Miracle-dz/UniFAR-FTUs huggingface dataset:
BAK α6 permits activation by BH3-only proteins and homooligomerization via the canonical hydrophobic groove

Significance Apoptosis is crucial for immune system function and limiting tumor development. Because BAK and BAX are essential effectors of apoptosis, understanding how they are activated to form the oligomeric mitochondrial pores that kill cells is a major goal of the field. We define a requirement for two sites on mitochondrial BAK for its interaction with, and activation by, BCL-2 homology 3 (BH3)-only proteins during apoptosis and determine that binding of BH3-only proteins at a distal site promotes exposure of a canonical site to allow terminal BAK activation and homooligomerization. Additionally, we provide insight into how BAK and BAX kill cells, identifying that the oligomeric pore is limited to interactions between the BH3 domain and canonical groove and does not involve additional protein interfaces. BAK and BAX are the essential effectors of apoptosis because without them a cell is resistant to most apoptotic stimuli. BAK and BAX undergo conformation changes to homooligomerize then permeabilize the mitochondrial outer membrane during apoptosis. How BCL-2 homology 3 (BH3)-only proteins bind to activate BAK and BAX is unclear. We report that BH3-only proteins bind inactive full-length BAK at mitochondria and then dissociate following exposure of the BAK BH3 and BH4 domains before BAK homodimerization. Using a functional obstructive labeling approach, we show that activation of BAK involves important interactions of BH3-only proteins with both the canonical hydrophobic binding groove (α2–5) and α6 at the rear of BAK, with interaction at α6 promoting an open groove to receive a BH3-only protein. Once activated, how BAK homodimers multimerize to form the putative apoptotic pore is unknown. Obstructive labeling of BAK beyond the BH3 domain and hydrophobic groove did not inhibit multimerization and mitochondrial damage, indicating that critical protein–protein interfaces in BAK self-association are limited to the α2–5 homodimerization domain.
Dedicated orthopedic trauma theatres: effect on morbidity and mortality in a single trauma centre.

BACKGROUND A general trend in orthopedic traumatology is the advent of daily, dedicated orthopedic trauma theatres. Availability of trauma theatres is believed to decrease morbidity and mortality, but this remains unproven. We performed a retrospective review comparing morbidity and mortality outcomes at a single institution before and after the establishment of a dedicated trauma room. The purpose was to determine whether a change in outcomes occurred for a single routine procedure with known outcome expectations (hemiarthroplasty of the hip after femoral neck fracture) with the implementation of a designated trauma theatre. METHODS We examined a cohort of 457 elderly patients (245 before and 212 after trauma theatre implementation) who underwent hemiarthroplasty for displaced low-energy subcapital hip fractures. RESULTS Patients in both groups were similar in terms of age, sex ratio and ASA classification. We found statistically significant differences favouring the dedicated trauma room system for postoperative morbidity. Despite this outcome, the average time to surgery for these patients significantly increased. We noted no difference in mortality between the 2 groups. CONCLUSION The hip fracture population can be treated safely in the context of dedicated trauma room time; however, there needs to be prioritization of hip fractures in a tertiary care centre or other trauma cases will tend to take precedence.
Probabilistic Relational Model Benchmark Generation

The validation of any database mining methodology goes through an evaluation process where benchmarks availability is essential. In this paper, we aim to randomly generate relational database benchmarks that allow to check probabilistic dependencies among the attributes. We are particularly interested in Probabilistic Relational Models (PRMs), which extend Bayesian Networks (BNs) to a relational data mining context and enable effective and robust reasoning over relational data. Even though a panoply of works have focused, separately , on the generation of random Bayesian networks and relational databases, no work has been identified for PRMs on that track. This paper provides an algorithmic approach for generating random PRMs from scratch to fill this gap. The proposed method allows to generate PRMs as well as synthetic relational data from a randomly generated relational schema and a random set of probabilistic dependencies. This can be of interest not only for machine learning researchers to evaluate their proposals in a common framework, but also for databases designers to evaluate the effectiveness of the components of a database management system.
BK Polyomavirus Genotypes Represent Distinct Serotypes with Distinct Entry Tropism

ABSTRACT BK polyomavirus (BKV) causes significant urinary tract pathogenesis in immunosuppressed individuals, including kidney and bone marrow transplant recipients. It is currently unclear whether BKV-neutralizing antibodies can moderate or prevent BKV disease. We developed reporter pseudoviruses based on seven divergent BKV isolates and performed neutralization assays on sera from healthy human subjects. The results demonstrate that BKV genotypes I, II, III, and IV are fully distinct serotypes. While nearly all healthy subjects had BKV genotype I-neutralizing antibodies, a majority of subjects did not detectably neutralize genotype III or IV. Surprisingly, BKV subgenotypes Ib1 and Ib2 can behave as fully distinct serotypes. This difference is governed by as few as two residues adjacent to the cellular glycan receptor-binding site on the virion surface. Serological analysis of mice given virus-like particle (VLP)-based BKV vaccines confirmed these findings. Mice administered a multivalent VLP vaccine showed high-titer serum antibody responses that potently cross-neutralized all tested BKV genotypes. Interestingly, each of the neutralization serotypes bound a distinct spectrum of cell surface receptors, suggesting a possible connection between escape from recognition by neutralizing antibodies and cellular attachment mechanisms. The finding implies that different BKV genotypes have different cellular tropisms and pathogenic potentials in vivo. Individuals who are infected with one BKV serotype may remain humorally vulnerable to other BKV serotypes after implementation of T cell immunosuppression. Thus, prevaccinating organ transplant recipients with a multivalent BKV VLP vaccine might reduce the risk of developing posttransplant BKV disease.
The gas phase reaction of singlet dioxygen with water: A water-catalyzed mechanism

Stimulated by the recent surprising results from Wentworth et al. [Wentworth, A. D. , Jones, L. H. , Wentworth, P., Janda, K. D. & Lerner, R. A. (2000) Proc. Natl. Acad. Sci. USA 97, 10930–10935] that Abs efficiently catalyze the conversion of molecular singlet oxygen (1O2) plus water to hydrogen peroxide (HOOH), we used quantum chemical methods (B3LYP density functional theory) to delineate the most plausible mechanisms for the observed efficient conversion of water to HOOH. We find two reasonable pathways. In Pathway I, (i) H2O catalyzes the reaction of 1O2 with a second water to form HOOOH; (ii) two HOOOH form a dimer, which rearranges to form the HOO-HOOO + H2O complex; (iii) HOO-HOOO rearranges to HOOH-OOO, which subsequently reacts with H2O to form H2O4 + HOOH; and (iv) H2O4 rearranges to the cyclic dimer (HO2)2, which in turn forms HOOH plus 1O2 or 3O2. Pathway II differs in that step ii is replaced with the reaction between HOOOH and 1O2, leading to the formation of HOO-HOOO. This then proceeds to similar products. For a system with 18O H2O, Pathway I leads to a 2.2:1 ratio of 16O:18O in the product HOOH, whereas Pathway II leads to 3:1. These ratios are in good agreement with the 2.2:1 ratio observed in isotope experiments by Wentworth et al. These mechanisms lead to two HOOH per initial 1O2 or one, depending on whether the product of step iv is 1O2 or 3O2, in good agreement with the experimental result of 2.0. In addition to the Ab-induced reactions, the hydrogen polyoxides (H2O3 and H2O4) formed in these mechanisms and their decomposition product polyoxide radicals (HO2, HO3) may play a role in combustion, explosions, atmospheric chemistry, and the radiation chemistry in aqueous systems.
Parallelism in the oxygen transport system of the lake whitefish: the role of physiological divergence in ecological speciation

In North America, populations of lake whitefish (Coregonus clupeaformis) have evolved sympatric ‘dwarf’ and ‘normal’ ecotypes that are associated with distinct trophic niches within lakes. Trophic specialization should place diverging physiological demands on individuals, and thus, genes and phenotypes associated with energy production represent ideal candidates for studies of adaptation. Here, we test for the parallel divergence of traits involved in oxygen transport in dwarf and normal lake whitefish from Québec, Canada and Maine, USA. We observed significant differences in red blood cell morphology between the ecotypes. Specifically, dwarfs exhibited larger nuclei and a higher nucleus area/total cell area than normal whitefish in all of the lakes examined. In addition, isoelectric focusing gels revealed variation in the haemoglobin protein components found in whitefish. Dwarf and normal whitefish exhibited a similar number of protein components, but the composition of these components differed, with dwarf whitefish bearing a greater proportion of cathodic components compared to the normals. Furthermore, dwarf whitefish showed significant haemoglobin gene upregulation in the brain compared with the levels shown in normals. Together, our results indicate that metabolic traits involved in oxygen transport differ between the whitefish ecotypes and the strong parallel patterns of divergence observed across lakes implicates ecologically driven selection pressures. We discuss the function of these traits in relation to the differing trophic niches occupied by the whitefish and the potential contributions of trait plasticity and genetic divergence to energetic adaptation.
Similar Structural Basis for Membrane Localization and Protein Priming by an RNA-dependent RNA Polymerase*

Protein primers are used to initiate genomic synthesis of several RNA and DNA viruses, although the structural details of the primer-polymerase interactions are not yet known. Poliovirus polymerase binds with high affinity to the membrane-bound viral protein 3AB but uridylylates only the smaller peptide 3B in vitro. Mutational analysis of the polymerase identified four surface residues on the three-dimensional structure of poliovirus polymerase whose wild-type identity is required for 3AB binding. These mutants also decreased 3B uridylylation, arguing that the binding sites for the membrane tether and the protein primer overlap. Mutation of flanking residues between the 3AB binding site and the polymerase active site specifically decreased 3B uridylylation, likely affecting steps subsequent to binding. The physical overlap of sites for protein priming and membrane association should facilitate replication initiation in the membrane-associated complex.
Fbx7 Functions in the SCF Complex Regulating Cdk1-Cyclin B-phosphorylated Hepatoma Up-regulated Protein (HURP) Proteolysis by a Proline-rich Region*[boxs]

F-box proteins, components of SCF ubiquitin-ligase complexes, are believed to be responsible for substrate recognition and recruitment in SCF-mediated proteolysis. F-box proteins that have been identified to function in the SCF complexes to date mostly have substrate-binding motifs, such as WD repeats or leucine-rich repeats in their C termini. However, many F-box proteins lack recognizable substrate-binding modules; whether they can function in the SCF complexes remains unclear. We show here that Fbx7, an F-box protein without WD repeats and leucine-rich repeats, is required for the proteasome-mediated proteolysis of the hepatoma up-regulated protein (HURP). Depletion of Fbx7 by small interfering RNA leads to depression of HURP ubiquitination and accumulation of HURP abundance. In the SCFFbx7 complex, Fbx7 recruits HURP through its C-terminal proline-rich region in a Cdk1-cyclin B-phosphorylation dependent manner. Mutation of the multiple Cdk1-cyclin B phosphorylation sites on HURP or the proline-rich region of Fbx7 abolishes the association between Fbx7 and HURP. Thus, Fbx7 is a functional adaptor of the SCF complex with a proline-rich region as the substrate-binding module. In addition to Fbx7, data base analyses reveal two putative mammalian proline-rich region-containing F-box proteins, KIAA1783 and RIKEN cDNA 2410015K21. Taken together, these findings further expound the diverse substrate-recognition abilities of the SCF complexes.
Krüppel-like factors in cancer progression: three fingers on the steering wheel

Krüppel-like factors (KLFs) comprise a highly conserved family of zinc finger transcription factors, that are involved in a plethora of cellular processes, ranging from proliferation and apoptosis to differentiation, migration and pluripotency. During the last few years, evidence on their role and deregulation in different human cancers has been emerging. This review will discuss current knowledge on Krüppel-like transcription in the epithelial-mesenchymal transition (EMT), invasion and metastasis, with a focus on epithelial cancer biology and the extensive interface with pluripotency. Furthermore, as KLFs are able to mediate different outcomes, important influences of the cellular and microenvironmental context will be highlighted. Finally, we attempt to integrate diverse findings on KLF functions in EMT and stem cell biology to ft in the current model of cellular plasticity as a tool for successful metastatic dissemination.
Combination Antibiotic Treatment of Serious Methicillin-Resistant Staphylococcus aureus Infections

Abstract Outcomes from methicillin-resistant Staphylococcus aureus (MRSA) infections are relatively poor, at least in part due to the limitations of vancomycin (the current standard treatment for MRSA). Combination antibiotic treatment for MRSA infections is an attractive alternative as it could address most of vancomycin's shortcomings, including poor tissue penetration, slow bacterial killing, and emerging resistance in some strains of MRSA. However, the theoretical promise of combination therapy for MRSA infections has not been borne out in most in vitro and animal studies. Multiple combinations have been tested and have been either antagonistic, indifferent, or have had conflicting findings in various studies. This includes combinations of two primarily active agents (such as vancomycin plus daptomycin or linezolid), or the addition of gentamicin or rifampin to either vancomycin or daptomycin. However, hope on this front has come from an unexpected quarter. Although MRSA is by definition inherently resistant to nearly all β-lactam antibiotics, this class of drugs has consistently shown evidence of synergy with either daptomycin or vancomycin in over 25 separate in vitro studies, and a limited number of animal and human observational studies. However, there are currently insufficient data to recommend β-lactam combination therapy in routine clinical use. Results of current and planned randomized controlled trials of this strategy are awaited.
Expression, Purification and Characterization of a Recombinant Plasmodium Vivax Thrombospondin Related Adhesive Protein (PvTRAP)

Thrombospondin Related Adhesive Protein (TRAP) is a transmembrane parasite molecule responsible in sporozoite-host interactions. This molecule is one of the most promising vaccine candidates against the pre-erythrocytic forms of malaria. In the present study, a gene encoding the Plasmodium vivax TRAP (PvTRAP) was expressed in Escherichia coli (M15 strain) using the expression plasmid pQE30. The expressed recombinant protein PvTRAP of about 70kDa was achieved, purified and refolded according to the standardized refolding procedure. This refolded protein (PvTRAP) showed a single band monomeric form with SDS-PAGE and blot analysis. In reduced and alkylated form, PvTRAP showed less binding to hepatoma (HepG2) liver cells, when compared to the normal purified and refolded form. Purified and refolded recombinant PvTRAP bound Duffy-positive human erythrocytes, while no binding was observed with Duffy-negative erythrocytes. Our report on PvTRAP is currently documented for the first time and it has been able to provide an experimental evidence of the biochemical and binding properties of PvTRAP in the invasion of hepatocytes and interaction with Duffy-positive and Duffy-negative human erythrocytes. In conclusion, our findings have been able to demonstrate the potential of PvTRAP as a promising target for vivax malaria vaccine candidate.
Hepatitis C Virus Attenuates Mitochondrial Lipid β-Oxidation by Downregulating Mitochondrial Trifunctional-Protein Expression

ABSTRACT The course of hepatitis C virus (HCV) infection and disease progression involves alterations in lipid metabolism, leading to symptoms such as hypocholesterolemia and steatosis. Steatosis can be induced by multiple mechanisms, including increases in lipid biosynthesis and uptake, impaired lipoprotein secretion, and/or attenuation of lipid β-oxidation. However, little is known about the effects of HCV on lipid β-oxidation. A previous proteomics study revealed that HCV interacted with both the α- and β-subunits of the mitochondrial trifunctional protein (MTP), an enzyme complex which catalyzes the last 3 steps of mitochondrial lipid β-oxidation for cellular energy production. Here we show that in HCV-infected Huh7.5 cells, lipid β-oxidation was significantly attenuated. Consistently with this, MTP protein and mRNA levels were suppressed by HCV infection. A loss-of-function study showed that MTP depletion rendered cells less responsive to alpha interferon (IFN-α) treatment by impairing IFN-stimulated gene expression. These aspects of host-virus interaction explain how HCV alters host energy homeostasis and how it may also contribute to the establishment of persistent infection in the liver. IMPORTANCE HCV infection triggers metabolic alterations, which lead to significant disease outcomes, such as fatty liver (steatosis). This study revealed that HCV impairs mitochondrial lipid β-oxidation, which results in low lipid combustion. On the other hand, the HCV-induced defects in metabolic status played an important role in the control of the type I interferon system. Under the conditions of impaired lipid β-oxidation, host cells were less responsive to the ability of exogenously added IFN-α to suppress HCV replication. This suggests that interference with lipid β-oxidation may assist the virus in the establishment of a long-term, persistent infection. Further understanding of this aspect of virus-host interaction may lead to improvements in the current standard therapy.
A National Survey of Musculoskeletal Impairment in Rwanda: Prevalence, Causes and Service Implications

Background Accurate information on the prevalence and causes of musculoskeletal impairment (MSI) is lacking in low income countries. We present a new survey methodology that is based on sound epidemiological principles and is linked to the World Health Organisation's International Classification of Functioning. Methods Clusters were selected with probability proportionate to size. Households were selected within clusters through compact segment sampling. 105 clusters of 80 people (all ages) were included. All participants were screened for MSI by a physiotherapist and medical assistant. Possible cases plus a random sample of 10% of non-MSI cases were examined further to ascertain diagnosis, aetiology, quality of life, and treatment needs. Findings 6757 of 8368 enumerated individuals (80.8%) were screened. There were 352 cases, giving an overall prevalence for MSI of 5.2%. (95% CI 4.5–5.9) The prevalence of MSI increased with age and was similar in men and women. Extrapolating these estimates, there are approximately 488,000 MSI diagnoses in Rwanda. Only 8.2% of MSI cases were severe, while the majority were moderate (43.7%) or mild (46.3%). Diagnostic categories comprised 11.5% congenital, 31.3% trauma, 3.8% infection, 9.0% neurological, and 44.4% non-traumatic non infective acquired. The most common individual diagnoses were joint disease (13.3%), angular limb deformity (9.7%) and fracture mal- and non-union (7.2%). 96% of all cases required further treatment. Interpretation This survey demonstrates a large burden of MSI in Rwanda, which is mostly untreated. The survey methodology will be useful in other low income countries, to assist with planning services and monitoring trends.
Effect of Exercise Training on Endogenous Stem Cells Activation in Ischemia Reperfusion Induced Skeletal Muscle Injury: A Physio- Histological Study

Background: This study aimed at investigating the possible role of exercise training in activating the migration of CD34 positive progenitor cells in a rat model of induced ischemia reperfusion injury (IRI) of limb skeletal muscle and related regeneration potential. Material and methods: 28 adult male albino rats were divided into three groups: group I: control group; group II: IRI with 2 hours ischemia and 2 hours reperfusion, followed by immediate sacrifice (subgroup IIa) or delayed sacrifice after two weeks (subgroup IIb); group III: exercise in the form of group and gradual swimming for 4 weeks, followed by IRI and immediate sacrifice (subgroup IIIa), or delayed sacrifice (subgroup IIIb). Muscle performance was evaluated by physiological tests. Histological study was done using H&E staining, and immunohistochemical staining using anti αSMA and anti CD34. Areas of regenerating fibers, area of αSMA and area percentage of CD34 were measured. Statistical analysis was performed. Results: IRI group showed severe muscle damage in IIa in the form of wavy, disrupted darkly acidophilic fibers, many dark nuclei, and extravasated blood. There was some improvement in IIb in the form of regenerating fibres with central nuclei and increased αSMA and CD34 immunostaining. Group III showed better preservation of muscle fibers in IIIa. It also showed significant increase in area of regenerating fibers and statistically significant increase in area of αSMA and CD34 and in physiological parameters in IIIb as compared to group II. Conclusion: Exercise training prior to skeletal muscle IRI markedly improved muscle outcome through preservation and regeneration. Two populations of skeletal muscle stem cells, namely progenitor cells and satellite cells were involved in the process.
Crystal Structure and Biological Implications of a Bacterial Albumin Binding Module in Complex with Human Serum Albumin*

Many bactericide species express surface proteins that interact with human serum albumin (HSA). Protein PAB from the anaerobic bacterium Finegoldia magna (formerly Peptostreptococcus magnus) represents one of these proteins. Protein PAB contains a domain of 53 amino acid residues known as the GA module. GA homologs are also found in protein G of group C and G streptococci. Here we report the crystal structure of HSA in complex with the GA module of protein PAB. The model of the complex was refined to a resolution of 2.7 Å and reveals a novel binding epitope located in domain II of the albumin molecule. The GA module is composed of a left-handed three-helix bundle, and residues from the second helix and the loops surrounding it were found to be involved in HSA binding. Furthermore, the presence of HSA-bound fatty acids seems to influence HSA-GA complex formation. F. magna has a much more restricted host specificity compared with C and G streptococci, which is also reflected in the binding of different animal albumins by proteins PAB and G. The structure of the HSA-GA complex offers a molecular explanation to this unusually clear example of bacterial adaptation.