Miracle-dz/UniFAR-FTUs huggingface dataset:
An Outward-Facing Aromatic Amino Acid Is Crucial for Signaling between the Membrane-Spanning and Nucleotide-Binding Domains of Multidrug Resistance Protein 1 (MRP1; ABCC1)

The 190-kDa human MRP1 is an ATP-binding cassette multidrug and multiorganic anion efflux transporter. The 17 transmembrane helices of its three membrane-spanning domains, together with its two nucleotide binding domains (NBDs), form a stabilizing network of domain-domain interactions that ensure substrate binding in the cytoplasm is efficiently coupled to ATP binding and hydrolysis to effect solute efflux into the extracellular milieu. Here we show that Ala substitution of Phe583 in an outward-facing loop between the two halves of the transporter essentially eliminates the binding of multiple organic anions by MRP1. Conservative substitutions with Trp and Tyr had little or no effect. The F583A mutation also caused a substantial increase in orthovanadate-induced trapping of azidoADP by the cytoplasmic NBDs of MRP1, although the binding of ATP was unaffected. These observations indicate that the loss of the aromatic side chain at position 583 impairs the release of ADP and thus effectively locks the transporter in a low-affinity solute binding state. Phe583 is the first outward-facing amino acid in MRP1 found to be critical for its transport function. Our data provide evidence for long-range coupling, presumably via allosteric interaction, between this outward-facing region of MRP1 and both the solute binding and nucleotide binding regions of the transporter. Cryoelectron microscopy structural and homology models of MRP1 indicate that the orientation of the Phe583 side chain is altered by ATP binding but are currently unable to provide insights into the molecular mechanism by which this long-range signaling is propagated.
Digestion-Free Analysis of Peptides from 30-year-old Formalin-Fixed, Paraffin-Embedded Tissue by Mass Spectrometry Imaging

Formalin-fixed neuroendocrine tissues from American cockroaches (Periplaneta americana) embedded in paraffin more than 30 years ago were recently analyzed by matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI), to reveal the histological localization of more than 20 peptide ions. These represented protonated, and other cationic species of, at least, 14 known neuropeptides. The characterization of peptides in such historical samples was made possible by a novel sample preparation protocol rendering the endogenous peptides readily amenable to MSI analysis. The protocol comprises brief deparaffinization steps involving xylene and ethanol, and is further devoid of conventional aqueous washing, buffer incubations, or antigen retrieval steps. Endogenous secretory peptides that are typically highly soluble are therefore retained in-tissue with this protocol. The method is fully “top-down”, that is, without laborious in situ enzymatic digestion that typically disturbs the detection of low-abundance endogenous peptides by MSI. Peptide identifications were supported by accurate mass, on-tissue tandem MS analyses, and by earlier MALDI-MSI results reported for freshly prepared P. americana samples. In contrast to earlier literature accounts stating that MALDI-MSI detection of endogenous peptides is possible only in fresh or freshly frozen tissues, or exceptionally, in formalin-fixed, paraffin-embedded (FFPE) material of less than 1 year old, we demonstrate that MALDI-MSI works for endogenous peptides in FFPE tissue of up to 30 years old. Our findings put forward a useful method for digestion-free, high-throughput analysis of endogenous peptides from FFPE samples and offer the potential for reinvestigating archived and historically interesting FFPE material, such as those stored in hospital biobanks.
Math Difficulties and Working Memory Growth in English Language Learner Children: Does Bilingual Proficiency Play a Significant Role?

Purpose The purpose of this study was to determine those components of working memory (WM) that play a significant role in predicting math growth in children who are English language learners (N = 157) with serious math difficulties (MD). Method A battery of tests was administered in English and Spanish that assessed computation, reading, vocabulary, inhibition, and components of WM in Grade 1 children with follow-up testing in Grades 2 and 3. Results The results indicated that growth in the executive component of WM was related to growth in math performance. Proficient bilingual children (proficient in both Spanish and English vocabulary) with MD outperformed less proficient bilingual children with MD on measures of math calculation, fluid intelligence, reading, and Spanish WM at Grade 3. Conclusion Growth in the executive component of WM is significantly related to growth in math computation, and increased bilingual proficiency across testing waves yielded positive gains in both math and cognitive performance in children with MD.
Coupling toxicokinetic–toxicodynamic and population models for assessing aquatic ecological risks to time‐varying pesticide exposures

Population modeling evaluations of pesticide exposure time series were compared with aspects of a currently used risk assessment process. The US Environmental Protection Agency's Office of Pesticide Programs models daily aquatic 30‐yr pesticide exposure distributions in its risk assessments, but does not routinely make full use of the information in such time series. We used mysid shrimp Americamysis bahia toxicity and demographic data to demonstrate the value of a toxicokinetic–toxicodynamic model coupled with a series of matrix population models in risk assessment refinements. This species is a small epibenthic marine crustacean routinely used in regulatory toxicity tests. We demonstrate how the model coupling can refine current risk assessments using only existing standard regulatory toxicity test results. Several exposure scenarios (each with the same initial risk characterization as determined by a more traditional organism‐based approach) were created within which population modeling documented risks different from those of assessments based on the traditional approach. We also present different acute and chronic toxicity data scenarios by which toxicokinetic–toxicodynamic coupled with population modeling can distinguish responses that traditional risk evaluations are not designed to detect. Our results reinforce the benefits of this type of modeling in risk evaluations, especially related to time‐varying exposure concentrations. Environ Toxicol Chem 2018;37:2633–2644. Published 2018 Wiley Periodicals Inc. on behalf of SETAC. This article is a US government work and, as such, is in the public domain in the United States of America.
Highly active antiretroviral therapy adherence among perinatally infected HIV adolescents at a teaching hospital in Ghana

ABSTRACT Increased accessibility to Antiretroviral Therapy (ART) has resulted in the decline of deaths among children with Perinatally Infected Human Immunodeficiency Virus (PIHIV). Their adherence to Highly Active ART (HAART) is vital for their survival and quality of life. This study aimed at determining HAART medication adherence among adolescents with PIHIV. The study was cross-sectional conducted from September 2015 to January 2016 at a teaching hospital in Ghana. It involved 106 adolescents aged 10–20 years. Morisky’s eight-item medication adherence scale was adapted and used to determine the adherence level. Factors influencing adherence were also determined by interviewing the adolescents. EpiData 3.1 and Stata version 12 were used for data entry and analysis respectively. There was low adherence in 76.4% of the adolescents, and the HAART regimen associated with high medication adherence was tenofovir, lamivudine and efavirenz combinations (p = .011). Forgetfulness (p = .001) and inability to come for refill (p = .013) were the main factors associated with low adherence. However adherence was not significantly associated with a lack of medication supply or stigmatization. Addressing the modifiable factors found in this study to be associated with low adherence are essential interventions for their long-term quality of life.
An Empirical Analysis on the Connection between Investor Sentiment and Activity in Chinese Stock Market

Investor sentiment is a market enterprise index which reflects investor's desire or expectation in the future.Basing investor sentiment on datum of CCTV security column investigation,the author analyzes the relation between investor sentiment index and activity index-trading volume,dollar volume,share turnover,by applying statistical analysis,Pearson analysis and Grainger analysis.The results suggest that there are very external relation and relatively consistent trend,strong correlation,mutual impact between investor sentiment and activity.Investor sentiment index provides means of analyzing investor's psychology and behavioral modes.Supervisory department can control the rhythm of market movement by adjusting and regulating investor sentiment.
Carotid Artery Atherosclerosis: A Review on Heritability and Genetics

Carotid atherosclerosis (CAS) is associated with increased cardiovascular risk, and therefore, assessing the genetic versus environmental background of CAS traits is of key importance. Carotid intima-media-thickness and plaque characteristics seem to be moderately heritable, with remarkable differences in both heritability and presence or severity of these traits among ethnicities. Although the considerable role of additive genetic effects is obvious, based on the results so far, there is an important emphasis on non-shared environmental factors as well. We aimed to collect and summarize the papers that investigate twin and family studies assessing the phenotypic variance attributable to genetic associations with CAS. Genes in relation to CAS markers were overviewed with a focus on genetic association studies and genome-wide association studies. Although the role of certain genes is confirmed by studies conducted on large populations and meta-analyses, many of them show conflicting results. A great focus should be on future studies elucidating the exact pathomechanism of these genes in CAS in order to imply them as novel therapeutic targets.
Comparison of Patient Impact and Clinical Characteristics Between Urgency and Passive Fecal Incontinence Phenotypes

Phenotyping women with fecal incontinence as urgency or passive fecal incontinence is clinically meaningful. Objective To determine if categorizing fecal incontinence (FI) as urgency or passive FI is clinically meaningful, we compared clinical severity, quality of life, physical examination findings, and functional and anatomic deficits between women with urgency and passive FI. Methods This study is a prospective cross-sectional study of women with at least monthly FI. All women completed the St Mark’s Vaizey and the Fecal Incontinence Quality of Life questionnaires and underwent anorectal manometry and endoanal ultrasound. We compared women with urgency FI to women with passive FI. Results Forty-six women were enrolled, 21 (46%) with urgency FI and 25 (54%) with passive FI. Clinical severity by Vaizey score did not differ between groups (urgency 11.7 ± 1.6 vs passive 11.0 ± 1.0, P = 0.51). Women with urgency FI had worse median (range) lifestyle and coping scores than passive FI (Fecal Incontinence Quality of Life: lifestyle domain 2.5 [1, 4] vs 3.8 [1, 4], P = 0.04; coping domain 1.7 [1, 3] vs 2.4 [0.9, 4], P < 0.01). Women with urgency FI had higher anal resting and squeeze pressure than passive FI (60 ± 4 mm Hg vs 49 ± 3 mm Hg, P = 0.03; 78 [48, 150] mm Hg vs 60 [40, 103], P = 0.05). Internal anal sphincter defects were more common in women with passive FI (41.7% vs 30.0%, P = 0.53) and external anal sphincter defects more common in women with urgency FI (25% vs 16.7%, P = 0.71), but this did not reach statistical significance. Conclusions We identified functional and anatomic differences between women with urgency FI and passive FI. Pheonotyping women with FI into these subtypes is clinically meaningful.
Clinical Studies of Cell Therapy in Cardiovascular Medicine: Recent Developments and Future Directions

Given the rising prevalence of cardiovascular disease worldwide and the limited therapeutic options for severe heart failure, novel technologies that harness the regenerative capacity of the heart are sorely needed. The therapeutic use of stem cells has the potential to reverse myocardial injury and improve cardiac function, in contrast to most current medical therapies that only mitigate heart failure symptoms. Nearly 2 decades and >200 trials for cardiovascular disease have revealed that most cell types are safe; however, their efficacy remains controversial, limiting the transition of this therapy from investigation to practice. Lessons learned from these initial studies are driving the design of new clinical trials; higher fidelity of cell isolation techniques, standardization of conditions, more consistent use of state of the art measurement techniques, and assessment of multiple end points to garner insights into the efficacy of stem cells. Translation to clinical trials has almost outpaced our mechanistic understanding, and individual patient factors likely play a large role in stem cell efficacy. Therefore, careful analysis of dosing, delivery methods, and the ideal patient populations is necessary to translate cell therapy from research to practice. We are at a pivotal stage in the field in which information from many relatively small clinical trials must guide carefully executed efficacy trials. Larger efficacy trials are being launched to answer questions about older, first-generation stem cell therapeutics, while novel, second-generation products are being introduced into the clinical realm. This review critically examines the current state of clinical research on cell-based therapies for cardiovascular disease, highlighting the controversies in the field, improvements in clinical trial design, and the application of exciting new cell products.
Oral contraceptive use and cutaneous melanoma risk: a French prospective cohort study

Cutaneous melanoma has been suspected to be influenced by female hormones. Several studies reported a positive association between oral contraceptive (OC) use and melanoma risk. However, findings were conflicting and data from large prospective studies are lacking. E3N is a prospective cohort of 98,995 French women aged 40–65 years at inclusion in 1990. Exposure to lifetime OC use was assessed in 1992 and through biennial questionnaire updates. To assess the association between OC use and melanoma risk, we used Cox models adjusted for age, pigmentary traits, residential ultraviolet (UV) exposure in county of birth and at inclusion and family history of skin cancer. Over 1992–2008, 539 melanoma cases were ascertained among 79,365 women. In age‐adjusted models, we found a modest positive association between ever use of OCs and melanoma risk (hazard ratio (HR) = 1.18, 95% confidence intervals (CIs) = 0.98–1.42), which was reduced after adjustment (HR = 1.14, 95% CI = 0.95–1.38). The association was stronger in long‐term users (duration ≥10 years: HR = 1.33, 95% CI = 1.00–1.75) and in women who used high‐estrogen OCs (HR = 1.27, 95% CI = 1.04–1.56). Among users, there was an inverse association with age at first use (ptrend < 0.01), but no evidence of an association with age at last use or time since last use. OC use was positively associated with tanning bed use (OR = 1.14, CI = 1.01–1.29), sunburns (ptrend = 0.5) and sunscreen use (OR = 1.13, CI = 1.00–1.28) since age 25. Overall, our findings do not support a strong association between OC use and melanoma risk and suggest intentional UV exposure in OC users, which supports a potential confusion by UV exposure in this relationship.
Neisseria gonorrhoeae employs two protein inhibitors to evade killing by human lysozyme

The bacterial pathogen Neisseria gonorrhoeae (Gc) infects mucosal sites rich in antimicrobial proteins, including the bacterial cell wall-degrading enzyme lysozyme. Certain Gram-negative bacteria produce protein inhibitors that bind to and inhibit lysozyme. Here, we identify Ng_1063 as a new inhibitor of lysozyme in Gc, and we define its functions in light of a second, recently identified lysozyme inhibitor, Ng_1981. In silico analyses indicated that Ng_1063 bears sequence and structural homology to MliC-type inhibitors of lysozyme. Recombinant Ng_1063 inhibited lysozyme-mediated killing of a susceptible mutant of Gc and the lysozyme-sensitive bacterium Micrococcus luteus. This inhibitory activity was dependent on serine 83 and lysine 103 of Ng_1063, which are predicted to interact with lysozyme’s active site residues. Lysozyme co-immunoprecipitated with Ng_1063 and Ng_1981 from intact Gc. Ng_1063 and Ng_1981 protein levels were also increased in Gc exposed to lysozyme. Gc lacking both ng1063 and ng1981 was significantly more sensitive to killing by lysozyme than wild-type or single mutant bacteria. When exposed to human tears or saliva, in which lysozyme is abundant, survival of Δ1981Δ1063 Gc was significantly reduced compared to wild-type, and survival was restored upon addition of recombinant Ng_1981. Δ1981Δ1063 mutant Gc survival was additionally reduced in the presence of human neutrophils, which produce lysozyme. We found that while Ng_1063 was exposed on the surface of Gc, Ng_1981 was both in an intracellular pool and extracellularly released from the bacteria, suggesting that Gc employs these two proteins at multiple spatial barriers to fully neutralize lysozyme activity. Together, these findings identify Ng_1063 and Ng_1981 as critical components for Gc defense against lysozyme. These proteins may be attractive targets for antimicrobial therapy aimed to render Gc susceptible to host defenses and/or for vaccine development, both of which are urgently needed against drug-resistant gonorrhea.
Long non‐coding RNA lnc‐PCTST predicts prognosis through inhibiting progression of pancreatic cancer by downregulation of TACC‐3

Pancreatic cancer (PC), which is one of the most lethal of malignancies and a major health burden, is associated with a dismal prognosis despite current therapeutic advances. Numerous long noncoding RNAs (lncRNA) have shown to be essential for PC tumorigenesis and progression. Nevertheless, the exact expression pattern of lnc‐PCTST and its clinical significance still remain unclear. This study investigates the expression pattern of lnc‐PCTST and its associated mRNA in three paired PC tissues and adjacent non‐tumor tissues by Microarray‐coarray approach. Briefly, our data demonstrated that lnc‐PCTST expression is down‐regulated in PC tissues. Also, lnc‐PCTST has shown to be negatively correlated with transforming acidic coiled‐coil 3 (TACC‐3) expression. This expression pattern was further confirmed following qRT‐PCR validation of 34 out of 48 paired cancer tissues. Furthermore, lnc‐PCTST overexpression in PC cell lines inhibited cell proliferation and invasion in vitro, and tumorigenesis in vivo (using nude mice as animal model), but did not altered cell migration. Moreover, lnc‐PCTST overexpression increased E‐cadherin and repressed vimentin expression in vitro. Additionally, TACC‐3 knockdown simulated the inhibiting effect of lnc‐PCTST overexpression on PC cell lines, and the impaired proliferation, invasion effect and E‐cadherin, vimentin expression on lnc‐PCTST over‐expressed cell lines can be rescued by overexpressed TACC‐3. Significantly, the expression of lnc‐PCTST was closely associated with its genomic neighboring gene TACC‐3 and inhibited its promoter activity. In conclusion, lnc‐PCTST is a potential tumor suppressor in PC, which inhibits cell proliferation, invasion, tumorigenesis and EMT by modulating TACC‐3.
‘In a blink of an eye your life can change’: experiences of players sustaining a rugby-related acute spinal cord injury

Background Though rare, rugby union carries a risk for serious injuries such as acute spinal cord injuries (ASCI), which may result in permanent disability. Various studies have investigated injury mechanisms, prevention programmes and immediate medical management of these injuries. However, relatively scant attention has been placed on the player’s experience of such an injury and the importance of context. Aim The aim of this study was to explore the injury experience and its related context, as perceived by the catastrophically injured player. Methods A qualitative approach was followed to explore the immediate, postevent injury experience. Semi-structured interviews were conducted with 48 (n=48) players who had sustained a rugby-related ASCI. Results Four themes were derived from the data. Participants described the context around the injury incident, which may be valuable to help understand the mechanism of injury and potentially minimise risk. Participants also described certain contributing factors to their injury, which included descriptions of foul play and aggression, unaccustomed playing positions, pressure to perform and unpreparedness. The physical experience included signs and symptoms of ASCI that is important to recognise by first aiders, fellow teammates, coaches and referees. Lastly, participants described the emotional experience which has implications for all ASCI first responders. Significance All rugby stakeholders, including players, first responders, coaches and referees, may gain valuable information from the experiences of players who have sustained these injuries. This information is also relevant for rugby safety initiatives in shaping education and awareness interventions.
Imperceptible Watermarking Scheme for Fundus Images Using Intra-Plane Difference Expanding

This paper proposes an imperceptible watermarking scheme for digital fundus images. It is a pooled approach of two schemes proposed in (1) and (2). Hiding a large amount of data (image, audio, text) file into color BMP images proposed in (1). It could achieve the better capacity in irreversible way which is not suitable for fundus images. The difference expanding method proposed for medical images in (2). It suffered from imperceptibility. Hence, these two schemes were combined in the proposed scheme by addressing better capacity, imperceptibility, reversibility and robustness. The embedding process in the proposed scheme involves two steps. First step selects the pixel according to the color characteristics of the fundus images. Second step embeds the secret information into selected pixels by using the difference expanding method of the two pixels from different color planes. It is known as intra-plane difference expanding. It embeds more than one bit at each byte in one pixel of the fundus image and give us imperceptible results. This scheme is robust to statistical and visual attacks. The comparison results showed the improvement of imperceptivity to 15% in the proposed scheme with respect to the scheme proposed in (1). It also identified that that 30000 bits is the optimum size of the watermark with good level of imperceptibility which is above 60 dB at an average.