Calcineurin as a Multifunctional Regulator: Unraveling Novel Functions in Fungal Stress Responses, Hyphal Growth, Drug Resistance, and Pathogenesis.

Calcineurin signaling plays diverse roles in fungi in regulating stress responses, morphogenesis and pathogenesis. Although calcineurin signaling is conserved among fungi, recent studies indicate important divergences in calcineurin-dependent cellular functions among different human fungal pathogens. Fungal pathogens utilize the calcineurin pathway to effectively survive the host environment and cause life-threatening infections. The immunosuppressive calcineurin inhibitors (FK506 and cyclosporine A) are active against fungi, making targeting calcineurin a promising antifungal drug development strategy. Here we summarize current knowledge on calcineurin in yeasts and filamentous fungi, and review the importance of understanding fungal-specific attributes of calcineurin to decipher fungal pathogenesis and develop novel antifungal therapeutic approaches.

Tissue-specific opposing functions of the inflammasome adaptor ASC in the regulation of epithelial skin carcinogenesis.

A chronic inflammatory microenvironment favors tumor progression through molecular mechanisms that are still incompletely defined. In inflammation-induced skin cancers, IL-1 receptor- or caspase-1-deficient mice, or mice specifically deficient for the inflammasome adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD) in myeloid cells, had reduced tumor incidence, pointing to a role for IL-1 signaling and inflammasome activation in tumor development. However, mice fully deficient for ASC were not protected, and mice specifically deficient for ASC in keratinocytes developed more tumors than controls, suggesting that, in contrast to its proinflammatory role in myeloid cells, ASC acts as a tumor-suppressor in keratinocytes. Accordingly, ASC protein expression was lost in human cutaneous squamous cell carcinoma, but not in psoriatic skin lesions. Stimulation of primary mouse keratinocytes or the human keratinocyte cell line HaCaT with UVB induced an ASC-dependent phosphorylation of p53 and expression of p53 target genes. In HaCaT cells, ASC interacted with p53 at the endogenous level upon UVB irradiation. Thus, ASC in different tissues may influence tumor growth in opposite directions: it has a proinflammatory role in infiltrating cells that favors tumor development, but it also limits keratinocyte proliferation in response to noxious stimuli, possibly through p53 activation, which helps suppressing tumors.

Prevalence, prenatal diagnosis and clinical features of oculo-auriculo-vertebral spectrum: a registry-based study in Europe.

Oculo-auriculo-vertebral spectrum is a complex developmental disorder characterised mainly by anomalies of the ear, hemifacial microsomia, epibulbar dermoids and vertebral anomalies. The aetiology is largely unknown, and the epidemiological data are limited and inconsistent. We present the largest population-based epidemiological study to date, using data provided by the large network of congenital anomalies registries in Europe. The study population included infants diagnosed with oculo-auriculo-vertebral spectrum during the 1990-2009 period from 34 registries active in 16 European countries. Of the 355 infants diagnosed with oculo-auriculo-vertebral spectrum, there were 95.8% (340/355) live born, 0.8% (3/355) fetal deaths, 3.4% (12/355) terminations of pregnancy for fetal anomaly and 1.5% (5/340) neonatal deaths. In 18.9%, there was prenatal detection of anomaly/anomalies associated with oculo-auriculo-vertebral spectrum, 69.7% were diagnosed at birth, 3.9% in the first week of life and 6.1% within 1 year of life. Microtia (88.8%), hemifacial microsomia (49.0%) and ear tags (44.4%) were the most frequent anomalies, followed by atresia/stenosis of external auditory canal (25.1%), diverse vertebral (24.3%) and eye (24.3%) anomalies. There was a high rate (69.5%) of associated anomalies of other organs/systems. The most common were congenital heart defects present in 27.8% of patients. The prevalence of oculo-auriculo-vertebral spectrum, defined as microtia/ear anomalies and at least one major characteristic anomaly, was 3.8 per 100,000 births. Twinning, assisted reproductive techniques and maternal pre-pregnancy diabetes were confirmed as risk factors. The high rate of different associated anomalies points to the need of performing an early ultrasound screening in all infants born with this disorder.

Baseline Results of an Acute Ischemic Stroke Registry Including Acute Multimodal Imaging (ASTRAL)

Background: The DEFUSE (n_74) and EPITHET (n_101) studies have in common that a baseline MRI was obtained prior to treatment (tPA in DEFUSE; tPA or placebo in EPITHET) in the 3-6 hour time-window. There were however important methodological differences between the studies. A standardized reanalysis of pooled data was undertaken to determine the effect of these differences on baseline characteristics and study outcomes. Methods: To standardize the studies 1) the DWI and PWI source images were reprocessed and segmented using automated image processing software (RAPID); 2) patients were categorized according to their baseline MRI profile as either Target Mismatch (PWITmax_6/DWI ratio_ 1.8 and an absolute mismatch _15mL), Malignant (DWI or PWITmax_10 lesion _ 100 mL), or No Mismatch. 3) favorable clinical response was defined as NIHSS score of 0-1 or a _8 points improvement on the NIHSSS at day 90. Results: Prior to standardization there was no difference in the proportion of Target Mismatch patients between EPITHET and DEFUSE (54% vs 49%, p_0.6), but the EPITHET study had more patients with the Malignant profile than DEFUSE (35% vs 9%, p_0.01) and fewer patients that had No Mismatch (11% vs 42%, p_0.01). These differences in baseline MRI profiles between EPITHET and DEFUSE were largely eliminated by standardized processing of PWI and DWI images with RAPID software (Target Mismatch 49% vs 48%; Malignant 15% vs 8%; No Mismatch 36% vs 25%; p_NS for all comparisons) Reperfusion was strongly associated with a favorable clinical response in mismatch patients (figure). This relationship was not affected by the standardization procedures (pooled odds ratio of 8.8 based on original data and 6.6 based on standardized data). Conclusion: Standardization of image analyses procedures in acute stroke is important as non-standardized techniques introduce significant variability in DWI and PWI imaging characteristics. Despite methodological differences, the DEFUSE and EPITHET studies show a consistent and robust association between reperfusion and favorable clinical response in Target Mismatch patients regardless of standardization. These data support an RCT of iv tPA in the 3-6 hour time-window for Target Mismatch patients identified using RAPID.

An international registry on autoinflammatory diseases: the Eurofever experience.

OBJECTIVE: To report on the demographic data from the first 18 months of enrollment to an international registry on autoinflammatory diseases in the context of the Eurofever project. METHODS: A web-based registry collecting baseline and clinical information on autoinflammatory diseases and related conditions is available in the member area of the PRINTO web-site. Anonymised data were collected with standardised forms. RESULTS: 1880 (M:F=916:964) individuals from 67 centers in 31 countries have been entered in the Eurofever registry. Most of the patients (1388; 74%), reside in western Europe, 294 (16%) in the eastern and southern Mediterranean region (Turkey, Israel, North Africa), 106 (6%) in eastern Europe, 54 in Asia, 27 in South America and 11 in Australia. In total 1049 patients with a clinical diagnosis of a monogenic autoinflammatory diseases have been enrolled; genetic analysis was performed in 993 patients (95%): 703 patients have genetically confirmed disease and 197 patients are heterozygous carriers of mutations in genes that are mutated in patients with recessively inherited autoinflammatory diseases. The median diagnosis delay was 7.3 years (range 0.3-76), with a clear reduction in patients born after the identification of the first gene associated with autoinflammatory diseases in 1997. CONCLUSIONS: A shared online registry for patients with autoinflammatory diseases is available and enrollment is ongoing. Currently, there are data available for analysis on clinical presentation, disease course, and response to treatment, and to perform large scale comparative studies between different conditions.

Characterization of Reward Functions in Networks with Costs

In this paper we study network structures in which the possibilities for cooperation are restricted and can not be described by a cooperative game. The benefits of a group of players depend on how these players are internally connected. One way to represent this type of situations is the so-called reward function, which represents the profits obtainable by the total coalition if links can be used to coordinate agents' actions. The starting point of this paper is the work of Vilaseca et al. where they characterized the reward function. We concentrate on those situations where there exist costs for establishing communication links. Given a reward function and a costs function, our aim is to analyze under what conditions it is possible to associate a cooperative game to it. We characterize the reward function in networks structures with costs for establishing links by means of two conditions, component permanence and component additivity. Finally, an economic application is developed to illustrate the main theoretical result.

Antagonistic functions of LMNA isoforms in energy expenditure and lifespan.

Alternative RNA processing of LMNA pre-mRNA produces three main protein isoforms, that is, lamin A, progerin, and lamin C. De novo mutations that favor the expression of progerin over lamin A lead to Hutchinson-Gilford progeria syndrome (HGPS), providing support for the involvement of LMNA processing in pathological aging. Lamin C expression is mutually exclusive with the splicing of lamin A and progerin isoforms and occurs by alternative polyadenylation. Here, we investigate the function of lamin C in aging and metabolism using mice that express only this isoform. Intriguingly, these mice live longer, have decreased energy metabolism, increased weight gain, and reduced respiration. In contrast, progerin-expressing mice show increased energy metabolism and are lipodystrophic. Increased mitochondrial biogenesis is found in adipose tissue from HGPS-like mice, whereas lamin C-only mice have fewer mitochondria. Consistently, transcriptome analyses of adipose tissues from HGPS and lamin C-only mice reveal inversely correlated expression of key regulators of energy expenditure, including Pgc1a and Sfrp5. Our results demonstrate that LMNA encodes functionally distinct isoforms that have opposing effects on energy metabolism and lifespan in mammals.

Redundant functions of TCF-1 and LEF-1 during T and NK cell development, but unique role of TCF-1 for Ly49 NK cell receptor acquisition.

Members of the TCF/LEF (T cell factor / lymphoid enhancer factor) family of DNA-binding factors play important roles during embryogenesis, the establishment and/or maintenance of self-renewing tissues such as the immune system and for malignant transformation. Specifically, it has been shown that TCF-1 is required for T cell development. A role for LEF-1 became apparent when mice harbored two hypomorphic TCF-1 alleles and consequently expressed low levels of TCF-1. Here we show that NK cell development is similarly regulated by redundant functions of TCF-1 and LEF-1, whereby TCF-1 contributes significantly more to NK cell development than LEF-1. Despite this role for NK cell development, LEF-1 is not required for the establishment of a repertoire of MHC class I-specific Ly49 receptors on NK cells. The proper formation of this repertoire depends to a large extent on TCF-1. These findings suggest common and distinct functions of TCF-1 and LEF-1 during lymphocyte development.

External validation of the ASTRAL score to predict 3- and 12-month functional outcome in the China National Stroke Registry.

BACKGROUND AND PURPOSE: The ASTRAL score was recently introduced as a prognostic tool for acute ischemic stroke. It predicts 3-month outcome reliably in both the derivation and the validation European cohorts. We aimed to validate the ASTRAL score in a Chinese stroke population and moreover to explore its prognostic value to predict 12-month outcome. METHODS: We applied the ASTRAL score to acute ischemic stroke patients admitted to 132 study sites of the China National Stroke Registry. Unfavorable outcome was assessed as a modified Rankin Scale score >2 at 3 and 12 months. Areas under the curve were calculated to quantify the prognostic value. Calibration was assessed by comparing predicted and observed probability of unfavorable outcome using Pearson correlation coefficient. RESULTS: Among 3755 patients, 1473 (39.7%) had 3-month unfavorable outcome. Areas under the curve for 3 and 12 months were 0.82 and 0.81, respectively. There was high correlation between observed and expected probability of unfavorable 3- and 12-month outcome (Pearson correlation coefficient: 0.964 and 0.963, respectively). CONCLUSIONS: ASTRAL score is a reliable tool to predict unfavorable outcome at 3 and 12 months after acute ischemic stroke in the Chinese population. It is a useful tool that can be readily applied in clinical practice to risk-stratify acute stroke patients.

Trends in risk factors, patterns and causes in hospitalized strokes over 25 years: The Lausanne Stroke Registry.

BACKGROUND AND OBJECTIVE: The Lausanne Stroke Registry includes, from 1979, all patients admitted to the department of Neurology of the Lausanne University Hospital with the diagnosis of first clinical stroke. Using the Lausanne Stroke Registry, we aimed to determine trends in risk factors, causes, localization and inhospital mortality over 25 years in hospitalized stroke patients. METHODS: We assessed temporal trends in stroke patients characteristics through the following consecutive periods: 1979-1987, 1988-1995 and 1996-2003. Age-adjusted cardiovascular risk factors, etiologies, stroke localizations and mortality were compared between the three periods. RESULTS: Overall, 5,759 patients were included. Age was significantly different among the analyzed periods (p < 0.001), showing an increment in older patients throughout time. After adjustment for age, hypercholesterolemia increased (p < 0.001), as opposed to cigarette smoking (p < 0.001), hypertension (p < 0.001) and diabetes and hyperglycemia (p < 0.001). In patients with ischemic strokes, there were significant changes in the distribution of causes with an increase in cardioembolic strokes (p < 0.001), and in the localization of strokes with an increase in entire middle cerebral artery (MCA) and posterior circulation strokes together with a decrease in superficial middle cerebral artery stroke (p < 0.001). In patients with hemorrhagic strokes, the thalamic localizations increased, whereas the proportion of striatocapsular hemorrhage decreased (p = 0.022). Except in the older patient group, the mortality rate decreased. CONCLUSIONS: This study shows major trends in the characteristics of stroke patients admitted to a department of neurology over a 25-year time span, which may result from referral biases, development of acute stroke management and possibly from the evolution of cerebrovascular risk factors.

Managing an intellectual property right portfolio in the software industry

Tutkimuksen tavoitteena oli määrittää etuja, joita huolellinen immateriaali-oikeussalkun hallinnointi ohjelmistoalalla luo yritykselle. Tutkimusaineisto on kerätty haastattelemalla eri asemissa olevia ihmisiä kolmesta suomalaisesta ohjelmistoalan tuote- ja palveluyrityksestä. Tutkimuksesta käy ilmi, että ohjelmistoyritysten immateriaalioikeussalkut koostuvat liikesalaisuuksista, tekijänoikeudesta, tavaramerkeistä, verkkotunnuksista ja muutamista patenteista. Kiinnostus patentteihin ohjelmistoalalla on kasvanut erityisesti niiden tuoman tekijänoikeutta vahvemman suojan takia. Tällä hetkellä Euroopassa suhtautuminen ohjelmistopatentteihin on kuitenkin vielä käymistilassa. Jos ohjelmistopatentit hyväksytään, immateriaalioikeussalkun strateginen merkitys kasvaa. Tällöin salkunn hallinnointi tukee yrityksen tavoitteita - esimerkiksi oman toimintavapauden turvaamista - avustaen hakemus-prosessissa, tarkkaillen markkinoita sekä arvioiden yrityksen oman immateriaalioikeussalkun erilaisia hyväksikäyttömahdollisuuksia.

Modelling the Knowledge Interface between Sales and Production Functions of a Company. Case: New Service Development Process.

Yrityksen sisäisten rajapintojen tunteminen mahdollistaa tiedonvaihdon hallinnan läpi organisaation. Idean muokkaaminen kannattavaksi innovaatioksi edellyttää organisaation eri osien läpi kulkevaa saumatonta prosessiketjua sekä tietovirtaa. Tutkielman tavoitteena oli mallintaa organisaation kahden toiminnallisesti erilaisen osan välinen tiedon vaihto. Tiedon vaihto kuvattiin rajapintana, tietoliittymänä. Kolmiulotteinen organisaatiomalli muodosti tutkimuksen pääteorian. Se kytkettiin yrityksen tuotanto- ja myyntiosiin, kuten myös BestServ-projektin kehittämään uuteen palvelujen kehittämisen prosessiin. Uutta palvelujen kehittämisen prosessia laajennettiin ISO/IEC 15288 standardin kuvaamalla prosessimallilla. Yritysarkkitehtuurikehikoita käytettiin mallintamisen perustana. Tietoliittymä nimenä kuvastaa näkemystä siitä, että tieto [tietämys] on olemukseltaan yksilöiden tai ryhmien välistä. Mallinnusmenetelmät eivät kuitenkaan vielä mahdollista tietoon [tietämykseen] liittyvien kaikkien ominaisuuksien mallintamista. Tietoliittymän malli koostuu kolmesta osasta, joista kaksi esitetään graafisessa muodossa ja yksi taulukkona. Mallia voidaan käyttää itsenäisesti tai osana yritysarkkitehtuuria. Teollisessa palveluliiketoiminnassa sekä tietoliittymän mallinnusmenetelmä että sillä luotu malli voivat auttaa konepajateollisuuden yritystä ymmärtämään yrityksen kehittämistarpeet ja -kohteet, kun se haluaa palvelujen tuottamisella suuremman roolin asiakasyrityksen liiketoiminnassa. Tietoliittymän mallia voidaan käyttää apuna organisaation tietovarannon ja tietämyksen mallintamisessa sekä hallinnassa ja näin pyrkiä yhdistämään ne yrityksen strategiaa palvelevaksi kokonaisuudeksi. Tietoliittymän mallinnus tarjoaa tietojohtamisen kauppatieteelliselle tutkimukselle menetelmällisyyden tutkia innovaatioiden hallintaa sekä organisaation uudistumiskykyä. Kumpikin tutkimusalue tarvitsevat tarkempaa tietoa ja mahdollisuuksia hallita tietovirtoja, tiedon vaihtoa sekä organisaation tietovarannon käyttöä.

Does land titling matter? The role of land property rights in the war on illicit crops in Colombia

This paper analyzes the role of formalization of land property rights in the war against illicit crops in Colombia. We argue that as a consequence of the increase of state presence and visibility during the period of 2000 and 2009, municipalities with a higher level of formalization of their land property rights saw a greater reduction in the area allocated to illicit crops. We hypothesize that this is due to the increased cost of growing illicit crops on formal land compared to informal, and due to the possibility of obtaining more benets in the newly in- stalled institutional environment when land is formalized. We exploit the variation in the level of formalization of land property rights in a set of municipalities that had their rst cadastral census collected in the period of 1994-2000; this selection procedure guarantees reliable data and an unbiased source of variation. Using fixed effects estimators, we found a signicant negative relationship between the level of formalization of land property rights and the number of hectares allocated to coca crops per municipality. These results remain robust through a number of sensitivity analyses. Our ndings contribute to the growing body of evidence on the positive effects of formal land property rights, and e ective policies in the war on drugs in Colombia.

Unifying Time to Contact Estimation and Collision Avoidance across Species

The -function and the -function are phenomenological models that are widely used in the context of timing interceptive actions and collision avoidance, respectively. Both models were previously considered to be unrelated to each other: is a decreasing function that provides an estimation of time-to-contact (ttc) in the early phase of an object approach; in contrast, has a maximum before ttc. Furthermore, it is not clear how both functions could be implemented at the neuronal level in a biophysically plausible fashion. Here we propose a new framework the corrected modified Tau function capable of predicting both -type ("") and -type ("") responses. The outstanding property of our new framework is its resilience to noise. We show that can be derived from a firing rate equation, and, as , serves to describe the response curves of collision sensitive neurons. Furthermore, we show that predicts the psychophysical performance of subjects determining ttc. Our new framework is thus validated successfully against published and novel experimental data. Within the framework, links between -type and -type neurons are established. Therefore, it could possibly serve as a model for explaining the co-occurrence of such neurons in the brain.