Application of Photoreactive Barium Titanate (BaTiO₃) Beam Fanning to the Photothermal Mirror Technique: An Experimental Analysis.
An adaptive spatial filter is used as an optical novelty filter to detect photothermal mirror (PM) signals in high absorbing materials using continuous wave laser excitation. The optical novelty filter uses an optical beam-fanning limiter based on single domain barium titanate (BaTiO3), cut and poled 45° relative to the c-axis. The optical novelty filter approach relaxes the requirement for high sample surface smoothness because the effect aperture adapts to the surface, reducing the stationary background from the optical signal and provides a means of developing the photothermal mirror signal. Time-dependent probe laser phase shifts due to photothermal surface deformation pass through the optical novelty filter and are detected as an intensity increase over the stationary or "mundane" signal. Experimental studies are performed using four well-characterized metals using both the conventional photothermal mirror and optical novelty filter apparatuses in order to understand the complicated signal behavior. Signal behavior is analyzed in different excitation intervals using pseudo-chopped sample excitation with different duty cycles. Optical novelty filter signals show fast response for changes in the spatial beam profile followed by long relaxation time. Reasons for the optical novelty filter response are described.


Topical tacrolimus (FK506) leads to profound phenotypic and functional alterations of epidermal antigen-presenting dendritic cells in atopic dermatitis.
Atopic dermatitis (AD) is a chronic inflammatory skin disease in which antigen-presenting epidermal dendritic cells (DCs), ie, Langerhans cells and the so-called inflammatory dendritic epidermal cells (IDECs) expressing the high-affinity receptor for IgE (FcepsilonRI) may play a significant pathophysiologic role. Therapeutic efficacy of the immunosuppressive macrolide tacrolimus (FK506) in AD has been demonstrated in clinical trials, but little is known of its mode of action. The present study focused on the effects of topical tacrolimus treatment on epidermal CD1a+/FcepsilonRI+ DC populations in lesional AD. Immunohistological analysis, epidermal DC phenotyping, and functional studies were performed on skin biopsy specimens from treated and untreated lesional skin of 10 patients with AD participating in a clinical trial with tacrolimus. Untreated lesional skin was characterized by a high proportion of CD1a+ cells, which was largely due to a high proportion of IDECs strongly expressing FcepsilonRI. Epidermal DCs isolated from untreated lesional skin exhibited high stimulatory activity toward autologous T cells, which was strongly reduced while clinical improvement was seen during application of tacrolimus. Concomitantly, a decreased FcepsilonRI expression was observed in both Langerhans cells and IDECs. Finally, topical tacrolimus led to a progressive decrease in the IDEC population within the pool of CD1a+ epidermal DCs and also to a decrease in their CD36 expression, which is indicative of lower local inflammation. Epidermal CD1a+ DCs may represent a target for topical tacrolimus in the treatment of AD.


Anatomical and functional connectivity of cytoarchitectonic areas within the human parietal operculum.
In monkeys, the somatosensory cortex on the parietal operculum can be differentiated into several distinct cortical fields. Potential human homologues for these areas have already been defined by cytoarchitectonic mapping and functional imaging experiments. Differences between the two most widely studied areas [operculum parietale (OP) 1 and OP 4] within this region particularly pertain to their connection with either the perceptive parietal network or the frontal motor areas. In the present study, we investigated differences in anatomical connection patterns probed by probabilistic tractography on diffusion tensor imaging data. Functional connectivity was then mapped by coordinate-based meta-analysis of imaging studies. Comparison between these two aspects of connectivity showed a good congruency and hence converging evidence for an involvement of these areas in matching brain networks. There were, however, also several instances in which anatomical and functional connectivity diverged, underlining the independence of these measures and the need for multimodal characterization of brain connectivity. The connectivity analyses performed showed that the two largest areas within the human parietal operculum region display considerable differences in their connectivity to frontoparietal brain regions. In particular, relative to OP 1, area OP 4 is more closely integrated with areas responsible for basic sensorimotor processing and action control, while OP 1 is more closely connected to the parietal networks for higher order somatosensory processing. These results are largely congruent with data on nonhuman primates. Differences between anatomical and functional connectivity as well as between species, however, highlight the need for an integrative view on connectivity, including comparison and cross-validation of results from different approaches.


Comparative studies on peptides representing the so-called tachykinin-like region of the Alzheimer Abeta peptide [Abeta(25-35)].
In an attempt to answer the question of whether or not the so-called tachykinin-like region of the Alzheimer beta-amyloid protein [Abeta(25-35)] can act as a tachykinin, the sequences Abeta(25-35), Abeta(25-35)amide and their norleucine-35 and phenylalanine-31 analogues were synthesized. These peptides were examined with ligand binding studies, electron microscopy, CD and NMR. In all cases some differences were found between the Abeta(25-35) analogue and the corresponding Phe31 peptide. In addition, in ligand displacement studies on tachykinin NK1 receptors, only the Phe31 analogue showed activity comparable to that of genuine tachykinins. We conclude that peptides based on Abeta(25-35) but with a Phe residue at position 31 do display properties typical of a tachykinin, but that peptides with Ile at this position do not.


Artificial light-at-night - a novel lifestyle risk factor for metabolic disorder and cancer morbidity.
Both obesity and breast cancer are already recognized worldwide as the most common syndromes in our modern society. Currently, there is accumulating evidence from epidemiological and experimental studies suggesting that these syndromes are closely associated with circadian disruption. It has been suggested that melatonin (MLT) and the circadian clock genes both play an important role in the development of these syndromes. However, we still poorly understand the molecular mechanism underlying the association between circadian disruption and the modern health syndromes. One promising candidate is epigenetic modifications of various genes, including clock genes, circadian-related genes, oncogenes, and metabolic genes. DNA methylation is the most prominent epigenetic signaling tool for gene expression regulation induced by environmental exposures, such as artificial light-at-night (ALAN). In this review, we first provide an overview on the molecular feedback loops that generate the circadian regulation and how circadian disruption by ALAN can impose adverse impacts on public health, particularly metabolic disorders and breast cancer development. We then focus on the relation between ALAN-induced circadian disruption and both global DNA methylation and specific loci methylation in relation to obesity and breast cancer morbidities. DNA hypo-methylation and DNA hyper-methylation, are suggested as the most studied epigenetic tools for the activation and silencing of genes that regulate metabolic and monostatic responses. Finally, we discuss the potential clinical and therapeutic roles of MLT suppression and DNA methylation patterns as novel biomarkers for the early detection of metabolic disorders and breast cancer development.


Functional Dissection of the Blocking and Bypass Activities of the Fab-8 Boundary in the Drosophila Bithorax Complex.
Functionally autonomous regulatory domains direct the parasegment-specific expression of the Drosophila Bithorax complex (BX-C) homeotic genes. Autonomy is conferred by boundary/insulator elements that separate each regulatory domain from its neighbors. For six of the nine parasegment (PS) regulatory domains in the complex, at least one boundary is located between the domain and its target homeotic gene. Consequently, BX-C boundaries must not only block adventitious interactions between neighboring regulatory domains, but also be permissive (bypass) for regulatory interactions between the domains and their gene targets. To elucidate how the BX-C boundaries combine these two contradictory activities, we have used a boundary replacement strategy. We show that a 337 bp fragment spanning the Fab-8 boundary nuclease hypersensitive site and lacking all but 83 bp of the 625 bp Fab-8 PTS (promoter targeting sequence) fully rescues a Fab-7 deletion. It blocks crosstalk between the iab-6 and iab-7 regulatory domains, and has bypass activity that enables the two downstream domains, iab-5 and iab-6, to regulate Abdominal-B (Abd-B) transcription in spite of two intervening boundary elements. Fab-8 has two dCTCF sites and we show that they are necessary both for blocking and bypass activity. However, CTCF sites on their own are not sufficient for bypass. While multimerized dCTCF (or Su(Hw)) sites have blocking activity, they fail to support bypass. Moreover, this bypass defect is not rescued by the full length PTS. Finally, we show that orientation is critical for the proper functioning the Fab-8 replacement. Though the inverted Fab-8 boundary still blocks crosstalk, it disrupts the topology of the Abd-B regulatory domains and does not support bypass. Importantly, altering the orientation of the Fab-8 dCTCF sites is not sufficient to disrupt bypass, indicating that orientation dependence is conferred by other factors.


The effects of weight loss on normal transaminase levels in obese patients.
Obesity is associated with insulin resistance, which is the main pathogenic factor for nonalcoholic fatty liver disease (NAFLD). NAFLD can progress without associated elevations in liver enzymes. Therefore, we investigated the effects of weight loss on normal transaminase levels in obese subjects who are at risk for NAFLD. Thirty-seven obese patients with normal ALT levels were evaluated. All patients received an individualized low-calorie diet over at least 6 months. Twenty-two patients who achieved weight loss of at least 5% body weight were identified as the study group and the others as the control group. Transaminases, insulin resistance, and body mass index were compared before and after the intervention. Hepatic steatosis was found in 83.8% of obese patients. ALT was correlated with HOMA-IR in all patients at baseline (r = 0.363, P = 0.027). At the end of the follow-up, mean weight loss achieved in the study and control groups were 9.2% (8.7 +/- 3.0 kg) and 0.3% (0.5 +/- 2.8 kg), respectively. In the study group, HOMA-IR and ALT decreased from 4.0 +/- 1.8 to 2.4 +/- 0.9 and from 21.4 +/- 6.6 IU/L to 16.8 +/- 5.5 IU/L, respectively (P = 0.005 and P = 0.044). The results demonstrate that weight loss results in a decrease in normal ALT levels as well as insulin resistance. Therefore, the normal range for ALT may need to be reassessed.


Periductal Stromal Tumor of the Breast: A Case Report and Review of the Literature.
We present a woman aged 50 years who underwent a Tru-cut biopsy for a BI-RADS 4 lesion on her right breast and received a histopathology diagnosis of a fibroadenoma. In her one year follow-up, the lesion had progressed and she underwent an excisional biopsy. Her final diagnosis was a periductal stromal tumor. Periductal stromal tumor is an extremely rare and different entity from phylloides tumor, which makes appropriate diagnosis difficult in Tru-cut biopsy and care should be taken. Lesion progression of should require a re-biopsy. Their tendency to recur warrants follow-up. We believe that radiologic, pathologic, and clinical correlation is key in decision-making and diagnosis of these tumors.


Verbal learning in Alzheimer's dementia.
Many recent findings in Western countries suggest that episodic recall is the most sensitive discriminator between patients with mild Alzheimer disease (AD) and the normal elderly, while semantic memory tends best to differentiate between moderate and severe AD patients. The present study is the first to examine in detail the episodic memory of Chinese AD patients in Hong Kong with a locally developed list learning test, comparing procedures that do or do not encourage the use of semantic organization. The performance of 28 AD patients was compared to that of 30 normal controls. AD patients did significantly worse in terms of acquisition and retention and also benefited significantly less from external organization cues. In the discriminant function analysis, the rate of forgetting in the random condition and the total retention score in the blocked condition were found to be the best predictors for differentiating between AD patients and controls. On the other hand, in the differentiation between mild and moderate AD, semantic clustering in the blocked condition was found to be the best predictor. Results of the present study were discussed in the light of the previous findings reported in the Western countries and the neuropathological changes of AD patients.


Utilising clinical parameters to improve the selection of nerve biopsy candidates.
Peripheral nerve biopsy is a valuable final diagnostic tool, however histopathological results can be non-diagnostic. We aim to identify quality improvement measures by evaluating the pre-biopsy assessment and diagnostic yield of specific histopathological diagnosis. This was a retrospective study based on ten years of experience with peripheral nerve biopsies at a single centre. Clinical data was obtained regarding pre-biopsy history, examination, serum and CSF investigations, neurophysiology and peripheral nerve imaging. Based upon a histopathological outcome, patients were grouped into vasculitis, granulomatous and infiltrative ("diagnostic") group, or a comparison group of non-specific axonal neuropathy and normal ("non-specific/normal") group. From a cohort of 64 patients, 21 (32.8%) were included in the diagnostic group and 30 (46.9%) in the non-specific/normal group. Clinical parameters associated with the diagnostic group were shorter history (mean 10.2 months vs 38.1), stepwise progression (81% vs 20%), neuropathic pain (85.7% vs 56.7%), vasculitic rash (23.8% vs 0%), mononeuritis multiplex (57.1% vs 10%), asymmetry (90.5% vs 60%), raised WCC (47.6% vs 16.7%), myeloperoxidase antibody (19.1% vs 0%) and abnormal peripheral nerve imaging (33.3% vs 10%). Selection of patients undergoing nerve biopsy requires careful consideration of clinical parameters, including peripheral nerve imaging. Several quality improvement measures are proposed to improve yield of clinically actionable information from nerve biopsy. This article is protected by copyright. All rights reserved.


Perching of Tengmalm's owl (Aegolius funereus) nestlings at the nest box entrance: effect of time of the day, age, wing length and body weight.
The behaviour of the nestlings of nocturnal cavity-nesting species has relatively rarely been studied in detail because of problems connected with use of the technical devices required to provide long-term monitoring of individuals. However, long-term observation of nestling behaviour is crucial in order to identify different types of behaviour which may be caused by sibling competition at the end of nesting period. We studied behaviour of 43 Tengmalm's owl (Aegolius funereus) nestlings at 14 nests using a camera and a chip system. The nestlings perched at the nest box entrance from an average age of 28 days from hatching (range 24-34 days) until fledging, spending around 2 hours per day here in total, in periods ranging from a few seconds to 147 min (7.6±10.9 min, mean ± SD). We found that individual duration of perching at the nest box entrance was significantly influenced by nestlings' age and wing length and that the duration of perching at the nest box entrance significantly decreased with time of night. However, during daylight hours, time of day had no effect on either probability or duration of nestlings' perching. We suggest daylight perching at the nest box entrance results from nestlings' preparation for fledging, while individuals perching here during the night may gain an advantageous position for obtaining food from the parents; another possibility at all times of day is that nestlings can reaffirm their social dominance status by monopolizing the nest box entrance.


A K-means multivariate approach for clustering independent components from magnetoencephalographic data.
Independent component analysis (ICA) is typically applied on functional magnetic resonance imaging, electroencephalographic and magnetoencephalographic (MEG) data due to its data-driven nature. In these applications, ICA needs to be extended from single to multi-session and multi-subject studies for interpreting and assigning a statistical significance at the group level. Here a novel strategy for analyzing MEG independent components (ICs) is presented, Multivariate Algorithm for Grouping MEG Independent Components K-means based (MAGMICK). The proposed approach is able to capture spatio-temporal dynamics of brain activity in MEG studies by running ICA at subject level and then clustering the ICs across sessions and subjects. Distinctive features of MAGMICK are: i) the implementation of an efficient set of "MEG fingerprints" designed to summarize properties of MEG ICs as they are built on spatial, temporal and spectral parameters; ii) the implementation of a modified version of the standard K-means procedure to improve its data-driven character. This algorithm groups the obtained ICs automatically estimating the number of clusters through an adaptive weighting of the parameters and a constraint on the ICs independence, i.e. components coming from the same session (at subject level) or subject (at group level) cannot be grouped together. The performances of MAGMICK are illustrated by analyzing two sets of MEG data obtained during a finger tapping task and median nerve stimulation. The results demonstrate that the method can extract consistent patterns of spatial topography and spectral properties across sessions and subjects that are in good agreement with the literature. In addition, these results are compared to those from a modified version of affinity propagation clustering method. The comparison, evaluated in terms of different clustering validity indices, shows that our methodology often outperforms the clustering algorithm. Eventually, these results are confirmed by a comparison with a MEG tailored version of the self-organizing group ICA, which is largely used for fMRI IC clustering.


Yamanaka factors critically regulate the developmental signaling network in mouse embryonic stem cells.
Yamanaka factors (Oct3/4, Sox2, Klf4, c-Myc) are highly expressed in embryonic stem (ES) cells, and their over-expression can induce pluripotency in both mouse and human somatic cells, indicating that these factors regulate the developmental signaling network necessary for ES cell pluripotency. However, systemic analysis of the signaling pathways regulated by Yamanaka factors has not yet been fully described. In this study, we identified the target promoters of endogenous Yamanaka factors on a whole genome scale using ChIP (chromatin immunoprecipitation)-on-chip in E14.1 mouse ES cells, and we found that these four factors co-occupied 58 promoters. Interestingly, when Oct4 and Sox2 were analyzed as core factors, Klf4 functioned to enhance the core factors for development regulation, whereas c-Myc seemed to play a distinct role in regulating metabolism. The pathway analysis revealed that Yamanaka factors collectively regulate a developmental signaling network composed of 16 developmental signaling pathways, nine of which represent earlier unknown pathways in ES cells, including apoptosis and cell-cycle pathways. We further analyzed data from a recent study examining Yamanaka factors in mouse ES cells. Interestingly, this analysis also revealed 16 developmental signaling pathways, of which 14 pathways overlap with the ones revealed by this study, despite that the target genes and the signaling pathways regulated by each individual Yamanaka factor differ significantly between these two datasets. We suggest that Yamanaka factors critically regulate a developmental signaling network composed of approximately a dozen crucial developmental signaling pathways to maintain the pluripotency of ES cells and probably also to induce pluripotent stem cells.


Using a machine learning approach to investigate factors associated with treatment-resistant depression among adults with chronic non-cancer pain conditions and major depressive disorder.
Presence of chronic non-cancer pain conditions (CNPC) among adults with major depressive disorder (MDD) may reduce benefits of antidepressant therapy, thereby increasing the possibility of treatment resistance. This study sought to investigate factors associated with treatment-resistant depression (TRD) among adults with MDD and CNPC using machine learning approaches. This retrospective cohort study was conducted using a US claims database which included adults with newly diagnosed MDD and CNPC (January 2007-June 2017). TRD was identified using a clinical staging algorithm for claims data. Random forest (RF), a machine learning method, and logistic regression was used to identify factors associated with TRD. Initial model development included 42 known and/or probable factors that may be associated with TRD. The final refined model included 20 factors. Included in the sample were 23,645 patients (73% female mean age: 55 years; 78% with ≥2 CNPC, and 91% with joint pain/arthritis). Overall, 11.4% adults (N = 2684) met selected criteria for TRD. The five leading factors associated with TRD were the following: mental health specialist visits, polypharmacy (≥5 medications), psychotherapy use, anxiety, and age. Cross-validated logistic regression model indicated that those with TRD were younger, more likely to have anxiety, mental health specialist visits, polypharmacy, and psychotherapy use with adjusted odds ratios (AORs) ranging from 1.93 to 1.27 (all ps < .001). Machine learning identified several factors that warrant further investigation and may serve as potential targets for clinical intervention to improve treatment outcomes in patients with TRD and CNPC.


Multiple emulsions: an overview.
Multiple emulsions are complex polydispersed systems where both oil in water and water in oil emulsion exists simultaneously which are stabilized by lipophillic and hydrophilic surfactants respectively. The ratio of these surfactants is important in achieving stable multiple emulsions. Among water-in-oil-in-water (w/o/w) and oil-in-water-in-oil (o/w/o) type multiple emulsions, the former has wider areas of application and hence are studied in great detail. Formulation, preparation techniques and in vitro characterization methods for multiple emulsions are reviewed. Various factors affecting the stability of multiple emulsions and the stabilization approaches with specific reference to w/o/w type multiple emulsions are discussed in detail. Favorable drug release mechanisms and/or rate along with in vivo fate of multiple emulsions make them a versatile carrier. It finds wide range of applications in controlled or sustained drug delivery, targeted delivery, taste masking, bioavailability enhancement, enzyme immobilization, etc. Multiple emulsions have also been employed as intermediate step in the microencapsulation process and are the systems of increasing interest for the oral delivery of hydrophilic drugs, which are unstable in gastrointestinal tract like proteins and peptides. With the advancement in techniques for preparation, stabilization and rheological characterization of multiple emulsions, it will be able to provide a novel carrier system for drugs, cosmetics and pharmaceutical agents. In this review, emphasis is laid down on formulation, stabilization techniques and potential applications of multiple emulsion system.


Pemetrexed disodium in combination with cisplatin versus other cytotoxic agents or supportive care for the treatment of malignant pleural mesothelioma.
Malignant pleural mesothelioma (MPM) is a highly aggressive malignancy whose incidence is expected to increase in the United Kingdom, Western Europe, and Australia over the next 20 years as a result of occupational exposure to asbestos fibres. Surgery is feasible in only a small proportion of cases, and radiotherapy and cytotoxic chemotherapy are used in palliation. Pemetrexed is the first and only chemotherapy agent that has been granted a marketing approval for use in combination with cisplatin for the treatment of chemo-naïve patients with unresectable MPM. To examine evidence on the clinical effectiveness of pemetrexed disodium used in combination with cisplatin for the treatment of unresectable malignant pleural mesothelioma in chemotherapy naïve patients compared with other cytotoxic agents used alone or in combination, or supportive care. CENTRAL (Issue 2, 2005), EMBASE (1980-2005), MEDLINE (1980-2005), HTA database (1990-2005), Web of Knowledge (1990-2005) and handsearching (including reference lists of retrieved articles and the pharmaceutical company submission to to NICE), up to October 2005. Randomised Controlled Trials (RCTs) where the use of pemetrexed disodium in combination with cisplatin is compared with other cytotoxic agents, or supportive care for the treatment of malignant pleural mesothelioma (or non-RCTs, in the absence of RCT data ). Outcomes included overall survival, tumour response, progression-free survival, toxicity and quality of life. Data extraction and quality assessment of included trials was completed independently. Trial data and quality assessment were tabulated and presented narratively. One RCT involving 448 patients and comparing pemetrexed plus cisplatin versus cisplatin alone for the treatment of unresectable malignant mesothelioma was included in the review. In the intention-to-treat study population, the median survival was statistically significantly longer in the combination arm of pemetrexed plus cisplatin when compared with the cisplatin alone arm. (12.1 and 9.3 months, respectively, p=0.002). The incidence of grade 3/4 toxicities was higher in the combination arm compared with the cisplatin alone arm. Pemetrexed disodium in combination with cisplatin and with folic acid and vitamin B(12 )supplementation may improve survival when used in combination with cisplatin in good performance status patients. Further studies including patients with poor performance status are needed in order to generalise the treatment findings. Further studies are also needed into the optimum chemotherapy, and a clear definition of what constitutes best supportive care.


First Report of the Occurrence of African cassava mosaic virus in a Mosaic Disease of Soybean in Nigeria.
African cassava mosaic virus (ACMV; genus Begomovirus, family Geminiviridae) is one of six viruses documented in cassava (Manihot esculenta Crantz.) plants showing cassava mosaic disease in sub-Saharan Africa (SSA). In addition to cassava, the natural host range of ACMV includes a few wild Manihot species, Jatropha multifida, and Ricinus communis L. in Euphorbiaceae, and Hewittia sublobata in Convolvulaceae. The experimental host range of ACMV includes Nicotiana sp. and Datura sp. in the Solanaceae (2). Recently, natural occurrence of ACMV was reported in Combretum confertum (Benth.), Leucana leucocephala (Lam.) De Witt, and Senna occidentalis (L.) Link belonging to Leguminasae from Nigeria (1,3). During reconnaissance studies conducted on soybean (Glycine max L. Merr.) in September and October of 2007 in the Ibadan (N = 19) and Benue (N = 23) regions and in February of 2008 in Ibadan (N = 16), we observed soybean showing yellow mosaic and mottling symptoms. Samples from these plants (N = 58) were tested by indirect ELISA and symptomatic leaves tested negative to Cucumber mosaic virus, Cowpea mottle virus, Southern bean mosaic virus, Tobacco ringspot virus, Soybean dwarf virus, Cowpea aphid-borne mosaic virus, Blackeye cowpea mosaic virus, Peanut mottle virus, and Broad bean mosaic virus, which have been documented in soybean in SSA. However, 8.6% of these samples (5 of 58) (one each from Ibadan and Benue in the 2007 survey and three from Ibadan in the 2008 survey) tested positive in triple-antibody sandwich-ELISA with a monoclonal antibody (SCR33) to ACMV. ELISA results were further confirmed by PCR with ACMV specific primers AL1/F and AR0/R that amplified a 987-bp DNA fragment corresponding to the intergenic region, AC-4 and AC-1 genes of DNA-A segment (4). The PCR product was cloned into pCR2.1 (Invitrogen, Carlsbad, CA) and three independent clones were sequenced in both orientations. Pairwise comparison of the derived consensus sequence (GenBank Accession No. EU367500) with corresponding ACMV sequence of ACMV isolate from Nigeria (GenBank Accession No. X17095) showed 98% identity at the nucleotide level. To further confirm the virus identity, complete nucleotide sequence of the DNA-A segment was determined by PCR amplification of viral DNA with four primers, cloning of overlapping products into pCR2.1 vector and sequencing. The derived sequence (2,781 nucleotides; GenBank Accession No. EU685385) was compared with the DNA sequences available at NCBI database using BLAST. This revealed 97% nucleotide sequence identity with ACMV-[NG:Ogo:90] (Accession No. AJ427910) and ACMV-[NG] (Accession No. X17095) from Nigeria. These results confirm the presence of ACMV in symptomatic soybean leaves. To our knowledge, this is the first report of soybean as a natural host of ACMV in SSA. On the basis of previous reports (1) and the results currently presented it seems that ACMV has a wide host range. References: (1) O. J. Alabi et al. Phytopathology (Abstr.) 97(suppl.):S3, 2007. (2) A. A. Brunt et al., eds. Plant viruses online: Descriptions and lists from the VIDE database. Version 20. Online publication, 1996. (3) F. O. Ogbe et al. Plant Dis. 90:548, 2006; (4) X. Zhou et al. J. Gen. Virol. 78:2101, 1997.


Mcl-1 ubiquitination: unique regulation of an essential survival protein.
Mcl-1 is an anti-apoptotic protein of the Bcl-2 family that is essential for the survival of multiple cell lineages and that is highly amplified in human cancer. Under physiological conditions, Mcl-1 expression is tightly regulated at multiple levels, involving transcriptional, post-transcriptional and post-translational processes. Ubiquitination of Mcl-1, that targets it for proteasomal degradation, allows for rapid elimination of the protein and triggering of cell death, in response to various cellular events. In the last decade, a number of studies have elucidated different pathways controlling Mcl-1 ubiquitination and degradation. Four different E3 ubiquitin-ligases (e.g., Mule, SCFβ-TrCP, SCFFbw7 and Trim17) and one deubiquitinase (e.g., USP9X), that respectively mediate and oppose Mcl-1 ubiquitination, have been formerly identified. The interaction between Mule and Mcl-1 can be modulated by other Bcl-2 family proteins, while recognition of Mcl-1 by the other E3 ubiquitin-ligases and deubiquitinase is influenced by phosphorylation of specific residues in Mcl-1. The protein kinases and E3 ubiquitin-ligases that are involved in the regulation of Mcl-1 stability vary depending on the cellular context, highlighting the complexity and pivotal role of Mcl-1 regulation. In this review, we attempt to recapitulate progress in understanding Mcl-1 regulation by the ubiquitin-proteasome system.


Metal fluoride nanotubes featuring square-planar building blocks in a high-pressure polymorph of AgF2.
At a pressure of ca. 15 GPa, AgF2 transforms to an unprecedented orthorhombic polymorph featuring an array of tubular subunits which are built of corner sharing [AgF4] squares. This seems to be the first type of a metal fluoride nanowire and also the only one showing rigid square planar rather than common hexagonal or octahedral moieties.


Taxis toward hydrogen gas by Methanococcus maripaludis.
Knowledge of taxis (directed swimming) in the Archaea is currently expanding through identification of novel receptors, effectors, and proteins involved in signal transduction to the flagellar motor. Although the ability for biological cells to sense and swim toward hydrogen gas has been hypothesized for many years, this capacity has yet to be observed and demonstrated. Here we show that the average swimming velocity increases in the direction of a source of hydrogen gas for the methanogen, Methanococcus maripaludis using a capillary assay with anoxic gas-phase control and time-lapse microscopy. The results indicate that a methanogen couples motility to hydrogen concentration sensing and is the first direct observation of hydrogenotaxis in any domain of life. Hydrogenotaxis represents a strategy that would impart a competitive advantage to motile microorganisms that compete for hydrogen gas and would impact the C, S and N cycles.


Quality of Life after Endoscopic Submucosal Dissection for Early Gastric Cancer: A Prospective Multicenter Cohort Study.
Endoscopic submucosal dissection (ESD) has been an established treatment for indicated early gastric cancer (EGC) without deterioration of quality of life (QOL) compared with surgical resection. The aim of this study was to evaluate long-term QOL in patients undergoing ESD for EGC. Patients scheduled to undergo curative ESD for EGC were prospectively enrolled from 12 institutions between May 2010 and December 2011. Assessments of QOL with Korean versions of the European Organization for Research and Treatment of Cancer (EORTC) QOL questionnaire-core (QLQ-C30) and a gastric cancer-specific questionnaire (STO22) were performed at baseline and at 7 days, 3 months, and 6 months after ESD. A total of 666 subjects were assessed for QLQ-C30 and QLQ-STO22. The mean QLQ-C30 score was 69.5 at baseline, 68.8 at 7 days, 73.1 at 3 months, and 73.2 at 6 months. The global health status on the EORTC QLQ-C30 was significantly improved after 3 and 6 months (p=0.0003 and p<0.0001, respectively). The QLQ-C30 and STO22 scores were not significantly different, or they only slightly deteriorated between before and immediately after ESD, but they were significantly improved after 3 and 6 months (p<0.05). QOL did not deteriorate immediately after ESD, and it improved more significantly at up to 6 months in patients who underwent curative ESD for EGC without significant complications.


Sugar-Sweetened Beverage Consumption in Relation to Obesity and Metabolic Syndrome among Korean Adults: A Cross-Sectional Study from the 2012⁻2016 Korean National Health and Nutrition Examination Survey (KNHANES).
It is well known that the consumption of sugar-sweetened beverages (SSBs) increases the risk of developing obesity and metabolic syndrome (MetS). However, there are not many studies investigating the link between SSBs and increased incidences of diseases in the Asian population, and in particular, in Korea. We explored the association of SSB consumption with the risk of developing obesity and MetS among Korean adults (12,112 participants from the 2012⁻2016 Korean National Health and Nutrition Examination Survey). We calculated the total SSB consumption frequency by counting each beverage item, including soda beverages, fruit juices, and sweetened rice drinks. Obesity was defined as a body mass index ≥25 kg/m², and MetS was defined using the National Cholesterol Education Program, Adult Treatment Panel III. A survey logistic regression analyses was conducted to examine the association of SSB consumption with obesity and MetS, adjusting for related confounders such as age, energy intake, household income, education, alcohol drinking, smoking status, and physical activity. The SSB consumption was positively associated with an increased risk of the prevalence for obesity (Odd ratio (OR): 1.60; 95% confidence interval (CI): 1.23⁻2.09; p for trend = 0.0009) and MetS (OR: 1.61; 95% CI: 1.20⁻2.16; p for trend = 0.0003) among women. In men, SSB consumption only contributed to a higher prevalence of obesity (OR: 1.38; 95% CI: 1.11⁻1.72; p for trend = 0.0041). In conclusion, increased consumption of SSBs was closely linked with a higher prevalence of obesity and MetS in the Korean population.


Fundamental limits of reconstruction-based superresolution algorithms under local translation.
Superresolution is a technique that can produce images of a higher resolution than that of the originally captured ones. Nevertheless, improvement in resolution using such a technique is very limited in practice. This makes it significant to study the problem: "Do fundamental limits exist for superresolution?" In this paper, we focus on a major class of superresolution algorithms, called the reconstruction-based algorithms, which compute high-resolution images by simulating the image formation process. Assuming local translation among low-resolution images, this paper is the first attempt to determine the explicit limits of reconstruction-based algorithms, under both real and synthetic conditions. Based on the perturbation theory of linear systems, we obtain the superresolution limits from the conditioning analysis of the coefficient matrix. Moreover, we determine the number of low-resolution images that are sufficient to achieve the limit. Both real and synthetic experiments are carried out to verify our analysis.


Immortalization of osteoclast precursors by targeting Bcl -XL and Simian virus 40 large T antigen to the osteoclast lineage in transgenic mice.
Cellular and molecular characterization of osteoclasts (OCL) has been extremely difficult since OCL are rare cells, and are difficult to isolate in large numbers. We used the tartrate-resistant acid phosphatase promoter to target the bcl-XL and/or Simian Virus 40 large T antigen (Tag) genes to cells in the OCL lineage in transgenic mice as a means of immortalizing OCL precursors. Immunocytochemical studies confirmed that we had targeted Bcl-XL and/or Tag to OCL, and transformed and mitotic OCL were readily apparent in bones from both Tag and bcl-XL/Tag mice. OCL formation in primary bone marrow cultures from bcl-XL, Tag, or bcl-XL/Tag mice was twofold greater compared with that of nontransgenic littermates. Bone marrow cells from bcl-XL/Tag mice, but not from singly transgenic bcl-XL or Tag mice, have survived in continuous culture for more than a year. These cells form high numbers of bone-resorbing OCL when cultured using standard conditions for inducing OCL formation, with approximately 50% of the mononuclear cells incorporated into OCL. The OCL that form express calcitonin receptors and contract in response to calcitonin. Studies examining the proliferative capacity and the resistance of OCL precursors from these transgenic mice to apoptosis demonstrated that the increased numbers of OCL precursors in marrow from bcl-XL/Tag mice was due to their increased survival rather than an increased proliferative capacity compared with Tag, bcl-XL, or normal mice. Histomorphometric studies of bones from bcl-XL/Tag mice also confirmed that there were increased numbers of OCL precursors (TRAP + mononuclear cells) present in vivo. These data demonstrate that by targeting both bcl-XL and Tag to cells in the OCL lineage, we have immortalized OCL precursors that form bone-resorbing OCL with an efficiency that is 300-500 times greater than that of normal marrow.


Malarial dihydrofolate reductase as a paradigm for drug development against a resistance-compromised target.
Malarial dihydrofolate reductase (DHFR) is the target of antifolate antimalarial drugs such as pyrimethamine and cycloguanil, the clinical efficacy of which have been compromised by resistance arising through mutations at various sites on the enzyme. Here, we describe the use of cocrystal structures with inhibitors and substrates, along with efficacy and pharmacokinetic profiling for the design, characterization, and preclinical development of a selective, highly efficacious, and orally available antimalarial drug candidate that potently inhibits both wild-type and clinically relevant mutated forms of Plasmodium falciparum (Pf) DHFR. Important structural characteristics of P218 include pyrimidine side-chain flexibility and a carboxylate group that makes charge-mediated hydrogen bonds with conserved Arg122 (PfDHFR-TS amino acid numbering). An analogous interaction of P218 with human DHFR is disfavored because of three species-dependent amino acid substitutions in the vicinity of the conserved Arg. Thus, P218 binds to the active site of PfDHFR in a substantially different fashion from the human enzyme, which is the basis for its high selectivity. Unlike pyrimethamine, P218 binds both wild-type and mutant PfDHFR in a slow-on/slow-off tight-binding mode, which prolongs the target residence time. P218, when bound to PfDHFR-TS, resides almost entirely within the envelope mapped out by the dihydrofolate substrate, which may make it less susceptible to resistance mutations. The high in vivo efficacy in a SCID mouse model of P. falciparum malaria, good oral bioavailability, favorable enzyme selectivity, and good safety characteristics of P218 make it a potential candidate for further development.


Early Chemistry of Nicotine Degradation in Heat-Not-Burn Smoking Devices and Conventional Cigarettes: Implications for Users and Second- and Third-Hand Smokers.
Nicotine exposure results in health risks not only for smokers but also for second- and third-hand smokers. Unraveling nicotine's degradation mechanism and the harmful chemicals that are produced under different conditions is vital to assess exposure risks. We performed a theoretical study to describe the early chemistry of nicotine degradation by investigating two important reactions that nicotine can undergo: hydrogen abstraction by hydroxyl radicals and unimolecular dissociation. The former contributes to the control of the degradation mechanism below 800 K due to a non-Arrhenius kinetics, which implies an enhancement of reactivity as temperature decreases. The latter becomes important at higher temperatures due to its larger activation energy. This change in the degradation mechanism is expected to affect the composition of vapors inhaled by smokers and room occupants. Conventional cigarettes, which operate at temperatures higher than 1000 K, are more prone to yield harmful pyridinyl radicals via nicotine dissociation, while nicotine in electronic cigarettes and vaporizers, with operating temperatures below 600 K, will be more likely degraded by hydroxyl radicals, resulting in a vapor with a different composition. Although low-temperature nicotine delivery devices have been claimed to be less harmful due to their nonburning operating conditions, the non-Arrhenius kinetics that we observed for the degradation mechanism below 873 K suggests that nicotine degradation may be more rapidly initiated as temperature is reduced, indicating that these devices may be more harmful than it is commonly assumed.


Variation between hospitals in patient outcome after stroke is only partly explained by differences in quality of care: results from the Netherlands Stroke Survey.
Patient outcome is often used as an indicator of quality of hospital care. The aim of this study is to investigate whether there is a straightforward relationship between quality of care and outcome, and whether outcome measures could be used to assess quality of care after stroke. In 10 centres in The Netherlands, 579 patients with acute stroke were prospectively and consecutively enrolled. Poor outcome was defined as a score on the modified Rankin scale >or=3 at 1 year. Quality of care was assessed by relating diagnostic, therapeutic and preventive procedures to indication. Multiple logistic regression models were used to compare observed proportions of patients with poor outcome with expected proportions, after adjustment for patient characteristics and quality of care parameters. A total of 271 (47%) patients were dead or disabled at 1 year. Poor outcome varied across the centres from 29% to 78%. Large differences between centres were also observed in clinical characteristics, prognostic factors and quality of care. For example, between hospital quartiles based on outcome, age >or=70 years varied from 50% to 65%, presence of vascular risk factors from 88% to 96%, intravenous fluids when indicated from 35% to 81%, and antihypertensive therapy when indicated from 60% to 85%. The largest part of variation in patient outcome between centres was explained by differences in patient characteristics (Akaike's Information Criterion (AIC) = 134.0). Quality of care parameters explained a small part of the variation in patient outcome (AIC = 5.5). Patient outcome after stroke varies largely between centres and is, for a substantial part, explained by differences in patient characteristics at time of hospital admission. Only a small part of the hospital variation in patient outcome is related to differences in quality of care. Unadjusted proportions of poor outcome after stroke are not valid as indicators of quality of care.


Prediction of clinical outcome using gene expression profiling and artificial neural networks for patients with neuroblastoma.
Currently, patients with neuroblastoma are classified into risk groups (e.g., according to the Children's Oncology Group risk-stratification) to guide physicians in the choice of the most appropriate therapy. Despite this careful stratification, the survival rate for patients with high-risk neuroblastoma remains <30%, and it is not possible to predict which of these high-risk patients will survive or succumb to the disease. Therefore, we have performed gene expression profiling using cDNA microarrays containing 42,578 clones and used artificial neural networks to develop an accurate predictor of survival for each individual patient with neuroblastoma. Using principal component analysis we found that neuroblastoma tumors exhibited inherent prognostic specific gene expression profiles. Subsequent artificial neural network-based prognosis prediction using expression levels of all 37,920 good-quality clones achieved 88% accuracy. Moreover, using an artificial neural network-based gene minimization strategy in a separate analysis we identified 19 genes, including 2 prognostic markers reported previously, MYCN and CD44, which correctly predicted outcome for 98% of these patients. In addition, these 19 predictor genes were able to additionally partition Children's Oncology Group-stratified high-risk patients into two subgroups according to their survival status (P = 0.0005). Our findings provide evidence of a gene expression signature that can predict prognosis independent of currently known risk factors and could assist physicians in the individual management of patients with high-risk neuroblastoma.


Sulfide catabolism ameliorates hypoxic brain injury.
The mammalian brain is highly vulnerable to oxygen deprivation, yet the mechanism underlying the brain's sensitivity to hypoxia is incompletely understood. Hypoxia induces accumulation of hydrogen sulfide, a gas that inhibits mitochondrial respiration. Here, we show that, in mice, rats, and naturally hypoxia-tolerant ground squirrels, the sensitivity of the brain to hypoxia is inversely related to the levels of sulfide:quinone oxidoreductase (SQOR) and the capacity to catabolize sulfide. Silencing SQOR increased the sensitivity of the brain to hypoxia, whereas neuron-specific SQOR expression prevented hypoxia-induced sulfide accumulation, bioenergetic failure, and ischemic brain injury. Excluding SQOR from mitochondria increased sensitivity to hypoxia not only in the brain but also in heart and liver. Pharmacological scavenging of sulfide maintained mitochondrial respiration in hypoxic neurons and made mice resistant to hypoxia. These results illuminate the critical role of sulfide catabolism in energy homeostasis during hypoxia and identify a therapeutic target for ischemic brain injury.


Accurate data processing improves the reliability of Affymetrix gene expression profiles from FFPE samples.
Formalin fixed paraffin-embedded (FFPE) tumor specimens are the conventionally archived material in clinical practice, representing an invaluable tissue source for biomarkers development, validation and routine implementation. For many prospective clinical trials, this material has been collected allowing for a prospective-retrospective study design which represents a successful strategy to define clinical utility for candidate markers. Gene expression data can be obtained even from FFPE specimens with the broadly used Affymetrix HG-U133 Plus 2.0 microarray platform. Nevertheless, important major discrepancies remain in expression data obtained from FFPE compared to fresh-frozen samples, prompting the need for appropriate data processing which could help to obtain more consistent results in downstream analyses. In a publicly available dataset of matched frozen and FFPE expression data, the performances of different normalization methods and specifically designed Chip Description Files (CDFs) were compared. The use of an alternative CDFs together with fRMA normalization significantly improved frozen-FFPE sample correlations, frozen-FFPE probeset correlations and agreement of differential analysis between different tumor subtypes. The relevance of our optimized data processing was assessed and validated using two independent datasets. In this study we demonstrated that an appropriate data processing can significantly improve the reliability of gene expression data derived from FFPE tissues using the standard Affymetrix platform. Tools for the implementation of our data processing algorithm are made publicly available at http://www.biocut.unito.it/cdf-ffpe/.


USP7 Cooperates with NOTCH1 to Drive the Oncogenic Transcriptional Program in T-Cell Leukemia.
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease, affecting children and adults. Chemotherapy treatments show high response rates but have debilitating effects and carry risk of relapse. Previous work implicated NOTCH1 and other oncogenes. However, direct inhibition of these pathways affects healthy tissues and cancer alike. Our goal in this work has been to identify enzymes active in T-ALL whose activity could be targeted for therapeutic purposes. To identify and characterize new NOTCH1 druggable partners in T-ALL, we coupled studies of the NOTCH1 interactome to expression analysis and a series of functional analyses in cell lines, patient samples, and xenograft models. We demonstrate that ubiquitin-specific protease 7 (USP7) interacts with NOTCH1 and controls leukemia growth by stabilizing the levels of NOTCH1 and JMJD3 histone demethylase. USP7 is highly expressed in T-ALL and is transcriptionally regulated by NOTCH1. In turn, USP7 controls NOTCH1 levels through deubiquitination. USP7 binds oncogenic targets and controls gene expression through stabilization of NOTCH1 and JMJD3 and ultimately H3K27me3 changes. We also show that USP7 and NOTCH1 bind T-ALL superenhancers, and inhibition of USP7 leads to a decrease of the transcriptional levels of NOTCH1 targets and significantly blocks T-ALL cell growth in vitro and in vivo. These results provide a new model for USP7 deubiquitinase activity through recruitment to oncogenic chromatin loci and regulation of both oncogenic transcription factors and chromatin marks to promote leukemia. Our studies also show that targeting USP7 inhibition could be a therapeutic strategy in aggressive leukemia.


Autism and genetics. A decade of research.
The last ten years of research on the genetics of infantile autism were critically reviewed. Epidemiologic findings have shown that autism is a rare disorder with a prevalence of two to five per 10,000, a male-female ratio of 3:1, and an association with mental retardation (66% to 75% of autistic subjects have full-scale IQ scores [70]). Autism is familial, as reflected in an empiric sibling recurrence risk of 3% and pooled monozygotic and dizygotic concordance rates of 64% and 9%, respectively, which are much greater than the population prevalence of 0.02% to 0.05%. Genetic heterogeneity is pronounced with potential genetic subgroups, including autosomal recessive inheritance, X-linked inheritance, and sporadic chromosomal anomalies. Studies of subclinical markers in autism have elucidated potential markers at various levels of phenotypic expression from the DNA to the behavioral level. Linkage and cytogenetic studies point to two chromosome regions as putative markers, 9q34 and Xq27. Results of family studies support a putative biochemical marker, low levels of plasma dopamine-beta-hydroxylase, and a putative cognitive marker, ie, normal visuospatial but low verbal functioning, in autism. The frequency of minor physical anomalies and presence or absence of mental retardation are two dimensions of the physical and behavioral phenotype that may demark etiologically distinct subgroups. Genetic heterogeneity is offered as one explanation of the observed sex difference in the prevalence of autism. Directions for potentially fruitful research should be considered.


In vitro evaluation of ivermectin, moxidectin, albendazole and pyrantel against cyathostomins of horses.
Cyathostomins are the most prevalent nematodes of horses, and multidrug resistance has been reported worldwide. There is a need to implement alternative drug monitoring analytical tests. The objective of this study was to determine the consistency (5 repetitions) of the larval migration on agar test (LMAT) using ivermectin, moxidectin, pyrantel or albendazole against cyathostomin infective-stage larvae in eight different concentrations. LMAT showed a strong coefficient of determination (R2 > 0.91), between the test repetitions (n=5). The average 50% effective concentration (EC50) for ivermectin, moxidectin, pyrantel and albendazole were 0.0404, 0.0558, 0.0864 and 0.0988 nMol, respectively. The results of the EC50 for albendazole showed the greatest range of concentration. Ivermectin and moxidectin had the lowest in between-test variation. In the future, internationally certified susceptible isolates could be used for screening new drug candidates, or to follow up the pattern of drug efficacy from field populations.


Spin dynamics of the 2D spin 1/2 quantum antiferromagnet copper deuteroformate tetradeuterate (CFTD).
The magnetic excitation spectrum in the two-dimensional (2D) S = 1/2 Heisenberg antiferromagnet copper deuteroformate tetradeuterate has been measured for temperatures up to T approximately J/2, where J = 6.31+/-0.02 meV is the 2D exchange coupling. For T<<J, a dispersion of the zone boundary energy is observed, which is attributed to a wave vector dependent quantum renormalization. At higher temperatures, spin-wavelike excitations persist, but are found to broaden and soften. By combining our data with numerical calculations, and with existing theoretical work, a consistent description of the behavior of the model system is found over the whole temperature interval investigated.


Ficus recemosa bark extract attenuates diabetic complications and oxidative stress in STZ-induced diabetic rats.
Context Ficus recemosa Linn. (Moraceae) has been reported as a natural folk medicine with diverse pathological activities such as antioxidant, antidiabetic, renoprotective and cardioprotective. Objective The present study evaluates the preventive effect of standardised ethanol extract of F. racemosa stem bark (EEFSB) on diabetic cardiomyopathy (DC) and diabetic nephropathy (DN). Materials and methods Animals were rendered diabetic by one time administration of STZ (45 mg kg(-1), i.v.) and, after 7 d, diabetic rats were randomised into four groups of eight rats each. EEFSB (200 and 400 mg kg(-1)) was administered to diabetic rats once daily for 8 weeks. Furthermore, the presence of phytochemicals was evaluated by HPTLC. Results Treatment with EEFSB markedly restores the blood glucose and lipid level (p < 0.001), also reduced creatinine kinase (p < 0.001), lactate dehydrogenase (p < 0.001), C-reactive protein (p < 0.001), creatinine (p < 0.001), blood urea nitrogen (p < 0.001), collagen (p < 0.05) and albumin (p < 0.001) levels. Reduced level of sodium (p < 0.001), creatinine (p < 0.001), albumin (p < 0.001) and malondialdehyde (p < 0.01) in heart and kidney tissue along with enhanced activities of superoxide dismutase (p < 0.001) and reduced glutathione (p < 0.001). Moreover, left ventricular hypertrophic index and cardiac hypertrophic index were markedly reduced by EEFSB treatment. Conclusion The findings of this study provided strong scientific evidence for the traditional use of F. racemosa and postulate protective effects against diabetes and its complications such as DC and DN.


Whole-Genome Resequencing and Pan-Transcriptome Reconstruction Highlight the Impact of Genomic Structural Variation on Secondary Metabolite Gene Clusters in the Grapevine Esca Pathogen Phaeoacremonium minimum.
The Ascomycete fungus Phaeoacremonium minimum is one of the primary causal agents of Esca, a widespread and damaging grapevine trunk disease. Variation in virulence among Pm. minimum isolates has been reported, but the underlying genetic basis of the phenotypic variability remains unknown. The goal of this study was to characterize intraspecific genetic diversity and explore its potential impact on virulence functions associated with secondary metabolism, cellular transport, and cell wall decomposition. We generated a chromosome-scale genome assembly, using single molecule real-time sequencing, and resequenced the genomes and transcriptomes of multiple isolates to identify sequence and structural polymorphisms. Numerous insertion and deletion events were found for a total of about 1 Mbp in each isolate. Structural variation in this extremely gene dense genome frequently caused presence/absence polymorphisms of multiple adjacent genes, mostly belonging to biosynthetic clusters associated with secondary metabolism. Because of the observed intraspecific diversity in gene content due to structural variation we concluded that a transcriptome reference developed from a single isolate is insufficient to represent the virulence factor repertoire of the species. We therefore compiled a pan-transcriptome reference of Pm. minimum comprising a non-redundant set of 15,245 protein-coding sequences. Using naturally infected field samples expressing Esca symptoms, we demonstrated that mapping of meta-transcriptomics data on a multi-species reference that included the Pm. minimum pan-transcriptome allows the profiling of an expanded set of virulence factors, including variable genes associated with secondary metabolism and cellular transport.


Spatial Pattern of Strawberry Powdery Mildew (Podosphaera aphanis) and Airborne Inoculum.
The relationship between strawberry powdery mildew and airborne conidium concentration (ACC) of Podosphaera aphanis was studied using data collected from 2006 to 2009 in 15 fields, and spatial pattern was described using 2 years of airborne inoculum and disease incidence data collected in fields planted with the June-bearing strawberry (Fragaria × ananassa) cultivar Jewel. Disease incidence, expressed as the proportion of diseased leaflets, and ACC were monitored in fields divided into 3 × 8 grids containing 24 100 m2 quadrats. Variance-to-mean ratio, index of dispersion, negative binomial distribution, Poisson distribution, and binomial and beta-binomial distributions were used to characterize the level of spatial heterogeneity. The relationship between percent leaf area diseased and daily ACC was linear, while the relationship between ACC and disease incidence followed an exponential growth curve. The V/M ratios were significantly greater than 1 for 100 and 96% of the sampling dates for ACC sampled at 0.35 m from the ground (ACC0.35m) and for ACC sampled at 1.0 m from the ground (ACC1.0m), respectively. For disease incidence, the index of dispersion D was significantly greater than 1 for 79% of the sampling dates. The negative binomial distribution fitted 86% of the data sets for both ACC1.0m and ACC0.35m. For disease incidence data, the beta-binomial distribution provided a good fit of 75% of the data sets. Taylor's power law indicated that, for ACC at both sampling heights, heterogeneity increased with increasing mean ACC, whereas the binary form of the power law suggested that heterogeneity was not dependent on the mean for disease incidence. When the spatial location of each sampling location was taken into account, Spatial Analysis by Distance Indices showed low aggregation indices for both ACCs and disease incidence, and weak association between ACC and disease incidence. Based on these analyses, it was found that the distribution of strawberry powdery mildew was weakly aggregated. Although a higher level of heterogeneity was observed for airborne inoculum, the heterogeneity was low with no distinct foci, suggesting that epidemics are induced by well-distributed inoculum. This low level of heterogeneity allows mean airborne inoculum concentration to be estimated using only one sampler per field with an overall accuracy of at least 0.841. The results obtained in this study could be used to develop a sampling scheme that will improve strawberry powdery mildew risk estimation.


An In-vitro Comparative Stereomicroscopic Analysis and Evaluation of Marginal Accuracy in Porcelain Fused to Metal Copings Fabricated in Two Different Finish Lines Using Variant Die Materials.
Limited published information is available about the influence of preparatory designs and die materials on marginal accuracy of porcelain fused to metal copings using recently developed die materials. To detect the influence of margin geometries and dimensional accuracy of contemporary die materials on vertical marginal gaps in Porcelain fused to metal coping using a Stereomicroscope (three dimensional analysis). Two chrome cobalt alloy models of mandibular first molars prepared to have shoulder and deep chamfer finish lines were CAD-CAM milled. Elastomeric impressions of these models were made in a custom tray, poured in Type IV Gypsum(n=10) and Resin modified Gypsum(n=10) and also packed with Epoxy resin (n=10) as a die material to form a total of 60 samples, 30 in each group (shoulder and deep chamfer). Wax patterns were fabricated, invested and castings in ceramic alloy were obtained in traditional manner. These copings were later analyzed on CAD/CAM models using stereomicroscope. Both the designs did not exhibit significant difference (p<0.05). Whereas, the three die materials exhibited significant difference (p<0.05) by Two way ANOVA test and Tukey's multiple Post Hoc test. Results from this study showed that vertical marginal gaps for copings fabricated on resin modified gypsum as a die material were within the clinically acceptable range. Margin geometries both shoulder and deep chamfer have equal influence on vertical marginal gaps in metal ceramic restorations. Copings fabricated on Epoxy resin dies exhibited highest value of vertical marginal discrepancy, where as least value was determined for copings constructed on dies fabricated from resin modified gypsum.


Probing the Reactivity of Singlet Oxygen with Cyclic Monoterpenes.
Monoterpenes represent a class of hydrocarbons consisting of two isoprene units. Like many other terpenes, monoterpenes emerge mainly from vegetation, indicating their significance in both atmospheric chemistry and pharmaceutical and food industries. The atmospheric recycling of monoterpenes constitutes a major source of secondary organic aerosols. Therefore, this contribution focuses on the mechanism and kinetics of atmospheric oxidation of five dominant monoterpenes (i.e., limonene, α-pinene, β-pinene, sabinene, and camphene) by singlet oxygen. The reactions are initiated via the ene-type addition of singlet oxygen (O2 1Δg) to the electron-rich double bond, progressing favorably through the concerted reaction mechanisms. The physical analyses of the frontier molecular orbitals agree well with the thermodynamic properties of the selected reagents, and the computed reaction rate parameters. The reactivity of monoterpenes with O2 1Δg follows the order of α-pinene > sabinene > limonene > β-pinene > camphene, i.e., α-pinene and camphene retain the highest and lowest reactivity toward singlet oxygen, with rate expressions of k(T) (M-1 s-1) = 1.13 × 108 exp(-48(kJ)/RT(K)) and 6.93 × 108 exp(-139(kJ)/RT(K)), respectively. The effect of solvent on the primary reaction pathways triggers a slight reduction in energy, ranging between 12 and 34 kJ/mol.


Bruton tyrosine kinase is a therapeutic target in stem-like cells from multiple myeloma.
Ibrutinib (Imbruvica), a small-drug inhibitor of Bruton tyrosine kinase (BTK), is currently undergoing clinical testing in patients with multiple myeloma, yet important questions on the role of BTK in myeloma biology and treatment are outstanding. Using flow-sorted side population cells from human myeloma cell lines and multiple myeloma primary samples as surrogate for the elusive multiple myeloma stem cell, we found that elevated expression of BTK in myeloma cells leads to AKT/WNT/β-catenin-dependent upregulation of key stemness genes (OCT4, SOX2, NANOG, and MYC) and enhanced self-renewal. Enforced transgenic expression of BTK in myeloma cells increased features of cancer stemness, including clonogenicity and resistance to widely used myeloma drugs, whereas inducible knockdown of BTK abolished them. Furthermore, overexpression of BTK in myeloma cells promoted tumor growth in laboratory mice and rendered side population-derived tumors that contained high levels of BTK more sensitive to the selective, second-generation BTK inhibitor, CGI1746, than side population-derived tumors that harbored low levels of BTK. Taken together, these findings implicate BTK as a positive regulator of myeloma stemness and provide additional support for the clinical testing of BTK-targeted therapies in patients with myeloma.


[Coronary artery calcium quantification with non-ECG-gated low-radiation dose CT of the chest].
To evaluate the feasibility of quantifying coronary artery calcification in low-radiation dose chest CT (LDCT) studies performed in an early lung cancer detection program by comparing the results of this technique with those of dedicated retrospectively ECG-gated cardiac CT. After obtaining informed consent, we evaluated the CT studies of 48 consecutive asymptomatic smokers (44 male, 4 female; mean age 59.7 years) included in an early lung cancer detection trial who underwent multislice LDCT (Volume Zoom, Siemens) of the chest and a retrospectively ECG-gated cardiac CT specifically dedicated to quantifying coronary artery calcification. LDCT examinations were reconstructed to reproduce cardiac CT parameters. Coronary calcium values were compared using the Wilcoxon signed-rank test. The concordance correlation coefficient (CCC) was calculated to determine the agreement between the two methods. Coronary calcium values ranged from 0 to 1,908.4 (median: 89.6; IQR: 3.2; 227.4) in LDCT exams and from 0 to 1,486.6 (median: 81.3; IQR: 2.5; 316.4) in cardiac CT studies. No statistically significant difference was observed in the estimation of total coronary calcium score (p=0.28). The concordance between the two techniques was excellent (CCC > or = 0.81). The LDCT study performed in lung cancer early detection trials enables coronary artery calcification to be quantified with the same accuracy as the dedicated retrospectively ECG-gated cardiac CT examination.


Karyotypic and fluorescent in situ hybridization study of the centromere of chromosome 7 in secondary myeloid neoplasms.
Secondary myeloid neoplasms comprise a group of secondary diseases following exposure to myelotoxic agents or due to congenital diseases. The improvement of anticancer agents and immunosuppressive drugs seem to be associated with an increased incidence of secondary myeloid neoplasms. Karyotyping of bone marrow is essential for diagnosis and prognosis. Previous use of alkylating agents and radiation are associated with clonal abnormalities such as recurrent unbalanced -5/5q-, -7/7q- and complex karyotypes, whereas topoisomerase-II inhibitors lead to changes such as the balanced 11q23 rearrangement, t(8;21), t(15;17) and inv(16). To study the clinical and cytogenetic data of patients with secondary myeloid neoplasms who took antineoplastic and/or immunosuppressive drugs or progressed from aplastic anemia. The clinical and cytogenetic characteristics of 42 patients diagnosed with secondary myeloid neoplasms in one institution were retrospectively evaluated. Of these, 25, 11 and 6 patients had had oncological diseases, aplastic anemia and other diseases, respectively. Conventional cytogenetic and FISH analyses were performed for monosomy 7. The cytogenetic study was conclusive in 32 cases with 84.4% of clonal abnormalities. Monosomy 7 and complex karyotypes were present in 44.4% and 37%, respectively. A high prevalence of unbalanced abnormalities (96.3%) was observed. Monosomy 7 was more prevalent in patients with myelodysplastic syndromes/myeloid neoplasms after aplastic anemia (66.6%). The median survival after diagnosis of myeloid neoplasms was only 5.7 months. Normal cytogenetics was associated to better survival (p-value = 0.03). There was a slightly worse trend of survival for patients with complex karyotypes (p-value = 0.057). Abnormal karyotype was an independent risk factor for poor survival (p-value = 0.012). This study enhances the importance of cytogenetic analysis of patients at the time of diagnosis of secondary myeloid neoplasms.


Value Narratives: A Novel Method for Understanding High-Cost Pediatric Hospital Patients.
To delineate the drivers of cost associated with the most-costly inpatients in a tertiary pediatric hospital. We identified the 10% most-costly inpatients treated at a large regional children's hospital in 2010. From this group we randomly selected, within representative specialties, 2 groups of 50 inpatients for detailed chart review. By using daily cost data and clinical records, 2 independent reviewers examined the clinical course of each patient to identify events that drove cost beyond that expected for standard of care. By using an iterative process, these events were grouped into themes or "cost drivers." Linear regression was used to measure the association of number of cost drivers and total 2010 inpatient cost. We identified 7 cost drivers: medical complications (49%), futile treatment (6%), failure to identify family care preferences (9%), system errors (65%), preventable admissions (21%), complex family dynamics (11%), and expensive diagnosis with no other cost driver (15%). Cost drivers were associated with increased total costs. We developed a novel method for understanding high-cost inpatients. This method allowed a more detailed understanding of cost drivers than could be achieved with administrative data alone. Many of these cost drivers were related to problems with communication.


Preservation of visual attention in older expert orienteers at rest and under physical effort.
This study investigated the visual attention of older expert orienteers and older adults not practicing activities with high attentional and psychomotor demands, and considered whether prolonged practice of orienteering may counteract the age-related deterioration of visual attentional performance both at rest and under acute exercise. In two discriminative reaction time experiments, performed both at rest and under submaximal physical workload, visual attention was cued by means of spatial cues of different sizes followed, at different stimulus-onset asynchronies, by compound stimuli with local and global target features. Orienteers, as compared to nonathletes, showed a faster reaction speed and a complex pattern of attentional differences depending on the time constraints of the attentional task, the demands on endogenous attentional control, and the presence or absence of a concomitant effortful motor task. Results suggest that older expert orienteers have developed attentional skills that outweigh, at least at rest, the age-related deficits of visual attentional focusing.


Progress Toward the Control and Management of the Thalassemias.
Because of the particularly high frequency of different severe forms of both α and β thalassemia in Asia, the development of approaches for their prevention and management is particularly challenging. However, because of earlier partnerships with richer countries, so-called North/South partnerships, and help from their governments, considerable progress toward the better control of the thalassemias has been achieved in some countries. It is vital that the global health importance of the thalassemias and related disorders, by far the commonest genetic diseases, is emphasized to the appropriate international health agencies.


Spotting the right location- imaging approaches to resolve the intracellular localization of invasive pathogens.
A common strategy of microbial pathogens is to invade host cells during infection. The invading microbes explore different intracellular compartments to find their preferred niche. Imaging has been instrumental to unravel paradigms of pathogen entry, to identify their exact intracellular location, and to understand the underlying mechanisms for the formation of pathogen-containing niches. Here, we provide an overview of imaging techniques that have been applied to monitor the intracellular lifestyle of pathogens, focusing mainly on bacteria that either remain in vacuolar-bound compartments or rupture the endocytic vacuole to escape into the host's cellular cytoplasm. We will depict common molecular and cellular paradigms that are preferentially exploited by pathogens. A combination of electron microscopy, fluorescence microscopy, and time-lapse microscopy has been the driving force to reveal underlying cell biological processes. Furthermore, the development of highly sensitive and specific fluorescent sensor molecules has allowed for the identification of functional aspects of niche formation by intracellular pathogens. Currently, we are beginning to understand the sophistication of the invasion strategies used by bacterial pathogens during the infection process- innovative imaging has been a key ingredient for this. This article is part of a Special Issue entitled Nanotechnologies - Emerging Applications in Biomedicine.


Effects of titanium dioxide nanoparticles exposure on parkinsonism in zebrafish larvae and PC12.
Nanomaterials hold significant potential for industrial and biomedical application these years. Therefore, the relationship between nanoparticles and neurodegenerative disease is of enormous interest. In this contribution, zebrafish embryos and PC12 cell lines were selected for studying neurotoxicity of titanium dioxide nanoparticles (TiO2 NPs). After exposure of different concentrations of TiO2 NPs to embryos from fertilization to 96 hpf, the hatching time of zebrafish was decreased, accompanied by an increase in malformation rate. However, no significant increases in mortality relative to control were observed. These results indicated that TiO2 NPs exposure hold a risk for premature of zebrafish embryos, but not fatal. The further investigation confirmed that TiO2 NPs could accumulate in the brain of zebrafish larvae, resulting in reactive oxygen species (ROS) generation and cell death of hypothalamus. Meanwhile, q-PCR analysis showed that TiO2 NPs exposure increased the pink1, parkin, α-syn and uchl1 gene expression, which are related with the formation of Lewy bodies. We also observed loss of dopaminergic neurons in zebrafish and in vitro. These remarkable hallmarks are all linked to these Parkinson's disease (PD) symptoms. Our results indicate that TiO2NPs exposure induces neurotoxicity in vivo and in vitro, which poses a significant risk factor for the development of PD.


Is the relationship between men's age at first birth and midlife health changing? Evidence from two British cohorts.
Becoming a father, particularly for the first time, is a central transition in men's lives, and whether this transition takes place early or later in life may have important ramifications on the whole later life course. Previous research has shown that men who father their first child early in life have poorer later-life health than men who postpone having children. However, it is not known how selection by cognitive ability and other childhood characteristics confound the association between the timing of fatherhood and later-life health, or how the association is changing over time as parenthood is postponed to an older age. We investigate the association between men's age at the birth of their first child and midlife self-rated health in two British cohorts born in 1958 and 1970. The study employs logit models. Relative to men who had their first child when they were between 25 and 29 years old, men who had their first child before the age of 20 have the poorest health, followed by men who had a child when they were 20-24 years old. This result was observed in both cohorts. Childhood cognitive ability, which previous research has not analyzed, strongly contributed to this association, and to a greater extent than other childhood characteristics. For the 1970 cohort, those who became fathers at age 35 or older had the best health. This advantage was not found for the 1958 cohort. These findings suggest that the relationship between young age at fatherhood and midlife health is strongly confounded by cognitive ability, and that in recent cohorts a new pattern of advantage among older fathers has emerged.


Patients With Brain Tumors: Who Receives Postacute Occupational Therapy Services?
Data on the utilization of occupational therapy among patients with brain tumors have been limited to those with malignant tumors and small samples of patients outside North America in specialized palliative care settings. We built on this research by examining the characteristics of patients with brain tumors who received postacute occupational therapy services in Ontario, Canada, using health care administrative data. Between fiscal years 2004-2005 and 2008-2009, 3,199 patients with brain tumors received occupational therapy services in the home care setting after hospital discharge; 12.4% had benign brain tumors, 78.2% had malignant brain tumors, and 9.4% had unspecified brain tumors. However, patients with benign brain tumors were older (mean age=63.3 yr), and a higher percentage were female (65.2%). More than 90% of patients received in-home occupational therapy services. Additional research is needed to examine the significance of these differences and to identify factors that influence access to occupational therapy services in the home care setting.


Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review.
We conducted a systematic review to determine changes in the worldwide incidence and prevalence of ulcerative colitis (UC) and Crohn's disease (CD) in different regions and with time. We performed a systematic literature search of MEDLINE (1950-2010; 8103 citations) and EMBASE (1980-2010; 4975 citations) to identify studies that were population based, included data that could be used to calculate incidence and prevalence, and reported separate data on UC and/or CD in full manuscripts (n = 260). We evaluated data from 167 studies from Europe (1930-2008), 52 studies from Asia and the Middle East (1950-2008), and 27 studies from North America (1920-2004). Maps were used to present worldwide differences in the incidence and prevalence of inflammatory bowel diseases (IBDs); time trends were determined using joinpoint regression. The highest annual incidence of UC was 24.3 per 100,000 person-years in Europe, 6.3 per 100,000 person-years in Asia and the Middle East, and 19.2 per 100,000 person-years in North America. The highest annual incidence of CD was 12.7 per 100,000 person-years in Europe, 5.0 person-years in Asia and the Middle East, and 20.2 per 100,000 person-years in North America. The highest reported prevalence values for IBD were in Europe (UC, 505 per 100,000 persons; CD, 322 per 100,000 persons) and North America (UC, 249 per 100,000 persons; CD, 319 per 100,000 persons). In time-trend analyses, 75% of CD studies and 60% of UC studies had an increasing incidence of statistical significance (P < .05). Although there are few epidemiologic data from developing countries, the incidence and prevalence of IBD are increasing with time and in different regions around the world, indicating its emergence as a global disease.


Three common assumptions about inflammation, aging, and health that are probably wrong.
Chronic inflammation contributes to the onset and progression of cardiovascular disease and other degenerative diseases of aging. But does it have to? This article considers the associations among inflammation, aging, and health through the lens of human population biology and suggests that chronic inflammation is not a normal nor inevitable component of aging. It is commonly assumed that conclusions drawn from research in affluent, industrialized countries can be applied globally; that aging processes leading to morbidity and mortality begin in middle age; and that inflammation is pathological. These foundational assumptions have shifted focus away from inflammation as a beneficial response to infection or injury and toward an understanding of inflammation as chronic, dysregulated, and dangerous. Findings from community-based studies around the world-many conducted in areas with relatively high burdens of infectious disease-challenge these assumptions by documenting substantial variation in levels of inflammation and patterns of association with disease. They also indicate that nutritional, microbial, and psychosocial environments in infancy and childhood play important roles in shaping inflammatory phenotypes and their contributions to diseases of aging. A comparative, developmental, and ecological approach has the potential to generate novel insights into the regulation of inflammation and how it relates to human health over the life course.


The World Health Organization--International Society of Hypertension Blood Pressure Lowering Treatment Trialists' Collaboration: prospective collaborative overviews of major randomized trials of blood pressure-lowering treatments.
Clear evidence shows that decreasing blood pressure reduces risks for major cardiovascular events in patients with hypertension. However, there is considerable uncertainty about the separate effects of the various classes of blood pressure-lowering agents and the effects of blood pressure lowering in patients at high risk, particularly in the absence of hypertension. Several new randomized controlled trials have been started in the past few years in an effort to address these questions. However, individually, these studies are unlikely to resolve all current uncertainties. For this reason, systematic overviews and meta-analyses of the major ongoing trials are planned. The overviews will be conducted as a collaboration among the principal investigators of the participating trials and will involve about 270,000 patients and 1.1 million patient-years of follow-up. The combined trial results should provide good statistical power to detect even modest differences in the effects of various treatments on major cardiovascular outcomes.


Activation of old carbon by erosion of coastal and subsea permafrost in Arctic Siberia.
The future trajectory of greenhouse gas concentrations depends on interactions between climate and the biogeosphere. Thawing of Arctic permafrost could release significant amounts of carbon into the atmosphere in this century. Ancient Ice Complex deposits outcropping along the ~7,000-kilometre-long coastline of the East Siberian Arctic Shelf (ESAS), and associated shallow subsea permafrost, are two large pools of permafrost carbon, yet their vulnerabilities towards thawing and decomposition are largely unknown. Recent Arctic warming is stronger than has been predicted by several degrees, and is particularly pronounced over the coastal ESAS region. There is thus a pressing need to improve our understanding of the links between permafrost carbon and climate in this relatively inaccessible region. Here we show that extensive release of carbon from these Ice Complex deposits dominates (57 ± 2 per cent) the sedimentary carbon budget of the ESAS, the world's largest continental shelf, overwhelming the marine and topsoil terrestrial components. Inverse modelling of the dual-carbon isotope composition of organic carbon accumulating in ESAS surface sediments, using Monte Carlo simulations to account for uncertainties, suggests that 44 ± 10 teragrams of old carbon is activated annually from Ice Complex permafrost, an order of magnitude more than has been suggested by previous studies. We estimate that about two-thirds (66 ± 16 per cent) of this old carbon escapes to the atmosphere as carbon dioxide, with the remainder being re-buried in shelf sediments. Thermal collapse and erosion of these carbon-rich Pleistocene coastline and seafloor deposits may accelerate with Arctic amplification of climate warming.


Road to disorder in smectic elastomers.
We present a high-resolution x-ray study of the effects of disorder induced by random cross-linking side-chain smectic elastomers. The influence of variation of the concentration and stiffness of the cross-link units on the disruption of the one-dimensional translational order is reported in detail. Precise analysis of the line shape of the quasi-Bragg peaks associated with the smectic layering indicates a transition from algebraic decaying ordering to disorder. The smectic line shapes can be described by the Caillé correlation function convoluted with a finite-size factor represented by a stretched Gaussian (compressed exponential). The transition to disorder is signaled by a change in the exponent of the stretched Gaussian from 1 (simple Gaussian describing finite-size domains) via 0.5 (Lorentzian describing exponentially decaying short-range correlations) to <0.5 (stretched exponential correlations). For a flexible cross linker the changeover occurs for concentration between 0.15 and 0.20, for a stiff cross linker below about 0.10. Broadening of the higher harmonics of the x-ray peak indicates strong nonuniform strain within finite-size domains and local deformations induced by randomly distributed dislocations.


Time-space clustering of date at birth in childhood-onset diabetes.
To investigate whether there was a temporal and geographical clustering of time of birth for infants with childhood-onset diabetes. The nationwide Swedish Childhood Diabetes Registry, which ascertains 99% of children with recent-onset diabetes (0-14 years), was linked with the Swedish Medical Birth Registry. Clustering of 3,725 patients as to place and time of birth was studied compared with the general population. For each municipality (and in the three large cities of Sweden for each parish), the observed number of patients was compared with the expected number calculated from the average total rate and the number of births in that municipality. Clustering in time of birth within municipality was analyzed using a modification of a set technique by Chen (14). There was no consistent variability in diabetes risk by calendar birth month, but for specific years, the risk varied during the year. When geographic localization for place of birth was studied on a municipality level, four municipalities showed a statistically significant case excess while one would have been expected by chance. When we looked for clusters in both time and space for date of birth, clearly more clusters than expected were identified (P < 0.01). Of the total of 198 primary clusters, 42 included three or more patients being born in the same municipality within an unlikely short period always < 2 years. This is the first study indicating a clustering according to place and time of birth for later risk to develop type I diabetes. Such a phenomenon would agree with the hypothesis that infections in early life, including fetal infections, can increase the risk for diabetes.


Neural stem cells as engraftable packaging lines can mediate gene delivery to microglia: evidence from studying retroviral env-related neurodegeneration.
The induction of spongiform myeloencephalopathy by murine leukemia viruses is mediated primarily by infection of central nervous system (CNS) microglia. In this regard, we have previously shown that CasBrE-induced disease requires late, rather than early, virus replication events in microglial cells (W. P. Lynch et al., J. Virol. 70:8896-8907, 1996). Furthermore, neurodegeneration requires the presence of unique sequences within the viral env gene. Thus, the neurodegeneration-inducing events could result from microglial expression of retroviral envelope protein alone or from the interaction of envelope protein with other viral structural proteins in the virus assembly and maturation process. To distinguish between these possible mechanisms of disease induction, we engineered the engraftable neural stem cell line C17-2 into packaging/producer cells in order to deliver the neurovirulent CasBrE env gene to endogenous CNS cells. This strategy resulted in significant CasBrE env expression within CNS microglia without the appearance of replication competent virus. CasBrE envelope expression within microglia was accompanied by increased expression of activation markers F4/80 and Mac-1 (CD11b) but failed to induce spongiform neurodegenerative changes. These results suggest that envelope expression alone within microglia is not sufficient to induce neurodegeneration. Rather, microglia-mediated disease appears to require neurovirulent Env protein interaction with other viral proteins during assembly or maturation. More broadly, the results presented here prove the efficacy of a novel method by which neural stem cell biology may be harnessed for genetically manipulating the CNS, not only for studying neurodegeneration but also as a paradigm for the disseminated distribution of retroviral vector-transduced genes.


Dying under pressure: cellular characterisation and in vivo functions of cell death induced by compaction.
Cells and tissues are exposed to multiple mechanical stresses during development, tissue homoeostasis and diseases. While we start to have an extensive understanding of the influence of mechanics on cell differentiation and proliferation, how excessive mechanical stresses can also lead to cell death and may be associated with pathologies has been much less explored so far. Recently, the development of new perturbative approaches allowing modulation of pressure and deformation of tissues has demonstrated that compaction (the reduction of tissue size or volume) can lead to cell elimination. Here, we discuss the relevant type of stress and the parameters that could be causal to cell death from single cell to multicellular systems. We then compare the pathways and mechanisms that have been proposed to influence cell survival upon compaction. We eventually describe the relevance of compaction-induced death in vivo, and its functions in morphogenesis, tissue size regulation, tissue homoeostasis and cancer progression.


Diabetes induces compositional, structural and functional alterations on rat skeletal soleus muscle revealed by FTIR spectroscopy: a comparative study with EDL muscle.
Diabetes Mellitus (DM) is a metabolic disorder, characterized by abnormally high blood glucose levels due to decreased secretion or effectiveness in function of insulin. Having a role in carbohydrate and lipid metabolism, skeletal muscle is affected by the absence of insulin in diabetic conditions. This current study reports the application of Fourier transform infrared (FTIR) spectroscopy in the determination of macromolecular alterations in streptozotocin (STZ)-induced diabetic rat skeletal Soleus (SOL) muscles, which highlight the promise of this technique in medical research. The results revealed that DM induced several alterations in macromolecular content and structure of slow-contracting SOL muscles. In diabetic SOL muscles, a decrease in the content of lipids, proteins and nucleic acids together with an increase in lipid order was observed. The decrease in the level of unsaturation and acyl chain length of lipids demonstrated the increased lipid peroxidation in DM. There were alterations in protein secondary structure in DM with a decrease in α-helix and β-sheet content of proteins, whereas the content of aggregated β-strands increased, which is generally seen when proteins denature. Besides, the integrity of collagen molecules was found to be decreased, demonstrating the alterations in its triple helical structure in diabetic muscles. Furthermore, the same alterations mentioned above were also observed in diabetic fast-contracting Extensor Digitorum Longus (EDL) muscles. However, having a high content of mitochondria and relying on an oxidative pathway, SOL muscle was found to be more affected by DM.


Ecological interactions drive evolutionary loss of traits.
Loss of traits can dramatically alter the fate of species. Evidence is rapidly accumulating that the prevalence of trait loss is grossly underestimated. New findings demonstrate that traits can be lost without affecting the external phenotype, provided the lost function is compensated for by species interactions. This is important because trait loss can tighten the ecological relationship between partners, affecting the maintenance of species interactions. Here, we develop a new perspective on so-called `compensated trait loss' and how this type of trait loss may affect the evolutionary dynamics between interacting organisms. We argue that: (1) the frequency of compensated trait loss is currently underestimated because it can go unnoticed as long as ecological interactions are maintained; (2) by analysing known cases of trait loss, specific factors promoting compensated trait loss can be identified and (3) genomic sequencing is a key way forwards in detecting compensated trait loss. We present a comprehensive literature survey showing that compensated trait loss is taxonomically widespread, can involve essential traits, and often occurs as replicated evolutionary events. Despite its hidden nature, compensated trait loss is important in directing evolutionary dynamics of ecological relationships and has the potential to change facultative ecological interactions into obligatory ones.


Simultaneous EEG-fMRI reveals a temporal cascade of task-related and default-mode activations during a simple target detection task.
Focused attention continuously and inevitably fluctuates, and to completely understand the mechanisms responsible for these modulations it is necessary to localize the brain regions involved. During a simple visual oddball task, neural responses measured by electroencephalography (EEG) modulate primarily with attention, but source localization of the correlates is a challenge. In this study we use single-trial analysis of simultaneously-acquired scalp EEG and functional magnetic resonance image (fMRI) data to investigate the blood oxygen level dependent (BOLD) correlates of modulations in task-related attention, and we unravel the temporal cascade of these transient activations. We hypothesize that activity in brain regions associated with various task-related cognitive processes modulates with attention, and that their involvements occur transiently in a specific order. We analyze the fMRI BOLD signal by first regressing out the variance linked to observed stimulus and behavioral events. We then correlate the residual variance with the trial-to-trial variation of EEG discriminating components for identical stimuli, estimated at a sequence of times during a trial. Post-stimulus and early in the trial, we find activations in right-lateralized frontal regions and lateral occipital cortex, areas that are often linked to task-dependent processes, such as attentional orienting, and decision certainty. After the behavioral response we see correlates in areas often associated with the default-mode network and introspective processing, including precuneus, angular gyri, and posterior cingulate cortex. Our results demonstrate that during simple tasks both task-dependent and default-mode networks are transiently engaged, with a distinct temporal ordering and millisecond timescale.


[Effect of pravastatin on hepatic cholesterol metabolism].
Inhibitors of the rate-limiting enzyme of cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, are now used frequently to treat hypercholesterolemia. We studied the effects of specific inhibition of cholesterol synthesis by one of these agents (pravastatin) on the hepatic metabolism of cholesterol in patients with gallstone disease who were scheduled to undergo cholecystectomy. Ten patients were treated with pravastatin (20 mg twice a day) for three weeks before cholecystectomy; 20 patients not treated served as controls. A liver specimen was obtained from each patient at operation, and the activities of rate-determining enzymes in cholesterol metabolism as well as low-density-lipoprotein (LDL)-receptor binding activity were determined. Pravastatin therapy reduced plasma total cholesterol by 26 percent and LDL cholesterol by 39 percent (p less than 0.005). Serum levels of free lathosterol, a precursor of cholesterol whose concentration reflects the rate of cholesterol synthesis in vivo, decreased by 63 percent (p less than 0.005), indicating reduced de novo biosynthesis of cholesterol. Microsomal HMG-CoA reductase activity, when analyzed in vitro in the absence of the inhibitor, was increased 11.8-fold (1344 +/- 311 vs. 105 +/- 14 pmol per minute per milligram of protein in the controls; p less than 0.001). The expression of LDL receptors was increased by 180 percent (p less than 0.005), whereas the activities of cholesterol 7 alpha-hydroxylase (which governs bile acid synthesis) and of acyl-coenzyme A: cholesterol O-acyltransferase (which regulates cholesterol esterification) were unaffected by treatment. Inhibition of hepatic HMG-CoA reductase by pravastatin results in an increased expression of hepatic LDL receptors, which explains the lowered plasma levels of LDL cholesterol.