OBJECTIVE

In the segmentation of sequential treatment-time CT prostate images acquired in image-guided radiotherapy, accurately capturing the intrapatient variation of the patient under therapy is more important than capturing interpatient variation. However, using the traditional deformable-model-based segmentation methods, it is difficult to capture intrapatient variation when the number of samples from the same patient is limited. This article presents a new deformable model, designed specifically for segmenting sequential CT images of the prostate, which leverages both population and patient-specific statistics to accurately capture the intrapatient variation of the patient under therapy.

METHODS

The novelty of the proposed method is twofold: First, a weighted combination of gradient and probability distribution function (PDF) features is used to build the appearance model to guide model deformation. The strengths of each feature type are emphasized by dynamically adjusting the weight between the profile-based gradient features and the local-region-based PDF features during the optimization process. An additional novel aspect of the gradient-based features is that, to alleviate the effect of feature inconsistency in the regions of gas and bone adjacent to the prostate, the optimal profile length at each landmark is calculated by statistically investigating the intensity profile in the training set. The resulting gradient-PDF combined feature produces more accurate and robust segmentations than general gradient features. Second, an online learning mechanism is used to build shape and appearance statistics for accurately capturing intrapatient variation.

RESULTS

The performance of the proposed method was evaluated on 306 images of the 24 patients. Compared to traditional gradient features, the proposed gradient-PDF combination features brought 5.2% increment in the success ratio of segmentation (from 94.1% to 99.3%). To evaluate the effectiveness of online learning mechanism, the authors carried out a comparison between partial online update strategy and full online update strategy. Using the full online update strategy, the mean DSC was improved from 86.6% to 89.3% with 2.8% gain. On the basis of full online update strategy, the manual modification before online update strategy was introduced and tested, the best performance was obtained; here, the mean DSC and the mean ASD achieved 92.4% and 1.47 mm, respectively.

CONCLUSIONS

The proposed prostate segmentation method provided accurate and robust segmentation results for CT images even under the situation where the samples of patient under radiotherapy were limited. A conclusion that the proposed method is suitable for clinical application can be drawn.

Q-space analysis is an alternative analysis technique for diffusion-weighted imaging (DWI) data in which the probability density function (PDF) for molecular diffusion is estimated without the need to assume a Gaussian shape. Although used in the human brain, q-space DWI has not yet been applied to study the human spinal cord in vivo. Here we demonstrate the feasibility of performing q-space imaging in the cervical spinal cord of eight healthy volunteers and four patients with multiple sclerosis. The PDF was computed and water displacement and zero-displacement probability maps were calculated from the width and height of the PDF, respectively. In the dorsal column white matter, q-space contrasts showed a significant (P < 0.01) increase in the width and a decrease in the height of the PDF in lesions, the result of increased diffusion. These q-space contrasts, which are sensitive to the slow diffusion component, exhibited improved detection of abnormal diffusion compared to perpendicular apparent diffusion constant measurements. The conspicuity of lesions compared favorably with magnetization transfer (MT)-weighted images and quantitative CSF-normalized MT measurements. Thus, q-space DWI can be used to study water diffusion in the human spinal cord in vivo and is well suited to assess white matter damage.

Chromatin immunoprecipitation with high-throughput sequencing (ChIP-seq) can identify genomic regions that bind proteins involved in various chromosomal functions. Although the development of next-generation sequencers offers the technology needed to identify these protein-binding sites, the analysis can be computationally challenging because sequencing data sometimes consist of >100 million reads/sample. Herein, we describe a cost-effective and time-efficient protocol that is generally applicable to ChIP-seq analysis; this protocol uses a novel peak-calling program termed DROMPA to identify peaks and an additional program, parse2wig, to preprocess read-map files. This two-step procedure drastically reduces computational time and memory requirements compared with other programs. DROMPA enables the identification of protein localization sites in repetitive sequences and efficiently identifies both broad and sharp protein localization peaks. Specifically, DROMPA outputs a protein-binding profile map in pdf or png format, which can be easily manipulated by users who have a limited background in bioinformatics.

BACKGROUND

In 5 consecutive pediatric and adolescent Hodgkin's disease trials DAL-HD since 1978 the invasive diagnostic procedures and the radiotherapy have gradually been reduced and chemotherapy modified to minimize toxicity and the risk of late effects. Since 1982 the overall survival increased up to 95%. In this trial the possibility of reducing local radiation doses to 20 Gy in patients with good response to chemotherapy and omitting radiotherapy totally for patients with complete remission after chemotherapy was tested.

METHODS

Over a period of 6 years, from August 1995 to July 2001, 1018 children and adolescents with Hodgkin's disease from Germany, Austria,Switzerland, the Netherlands, Sweden, Norway and Denmark were enrolled in this trial. The chemotherapy was equivalent to previous trial DAL-HD 90. The treatment group (TG) 1 (stages I and IIA) received 2 cycles OPPA for girls and 2 cycles OEPA for boys, TG2 (stages IIEA, IIB, IIIA) and TG3 (stages IIEB, IIIEA, IIIB, IV) received additional 2 or 4 cycles COPP respectively. In contrast to trial DAL-HD 90 boys in stage IIIB and IIIEB received OPPA instead of OEPA. The initial staging as well as the restaging for evaluating tumor volume reduction after chemotherapy was reviewed by the study center. Radiotherapy was planned accordingly: patients with complete remission after chemotherapy were not irradiated (21.9%); all other patients received local radiotherapy to the initially involved sites, depending on the tu-mor response. Patients with a partial remission of> 75 tumor regression were irradiated with 20 Gy (50AX), partial remission of< 75% with 30 Gy (4.1 %), and residual masses of>> 50 ml were boosted up to 35 Gy (20.2 %).

RESULTS

36 tumor progressions and 49 relapses occurred over a period of 7 1/2 years (median followup 3 years, data deadline 12/19/02). Kaplan-Meier-analysis after 5 years showed a probability for event-free survival (pEFS) for all patients of 0.88 and for overall survival (pOS) of 0.97. For the total group the pDFS (disease free survival) was lower in 222 non irradiated patients than in the 758 irradiated patients (0.88 vs. 0.92,p - 0.049). But there was a difference between the individual treatment groups. In TG 1 there was no difference between nonirradiated and irradiated patients (0.97 vs. 0.94) and the non-ir-radiated patients showed a better trend. In TG 2, and in TG 2 and TG 3 combined, the pDFS was significantly worse for non irradiated patients in comparison with the irradiated patients (TG2:0.78 vs. 0.92; TG 2 +3:0.79 vs. 0.91). Compared to former DAL-HD trials the pOS stayed stable despite therapy reduction.

CONCLUSIONS

A reduction of radiotherapy to 20 Gy for patients in all stages with good response to chemotherapy is possible without deterioration of the results. The omission of radiotherapy for patients in complete remission after chemotherapy is recommended only for patients in early stages (TG1). In future trials the possibility of a wider selection for chemotherapy alone for this group needs to be evaluated. In intermediate (TG2) and advanced (TG3) stages omission of radiotherapy for patients incomplete remission results in a lower pEFS, but the pOS is not significantly reduced. Only with knowledge of the long term effects of today's therapy we can give a satisfactory answer to the question whether in future trials the primary aim should be pEFS as high as possible due to front-line-therapy or reduction of late effects.

Pharmacokinetic drug interactions can lead to serious adverse events or decreased drug efficacy. The evaluation of a new molecular entity's (NME's) drug-drug interaction potential is an integral part of risk assessment during drug development and regulatory review. Alteration of activities of enzymes or transporters involved in the absorption, distribution, metabolism, or excretion of a new molecular entity by concomitant drugs may alter drug exposure, which can impact response (safety or efficacy). The recent Food and Drug Administration (FDA) draft drug interaction guidance (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072101.pdf) highlights the methodologies and criteria that may be used to guide drug interaction evaluation by industry and regulatory agencies and to construct informative labeling for health practitioner and patients. In addition, the Food and Drug Administration established a "Drug Development and Drug Interactions" website to provide up-to-date information regarding evaluation of drug interactions (http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm080499.htm). This review summarizes key elements in the FDA drug interaction guidance and new scientific developments that can guide the evaluation of drug-drug interactions during the drug development process.

Neuropeptide PDF (pigment-dispersing factor)-secreting large ventrolateral neurons (lLN(v)s) in the Drosophila brain regulate daily patterns of rest and arousal. These bilateral wake-promoting neurons are light responsive and integrate information from the circadian system, sleep circuits, and light environment. To begin to dissect the synaptic circuitry of the circadian neural network, we performed simultaneous dual whole-cell patch-clamp recordings of pairs of lLN(v)s. Both ipsilateral and contralateral pairs of lLN(v)s exhibit synchronous rhythmic membrane activity with a periodicity of ∼ 5-10 s. This rhythmic lLN(v) activity is blocked by TTX, voltage-gated sodium blocker, or α-bungarotoxin, nicotinic acetylcholine receptor antagonist, indicating that action potential-dependent cholinergic synaptic connections are required for rhythmic lLN(v) activity. Since injecting current into one neuron of the pair had no effect on the membrane activity of the other neuron of the pair, this suggests that the synchrony is attributable to bilateral inputs and not coupling between the pairs of lLN(v)s. To further elucidate the nature of these synaptic inputs to lLN(v)s, we blocked or activated a variety of neurotransmitter receptors and measured effects on network activity and ionic conductances. These measurements indicate the lLN(v)s possess excitatory nicotinic ACh receptors, inhibitory ionotropic GABA(A) receptors, and inhibitory ionotropic GluCl (glutamate-gated chloride) receptors. We demonstrate that cholinergic input, but not GABAergic input, is required for synchronous membrane activity, whereas GABA can modulate firing patterns. We conclude that neuropeptidergic lLN(v)s that control rest and arousal receive synchronous synaptic inputs mediated by ACh.

Accurate modeling of the respiratory cycle is important to account for the effect of organ motion on dose calculation for lung cancer patients. The aim of this study is to evaluate the accuracy of a respiratory model for lung cancer patients. Lujan et al. [Med. Phys. 26(5), 715-720 (1999)] proposed a model, which became widely used, to describe organ motion due to respiration. This model assumes that the parameters do not vary between and within breathing cycles. In this study, first, the correlation of respiratory motion traces with the model f(t) as a function of the parameter n (n = 1, 2, 3) was undertaken for each breathing cycle from 331 four-minute respiratory traces acquired from 24 lung cancer patients using three breathing types: free breathing, audio instruction, and audio-visual biofeedback. Because cos2 and cos4 had similar correlation coefficients, and cos2 and cos1 have a trigonometric relationship, for simplicity, the cos1 value was consequently used for further analysis in which the variations in mean position (z0), amplitude of motion (b) and period (tau) with and without biofeedback or instructions were investigated. For all breathing types, the parameter values, mean position (z0), amplitude of motion (b), and period (tau) exhibited significant cycle-to-cycle variations. Audio-visual biofeedback showed the least variations for all three parameters (z0, b, and tau). It was found that mean position (z0) could be approximated with a normal distribution, and the amplitude of motion (b) and period (tau) could be approximated with log normal distributions. The overall probability density function (pdf) of f(t) for each of the three breathing types was fitted with three models: normal, bimodal, and the pdf of a simple harmonic oscillator. It was found that the normal and the bimodal models represented the overall respiratory motion pdfs with correlation values from 0.95 to 0.99, whereas the range of the simple harmonic oscillator pdf correlation values was 0.71 to 0.81. This study demonstrates that the pdfs of mean position (z0), amplitude of motion (b), and period (tau) can be used for sampling to obtain more realistic respiratory traces. The overall standard deviations of respiratory motion were 0.48, 0.57, and 0.55 cm for free breathing, audio instruction, and audio-visual biofeedback, respectively.

Histone proteins are often noted for their high degree of sequence conservation. It is less often recognized that the histones are a heterogeneous protein family. Furthermore, several classes of non-histone proteins containing the histone fold motif exist. Novel histone and histone fold protein sequences continue to be added to public databases every year. The Histone Database (http://genome.nhgri.nih.gov/histones/) is a searchable, periodically updated collection of histone fold-containing sequences derived from sequence-similarity searches of public databases. Sequence sets are presented in redundant and non-redundant FASTA form, hotlinked to GenBank sequence files. Partial sequences are also now included in the database, which has considerably augmented its taxonomic coverage. Annotated alignments of full-length non-redundant sets of sequences are now available in both web-viewable (HTML) and downloadable (PDF) formats. The database also provides summaries of current information on solved histone fold structures, post-translational modifications of histones, and the human histone gene complement.

BACKGROUND

As the clinical significance of chronic bronchitis among smokers without airflow obstruction is unclear, we sought to determine morbidity associated with this disorder.

METHODS

We examined subjects from the COPDGene study and compared those with FEV1/FVC ≥ 0.70, no diagnosis of asthma and chronic bronchitis as defined as a history of cough and phlegm production for ≥ 3 months/year for ≥ 2 years (NCB) to non-obstructed subjects without chronic bronchitis (CB-). Multivariate analysis was used to determine factors associated with and impact of NCB.

RESULTS

We identified 597 NCB and 4283 CB- subjects. NCB participants were younger (55.4 vs. 57.2 years, p < 0.001) with greater tobacco exposure (42.9 vs. 37.8 pack-years, p < 0.001) and more often current smokers; more frequently reported occupational exposure to fumes (52.8% vs. 42.2%, p < 0.001), dust for ≥ 1 year (55.3% vs. 42.0%, p < 0.001) and were less likely to be currently working. NCB subjects demonstrated worse quality-of-life (SGRQ 35.6 vs. 15.1, p < 0.001) and exercise capacity (walk distance 415 vs. 449 m, p < 0.001) and more frequently reported respiratory "flare-ups" requiring treatment with antibiotics or steroids (0.30 vs. 0.10 annual events/subject, p < 0.001) prior to enrollment and during follow-up (0.34 vs. 0.16 annual events/subject, p < 0.001). In multivariate analysis, current smoking, GERD, sleep apnea and occupational exposures were significantly associated with NCB.

CONCLUSIONS

While longitudinal data will be needed to determine whether NCB progresses to COPD, NCB patients have poorer quality-of-life, exercise capacity and frequent respiratory events. Beyond smoking cessation interventions, further research is warranted to determine the benefit of other therapeutics in this population. Clinical Trials Registration # NCT00608764 (http://clinicaltrials.gov/show/NCT00608764). Link to study protocol: http://www.copdgene.org/sites/default/files/COPDGeneProtocol-5-0_06-19-2009.pdf.

Gross dissection has a long history as a tool for the study of human or animal soft- and hard-tissue anatomy. However, apart from being a time-consuming and invasive method, dissection is often unsuitable for very small specimens and often cannot capture spatial relationships of the individual soft-tissue structures. The handful of comprehensive studies on avian anatomy using traditional dissection techniques focus nearly exclusively on domestic birds, whereas raptorial birds, and in particular their cranial soft tissues, are essentially absent from the literature. Here, we digitally dissect, identify, and document the soft-tissue anatomy of the Common Buzzard (Buteo buteo) in detail, using the new approach of contrast-enhanced computed tomography using Lugol's iodine. The architecture of different muscle systems (adductor, depressor, ocular, hyoid, neck musculature), neurovascular, and other soft-tissue structures is three-dimensionally visualised and described in unprecedented detail. The three-dimensional model is further presented as an interactive PDF to facilitate the dissemination and accessibility of anatomical data. Due to the digital nature of the data derived from the computed tomography scanning and segmentation processes, these methods hold the potential for further computational analyses beyond descriptive and illustrative proposes.

BACKGROUND

Long-term peritoneal dialysis (PD) is associated with the development of various structural and functional changes to the peritoneal membrane when bioincompatible conventional peritoneal dialysis fluids (PDFs) are used. In this study, we looked at patients that were treated with conventional PDFs and then changed to novel biocompatible PDFs with a neutral pH and a low concentration of glucose degradation products (GDPs) to investigate whether this change could result in the arrest or reversal of peritoneal membrane deterioration.

METHODS

In an open label, randomized prospective trial, the clinical effects of conventional PDFs and biocompatible PDFs with neutral pH and very low concentration of GDPs were compared in 104 patients equally divided between both study PDFs. Blood and effluent dialysate samples, peritoneal equilibration tests, and adequacy evaluation were undertaken at baseline, 4, 8, and 12 months. The target variables were the ratio of dialysate-to-plasma (D/P) creatinine, peritoneal ultrafiltration, residual renal function, dialysis adequacy indices, and effluent cancer antigen 125 (CA125).

RESULTS

D/P creatinine values were not different in the two groups. Peritoneal ultrafiltration was significantly higher in the low-GDP PDF group than in the conventional PDF group at all follow-up times (4 months: 9.1 +/- 4.3 vs 6.0 +/- 3.0; 8 months: 8.3 +/- 3.4 vs 6.0 +/- 3.0; 12 months: 8.9 +/- 3.3 vs 6.1 +/- 3.3 mL/g dextrose/day; p < 0.05). Peritoneal Kt/V urea values and total weekly Kt/V urea values at 4 months were significantly higher in the low-GDP PDF group than in the conventional PDF group. Residual renal function was not statistically significant. Effluent CA125 levels were significantly higher in the low-GDP PDF group at all follow-up visits (4 months: 37.8 +/- 20.8 vs 22.0 +/- 9.5; 8 months: 41.2 +/- 20.3 vs 25.9 +/- 11.3; 12 months: 40.4 +/- 21.4 vs 28.6 +/- 13.0 U/mL; p < 0.05). Among anuric patients, peritoneal ultrafiltration at 4, 8, and 12 months, total weekly Kt/V at 4 and 8 months, and CA125 levels at all follow-up visits were significantly higher in patients treated with low-GDP PDF than those treated with conventional PDF. However, among anuric patients, D/P creatinine showed no significant differences between the low-GDP PDF group and the conventional PDF group.

CONCLUSIONS

The use of biocompatible PDFs with neutral pH and low GDP concentration can contribute to improvement of peritoneal ultrafiltration and peritoneal effluent CA125 level, an indicator of peritoneal membrane integrity in PD patients.

BACKGROUND

Proteins with obscure features (POFs), which lack currently defined motifs or domains, represent between 18% and 38% of a typical eukaryotic proteome. To evaluate the contribution of this class of proteins to the diversity of eukaryotes, we performed a comparative analysis of the predicted proteomes derived from 10 different sequenced genomes, including budding and fission yeast, worm, fly, mosquito, Arabidopsis, rice, mouse, rat, and human.

RESULTS

Only 1,650 protein groups were found to be conserved among these proteomes (BLAST E-value threshold of 10(-6)). Of these, only three were designated as POFs. Surprisingly, we found that, on average, 60% of the POFs identified in these 10 proteomes (44,236 in total) were species specific. In contrast, only 7.5% of the proteins with defined features (PDFs) were species specific (17,554 in total). As a group, POFs appear similar to PDFs in their relative contribution to biological functions, as indicated by their expression, participation in protein-protein interactions and association with mutant phenotypes. However, POF have more predicted disordered structure than PDFs, implying that they may exhibit preferential involvement in species-specific regulatory and signaling networks.

CONCLUSIONS

Because the majority of eukaryotic POFs are not well conserved, and by definition do not have defined domains or motifs upon which to formulate a functional working hypothesis, understanding their biochemical and biological functions will require species-specific investigations.

OBJECTIVE

The aims of this study were (1) to establish a prospective community-based stroke registry in Mumbai of subjects having 'first-ever stroke' (FES) and (2) to collect standardized data on annual incidence, stroke subtypes, and case fatality rate at 28 days during the years 2005 and 2006.

BACKGROUND

An estimated 5.8 million people died from stroke (cerebrovascular disease) in 2005, two thirds of them were from low-/middle-income countries but reliable population-based studies are scarce.

METHODS

The manual on WHO STEPwise approach to stroke surveillance (STEPS Stroke; http://www.who.int/chp/steps/Manual pdf) was the operational protocol. We selected a well-defined community (H-district) having verifiable census data and being representative of the population structure of Mumbai (Bombay). Of 337,391 permanent residents, 156,861 persons between the age of 25 and 94+ years who were eligible for survey were screened. The responses to a predefined questionnaire (version 2.0) were entered in coded data sheets for analysis.

RESULTS

During the 2-year study period (January 2005 to December 2006), 456 (238 males and 218 females) had FES, indicating an annual incidence in subjects of 25 years and above of 145/100,000 persons (CI 95%: 120-170); for males it is 149/100,000 persons (CI 95%: 120-170) and for females it is 141/100,000 persons (CI 95%: 120-160). The age-standardized rate for study population (both sexes) by the direct method using Segi's 1996 world population is 152/100,000/year (CI 95%: 132-172). Stroke diagnosis was supported by computed tomography in 407 (89.2%) of 456 FES cases: 366 (80.2%) had ischemic stroke, 81 (17.7%) had hemorrhagic stroke and 9 (1.9%) were in the unspecified category. The mean age was 66 +/- (SD) 13.60 years, women were older as compared to men (mean age 68.9 +/- 13.12 years vs. 63.4 +/- 13.53 years). Case fatality: at 28 days, 320 (70%) of 456 FES cases were still alive and 136 (29.8%) had died. Of the 320 surviving patients 38.5% had moderate to severe disability by the modified Rankin scale.

CONCLUSIONS

The results of Mumbai stroke study, using uniform definitions and methodologies, show that the annual standardized incidence rates, stroke subtypes and case fatality rate are very similar to those reported from developed nations. To plan effective intervention and prevention strategies, standardized data in representative samples of regional populations are urgently needed.

Peritoneal dialysis is limited by morphologic changes of the peritoneal membrane. Use of peritoneal dialysis fluids (PDF) that contain glucose degradation products (GDP) generates advanced glycation end-products (AGE) within the peritoneal cavity. It is unknown whether peritoneal damage is causally related to AGE-receptor for AGE (RAGE) interaction. The effects of PDF were compared with different amounts of GDP on morphologic changes of the peritoneal membrane in 48 wild-type (WT) and 48 RAGE-deficient mice. PDF (1 ml) were instilled twice daily over a period of 12 wk. Groups with eight animals each received no manipulation (sham); sham instillation (sham i.p.); or filter-sterilized, glucose-free, conventional low GDP- or high GDP PDF. In vitro (generation of AGE fluorescence in PDF) and in vivo (immunohistochemistry for carboxymethyllysine), a GDP-dependent increase of AGE formation occurred. Inflammation and neoangiogenesis were augmented in WT mice that were treated with high GDP accompanied by upregulation of CD3+ T cells, increased NF-kappaB binding activity, increased lectin, and vascular endothelial growth factor expression. Furthermore, pronounced submesothelial fibrosis was found with increased expression of TGF-beta1. Exposure to low GDP resulted in only mild inflammation and neoangiogenesis (compared with sham i.p.) and no fibrosis in WT mice. The findings in WT contrasted with those in RAGE-deficient mice, which showed no increased inflammation (CD3+ T cells and NF-kappaB binding activity), neoangiogenesis (by lectin and vascular endothelial growth factor expression), or fibrosis (expression of TGF-beta1) after long-term exposure to GDP-containing PDF. Peritoneal damage by GDP in PDF is dependent at least in part on AGE-RAGE interaction.

Appropriate preferences for light or dark conditions can be crucial for an animal's survival. Innate light preferences are not static in some animals, including the fruit fly Drosophila melanogaster, which prefers darkness in the feeding larval stage but prefers light in adulthood. To elucidate the neural circuit underlying light preference, we examined the neurons involved in larval phototactic behavior by regulating neuronal functions. Modulating activity of two pairs of isomorphic neurons in the central brain switched the larval light preference between photophobic and photophilic. These neurons were found to be immediately downstream of pdf-expressing lateral neurons, which are innervated by larval photoreceptors. Our results revealed a neural mechanism that could enable the adjustment of animals' response strategies to environmental stimuli according to biological needs.

We introduce two independent component analysis (ICA) methods, spatiotemporal ICA (stICA) and skew-ICA, and demonstrate the utility of these methods in analyzing synthetic and event-related fMRI data. First, stICA simultaneously maximizes statistical independence over both time and space. This contrasts with conventional ICA methods, which maximize independence either over time only or over space only; these methods often yield physically improbable solutions. Second, skew-ICA is based on the assumption that images have skewed probability density functions (pdfs), an assumption consistent with spatially localized regions of activity. In contrast, conventional ICA is based on the physiologically unrealistic assumption that images have symmetric pdfs. We combine stICA and skew-ICA, to form skew-stICA, and use it to analyze synthetic data and data from an event-related, left-right visual hemifield fMRI experiment. Results obtained with skew-stICA are superior to those of principal component analysis, spatial ICA (sICA), temporal ICA, stICA, and skew-sICA. We argue that skew-stICA works because it is based on physically realistic assumptions and that the potential of ICA can only be realized if such prior knowledge is incorporated into ICA methods.

As there has been a paradigm shift in the learning load from a human subject to a computer, machine learning has been considered as a useful tool for Brain-Computer Interfaces (BCIs). In this paper, we propose a novel Bayesian framework for discriminative feature extraction for motor imagery classification in an EEG-based BCI in which the class-discriminative frequency bands and the corresponding spatial filters are optimized by means of the probabilistic and information-theoretic approaches. In our framework, the problem of simultaneous spatiospectral filter optimization is formulated as the estimation of an unknown posterior probability density function (pdf) that represents the probability that a single-trial EEG of predefined mental tasks can be discriminated in a state. In order to estimate the posterior pdf, we propose a particle-based approximation method by extending a factored-sampling technique with a diffusion process. An information-theoretic observation model is also devised to measure discriminative power of features between classes. From the viewpoint of classifier design, the proposed method naturally allows us to construct a spectrally weighted label decision rule by linearly combining the outputs from multiple classifiers. We demonstrate the feasibility and effectiveness of the proposed method by analyzing the results and its success on three public databases.

It has been known for some time that regional blood flows within an organ are not uniform. Useful measures of heterogeneity of regional blood flows are the standard deviation and coefficient of variation or relative dispersion of the probability density function (PDF) of regional flows obtained from the regional concentrations of tracers that are deposited in proportion to blood flow. When a mathematical model is used to analyze dilution curves after tracer solute administration, for many solutes it is important to account for flow heterogeneity and the wide range of transit times through multiple pathways in parallel. Failure to do so leads to bias in the estimates of volumes of distribution and membrane conductances. Since in practice the number of paths used should be relatively small, the analysis is sensitive to the choice of the individual elements used to approximate the distribution of flows or transit times. Presented here is a method for modeling heterogeneous flow through an organ using a scheme that covers both the high flow and long transit time extremes of the flow distribution. With this method, numerical experiments are performed to determine the errors made in estimating parameters when flow heterogeneity is ignored, in both the absence and presence of noise. The magnitude of the errors in the estimates depends upon the system parameters, the amount of flow heterogeneity present, and whether the shape of the input function is known. In some cases, some parameters may be estimated to within 10% when heterogeneity is ignored (homogeneous model), but errors of 15-20% may result, even when the level of heterogeneity is modest. In repeated trials in the presence of 5% noise, the mean of the estimates was always closer to the true value with the heterogeneous model than when heterogeneity was ignored, but the distributions of the estimates from the homogeneous and heterogeneous models overlapped for some parameters when outflow dilution curves were analyzed. The separation between the distributions was further reduced when tissue content curves were analyzed. It is concluded that multipath models accounting for flow heterogeneity are a vehicle for assessing the effects of flow heterogeneity under the conditions applicable to specific laboratory protocols, that efforts should be made to assess the actual level of flow heterogeneity in the organ being studied, and that the errors in parameter estimates are generally smaller when the input function is known rather than estimated by deconvolution.

Colonization of human stomach by the bacterium Helicobacter pylori is a major causative factor for gastrointestinal illnesses and gastric cancer. However, the discovery of anti-H. pylori agents is a difficult task due to lack of mature protein targets. Therefore, identifying new molecular targets for developing new drugs against H. pylori is obviously necessary. In this study, the in-house potential drug target database (PDTD, http://www.dddc.ac.cn/tarfisdock/) was searched by the reverse docking approach using an active natural product (compound 1) discovered by anti-H. pylori screening as a probe. Homology search revealed that, among the 15 candidates discovered by reverse docking, only diaminopimelate decarboxylase (DC) and peptide deformylase (PDF) have homologous proteins in the genome of H. pylori. Enzymatic assay demonstrated compound 1 and its derivative compound 2 are the potent inhibitors against H. pylori PDF (HpPDF) with IC50 values of 10.8 and 1.25 microM, respectively. X-ray crystal structures of HpPDF and the complexes of HpPDF with 1 and 2 were determined for the first time, indicating that these two inhibitors bind well with HpPDF binding pocket. All these results indicate that HpPDF is a potential target for screening new anti-H. pylori agents. In addition, compounds 1 and 2 were predicted to bind to HpPDF with relatively high selectivity, suggesting they can be used as leads for developing new anti-H. pylori agents. The results demonstrated that our strategy, reverse docking in conjunction with bioassay and structural biology, is effective and can be used as a complementary approach of functional genomics and chemical biology in target identification.

The COVID-19 pandemic elicited a global response to limit associated mortality, with social distancing and lockdowns being imposed. In India, human activities were restricted from late March 2020. This 'anthropogenic emissions switch-off' presented an opportunity to investigate impacts of COVID-19 mitigation measures on ambient air quality in five Indian cities (Chennai, Delhi, Hyderabad, Kolkata, and Mumbai), using in-situ measurements from 2015 to 2020. For each year, we isolated, analysed and compared fine particulate matter (PM_2.5) concentration data from 25 March to 11 May, to elucidate the effects of the lockdown. Like other global cities, we observed substantial reductions in PM_2.5 concentrations, from 19 to 43% (Chennai), 41-53% (Delhi), 26-54% (Hyderabad), 24-36% (Kolkata), and 10-39% (Mumbai). Generally, cities with larger traffic volumes showed greater reductions. Aerosol loading decreased by 29% (Chennai), 11% (Delhi), 4% (Kolkata), and 1% (Mumbai) against 2019 data. Health and related economic impact assessments indicated 630 prevented premature deaths during lockdown across all five cities, valued at 0.69 billion USD. Improvements in air quality may be considered a temporary lockdown benefit as revitalising the economy could reverse this trend. Regulatory bodies must closely monitor air quality levels, which currently offer a baseline for future mitigation plans.

Keywords: AOD, aerosol optical depth; AQI, air quality index; Air pollution; CO, carbon monoxide; CO2, carbon dioxide; COVID-19, Coronavirus disease 2019; Coronavirus pandemic; EPA, Environmental Protection Agency; ER, excess risk; ESA, European Space Agency; Emission switch-off; GEV, generalized extreme value; GoI, Government of India; HB, health burden; Health and economic impacts; MODIS, moderate resolution imaging spectroradiometer; MSL, mean sea level; NASA, National Aeronautics and Space Administration; NH3, ammonia; NO2, nitrogen dioxide; O3, ozone; PDF, probability density function; PM, particulate matter; PM10, PM with aerodynamic diameter of ≤ 10 μm; PM2.5 concentration; PM2.5, PM with aerodynamic diameter of ≤ 2.5 μm; RH, relative humidity; RR, relative risk; SARS-CoV-2 Virus; SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus 2; SO2, sulphur dioxide; SSEC, Space Science and Engineering Centre; TROPOMI, TROPOspheric monitoring instrument; UK, United Kingdom; USA, United States of America; USD, United States Dollar; VSL, value of statistical life; WHO, World Health Organization.

By screening etiolated Arabidopsis seedlings for mutants with aberrant ethylene-related phenotypes, we identified a mutant that displays features of the ethylene-mediated triple response even in the absence of ethylene. Further characterization showed that the phenotype observed for the dark-grown seedlings of this mutant is reversible by prevention of ethylene perception and is dependent on a modest increase in ethylene production correlated with an increase in 1-aminocyclopropane-1-carboxylic acid (ACC) oxidase (ACO) activity in the hypocotyl. Molecular characterization of leaves of the mutant revealed severely impaired induction of basic chitinase (chiB) and plant defensin (PDF)1.2 following treatment with jasmonic acid and/or ethylene. Positional cloning of the mutation resulted in identification of a 49-bp deletion in RCE1 (related to ubiquitin 1 (RUB1)-conjugating enzyme), which has been demonstrated to be responsible for covalent attachment of RUB1 to the SCF (Skpl Cdc 53 F-box) ubiquitin ligase complex to modify its activity. Our analyses with rce1-2 demonstrate a previously unknown requirement for RUB1 modification for regulation of ethylene biosynthesis and proper induction of defense-related genes in Arabidopsis.

Protein-protein interaction (PPI) extraction has been an important research topic in bio-text mining area, since the PPI information is critical for understanding biological processes. However, there are very few open systems available on the Web and most of the systems focus on keyword searching based on predefined PPIs. PIE (Protein Interaction information Extraction system) is a configurable Web service to extract PPIs from literature, including user-provided papers as well as PubMed articles. After providing abstracts or papers, the prediction results are displayed in an easily readable form with essential, yet compact features. The PIE interface supports more features such as PDF file extraction, PubMed search tool and network communication, which are useful for biologists and bio-system developers. The PIE system utilizes natural language processing techniques and machine learning methodologies to predict PPI sentences, which results in high precision performance for Web users. PIE is freely available at http://bi.snu.ac.kr/pie/.

Pure cultures of fibroblasts displayed marked differences in their activity in the plasma of young, middle aged, and old chickens. The rate of cell multiplication varied in inverse ratio to the age of the animal from which the plasma was taken. There was a definite relation between the age of the animal and the amount of new tissue produced in its plasma in a given time (Text-figs. 1 to 10). The chart obtained by plotting the rate of cell proliferation in ordinates, and the age of the animal in abscissae, showed that the rate of growth decreased more quickly than the age increased (Text-fig. 12). The decrease in the rate of growth was 50 per cent during the first 3 years of life, while in the following 6 years it was only 30 per cent. When the duration of the life of the cultures in the four plasmas was compared, a curve was obtained which showed about the same characteristics (Text-fig. 11). The duration of life of the fibroblasts in vitro varied in inverse ratio to the age of the animal, and decreased more quickly than the age increased. As the differences in the amount of new tissue produced in the plasma of young, middle aged, and old chickens were large, the growth of a pure culture of fibroblasts could be employed as a reagent for detecting certain changes occurring in the plasma under the influence of age. But the method possesses the necessary accuracy only when it is used as has already been described, and by technicians thoroughly trained in the details of its application. A comparative study of the growth of fibroblasts in media containing no serum, and serum under low and high concentrations, was made in order to ascertain whether the decreasing rate of cell multiplication was due to the loss of an accelerating factor, or to the increase See PDF for Structure of an inhibiting one. In high and low concentrations of the serum of young animals, no difference in the rate of multiplication of fibroblasts was observed. This showed that the serum of an actively growing animal did not contain any accelerating agent. The same experiments were repeated with the serum of a 3 year old and a 9 year old chicken. The medium made of a high concentration of serum had a markedly depressing effect on the growth, and this effect was greater in the serum of the older animal (Text-fig. 13). The results of the experiments showed in a very definite manner that certain changes occurring in the serum during the course of life can be detected by modifications in the rate of growth of pure cultures of fibroblasts, and that these changes are characterized by the increase of an inhibiting factor, and not by the loss of an accelerating one. It appeared, therefore,that the substances which greatly accelerate the multiplication of fibroblasts and are found in the tissues do not exist in the blood serum, or are constantly shielded by more active inhibiting factors. The curve which expresses the variations of the inhibiting factor in function of the age was compared with that showing the variations of the rate of healing of a wound according to the age of the subject. For wounds of equal size, the index of cicatrization, which expresses the rate of healing, varies in inverse ratio to the age. The different values of the index of cicatrization of a wound 40 sq. cm. in area, taken from measurements made by du Noüy, were plotted in ordinates, and the age of the subject in abscissae (Text-fig. 14). The curve showed a decrease in the activity of cicatrization which resembled the decrease in the rate of growth of fibroblasts in function of the age of the animal. This suggested the existence of a relation between the factors determining both phenomena.

Resistance to L-asparaginase in leukemic cells may be caused by an elevated cellular expression of asparagine synthetase (AS). Previously, we reported that high AS expression did not correlate to L-asparaginase resistance in TEL-AML1-positive B-lineage acute lymphoblastic leukemia (ALL). In the present study we confirmed this finding in TEL-AML1-positive patients (n = 28) using microarrays. In contrast, 35 L-asparaginase-resistant TEL-AML1-negative B-lineage ALL patients had a significant 3.5-fold higher AS expression than 43 sensitive patients (P < .001). Using real-time quantitative polymerase chain reaction (RTQ-PCR), this finding was confirmed in an independent group of 39 TEL-AML1-negative B-lineage ALL patients (P = .03). High expression of AS was associated with poor prognosis (4-year probability of disease-free survival [pDFS] 58% +/- 11%) compared with low expression (4-year pDFS 83% +/- 7%; P = .009). We conclude that resistance to l-asparaginase and relapse risk are associated with high expression of AS in TEL-AML1-negative but not TEL-AML1-positive B-lineage ALL.