Miracle-dz/UniFAR-FTUs huggingface dataset:
Common denominator of Cu/Zn superoxide dismutase mutants associated with amyotrophic lateral sclerosis: Decreased stability of the apo state

More than 100 point mutations of the superoxide scavenger Cu/Zn superoxide dismutase (SOD; EC ) have been associated with the neurodegenerative disease amyotrophic lateral sclerosis (ALS). However, these mutations are scattered throughout the protein and provide no clear functional or structural clues to the underlying disease mechanism. Therefore, we undertook to look for folding-related defects by comparing the unfolding behavior of five ALS-associated mutants with distinct structural characteristics: A4V at the interface between the N and C termini, C6F in the hydrophobic core, D90A at the protein surface, and G93A and G93C, which decrease backbone flexibility. With the exception of the disruptive replacements A4V and C6F, the mutations only marginally affect the stability of the native protein, yet all mutants share a pronounced destabilization of the metal-free apo state: the higher the stability loss, the lower the mean survival time for ALS patients carrying the mutation. Thus organism-level pathology may be directly related to the properties of the immature state of a protein rather than to those of the native species.
Structural Determinants That Target the Hepatitis C Virus Core Protein to Lipid Droplets*

Hepatitis C virus core protein is targeted to lipid droplets, which serve as intracellular storage organelles, by its C-terminal domain, termed D2. From circular dichroism and nuclear magnetic resonance analyses, we demonstrate that the major structural elements within D2 consist of two amphipathic α-helices (Helix I and Helix II) separated by a hydrophobic loop. Both helices require a hydrophobic environment for folding, indicating that lipid interactions contribute to their structural integrity. Mutational studies revealed that a combination of Helix I, the hydrophobic loop, and Helix II is essential for efficient lipid droplet association and pointed to an in-plane membrane interaction of the two helices at the phospholipid layer interface. Aside from lipid droplet association, membrane interaction of D2 is necessary for folding and stability of core following maturation at the endoplasmic reticulum membrane by signal peptide peptidase. These studies identify critical determinants within a targeting domain that enable trafficking and attachment of a viral protein to lipid droplets. They also serve as a unique model for elucidating the specificity of protein-lipid interactions between two membrane-bound organelles.
Adiposity and metabolic dysfunction in polycystic ovary syndrome

Abstract Polycystic ovary syndrome (PCOS) is the most common hormonal disorder among reproductive-age women and is associated with a high risk for metabolic disorders. Adiposity and insulin resistance are two prevalent conditions in PCOS and the likely culprits for the heightened metabolic risk. Up to 60% of women with PCOS are considered to be overweight or obese, and even among non-obese women with PCOS there is an increased accumulation of adipose tissue in abdominal depots. Insulin resistance in PCOS is unique and independent of obesity, as even non-obese women with this condition are frequently insulin resistant. However, obesity substantially aggravates the insulin resistance and the metabolic and reproductive abnormalities in women with PCOS. Recently, it has been shown that many aspects of adipose tissue function in PCOS are abnormal, and these abnormalities likely predispose to development of insulin resistance even in the absence of obesity. This review provides an overview of these abnormalities and their impact on development of metabolic disorders. At the end, an overview of the therapeutic options for management of adiposity and its complications in PCOS are discussed.
A Retrospective Assessment of Risk Factors for Peritonitis among An Urban Capd Population

Peritonitis is a major reason why patients transfer from peritoneal dialysis (PD) to hemodialysis. We evaluated the peritonitis infection rates In 146 peritoneal dialysis patients who underwent dialysis at our facility between 1 January 1981 and 31 December 1989. Peritonit Is was the primary cause for changing treatment, with 24 (16.4%) of the patients transferring because of this complication. This represented 54.5% of all patients discontinuing CAPD due to method failure. A gamma-Poisson regression analysis was performed in an attempt to Identify potential risk factors associated with an increased Incidence of peritonitis. The results indicated that race, education level, and PD system used were significantly associated with the rate at which peritonitis occurred in our patient population. There was an almost twofold increase in the rate of peritonitis among blacks as compared to whites (2.2 vs 1.2 episodes/patient year). The level of education completed at the start of dialysis had a negative correlation with peritonitis rates. Patients with ≤8, 9–12, and ≥13 years of education had peritonitis rates of 2.4, 1.8, and 1.2 episodes/patient year, respectively. Finally, the system used had a significant effect with our patients on CCPD having lower peritonitis rates as compared to patients on either a connect or disconnect system (0.6 vs 2.5 vs 1.8 episodes/patient year, respectively). Recognizing potential risk factors for peritonitis will help us better understand and address this significant problem in our PD programs. Reducing peritonitis rates should facilitate a decrease in patient transfer due to method failure.
Cross-Sectional Analysis of Clinical and Environmental Isolates of Pseudomonas aeruginosa: Biofilm Formation, Virulence, and Genome Diversity

ABSTRACT Chronic lung infections with Pseudomonas aeruginosa biofilms are associated with refractory and fatal pneumonia in cystic fibrosis (CF). In this study, a group of genomically diverse P. aeruginosa isolates were compared with the reference strain PAO1 to assess the roles of motility, twitching, growth rate, and overproduction of a capsular polysaccharide (alginate) in biofilm formation. In an in vitro biofilm assay system, P. aeruginosa displayed strain-specific biofilm formation that was not solely dependent on these parameters. Compared with non-CF isolates, CF isolates expressed two opposing growth modes: reduced planktonic growth versus efficient biofilm formation. Planktonic cells of CF isolates showed elevated sensitivity to hydrogen peroxide, a reactive oxygen intermediate, and decreased lung colonization in an aerosol infection mouse model. Despite having identical genomic profiles, CF sequential isolates produced different amounts of biofilm. While P. aeruginosa isolates exhibited genomic diversity, the genome size of these isolates was estimated to be 0.4 to 19% (27 to 1,184 kb) larger than that of PAO1. To identify these extra genetic materials, random amplification of polymorphic DNA was coupled with PAO1-subtractive hybridization. Three loci were found within the genomes of two CF isolates encoding one novel homolog involved in retaining a Shigella virulence plasmid (mvpTA) and two divergent genes that function in removing negative supercoiling (topA) and biosynthesis of pyoverdine (PA2402). Together, P. aeruginosa biodiversity could provide one cause for the variation of morbidity and mortality in CF. P. aeruginosa may possess undefined biofilm adhesins that are important to the development of an antibiofilm therapeutic target.
Telemedicine versus face-to-face evaluation in the delivery of thrombolysis for acute ischaemic stroke: a single centre experience

Background Telemedicine is increasingly used in the UK to deliver thrombolysis. It is primarily used to enable assessment of people presenting with an acute stroke by a remote specialist in stroke care, and to determine eligibility for thrombolysis with alteplase (recombinant tissue plasminogen activator). This study aims to evaluate the process of acute stroke care, safety and outcome profiles when comparing face-to-face evaluation and telemedicine in the delivery of thrombolysis. Methods This was a retrospective single centre cohort study, evaluating patients thrombolysed from July 2007 to December 2009 inclusive. All patients were given treatment within a 3-hour window from onset of symptoms. Of the 97 patients thrombolysed, 45 (46%) were evaluated by telemedicine. Process times of the steps taken to deliver thrombolysis for the two groups were compared. The authors include the rates of symptomatic intracranial haemorrhage (SICH). Outcome data include 3-month mortality and functional status. Results Process times were significantly better in face-to-face: Admission to CT (p=0.001), CT to treatment (p≤0.001) and admission to treatment (p≤0.001). SICH occurred in four patients (7.7%) in the face-to-face group compared with the two patients (4.4%) in the telemedicine group (p=0.7). Favourable outcome: a modified Rankin score of 0–2 was observed in 19 patients (36.5%) in the face-to-face group compared with 19 patients (42%) in the telemedicine group (p=0.9). Conclusions This analysis shows that the use of telemedicine compared with face-to-face evaluation is feasible in the delivery of thrombolysis during out of hours. There are several areas of our emergency process of hyper-acute stroke care that need improving when using telemedicine.
Comment on Jean-Claude Berthélemy: Aid Allocation: Comparing donors' behaviours

Berthelemy investigates how the aid allocation of bilateral donors, the European Commission and the non-EC multilaterals is influenced by the self-interest of the donor (geopolitical or commercial), the needs of the recipients, and their merits. One concern is that the study only uses data up to 1999, which means that changes that may have occurred after that point in time are not picked up. First, after quite extensive critique against EC’s aid policy, changes were announced at the turn of the century seeking to address the concerns of the critics. This has led to some changes in policies and procedures and possibly some improvements in efficiency, but the inter-country allocation does not seem to have changed significantly (Berlin and Resare, 2005). Second, much of the shift in the debate in favour of aid allocation on the basis of merit1 also took place after the survey period. Still, the actual changes in aid allocation of most donors because of this do not seem to have been very extensive. So overall, it seems reasonable to assume that the broad picture that emerges from Berthelemy’s study remains valid. He finds that self-interest in the form of trade interests is an important determinant of the allocation of bilateral aid, but also that needs and political governance matter. EC aid is very much focused on the ACP countries, but it is not significantly determined by either needs or merit. For other multilaterals, recipients’ needs play a major role, while merits do not. On the whole, bilaterals and non-EC multilaterals behave very similarly. A key question that emerges is why EC aid is so differently allocated, and why donor countries seem to be able to steer the allocation of non-EC multilaterals but not the EC in accordance with their own preferences. This is particularly important in a situation where we are discussing the need for donor harmonisa-
Bone Marrow Failure Following Severe Injury in Humans

Background: Hematopoietic failure has been observed in experimental animals following shock and injury. In humans, bone marrow dysfunction has been observed in the red cell component and characterized by a persistent anemia, low reticulocyte counts, and the need for repeated transfusions despite adequate iron stores. While a quantitative defect in white blood cell count has not been noted, an alteration in white blood cell function manifesting as an increased susceptibility to infection is well established. Since the etiology of this anemia remains unknown and the bone marrow has been rarely studied following injury, we measured various parameters of hematopoiesis directly using bone marrow from trauma patients and tested the hypothesis that trauma results in profound bone marrow dysfunction, which could explain both the persistent anemia and the alteration in white blood cell function. Methods: Bone marrow aspirates and peripheral blood were obtained between day 1 and 7 following injury from 45 multiple trauma patients. Normal volunteers served as controls. Peripheral blood was assayed for hemoglobin concentration, reticulocyte count, erythropoietin levels, white blood cell count, and differential. Peripheral blood and bone marrow were cultured for hematopoietic progenitors (CFU-GM, BFU-E, and CFU-E colonies). Results: Bone marrow CFU-GM, BFU-E, and CFU-E colony formation was significantly reduced while peripheral blood CFU-GM, BFU-E, and CFU-E was increased in the trauma patients compared with normal volunteers. Bone marrow stroma failed to grow to confluence by day 14 in >90% of trauma patients. In contrast, bone marrow stroma from volunteers always reached confluence between days 10 and 14 in culture. The mean hemoglobin concentration and reticulocyte counts of the trauma patients were 8.6 ± 1.0 g/dL and 2.75 ± 0.7% respectively, while their plasma erythropoietin levels were 2 to 10 times greater than control values. Conclusions: Release of immature white blood cells into the circulation may also contribute to a failure to clear infection and an increased propensity to organ failure. Concomitantly, profound changes occur within the bone marrow, which include the increased release of erythroid and myeloid progenitors into the circulation, a decrease in progenitor cell growth within the bone marrow, and an impaired growth of the bone marrow stroma. Erythropoietin levels are preserved following trauma, implying that the persistent anemia of injury is related to the failure of the bone marrow to respond to erythropoietin.
Age-Friendly Communities Are We Expecting Too Much?

Summary ■ ■ Aging successfully depends not only on the behaviours of individual seniors, but also on the quality of the places where they live and receive care. ■ ■ The age-friendly-communities movement proposes policies and programs that attempt to improve the material and social environments of older people and help them age successfully. ■ ■ Given limited funding and competing demands for resources, proponents of this movement must prioritize over-ambitious agendas and offer verifiable solutions that do not overlap with other housing, service and care programs.
Discovery and development of lantibiotics; antimicrobial agents that have significant potential for medical application

Introduction: Antimicrobial drug resistance is driving the need for novel therapeutics. Amongst the most promising antibacterial agents that are being investigated as replacements for current therapeutic antibiotics are antibacterial peptides, such as the lanthionine-containing peptide antibiotics (lantibiotics). Areas covered: This review focuses on the current methods used for discovery of potentially exploitable lantibiotics for medical applications and discusses relevant recent innovations that will have a positive impact on the discovery of useful lantibiotics. Expert opinion: Recent technological advances in a number of fields mean that increased research into the identification and characterisation of new lantibiotics is feasible. We need to increase our understanding of the various mechanisms of antibacterial action exhibited by lantibiotics and apply this knowledge to peptide engineering or novel practical applications. The advent of next-generation sequencing approaches now negate the need for extensive reverse genetics and employment of bioinformatics approaches is greatly assisting the identification of potentially useful inhibitors in the genomes of a range of clinically significant bacteria. These advances in genetic analysis and engineering will facilitate increased exploitation of lantibiotics in medical therapy.
The effects of caffeine on intracellular calcium, force and the rate of relaxation of mouse skeletal muscle.

1. Intracellular calcium concentration ([Ca2+]i) and force were measured from isolated single fibres of mouse skeletal muscle. The effects of 5 mM caffeine on muscle fibres at rest and during short tetani were examined. 2. Caffeine increased tetanic tension and slowed the rate of relaxation. [Ca2+]i was increased in the presence of caffeine both in the resting muscle and during tetani. The time course of decline of [Ca2+]i after a tetanus is complex with a large, early, rapid phase followed by a smaller and slower phase. Caffeine accelerated the early phase but slowed the later phase. 3. The sensitivity of the myofibrillar proteins to Ca2+ measured in the intact fibre was increased in the presence of caffeine, confirming earlier findings on skinned muscle fibres. 4. Analysis of the late phase of the decline of [Ca2+]i after a tetanus provides information about the properties of the sarcoplasmic reticulum (SR) Ca2+ pump. Caffeine slowed the pump to 60‐70% of the control value at a given [Ca2+]i but had no effect on the Ca2+ leak from the SR. 5. Analysis of relaxation made use of the Ca(2+)‐derived force in which the [Ca2+]i during relaxation was converted to the Ca(2+)‐derived force by means of the steady‐state relation between [Ca2+]i and force. The Ca(2+)‐derived force fell more slowly in the presence of caffeine but the lag between Ca(2+)‐derived force and measured force was unaffected. Thus, the slowed relaxation was caused by changes in Ca2+ handling and not by slowed cross‐bridge kinetics. 6. A model of the Ca2+ movements and force production of muscle was used to examine independently the effects of increased Ca2+ sensitivity, slowing of the SR Ca2+ pump and increased SR Ca2+ permeability. The effects of caffeine on [Ca2+]i, tetanic force and relaxation could be explained by a combination of these three effects.
The origin of vimentin expression in invasive breast cancer: epithelial–mesenchymal transition, myoepithelial histogenesis or histogenesis from progenitor cells with bilinear differentiation potential?

Vimentin expression is a rather rare finding in invasive breast cancer, and is associated with high tumour invasiveness and chemoresistance. It is currently explained by two different biological theories: direct histogenetic derivation from myoepithelial cells, and epithelial–mesenchymal transition (EMT) reflecting the end‐stage of breast cancer dedifferentiation. In this study we aimed to obtain further insights into the biological hallmarks of these vimentin‐expressing breast cancers. We applied immunohistochemistry for vimentin and 15 other differentiation markers to a series of 364 invasive breast cancer cases, using tissue microarray technology. 7.7% of all tumours expressed vimentin. Almost all of these cases (19/21) were Grade 3 invasive ductal carcinomas, and the majority (13/21) of these were associated with a ductal in situ component. Vimentin expression was also seen in the respective in situ components and correlated positively with the expression of SMA, CD10, CK 5, p53, Mib‐1 and EGFR. A negative correlation was seen for the expression of CK 8/18 and the oestrogen receptor. Vimentin‐expressing carcinomas revealed a significantly higher average absolute number of cytogenetic alterations per case, but a significantly lower frequency of chromosome 16q losses compared to vimentin‐negative cases. Our present results demonstrate that, despite analogies between vimentin‐positive breast cancers and myoepithelial cells in their expression of differentiation‐related proteins, neither myoepithelial histogenesis nor EMT can exclusively explain the biology of these distinct tumours. This is mainly supported by the significantly higher incidence of vimentin‐expressing breast cancers compared to any other myoepithelial breast tumours and the fact that vimentin is already observed in ductal in situ components. We therefore propose the alternative hypothesis that vimentin‐expressing breast carcinomas may derive from breast progenitor cells with bilinear (glandular and myoepithelial) differentiation potential. Copyright © 2005 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Sustainability practices of family firms: the interplay between family ownership and long-term orientation

ABSTRACT Sustainability practices are critical for family firms, as they relate directly to the continuity of the business and relationships with important stakeholders, such as members of the local community. Nevertheless, not all family firms wish to adopt sustainability practices. To examine this, we draw upon the socioemotional wealth perspective in order to develop a theoretical model of the direct negative effects of family ownership on the adoption of sustainability practices. We also suggest moderating effects of long-term orientation (LTO) on this link. Our model is tested on a sample of 195 family firms in the tourism and hospitality sector. The results support our hypothesis that family ownership negatively influences the adoption of sustainability practices. Additionally, LTO moderates the relationship between family ownership and the adoption of sustainability practices, such that family owners with a high LTO are more likely to adopt this particular practice compared to those with a low LTO.
Technological innovation, social learning and natural hazard mitigation: evidence on earthquake fatalities

Abstract How do people learn from disasters? Do they constantly develop and accumulate new knowledge that enables them to address recurrent disaster risks? This paper investigates whether social learning and, in particular, the development of earthquake-mitigating technologies reduces earthquake-induced fatalities. Combining patent data with a global cross-section of 894 earthquakes that occurred between 1980 and 2010, we find that countries with more disaster-mitigating innovations and more earthquake exposure in the past suffer fewer fatalities. This study is the first to empirically examine the role of technological change and social learning in disaster mitigation. It sheds light on knowledge as a key element of adaptive capacity, and suggests the importance of incorporating technology development into a long-term hazard mitigation and adaptation policy. The paper also contributes to the empirical disaster literature as the first to address the problem of missing data on disaster losses.
The Dimerization Domain of the b Subunit of theEscherichia coli F1F0-ATPase*

In this study a series of N- and/or C-terminal truncations of the cytoplasmic domain of the b subunit of the Escherichia coli F1F0 ATP synthase were tested for their ability to form dimers using sedimentation equilibrium ultracentrifugation. The deletion of residues between positions 53 and 122 resulted in a strongly decreased tendency to form dimers, whereas all the polypeptides that included that sequence exhibited high levels of dimer formation. b dimers existed in a reversible monomer-dimer equilibrium and when mixed with other b truncations formed heterodimers efficiently, provided both constructs included the 53–122 sequence. Sedimentation velocity and 15N NMR relaxation measurements indicated that the dimerization region is highly extended in solution, consistent with an elongated second stalk structure. A cysteine introduced at position 105 was found to readily form intersubunit disulfides, whereas other single cysteines at positions 103–110 failed to form disulfides either with the identical mutant or when mixed with the other 103–110 cysteine mutants. These studies establish that the bsubunit dimer depends on interactions that occur between residues in the 53–122 sequence and that the two subunits are oriented in a highly specific manner at the dimer interface.