Miracle-dz/UniFAR-FTUs huggingface dataset:
Wild tobacco genomes reveal the evolution of nicotine biosynthesis

Significance Plants produce structurally diverse specialized metabolites, many of which have been exploited in medicine or as pest control agents, whereas some have been incorporated in our daily lives, such as nicotine. In nature, these metabolites serve complex functions for plants’ ecological adaptations to biotic and abiotic stresses. By analyzing two high-quality wild tobacco genomes, we provide an in-depth genomic study that directly associates genome evolution with the assembly and evolution of the nicotine biosynthetic machinery. These results demonstrate the importance of the interplay of gene duplications and transposable element insertions in the evolution of specialized metabolism biosynthetic pathways and illuminate how complex adaptive traits could evolve. Nicotine, the signature alkaloid of Nicotiana species responsible for the addictive properties of human tobacco smoking, functions as a defensive neurotoxin against attacking herbivores. However, the evolution of the genetic features that contributed to the assembly of the nicotine biosynthetic pathway remains unknown. We sequenced and assembled genomes of two wild tobaccos, Nicotiana attenuata (2.5 Gb) and Nicotiana obtusifolia (1.5 Gb), two ecological models for investigating adaptive traits in nature. We show that after the Solanaceae whole-genome triplication event, a repertoire of rapidly expanding transposable elements (TEs) bloated these Nicotiana genomes, promoted expression divergences among duplicated genes, and contributed to the evolution of herbivory-induced signaling and defenses, including nicotine biosynthesis. The biosynthetic machinery that allows for nicotine synthesis in the roots evolved from the stepwise duplications of two ancient primary metabolic pathways: the polyamine and nicotinamide adenine dinucleotide (NAD) pathways. In contrast to the duplication of the polyamine pathway that is shared among several solanaceous genera producing polyamine-derived tropane alkaloids, we found that lineage-specific duplications within the NAD pathway and the evolution of root-specific expression of the duplicated Solanaceae-specific ethylene response factor that activates the expression of all nicotine biosynthetic genes resulted in the innovative and efficient production of nicotine in the genus Nicotiana. Transcription factor binding motifs derived from TEs may have contributed to the coexpression of nicotine biosynthetic pathway genes and coordinated the metabolic flux. Together, these results provide evidence that TEs and gene duplications facilitated the emergence of a key metabolic innovation relevant to plant fitness.
Ezrin mediates both HGF/Met autocrine and non‐autocrine signaling‐induced metastasis in melanoma

Aberrant HGF/Met signaling promotes tumor migration, invasion, and metastasis through both autocrine and non‐autocrine mechanisms; however, the molecular downstream signaling mechanisms by which HGF/Met induces metastasis are incompletely understood. We here report that Ezrin expression is stimulated by HGF and correlates with activated HGF/Met, indicating that HGF/Met signaling regulates the expression of Ezrin. We show that HGF/Met signaling activates the transcription factor Sp1 through the MAPK pathway, and activated Sp1 can in turn directly bind to the promoter of Ezrin gene and regulate its transcription. Notably, knockdown of Ezrin expression by shRNAs inhibits the metastasis induced by either HGF/Met autocrine or non‐autocrine signaling in syngeneic wildtype and HGF transgenic mouse hosts. We also used small molecule drugs in preclinical mouse models to confirm that Ezrin is one of the downstream molecules mediating HGF/Met signaling‐induced metastasis in melanoma. We conclude that Ezrin is a key downstream factor involved in the regulation of HGF/Met signaling‐induced metastasis and demonstrate a link between Ezrin and HGF/Met/MAPK/Sp1 activation in the metastatic process. Our data indicate that Ezrin represents a promising therapeutic target for patients bearing tumors with activated HGF/Met signaling.
Economic Analysis of Cleft Palate Repair in International Adoptees

Design Retrospective cohort study. Setting Major international tertiary care referral center for cleft palate repair. Patients One hundred thirty-eight patients at the Children's Hospital of Philadelphia who had palate repair performed between 2010 and 2013, excluding syndromic patients, patients undergoing palate revision, and patients with incomplete payment information. Interventions None. Main Outcome Measure Fees and charges for procedures. Results Surgeon payment was significantly higher for international adoptees (Δ = $2047.51 [$128.35 to $3966.66], P = .038). Medicaid-adjusted surgeon payments averaged $1006 more for adoptees ([-$394.19 to $2406.98], P = .158). Conclusions Hospital and anesthesiology costs for adoptee palate repair were highly variable but did not differ significantly from those for nonadoptees. Partly due to payer mix, surgeon reimbursement was somewhat higher for international adoptees. No difference in total payment was found.
Fibroblastic Reticular Cells Guide T Lymphocyte Entry into and Migration within the Splenic T Cell Zone1

Although a great deal is known about T cell entry into lymph nodes, much less is understood about how T lymphocytes access the splenic white pulp (WP). We show in this study that, as recently described for lymph nodes, fibroblastic reticular cells (FRCs) form a network in the T cell zone (periarteriolar lymphoid sheath, PALS) of the WP on which T lymphocytes migrate. This network connects the PALS to the marginal zone (MZ), which is the initial site of lymphocyte entry from the blood. T cells do not enter the WP at random locations but instead traffic to that site using the FRC-rich MZ bridging channels (MZBCs). These data reveal that FRCs form a substrate for T cells in the spleen, guiding these lymphocytes from their site of entry in the MZ into the PALS, within which they continue to move on the same network.
Ethnography and Grounded Theory: a Happy Marriage?

As qualitative methods are experiencing increasing popularity in consumer research, methods are being introduced from other disciplines, particularly anthropology and sociology. Ethnography has received attention as a promising consumer research method, although it has yet to achieve mainstream status within the discipline. This paper discusses the compatibility of ethnography with the grounded theory method of theory induction as employed in sociology. Combined, it is proposed that these two methods have the potential to offer a detailed understanding of consumption as experienced by consumers.
One complex world of mitochondrial parkinsonism.

Rare neurological diseases are back in the spotlight (Rohn, 2013). Technological advances linked to massively parallel ‘second generation’ sequencing have catalysed an upsurge of interest in monogenic disorders (Singleton, 2011), leading to an unexpected and unprecedented explosion in disease gene discovery (over 20/month in the early part of 2013, of which Brain has published its fair share). These advances are clearly important for the families and patients concerned, providing a clear diagnosis culminating years, and sometimes decades of investigation. This new knowledge enables reliable prognostic and genetic counselling, and disease prevention through prenatal diagnosis. However, there is now additional excitement based on the realization that, in many instances, discovering a new gene responsible for an esoteric familial disorder can have much greater significance, casting light on a disease mechanism relevant for the common diseases seen in general neurological practice. These observations have not escaped the attention of the pharmaceutical industry and Governments (Rohn, 2013). Both now recognize the importance of the common phenotypes seen as part of a rare disease. The precision offered by a molecular diagnosis allows the assembly of near homogenous patient cohorts. When deeply phenotyped over time, these cohorts provide an ideal test bed for novel treatments targeting the known mechanism. If successful, this provides the rationale for much more expensive randomized controlled trials manipulating the same biochemical pathway in patients with a more common disorder sharing some of the clinical characteristics of the rare disease. Although discovered in the ‘pre-exome’ era, mutations in POLG raise just this possibility. POLG mutations are a rare cause of neurological disease, but the tantalizing observation of l-DOPA responsive parkinsonism in some patients (Luoma et al. , 2004) rekindled interest in the role of the mitochondria in idiopathic Parkinson’s disease, and raised the possibility of testing new mitochondria-enhancing antiparkinsonian drugs …
Does activating the need to belong alter things important for happiness and what makes life complete

Past research on the need to belong in groups has largely examined the circumstances under which individuals go against their personal preferences and conform to group norms. The current research examines how the need to belong may shape the things people view as important for happiness, and what makes their lives complete. Two studies tested the main hypothesis that after activating belongingness needs, participants will be more likely to emphasize the importance of things valued by society (e.g., a lot of money, a successful career, etc.). In Study 1, the need to belong was activated by asking participants to recall a time when they engaged in an action that enabled them to gain social approval from others (vs. doing what they wanted), following which they rated the extent to which different pathways were key to their happiness. The results did not support the hypothesis that activating the need to belong would heighten the preference for what society saw as important for happiness. We identified two limitations in Study 1, which we sought to rectify in Study 2. First, it is possible that actions taken to gain social approval and following personal preferences may not be mutually exclusive despite how it is often examined in the literature. Therefore, in Study 2, we changed the manipulation to ask participants to recall a time in which they faced social rejection (to activate the need to belong) vs. a time which they experienced social acceptance. We also added a non-social, negative valence control group (i.e., failure) to test whether all negative experiences will have a similar effect on the dependent measure. The second limitation we identified was that people may have a preconceived idea of what is important for happiness that cannot be easily changed by activating belongingness needs. Therefore, we asked participants what would make their lives complete instead, something which may be less subject to preconceived notions. The results showed that contrary to expectations, participants in the social rejection condition did not evince a preference for societal completeness items as compared to those in the social acceptance and failure conditions. Various limitations and improvements for future research are discussed.
Relations between the Big Five Personality Traits and Sales Performance as Moderated by Attributional Style among Japanese Life Insurance Sales Agents (杉山武彦教授退任記念号)

Past studies have shown that a sales agent’s attributional style for positive and negative events is related to sales performance. Also, past studies have shown that Big Five personality traits predict sales performance. The aim of the present study was threefold: The first aim was to examine the relationship between the Big Five personality traits and sales performance among Japanese life insurance sales agents. The second aim was to examine the relationship between attribution style and sales performance. Finally, the study aimed to examine a sales agent’s attributional style as a moderator of the relation between sales performance and the Big Five personality traits. 224 Japanese life insurance sales agents were assessed with the Big Five personality traits, attributional style, and sales performance. All the five personality traits were significantly related to sales performance, which may be explained by the tendency of Japanese insurance buyers to make decisions based on perceived trustworthiness of their sales agent through face-to-face interaction. Attributional style was also significantly related to sales performance. Optimistic attributional style was related to higher sales performance. Finally, attributional style was found to moderate the relationship between Extraversion and sales performance, as well as Openness to Experience and sales performance. Specifically, among sales agents with optimistic attributional style, Extraversion was not related sales
Supramodal Theta, Gamma, and Sustained Fields Predict Modality-specific Modulations of Alpha and Beta Oscillations during Visual and Tactile Working Memory

Flexible control over currently relevant sensory representations is an essential feature of primate cognition. We investigated the neurophysiological bases of such flexible control in humans during an intermodal working memory task in which participants retained visual or tactile sequences. Using magnetoencephalography, we first show that working memory retention engages early visual and somatosensory areas, as reflected in the sustained load-dependent suppression of alpha and beta oscillations. Next, we identify three components that are also load dependent but modality independent: medial prefrontal theta synchronization, frontoparietal gamma synchronization, and sustained parietal event-related fields. Critically, these domain-general components predict (across trials and within load conditions) the modality-specific suppression of alpha and beta oscillations, with largely unique contributions per component. Thus, working memory engages multiple complementary frontoparietal components that have discernible neuronal dynamics and that flexibly modulate retention-related activity in sensory areas in a manner that tracks the current contents of working memory.
How do formative objective structured clinical examinations drive learning? Analysis of residents’ perceptions

Abstract Introduction: Although several studies have explored the relationship between learning and written tests, little is understood about how performance-based examinations influence learning. The purpose of this study was to explore how a formative objective structured clinical examination (OSCE) drives learning. Methods: We administered surveys to residents (n = 35) at three time points to determine if and how an OSCE influenced their learning: before and immediately following the OSCE, and after the distribution of their results. Differences in quantitative responses between high- and low-performing residents and across time were compared using repeated-measures ANOVA. Thematic analysis was used to analyze narrative comments. Results: Participants’ goals for the OSCE related to performance, mastery and feedback. Almost all participants reported that they had learned something from the OSCE (94%) and most participants generated learning goals after the OSCE (71%). High performers appeared to recognize the importance of content-related knowledge for scoring well before and after the OSCE, whereas low performers may have under-estimated its importance until after the examination. Discussion: Participants viewed a formative OSCE as both a hurdle to overcome (assessment of learning) and an opportunity to learn (assessment for learning). Understanding how OSCEs influence study behavior can help guide the development of assessments that promote learning.
Immunization with SARS Coronavirus Vaccines Leads to Pulmonary Immunopathology on Challenge with the SARS Virus

Background Severe acute respiratory syndrome (SARS) emerged in China in 2002 and spread to other countries before brought under control. Because of a concern for reemergence or a deliberate release of the SARS coronavirus, vaccine development was initiated. Evaluations of an inactivated whole virus vaccine in ferrets and nonhuman primates and a virus-like-particle vaccine in mice induced protection against infection but challenged animals exhibited an immunopathologic-type lung disease. Design Four candidate vaccines for humans with or without alum adjuvant were evaluated in a mouse model of SARS, a VLP vaccine, the vaccine given to ferrets and NHP, another whole virus vaccine and an rDNA-produced S protein. Balb/c or C57BL/6 mice were vaccinated IM on day 0 and 28 and sacrificed for serum antibody measurements or challenged with live virus on day 56. On day 58, challenged mice were sacrificed and lungs obtained for virus and histopathology. Results All vaccines induced serum neutralizing antibody with increasing dosages and/or alum significantly increasing responses. Significant reductions of SARS-CoV two days after challenge was seen for all vaccines and prior live SARS-CoV. All mice exhibited histopathologic changes in lungs two days after challenge including all animals vaccinated (Balb/C and C57BL/6) or given live virus, influenza vaccine, or PBS suggesting infection occurred in all. Histopathology seen in animals given one of the SARS-CoV vaccines was uniformly a Th2-type immunopathology with prominent eosinophil infiltration, confirmed with special eosinophil stains. The pathologic changes seen in all control groups lacked the eosinophil prominence. Conclusions These SARS-CoV vaccines all induced antibody and protection against infection with SARS-CoV. However, challenge of mice given any of the vaccines led to occurrence of Th2-type immunopathology suggesting hypersensitivity to SARS-CoV components was induced. Caution in proceeding to application of a SARS-CoV vaccine in humans is indicated.
Determining optimal dosing regimen of oral administration of dicloxacillin using Monte Carlo simulation

Background Dicloxacillin, a semisynthetic isoxazolyl penicillin, exhibits antimicrobial activity against a wide variety of Gram-positive bacteria, as well as stability against penicillinases and low level of toxicity. The objective of this study was to obtain optimal dosing regimen of oral administration of dicloxacillin by analyzing the pharmacokinetic (PK) index in healthy volunteers and in vitro antibacterial activity by using Monte Carlo simulation. Materials and methods A total of 867 clinical isolates from community-onset infections were collected from 31 secondary hospitals in People’s Republic of China. The minimum inhibitory concentration (MIC) values of dicloxacillin were determined by the agar dilution method. Based on the MICs and the PK parameters of different dosage regimens, Monte Carlo simulation was performed to simulate the PK/pharmacodynamic indices of 250 mg once-daily (qd), 500 mg qd, 1,000 mg qd, 2,000 mg qd, 250 mg every 6 hours (q6h), and 500 mg q6h, respectively. The probability of target attainment was estimated at each MIC value, and the cumulative fraction of response (CFR) was calculated to evaluate the efficacy of these regimens. Results Dicloxacillin showed poor antibacterial activity against Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae. Resistance to dicloxacillin was observed in 7.5% of coagulase-negative Staphylococcus (CNS) isolates and 9.2% of other Streptococcus isolates, whereas 1.5% of methicillin-sensitive Staphylococcus aureus (MSSA) was resistant to dicloxacillin. Multiple-dose regimens could obtain higher CFR than single-dose regimens against H. influenza and S. pneumoniae. However, all dosing regimens against MSSA achieved CFR ≥$90%. Meanwhile, dosing regimen of 2,000 mg qd, 250 mg q6h, and 500 mg q6h could achieve >90% of CFR for CNS. For other Streptococcus isolates, multiple-dose regimens achieved CFR ≥90%. Conclusion Dicloxacillin has a significant antibacterial activity against MSSA, CNS, and other Streptococcus isolates. The simulation results suggest that dicloxacillin 250 mg q6h and 500 mg q6h dosing regimens may be recommended for clinical applications, especially for community-onset infections.
Behavioral and emotional problems in high-functioning girls and boys with autism spectrum disorders: Parents’ reports and adolescents’ self-reports

The purpose of this study was to investigate sex differences in behavioral and emotional problems in high-functioning girls and boys with autism spectrum disorder. The results obtained by adolescents with autism spectrum disorder were compared with those of typically developing girls and boys. Correlations between parents’ and adolescents’ ratings were also analyzed. Participants were 35 girls and 35 boys with autism spectrum disorder, aged 11–18 years, matched for chronological age and full-scale IQ. The control group consisted of 24 typically developing girls and 24 boys of the same age and IQ. The parents of adolescent participants were also included in the study. The measures used were the Child Behavior Checklist (4–18) completed by parents and Youth Self-Report (11–18) completed by adolescents. The adolescents with autism spectrum disorder presented higher levels of behavioral and emotional problems than the control group, according to both the parents’ reports and the adolescents’ self-reports. No sex differences were found in that respect. More differences between the assessments of adolescents and their parents occurred in the control group, and the effect size was larger.
Analysis of the Masked Metabolite of Deoxynivalenol and Fusarium Resistance in CIMMYT Wheat Germplasm

Fusarium head blight (FHB) causes significant grain loss and contamination of grains with harmful mycotoxins, especially deoxynivalenol (DON). Fusarium resistance and DON accumulation have been extensively investigated in various cultivars; however, the level of DON-3-O-glucoside (D3G) has not been as carefully studied. In this study, we measured accumulated DON and D3G levels in CIMMYT wheat elite germplasm using an analytical method validated in-house. Co-occurring nivalenol (NIV) and ergostrerol (ERG) were also analyzed. LC-MS/MS and LC-UV analyses were applied to the 50 CIMMYT elite wheat lines. D3G showed rather high correlation with DON (r = 0.82), while FHB symptoms showed slight correlation with DON and D3G (r = 0.36 and 0.32, respectively). D3G/DON ratio varied widely from 8.1 to 37.7%, and the ratio was not related with FHB resistance in this dataset.