Miracle-dz/UniFAR-FTUs huggingface dataset:
JIP3 Mediates TrkB Axonal Anterograde Transport and Enhances BDNF Signaling by Directly Bridging TrkB with Kinesin-1

Brain-derived neurotrophic factor (BDNF), secreted from target tissues, binds and activates TrkB receptors, located on axonal terminals of the innervating neurons, and thereby initiates retrograde signaling. Long-range anterograde transport of TrkB in axons and dendrites requires kinesin-mediated transport. However, it remains unknown whether anterograde TrkB transport mechanisms are the same in axons versus in dendrites. Here, we show that c-Jun NH2-terminal kinase-interacting protein 3 (JIP3) binds directly to TrkB, via a minimal 12 aa domain in the TrkB juxtamembrane region, and links TrkB to kinesin-1. The JIP3/TrkB interaction selectively drives TrkB anterograde transport in axons but not in dendrites of rat hippocampal neurons. Moreover, we find that TrkB axonal transport mediated by JIP3 could regulate BDNF-induced Erk activation and axonal filopodia formation. Our findings demonstrate a role for JIP3-mediated TrkB anterograde axonal transport in recruiting more TrkB into distal axons and facilitating BDNF-induced retrograde signaling and synapse modulation, which provides a novel mechanism of how the TrkB anterograde transport can be coupled to BDNF signaling in distal axons.
Calculation of DNA strand breaks due to direct and indirect effects of Auger electrons from incorporated 123I and 125I radionuclides using the Geant4 computer code

Abstract Purpose: In this work the number of DNA single-strand breaks (SSB) and double-strand breaks (DSB) due to direct and indirect effects of Auger electrons from incorporated 123I and 125I have been calculated by using the Geant4-DNA toolkit. We have performed and compared the calculations for several cases: 125I versus 123I, source positions and direct versus indirect breaks to study the capability of the Geant4-DNA in calculations of DNA damage yields. Materials and methods: Two different simple geometries of a 41 base pair of B-DNA have been simulated. The location of 123I has been considered to be in 123IdUrd and three different locations for 125I. Results: The results showed that the simpler geometry is sufficient for direct break calculations while indirect damage yield is more sensitive to the helical shape of DNA. For 123I Auger electrons, the average number of DSB due to the direct hits is almost twice the DSB due to the indirect hits. Furthermore, a comparison between the average number of SSB or DSB caused by Auger electrons of 125I and 123I in 125IdUrd and 123IdUrd shows that 125I is 1.5 times more effective than 123I per decay. Conclusions: The results are in reasonable agreement with previous experimental and theoretical results which shows the applicability of the Geant-DNA toolkit in nanodosimetry calculations which benefits from the open-source accessibility with the advantage that the DNA models used in this work enable us to save the computational time. Also, the results showed that the simpler geometry is suitable for direct break calculations, while for the indirect damage yield, the more precise model is preferred.
Common Agency and Coordinated Bids in Sponsored Search Auctions

As auctions are becoming the main mechanism for selling advertisement space on the web, marketing agencies specialized in bidding in online auctions are proliferating. We analyze theoretically how bidding delegation to a common marketing agency can undermine both revenues and efficiency of the generalized second price auction, the format used by Google and Microsoft-Yahoo! Our characterization allows us to quantify the revenue losses relative to both the case of full competition and the case of agency bidding under an alternative auction format (specifically, the VCG mechanism). We propose a simple algorithm that a search engine can use to reduce efficiency and revenue losses.
Role of MicroRNA Modulation in the Interferon-α/Ribavirin Suppression of HIV-1 In Vivo

Background Interferon-α (IFN-α) treatment suppresses HIV-1 viremia and reduces the size of the HIV-1 latent reservoir. Therefore, investigation of the molecular and immunologic effects of IFN-α may provide insights that contribute to the development of novel prophylactic, therapeutic and curative strategies for HIV-1 infection. In this study, we hypothesized that microRNAs (miRNAs) contribute to the IFN-α-mediated suppression of HIV-1. To inform the development of novel miRNA-based antiretroviral strategies, we investigated the effects of exogenous IFN-α treatment on global miRNA expression profile, HIV-1 viremia, and potential regulatory networks between miRNAs and cell-intrinsic anti-HIV-1 host factors in vivo. Methods Global miRNA expression was examined in longitudinal PBMC samples obtained from seven HIV/HCV-coinfected, antiretroviral therapy-naïve individuals before, during, and after pegylated interferon-α/ribavirin therapy (IFN-α/RBV). We implemented novel hybrid computational-empirical approaches to characterize regulatory networks between miRNAs and anti-HIV-1 host restriction factors. Results miR-422a was the only miRNA significantly modulated by IFN-α/RBV in vivo (p<0.0001, paired t test; FDR<0.037). Our interactome mapping revealed extensive regulatory involvement of miR-422a in p53-dependent apoptotic and pyroptotic pathways. Based on sequence homology and inverse expression relationships, 29 unique miRNAs may regulate anti-HIV-1 restriction factor expression in vivo. Conclusions The specific reduction of miR-422a is associated with exogenous IFN-α treatment, and likely contributes to the IFN-α suppression of HIV-1 through the enhancement of anti-HIV-1 restriction factor expression and regulation of genes involved in programmed cell death. Moreover, our regulatory network analysis presents additional candidate miRNAs that may be targeted to enhance anti-HIV-1 restriction factor expression in vivo.
Initial Acquisition of Mutans Streptococci by Infants: Evidence for a Discrete Window of Infectivity

Oral bacterial levels of 46 mother-child pairs were monitored from infant birth up to five years of age so that the acquisition of mutans streptococci (MS) by children could be studied. The initial acquisition of MS occurred in 38 children at the median age of 26 months during a discrete period we designated as the "window of infectivity". MS remained undetected in eight children (17%) until the end of the study period (median age of 56 mo). The levels of both MS and lactobacilli in saliva of mothers of children with and without MS were not significantly different. Comparisons between a caries-active cohort colonized by MS (nine of 38) and children without detectable MS revealed similar histories in terms of antibiotic usage, gestational age, and birth weight. Interestingly, half of the children between the ages of one and two years who were not colonized by MS were attended by caretakers other than the mother, while all of the caries-active children during this same time period were cared for by their mothers; the difference was statistically significant. Here we report for the first time that MS is acquired by infants during a defined period in the ontogeny of a child. Support for the notion of a discrete window of infectivity comes from other sources, including animal models.
Genetic and Dietary Regulation of Glyburide Efflux by the Human Placental Breast Cancer Resistance Protein Transporter

Glyburide is frequently used to treat gestational diabetes owing to its low fetal accumulation resulting from placental efflux by the breast cancer resistance protein (BCRP)/ABCG2 transporter. Here we sought to determine how exposure to the dietary phytoestrogen genistein and expression of a loss-of-function polymorphism in the ABCG2 gene (C421A) impacted the transport of glyburide by BCRP using stably transfected human embryonic kidney 293 (HEK) cells, human placental choriocarcinoma BeWo cells, and human placental explants. Genistein competitively inhibited the BCRP-mediated transport of 3H-glyburide in both wild-type (WT) and C421A-BCRP HEK-expressing cells, with greater accumulation of 3H-glyburide in cells expressing the C421A variant. In BeWo cells, exposure to genistein for 60 minutes increased the accumulation of 3H-glyburide 30%–70% at concentrations relevant to dietary exposure (IC50 ∼180 nM). Continuous exposure of BeWo cells to genistein for 48 hours reduced the expression of BCRP mRNA and protein by up to 40%, which impaired BCRP transport activity. Pharmacologic antagonism of the estrogen receptor attenuated the genistein-mediated downregulation of BCRP expression, suggesting that phytoestrogens may reduce BCRP levels through this hormone receptor pathway in BeWo cells. Interestingly, genistein treatment for 48 hours did not alter BCRP protein expression in explants dissected from healthy term placentas. These data suggest that whereas genistein can act as a competitive inhibitor of BCRP-mediated transport, its ability to downregulate placental BCRP expression may only occur in choriocarcinoma cells. Overall, this research provides important mechanistic data regarding how the environment (dietary genistein) and a frequent genetic variant (ABCG2, C421A) may alter the maternal-fetal disposition of glyburide.
Profiles of Organic Food Consumers in a Large Sample of French Adults: Results from the Nutrinet-Santé Cohort Study

Background Lifestyle, dietary patterns and nutritional status of organic food consumers have rarely been described, while interest for a sustainable diet is markedly increasing. Methods Consumer attitude and frequency of use of 18 organic products were assessed in 54,311 adult participants in the Nutrinet-Santé cohort. Cluster analysis was performed to identify behaviors associated with organic product consumption. Socio-demographic characteristics, food consumption and nutrient intake across clusters are provided. Cross-sectional association with overweight/obesity was estimated using polytomous logistic regression. Results Five clusters were identified: 3 clusters of non-consumers whose reasons differed, occasional (OCOP, 51%) and regular (RCOP, 14%) organic product consumers. RCOP were more highly educated and physically active than other clusters. They also exhibited dietary patterns that included more plant foods and less sweet and alcoholic beverages, processed meat or milk. Their nutrient intake profiles (fatty acids, most minerals and vitamins, fibers) were healthier and they more closely adhered to dietary guidelines. In multivariate models (after accounting for confounders, including level of adherence to nutritional guidelines), compared to those not interested in organic products, RCOP participants showed a markedly lower probability of overweight (excluding obesity) (25≤body mass index<30) and obesity (body mass index ≥30): −36% and −62% in men and −42% and −48% in women, respectively (P<0.0001). OCOP participants (%) generally showed intermediate figures. Conclusions Regular consumers of organic products, a sizeable group in our sample, exhibit specific socio-demographic characteristics, and an overall healthy profile which should be accounted for in further studies analyzing organic food intake and health markers.
Development of a screening score for undiagnosed diabetes and its application in estimating absolute risk of future type 2 diabetes in Japan: Toranomon Hospital Health Management Center Study 10 (TOPICS 10).

OBJECTIVE The objective of the study was to develop a screening score for undiagnosed diabetes by eliciting information on noninvasive clinical markers and to assess its effectiveness for identifying the presence of diabetes and predicting future diabetes. DESIGN, SETTING, AND PARTICIPANTS A screening score was cross-sectionally developed for 33 335 Japanese individuals aged 18-88 years without known diabetes who underwent a health examination. We validated its utility and compared it with existing screening tools in an independent population (n = 7477). After initial assessment of the instrument, 7332 nondiabetic individuals were followed up for a mean 4.0 years. RESULTS Prevalence of undiagnosed diabetes (fasting plasma glucose ≥ 7.0 mmol/L or glycated hemoglobin ≥ 6.5%) was 2.9% (n = 965). Diabetes score included age, sex, family history of diabetes, current smoking habit, body mass index, and hypertension with an area under the receiver-operating characteristics curve of 0.771. Screening with 8 or more points yielded a sensitivity of 72.7% and a specificity of 68.1%. In the validation cohort, the area under the receiver-operating characteristics curve was 0.806. The developed score with 8 or more points had better positive predictive value (9.6%) and positive likelihood ratio (2.52) compared with existing tools (positive predictive value, from 6.9% to 9.4%; positive likelihood ratio, from 1.77 to 2.46) in which each tool's highest combination of sensitivity and specificity was observed. The 4-year cumulative risk of developing diabetes gradually escalated in association with higher screening scores at the initial examination. CONCLUSIONS Our algorithm could serve as a self-assessment tool for undiagnosed diabetic patients needing timely medical care and as a prognostic tool for individuals without present diabetes who must be closely followed up to prevent future diabetes.
Time modeling in office information systems

__-Time management 1s d feature essential to offlce informnat1on systems. I? the OI\ environnent, in dddltlon to a static deflnltlon of time attrlbutes attached to data, a more complete definition 1s needed, to handle both static and transltlon times and representation of temporal relatlonshlps The TSOS model, an extension of the SOS model for office descrtptlon, contains a time model suitable for both of these requirements. In addition, the TSOS time model allows the representation of calendar times at different levels of abstractIon and contains a prectse deEinitlon of temporal and logical functions on time. Another main goal of the TSOS time model is to allow a f lexlble representation of temporal conditions for triegering and cant rol rules In the office environment, so that dn Intelligent rule invocatlon is possible. 1. IUTRODUCTLON Offlce Informatlon Systems (015) are a class of Informatlon C,ystems where some features are novel or more crltlcal than In tradItIona Information systems. Among these aspects, In thli paper we address the prohlrrl of time modeling and management. Several models for time handling have been proposed in the literature, In dlEferent computer science research areas [Bol 82) As It wrll be Illustrated in Section 2. , each of these models takes into account sonew'lat different aspects in ttme manaqement. The purpose of this paper 1s to define the TSOS (Temporal Semantic Office System) time model to specify rule lnvocatlon condlt ions of control rule5, and to present d Formal deEinltLon of temporal functions in the presence of time abstrdctlons. PermissIon to copy wlthout fee all or part of this material IS granted provided that the copies are not made or dlstrlbuted for direct commercial advantage, the ACM copyrlght notlce and the title of the pubhcatlon and its date appear, and notlce 1s given that copying 15 by permlsslon of the Assoclatlon for Computmg Machmery To copy otherwIse, or lo repubhsh, reqmres a fee and/or specdic permlsslon T\OS 1s an extension of the Semantic OffLce System (SOS) for office systems descrlptlon [Bra 841 In TSOS It is possible to handle temporal attributes-____-of data and to verify static and dyndmlc con$tral? tS on them. Functions ? re provided for handling relationships-_-between e, as It is necessary, for Instance, in-planning systems, where causality relatlonships between times are more lmportdnt that the corresponding precise times. For instance, the time of response to a letter may not be relevant as a precise time, while it …
Age at Which Larvae Are Orphaned Determines Their Development into Typical or Rebel Workers in the Honeybee (Apis mellifera L.)

In the honeybee, diploid larvae fed with royal jelly develop into reproductive queens, whereas larvae fed with royal jelly for three days only and subsequently with honey and pollen develop into facultatively sterile workers. A recent study showed that worker larvae fed in a queenless colony develop into another female polyphenic form: rebel workers. These rebel workers are more queenlike and have greater reproductive potential than normal workers. However, it was unclear whether larvae orphaned at any time during their feeding period can develop into rebels. To answer this question, the anatomical features of newly emerged workers reared in queenless conditions at different ages during the larval period were evaluated. Our results showed that larvae orphaned during the final four or more days of their feeding life develop into rebel workers with more ovarioles in their ovaries, smaller hypopharyngeal glands, and larger mandibular and Dufour’s glands compared with typical workers with low reproductive potential that were reared with a queen or orphaned at the third to last or a later day of feeding life.
Fine-Grained Categorization and Dataset Bootstrapping Using Deep Metric Learning with Humans in the Loop

Existing fine-grained visual categorization methods often suffer from three challenges: lack of training data, large number of fine-grained categories, and high intraclass vs. low inter-class variance. In this work we propose a generic iterative framework for fine-grained categorization and dataset bootstrapping that handles these three challenges. Using deep metric learning with humans in the loop, we learn a low dimensional feature embedding with anchor points on manifolds for each category. These anchor points capture intra-class variances and remain discriminative between classes. In each round, images with high confidence scores from our model are sent to humans for labeling. By comparing with exemplar images, labelers mark each candidate image as either a "true positive" or a "false positive. " True positives are added into our current dataset and false positives are regarded as "hard negatives" for our metric learning model. Then the model is retrained with an expanded dataset and hard negatives for the next round. To demonstrate the effectiveness of the proposed framework, we bootstrap a fine-grained flower dataset with 620 categories from Instagram images. The proposed deep metric learning scheme is evaluated on both our dataset and the CUB-200-2001 Birds dataset. Experimental evaluations show significant performance gain using dataset bootstrapping and demonstrate state-of-the-art results achieved by the proposed deep metric learning methods.
In Vitro and in Vivo Antitumor Effects of Cytotoxic Camptothecin-Bombesin Conjugates Are Mediated by Specific Interaction with Cellular Bombesin Receptors

Most human tumors overexpress or ectopically express peptide hormone/neurotransmitter receptors, which are being increasingly studied as a means to selectively deliver cytotoxic agents. Although a number of peptide ligand-constructs demonstrate tumor cytotoxicity, the role of specific tumoral receptor interaction in its mediation is unclear. To address this question, we synthesized camptothecin (CPT) bombesin (Bn) analogs, in which CPT was coupled via a novel carbamate linker, L2 [N-(N-methyl-amino-ethyl)-glycine carbamate], that were chemically similar but differed markedly in their potency/affinity for human Bn receptors. We then examined their ability to interact with Bn receptors and cause in vitro and in vivo tumor cytotoxicity. CPT-L2-[d-Tyr6,β-Ala11,d-Phe13,Nle14] Bn (6-14) (BA3) bound with high affinity and had high potency for all three human Bn receptor subtypes, whereas CPT-L2-[d-Tyr6,β-Ala11, d-Phe13,Nle14] Bn (6-14) [d-Phe-CPT-L2-BA3] had >1400-fold lower affinity/potency. 125I-CPT-L2-BA3 but not 125I-d-Phe-CPT-L2-BA3 was internalized by Bn receptor subtype-containing cells. CPT-L2-BA3 displayed significantly more cytotoxicity than d-Phe-CPT-L2-BA3 toward NCI-H1299 lung cancer cells in both 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide and clonogenic assays and more potently inhibited H1299 xenograft growth in nude mice. CPT-L2-BA3 was also metabolically more stable than its parent peptide and inhibited growth of a number of other tumor cell lines in vitro and in vivo. These results demonstrate that specific tumoral receptor interaction is important in mediating the ability of peptide ligand-cytotoxic constructs to cause cytotoxicity. Because many tumors overexpress Bn receptors, these results also demonstrate that CPT-L2-BA3 will be a useful agent for delivering receptor-mediated cytotoxicity to many different human tumors.
Intelligent Agents on the Internet: Fact, Fiction, and Forecast

In the future, intelligent software agents will help us navigate the information superhighway by serving as backseat drivers or taxi drivers. Better yet, they have the potential to act as sophisticated concierges who make it unnecessary for us to approach the highway at all. We describe a selective sample of software agents currently under development, to give an idea of the agents that will emerge in the next few years. We organize our discussion by the agents' sophistication and the degree to which they make the information superhighway disappear. Following the information superhighway metaphor, an intelligent agent may be a backseat driver who makes suggestions at every rum, a taxi driver who takes you to your destination, or even a concierge whose knowledge and skills make it unnecessary for you to approach the superhighway at all. The Internet Softbot is discussed as a case study. >
A Genome-Wide Association Study Reveals a Quantitative Trait Locus of Adiponectin on CDH13 That Predicts Cardiometabolic Outcomes

OBJECTIVE The plasma adiponectin level, a potential upstream and internal facet of metabolic and cardiovascular diseases, has a reasonably high heritability. Whether other novel genes influence the variation in adiponectin level and the roles of these genetic variants on subsequent clinical outcomes has not been thoroughly investigated. Therefore, we aimed not only to identify genetic variants modulating plasma adiponectin levels but also to investigate whether these variants are associated with adiponectin-related metabolic traits and cardiovascular diseases. RESEARCH DESIGN AND METHODS We conducted a genome-wide association study (GWAS) to identify quantitative trait loci (QTL) associated with high molecular weight forms of adiponectin levels by genotyping 382 young-onset hypertensive (YOH) subjects with Illumina HumanHap550 SNP chips. The culpable single nucleotide polymorphism (SNP) variants responsible for lowered adiponectin were then confirmed in another 559 YOH subjects, and the association of these SNP variants with the risk of metabolic syndrome (MS), type 2 diabetes mellitus (T2DM), and ischemic stroke was examined in an independent community–based prospective cohort, the CardioVascular Disease risk FACtors Two-township Study (CVDFACTS, n = 3,350). RESULTS The SNP (rs4783244) most significantly associated with adiponectin levels was located in intron 1 of the T-cadherin (CDH13) gene in the first stage (P = 7.57 × 10−9). We replicated and confirmed the association between rs4783244 and plasma adiponectin levels in an additional 559 YOH subjects (P = 5.70 × 10−17). This SNP was further associated with the risk of MS (odds ratio [OR] = 1.42, P = 0.027), T2DM in men (OR = 3.25, P = 0.026), and ischemic stroke (OR = 2.13, P = 0.002) in the CVDFACTS. CONCLUSIONS These findings indicated the role of T-cadherin in modulating adiponectin levels and the involvement of CDH13 or adiponectin in the development of cardiometabolic diseases.