Miracle-dz/UniFAR-FTUs huggingface dataset:
Regulation of the Hypoxia-inducible Transcription Factor 1α by the Ubiquitin-Proteasome Pathway*

HIF-1α (hypoxia-inducible factor 1α) is a basic-helix-loop-helix PAS (Per/Arnt/Sim) transcription factor that, under hypoxic conditions, dimerizes with a partner factor, the basic-helix-loop-helix/PAS protein Arnt, to recognize hypoxia-responsive elements of target genes. It has recently been demonstrated that HIF-1α protein but not mRNA levels are dramatically up-regulated in response to hypoxia. Here we show that inhibitors of 26 S proteasome activity produced a dramatic accumulation of endogenous as well as transfected HIF-1α protein under normoxic conditions, whereas the levels of Arnt protein were not affected. HIF-1α was polyubiquitinated in vivo under normoxic conditions, indicating rapid degradation via the ubiquitin-proteasome pathway. This degradation process appeared to target a region within the C terminus of HIF-1α. Importantly, HIF-1α ubiquitination was drastically decreased under hypoxic conditions. Up-regulation of HIF-1α protein by proteasome inhibitors did not result in transcriptional activation of reporter genes, indicating either the requirement of additional regulatory steps to induce functional activity of HIF-1α or the inability of polyubiquitinated forms of HIF-1α to mediate hypoxic signal transduction. In support of both these notions, we demonstrate that HIF-1α showed hypoxia-dependent translocation from the cytoplasm to the nucleus and that this regulatory mechanism was severely impaired in the presence of proteasome inhibitors. Taken together, these data demonstrate that the mechanism of hypoxia-dependent activation of HIF-1α is a complex multistep process and that stabilization of HIF-1α protein levels is not sufficient to generate a functional form.
OPTIMIZATION MODELS, QUANTITATIVE GENETICS, AND MUTATION

The process of selection on a multivariate set of characters subject to functional constraints is considered from the points of view of both evolutionary optimization theory and quantitative genetics. Special attention is given to life‐history characteristics. It is shown that, under suitable conditions (including weak selection), useful approximate formulas for the relations between the functional constraints and the additive genetic variance‐covariance matrix can be derived. These can be used to show that the conditions for equilibrium under selection according to the two different approaches are approximately equivalent. Although large negative genetic correlations are to be expected between some pairs of life‐history traits in populations at equilibrium under selection, in general some small negative genetic correlations and some positive genetic correlations will also be present. Thus, the observation of a positive genetic correlation between a pair of life‐history traits does not necessarily refute the possibility of trade‐offs among a multivariate set of traits that contains the pair in question. The relation between the pattern of functional constraints and the genetic correlations is often complex, and little insight into the former can be derived from the latter. The effects of mutations that lower the overall efficiency of resource utilization, thereby creating a positive component to the genetic covariances among life‐history traits, are also considered for a specific model. Although such mutations can have a substantial effect on the form of the life history, extreme conditions seem to be needed for them to produce a large effect on the pattern of genetic correlations in a random‐mating population. They can, however, cause the appearance of positive correlations following inbreeding, due to the exposure of deleterious recessive or partially recessive mutations. The analysis also suggests that the population means of individual components of a constrained multivariate system may often equilibrate at values that are far from the optima that would be attained if they were selected in isolation from the other members of the system.
Mutant B3GALT6 in a Multiplex Family: A Dominant Variant Co-Segregated With Moderate Malformations

B3GALT6 is a well-documented disease-related gene. Several B3GALT6-recessive variants have been reported to cause Ehlers–Danlos syndrome (EDS). To the best of our knowledge, no dominant B3GALT6 variant that causes human disease has been reported. In 2012, we reported on a three-generation, autosomal-dominant family with multiple members who suffered from radioulnar joint rotation limitation, scoliosis, thick vermilion of both lips, and others, but the genetic cause was unknown. Here, exome sequencing of the family identified mutant B3GALT6 as the cause of the multiplex affected family. We observed that, in the compound heterozygous pattern (i.e., c.883C>T:p.R295C and c.510_517del:p.L170fs*268), mutant B3GALT6 led to severe consequences, and in the dominant pattern, an elongated B3GALT6 variant co-segregated with moderate phenotypes. The functional experiments were performed in vitro. The R295C variant led to subcellular mislocalization, whereas the L170fs*268 showed normal subcellular localization, but it led to an elongated protein. Given that most of the catalytic galactosyltransferase domain was disrupted for the L170fs*268 (it is unlikely that such a protein has activity), we propose that the L170fs*268 occupies the normal B3GALT6 protein position in the Golgi and exerts a dominant-negative effect.
Use of information-seeking strategies for developing systematic reviews and engaging in evidence-based practice: the application of traditional and comprehensive Pearl Growing. A review.

BACKGROUND Efficient library searches for research evidence are critical to practitioners who wish to engage in evidence-based practice (EBP) as well as researchers who seek to develop systematic reviews. AIMS This review will propose the benefits of the search technique 'Pearl Growing' ('Traditional Pearl Growing') as well as an adaptation of this technique ('Comprehensive Pearl Growing'), until now ignored by the literature on EBP and systematic reviews, to aid in the retrieval of research evidence. These search techniques are illustrated with examples from the field of augmentative and alternative communication. MAIN CONTRIBUTIONS Traditional Pearl Growing is proposed as an important addition to the arsenal of EBP search strategies for practitioners. The literature on Traditional Pearl Growing is extended in that EBP presents a newly identified purpose for this technique and the benefits in identifying appropriate quality filter goes beyond its previously exclusive focus on keywords. Comprehensive Pearl Growing is projected as a new strategy for researchers searching for studies to be included in systematic reviews. Not only does it provide data-based guidance in selecting effective keywords and quality filters, but also it provides appropriate databases. CONCLUSIONS Although the techniques Traditional Pearl Growing and Comprehensive Pearl Growing are believed to be useful for locating research evidence in any field, it may be particularly important for interdisciplinary topics where the use of effective controlled vocabulary plays a greater role in bringing together evidence that may be scattered across databases.
Endovascular treatment of aneurysms: gene expression of neointimal cells recruited on the embolic agent and evolution with recurrence in an experimental model.

PURPOSE The authors attempted to identify genes associated with healing or recurrence after embolization in an aneurysm model in which neointima formation at the neck varies according to flow zones. A better understanding of the relationship between blood flow, molecular events, and healing or recurrence may provide future avenues to improve results of endovascular treatment of aneurysms. METHODS Bilateral carotid venous pouch aneurysms were constructed in 36 dogs and embolized with gelatin sponges. Angiography and pathological studies were performed at T0 and/or 3 weeks (n=22). Angiographic results and neointima formation were scored using a qualitative index applied to the distal (inflow) and proximal (outflow) zones of the neck. In 14 animals, mRNA expression 1 to 14 days after embolization at the proximal or distal segment of the sponge was analyzed by RT-PCR, attempting to correlate flow zones, gene expression, and neointima formation. RESULTS Aneurysms recurred at 3 weeks, as shown by significantly worse angiographic scores as compared to T0 (P<.01). Neointimal scores differed at pathology, with a more complete neointima at the proximal as compared to the distal aspect of the sponge at 3 weeks (P=.027). Embolization was followed by migration of CD31+, CD14+, smooth muscle alpha-actin+ (SMA+) cells that progressively expressed metalloproteinases (MMP-9,-12,-14), but stable or lesser, retarded expression of inhibitors (TIMP1-4). Growth factors (PDGF-BB, TGF-beta1, TNF-alpha, MCP-1 and Ang-1) were expressed at increasing levels, maximal at 7 to 14 days. Differences between distal and proximal zones were limited to increased expression of MMP-2 proximally (P<.035). CONCLUSION Gene expression after embolization is compatible with patterns associated with neointima formation. The authors have not identified key factors involved in recurrence.
True Collaboration: Envisioning New Ways of Working Together

An Invitation The American Association of Critical-Care Nurses released its Standards for Establishing and Sustaining Healthy Work Environments in 2005. Through literature review and focus groups, 6 key components emerged as essential for the creation of a healthy work environment. True collaboration, one of the six, is the focus of our discussion. In the paragraphs that follow, we invite you to imagine what collaboration could look like in your organization and how you can implement strategies for enhancing collaboration. Through this vision, we can improve patient safety and create work environments that foster engagement and meaningful contribution. Together, we can bring into existence clinical environments in which we are all working together, not just side by side.
Emerging Insight Into the Role of Circadian Clock Gene BMAL1 in Cellular Senescence

Cell senescence is a crucial process in cell fate determination and is involved in an extensive array of aging-associated diseases. General perceptions and experimental evidence point out that the decline of physical function as well as aging-associated diseases are often initiated by cell senescence and organ ageing. Therefore, regulation of cell senescence process can be a promising way to handle aging-associated diseases such as osteoporosis. The circadian clock regulates a wide range of cellular and physiological activities, and many age-linked degenerative disorders are associated with the dysregulation of clock genes. BMAL1 is a core circadian transcription factor and governs downstream genes by binding to the E-box elements in their promoters. Compelling evidence has proposed the role of BMAL1 in cellular senescence and aging-associated diseases. In this review, we summarize the linkage between BMAL1 and factors of cell senescence including oxidative stress, metabolism, and the genotoxic stress response. Dysregulated and dampened BMAL1 may serve as a potential therapeutic target against aging- associated diseases.
BLOOD PRESSURE CHANGES DURING RETROGRADE BRACHIAL ANGIOGRAPHY.

Investigation of the vascular system by angiographic technics requires the rapid injection of varying amounts of foreign material. This produces numerous chemical and physiological changes in the patient (3, 6, 7, 11, 14). Many of these parameters have been studied previously; however, we have been unable to find any serious investigation of intra-arterial pressure changes during the actual performance of angiography in man. The purpose of this study was to investigate the pressure changes that might occur during and shortly after retrograde brachial angiography, as measured in the brachial artery proximal to the injection site, the carotid arteries, and the systemic circulation as represented by the femoral artery. Material and Methods Our technic of retrograde brachial angiography consists of percutaneous puncture of the brachial artery in the mid-forearm with a 15- or 16-gauge Cournand needle and the injection of 30 c.c. of 50 per cent sodium diatrizoate (50 per cent Hypaque, Squibb) with 15 c.c. of sa.
CAN GENE FLOW PREVENT REINFORCEMENT?

A model of reinforcement in a hybrid zone is developed in which an allele causing reinforcement may only be favored in the center of the hybrid zone and is selected against elsewhere. When reinforcement is favored only in the hybrid zone, the swamping effect of gene flow severely impedes the evolution of reinforcement: reinforcement can only occur when β < sγ2/4 (s is selection against hybrids, γ is the strength of reinforcement, and β is the strength of selection against reinforcement). Although the region in which reinforcement can occur is narrower when selection against hybrids is stronger, strong selection is still more likely to be reinforced despite the effects of gene flow. Another modifier is considered which reduces postmating isolation. The conditions for increase in frequency of this modifier reduce to the same conditions as those for the reinforcing allele. Both kinds of modification reduce the strength of selection and, therefore, cause the cline to widen. Reinforcement causes an increase in premating isolation between races, while modification of selection reduces postmating isolation.
An increase in Giardia duodenalis infection among children receiving periodic Anthelmintic treatment in Bangladesh.

During a deworming study in northern Bangladesh, the prevalence of Giardia duodenalis increased significantly among three groups of children receiving periodic treatment with mebendazole. This was first observed in the treatment group (Group A) of a 12-month study. Giardia increased from 5 to 31 per cent in Group A (n = 49 chi 2 = 10.42, P < 0.005), but did not increase significantly in the placebo group (Group B) (11 to 18 per cent; chi 2 = 0.4, P = NS). The prevalence of Giardia in the treatment and placebo groups was not significantly different at the beginning of the study (n = 89, chi 2 = 0.8, P = NS). During a 6-month follow-up study, children in Groups A and B received 2-monthly treatment with mebendazole. Within 6 months the prevalence of Giardia increased significantly in Group B from 18 to 44 per cent (chi 2(1) = 6.14, P < 0.05). The prevalence of Giardia was also examined in 265 children at the end of an 18-month deworming study in the same area and found to be significantly higher among the treatment group (Group C) compared with the placebo group (Group D) (38 v. 21 per cent, chi 2 = 8.87, P < 0.005). Finally, the prevalence of Giardia was significantly higher in Group B after being treated than in Group D which had not been treated (44 and 21 per cent, respectively, chi 2 = 9.08, P < 0.005). These children were from the same villages and measured during the same month of the monsoon season. (ABSTRACT TRUNCATED AT 250 WORDS)
Cerebral venous sinuses thrombosis in both transverse sinus and torcula: Multistep endovascular treatment and stenting

Purpose Cerebral venous sinus thrombosis (CVST) is an unusual and potentially life-threatening condition with variable and nonspecific clinical symptoms and high morbimortality rates. Standard therapy consists of systemic anticoagulation; although there is no clear evidence about the best choice for treatment, intravenous heparin is used as the first-line treatment modality. Intravenous sinus thrombolysis can be an effective and relatively safe treatment for acutely deteriorating patients who have not responded to conventional therapy. This case report presents the possibility of endovascular treatment in multiple steps with mechanical thrombolysis with balloon, local pharmacological thrombolysis and stenting, in a patient with a severe form of CVST. Case summary A 67-year-old woman presented severe headache, agitation and confusion with diagnosis of venous sinus dural thrombosis in both lateral sinus and torcula. After 24 h there was neurological worsening evolving with seizures and numbness even after starting heparin, without sinus recanalization; CT scan showed left temporal intracerebral hemorrhage. We decided to take an endovascular approach in multiple steps. The first step was mechanical static thrombolysis with balloon; the second step was dynamic mechanical thrombolysis with a balloon partially deflated and “pulled”; the third step was local thrombolysis with Actilyse™; finally, the fourth step was angioplasty and reconstruction of the sinuses using multiple carotid stents and complete angiographic recanalization of both sinuses and torcula. After 24 h of endovascular treatment there was full clinical recovery and no tomographic complications. Conclusion This result shows that mechanical clot disruption, intrasinus thrombolysis and reconstruction of wall sinuses with stenting can be an endovascular option in the severe form of CVST with intracerebral hemorrhage and rapid worsening of neurological symptoms. Although this type of treatment can re-channel the occluded sinuses, further comparative and randomized studies are needed to clarify its efficacy versus other therapeutic modalities.
Thermal Inactivation of African Swine Fever Virus in Swill

The indirect transmission of the African swine fever virus (ASFV) is through contaminated fomite, feed ingredients, pork- and pig-derived products, including swill, as ASFV is highly stable within suitable organic material. Some previous studies have indicated that ASFV outbreaks were associated with swill feeding, particularly in smallholder pig farms. These outbreaks emphasize the significance of the appropriate heat treatment of swill to eliminate ASFV residual titer. The World Organization for Animal Health (OIE) recommended the heat treatment of swill at a temperature of at least 90°C for at least 60 min, with continuous stirring, while the Food and Agriculture Organization (FAO) recommended heat treatment at 70°C for 30 min. The lack of scientific evidence regarding ASFV inactivation by heat treatment of swill leads to such inconsistent recommendations. Therefore, the objectives of this study were to assess the thermal inactivation of ASFV in three swill formulae and to develop a DT model to predict DT at some other inactivation temperatures. The significant reduction of ASFV in swill occurred at temperatures as low as 60°C. DT or decimal reduction time (DRT) is defined as the time required to reduce the virus titer by 1 log, and this was also used as a comparative index of heat resistance. The mean D60, D70, D75, and D80 of ASFV in three swill formulae were in the ranges 23.21–33.47, 5.83–10.91, 2.15–2.22, and 1.36–1.47 min, respectively. These DT could be widely used for any nutritive composition of swill other than the three swill formulae in this study since there was no statistical difference of all DT of ASFV across three swill formulae. Based on D70 and the predicted D90 from the DT model in this study, including the highest ASFV titer in pork products, the calculated inactivation times at 70 and 90°C were 119 and 4 min, respectively.
Systemic Lupus Erythematosus Presenting as Splenic Infarcts – A Rare Case Report

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease. In patients with SLE, the prevalence of antiphospholipid antibodies is considerably higher, and is largely responsible for thrombosis. Splenic infarction is a rare complication of arterial thrombosis in patients with SLE. We hereby present a rare case report of SLE with AIHA with splenic infarcts in a negative antiphospholipid antibody patient who responded well to steroid therapy.
Large scale variation in the rate of de novo mutation, base composition, divergence and diversity in humans

It has long been suspected that the rate of mutation varies across the human genome at a large scale based on the divergence between humans and other species. It is now possible to directly investigate this question using the large number of de novo mutations (DNMs) that have been discovered in humans through the sequencing of trios. We show that there is variation in the mutation rate at the 100KB, 1MB and 10MB scale that cannot be explained by variation at smaller scales, however the level of this variation is modest at large scales – at the 1MB scale we infer that ~90% of regions have a mutation rate within 50% of the mean. Different types of mutation show similar levels of variation and appear to vary in concert which suggests the pattern of mutation is relatively constant across the genome and hence unlikely to generate variation in GC-content. We confirm this using two different analyses. We find that genomic features explain less than 50% of the explainable variance in the rate of DNM. As expected the rate of divergence between species and the level of diversity within humans are correlated to the rate of DNM. However, the correlations are weaker than if all the variation in divergence was due to variation in the mutation rate. We provide evidence that this is due the effect of biased gene conversion on the probability that a mutation will become fixed. We find no evidence that linked selection affects the relationship between divergence and DNM density. In contrast to divergence, we find that most of the variation in diversity can be explained by variation in the mutation rate. Finally, we show that the correlation between divergence and DNM density declines as increasingly divergent species are considered. Author summary Using a dataset of 40,000 de novo mutations we show that there is large-scale variation in the mutation rate at the 100KB and 1MB scale. We show that different types of mutation vary in concert and in a manner that is not expected to generate variation in base composition; hence mutation bias is not responsible for the large-scale variation in base composition that is observed across human chromosomes. As expected large-scale variation in the rate of divergence between species and the variation within species across the genome, are correlated to the rate of mutation, but the correlation between divergence and the mutation rate is not as strong as they could be. We show that biased gene conversion is responsible for weakening the correlation. In contrast we find that most of the variation across the genome in diversity can be explained by variation in the mutation rate. Finally, we show that the correlation between the rate of mutation in humans and the divergence between humans and other species, weakens as the species become more divergent.