bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dual-acting stapled peptides target both HIV-1 entry and assembly
Authors: Zhang Hongtao , Curreli Francesca , Waheed Abdul A , Mercredi Peter Y , Mehta Mansi , Bhargava Pallavi , Scacalossi Daniel , Tong Xiaohe , Lee Shawn , Cooper Alan , Summers Michael F , Freed Eric O , Debnath Asim K 
Published: November 2013

Abstract

Background
Previously, we reported the conversion of the 12-mer linear and cell-impermeable peptide CAI to a cell-penetrating peptide NYAD-1 by using an i,i + 4 hydrocarbon stapling technique and confirmed its binding to the C-terminal domain (CTD) of the HIV-1 capsid (CA) protein with an improved affinity (Kd ~ 1 μM) compared to CAI (Kd ~ 15 μM). NYAD-1 disrupts the formation of both immature- and mature-like virus particles in in vitro and cell-based assembly assays. In addition, it displays potent anti-HIV-1 activity in cell culture against a range of laboratory-adapted and primary HIV-1 isolates.

Results
In this report, we expanded the study to i,i + 7 hydrocarbon-stapled peptides to delineate their mechanism of action and antiviral activity. We identified three potent inhibitors, NYAD-36, -66 and -67, which showed strong binding to CA in NMR and isothermal titration calorimetry (ITC) studies and disrupted the formation of mature-like particles. They showed typical α-helical structures and penetrated cells; however, the cell penetration was not as efficient as observed with the i,i + 4 peptides. Unlike NYAD-1, the i,i + 7 peptides did not have any effect on virus release; however, they impaired Gag precursor processing. HIV-1 particles produced in the presence of these peptides displayed impaired infectivity. Consistent with an effect on virus entry, selection for viral resistance led to the emergence of two mutations in the gp120 subunit of the viral envelope (Env) glycoprotein, V120Q and A327P, located in the conserved region 1 (C1) and the base of the V3 loop, respectively.

Conclusion
The i,i + 7 stapled peptides derived from CAI unexpectedly target both CA and the V3 loop of gp120. This dual-targeted activity is dependent on their ability to penetrate cells as well as their net charge. This mechanistic revelation will be useful in further modifying these peptides as potent anti-HIV-1 agents.
Drug development for exceptionally rare metabolic diseases: challenging but not impossible
Authors: Putzeist Michelle , Mantel-Teeuwisse Aukje K , Wied Christine C Gispen-de , Hoes Arno W , Leufkens Hubert GM , de Vrueh Remco LA 
Published: November 2013

Abstract

Background
We studied to what extent the level of scientific knowledge on exceptionally rare metabolic inherited diseases and their potential orphan medicinal products is associated with sponsors deciding to apply for an orphan designation at the US Food and Drug Administration (FDA) or the European Medicines Agency (EMA).

Methods
All metabolic diseases with a genetic cause and prevalence of less than 10 patients per 1 million of the population were selected from the ‘Orphanet database of Rare diseases’. The outcome of interest was the application for an orphan designation at FDA or EMA. The level of publicly available knowledge of the disease and drug candidate before an orphan designation application was defined as whether the physiological function corresponding with the pathologic gene and initiation of the pathophysiological pathway was known, whether an appropriate animal study was identified for the disease, whether preclinical proof of concept was ascertained and the availability of data in humans. Other determinants included in the study were metabolic disease class, the prevalence of the disease, prognosis and time of first description of the disease in the literature. Univariate relative risks (RRs) and 95% confidence intervals (CIs) of an orphan designation application were calculated for each of these determinants. In addition, a multivariate Cox regression analysis was conducted (Forward LR).

Results
In total, 166 rare metabolic genetic diseases were identified and included in the analysis. For only 42 (25%) of the diseases an orphan designation application was submitted at either FDA or EMA before January 2012. The multivariate analysis identified preclinical proof of concept of a potential medicinal product as major knowledge related determinant associated with an orphan designation application (RRadj 3.9, 95% CI 1.9-8.3) and confirmed that prevalence of the disease is also associated with filing an application for an orphan designation (RRadj 2.8, 95% CI 1.4-5.4).

Conclusion
For only one out of four known exceptionally rare metabolic inherited diseases sponsors applied for an orphan designation at FDA or EMA. These applications were found to be associated with the prevalence of the rare disease and the level of available scientific knowledge on the proof of concept linking possible drug candidates to the disease of interest.
Histological assessments of intestinal immuno-morphology of tiger grouper juvenile, Epinephelus fuscoguttatus
Authors: Firdaus-Nawi Mohd , Zamri-Saad Mohd , Nik-Haiha Nik Yusoff , Zuki Md Abu Bakar , Effendy Abd Wahid Mohd 
Published: November 2013

Abstract
Histological assessments on the intestinal morphology and immunity of tiger grouper juveniles, Epinephelus fuscoguttatus help in determining the earliest age to start an oral vaccination. This study describes the morphological development of the intestinal immunity of tiger grouper of various ages. Clinically healthy tiger groupers were selected and divided into 4 groups of 20 fish per group. Groups 1, 2, 3 and 4 consisted of juveniles of 30, 60, 90 and 120 days old, respectively. The whole intestine was collected and divided into three regions, the anterior, mid and posterior intestine and fixed in 10% buffered formalin before slides were prepared for microscopic examinations. It was found that the histological structures of the anterior intestine were for absorption of nutrient from digested food particles. The significantly (p < 0.05) higher number and length of the intestinal villi and smaller gap between villi were observed in the anterior intestine, which were structures for absorption. Structures of the posterior intestine were for immunity especially the adaptive immunity with included significantly (p < 0.05) higher numbers of the lymphoid and goblet cells, and significantly (p < 0.05) thicker lamina propria, which were structures for immunity. The mid intestine was the transition structure that involved in both absorption and innate immunity. The results also revealed that leukocytes existed in the lamina propria of 30-days old tiger groupers, an indication that the immune system was present at that particular age.
The effect of temperature on the viability of human mesenchymal stem cells
Authors: Reissis Yannis , García-Gareta Elena , Korda Michelle , Blunn Gordon W , Hua Jia 
Published: November 2013

Abstract
Introduction
Impaction allograft with cement is a common technique used in revision hip surgeries for the last 20 years. However, its clinical results are inconsistent. Recent studies have shown that mesenchymal stem cells (MSCs) seeded onto allograft can enhance bone formation. This in vitro study investigates whether the increase in temperature related to the polymerisation of bone cement will affect the viability of human MSCs.

Methods
The viability of human MSCs was measured after incubating them at temperatures of 38°C, 48°C and 58°C; durations 45 seconds, 80 seconds and 150 seconds. A control group was kept at 37°C and 5% carbon dioxide for the duration of the investigation (7 days). During the course of the study the human MSCs were analysed for cell metabolic activity using the alamarBlue™ assay, cell viability using both Trypan Blue dye exclusion and calcein staining under fluorescent microscopy, and necrosis and apoptosis using Annexin V and propidium iodide for flow cytometric analysis. A one-way analysis of variance with a priori Dunnett’s test was used to indicate the differences between the treatment groups, when analysed against the control. This identified conditions with a significant difference in cell metabolic activity (alamarBlue™) and cell viability (Trypan Blue).

Results
Results showed that cell metabolism was not severely affected up to 48°C/150 seconds, while cells in the 58°C group died. Similar results were shown using Trypan Blue and calcein analysis for cell viability. No significant difference in apoptosis and necrosis of the cells was observed when human MSCs treated at 48°C/150 seconds were compared with the control group.

Conclusions
The study suggests that human MSCs seeded onto allograft can be exposed to temperatures up to 48°C for 150 seconds. Exposure to this temperature for this time period is unlikely to occur during impaction allograft surgery when cement is used. Therefore, in many situations, the addition of human MSCs to cemented impaction grafting may be carried out without detrimental effects to the cells. Furthermore, previous studies have shown that this can enhance new bone formation and repair the defects in revision situations.
Virus-specific CD4 and CD8 T cell responses in the absence of Th1-associated transcription factors
Authors: Mollo Sarah B , Ingram Jennifer T , Kress Robert L , Zajac Allan J , Harrington Laurie E 
Published: November 2013

ABSTRACTEffector and memory CD4 and CD8 T cell responses are critical for the control of many intracellular pathogens. The development of these populations is governed by transcription factors that molecularly control their differentiation, function, and maintenance. Two transcription factors known to be involved in these processes are Tbet and STAT4. Although Tbet has been shown to regulate CD8 T cell fate decisions and effector CD4 T cell choices, the contribution of STAT4 is less well understood. To address this, we examined the impact of STAT4 on T cell responses in the presence or absence of Tbet, following LCMV infection by using mice lacking Tbet, STAT4, or both transcription factors. STAT4 was not required for Tbet or Eomes expression; however, virus-specific effector CD8 T cells are skewed toward a memory-precursor phenotype in the absence of STAT4. This altered proportion of memory precursors did not result in an increase in memory CD8 T cells after the resolution of the infection. We also demonstrate that virus-specific effector and memory CD4 T cells formed independently of Tbet and STAT4, although a slight reduction in the number of antigen-specific CD4 T cells was apparent in mice lacking both transcription factors. Collectively, we have discovered distinct roles for Tbet and STAT4 in shaping the phenotype and function of virus-specific T cell responses.
No psychological effect of color context in a low level vision task
Authors: Pedley Adam , Wade Alex R 
Published: November 2013

Background: A remarkable series of recent papers have shown that colour can influence performance in cognitive tasks. In particular, they suggest that viewing a participant number printed in red ink or other red ancillary stimulus elements improves performance in tasks requiring local processing and impedes performance in tasks requiring global processing whilst the reverse is true for the colour blue. The tasks in these experiments require high level cognitive processing such as analogy solving or remote association tests and the chromatic effect on local vs. global processing is presumed to involve widespread activation of the autonomic nervous system. If this is the case, we might expect to see similar effects on all local vs. global task comparisons. To test this hypothesis, we asked whether chromatic cues also influence performance in tasks involving low level visual feature integration.Methods: Subjects performed either local (contrast detection) or global (form detection) tasks on achromatic dynamic Glass pattern stimuli. Coloured instructions, target frames and fixation points were used to attempt to bias performance to different task types. Based on previous literature, we hypothesised that red cues would improve performance in the (local) contrast detection task but would impede performance in the (global) form detection task. Results: A two-way, repeated measures, analysis of covariance (2×2 ANCOVA) with gender as a covariate, revealed no influence of colour on either task, F(1,29) = 0.289, p = 0.595, partial η2 = 0.002. Additional analysis revealed no significant differences in only the first attempts of the tasks or in the improvement in performance between trials.Discussion: We conclude that motivational processes elicited by colour perception do not influence neuronal signal processing in the early visual system, in stark contrast to their putative effects on processing in higher areas.
A new Cocconeis (Bacillariophyceae) from Moorea Island, Society Archipelago, South Pacific Ocean with distinctive valvocopula morphology and linking system
Authors: Riaux-Gobin Catherine , Romero Oscar E. , Coste Michel , Galzin René 
Published: November 2013

Abstract
The study of coral reef diatoms on Moorea Island in the Society Archipelago, South Pacific Ocean revealed a strong representation of the Achnanthales, with many taxa of Cocconeis. One of these Cocconeis, examined by light and scanning electron microscopy, shows a sternum valve (SV) with a close resemblance to the Cocconeis scutellum lineage, whereas the raphe valve (RV) and the valvocopula system are different from that of C. scutellum, therefore a new name has been given to it, Cocconeis spina-christi sp. nov. This new taxon has several remarkable features: 1) the RV stria density is, on average, twice as high as that of the SV; 2) the RV valvocopula extended and structurally complex, has large marginal fenestrae, irregular digitiform fimbriae and one longer spine-like fimbria at each apex; and 3) an anchor system between the valvocopula of each valve is observed, consisting of a rounded papilla with transverse furrows lying on each basal RV valvocopula fimbria and fitting into a rounded concavity – or cupule – in the corresponding marginal edge of the SV valvocopula. Such an anchor system between valvocopulae seems a characteristic common to several Cocconeis species bearing fimbriae on each valvocopula. The definition and limit of the concept of varieties in the C. scutellum lineage is also addressed.
Drug knowledge of expatriate adolescents in the United Arab Emirates and their attitudes towards self-medication
Authors: Shehnaz Syed Ilyas , Khan Nelofer , Sreedharan Jayadevan , Arifulla Mohamed 
Published: November 2013

Abstract
Background: Adolescents have limited knowledge about medicines and their potential adverse effects. In this context, we aimed to investigate the basic knowledge of medicines, any differences in knowledge related to practice of self-medication (SM), attitudes towards SM and sources of information about medicines among expatriate adolescents in the United Arab Emirates (UAE).
Methods: A cross-sectional survey was conducted among 324 students from four schools in the UAE using a self-administered questionnaire. Data were analyzed using SPSS version 19.
Results: The sample of multi-ethnic students, with ages ranging from 14 to 19 years, was almost equally distributed between the genders. A total of 289 students reported to be self-medicating. More than 60% of adolescents had responded incorrectly to eight questions related to knowledge about medicines. There were no significant differences between mean scores for drug knowledge (maximum score=22) of self-medicating adolescents (12.1±4.32; SMAs) and those not practicing SM (12±4.53; NSMAs). Self-assessment of drug knowledge was perceived as good by 33% and satisfactory by 34% of SMAs. The majority of adolescents (87%) believed that SM was acceptable and reported being aware of its advantages and disadvantages. Parents and pharmacists were common sources of information about medicines.
Conclusion: The participants showed a positive inclination towards SM. The SMAs and NSMAs had similar knowledge about medicines. However, gaps in knowledge may lead to drug misuse and toxicity. Healthcare providers, pharmacists, educators and parents should be actively involved in health education strategies for rational use of medicines among adolescents in the UAE.
Quantification of healthy and atretic germ cells and follicles in the developing and post-natal ovary of the South American plains vizcacha, Lagostomus maximus: evidence of continuous rise of the germinal reserve
Authors: Inserra P I F , Leopardo N P , Willis M A , Freysselinard A L , Vitullo A D 
Published: November 2013

The female germ line in mammals is subjected to massive cell death that eliminates 60–85% of the germinal reserve by birth and continues from birth to adulthood until the exhaustion of the germinal pool. Germ cell demise occurs mainly through apoptosis by means of a biased expression in favour of pro-apoptotic members of theBCL2gene family. By contrast, the South American plains vizcacha,Lagostomus maximus, exhibits sustained expression of the anti-apoptoticBCL2gene throughout gestation and a low incidence of germ cell apoptosis. This led to the proposal that, in the absence of death mechanisms other than apoptosis, the female germ line should increase continuously from foetal life until after birth. In this study, we quantified all healthy germ cells and follicles in the ovaries ofL. maximusfrom early foetal life to day 60 after birth using unbiased stereological methods and detected apoptosis by labelling with TUNEL assay. The healthy germ cell population increased continuously from early-developing ovary reaching a 50 times higher population number by the end of gestation. TUNEL-positive germ cells were <0.5% of the germ cell number, except at mid-gestation (3.62%). Mitotic proliferation, entrance into prophase I stage and primordial follicle formation occurred as overlapping processes from early pregnancy to birth. Germ cell number remained constant in early post-natal life, but a remnant population of non-follicular VASA- and PCNA-positive germ cells still persisted at post-natal day 60.L. maximusis the first mammal so far described in which female germ line develops in the absence of constitutive massive germ cell elimination.Free Spanish abstractSpanish translation of this abstract is freely available athttp://www.reproduction-online.org/content/147/2/199/suppl/DC1
Predicting Adaptive Phenotypes From Multilocus Genotypes in Sitka Spruce (Picea sitchensis) Using Random Forest
Authors: Holliday Jason A , Wang Tongli , Aitken Sally 
Published: November 2013

Abstract
Climate is the primary driver of the distribution of tree species worldwide, and the potential for adaptive evolution will be an important factor determining the response of forests to anthropogenic climate change. Although association mapping has the potential to improve our understanding of the genomic underpinnings of climatically relevant traits, the utility of adaptive polymorphisms uncovered by such studies would be greatly enhanced by the development of integrated models that account for the phenotypic effects of multiple single-nucleotide polymorphisms (SNPs) and their interactions simultaneously. We previously reported the results of association mapping in the widespread conifer Sitka spruce (Picea sitchensis). In the current study we used the recursive partitioning algorithm ‘Random Forest’ to identify optimized combinations of SNPs to predict adaptive phenotypes. After adjusting for population structure, we were able to explain 37% and 30% of the phenotypic variation, respectively, in two locally adaptive traits—autumn budset timing and cold hardiness. For each trait, the leading five SNPs captured much of the phenotypic variation. To determine the role of epistasis in shaping these phenotypes, we also used a novel approach to quantify the strength and direction of pairwise interactions between SNPs and found such interactions to be common. Our results demonstrate the power of Random Forest to identify subsets of markers that are most important to climatic adaptation, and suggest that interactions among these loci may be widespread.
Evolutionary History and Genome Organization of DUF1220 Protein Domains
Authors: O’Bleness Majesta S , Dickens C Michael , Dumas Laura J , Kehrer-Sawatzki Hildegard , Wyckoff Gerald J , Sikela James M 
Published: November 2013

AbstractDUF1220 protein domains exhibit the most extreme human lineage–specific (HLS) copy number increase of any protein coding region in the human genome and have recently been linked to evolutionary and pathological changes in brain size (e.g., 1q21-associated microcephaly). These findings lend support to the view that DUF1220 domain dosage is a key factor in the determination of primate (and human) brain size. Here we analyze 41 animal genomes and present the most complete account to date of the evolutionary history and genome organization of DUF1220 domains and the gene family that encodes them (NBPF). Included among the novel features identified by this analysis is a DUF1220 domain precursor in nonmammalian vertebrates, a unique predicted promoter common to all mammalian NBPF genes, six distinct clades into which DUF1220 sequences can be subdivided, and a previously unknown member of the NBPF gene family (NBPF25). Most importantly, we show that the exceptional HLS increase in DUF1220 copy number (from 102 in our last common ancestor with chimp to 272 in human; an average HLS increase of ∼28 copies every million years since the Homo/Pan split) was driven by intragenic domain hyperamplification. This increase primarily involved a 4.7 kb, tandemly repeated three DUF1220 domain unit we have named the HLS DUF1220 triplet, a motif that is a likely candidate to underlie key properties unique to the Homo sapiens brain. Interestingly, all copies of the HLS DUF1220 triplet lie within a human-specific pericentric inversion that also includes the 1q12 C-band, a polymorphic heterochromatin expansion that is unique to the human genome. Both cytogenetic features likely played key roles in the rapid HLS DUF1220 triplet hyperamplification, which is among the most striking genomic changes specific to the human lineage.
Variant in the 5′ Untranslated Region of Insulin-Like Growth Factor 1 Receptor Is Associated With Susceptibility to Mastitis in Cattle
Authors: Sugimoto Mayumi , Sugimoto Yoshikazu 
Published: November 2013

Abstract
Mastitis is a common infectious disease of the mammary gland and generates large losses in the dairy industry. By means of positional cloning and functional analysis techniques, we here show that insulin-like growth factor 1 receptor (IGF1R) can possibly mediate susceptibility to mastitis through autophagy. Scanning the whole genome of cows (Bos taurus) that were susceptible or resistant to mastitis in the half-sib families revealed that susceptible cows had a relatively long stretch of cytosine residues (C stretch) in the 5′ untranslated region of IGF1R. The forebrain embryonic zinc finger-like (FEZL) transcription factor, which was previously identified as a factor controlling mastitis resistance in the same half-sib families, bound the C stretch of IGF1R. The susceptible type of FEZL with a glycine stretch containing 13 glycines (13G) and the longer C stretch of IGF1R together enhanced expression of IGF1R. Enhancing IGF1R inhibited autophagy in response to Streptococcus agalactiae invasion of mammary epithelial cells, whereas treatment with rapamycin, a known inducer of autophagy, rescued it. Cows carrying the variant combination of 13GFEZL might be more susceptible to mastitis as the result of impaired autophagy. Our results suggest that IGF1R could control innate immunity in mammals and serve as a potential tool for preventing mastitis.