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Chronic myeloid leukemia (CML) is a blood cancer characterized by dysregulated production of maturing myeloid cells driven by the product of the Philadelphia chromosome, the BCR-ABL1 tyrosine kinase. Tyrosine kinase inhibitors (TKIs) have proved effective in treating CML, but there is still a cohort of patients who do not respond to TKI therapy even in the absence of mutations in the BCR-ABL1 kinase domain that mediate drug resistance. To discover novel strategies to improve TKI therapy in CML, we developed a nonlinear mathematical model of CML hematopoiesis that incorporates feedback control and lineage branching. Cell-cell interactions were constrained using an automated model selection method together with previous observations and new in vivo data from a chimeric BCR-ABL1 transgenic mouse model of CML. The resulting quantitative model captures the dynamics of normal and CML cells at various stages of the disease and exhibits variable responses to TKI treatment, consistent with those of CML patients. The model predicts that an increase in the proportion of CML stem cells in the bone marrow would decrease the tendency of the disease to respond to TKI therapy, in concordance with clinical data and confirmed experimentally in mice. The model further suggests that, under our assumed similarities between normal and leukemic cells, a key predictor of refractory response to TKI treatment is an increased maximum probability of self-renewal of normal hematopoietic stem cells. We use these insights to develop a clinical prognostic criterion to predict the efficacy of TKI treatment and design strategies to improve treatment response. The model predicts that stimulating the differentiation of leukemic stem cells while applying TKI therapy can significantly improve treatment outcomes. [ABSTRACT FROM AUTHOR]

There is limited knowledge about inequalities regarding palliative care access among patients with intellectual disability. The present scoping review aimed to identify the existing barriers that limit access to palliative care (PC) in patients with intellectual disability.Methods: We conducted a literature review on publications since 2014 from three databases (MEDLINE, Biomed Central, and Elsevier Scopus), along with hand searches in scientific journals. The review included peer-reviewed studies written in English and Spanish language with quantitative and qualitative study designs. The participants were patients with intellectual disability and health professionals who had worked with them or had experience in palliative care.Results: 22 studies met the selection criteria. The barriers identified were under referral to palliative care, reduced access, communication, and limited knowledge and experience by health professionals.Conclusion: Patients with intellectual disability do not get referred to PC frequently. Health professionals and caregivers do not recognize when it is necessary to make a referral, and they need to improve their communication abilities. Also, health care workers need more training in PC, pain management, anticipation of death, and use of opioids. More research and education on the palliative care needs and care for patients with intellectual disabilities is needed. [ABSTRACT FROM AUTHOR]

Incidence of visceral leishmaniasis (VL) in the Indian subcontinent (ISC) has declined by more than 95% since initiation of the elimination program in 2005. As the ISC transitions to the postelimination surveillance phase, an accurate measurement of human-vector contact is needed to assure long-term success. To develop this tool, we identified PagSP02 and PagSP06 from saliva of Phlebotomus argentipes, the vector of Leishmania donovani in the ISC, as immunodominant proteins in humans. We also established the absence of cross-reactivity with Phlebotomus papatasi saliva, the only other human-biting sand fly in the ISC. Importantly, by combining recombinant rPagSP02 and rPagSP06 we achieved greater antibody recognition and specificity than single salivary proteins. The receiver operating characteristics curve for rPagSP02 + rPagSP06 predicts exposure to Ph. argentipes bites with 90% specificity and 87% sensitivity compared to negative control sera (P >.0001). Overall, rPagSP02 + rPagSP06 provides an effective surveillance tool for monitoring vector control efforts after VL elimination. [ABSTRACT FROM AUTHOR]

Many drugs have been evaluated to reactivate HIV-1 from cellular reservoirs, but the off-target effects of these latency reversal agents (LRA) remain poorly defined. Transposable elements (TEs) are reactivated during HIV-1 infection, but studies of potential off-target drug effects on TE expression have been limited. We analyzed the differential expression of TEs induced by canonical and non-canonical NF-κB signaling. We evaluated the effect of PKC agonists (Bryostatin and Ingenol B) on the expression of TEs in memory CD4+ T cells. Ingenol B induced 38 differentially expressed TEs (17 HERV (45%) and 21 L1 (55%)). Interestingly, TE expression in effector memory CD4+ T cells was more affected by Bryostatin compared to other memory T-cell subsets, with 121 (107 upregulated and 14 downregulated) differentially expressed (DE) TEs. Of these, 31% (n = 37) were HERVs, and 69% (n = 84) were LINE-1 (L1). AZD5582 induced 753 DE TEs (406 HERV (54%) and 347 L1 (46%)). Together, our findings show that canonical and non-canonical NF-κB signaling activation leads to retroelement expressions as an off-target effect. Furthermore, our data highlights the importance of exploring the interaction between LRAs and the expression of retroelements in the context of HIV-1 eradication strategies. [ABSTRACT FROM AUTHOR]

Purpose: Meniscus preservation is key in knee surgery. The newly documented crevice sign indicates instability of the medial meniscus in ACL-deficient knees. Once the sign is visualised, it is imperative that the stability of the medial meniscus is assessed and potentially treated. It was hypothesized that there would be a strong correlation between the presence of an unstable medial meniscal tear in patients with the crevice sign in ACL-deficient knees.Methods: This was a multicenter prospective study carried out to evaluate the incidence of medial meniscal tears in patients with ACL-deficient knees and their correlation with a crevice sign. All patients (128) who had undergone ACL reconstruction between May 2020 and November 2020 were assessed arthroscopically for meniscal stability and divided in to two groups: stable (n = 84) and unstable (n = 44). Thereafter, the presence of the crevice sign was determined in each case.Results: The populations were comparable in terms of sex and age (Table 1). Fisher's exact test showed a significant association between the presence of the crevice sign and the instability of the medial meniscus (p < 0.001). Descriptive statistics suggest that the presence of crevice sign was associated more frequently to MM instability (38.6% vs 1.2%; p < 0.001). The specificity of this test was 98.8% and its sensitivity was 38.6%. The positive predictive value (PPV) was 94.4% and the negative predictive value (NPV) was 75.5%. Table 1 Descriptions and comparisons of internal meniscus instability of patients by presence of crevice sign Internal meniscus instability (N = 44) Internal meniscus stability (N = 84) Total (N = 128) Gender  N 44 84 128   Male 33 (75.0) 58 (69.0) 91 (71.1)   Female 11 (25.0) 26 (31.0) 37 (28.9) Fisher's exact test (n.s.) Age (years)  N 44 84 128   Mean (ET) 28.6 (9.4) 30.1 (10.2) 29.6 (9.9)   Median (IIQ) 26.5 (22.0;34.5) 27.0 (22.5;37.0) 27.0 (22.0;36.0)   [Min-Max] [14-54] [14-52] [14-54] Wilcoxon test bilateral (n.s.) Crevice sign  N 44 84 128   Absent 27 (61.4) 83 (98.8) 110 (85.9)   Present 17 (38.6) 1 (1.2) 18 (14.1) Fisher's exact test p < 0.001 CONCLUSION: The hypothesis was confirmed since medial meniscal instability was strongly correlated with the existence of the crevice sign and showed high specificity and PPV.Level Of Evidence: III. [ABSTRACT FROM AUTHOR]

In this study, we investigated the polyphenol content and antioxidant activity of three apple cultivars ('WA 38', 'Granny Smith', and 'Cripps Pink') and assessed the impact of the production system (organic and conventional) and long-term commercial storage (refrigerated air and controlled atmosphere) on their content. Across all cultivars, apple peels consistently exhibited higher levels of total polyphenol content (TPC), total flavonoid content, and antioxidant activity compared to the flesh. TPC was influenced by the apple cultivar, production system, and storage conditions, with cultivar being the most influential variable. 'Granny Smith' apple flesh and peels maintained stable TPC levels during storage, while 'WA 38' and 'Cripps Pink' apple peels declined. Additionally, conventionally grown apples generally maintained higher phytochemical contents during storage when compared to their organic counterparts. These findings provide valuable insights into the impact of cultivation practices and storage conditions on apple polyphenols, offering potential strategies to enhance the nutritional quality of apples. [Display omitted] • 'Granny Smith' apples retained total polyphenol contents during storage. • Polyphenol contents declined in 'WA 38' and 'Cripps Pink' apples during storage. • Conventional apples exhibit superior phytochemical preservation over organic ones. • Cultivar is the most influential variable on biochemical and antioxidant activity. [ABSTRACT FROM AUTHOR]

Background: Linguistic and cultural discordance between clinicians and patients contributes to suboptimal care of Latinx patients with diabetes. Bilingual pedagogies may help learners with pre‐existing Spanish skills to improve health communication with linguistic minorities. Approach: We designed a diabetes workshop for health professions students that applied the educational principles of bilingual pedagogies, focus on learners with prior Spanish skills, and intersectionality of language and culture. The session introduced diabetes concepts in Spanish and English, applied Latinx cultural beliefs to clinical conversations about diabetes and explored the impact of clinician language and cultural skills on diabetes‐related communication. Evaluation: Voluntary surveys evaluated learner knowledge, confidence and attitudes before and after the intervention. Of 60 attendees, 57 participants (95%) completed surveys. Comparison of pre and post responses yielded statistically significant increases in respondents' cultural knowledge and confidence in explaining diabetes concepts in Spanish (all p < 0.001). When controlling for Spanish level, most items still showed a significant improvement. Latinx and heritage learners were more likely to express lower confidence in explaining diabetes post‐workshop (p < 0.05), suggesting an increased awareness of limitations. Implications: Bilingual educational interventions that emphasise culturally appropriate clinical skills may be an effective way to prepare health professions students who are heritage Spanish or second‐language learners to better communicate with Latinx patients about diabetes. We provide actionable recommendations for clinical educators interested in incorporating communication skills training for linguistically diverse patient care. [ABSTRACT FROM AUTHOR]

This work analyzes the impact of doping concentration on the temperature-dependent subthreshold current and swing saturation due to direct source-to-drain tunneling (DSDT) in short-channel silicon nanosheet (SiNS) metal–oxide–semiconductor field-effect transistors (MOSFETs). Furthermore, their influence on the drain-induced barrier lowering (DIBL) effect is investigated. Special attention is paid to the importance of the Fermi level and the average tunneling energy, whose energetic positions and distance from each other in the band diagram has a significant role in the temperature-dependent saturation behavior of the subthreshold current and swing, as well as the value of DIBL. Furthermore, we model and present with device simulation the existence of two merging subthreshold swings ($\textit {S}_ {\text {sth}}$) and DIBL effects with increasing gate bias at cryogenic temperatures. The merging is achieved by the superposition of the DSDT and thermionic emission (TE) current, which originate from their own dominated and visibly separated gate-bias regions. [ABSTRACT FROM AUTHOR]

By means of Monte Carlo simulations of gallium nitride (GaN) planar Gunn diodes, the epilayer structure on which they are fabricated is optimized in order to achieve ultrahigh-frequency oscillations. Practical considerations, such as the limitations of the technological fabrication process and the mitigation of the huge self-heating effects expected to appear in the devices, have been also contemplated for the choice of the optimal epilayer parameters. The best results are obtained for an active layer thickness of 150 nm with doping of 5 $\times 10^{{18}}$ cm−3, which would provide 350 GHz Gunn oscillations when using a contact separation of $0.5~\mu \text{m}$. [ABSTRACT FROM AUTHOR]

We present an analytical approach for the calculation of direct source-to-drain tunneling (DSDT) probability of electrons in gate-all-around (GAA) silicon nanosheet (SiNS) MOSFETs. The used method is based on the wavelet transform and leads to a quasi-compact model (QCM) for the DSDT current of ultrashort-channel devices. Among them, we introduce a four-piece parabolic approximation method for the conduction band edge and present analytical expressions for the tunneling distances of electrons with different energy levels. The development of a QCM is achieved by limiting the number of interpolation points for the tunneling current density to seven specific electron energies, distributed around the energy level that makes the largest contribution to the tunneling current. A further simplification is achieved by the Gaussian approximation of the tunneling current density in transverse direction so that only the center and surface potentials ($\Phi _ {\text {C}}$ and $\Phi _ {\text {S}}$) at the barrier are of interest for the modeling. For comparison, all those approximations are also implemented in the Wentzel–Kramer–Brillouin (WKB) approximation. Furthermore, the approach is verified by nonequilibrium Green’s function (NEGF) simulation. [ABSTRACT FROM AUTHOR]

Objective: Evidence has shown that the environment is an often overlooked social determinant of health (SDoH) of emotional, neural, and cognitive development. Aspects of the built environment relate to health factors and equity in living conditions, and may contribute to racial, ethnic, or economic health disparities. For example, urbanicity is linked with negative factors including less access to green space (i.e. gray space), increase in air pollution, temperatures, and socio-economic inequalities. While there is existing research on access to green space on some mental health and cognitive outcomes, there is limited research on the presence of gray space linked with cognitive functioning in youth. While some studies have shown that aspects of the neighborhood environment (e.g. access to healthy food, air pollution, heat exposure, and walkability) can impact neural and cognitive functioning, few to date have disentangled unique contributions of these factors in a large, national cohort. Therefore, the aim of the present study was to identify the best fitting model testing multiple SDoHs related to gray space on overall cognitive functioning in youth enrolled in the Adolescent Brain Cognitive Development (ABCD) Study. Participants and Methods: Using baseline data (n = 8,802) from ABCD 4.0 data, this study used environmental measures and linked external databases to characterize SDoH variables predicting youths' cognitive functioning via the NIH Toolbox (e.g. total cognitive composite score). This study used geospatial mapping to estimate exposure to air pollutants and heat. Additionally, the National Walkability Index was linked to assess walkability of neighborhood. Exposure to gray space (e.g. impervious surfaces) and access to healthy food were assessed via the Child Opportunity Index 2.0. An exhaustive search for the best subsets of these variables (gray space, access to healthy food, walkability, air pollution, and heat exposure) predicting cognitive performance was run to examine the best fitting model based on adjusted R2, using the 'leaps' package in R. Then, a multiple linear mixed effects regression model, using the lmer package in R, was fitted adjusting for various and relevant demographic factors. Results: The results of the regression indicated that walkability index (F(1, 1322.4) = 11.07, p < 0.001) and heat exposure (F(1, 81.1) = 5.54, p < 0.001) explained a significant amount of the variance (Adjusted R2 = 20%) predicting total cognitive performance while controlling for sex, age, household income, parent education, marital status, family relatedness, and site. Conclusions: Findings suggest that walkability of the neighborhood and heat exposure may play a role in cognitive development over and above other SDoHs and demographic factors. However, this study was limited to baseline assessment and a single measurement of total composite cognitive score, thus it is crucial for future research to investigate relationships over the life course across cognitive domains to further clarify these findings. The present study can help inform future public policy on improving lived and built environments, which may aid in supporting cognitive development in youth. These findings identify key factors, walkability and heat exposure, to consider when investigating the interaction between poverty, health, and environmental justice. [ABSTRACT FROM AUTHOR]

Extracting and analyzing relevant information from bio-signal recordings are complex tasks in which action potential detection and sorting processes take place, moreover if these are performed in real time. In this regard, the present paper introduces real-time FPGA-based architectures for detection and sorting of bio-signals, in particular macaque and human pancreatic signals. Action potential detection is performed by using an adaptive threshold. Also, during this process we have identified six different action potential shapes from the signals, which have been used to classify the action potentials. Our implementation runs at a frequency of 100 MHz with a low resource consumption for both architectures, and action potentials can be also observed in real time during a simulation in an OLED display. [ABSTRACT FROM AUTHOR]

Nutrition-related noncommunicable diseases (NR-NCDs) such as cardiovascular disease and type 2 diabetes both negatively impact the quality of life of many individuals and generate a substantial burden on society, demonstrating a need for intervention. Phytochemicals are investigated as a potential approach for combating NR-NCDs, and those found in hops have gained increased attention in recent decades. Hops, the strobile of the plant Humulus lupulus, are grown primarily for the brewing industry as they confer taste and increased shelf-life. The bitter acids represent the main compounds of interest for improving beer quality. Additionally, bitter acids as well as the prenylated chalcone xanthohumol, exhibit a wide range of health beneficial properties. This review summarizes those beneficial effects of bitter acids and xanthohumol on NR-NCDs, including inflammatory and immune diseases, obesity and metabolic disorders, as well as cancer prevention. [ABSTRACT FROM AUTHOR]

Advanced airway management is a treatment priority in trauma care. It is likely that a proportion of patients who receive urgent airway management on arrival in the emergency department represent an unmet demand for airway intervention in the pre-hospital phase. This study aimed to investigate emergency airway practice in major trauma patients and establish any unmet demand in this patient group. A retrospective review of the Trauma Audit and Research Network database was performed to identify airway intervention(s) performed for patients admitted to major trauma centres in England from 01 April 2012 to 27 June 2016. In total, 11,010 patients had airway interventions: 4375 patients (43%) had their tracheas intubated in the pre-hospital setting compared with 5889 patients (57%) in the emergency department. Of the patients whose tracheas were intubated in the emergency department, this was done within 30 min of hospital arrival in 3264 patients (75%). Excluding tracheal intubation, 1593 patients had a pre-hospital airway intervention of which 881 (55%) subsequently had their trachea intubated in the emergency department; tracheal intubation was done within 30 min of arrival in the majority of these cases (805 patients (91%)). Over 70% of emergency department tracheal intubations in patients with traumatic injuries were performed within 30 min of hospital arrival; this suggests there may be an unmet demand in pre-hospital advanced airway management for trauma patients in England. [ABSTRACT FROM AUTHOR]

Introduction: Within the United Kingdom's major trauma networks, limited consideration is given to the management of concomitant burns and trauma injuries, prominently highlighted in the arrangement of specialist services for major trauma and burns care. The majority of the literature regarding this topic, based almost exclusively on North American studies, predicts between 5 and 7% of all patients admitted to burns centres will suffer from concomitant (non-thermal) trauma injuries, in addition to their burn injuries. The aim of this study is to understand the epidemiology and outcomes for patients sustaining burns and trauma injuries in England and Wales. Methods: A retrospective review of patients sustaining concomitant burns and trauma injuries was made over a 71-month period from January 2010 to November 2016, using the national trauma registry for England and Wales, the Trauma Audit and Research Network database, identifying all patients with injury codes for burns and trauma (AIS >3). Data collected comprised patient demographic information, burn injury percentages, details of trauma injuries, details of hospital stay, and patient outcome. Comparison of information was made against the total burns and total trauma cohort to form a base standard for burns and trauma injuries, respectively. Results: Over the period analysed, 188 patients were found to have concomitant burns and trauma injuries. The patients were stratified according to age and the percentage of total body surface area burned. Hospital length of stay for concomitant burns and trauma patients was found to be higher than that of patients with isolated burns injuries. Mortality rates, although low overall, were found to be relatively higher for patients with concomitant burns and trauma injuries. Conclusions: This study demonstrated the rarity of this combination of injury pattern, in particular the occurrence of severe burns in the presence of major trauma, in UK. Improvements in burns care and trauma care hopefully contributes to the higher level of survival in concomitantly injured patients against data from previous literature. However, the synergistic effect of burns and trauma injuries appears to impact on the course of such patients, although larger scale analysis is required to determine the true prognostic factors. [ABSTRACT FROM AUTHOR]

The incidence of colorectal cancer (CRC) is closely linked to metabolic diseases. Accumulating evidence suggests the regulatory role of AMP-activated protein kinase (AMPK) in cancer metabolic reprogramming. In this study, wild-type and AMPK knockout mice were subjected to azoxymethane-induced and dextran sulfate sodium (AOM/DSS)-promoted colitis-associated CRC induction. A stable AMPK-deficient Caco-2 cell line was also established for the mechanistic studies. The data showed that AMPK deficiency accelerated CRC development, characterized by increased tumor number, tumor size, and hyperplasia in AOM/DSS-treated mice. The aggravated colorectal tumorigenesis resulting from AMPK ablation was associated with reduced α-ketoglutarate production and ten-eleven translocation hydroxylase 2 (TET2) transcription, correlated with the reduced mismatch repair protein mutL homolog 1 (MLH1) protein. Furthermore, in AMPK-deficient Caco-2 cells, the mRNA expression of mismatch repair and tumor suppressor genes, intracellular α-ketoglutarate, and the protein level of TET2 were also downregulated. AMPK deficiency also increased hypermethylation in the CpG islands of Mlh1 in both colonic tissues and Caco-2 cells. In conclusion, AMPK deficiency leads to reduced α-ketoglutarate concentration and elevates the suppressive epigenetic modifications of tumor suppressor genes in gut epithelial cells, thereby increasing the risk of colorectal tumorigenesis. Given the modifiable nature of AMPK activity, it holds promise as a prospective molecular target for the prevention and treatment of CRC. [ABSTRACT FROM AUTHOR]

Intuitive eating emphasizes eating in response to physiological cues of hunger and satiety and is associated with multiple positive health outcomes. Unconditional permission to eat (UPE), a domain of intuitive eating, encourages removing food classifications and permission to eat all foods. However, the categorization of food is described as a method to simplify decision making and moralization of foods can help prioritize food items in consumption. Thus, we were interested in understanding how foods are labeled and applied, the moralization of foods, and how individuals with low UPE labeled and moralize foods. Using Prolific Academic, we recruited 49 adults 18 years and older living in the United States to complete an online survey and interview. The survey assessed intuitive eating (IES-2) and the interview explored what and how participants eat and their thoughts and feelings about their body. Participants frequently used multiple labels when talking about foods. Healthy and unhealthy were common and offered a rationale for consumption, emotions were used to label foods, and taste and cost were important to food choice. Participants frequently moralized foods, although three participants explicitly stated they choose not to moralize foods. Individuals reporting low UPE described the importance of restriction and were following strict dietary recommendations. While labeling foods has been proposed to simplify decision-making, the use of labels is highly nuanced and thus understanding the connections between how foods are labeled and behaviors may be highly complex. We suggest future research explore how the categorization and moralization of food are associated with health behaviors and outcomes, how differing definitions of "healthy/unhealthy" foods are associated with behaviors, and the impacts of food insecurity and chronic disease management on food categorization and moralization. [ABSTRACT FROM AUTHOR]

This Special Issue is dedicated to recent research in the field of compact modeling for circuit design. The topics included all device structures, provided it was demonstrated that the presented compact modeling solutions were implementable in circuit design tools. The last Special Issue addressing compact modeling of all types of semiconductor devices was published in 2006. Since then, new device structures, and with different materials, have emerged, and significant and successful research in compact advance device modeling has been done, as well in the application of compact models to circuit design. Therefore, a new Special Issue was needed that could include high-quality papers in these topics. [ABSTRACT FROM AUTHOR]

• We studied changes in brain structure and function in children ages 9–13 years. • Cortical directed intracellular diffusion decreased, but subcortical increased. • Functional connectivity changes show network segregation, but limited integration. • Cortical microstructure varied most pre- or mid-puberty depending on the region. • Sparse sex differences show limited greater male variability in brain development. As we move toward population-level developmental neuroscience, understanding intra- and inter-individual variability in brain maturation and sources of neurodevelopmental heterogeneity becomes paramount. Large-scale, longitudinal neuroimaging studies have uncovered group-level neurodevelopmental trajectories, and while recent work has begun to untangle intra- and inter-individual differences, they remain largely unclear. Here, we aim to quantify both intra- and inter-individual variability across facets of neurodevelopment across early adolescence (ages 8.92 to 13.83 years) in the Adolescent Brain Cognitive Development (ABCD) Study and examine inter-individual variability as a function of age, sex, and puberty. Our results provide novel insight into differences in annualized percent change in macrostructure, microstructure, and functional brain development from ages 9–13 years old. These findings reveal moderate age-related intra-individual change, but age-related differences in inter-individual variability only in a few measures of cortical macro- and microstructure development. Greater inter-individual variability in brain development were seen in mid-pubertal individuals, except for a few aspects of white matter development that were more variable between prepubertal individuals in some tracts. Although both sexes contributed to inter-individual differences in macrostructure and functional development in a few regions of the brain, we found limited support for hypotheses regarding greater male-than-female variability. This work highlights pockets of individual variability across facets of early adolescent brain development, while also highlighting regional differences in heterogeneity to facilitate future investigations in quantifying and probing nuances in normative development, and deviations therefrom. [ABSTRACT FROM AUTHOR]

Leishmania major (L. major) is a protozoan parasite that causes cutaneous leishmaniasis. About 12 million people are currently infected with an annual incidence of 1.3 million cases. The purpose of this study was to synthesize a small library of novel thiophene derivatives, and evaluate its parasitic activity, and potential mechanism of action (MOA). We developed a structure–activity relationship (SAR) study of the thiophene molecule 5A. Overall, eight thiophene derivatives of 5A were synthesized and purified by silica gel column chromatography. Of these eight analogs, the molecule 5D showed the highest in vitro activity against Leishmania major promastigotes (EC50 0.09 ± 0.02 µM), with an inhibition of the proliferation of intracellular amastigotes higher than 75% at only 0.63 µM and an excellent selective index. Moreover, the effect of 5D on L. major promastigotes was associated with generation of reactive oxygen species (ROS), and in silico docking studies suggested that 5D may play a role in inhibiting trypanothione reductase. In summary, the combined SAR study and the in vitro evaluation of 5A derivatives allowed the identification of the novel molecule 5D, which exhibited potent in vitro anti-leishmanial activity resulting in ROS production leading to cell death with no significant cytotoxicity towards mammalian cells. [ABSTRACT FROM AUTHOR]

Worldwide, over 1.1 billion people have no access to electricity. The consequences for the affected people include health hazards from fuels used for lighting, limits to learning when it gets dark, a short productive day and high expenditures on lighting alternatives. Since 85% of affected people live in rural areas in developing countries, increasing access to electricity through grid supply is logistically and financially challenging. As a potential solution to this issue off-grid solar chargers have been gaining popularity. This technology is under continuous development to achieve lower costs, faster battery charge and more electricity generation to prolong light hours. This review contains a comprehensive analysis of possible improvements to solar lights and the role solar PV concentrators can play in it. It aims to provide the reader with a critical comparison of existing solar PV concentrators and to consider the advantages and drawbacks if applied to portable solar systems used in developing countries. From this review, static nonimaging concentrators have been identified as best suited since they are easy to operate and maintain and have shown high reliability. A detailed comparison of existing static nonimaging concentrators is presented in this work and their suitability for being deployed in portable solar systems in developing countries is evaluated. It concludes that the existing designs need adjustment if to be used for this purpose. Thus, novel concentrator designs for portable solar systems for developing countries are needed to facilitate more off-grid solar power generation. It is the aim therefore of this review to stimulate more research in this field. [ABSTRACT FROM AUTHOR]

Background The benefits of minimally invasive versus open thymectomy for the management of thymoma are debatable. Further, patient factors contributing to the selection of operative technique are not well elucidated. We aim to identify the association between baseline patient characteristics with choice of surgical approach. Methods Medical records of early stage thymoma (stages I and II) patients undergoing thymectomy between 2005 and 2015 at a single center were identified. Baseline characteristics and surgical outcomes such as prolonged length of stay (LOS ≥ 4 days), 90-day postoperative morbidity, completeness of resection, and recurrence or mortality free rates were compared by surgical approach. Results Fifty-three patients underwent thymectomy (34 open [64.15%] vs. 19 minimally invasive [35.85%]). There were no statistical differences between the two surgical approaches in demographic variables, smoking status, lung function, comorbidity, tumor size, or staging. Open thymectomy had significantly prolonged LOS (≥4 days) compared with minimally invasive procedures (odds ratio: 11.65; p < 0.01). There were no significant differences in postoperative composite morbidity (p = 0.56), positive margin (p = 0.40), tumor within 0.1 cm of resection margin (p = 0.38), and survival probability estimates (log rank test; p = 0.48) between the two groups. Conclusion Baseline patient characteristics were not associated with surgical approach selected for thymectomy. Minimally invasive thymectomy patients had shorter LOS but no significant differences in 90-day composite morbidity and recurrence or mortality. Larger multicenter studies are needed to evaluate factors contributing to patient selection for each approach, which may include surgeon preference. [ABSTRACT FROM AUTHOR]

Background: Protozoan parasites from the genus Leishmania cause broad clinical manifestations known as leishmaniases, which affect millions of people worldwide. Cutaneous leishmaniasis (CL), caused by L. major, is one the most common forms of the disease in the Old World. There is no preventive or therapeutic human vaccine available for L. major CL, and existing drug treatments are expensive, have toxic side effects, and resistant parasite strains have been reported. Hence, further therapeutic interventions against the disease are necessary. Terminal, non-reducing, and linear α-galactopyranosyl (α-Gal) epitopes are abundantly found on the plasma membrane glycolipids of L. major known as glycoinositolphospholipids. The absence of these α-Gal epitopes in human cells makes these glycans highly immunogenic and thus potential targets for vaccine development against CL. Methodology/Principal findings: Here, we evaluated three neoglycoproteins (NGPs), containing synthetic α-Gal epitopes covalently attached to bovine serum albumin (BSA), as vaccine candidates against L. major, using α1,3-galactosyltransferase-knockout (α1,3GalT-KO) mice. These transgenic mice, similarly to humans, do not express nonreducing, linear α-Gal epitopes in their cells and are, therefore, capable of producing high levels of anti-α-Gal antibodies. We observed that Galα(1,6)Galβ-BSA (NGP5B), but not Galα(1,4)Galβ-BSA (NGP12B) or Galα(1,3)Galα-BSA (NGP17B), was able to significantly reduce the size of footpad lesions by 96% in comparison to control groups. Furthermore, we observed a robust humoral and cellular immune response with production of high levels of protective lytic anti-α-Gal antibodies and induction of Th1 cytokines. Conclusions/Significance: We propose that NGP5B is an attractive candidate for the study of potential synthetic α-Gal-neoglycoprotein-based vaccines against L. major infection. [ABSTRACT FROM AUTHOR]

Microtubule (MT) 'age' can be interpreted as nucleotide state, lattice defects, or post-translational modification (PTM) such as acetylation and detyrosination. In all three cases, these have been recently shown to have functionally-important effects on the dynamics of MT arrays, and can present spatial and temporal heterogeneity. While mathematical models for MT array densities are well-established, here we present equations describing MT age, defined as the mean time since the MT's building blocks (tubulin) were polymerized from their soluble dimer state. We derive the age equations using a mean first-passage time calculation and two complementary approaches: The continuum limit of spatial discretization model, and an adjoint operator approach. These equations can recapitulate the observation that the oldest (most de-tyrosinated) tubulin in axons is near the middle of axons during neuronal development in chick embryos. Furthermore, PTMs influence motor kinetics up to approximately twofold for off-rates and velocities. Our simulations demonstrate that this relatively weak dependence of motor kinetics is sufficient to target motor cargo to a specific location along the array. This localization is tightly peaked in a way that magnifies the relatively small signal of PTM spatial heterogeneity. Thus, MT age can produce long-range spatial patterning without feedbacks or diffusing signals. [ABSTRACT FROM AUTHOR]

In previous studies we reported a novel series of organometallic compounds, Ru II complexed with clotrimazole, displaying potent trypanosomatid activity with unnoticeable toxicity toward normal mammalian cells. In view of the promising activity of Ru-clotrimazole complexes against Leishmania major ( L. major ), the present work sought to investigate the anti-leishmanial activity of the AM162 complex in the murine model of cutaneous leishmaniasis. In addition, to facilitate the design of new therapeutic strategies against this disease, we investigated the mode of action of two Ru-clotrimazole complexes in L. major promastigotes. Overall, we demonstrate that AM162 significantly reduced the lesion size in mice exposed to L. major infection. In addition, Ru-clotrimazole compounds are able to induce a mitochondrial dependent apoptotic-like death in the extracellular form of the parasite based on labeling of DNA fragments, mitochondrial depolarization, cell cycle alteration profile and plasma membrane phospholipid externalization. Our findings reveal a promising efficacy of the Ru-clotrimazole AM162 complex for the treatment of cutaneous leishmaniasis, as well as pro-apoptotic activity and thus guarantees further evaluation in pre-clinical studies. [ABSTRACT FROM AUTHOR]

Background: Adverse childhood experiences (ACEs), including emotional abuse, substance abuse in the household, separation or divorce, physical abuse, violence between adults, mental illness in the household, sexual abuse, or incarceration of a household member, have the potential to profoundly impact health and well-being in adulthood. To assess whether previously reported relationships between ACEs and health outcomes withstand validation, we conducted a community-based ACE study with the unique capacity to link self-reported ACEs and other survey results to validated health data in an electronic medical record (EMR). Methods: Information regarding ACEs and health outcomes was captured from 2013-2014 via a telephone survey of residents of the predominantly rural northern and central regions of Wisconsin and electronic abstraction of EMR data. ACE score was calculated by counting each exposure as one point. We examined the relationship between ACE score, type, and self-reported and validated health outcomes. Results: A total of 800 participants completed the telephone survey. Overall, 62% reported at least one ACE and 15% reported experiencing four or more. All self-reported measures of poor health were associated with increased ACE score. EMR data were positively correlated with ACE score for increased body mass index and diagnoses of depression, anxiety, and asthma. In contrast, diagnoses of hypertension, hypercholesterolemia, myocardial infarction, and skin and other cancers were inversely related to ACE score. Emotional abuse was the most common ACE reported followed by substance abuse in the household. ACEs tended to cluster so that people who reported at least one ACE were likely to have experienced multiple ACEs. There was no clear correlation between abuse type (e.g., direct abuse vs. household dysfunction) and health outcomes. Conclusions: In the first community-based study to link self-reported ACEs to comprehensive health measures documented in the medical record, we observed previously reported associations between childhood adversity and poor outcomes in adulthood, but also noted an inverse relationship between ACE score and certain medical diagnoses. Potential explanations for this finding warrant further investigation. [ABSTRACT FROM AUTHOR]

When seasonal journeys take place in nature, birds and fishes migrate in groups. This provides them not only with security but also a considerable saving of energy. The power they need to travel requires overcoming aerodynamic or hydrodynamic drag forces, which can be substantially reduced when the group travels in an optimal arrangement. Also in this area, humans imitate nature, which is especially evident in the practice of outdoor sports and motor competitions. Cycle races, in which speeds of up to 15 m s[?]1 are frequent, offer great opportunities to appreciate the advantage of travelling in a group. Here we present a brief analysis of the aerodynamics of a cycling team in a time-trial challenge, showing how each rider is favoured according to his position in the group. We conclude that the artificial tail wind created by the team also benefits the cyclist at the front by about 5%. [ABSTRACT FROM AUTHOR]

Aim The purpose of this study was to examine the influence of moisture and fire on historical ponderosa pine (Pinus ponderosa Dougl. ex Laws.) age structure patterns. Location We used a natural experiment created over time by the unique desert island geography of southern Arizona. Methods We sampled tree establishment dates in two sites on Rincon Peak and another site in the Santa Catalina Mountains. The influence of regional moisture patterns was investigated by examining synchrony among tree age peaks and periods of favourable moisture. The influence of fire was investigated by examining the relationship between local fire histories and age peaks. Results Tree age peaks (recruitment events) were synchronized with periods of reduced fire frequencies, suggesting that periods of reduced fire activity allowed time for young trees to develop fire-resistant characteristics. For example, two age peaks (1670s-1680s and 1770s-1780s) in the Rincon Peak-north site coincided with a period of reduced fire frequency. These age peaks were absent in the Rincon Peak-south site where fires were more frequent during that time. All three sites had age peaks in the early 19th century, coinciding with regional climate variability (i.e. El Ni~no Southern Oscillation patterns) that reduced fire activity. Main conclusions Historically prior to fire suppression, the survivorship, and thus cohort establishment, of ponderosa pine was ultimately determined by local fire history patterns. The importance of fire as a tree establishment regulator highlights the need to use fire at appropriate intervals not just to restore but to maintain healthy forests. [ABSTRACT FROM AUTHOR]

Affective biases toward racial out-group members, characterized by White perceivers' negative evaluations of Black individuals, prevail in U.S. culture. Such affective associations have been found to guide race-based impression formation. Accordingly, individuals may strive to resolve inconsistencies when perceiving targets violating their expectations. The current study focuses on the impact of evaluative incongruence on the activity of the dorsomedial prefrontal cortex (dmPFC) — a brain region previously shown to support impression formation. When asking participants to form impressions of positively and negatively evaluated Black and White individuals, we found preferential dmPFC activity in response to individuals paired with information that violates race-based affective associations. Importantly, individual differences in internal motivation to respond without prejudice (IMS) were found to shape the extent to which dmPFC activity indexes the interactive effects of race and affective associations during impression formation. Specifically, preferential dmPFC activity in response to evaluatively incongruent targets (i.e., Black-positive & White-negative) was present among participants with lower, but not those with higher, levels of IMS. Implications and future directions are discussed in the context of dmPFC involvement in social cognition. [ABSTRACT FROM AUTHOR]

Leishmania major ( L. major ) is a protozoan parasite causal agent of Leishmaniasis. It is estimated that 12 million people are currently infected and around 2 million infections occur each year. Current treatments suffer of high toxicity for the patient, low efficacy toward the parasite, high cost, and are losing effectiveness due to parasite resistance. Discovering novel small molecule with high specificity/selectivity and drug-like properties for anti-leishmanial activity remains a significant challenge. The purpose of this study is to communicate the design and synthesis strategies of novel chemical compounds based of the arylalkylamine scaffold with selective toxicity towards L. major and less toxicity to human cells in vitro. Here, we have developed a structure activity relationship (SAR) study of arylalkylamine AA1 in order to study their anti-parasitic effect in L. major . Overall, 27 arylalkylamine compounds derived from AA1 were synthesized and purified by silica gel column chromatography. The purity of each analog was confirmed by spectroscopic methods ( 1 H, 13 C NMR and LC/MS). Among these analogs, the compound AA9 showed the best toxic activity on L. major (LD 50 = 3.34 μM), which represents a 9 fold higher lethality as compared with its parental AA1 (Fer-1) compound (LD 50 = 28.75 μM). In addition, AA9 showed no significant toxicity at 80 μM on U20S Human Osteoblasts, Raw 264.7 Macrophages or intraperitoneal macrophages. In summary, our combined SAR study and biological evaluation data of AA1–AA27 compounds allow the identification of novel arylalkylamine compound AA9 that exhibits potent cytotoxicity against L. major promastigote with minimum toxic effect on human cells. [ABSTRACT FROM AUTHOR]

Background: Flowering time, plant height and seed yield are strongly influenced by climatic and day-length adaptation in crop plants. To investigate these traits under highly diverse field conditions in the important oilseed crop Brassica napus, we performed a genome-wide association study using data from diverse agroecological environments spanning three continents. Methods: A total of 158 European winter-type B.napus inbred lines were genotyped with 21,623 unique, single-locus single-nucleotide polymorphism (SNP) markers using the Brassica 60 K-SNP Illumina® Infinium consortium array. Phenotypic associations were calculated in the panel over the years 2010–2012 for flowering time, plant height and seed yield in 5 highly diverse locations in Germany, China and Chile, adding up to 11 diverse environments in total. Results: We identified 101 genome regions associating with the onset of flowering, 69 with plant height, 36 with seed yield and 68 cross-trait regions with potential adaptive value. Within these regions, B.napus orthologs for a number of candidate adaptation genes were detected, including central circadian clock components like CIRCADIAN CLOCK- ASSOCIATED 1 (Bna.CCA1) and the important flowering-time regulators FLOWERING LOCUS T (Bna.FT) and FRUITFUL (Bna.FUL). Discussion: Gene ontology (GO) enrichment analysis of candidate regions suggested that selection of genes involved in post-transcriptional and epigenetic regulation of flowering time may play a potential role in adaptation of B. napus to highly divergent environments. The classical flowering time regulators Bna.FLC and Bna.CO were not found among the candidate regions, although both show functional variation. Allelic effects were additive for plant height and yield, but not for flowering time. The scarcity of positive minor alleles for yield in this breeding pool points to a lack of diversity for adaptation that could restrict yield gain in the face of environmental change. Conclusions: Our study provides a valuable framework to further improve the adaptability and yield stability of this recent allopolyploid crop under changing environments. The results suggest that flowering time regulation within an adapted B. napus breeding pool is driven by a high number of small modulating processes rather than major transcription factors like Bna.CO. In contrast, yield regulation appears highly parallel, therefore yield could be increased by pyramiding positively associated haplotypes. [ABSTRACT FROM AUTHOR]

The present global energy scenario, in which fossil fuels play a preponderant role, faces significant energy and environmental challenges. To help address these challenges, countries across the world are increasing the contribution made by renewable energy (RE) resources to their energy supplies. Feed-in Tariff (FiT) is one of the most effective incentive policies used to promote the RE sector especially at the micro-generation level. The key objective of the FiT schemes is to provide financial support to residential, industrial and commercial consumers to encourage them to become RE producers. Solar photovoltaic (PV) is one of the most promising RE technologies. This paper provides an overview of the solar PV developments in the Association of South East Asian Nation (ASEAN) countries. It reflects upon the RE trends in the world as well as providing an introduction to the ASEAN countries. It reviews the progress of solar PV in each of the ASEAN countries especially in terms of RE policies, growth in terms of PV installations and research and development activities. Finally, the paper presents conclusions and a set of recommendations. Out of the 10 ASEAN countries, 5 have implemented FiT as a key policy incentive to stimulate the progress of RE. It is found that the ASEAN countries have great potential for solar PV in term of their annual solar insolation levels, which ranging from 1460 to 1892 kWh/m 2 per year. [ABSTRACT FROM AUTHOR]

Background: Common bean (Phaseolus vulgaris) is grown throughout the world and comprises roughly 50% of the grain legumes consumed worldwide. Despite this, genetic resources for common beans have been lacking. Next generation sequencing, has facilitated our investigation of the gene expression profiles associated with biologically important traits in common bean. An increased understanding of gene expression in common bean will improve our understanding of gene expression patterns in other legume species. Results: Combining recently developed genomic resources for Phaseolus vulgaris, including predicted gene calls, with RNA-Seq technology, we measured the gene expression patterns from 24 samples collected from seven tissues at developmentally important stages and from three nitrogen treatments. Gene expression patterns throughout the plant were analyzed to better understand changes due to nodulation, seed development, and nitrogen utilization. We have identified 11,010 genes differentially expressed with a fold change ≥ 2 and a P-value < 0.05 between different tissues at the same time point, 15,752 genes differentially expressed within a tissue due to changes in development, and 2,315 genes expressed only in a single tissue. These analyses identified 2,970 genes with expression patterns that appear to be directly dependent on the source of available nitrogen. Finally, we have assembled this data in a publicly available database, The Phaseolus vulgaris Gene Expression Atlas (Pv GEA), http://plantgrn.noble.org/PvGEA/ . Using the website, researchers can query gene expression profiles of their gene of interest, search for genes expressed in different tissues, or download the dataset in a tabular form. Conclusions: These data provide the basis for a gene expression atlas, which will facilitate functional genomic studies in common bean. Analysis of this dataset has identified genes important in regulating seed composition and has increased our understanding of nodulation and impact of the nitrogen source on assimilation and distribution throughout the plant. [ABSTRACT FROM AUTHOR]

L7921 --> 916.2 --> A solid mastery of Pharmacodynamics concepts is a cornerstone of effective pharmacology education. Understanding the meaning and appropriate use of pharmacodynamics terms such as potency, affinity, intrinsic efficacy, or receptor reserve is extremely valuable but challenging for most trainees. The onus, therefore, is on the educators to devise effective strategies and tools to facilitate the acquisition of this critical competency. When approaching pharmacodynamics, the ability of learners to explore the influence of driving parameters on the magnitude and position of concentration response curves is a powerful way to visualize and make concrete the basic concepts of pharmacodynamics. To this end, I have developed VeSPha, a Versatile Simulation tool for Pharmacodynamics based on a rapid equilibrium generalization of Furchgott's views on agonism. Through multiple sliders, the user can vary the parameters of the system, such as the concentrations of orthosteric and allosteric ligands, their respective affinities, the allosteric coupling constant, the intrinsic efficacies of each of the receptor species, the total number of receptors and the sensitivity of the system to the stimulus. A graph panel allows the display of the resulting response curves as a function of the concentration of ligand as well as orthosteric and allosteric ligand occupancy curves. Dropdown lines with corresponding EC50 as well as apparent Kd values for each ligand are also displayed. VeSPha also includes bar graphs as well as an intuitive graphic representation of the model displaying the values of the parameters, the distribution of the receptor species at the chosen state, the total stimulus as well as the resulting responses. The tool allows easy exploration of a wide gamut of possibilities that illustrate basic concepts of affinity, intrinsic efficacy, partial agonism, constitutive activity, inverse agonism, competitive antagonism, as well as allosteric modulation of both affinity and efficacy in any combination. The tool is implemented as an easy‐to‐use Excel file. This allows for flexible standalone use and for straightforward embedding into PowerPoint presentations for real‐time illustrations during lectures. The tool also readily generates simulated data including sampling errors for composing realistic, internally consistent assessment items such as quiz, problem set and exam questions. Implementation of this didactic tool is straightforward and effective in the author's experience across a wide range of learners spanning from undergraduates, Master's, Ph.D. M.D. Pharm D and DDS students. The tool, including a tutorial video can be made available to the Pharmacology teaching community upon request and an online version is under development. [ABSTRACT FROM AUTHOR]

R5000 --> 582.5 --> Background: Alpha‐ketoglutarate (aKG) is a key intermediate of the tricarboxylic acid (TCA) cycle. Previously, we demonstrated that aKG supplementation mitigates inflammation, enhances epithelial barrier integrity, and promotes oxidative phosphorylation in dextran sulfate sodium (DSS)‐induced colitis of mice. Intestinal epithelial homeostasis is regulated by cell energetics and metabolites from the microbiome. Given the importance of the mucosal layer in maintaining gut epithelial barrier function and microbiome composition, we hypothesized that dietary aKG facilitates the differentiation of secretory lineage epithelial cells and improves the gut metabolome. Methods: C57BL/6 male mice received drinking water with or without 1% aKG for three weeks, when mice were subjected to DSS induction for 7 days followed by 7 days recovery. The GC‐MS analysis was used to profile the cecal metabolomic changes due to aKG supplementation. In addition, colonic tissues were sampled for both biological and histochemical analyses. Results: GC‐MS metabolomics revealed separation of the cecal metabolites between control (CON) and aKG supplemented (aKG) mice. In total, the contents of 40 metabolites were found to be different between CON and aKG groups. These metabolites include amino acids, fatty acids, and the B vitamin, niacin, succinic acid (butanedioic acid), the conjugate acid of succinate. Putrescine, a polyamine produced by intestinal microbiota and methysuccinic acid were among the metabolites with the largest fold change increased by dietary aKG. Amino acids including essential amino acids and those involved in the TCA cycle such as threonine and aspartic acid were elevated in the aKG group, of which, glycine displayed a 10‐fold increase. On the other hand, ornithine, an intermediate of the urea cycle, and amide products such as oleamide and urea were significantly decreased in aKG group. Pathway analysis revealed that the urea cycle, along with and arginine and proline metabolism and glutathione metabolism were altered due to aKG supplementation. Furthermore, aKG supplementation increased goblet cells based on Alcian blue staining, associated with increased mRNA expression of Mucin 2 and goblet cell differentiation markers Trefoil factor 3 and Krüppel‐like factor 4. Conclusion: Together, dietary aKG enhances intestinal epithelial differentiation to favor goblet cell differentiation, which correlates with improvement in metabolome. [ABSTRACT FROM AUTHOR]

Summary: This paper constitutes an attempt to determine the relative contribution of changes in economic growth and in the distribution of income to changes in poverty in Mexico. Our findings clearly indicate that growth with redistribution (lower income inequality) was the key to reducing poverty continuously and in an important manner during 2000–2006. However, after 2006, decreasing per-capita income, coupled with the persistently high inequality (Gini of 52%), caused the reversal of the favorable trend observed since 1996, raising poverty to pre-2002 levels. Consequently, it is argued that, for Mexico, a middle-income country exhibiting quite low growth rates and high inequality levels, the further improvement in its distribution of income and assets is essential if the economy is to succeed in making a real dent in poverty. For that purpose, the implementation of an active pro-poor growth policy should be strongly encouraged. [Copyright &y& Elsevier]

In our ongoing search for new metal-based chemotherapeutic agents against leishmaniasis and Chagas disease, six new ruthenium-ketoconazole (KTZ) complexes have been synthesized and characterized, including two octahedral coordination complexes- cis, fac-[RuCl(DMSO)(KTZ)] ( 1) and cis-[RuCl(bipy)(DMSO)(KTZ)] ( 2) (where DMSO is dimethyl sulfoxide and bipy is 2,2′-bipyridine)-and four organometallic compounds-[Ru(η- p-cymene)Cl(KTZ)] ( 3), [Ru(η- p-cymene)(en)(KTZ)][BF] ( 4), [Ru(η- p-cymene)(bipy)(KTZ)][BF] ( 5), and [Ru(η- p-cymene)(acac)(KTZ)][BF] ( 6) (where en is ethylenediamine and acac is acetylacetonate); the crystal structure of 3 is described. The central hypothesis of our work is that combining a bioactive compound such as KTZ and a metal in a single molecule results in a synergy that can translate into improved activity and/or selectivity against parasites. In agreement with this hypothesis, complexation of KTZ with Ru in compounds 3- 5 produces a marked enhancement of the activity toward promastigotes and intracellular amastigotes of Leishmania major, when compared with uncomplexed KTZ, or with similar ruthenium compounds not containing KTZ. Importantly, the selective toxicity of compounds 3- 5 toward the leishmania parasites, in relation to human fibroblasts and osteoblasts or murine macrophages, is also superior to the selective toxicities of the individual constituents of the drug. When tested against Trypanosoma cruzi epimastigotes, some of the organometallic complexes displayed activity and selectivity comparable to those of free KTZ. A dual-target mechanism is suggested to account for the antiparasitic properties of these complexes. [ABSTRACT FROM AUTHOR]

Projection neurons (PNs), located in the antennal lobe region of the insect brain, play a key role in processing olfactory information. To explore how activity is regulated at the level of single PNs within this central circuit we have recorded from these neurons in adult Drosophila melanogaster brains. Our previous study demonstrated that PNs express voltage-gated calcium currents with a transient and sustained component. We found that the sustained component is mediated by cac gene-encoded Cav2-type channels involved in regulating action potential-independent release of neurotransmitter at excitatory cholinergic synapses. The function of the transient calcium current and the gene encoding the underlying channels, however, were unknown. Here we report that the transient current blocked by prepulse inactivation is sensitive to amiloride, a vertebrate Cav3-type channel blocker. In addition PN-specific RNAi knockdown of αlT, the Drosophila Cav3-type gene, caused a dramatic reduction in the transient current without altering the sustained component. These data demonstrate that the α1T gene encodes voltage-gated calcium channels underlying the amiloride-sensitive transient current. Alterations in evoked firing and spontaneous burst firing in the 1T knockdowns demonstrate that the Cav3-type calcium channels are important in regulating excitability in adult PNs. [ABSTRACT FROM AUTHOR]

With 2 figures and 1 table Abstract High-throughput genomics technologies today offer unprecedented possibilities for gene discovery, complex trait analysis by genome-wide association studies, global gene expression analyses, genomic selection and predictive breeding strategies. Dissection of the complex Brassica napus genome using mapping-by-sequencing techniques provides a powerful bridge between genetic maps and genome sequences. The completed sequence of the Brassica rapa A genome and the expected forthcoming publication of the C genome ( Brassica oleracea) will greatly accelerate the release of public reference sequences for B. napus (genome AC). Dramatically falling DNA costs for targeted or genomic resequencing and the availability of a new, high-density B. napus single-nucleotide polymorphism (SNP) array open the way for considerably more efficient mining and exploitation of genetic variation within the primary and secondary gene pools of B. napus. In this review, we outline some of the most significant recent advances in high-throughput genomics of Brassica crops and their potential impact on germplasm development and breeding of oilseed rape and canola in the coming years and decades. [ABSTRACT FROM AUTHOR]

Abstract: We analyzed the potential influence of family relationships and history of psychiatric disorders on the presentation and course of early psychotic disorders. We recruited 110 subjects aged 9–17years with a first psychotic episode and 98 matched healthy controls, and followed them for 1 year. Data were collected through clinical interviews and the Parent–Adolescent Communication Inventory. A family history of psychosis-related disorders was more common in patients'' families, with a five-fold higher risk for psychoses related disorders than families of healthy controls. If we consider psychoses related disorder in first-degree relatives, the risk is even higher, rising to 15-fold. The families of patients with a first psychotic episode score themselves worse in communication than the families of healthy controls. More problems in communication at baseline correlated with a higher degree of psychopathology and a lower clinical improvement after 12months of follow-up. [Copyright &y& Elsevier]

We define an opinion formation model of agents in a one-dimensional ring, where the opinion of an agent evolves due to its interactions with close neighbors and due to its either positive or negative attitude toward the overall mood of all the other agents. While the dynamics of the agent's opinion is described with an appropriate differential equation, from time to time pairs of agents are allowed to change their locations to improve the homogeneity of opinion (or comfort feeling) with respect to their short-range environment. In this way the timescale of transaction dynamics and that of environment update are well separated and controlled by a single parameter. By varying this parameter we discovered a phase change in the number of undecided individuals. This phenomenon arises from the fact that too frequent location exchanges among agents result in frustration in their opinion formation. Our mean field analysis supports this picture. [ABSTRACT FROM AUTHOR]

Abstract: Heme degradation plays a pivotal role in the availability of the essential nutrient, iron, in pathogenic bacteria. A previously unannotated protein from Mycobacterium tuberculosis, Rv3592, which shares homology to heme-degrading enzymes, has been identified. Biochemical analyses confirm that Rv3592, which we have termed MhuD (mycobacterial heme utilization, degrader), is able to bind and degrade heme. Interestingly, contrary to previously reported stoichiometry for the Staphylococcus aureus heme degraders, iron-regulated surface determinant (Isd)G and IsdI, MhuD has the ability to bind heme in a 1:2 protein-to-heme ratio, although the MhuD–diheme complex is inactive. Furthermore, the 1.75-Å crystal structure of the MhuD–diheme complex reveals two stacked hemes forming extensive contacts with residues in the active site. In particular, the solvent-exposed heme is axially liganded by His75 and is stacked planar upon the solvent-protected heme. The solvent-protected heme is coordinated by a chloride ion, which is, in turn, stabilized by Asn7. Structural comparison between MhuD–diheme and inactive IsdG and IsdI bound to only one highly distorted metalloporphyrin ring reveals that several residues located in α-helix 2 and the subsequent loop appear to be responsible for heme stoichiometric differences and suggest open and closed conformations for substrate entry and product exit. [Copyright &y& Elsevier]

Publicly available genomic tools help researchers integrate information and make new discoveries. In this paper, we describe the development of immortal mapping populations of rapid cycling, self-compatible lines, molecular markers, and linkage maps for Brassica rapa and B. oleracea and make the data and germplasm available to the Brassica research community. The B. rapa population consists of 160 recombinant inbred (RI) lines derived from the cross of highly inbred lines of rapid cycling and yellow sarson B. rapa. The B. oleracea population consists of 155 double haploid (DH) lines derived from an F1 cross between two DH lines, rapid cycling and broccoli. A total of 120 RFLP probes, 146 SSR markers, and one phenotypic trait (flower color) were used to construct genetic linkage maps for both species. The B. rapa map consists of 224 molecular markers distributed along 10 linkage groups (A1–A10) with a total distance of 1125.3 cM and a marker density of 5.7 cM/marker. The B. oleracea genetic map consists of 279 molecular markers and one phenotypic marker distributed along nine linkage groups (C1–C9) with a total distance of 891.4 cM and a marker density of 3.2 cM/marker. A syntenic analysis with Arabidopsis thaliana identified collinear genomic blocks that are in agreement with previous studies, reinforcing the idea of conserved chromosomal regions across the Brassicaceae. [ABSTRACT FROM AUTHOR]

Aim: We investigated whether the insulin-like growth factor (IGF)-I response to growth hormone (GH) is regulated by body mass index (BMI) in short children with normal weight. Methods: We studied 37 prepubertal children with idiopathic short stature (ISS), comparing children with high-normal BMI (standard deviation scores, SDS 1.23 ± 0.11, n = 20) and low-normal BMI (SDS –0.93 ± 0.12, n = 17). The IGF-I response to GH was determined with an abbreviated IGF-I generation test, by measuring serum IGF-I concentrations at baseline and 24 h after the administration of GH (0.033 mg/kg). Results: Children with high- and low-normal BMI had similar age (8.5 ± 0.7 vs. 8.7 ± 0.7 years) and height (–2.0 ± 0.1 vs. –2.2 ± 0.2 SDS). However, children with high-normal BMI exhibited higher mean basal IGF-I (191 ± 15 vs. 139 ± 11 ng/ml, p < 0.05), higher mean IGF-I levels 24 h after GH administration (261 ± 22 vs. 164 ± 14 ng/ml, p < 0.05) and a higher IGF-I percent increase after GH administration (37 ± 5 vs. 17 ± 4%, p < 0.05) compared with children with normal-low BMI. Conclusion: BMI modulates the IGF-I response to GH, suggesting that GH sensitivity may be influenced by the nutritional status in children with ISS and normal body weight. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]