Miracle-dz/UniFAR-FTUs huggingface dataset:
The RNA-binding Protein RNPC1 Stabilizes the mRNA Encoding the RNA-binding Protein HuR and Cooperates with HuR to Suppress Cell Proliferation*

Background: The mechanism by which HuR expression is controlled is poorly understood. Results: HuR mRNA is stabilized by RNPC1. Furthermore, HuR, by repressing c-Myc expression, facilitates RNPC1-induced growth suppression. Conclusion: HuR is a target of RNPC1 and a mediator of RNPC1-induced growth suppression. Significance: Our results reveal a novel regulation of HuR by RNPC1 via mRNA stability. The RNA-binding protein HuR, a member of the embryonic lethal abnormal vision/Hu protein family, plays a critical role in many cellular processes, including cell proliferation, angiogenesis, and inflammatory response. Despite significant progresses in understanding how HuR functions, the mechanism by which HuR expression is controlled is still poorly understood. Here, we showed that RNA-binding protein RNPC1 post-transcriptionally regulates HuR expression via mRNA stability. Specifically, we showed that overexpression of RNPC1 increases, whereas knockdown or knock-out of RNPC1 decreases, the level of HuR transcript and protein. Moreover, we showed that RNPC1, but not mutant RNPC1 deficient in RNA binding, stabilizes HuR transcript via binding to its 3′-untranslated region. Furthermore, to determine the biological significance of RNPC1-enhanced HuR expression, we showed that HuR, by repressing c-Myc expression, facilitates RNPC1-mediated growth suppression. Together, we have uncovered a novel mechanism by which HuR is regulated by RNPC1 via mRNA stability and HuR is a mediator of RNPC1-induced growth suppression.
Sudden natural death in Khartoum Mortuary

Background: The sudden natural death is defined as: Death occurs within 24 hours from the onset of symptoms. The disclosing of the causes of sudden natural death is important for prevention and improving outcome. The objectives of this study were to determine the causes of sudden natural death in Khartoum Mortuary Methods: Descriptive, cross- sectional study of natural sudden death in Khartoum Mortuary, which was located in Khartoum Teaching Hospital and offers services to the state. The autopsy records of 2007, which were 150, were considered. Data were collected by a structured check list, and analysis was done by the SPSS soft ware. Results:The most important systems involved in sudden natural deaths were respiratory (49.3%), cardiovascular (24%), gastro intestinal (15.3%) and cerebral (4%), while the leading causes of sudden natural death were pneumonia (20%), myocardial infarction (17.3%) and tuberculosis (14%). Sudden natural death occurred in slightly higher ratio in the age group 40 years and below (50.1%), males were dominating (83%). Conclusion: The commonest causes of sudden natural death, which were pneumonia, myocardial infarction and tuberculosis, were different from the literature in which the commonest causes were myocardial infarction followed by pulmonary embolism. The study highlighted the importance of respiratory diseases besides myocardial infarction as leading causes of sudden natural death, and the need for further researches in this issue. Keywords : pneumonia, myocardial infarction and tuberculosis, postmortem Sudan Journal of Medical Science Vol. 3 (4) 2008: pp. 319-324
A vascular and thrombotic model of gastroschisis

A binary vascular/thrombotic pathogenesis for gastroschisis, a form of congenital bowel herniation, is proposed, where normal right umbilical vein involution creates a possible site for thrombosis adjacent to the umbilical ring. If thrombosis occurs, it weakens the area, explaining overwhelmingly right‐sided lesions. The model arises from the existence of two groups of risk factors with different maternal age associations. Older mothers show a greater association with vascular factors (although this may actually represent a lack of any significant maternal age effect), consistent with associations of gastroschisis with congenital heart lesions and with amyoplasia. Alternatively, other predispositions, and especially decreased maternal age, the greatest known risk factor, associate with factors raising maternal estrogen, with evidence that estrogen in turn acts here as a predisposition to thrombosis. Absorption of thrombotic by‐products from the amniotic fluid can explain the unusual amniocyte inclusions that are common with gastroschisis, while a role for estrogens suggests a connection between rising gastroschisis prevalence and increasing environmental contamination with estrogen disruptors. This model explains a variety of structural and epidemiological findings, and suggests that stratification of data based on binary effects may clarify associated risks and mechanisms. The model also shows that what is often referred to as vascular disruption may actually reflect alternative or additional factors instead, including thrombosis as a primary mechanism. © 2014 Wiley Periodicals, Inc.
The quadriceps angle and the incidence of knee injury in Indian long-distance runners

Objective. To investigate the incidence of knee injuries in runners and to determine the proportion of injuries involving abnormal quadriceps (Q)-angles. Design. One hundred male Indian runners between the ages of 25 and 65 years from 5 athletic clubs in Durban volunteered to participate in the study. The Q-angle was measured using a goniometer. Other relevant information was obtained using a validated questionnaire. The data were analysed by comparing measured Q-angles with ‘normal' values of Q-angles obtained from the literature. A paired t-test at a probability of 0.05 was used. Setting. Data were collected at club meetings. Main outcome measure. The primary outcome of the study was to determine the proportion of runners with abnormal Q-angles. Thereafter the rate of knee injuries in runners with abnormal Q-angles was determined. Results. Data from 88 runners were usable. Fifty-one per cent of the runners sustained knee injuries. Fifty-eight per cent of the sample had abnormal Q-angles. Sixty-seven per cent of the runners with abnormal Q-angles sustained knee injuries. Conclusion. More runners with abnormal Q-angles sustained knee injuries. There is a need to determine reference values for Q-angles for the South African population, the proportion of the population that present with abnormal Q-angles, and the reasons for this. South African Journal of Sports Medicine Vol. 19 (1) 2007: pp. 9-11
Neutralization of Macrophage Migration Inhibitory Factor (MIF) by Fully Human Antibodies Correlates with Their Specificity for the β-Sheet Structure of MIF*

Background: A diverse panel of fully human antibodies specific for the macrophage migration inhibitory factor (MIF) has been generated. Results: In vitro and in vivo studies revealed that antibodies specific for a β-sheet structure are potent inhibitors of MIF. Conclusion: This β-sheet structure is a promising target for anti-MIF antibody therapy. Significance: Fully human antibodies with high therapeutic potential have been identified. The macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that recently emerged as an attractive therapeutic target for a variety of diseases. A diverse panel of fully human anti-MIF antibodies was generated by selection from a phage display library and extensively analyzed in vitro. Epitope mapping studies identified antibodies specific for linear as well as structural epitopes. Experimental animal studies revealed that only those antibodies binding epitopes within amino acids 50–68 or 86–102 of the MIF molecule exerted protective effects in models of sepsis or contact hypersensitivity. Within the MIF protein, these two binding regions form a β-sheet structure that includes the MIF oxidoreductase motif. We therefore conclude that this β-sheet structure is a crucial region for MIF activity and a promising target for anti-MIF antibody therapy.
Arthritis Impact on Employment Participation among U.S. Adults: A Population-based Perspective

Background: Arthritis is a large and growing problem, affecting 53 million U.S. adults, more than two-thirds of whom are younger than age 65. Approximately 1/3 of working-age (18-64 years) U.S adults with arthritis report arthritis-attributable work limitation (5% of the total working-age population).
Blepharophimosis, short humeri, developmental delay and hirschsprung disease: Expanding the phenotypic spectrum of MED12 mutations

We report on two male sibs, a fetus and a newborn, with short humeri and dysmorphic facial features including blepharophimosis. The newborn also had Hirschsprung disease. Goldberg–Shprintzen syndrome and the Say–Barber–Biesecker–Young–Simpson type of Ohdo syndrome were suspected but direct sequencing of KBP and KAT6B failed to identify a mutation. Finally, direct sequencing of MED12, the gene mutated in Opitz–Kaveggia syndrome, Lujan–Fryns syndrome and X‐linked Ohdo syndrome identified in the two sibs the missense mutation c.3443G>A (p.Arg1148His) inherited from the mother. This report further expands the phenotypic spectrum of MED12 mutations. © 2014 Wiley Periodicals, Inc.
Triple negative, basal-like and BRCA1-associated breast cancers – what’s the difference and should anyone care?

Abstract Breast carcinoma is common in women and forms an integral part of the BRCA familial cancer syndromes. As breast cancer is considered a heterogeneous disease, clinicians have traditionally relied on clinical and morphologic findings, as well as hormone receptor/HER-2 status for prognostic and predictive categorisation of tumours. Recently, breast cancer subclassification has been aided by the discovery of various gene expression profiles, compiled after simultaneous examination of multiple tumour biomarker genes. Basal-like breast cancer was delineated using this methodology and demonstrates significant overlap with so-called triple negative and BRCA1-associated breast carcinomas. This article describes the pathology and biology of these three groups of tumours and examines the relationship between them. Therapeutic implications are also briefly discussed.
Glioblastoma-derived Tumor Cells Induce Vasculogenic Mimicry through Flk-1 Protein Activation*

Background: The malignancy of glioblastoma is characterized by strong vascularization, including vasculogenic mimicry and angiogenesis. Results: Glioblastoma cells promote vasculogenic mimicry and tumor development via Flk-1 activation. Conclusion: Glioblastoma cells display the ability to constitute vascular channels. Significance: Identification of Flk-1 as a key factor regulating vasculogenic mimicry could offer a novel therapeutic target for patient treatment. Glioblastoma (GBM) is extremely aggressive and essentially incurable. Its malignancy is characterized by vigorous microvascular proliferations. Recent evidence has shown that tumor cells display the ability to drive blood-perfused vasculogenic mimicry (VM), an alternative microvascular circulation independent of endothelial cell angiogenesis. However, molecular mechanisms underlying this vascular pathogenesis are poorly understood. Here, we found that vascular channels of VM in GBM were composed of mural-like tumor cells that strongly express VEGF receptor 2 (Flk-1). To explore a potential role of Flk-1 in the vasculogenesis, we investigated two glioblastoma cell lines U87 and GSDC, both of which express Flk-1 and exhibit a vascular phenotype on Matrigel. Treatment of both cell lines with either Flk-1 gene knockdown or Flk-1 kinase inhibitor SU1498 abrogated Flk-1 activity and impaired vascular function. Furthermore, inhibition of Flk-1 activity suppressed intracellular signaling cascades, including focal adhesion kinase and mitogen-activated protein kinase ERK1/2. In contrast, blockade of VEGF activity by the neutralizing antibody Bevacizumab failed to recapitulate the impact of SU1498, suggesting that Flk-1-mediated VM is independent of VEGF. Xenotransplantation of SCID/Beige mice with U87 cells and GSDCs gave rise to tumors harboring robust mural cell-associated vascular channels. Flk-1 shRNA restrained VM in tumors and subsequently inhibited tumor development. Collectively, all the data demonstrate a central role of Flk-1 in the formation of VM in GBM. This study has shed light on molecular mechanisms mediating tumor aggressiveness and also provided a therapeutic target for patient treatment.
Melanocortin 1 Receptor Regulates Melanoma Cell Migration by Controlling Syndecan-2 Expression*

Background: The melanocortin 1 receptor is known to regulate inflammation. Results: The melanocortin 1 receptor inhibits activation of p38 MAPK, subsequently enhancing syndecan-2 expression and migration in melanoma cells. Conclusion: The melanocortin 1 receptor regulates melanoma cell migration by controlling syndecan-2 expression. Significance: This work shows the melanocortin 1 receptor plays a role during cell migration. The melanocortin 1 receptor (MC1R), a key regulator of melanogenesis, is known to control inflammation, acting in concert with the MC1R ligand α-melanocyte-stimulating hormone. Although cell migration is a key event in inflammation, few studies have addressed the function of MC1R in this context. Using highly motile melanoma cells, we found that the expression level of MC1R was associated with the extent of migration of mouse melanoma cells, suggesting that MC1R plays a functional role in controlling this migration. Overexpression of MC1R enhanced melanoma cell migration, whereas the opposite was true when MC1R levels were knocked down using small inhibitory RNAs. Interestingly, MC1R expression enhanced the synthesis of syndecan-2, a cell surface heparan sulfate proteoglycan known to be involved in melanoma cell migration. Knockdown of syndecan-2 expression decreased MC1R-mediated cell migration. Further, MC1R inhibited the activation of p38 MAPK, subsequently enhancing expression of sydnecan-2, in parallel with an increase in the extent of cell migration. Consistently, activation of p38 by H2O2 inhibited syndecan-2 expression and cell migration, whereas inhibition of p38 activation enhanced syndecan-2 expression and cell migration. Finally, we found that α-melanocyte-stimulating hormone inhibited MC1R-mediated cell migration via activation of p38 and inhibition of syndecan-2 expression. Together, the data strongly suggest that MC1R regulates melanoma cell migration via inhibition of syndecan-2 expression.
Activation of Mitochondrial Calcium-independent Phospholipase A2γ (iPLA2γ) by Divalent Cations Mediating Arachidonate Release and Production of Downstream Eicosanoids*♦

Background: Calcium-independent PLA2γ is a major phospholipase in cardiac mitochondria that modulates multiple mitochondrial functions, but its mechanism of activation is unknown. Results: Divalent cations activate iPLA2γ leading to release of eicosanoids and lysolipids from mitochondrial phospholipids. Conclusion: Divalent cation-activated mitochondrial iPLA2γ initiates the production of biologically active signaling metabolites. Significance: iPLA2γ contributes to regulation of myocardial bioenergetic and electrophysiologic functions by production of eicosanoids. Calcium-independent phospholipase A2γ (iPLA2γ) (PNPLA8) is the predominant phospholipase activity in mammalian mitochondria. However, the chemical mechanisms that regulate its activity are unknown. Here, we utilize iPLA2γ gain of function and loss of function genetic models to demonstrate the robust activation of iPLA2γ in murine myocardial mitochondria by Ca2+ or Mg2+ ions. Calcium ion stimulated the production of 2-arachidonoyl-lysophosphatidylcholine (2-AA-LPC) from 1-palmitoyl-2-[14C]arachidonoyl-sn-glycero-3-phosphocholine during incubations with wild-type heart mitochondrial homogenates. Furthermore, incubation of mitochondrial homogenates from transgenic myocardium expressing iPLA2γ resulted in 13- and 25-fold increases in the initial rate of radiolabeled 2-AA-LPC and arachidonic acid (AA) production, respectively, in the presence of calcium ion. Mass spectrometric analysis of the products of calcium-activated hydrolysis of endogenous mitochondrial phospholipids in transgenic iPLA2γ mitochondria revealed the robust production of AA, 2-AA-LPC, and 2-docosahexaenoyl-LPC that was over 10-fold greater than wild-type mitochondria. The mechanism-based inhibitor (R)-(E)-6-(bromomethylene)-3-(1-naphthalenyl)-2H-tetrahydropyran-2-one (BEL) (iPLA2γ selective), but not its enantiomer, (S)-BEL (iPLA2β selective) or pyrrolidine (cytosolic PLA2α selective), markedly attenuated Ca2+-dependent fatty acid release and polyunsaturated LPC production. Moreover, Ca2+-induced iPLA2γ activation was accompanied by the production of downstream eicosanoid metabolites that were nearly completely ablated by (R)-BEL or by genetic ablation of iPLA2γ. Intriguingly, Ca2+-induced iPLA2γ activation was completely inhibited by long-chain acyl-CoA (IC50 ∼20 μm) as well as by a nonhydrolyzable acyl-CoA thioether analog. Collectively, these results demonstrate that mitochondrial iPLA2γ is activated by divalent cations and inhibited by acyl-CoA modulating the generation of biologically active metabolites that regulate mitochondrial bioenergetic and signaling functions.
Infection dynamics of endemic malaria in a wild bird population: parasite species-dependent drivers of spatial and temporal variation in transmission rates.

1. Investigating the ecological context in which host-parasite interactions occur and the roles of biotic and abiotic factors in forcing infection dynamics is essential to understanding disease transmission, spread and maintenance. 2. Despite their prominence as model host-pathogen systems, the relative influence of environmental heterogeneity and host characteristics in influencing the infection dynamics of avian blood parasites has rarely been assessed in the wild, particularly at a within-population scale. 3. We used a novel multievent modelling framework (an extension of multistate mark-recapture modelling) that allows for uncertainty in disease state, to estimate transmission parameters and assess variation in the infection dynamics of avian malaria in a large, longitudinally sampled data set of breeding blue tits infected with two divergent species of Plasmodium parasites. 4. We found striking temporal and spatial heterogeneity in the disease incidence rate and the likelihood of recovery within this single population and demonstrate marked differences in the relative influence of environmental and host factors in forcing the infection dynamics of the two Plasmodium species. 5. Proximity to a permanent water source greatly influenced the transmission rates of P. circumflexum, but not of P. relictum, suggesting that these parasites are transmitted by different vectors. 6. Host characteristics (age/sex) were found to influence infection rates but not recovery rates, and their influence on infection rates was also dependent on parasite species: P. relictum infection rates varied with host age, whilst P. circumflexum infection rates varied with host sex. 7. Our analyses reveal that transmission of endemic avian malaria is a result of complex interactions between biotic and abiotic components that can operate on small spatial scales and demonstrate that knowledge of the drivers of spatial and temporal heterogeneity in disease transmission will be crucial for developing accurate epidemiological models and a thorough understanding of the evolutionary implications of pathogens.
Topological plasticity increases robustness of mutualistic networks.

1. Earlier studies used static models to evaluate the responses of mutualistic networks to external perturbations. Two classes of dynamics can be distinguished in ecological networks; population dynamics, represented mainly by changes in species abundances, and topological dynamics, represented by changes in the architecture of the web. 2. In this study, we model the temporal evolution of three empirical plant-pollination networks incorporating both population and topological dynamics. We test the hypothesis that topological plasticity, realized through the ability of animals to rewire their connections after depletion of host abundances, enhances tolerance of mutualistic networks to species loss. We also compared the performance of various rewiring rules in affecting robustness. 3. The results show that topological plasticity markedly increased the robustness of mutualistic networks. Our analyses also revealed that network robustness reached maximum levels when animals with less host plant availability were more likely to rewire. Also, preferential attachment to richer host plants, that is, to plants exhibiting higher abundance and few exploiters, enhances robustness more than other rewiring alternatives. 4. Our results highlight the potential role of topological plasticity in the robustness of mutualistic networks to species extinctions and suggest some plausible mechanisms by which the decisions of foragers may shape the collective dynamics of plant-pollinator systems.
Spatial variation in egg size and egg number reflects trade-offs and bet-hedging in a freshwater fish.

1. Maternal reproductive investment is thought to reflect a trade-off between offspring size and fecundity, and models generally predict that mothers inhabiting adverse environments will produce fewer, larger offspring. More recently, the importance of environmental unpredictability in influencing maternal investment has been considered, with some models predicting that mothers should adopt a diversified bet-hedging strategy whilst others a conservative bet-hedging strategy. 2. We explore spatial egg size and fecundity patterns in the freshwater fish southern pygmy perch (Nannoperca australis) that inhabits a diversity of streams along gradients of environmental quality, variability and predictability. 3. Contrary to some predictions, N. australis populations inhabiting increasingly harsh streams produced more numerous and smaller eggs. Furthermore, within-female egg size variability increased as environments became more unpredictable. 4. We argue that in harsh environments or those prone to physical disturbance, sources of mortality are size independent with offspring size having only a minor influence on offspring fitness. Instead, maternal fitness is maximized by producing many small eggs, increasing the likelihood that some offspring will disperse to permanent water. We also provide empirical support for diversified bet-hedging as an adaptive strategy when future environmental quality is uncertain and suggest egg size may be a more appropriate fitness measure in stable environments characterized by size-dependent fitness. These results likely reflect spatial patterns of adaptive plasticity and bet-hedging in response to both predictable and unpredictable environmental variance and highlight the importance of considering both trait averages and variance. 5. Reproductive life-history traits can vary predictably along environmental gradients. Human activity, such as the hydrological modification of natural flow regimes, alters the form and magnitude of these gradients, and this can have both ecological and evolutionary implications for biota adapted to now non-existent natural environmental heterogeneity.