinces, where high levels of co-infection are infrequent, co-existence is common in Tucumán. RFLP analysis showed the presence of SrMV strains M (68%) and I (14%), while co-infection between M and H strains was present in 18% of samples. Other SCMV subgroup members and the Sugarcane streak mosaic virus (SCSMV) were not detected. Our results also showed that sequencing is currently the only reliable method to assess SCMV and SrMV genetic diversity, because RT-PCR-RFLP may not be sufficiently discriminating.

Effect of fragarin on the cytoplasmic membrane of the phytopathogen Clavibacter michiganensis.

Fragarin, an antibiotic that was isolated and purified from a soluble fraction of strawberry leaves, may be a new type of preformed antimicrobial compound (phytoanticipin). Here, we report that the growth and oxygen consumption of the phytopathogenic bacterium Clavibacter michiganensis were rapidly inhibited after the addition of fragarin to cultures. Also, dissipation of the membrane potential and an increase of cell membrane permeability were observed in the presence of fragarin. The ability of fragarin to dissipate the membrane potential was confirmed with the use of small unilamellar liposomes made with lipids extracted from C. michiganensis. Our results suggest that fragarin is able to act at the membrane level, and that this action is correlated with a decrease in cell viability.

Isolation and purification of a 316 Da preformed compound from strawberry (Fragaria ananassa) leaves active against plant pathogens.

An antibiotic called fragarin showing activities against bacterial and fungal plant pathogens was isolated and purified by FPLC chromatography from the soluble fraction of strawberry leaves. The molecular weight value determined by mass spectrometry is 316 Da. Fragarin remains fully active after protease treatment or alkaline hydrolysis at 100 degrees C for 20 min. Biological and chemical analyses suggest that fragarin may be a new type of an antimicrobial preformed compound--phytoanticipin--and would constitute a primary non-specific barrier of strawberry defense.

Effect of disodium cromoglycate on ventilation and gas exchange during exercise in asthmatic children with a postexertion FEV1 fall less than 15 percent.

The purpose of this study is to evaluate the effect of disodium cromoglycate (DSCG) on gas exchange and ventilation during incremental exercise in asthmatic children with an FEV1 fall less than 15 percent from the baseline after the exercise. Seventeen children (aged 8 to 14 years) with a history of mild to moderate asthma but no clinical and spirometric evidence of exercise-induced asthma (EIA) underwent two maximal exercise tests in a randomized order: test A without premidication and test B after inhalation of DSCG, 40 mg. To evaluate the effect of DSCG on normal airways, nine healthy children performed the same exercise protocol. Pulmonary function was normal at rest and after treadmill exercise test (the mean postexercise fall in FEV1 was 5.9 percent in test A and 1.5 percent in test B). Gas exchange, minute ventilation (VE) and heart rate (HR) were monitored during running in both tests. In the asthmatic subjects, there were no differences in oxygen uptake (VO2), carbon dioxide output (VCO2), and VE at rest between the two tests. During exercise, VE, VO2, VCO2, and energy cost (EC[O2 ml.kg-1.m-1]) of running in the asthmatic subjects were significantly lower in test B than in test A (analysis of variance, p < 0.01) for comparable work rates. Maximal minute ventilation (VEmax) was significantly higher in test A (46.9 +/- 14.6[+/- SD]L.min-1) than in test B (43.2 +/- 14 L. min-1; p < 0.05). We found no significant effect of DSCG on gas exchange and ventilation during exercise in the healthy children (VEmax 47.8 +/- 25 and 48.4 +/- 25 L.min-1 in test A and B, respectively). In conclusion, premedication with DSCG appears to decrease the ventilatory cost of exercise in asthmatic children who do not present a substantial fall in FEV1 after an exercise test without pretreatment.

Rapid improvement of static compliance after surfactant treatment in preterm infants with respiratory distress syndrome.

Respiratory mechanics were measured in 20 preterm infants before and in the 24-hr period after treatment with surfactant. All infants were enrolled in the rescue clinical trial with Curosurf carried out in the Neonatal Intensive Care Unit. They received a dose of 200 mg/kg lipid surfactant intratracheally after birth. Static compliance of the respiratory system (Crs) was measured by the single breath occlusion technique during both spontaneous and mechanical ventilation. Resistance of the respiratory system (Rrs) and expiratory time constant (Trs) were also measured. As early as 3 hr after surfactant administration a significant improvement of 45% in Crs measured during mechanical ventilation (CrsV) was noted (0.40 +/- 0.14 vs 0.58 +/- 0.17 mL/cm H2O/kg, P < 0.001), together with a significant improvement of the arterial/alveolar O2 tension ratio (Pa/AO2) (0.12 +/- 0.03 vs 0.30 +/- 0.16, P < 0.01). The improvement of CrsV and Pa/AO2 was confirmed 24 hr later (0.55 +/- 0.15 mL/cm H2O/kg and 0.33 +/- 0.18, respectively). A significant correlation was found between Crs and Pa/AO2 ratio (r = 0.56, P < 0.001). Time constant values were significantly higher after surfactant treatment (0.15 +/- 0.07 vs 0.09 +/- 0.03 sec; P < 0.01). Rrs remained unchanged. These data indicate that Curosurf given intratracheally after birth determines a rapid improvement of respiratory mechanics as soon as 3 hr after dosing, together with the improvement of oxygenation. From the findings obtained with the present study we show evidence that respiratory system mechanics may be a useful physiological measure to guide ventilatory strategy following surfactant therapy.

Gas exchange during exercise in diabetic children.

The purpose of this study was to evaluate the cardiorespiratory and metabolic response to exercise in 33 children, aged 9 to 15 years, affected by type I diabetes mellitus, in comparison with 47 age-, sex-, weight-, and height-matched healthy children. All diabetic children were on a mixed split-dose insulin regimen, consisting of both regular and long-acting insulin in the morning and evening. The last insulin injection was administered on average 6 hours before the test. The mean duration of diabetes mellitus was 5.0 +/- 3.1 years. The metabolic control was evaluated on the basis of HbA1 levels (mean, 8.9 +/- 1.8%). Pulmonary function tests and progressive exercise tests on the treadmill were performed. Gas exchange, ventilation, and heart rate (HR) were monitored during the tests. The O2 pulse (VO2/HR) was calculated. There was no difference in the baseline oxygen uptake (VO2) between the diabetic children and the control group. VO2 peak was significantly lower (P less than 0.01) in the diabetic adolescents (41.2 +/- 5.9 mL/min/kg) compared to control subjects (46.3 +/- 9.6 mL/min/kg) and it was achieved at an earlier (P less than 0.01) time of run (7.5 +/- 1.8 vs. 9.1 +/- 2.8 min). Anaerobic threshold and minute ventilation were similar in the two groups. The O2 pulse throughout the test was significantly lower (ANOVA, P less than 0.001) in the diabetic group compared to the controls. No differences were found in resting and post-exercise spirometric values. In conclusion, our study shows that well-controlled diabetic adolescents have a reduced working capacity.(ABSTRACT TRUNCATED AT 250 WORDS)

Metabolic and respiratory effects of theophylline in the preterm infant.

BACKGROUND: Methylxanthines are often administered to preterm infants for the treatment of apnoea. AIMS: To study the effects of theophylline on energy metabolism, physical activity, and lung mechanics in preterm infants. METHODS: Indirect calorimetry was performed for six hours before and after administration of a bolus of theophylline (5 mg/kg) in 18 preterm infants while physical activity was recorded with a video camera. Lung mechanics measurements were performed at baseline and 12 and 24 hours after theophylline treatment. RESULTS: Theophylline increased mean (SEM) energy expenditure by 15 (5) kJ/kg/day and augmented carbohydrate utilisation from 6.8 to 8.0 g/kg/day, but fat oxidation was unchanged. After theophylline treatment, preterm infants had faster respiration, lower transcutaneous CO2, and improved static respiratory compliance without increased physical activity. CONCLUSIONS: A bolus of 5 mg/kg theophylline increased energy expenditure independently of physical activity, increased carbohydrate utilisation, and improved respiratory compliance. The increased energy expenditure could be detrimental to the growth of the preterm infant.

Temporal bone findings in Pierre Robin syndrome.

This is the first complete report on the histopathologic study of the temporal bones from an infant with a well-documented Pierre Robin syndrome (micrognathia, glossoptosis and cleft palate), demonstrating multiple middle and inner ear anomalies. The anomalies are basically architectural malformations rather than neutral or end organ developmental anomalies. The anomalies in this case, except for a few points, are somewhat similar in both ears. Multiple anomalies include: abnormal narrowing of the crus commune-utricle junction, superiorly located crus commune and posterior semicircular canal, underdeveloped modiolus, absence of the bony septum between the middle and apical coil (existence of scala communis in left ear), abnormally small internal auditory meatus, and abnormal direction of internal auditory canal, large cartilaginous mass around the superior semicircular canal and in the tympanic end of the fissula ante fenestram, small facial nerve, large facial bony canal dehiscence, anomalic stapes, etc.

Metastatic carcinomatous cirrhosis and hepatic hemosiderosis in a patient heterozygous for the H63D genotype.

A 38-year-old woman had a mastectomy for infiltrating ductal carcinoma of the breast 3 years before her last admission and had received chemotherapy for known liver metastases. She developed the rapid onset of liver failure with portal hypertension and died in a hospice. Autopsy revealed macronodular cirrhosis of the liver secondary to metastatic carcinoma of the breast with associated florid fibrosis. This rare lesion, previously called metastatic carcinomatous cirrhosis, was also found, in this case, to have marked hepatic hemosiderosis, and analysis of the patient's DNA showed heterozygosity for the H63D genotype. The possibility of cirrhosis-associated hemosiderosis secondary to an iron metabolism abnormality associated with the H63D mutation of the HFE gene is proposed. Computed tomographic scans showed the development of cirrhosis during the 3-month period before the patient's last admission and suggested the possibility of a postnecrotic type origin.

First Report of Colletotrichum acutatum on Strawberry in Northwestern Argentina.

Isolates were obtained from strawberry tissue with anthracnose symptoms from several locations near Tucumán, Argentina. Isolates were characterized using several criteria. Isolates produced fusiform conidia, tapered to a point at both ends, and averaged 13.5 × 4.9 µm. On potato dextrose agar, colonies produced a white cottony mycelial colony that turned orange in older cultures. Compared with Colletotrichum fragariae, the new isolates produced fewer appressoria. Pathogenicity tests were conducted on detached leaves and plants in the greenhouse and field. Detached immature leaves of cvs. Chandler, Fern, and Sweet Charlie were inoculated with a 20-µl droplet of an aqueous conidial suspension (106 conidia per ml) placed on the adaxial surface. Control leaves were inoculated with sterile distilled water. Leaves were maintained under white light (2,000 lux, 12 h/day) at 26°C, and 100% relative humidity. Necrotic spots were visible 4 days after inoculation. Greenhouse and field plants were spray-inoculated and covered for 48 h. Disease symptoms were mainly observed on petioles and runners 9 days after inoculation. No lesions were observed on control detached leaves or plants. Koch's postulates were confirmed in all cases. Based on morphological and cultural characteristics, isolates were identified as C. acutatum Simmonds (1). This is the first report of C. acutatum causing strawberry anthracnose in northwestern Argentina. Reference: (1) B. Smith and L. L. Black. Plant Dis. 74:69, 1990.

Passive respiratory mechanics to assess lung function in infants.

In the last decade, the development of a number of ingenious techniques has led to the possibility of evaluating respiratory mechanics from the neonate up to children 3-4 yrs of age. Among these methods, the single-breath occlusion (SBO) technique and the multiple occlusion (MO) technique have gained extensive acceptance, and are used both in spontaneously breathing and mechanically-ventilated infants. These techniques allow the assessment of the passive mechanics of the total respiratory system (compliance, resistance and time constant), by evoking the Hering-Breuer inflation reflex, which results in relaxation of both inspiratory and expiratory muscles. These methods are suitable for repeated assessment in small infants and for longitudinal studies, because of their low invasivity, high reproducibility and relatively simple application. Pulmonary function tests may represent a useful guide in diagnosis, monitoring, prediction of outcome, and management assessment in infants and children with lung diseases. However all these techniques are limited by implicit assumptions and further developments towards simpler methods are needed.

Pax8 has a critical role in epithelial cell survival and proliferation.

The transcription factor Pax8, a member of the Paired-box gene family, is a critical regulator required for proper development and differentiation of thyroid follicular cells. Despite being Pax8 well characterized with respect to its role in regulating genes responsible for thyroid differentiation, its involvement in cell survival and proliferation has been hypothesized but remains unclear. Here, we show that Pax8 overexpression significantly increases proliferation and colony-forming efficiency of Fischer rat thyroid line 5 epithelial cells, although it is not sufficient to overcome their hormone dependence. More interestingly, we show that Pax8-specific silencing induces apoptosis through a p53-dependent pathway that involves caspase-3 activation and cleavage of poly(ADP)ribose polymerase. Our data indicate that tumor protein 53 induced nuclear protein 1 (tp53inp1), a positive regulator of p53-dependent cell cycle arrest and apoptosis, is a transcriptional target of Pax8 and is upregulated by Pax8 knockdown. Remarkably, tp53inp1 silencing significantly abolishes Pax8-induced apoptosis thus suggesting that tp53inp1 may be the mediator of the observed effects. In conclusion, our data highlight that Pax8 is required for the survival of differentiated epithelial cells and its expression levels are able to modulate the proliferation rate of such cells.

PROBABILISTIC PREDICTION OF NEUROLOGICAL DISORDERS WITH A STATISTICAL ASSESSMENT OF NEUROIMAGING DATA MODALITIES.

For many neurological disorders, prediction of disease state is an important clinical aim. Neuroimaging provides detailed information about brain structure and function from which such predictions may be statistically derived. A multinomial logit model with Gaussian process priors is proposed to: (i) predict disease state based on whole-brain neuroimaging data and (ii) analyze the relative informativeness of different image modalities and brain regions. Advanced Markov chain Monte Carlo methods are employed to perform posterior inference over the model. This paper reports a statistical assessment of multiple neuroimaging modalities applied to the discrimination of three Parkinsonian neurological disorders from one another and healthy controls, showing promising predictive performance of disease states when compared to nonprobabilistic classifiers based on multiple modalities. The statistical analysis also quantifies the relative importance of different neuroimaging measures and brain regions in discriminating between these diseases and suggests that for prediction there is little benefit in acquiring multiple neuroimaging sequences. Finally, the predictive capability of different brain regions is found to be in accordance with the regional pathology of the diseases as reported in the clinical literature.

Exercise performance in children with asthma: is it different from that of healthy controls?

Exercise tolerance and possible limitation in work capacity of asthmatic children is still a matter of debate. The aim of this study was to compare ventilation and gas exchange response to exercise of asthmatic children with that of healthy controls. Exercise performance was evaluated in 80 children with mild-to-moderate asthma, aged 7-15 yrs, and in 80 healthy controls matched for age, height, weight and habitual level of physical activity. The children performed a maximal exercise test on a treadmill, during which oxygen uptake (V'O2), carbon dioxide output (V'CO2) and minute ventilation (V'E) were measured continuously. No premedication was given to the asthmatic children. Forced expiratory volume in one second (FEV1) at rest was 93+/-11% of predicted in asthmatic children and 95+/-9% pred in controls. After the run, the mean fall in FEV1 was 13.9% (range 0-57%) and 1.6% (0-9%), respectively (p<0.001). The two groups achieved similar maximum oxygen uptake (V'O2,max) ((mean+/-SD) 40.3+/-8.4 and 42.6+/-9.6 mL x min(-1) x kg(-1) in asthmatics and controls, respectively; NS) and maximum minute ventilation output (V'E,max) (42.9+/-14.8 and 45.7+/-14.9 L x min(-1) respectively; NS). The kinetics of V'O2, V'CO2 and V'E during the test revealed no differences between the two populations. Moreover, anaerobic threshold and oxygen pulse were the same in the two groups. Asthmatics showed a ventilatory pattern with lower respiratory frequencies and greater tidal volumes during the run. These results suggest that asthmatic children can achieve a level of exercise performance similar to that of healthy children, provided that they have a comparable level of habitual physical activity. The only difference found concerned the ventilatory pattern of the asthmatic children, which was characterized by a reduced respiratory frequency and greater tidal volume at the same minute ventilation. The level of physical conditioning was found to be the main determinant of exercise tolerance for children with controlled asthma.

Factors limiting exercise performance in long-term survivors of bronchopulmonary dysplasia.

The long-term impairment of pulmonary function during exercise was assessed in 12 children, aged 6 to 12 yr, who developed BPD after prematurity (gestational age 30 +/- 2 wk [mean +/- SD] and birth weight 1,400 +/- 335 g) and 16 age-, sex-, and physical activity-matched healthy children born at term, who served as controls. The children performed pulmonary function tests at rest and a maximal stepwise exercise on a treadmill. Oxygen consumption (VO2), carbon dioxide output (VCO2), and minute ventilation (VE) were monitored during the run. Baseline mean spirometric values (% of predicted) were in the normal range for both groups but were lower in BPD children with respect to control children (p < 0.05). At rest, arterial oxygen saturation (SaO2) was > or = 98% in all BPD children, but at peak exercise, 4 of them had a SaO2 fall > or = 4%. The postexercise FEV1 fall, with respect to the baseline, was 8 +/- 6%, in BPD and 2 +/- 1% in control children (p < 0.01). Maximum VO2 and VE were significantly lower in BPD children with respect to the control group (25.2 +/- 10.3 versus 37.1 +/- 10.4 ml/min/kg and 20.8 +/- 9.4 versus 30.7 +/- 7.9 L/min, respectively, both p < 0.01). Also, at submaximal levels of exercise dynamic, VO2 and VE responses were significantly lower in the BPD group (ANOVA, p < 0.001), with a ventilatory pattern characterized by lower tidal volumes. Anaerobic threshold was 20.6 +/- 9 in BPD and 28.8 +/- 8.6 ml O2/min/kg in healthy children (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Functional approach to infants and young children with noisy breathing: validation of pneumotachography by blinded comparison with bronchoscopy.

Flow-volume loop evaluation yields considerable diagnostic information about adult patients with upper airway obstruction. No conclusive data support the reliability of this method in young children with noisy breathing. We used analysis of flow-volume loops at tidal breathing (TB-FV) as a first diagnostic approach to young children presenting with persistent noisy breathing (chronic stridor and/or wheezing). Flexible fiberoptic bronchoscopy was performed to establish a conclusive diagnosis and was used to verify the accuracy of the preliminary functional localization of the airway obstruction causing noisy breathing. The physician conducting pneumotachography was blinded to the bronchoscopic findings in the study, and the investigators conducting bronchoscopy were blinded to the pneumotachographic findings. Through a 6-yr period, 113 consecutive young children (ranging in age from 15 to 48 mo) with noisy breathing were enrolled in the study. Three morphologically abnormal TB-FV patterns, as compared with the normal round-shaped TB-FV loops obtained with 15 healthy children, were identified in 110 patients. A TB-FV pattern of inspiratory fluttering was found in 26 subjects and in the first 3 yr of the study was always associated with an endoscopic diagnosis of isolated laryngomalacia. Subsequently, this pattern was used to diagnose isolated laryngomalacia in 18 other infants, in whom endoscopy was avoided. Of infants with endoscopic evidence of airway obstruction ranging from the glottis to the mainstem bronchi (49 subjects), all but three showed a TB-FV loop pattern characterized by expiratory-limb flattening. A concave expiratory loop, with early expiratory peak flow and low flow at low volume, was invariably associated with peripheral bronchoconstriction, without endoscopic evidence of anatomic abnormalities (20 cases). In conclusion, TB- FV loop analysis is a noninvasive, accurate method of establishing the site of airway obstruction in young children with recurrent stridor and/or wheezing. Clinical use of this method may provide interesting pathophysiologic information and may be useful in addressing the diagnostic management of such children.