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In the present study, we propose a transdisciplinary investigation aimed at developing an index to assess the vulnerability to landslides in the Brazilian municipality of São José dos Campos. The proposed Socio-Geoenvironmental Vulnerability Index (SGeoVI) was developed using a hybrid modeling approach that integrates socioeconomic data with landslide susceptibility mapping. Landslide susceptibility was derived from the FS FIORI deterministic model, which calculates the Safety Factor (FS) using the concept of limit equilibrium. The mapping of land use and land cover enabled the inclusion of new parameters related to certain anthropogenic conditions and vegetation cover, such as the overabundance of buildings and the presence or absence of tree vegetation, which are significant factors influencing landslide occurrence. Socioeconomic indicators were extracted from Brazilian Institute of Geography and Statistics (IBGE) census data, and variables were selected and spatially represented for each of São José dos Campos's 1073 census tracts. Socioeconomic indicators were taken into account for the SGeoVI proposal and categorized into five thematic groups: economic; educational; housing infrastructure; social dependency; e family structure. Based on the Socio-geoenvironmental vulnerability indicators, several neighborhoods in São José dos Campos, SP, were selected for a detailed SGeoVI assessment. In Pinheirinhos, a neighborhood situated in the southernmost part of São José dos Campo, the highest SGeoVI value reached to 0.91. In contrast, Jardim Apolo I, an established neighborhood located in the Central Region of São José dos Campos, exhibited a considerably lower SGeoVI value of only 0.04, for instance. The verification results of SGeoVI revealed socioeconomic disparities that align with geomorphological variations. The northern and southern parts of the municipality exhibit high susceptibility to landslides, coupled with low-income communities and inadequate housing structures, contributing to elevated socio-geoenvironmental vulnerability. In contrast, central regions feature flat terrain, reduced natural susceptibility, higher income levels, and improved access to housing infrastructure, resulting in lower vulnerability values. Given its ability to assess intra-municipal socio-geoenvironmental vulnerability, SGeoVI holds potential for extrapolation to other municipalities. Consequently, it can serve as a valuable tool for municipal authorities in formulating public policies aimed at landslide risk management. [ABSTRACT FROM AUTHOR]

This study evaluates the psychological impact of stay-at-home extension orders during COVID-19 and its relationship with individuals' expectations on the duration of the extensions. An online survey was administered to 1259 US adult residents to measure symptoms of post-traumatic stress disorder (PTSD), anxiety and stress induced by different stay-at-home order extensions using hypothetical length scenarios. We find that individuals exposed to two 2-week order extensions exhibit higher levels of stress and anxiety compared to those exposed to a single 4-week extension. We also find that subjects with longer expected extensions exhibit more signs of psychological damage than those with shorter expected extensions. Furthermore, we find that the negative psychological consequences of providing two shorter extensions is observed only among subjects with extension expectations of four weeks or less. Our results demonstrate that people's expectations affect the level of psychological damage caused by lockdown mandates. Our findings suggest that whenever lockdown extensions are necessary, reduced psychological distress may be possible by implementing a one-time restriction, rather than extending multiple smaller extensions perhaps due to manipulation of personal expectations. [ABSTRACT FROM AUTHOR]

Chronic degenerative diseases affect Enteric Neuron Cells (ENC) and Enteric Glial Cells (EGC) in shape and quantity. Thus, searching for automatic methods to evaluate when these cells are affected is quite opportune. In addition, preclinical imaging analysis is outstanding because it is non-invasive and avoids exposing patients to the risk of death or permanent disability. We aim to identify a specific cancer experimental model (Walker-256 tumor) in the Enteric Nervous System (ENS) cells. The ENS image database used in our experimental evaluation comprises 1248 images taken from thirteen rats distributed in two classes: control/healthy or sick. The images were created with three distinct contrast settings targeting different ENS cells: ENC, EGC, or both. We extracted handcrafted and non-handcrafted features to provide a comprehensive classification approach using SVM as the core classifier. We also applied Late Fusion techniques to evaluate the complementarity between feature sets obtained in different scenarios. In the best case, we achieved an F1-score of 0.9903 by combining classifiers built from different image types (ENC and EGC), using Local Phase Quantization (LPQ) features. [ABSTRACT FROM AUTHOR]

Two experiments were conducted to evaluate the effect of supplementation with two sources of non-protein nitrogen at different feeding times on the performance, ingestive behavior, and rumen metabolism of growing Nellore bulls during the dry season. Exp. 1: One hundred and twenty Nellore bulls, weighing 206 ± 39 kg of initial body weight (BW) and 12 months of age, were divided into 20 paddocks, and they were used in randomized block design in a 2 × 2 factorial arrangement to evaluate performance and ingestive behavior. Exp. 2: 12 rumen cannulated animals with 509 ± 59 BW, divided into 4 paddocks, were used in a triple Latin square 4 × 4 in a 2 × 2 factorial arrangement to evaluate metabolism. The factors were 2 non-protein nitrogen sources (urea or slow-release urea) and 2 feeding times (07:00 or 13:00 at 4 g/kg BW of supplement). There was no influence of non-protein sources, supplementation time, or their interaction on the grazing time or the trough time during daytime, nighttime, or total (P ≥ 0.16). There were no interactions or factor effects on ADG (P ≥ 0.45) or final body weight (P ≥ 0.39). There was an interaction between supplementation time and collection time (P < 0.01) on ruminal pH. Animals supplemented in the morning had greater total SCFA at 18 h after supplementation (P = 0.03). The supplementation time and the non-protein nitrogen sources did not alter the ingestive behavior or animal performance of young Nellore cattle. [ABSTRACT FROM AUTHOR]

We elicited incentivized measures of risk and time preferences from a sample of undergraduate students in Athens, Greece, in waves that preceded and overlapped with the COVID-19 pandemic. We exploited the timing of several events that occurred in the course of the pandemic (e.g., first occurrence of cases and deaths, curfew, relaxation of curfew etc.) and estimated structural parameters for various theories of risk and time preferences comparing these with pre-pandemic estimates. We find no effect between the different waves or other key events of the pandemic, despite the fact that we have about 1000 responses across all waves. Overall, our subjects exhibit intertemporal stability of risk and time preferences despite the significant effect of the COVID-19 pandemic on public health and the global economy. [ABSTRACT FROM AUTHOR]

Movie genre classification is a challenging task that has increasingly attracted the attention of researchers. The number of movie consumers interested in taking advantage of automatic movie genre classification is overgrowing, thanks to media streaming service providers' popularization. In this paper, we addressed the multi-label classification of movie genres in a multimodal way. To this end, we created a dataset composed of trailer video clips, subtitles, synopses, and movie posters from 152,622 movie titles of the Movie Database (TMDb). Such a large dataset was carefully curated, organized, and made available as a contribution of this work. We labeled each movie of the dataset according to a set of eighteen genre labels. In the experimental evaluation performed in this paper, we computed different kinds of descriptors, such as Mel Frequency Cepstral Coefficients (MFCCs), Statistical Spectrum Descriptor (SSD), Local Binary Pattern (LBP) from spectrograms, Long-Short Term Memory (LSTM), and Convolutional Neural Networks (CNN). With these descriptors, we trained different monolithic classifiers using BinaryRelevance and ML-kNN techniques. Besides, we also explored the combination of classifiers/features using a late fusion strategy. The fusion of a LSTM trained on synopses and another LSTM trained on the movie subtitles provided our best results in F-Score (0.674) and AUC-PR (0.725) metrics. These results corroborate the existence of complementarity among classifiers trained on different sources of information in this field of application. As far as we know, this is the most comprehensive study developed in terms of diversity of multimedia sources of information to perform movie genre classification. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic significantly increased food insecurity despite emergency legislation that put more resources into food assistance programs, increased unemployment benefits, and provided stimulus payments. We conducted a survey in the US on food insecurity among low-income Americans during the early months of the pandemic. While we cannot estimate causal effects, we are able to show important associations between food insecurity and nutritional and economic assistance that highlight the need to ensure that those newly at risk for food insecurity are able to connect to resources. For example, our results indicate that those who lost jobs due to the pandemic reported the highest level of food insecurity and also the lowest engagement with food assistance programs. The SNAP expansion appears to be important only among groups with higher levels of income stability including non-minority households and those not experiencing a job loss. Thus, the SNAP expansion may not have had a meaningful impact on those most at risk for food insecurity. Finally, our data highlight the importance of school meal programs during normal times. Those who took advantage of school meals before the outbreak are more likely to have experienced food insecurity during the pandemic-related school closures. [ABSTRACT FROM AUTHOR]

The literature identifies cultural values and beliefs as key drivers of climate change risk perception, but evidence is lacking about how media narratives and cultural values influence preferences for adapting to environmental consequences of climate change, including groundwater shortage. We elicited groundwater preferences using a choice experiment survey involving outcomes of the Mississippi River Valley Alluvial Aquifer. We randomly assigned respondents to an individualistic cultural narrative about climate change to test for framing effects predicted by culturally congruent and incongruent messaging. Results suggest that culturally incongruent messaging (i.e., to non-individualists) emboldens opposition and makes promoted groundwater policies less tractable. This is instructive to policy makers that identifying different stakeholders and avoiding incongruent messages about climate change could improve the effectiveness of collaborative water governance. [ABSTRACT FROM AUTHOR]

Background: Macroeconomic conditions are widely known to influence health outcomes through direct behavioral change or indirect mental effects of individuals. However, they have not received much attention in relation to childhood obesity. Methods: Using gender-specific predicted employment growth rates as an index for labor market conditions, we analyze how economic shocks affect children's weight status in Arkansas. To understand the underlying mechanisms behind these results, we use data on individual time use to examine how economic shocks are related to activities related to children's weight. Results: Improvement in the female labor market is associated with an increase in body mass index (BMI) and the probability that a child is overweight or obese, while an improvement in the male labor market has no significant effects on children's weight. This impact is particularly evident among female children, older children, and African-American children. We also find a negative effect of improvements in the female labor market on time spent on preparation for foods at home. Conclusions: These results suggest that a decrease in time spent preparing home-cooked foods might be a plausible explanation for the pro-cyclical relationship between children's weight and improvement in the labor market conditions. Thus, the policy implications of our paper should be aimed at mitigating the adverse effects of women's labor participation. [ABSTRACT FROM AUTHOR]

Studies recently accomplished on the Enteric Nervous System have shown that chronic degenerative diseases affect the Enteric Glial Cells (EGC) and, thus, the development of recognition methods able to identify whether or not the EGC are affected by these type of diseases may be helpful in its diagnoses. In this work, we propose the use of pattern recognition and machine learning techniques to evaluate if a given animal EGC image was obtained from a healthy individual or one affect by a chronic degenerative disease. In the proposed approach, we have performed the classification task with handcrafted features and deep learning-based techniques, also known as non-handcrafted features. The handcrafted features were obtained from the textural content of the ECG images using texture descriptors, such as the Local Binary Pattern (LBP). Moreover, the representation learning techniques employed in the approach are based on different Convolutional Neural Network (CNN) architectures, such as AlexNet and VGG16, with and without transfer learning. The complementarity between the handcrafted and non-handcrafted features was also evaluated with late fusion techniques. The datasets of EGC images used in the experiments, which are also contributions of this paper, are composed of three different chronic degenerative diseases: Cancer, Diabetes Mellitus, and Rheumatoid Arthritis. The experimental results, supported by statistical analysis, show that the proposed approach can distinguish healthy cells from the sick ones with a recognition rate of 89.30% (Rheumatoid Arthritis), 98.45% (Cancer), and 95.13% (Diabetes Mellitus), being achieved by combining classifiers obtained on both feature scenarios. [ABSTRACT FROM AUTHOR]

The task of learning from imbalanced datasets has been widely investigated in the binary, multi-class and multi-label classification scenarios. Although this problem also affects hierarchical datasets, there are few work in the literature dealing with it. Meanwhile, the local classifier approaches are the most used techniques in the literature to deal with Hierarchical Classification problems. In this paper, we present new ways to handle data imbalance in hierarchical classification problems when using local classifiers approaches. We propose three different resampling schemas, according to the local classification approach: (1) Local Classifiers per Node; (2) Local Classifiers per Parent Node; and (3) Local Classifiers per Level. In order to define how imbalanced a certain hierarchical dataset is, we also propose three novel metrics to measure the imbalance in hierarchical datasets considering the different local classification approaches. The experimental evaluation in eight well-known datasets showed that the imbalance metrics can indeed measure the datasets imbalance and the proposed resampling schemas are able to improve the classification results when compared to baselines, state-of-the-art and related work approaches. [ABSTRACT FROM AUTHOR]

The objective of this study was to use physically based models to carry out a back-analysis of the set of factors that may have influenced slope instability and the consequent development of 65 landslides in the Bengalar Stream basin, located in the Northern Region of São José dos Campos, São Paulo State, Brazil, associated with rainfall between March 7 and 8, 2016. Unlike other models, the FS FIORI model used in this study allowed extra variables to be added to the model that can influence hillslope stability and is associated with land use and land cover (LULC) variability. Analysis of intense short-term and accumulated long-term rainfall influence on slope instability was possible via a TRIGRS model. A comparative analysis was also carried out between a static model (FS FIORI) and a transient model (TRIGRS) which considered the factor of safety and pore pressure to be a function of precipitation and infiltration rates. Despite the differences in their hydrological components, both models were shown to present relatively similar and demonstrated stability rates coherence, according to the characteristics of each model. The FS FIORI model only classified 1.3% of the entire basin as unstable (FS ≤ 1), whereas the TRIGRS model classified 4.5% and 2.9% of the entire basin as unstable in scenarios 1 and 2, respectively. The validity and the accuracy of each model were tested via a receiver operating characteristic (ROC) curve and an area under the curve (AUC). AUC values were: 0.6552 for the FS FIORI model, and 0.7238 and 0.7186 for scenarios 1 and 2 of the TRIGRS model, respectively. The models performed well, with values considered to be acceptable. These results demonstrate an advancement in slope stability modeling studies, including conditioning factors associated with LULC for slope stability calculations. [ABSTRACT FROM AUTHOR]

The objective of the current study was to isolate and identify Staphylococcus (S.) aureus strains resistant to beta-lactam antibiotics from primiparous cows' milk. A total of 432 milk samples were collected from all primiparous dairy cows in early lactation that originated from 9 dairy properties. All samples were cultured in Mannitol salt agar enriched with egg yolk emulsion. Determination of genotypic resistance of S. aureus was achieved by polymerase chain reaction (PCR) for amplification of the blaZ, mecA, and mecC genes. Phenotypic resistance of S. aureus strains was evaluated by minimal inhibitory concentration (MIC) technique using broth microdilutions of penicillin G and oxacillin. From all the mammary quarters examined, S. aureus strains were detected in 27 out of 432 (6.25%) milk samples (CI95%, 4.33–8.84). From all dairy properties visited, only two out of 9 were found to have S. aureus. Hence, it was possible to evaluate genotypic and phenotypic resistance in 27 samples from two dairy farms. The isolates of S. aureus had a frequency of (20/27) 74.07% to blaZ gene (CI95%, 57.5–90.6), whereas mecA and mecC genes were not observed. According to MIC results, penicillin G had a 74.07% (20/27) resistance rate (CI95%, 57.5–90.6) and oxacillin had a 14.81% (4/27) resistance rate (CI95%, 1.4–28.2). Thus, the circulation of S. aureus strains resistant to beta-lactams has been confirmed in primiparous dairy cows in the northeastern region of Brazil, indicating the need for new management strategies involving the use of beta-lactam drugs to treat mastitis, discouraging and/or limiting their use. Also, it is important to highlight the need for further studies on epidemiology and traceability of the pathogen. [ABSTRACT FROM AUTHOR]

The study evaluated the effect of gain rates during the growing phase and the possible interaction with finishing phase forage allowance in beef cattle. In Exp. 1, eighty Nellore cattle (386 ± 7.90 kg; divided into 16 paddocks) were used in a randomized block design in a 2 × 2 factorial arrangement of treatments: (1) gain rate during the growing phase (low and high); (2) forage allowance during the finishing phase (low and high). In Exp. 2, twelve cannulated animals were used to evaluate ruminal parameters at the finishing phase. The animals were supplemented (2% of body weight [BW]) during 112 days. The average forage mass was 6507 and 2712 kg DM/ha, resulting in a forage allowance of 2.91 and 1.31 kg DM/kg BW, respectively, for high and low supply. In Exp. 1, there was interaction among factors (P = 0.01) for average daily gain (ADG): low gain rate animals that were finished on high forage allowance had an ADG 0.203 kg/day greater than average of other treatments (0.917 kg/day). Animals with a high gain rate in the growing phase started the finishing phase 51.5 kg heavier than low gain rate animals; this difference dropped to 35.5 kg in final BW (P < 0.01). In terms of the carcass, this difference was 27 kg at the beginning and dropped to 25 kg at the final carcass weight (P < 0.01). In Exp. 2, the acetate concentration at the end was higher for animals fed high forage allowance compared to low. However, propionate concentration was higher for animals fed low forage allowance compared to high (P = 0.01). Our results showed that the growing phase influences performance during the finishing phase; however, forage allowance with high supplementation at the finishing phase had negligible effects under these experimental conditions. [ABSTRACT FROM AUTHOR]

The ribonuclease III (RNase III) cleaves dsRNA in specific positions generating mature RNAs. RNase III enzymes play important roles in RNA processing, post-transcriptional gene expression, and defense against viral infection. The enzyme's active site contains Mg2+ ions bound by a network of acidic residues and water molecules, but there is a lack of information about their specific roles. In this work, multiple steered molecular dynamics simulations at QM/MM level were performed to explore the hydrolysis reaction carried out by the enzyme. Free energy profiles modifying the features of the active site are obtained and the role of Mg2+ ions, the solvent molecules and the residues of the active site are discussed in detail. Our results show that Mg2+ ions carry out different roles in the hydrolysis process positioning the substrate for the attack from a coordinated nucleophile and activating it to perform hydrolysis reaction, cleaving the dsRNA backbone in a SN2 substitution. In addition, water molecules present in the active site lower the energy barrier of the process. RNase III hydrolyzes dsRNA to generate mature RNAs. For this purpose, its active site contains Mg2+ which has an important role during the reaction. Results show that the Mg2+ activates the solvent molecule that produces the nucleophilic attack and the surrounding waters contribute significantly to the hydrolysis process. [ABSTRACT FROM AUTHOR]

Natural hazards, occurring all over the world, may become a disaster when humans and nature interact. In Brazil, landslides triggered by heavy rainfall are the most common phenomenon that affects the population. Due to the economic and social losses and deaths, the identification and monitoring of risk areas are extremely important. Therefore, this study aims to identify the landslide-susceptible areas in Vila Albertina and Britador neighborhood, located in Campos do Jordão city in São Paulo state, Brazil. Using the Shalstab mathematical model, which analyzes the slope stability, and satellite images from WorldView-2 sensor with data mining techniques, it was identified the most susceptible areas for this phenomenon and the main characteristics of human occupation that might induce landslides. To achieve this goal, three scenarios were simulated for each neighborhood, changing the values of the geotechnical parameters, used as input on Shalstab. The results of susceptibility areas were consistent with the reality observed in these neighborhoods and the landslide scars corroborate with the assumption that anthropic changes induce landslides. The satellite image allowed the identification of different types of human interaction and its changes in steep slope areas. [ABSTRACT FROM AUTHOR]

In this study, we investigated the carbon-supported PtRu nanoparticles with atomic ratios of Pt:Ru of 100:0, 90:10, 70:30, and 50:50 for ethanol and ethylene glycol electrooxidation in alkaline media. The nanoparticles were synthesized using sodium borohydride method with 20 wt% of metals loading on carbon. The nanoparticle mean sizes were 7.3 nm, 5.7 nm, 5.2 nm, and 5.1 nm for Pt/C, Pt90Ru10/C, Pt70Ru30/C, and Pt50Ru50/C, respectively. X-ray diffraction (XRD) analysis revealed that Pt and PtRu electrocatalysts have face-centered cubic (fcc) structure and suggests the alloy formation for all PtRu/C materials, which was further supported by the X-ray photoelectron spectroscopy (XPS). Based on XPS analysis, Pt50Ru50/C has higher amount of Pt oxides on the surface than Pt70Ru30/C. Electrochemical results demonstrated that the addition of Ru to Pt enhances the catalytic activity towards ethanol and ethylene glycol electrooxidadion. The catalyst of Pt50Ru50/C composition showed the lowest onset potential for ethanol and ethylene glycol electrooxidation, which were 160 and 70 mV lower than for Pt/C, respectively. Furthermore, this catalyst outperformed Pt/C and other PtRu/C compositions in chronoamperometric and direct alcohol fuel cell (DAFC) experiments. DAFC experiments using Pt50Ru50/C as anode had the power density 40 and 14% higher than using Pt/C for ethanol and ethylene glycol, respectively. The promotion is due to the bi-functional mechanism and/or electronic effect of two metals in the alloy. [ABSTRACT FROM AUTHOR]

In the context of testing the construct validity of stated preference studies, some researchers advocate the use of an “adding-up test” designed to gauge whether elicited values are sufficiently sensitive to a change in the scope (i.e. size) of a good. Crucial to the applicability of this test in practice, which relies on endowing a subsample of respondents with a good free of charge, is that the income effects due to endowment are negligible. In this study, we apply the adding-up test in an experimental value elicitation format to examine the potential effect of endowment as part of the test design on the adding-up property of elicited values. The results show that the adding-up property can be affected by free provision of part of the bundle. [ABSTRACT FROM AUTHOR]

This paper examines the factors that are associated with nutrient intake status of the elderly. Our study places special attention on the roles of physical functions, mental health, and dietary knowledge on the risk of inadequate nutrition consumption (nutrition consumption deficiencies). Using a nationwide survey of the elderly in Taiwan, we conduct empirical analysis separately by gender. Our results suggest that improving the physical conditions of male elders, the mental health of female elders, and dietary knowledge can decrease the nutrient consumption deficiencies of the elderly. [ABSTRACT FROM AUTHOR]

A growing body of literature has examined the determinants of childhood obesity, but little is known about children’s subjective wellbeing. To fulfill this gap, this paper examines the effects of fast food and soft drink consumption on children’s overweight and unhappiness. Using a nationwide survey data in Taiwan and estimating a simultaneous mixed equation system, our results generally suggest a tradeoff in policy implication. Fast food and soft drink consumption tend to be positively associated with children’s increased risk of being overweight but they are also negatively associated with their degree of unhappiness. Current and future policy/program interventions that aim to decrease fast food and soft drinks consumption of children to reduce childhood obesity may be more effective if these interventions also focus on ways that could compensate the increase in degree of unhappiness among children. [ABSTRACT FROM AUTHOR]

Worldwide obesity rates have stimulated interest in healthy dietary patterns. One well-known dietary pattern is the Mediterranean diet, which has been linked with several beneficial health effects. However, concerns have also been raised regarding the Mediterranean diet’s role in promoting weight gain. We explored the effect of the Mediterranean diet on body mass index using the propensity score matching approach. We found no statistically significant average treatment effect on the treated and therefore cannot confirm that a causal link exists between Mediterranean diet and body mass index. [ABSTRACT FROM AUTHOR]

Heckman’s sample selection model was applied to data from the Malaysian Household Expenditure Survey 2004/2005 to examine the factors influencing the likelihood of purchasing and the amount spent on alcohol in Malaysia. Results of the marginal effects suggest that while socio-demographic factors are important determinants of household purchase decisions and expenditure levels on alcohol in Malaysia, the effects vary across ethnic groups. Specifically, although education had a significant but modest impact in reducing the probability of alcohol purchases and expenditure levels among ethnic Chinese households, this effect was not evident among the ethnic Indians and other races. While increasing household size lowered the likelihood of purchasing alcohol and its expenditure levels for all ethnic groups, the reinforcing effects of both income and gender were relevant only for ethnic Chinese and Indian households. Last, urban Indian households were less likely to purchase alcohol and spend less compared to rural Indian households. [ABSTRACT FROM AUTHOR]

The cAMP–protein kinase A (PKA) pathway is the major signal transduction pathway involved in melanocyte-stimulating hormone receptor-mediated signaling and melanin production, whereas its role in the control of melanocyte proliferation is still controversial. In this study, we evaluated the effects of selective activation of the different PKA regulatory subunits type 1A (R1A) and type 2B (R2B) on melanocyte proliferation. Immunohistochemistry demonstrated that normal melanocytes lacked R1A protein whereas this subunit was highly expressed in all human melanomas studied (N=20) and in six human melanoma cell lines. Pharmacological activation of the R2 subunits by the cAMP analogue 8-Cl-cAMP inhibited proliferation and increased caspase-3 activity by 68.77±10.5 and 72±9% respectively, in all cell lines with the exception of the only p53-mutated one. Similar effects were obtained by activating R2 subunits with other analogues and by silencing R1A expression. The antiproliferative and proapoptotic effects of 8-Cl-cAMP were comparable to those observed with commonly used antitumoral drugs. Moreover, 8-Cl-cAMP potentiated the effects of these drugs on both cell proliferation and caspase-3 activity. In conclusion, this study first reports that human melanomas are characterized by a high R1/R2 ratio and that pharmacological and genetic manipulations able to revert this unbalanced expression cause significant antiproliferative and proapoptotic effects in melanoma cells.Oncogene (2008) 27, 1834–1843; doi:10.1038/sj.onc.1210831; published online 1 October 2007 [ABSTRACT FROM AUTHOR]

Behavioral problems produce excess disability, potentially devastating in cognitively impaired patients. These behavioral symptoms can be a major cause of stress, anxiety and concern for caregivers. While psychotropic drugs are frequently used to control these symptoms, they have the potential for significant side effects, which include sedation, disinhibition, depression, falls, incontinence, parkinsonism and akathisia. We followed up (for 12 months) a group of 346 consecutive outpatients, with a diagnosis of subcortical vascular dementia or multi–infarctual dementia. Patients eligible for this open–label study were required to have behavioral problems (BPSD). Patients were divided into two groups, Group A received olanzapine 2.5–7.5 mg/day while Group B received typical antipsychotics. Patients in both groups were allowed to continue any previous therapy. Patients in both groups were significantly improved in their BPSD. Our patients had a host of medical conditions and received numerous concomitant medications. Given the potential complications associated with these therapeutic agents, these patients tolerated olanzapine quite well. On examination of consequences of adverse events, particularly somnolence, postural instability, and postural hypotension, it appeared that cerebrovascular events were not present. Moreover, no anticholinergic effect was recorded. These findings suggest that olanzapine could be a safe and effective treatment even for elderly population in suitable doses and receiving the adequate follow–up. [ABSTRACT FROM AUTHOR]

Objective: This preliminary open-label study aims to investigate the effects of rivastigmine, an inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), in 20 patients diagnosed with frontotemporal dementia (FTD). Patients and Methods: Study subjects were men and women 60–75 years of age diagnosed with probable FTD. The rivastigmine group received doses of 3–9 mg/day. The control group included matched patients receiving antipsychotics, benzodiazepines and selegiline (deprenyl). All patients completed a 12-month follow-up period. Results: Rivastigmine treatment was well tolerated. At 12 months, there was a general amelioration of behavioural changes as demonstrated by reductions in Neuropsychiatric Inventory (p < 0.001 vs baseline and control), Behavioral Pathology in Alzheimer’s Disease Rating Scale (p < 0.001 vs baseline and control) and Cornell Scale for Depression in Dementia scores (p < 0.05 vs baseline, p < 0.001 vs control) in the rivastigmine group. Caregiver burden was reduced, as shown by reduced Relative Stress Scale scores (p < 0.001 vs baseline and control). Mean scores on outcome measures evaluating executive function stabilised in the rivastigmine group (p < 0.05 vs controls). Rivastigmine did not prevent the disease-related deterioration of cognition as assessed using the Mini-Mental State Examination. Conclusion: In this open-label study, rivastigmine-treated patients were less behaviourally impaired, and caregiver burden was reduced, at 12 months, compared with baseline. The use of cholinesterase inhibitors in FTD warrants further research. [ABSTRACT FROM AUTHOR]

Medication-overuse headaches are a relevant medical and social problem, for which specific treatments have not yet been defined. In patients with chronic daily headache who take analgesics every day, this headache is most likely to be caused by drugs and will vanish with abstinence. Nonetheless, there is anecdotal evidence that selective serotonin reuptake inhibitors (SSRI) are effective in chronic daily headache, because of the concomitant presence of psychiatric comorbidities (depression, anxiety, or a combination of both). Six migraineurs were admitted to the Neurology Clinic for medicationoveruse headache and associated depression, anxiety and behavioural changes. Treatment consisted in suppressing other drugs and by using an SSRI, citalopram, at modest dosage (≤30 mg daily). Analgesic withdrawal was performed in hospital and was not particularly problematic. Over a 1-year follow-up, pain coping strategies ameliorated and depression decreased; drug withdrawal was easy, even from barbiturates, and pain control was good. Further investigation into the possible use of citalopram or other SSRIs in medication-overuse headache is waranted. [ABSTRACT FROM AUTHOR]

Background: Although the core feature of dementia is progressive cognitive disruption, non-cognitive behavioural problems are expressed in most patients with dementia during the course of their illness. While psychotropic drugs are frequently used to control behavioural symptoms, comorbidities, which are very common in the geriatric population, could often limit their use. Gabapentin may be a potential treatment in such situations. Methods: In this open, baseline comparison study 20 patients with probable Alzheimer's disease with behavioural alterations and serious comorbidities (paralytic ileus, open-angle glaucoma, ischaemic cardiopathy, hepatic failure or severe prostatic hyperplasia) received gabapentin for 15 months. Patients were allowed to continue any previous therapy for concurrent diseases. However, concomitant antipsychotic or benzodiazepine intake was not permitted. Results: Gabapentin appeared to be efficacious and well tolerated in this patient population, and did not appear to interact with other drugs. General benefit is reflected by a reduction of caregiver stress. No patients withdrew before the end of the study and no serious adverse events were reported. Conclusion: The results of this study in patients with probable Alzheimer's disease with behavioural alterations and serious comorbidities indicate that gabapentin provides significant and sustained efficacy in terms of behaviour, with associated reductions in caregiver burden. The results of an ongoing larger, randomised, double-blind study of gabapentin are keenly awaited and may help to provide a safer and more efficacious treatment option for this group of patients. [ABSTRACT FROM AUTHOR]

Dyslexia, both developmental and acquired, has been considered the result of cerebrocortical dysfunction, affecting the temporo-parieto-occipital brain regions. However, dyslexia may involve abnormalities of the magnocellular component of the visual system, leading to binocular instability or alterations of accommodation. To test the hypothesis of cerebellar involvement in the reading process – justified by its emergent role in language and cognition – we studied 10 patients with cerebellar vermis/paravermis lesions using reading tests and we compared the results with those produced by 10 normal volunteers. The data obtained demonstrate an increased number of reading mistakes in the patient group, resulting from a possible alteration of the diffuse connection system from the cerebellum to different cerebrocortical and subcortical structures. Acquired dyslexia due to cerebellar impairment may be due to oculomotor alteration or, more subtly, to the intimate cerebellar-encephalic projections, connecting the cerebellum to the attentive and alerting processes and to the language system. We discuss the data with an overview of literature. [ABSTRACT FROM AUTHOR]

Physical interaction between CDKN2A/p16 and CDK4 proteins regulates the cell cycle progression through the G1 phase and dysfunction of these proteins by gene mutation is implicated in genetic predisposition to melanoma. We analysed 15 Italian melanoma families for germ line mutations in the coding region of theCDKN2A gene and exon 2 of theCDK4 gene. One novel disease-associated mutation (P48T), 3 known pathological mutations (R24P, G101W and N71S) and 2 common polymorphisms (A148T and Nt500 G>C) were identified in the CDKN2A gene. In a family harbouring the R24P mutation, an intronic variant (IVS1, +37 G>C) of uncertain significance was detected in a non-carrier melanoma case. The overall incidence ofCDKN2A mutations was 33.3%, but this percentage was higher in families with 3 or more melanoma cases (50%) than in those with only 2 affected relatives (25%). Noteworthy, functional analysis established that the novel mutated protein, while being impaired in cell growth and inhibition assays, retains some in vitro binding toCDK4/6. No variant in the p16-binding region of CDK4 was identified in our families. Our results, obtained in a heterogeneous group of families, support the view that inactivating mutations of CDKN2A contribute to melanoma susceptibility more than activating mutations ofCDK4 and that other genetic factors must be responsible for melanoma clustering in a high proportion of families. In addition, they indicate the need for a combination of functional assays to determine the pathogenetic nature of new CDKN2A mutations. [ABSTRACT FROM AUTHOR]

Pain is a common situation and it is one of the most frequent presenting symptoms of different pathologies. Treating pain could be a precise request to the doctor, from the patient and his caregiver. Management of neuropathic pain is particularly challenging and many patients presenting with chronic or subacute head and neck pain need a multidisciplinary approach. The principal targets of effective pain control are to ameliorate nociception, to reduce threshold of pain sensation and to improve quality of life. We offer a panoramic view of nociception, from a central perspective, and discuss various pharmacological options available to treat headache and neck pain. We also debate the role of a new antiepileptic drug, gabapentin, in the management of headache and neck pain. It is now considered to be an emergent treatment for pain syndrome. We delineate its pharmacological, laboratory and clinical profiles, with a review of the world literature. [ABSTRACT FROM AUTHOR]

The colon adenocarcinoma C26, carrying two endogenous tumor-associated antigens (TAA) recognized by CTL, has been transduced with the gene coding for the human folate receptor α (FRα) as an additional antigen in order to study the efficacy of vaccination against a tumor expressing multiple antigens. A dicistronic vector was used to transduce the IL-12 genes to create C26/IL-12/FRα that has been used as a cellular vaccine to treat mice bearing lung metastases of C26/FRα. After vaccination mice were partially splenectomized and splenic lymphocytes frozen and used retrospectively to study in vitro CD8 T cell response related to the treatment outcome. Vaccination cured 50% of mice and the effect was CD8 T cell dependent. Mice either cured (responders) or not cured (nonresponders) by vaccination developed tumor-specific CTL. However, analysis of CTL specificity and pCTL frequencies revealed that responders had a predominant CTL activity against endogenous C26- related tumor antigens, whereas nonresponders had CTL that recognized preferentially the FRα antigen. CD8 from responder mice were characterized to release high levels of granulocyte–macrophage (GM)-CSF upon antigen stimulation. Tumors obtained from mice that died despite vaccination lost expression of the FRα transgene but maintained expression of endogenous C26 antigens. Immunoselection against FRα antigen was not observed in tumors from non-vaccinated controls and from CD8-depleted vaccinated mice. Down-regulation of FRα antigen expression was due, at least in part, to methylation of retroviral vector long terminal repeat promoter since FRα expression was partially restored, ex vivo, by treatment with 5-aza-2′-deoxy-cytidine (aza). These results indicate that CD8 T cell-mediated immunoselection and production of GM-CSF are determining factors for the efficacy of tumor vaccines. [ABSTRACT FROM AUTHOR]

Deregulated c-Myc expression leads to a cellular state where proliferation and apoptosis are equally favored depending on the cellular microenvironment. Since the apoptotic sensitivity of many cells is influenced by the status of the p53 tumor suppressor gene, we investigated whether the induction of apoptosis by DNA damage or non-genotoxic stress are also influenced by the p53 status of cells with altered c-Myc activity. Rat-1 fibroblasts expressing a conditional c-Myc allele (cMycER), were transfected to express an antisense RNA complimentary to p53 mRNA. Expression of antisense p53 RNA decreased p53 protein levels and delayed p53 accumulation following c-Myc activation. Under hypoxic or low serum conditions, cells expressing antisense p53 were substantially more resistant to c-Myc-induced apoptosis than were control cells, c-Myc activation also sensitized Rat-1 cells to radiationinduced apoptosis. Rat-1 cells expressing antisense p53 RNA were more resistant to apoptosis induced by the combined effects of c-Myc activation and gamma irradiation. In a similar manner, apoptosis induced by c-Myc in serum starved, hypoxic or gamma irradiated fibroblasts was also inhibited by Bcl-2. These data indicate that p53 is involved in c-Mycmediated apoptosis under a variety of stresses which may influence tumor growth, evolution and response to therapy. [ABSTRACT FROM AUTHOR]

The serine-threonine kinase AKT1 is a central player in the oncogenic pathway controlled by PI3K. Recently, a somatic mutation in AKT1 (E17K) has been detected in breast, colorectal, lung and ovarian cancers. The E17K change results in constitutive AKT1 activation and induces leukaemia in mice. We determined the occurrence of the E17K variant in a panel of 764 tumour samples. These included breast, lung, ovarian, colorectal and pancreatic carcinomas as well as melanomas and glioblastomas. Despite the fact that these tumours are known to bear alterations in genes involved in the PI3K signalling pathway, AKT1E17K was detected only in breast (16/273), colorectal (1/88) and lung (1/155) cancers. Within the neoplasms of breast origin, the AKT1E17K variant was mutually exclusive with respect to the PIK3CAE454KorH1047R alleles and was present only in ductal and lobular histotypes. Our results, showing that AKT1 mutations seem to occur in a tissue-specific fashion have basic and clinical implications. First, the activity of mutated AKT1 in oncogenic PI3K signalling could be strictly dependent on the cell and tissue milieu. Second, therapeutic efforts aimed at selective targeting the AKT1E17K variant could be effective mainly in specific cancer types.Oncogene (2008) 27, 5648–5650; doi:10.1038/onc.2008.170; published online 26 May 2008 [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are endogenous small RNAs of ∼21 nt that regulate multiple biological pathways in multicellular organisms. They derive from longer transcripts that harbor an imperfect stem-loop structure. In plants, the ribonuclease type III DICER-LIKE1 assisted by accessory proteins cleaves the precursor to release the mature miRNA. Numerous studies highlight the role of the precursor secondary structure during plant miRNA biogenesis; however, little is known about the relevance of the precursor sequence. Here, we analyzed the sequence composition of plant miRNA primary transcripts and found specifically located sequence biases. We show that changes in the identity of specific nucleotides can increase or abolish miRNA biogenesis. Most conspicuously, our analysis revealed that the identity of the nucleotides at unpaired positions of the precursor plays a crucial role during miRNA biogenesis in Arabidopsis. The secondary structure of miRNA precursor sequences is known to affect processing by DICER-like proteins. Here Rojas et al. show that additional sequence features also play a regulatory role in plants with nucleotide identity at unpaired positions substantially impacting processing efficiency. [ABSTRACT FROM AUTHOR]

Dengue virus nonstructural protein 3 (NS3) fulfills multiple essential functions during the viral replication and constitutes a prominent drug target. NS3 is composed by a superfamily-2 RNA helicase domain joined to a serine protease domain. Quantitative fluorescence titrations employing a fluorescein-tagged RNA oligonucleotide were used to investigate the effect of salts on the interaction between NS3 and single stranded RNA (ssRNA). We found a strong dependence of the observed equilibrium binding constant, Kobs, with the salt concentration, decreasing at least 7-fold for a 1-fold increase on cation concentration. As a result of the effective neutralization of ~10 phosphate groups, binding of helicase domain of NS3 to ssRNA is accompanied by the release of 5 or 7 monovalent cations from an oligonucleotide or a polynucleotide, respectively and of 3 divalent cations from the same oligonucleotide. Such estimates are not affected by the type of cation, either monovalent (KCl, NaCl and RbCl) or divalent (MgCl2 and CaCl2), nor by the presence of the protease domain or the fluorescein label. Combined effect of mono and divalent cations was well described by a simple equilibrium binding model which allows to predict the values of Kobs at any concentration of cations. [ABSTRACT FROM AUTHOR]

Thioredoxin is a ubiquitous small protein that catalyzes redox reactions of protein thiols. Additionally, thioredoxin from E. coli (EcTRX) is a widely-used model for structure-function studies. In a previous paper, we characterized several single-point mutants of the C-terminal helix (CTH) that alter global stability of EcTRX. However, spectroscopic signatures and enzymatic activity for some of these mutants were found essentially unaffected. A comprehensive structural characterization at the atomic level of these near-invariant mutants can provide detailed information about structural variability of EcTRX. We address this point through the determination of the crystal structures of four point-mutants, whose mutations occurs within or near the CTH, namely L94A, E101G, N106A and L107A. These structures are mostly unaffected compared with the wild-type variant. Notably, the E101G mutant presents a large region with two alternative traces for the backbone of the same chain. It represents a significant shift in backbone positions. Enzymatic activity measurements and conformational dynamics studies monitored by NMR and molecular dynamic simulations show that E101G mutation results in a small effect in the structural features of the protein. We hypothesize that these alternative conformations represent samples of the native-state ensemble of EcTRX, specifically the magnitude and location of conformational heterogeneity. [ABSTRACT FROM AUTHOR]