Miracle-dz/UniFAR-FTUs huggingface dataset:
Human ESCRT-III and VPS4 proteins are required for centrosome and spindle maintenance

The ESCRT pathway helps mediate the final abscission step of cytokinesis in mammals and archaea. In mammals, two early acting proteins of the ESCRT pathway, ALIX and TSG101, are recruited to the midbody through direct interactions with the phosphoprotein CEP55. CEP55 resides at the centrosome through most of the cell cycle but then migrates to the midbody at the start of cytokinesis, suggesting that the ESCRT pathway may also have centrosomal links. Here, we have systematically analyzed the requirements for late-acting mammalian ESCRT-III and VPS4 proteins at different stages of mitosis and cell division. We found that depletion of VPS4A, VPS4B, or any of the 11 different human ESCRT-III (CHMP) proteins inhibited abscission. Remarkably, depletion of individual ESCRT-III and VPS4 proteins also altered centrosome and spindle pole numbers, producing multipolar spindles (most ESCRT-III/VPS4 proteins) or monopolar spindles (CHMP2A or CHMP5) and causing defects in chromosome segregation and nuclear morphology. VPS4 proteins concentrated at spindle poles during mitosis and then at midbodies during cytokinesis, implying that these proteins function directly at both sites. We conclude that ESCRT-III/VPS4 proteins function at centrosomes to help regulate their maintenance or proliferation and then at midbodies during abscission, thereby helping ensure the ordered progression through the different stages of cell division.
Supradapedon revisited: geological explorations in the Triassic of southern Tanzania

The upper Triassic deposits of the Selous Basin in south Tanzania have not been prospected for fossil tetrapods since the middle of last century, when Gordon M. Stockley collected two rhynchosaur bone fragments from the so called “Tunduru beds”. Here we present the results of a field trip conducted in July 2015 to the vicinities of Tunduru and Msamara, Ruvuma Region, Tanzania, in search for similar remains. Even if unsuccessful in terms of fossil discoveries, the geological mapping conducted during the trip improved our knowledge of the deposition systems of the southern margin of the Selous Basin during the Triassic, allowing tentative correlations to its central part and to neighbouring basins. Moreover, we reviewed the fossil material previously collected by Gordon M. Stockley, confirming that the remains correspond to a valid species, Supradapedon stockleyi, which was incorporated into a comprehensive phylogeny of rhynchosaurs and found to represent an Hyperodapedontinae with a set of mostly plesiomorphic traits for the group. Data gathered form the revision and phylogenetic placement of Su. stockleyi helps understanding the acquisition of the typical dental traits of Late Triassic rhynchosaurs, corroborating the potential of hyperodapedontines as index fossils of the Carnian-earliest Norian.
Toward quantitative understanding on microbial community structure and functioning: a modeling-centered approach using degradation of marine oil spills as example

Molecular ecology approaches are rapidly advancing our insights into the microorganisms involved in the degradation of marine oil spills and their metabolic potentials. Yet, many questions remain open: how do oil-degrading microbial communities assemble in terms of functional diversity, species abundances and organization and what are the drivers? How do the functional properties of microorganisms scale to processes at the ecosystem level? How does mass flow among species, and which factors and species control and regulate fluxes, stability and other ecosystem functions? Can generic rules on oil-degradation be derived, and what drivers underlie these rules? How can we engineer oil-degrading microbial communities such that toxic polycyclic aromatic hydrocarbons are degraded faster? These types of questions apply to the field of microbial ecology in general. We outline how recent advances in single-species systems biology might be extended to help answer these questions. We argue that bottom-up mechanistic modeling allows deciphering the respective roles and interactions among microorganisms. In particular constraint-based, metagenome-derived community-scale flux balance analysis appears suited for this goal as it allows calculating degradation-related fluxes based on physiological constraints and growth strategies, without needing detailed kinetic information. We subsequently discuss what is required to make these approaches successful, and identify a need to better understand microbial physiology in order to advance microbial ecology. We advocate the development of databases containing microbial physiological data. Answering the posed questions is far from trivial. Oil-degrading communities are, however, an attractive setting to start testing systems biology-derived models and hypotheses as they are relatively simple in diversity and key activities, with several key players being isolated and a high availability of experimental data and approaches.
A Connexin50 Mutant, CX50fs, That Causes Cataracts Is Unstable, but Is Rescued by a Proteasomal Inhibitor*

Background: The mechanism by which CX50fs, a mutant connexin50 containing a frameshift after amino acid 255, causes cataracts is unknown. Results: CX50fs was unstable in HeLa cells, but epoxomicin treatment restored gap junction abundance and intercellular communication. Conclusion: CX50fs undergoes enhanced endoplasmic reticulum-associated proteasomal degradation leading to decreased function. Significance: The results suggest protease inhibition as a novel therapeutic approach to treat connexin mutant-associated diseases. The mechanisms by which mutant connexins lead to disease are diverse, including those of connexin50 (CX50) encoded by the GJA8 gene. We investigated the cellular and functional behavior of CX50fs, a mutant CX50 that has a frameshift after amino acid 255 and causes recessive congenital cataracts. Cellular levels of CX50fs were much lower than those of wild type CX50 in stably transfected HeLa cells. Whereas CX50 localized at distinct gap junction plaques and supported extensive intercellular transfer of Neurobiotin, CX50fs gap junctions were rare, and their support of Neurobiotin transfer was reduced by >90%. After inhibition of new protein synthesis with cycloheximide, CX50fs disappeared much more rapidly than CX50, suggesting increased degradation of the mutant. Treatment of cells with epoxomicin (a proteasomal inhibitor) led to a dramatic increase in CX50fs levels and in the abundance of gap junctions. Epoxomicin treatment also rescued intercellular transfer of Neurobiotin to levels similar to those in cells expressing the wild type protein. Treatment with eeyarestatin I (an inhibitor of p97-dependent protein degradation) resulted in many abundant slowly migrating CX50 and CX50fs bands consistent with polyubiquitination of the proteins. These results demonstrate that the CX50fs mutant is rapidly degraded by endoplasmic reticulum-associated degradation in mammalian cells. This accelerated degradation reduces the abundance of gap junctions and the extent of intercellular communication, potentially explaining the pathogenesis of cataracts linked to this mutant. The efficacy of epoxomicin in restoring function suggests that protease inhibition might have therapeutic value for this and other diseases caused by mutants with similar defects.
A reconfigurable buck-boost switched capacitor converter with adaptive gain and discrete frequency scaling control

This paper presents the design of a reconfigurable buck-boost switched capacitor converter using a novel control method that allows coarse and fine control of the output voltage. The converter uses adaptive gain control, discrete frequency scaling and burst mode switching to regulate the power delivered to a range of output voltages and loads. This control scheme has been implemented in a fully-integrated switched capacitor converter design using a standard bulk CMOS 0. 18μm process. Simulation results show that the converter has an output voltage range of 0.8-2.2V, can deliver up to 5mA in load current and can be up to 68% efficient.
The Substrate Specificity of Purified Rat Lung Semicarbazide-Sensitive Amine Oxidase

Objectives: The aim of this study was to investigate the substrate specificity of purified rat lung semicarbazide-sensitive amine oxidase. Methods: Substrate specificity and kinetics of purified rat lung semicarbazide sensitive amine oxidase were studied using benzylamine and methylamine as substrates. Substrate competition studies were also performed. Results: Semicarbazide-sensitive amine oxidase was purified from the crude microsomal fractions of rat lung by Cibacron Blue 3GA-agarose and Concanavalin A-Sepharose 4B affinity chromatographies with a specific activity of 5.6 nmol/ min/mg protein by using benzylamine as a substrate. Km and Vmax values for benzylamine and methylamine were determined to be 3.7 μM and 5.6 nmol/min/mg protein; and 141.5 μM and 4.2 nmol/min/mg protein, respectively. Conclusion: The velocity of the reaction decreased with increasing substrate concentration in the case of benzylamine indicating that Michaelis-Menten enzyme behaviour was obeyed at only low concentrations for this substrate. Oxidation of methylamine by purified SSAO obeyed to the Michaelis-Menten behaviour. Substrate inhibition was not detected for the oxidation of methylamine by SSAO at high concentrations. Substrate competition studies showed that methylamine, dopamine, phenylethylamine, kynuramine and serotonin inhibited the oxidation of benzylamine by semicarbazide-sensitive amine oxidase.
Transposition of the cephalic vein in therapeutic rescue of cephalic arch stenosis

Autogenous arteriovenous fistulas (AVFs) are considered the most reliable long-term vascular access in patients undergoing haemodialysis. Although AVFs generally require fewer interventions than arteriovenous grafts (AVGs) to maintain patency, some sites of venous stenosis account for a large portion of repeated interventions. A particularly troublesome site within brachiocephalic AVFs is the cephalic arch. Cephalic arch stenosis (CAS) has been implicated in 19–77% of brachiocephalic fistula failures [1]. The cephalic arch has a unique architecture. In addition to containing a high concentration of valves and having a steep angulation, it crosses multiple tissue planes, bridging the superficial and deep venous systems while being tethered to rigid extravascular structures. These factors combine to make the cephalic arch particularly vulnerable to the development of stenotic lesions, as changes in vessel compliance produce turbulent flow. When an anastomosis is created between the brachial artery and the cephalic vein, the flow within the cephalic vein increases and the vessel starts dilating. However, the tissues surrounding the cephalic arch preclude its expansion, so that the cephalic vein narrows as it approaches its junction with the central veins. This sudden reduction in the circumference of a high-flow pathway results in an inflow–outflow mismatch, potentiating turbulence and the increased shear stress associated with it [1, 2]. When a CAS occurs, the management is not easy. Angioplasty of stenotic lesions involving the cephalic arch has limited effectiveness, which led investigators to seek surgical alternatives to treat these lesions and to preserve current fistula [1]. The option for cephalic vein transposition (CVT), described by Chen et al., involves surgical revision to redirect the blood flow to the adjacent patient veins. The surgical procedure entailed transecting the healthy portion of the cephalic vein distal to the stenotic segment in the arch, transposing and anastomosing it to the upper basilic [2] (Figure ​(Figure11). Fig. 1. Illustration of the cephalic vein transposition technique. We present the experience of our centre with upper arm CVT procedures in three haemodialysis patients who underwent haemodialysis treatment in the haemodialysis unit of Centro Hospitalar de Setubal E.P.E. Two of the 3 cases did not have the possibility of endovascular treatment. In these cases CVT to basilic vein made possible the preservation of vascular access. Both accesses are patents to date, 6 and 9 months, respectively. In the other case, the CVT allowed the reduction of percutaneous transluminal angioplasties (PTAs)/access-year in a patient with frequent recurrent CAS (requiring angioplasty in <3-month intervals) and is also patent to date (52 months).
Effect of Raloxifene on Mammographic Density and Breast Magnetic Resonance Imaging in Premenopausal Women at Increased Risk for Breast Cancer

Background: Mammographic density is a risk factor for breast cancer. Mammographic density and breast magnetic resonance imaging (MRI) volume (MRIV) assess the amount of fibroglandular tissue in the breast. Mammographic density and MRIV can be modulated with hormonal interventions, suggesting that these imaging modalities may be useful as surrogate endpoint biomarkers for breast cancer chemoprevention trials. We evaluated the effect of raloxifene on mammographic density and MRIV in premenopausal women at increased risk for breast cancer. Methods: Mammograms and MRI were obtained at baseline and after 1 and 2 years of 60 mg raloxifene by mouth daily for 27 premenopausal women. Mammographic percent dense area was calculated using a semiquantitative thresholding technique. T1-weighted spoiled gradient-echo MRI with fat suppression was used to determine breast MRIV using a semiautomatic method. Mean change in mammographic density and median change in MRIV were assessed by the Wilcoxon signed-rank test. Results: No significant change in mammographic density was seen after treatment with raloxifene. Mean change after 1 year was 1% [95% confidence interval (95% CI), −3 to +5] and after 2 years was 1% (95% CI, −2 to +5). MRIV decreased on raloxifene. Median relative change in MRIV after 1 year was -17% (95% CI, -28 to -9; P = 0.0017) and after 2 years was -16% (95% CI, -31 to -4; P = 0.0004). Conclusions: In high-risk premenopausal women, mammographic density did not change on raloxifene, whereas MRIV significantly declined. Our findings suggest that MRIV is a promising surrogate biomarker in premenopausal women at increased risk for breast cancer and should be investigated further in breast cancer prevention trials. (Cancer Epidemiol Biomarkers Prev 2008;17(7):1696–701)
Short telomeres in short-lived males: what are the molecular and evolutionary causes?

Telomere length regulation is an important aspect of cell maintenance in eukaryotes, since shortened telomeres can lead to a number of defects, including impaired cell division. Although telomere length is correlated with lifespan in some bird species, its possible role in aging and lifespan determination is still poorly understood. Here we investigate telomere dynamics (changes in telomere length and attrition rate) and telomerase activity in the ant Lasius niger, a species in which different groups of individuals have evolved extraordinarily different lifespans. We found that somatic tissues of the short‐lived males had dramatically shorter telomeres than those of the much longer‐lived queens and workers. These differences were established early during larval development, most likely through faster telomere shortening in males compared with females. Workers did not, however, have shorter telomeres than the longer‐lived queens. We discuss various molecular mechanisms that are likely to cause the observed sex‐specific telomere dynamics in ants, including cell division, oxidative stress and telomerase activity. In addition, we discuss the evolutionary causes of such patterns in ants and in other species.
Pds1p, an inhibitor of anaphase in budding yeast, plays a critical role in the APC and checkpoint pathway(s)

We report the isolation and characterization of pds1 mutants in Saccharomyces cerevisiae. The initial pds1-1 allele was identified by its inviability after transient exposure to microtubule inhibitors and its precocious dissociation of sister chromatids in the presence of these microtubule inhibitors. These findings suggest that pds1 mutants might be defective in anaphase arrest that normally is imposed by a spindle-damage checkpoint. To further examine a role for Pds1p in anaphase arrest, we compared the cell cycle arrest of pds1 mutants and PDS1 cells after: (a) the inactivation of Cdc16p or Cdc23p, two proteins that are required for the degradation of mitotic cyclins and are putative components of the yeast anaphase promoting complex (APC); (b) the inactivation of Cdc20p, another protein implicated in the degradation of mitotic cyclins; and (c) the inactivation of Cdc13 protein or gamma irradiation, two circumstances that induce a DNA- damage checkpoint. Under all these conditions, anaphase is inhibited in PDS1 cells but not in pds1 mutants. From these results we suggest that Pds1 protein is an anaphase inhibitor in PDS1 cells but not in pds1 mutants. From these results we suggest that Pds1 protein is an anaphase inhibitor that plays a critical role in the control of anaphase by both APC and checkpoints. We also show that pds1 mutants exit mitosis and initiate new rounds of cell division after gamma irradiation and Cdc13p inactivation but no after nocodazole-treatment or inactivation of Cdc16p, Cdc20p or Cdc23p function. Therefore, in the DNA-damage checkpoint, Pds1p is required for the inhibition of cytokinesis and DNA replication as well as anaphase. The role of Pds1 protein in anaphase inhibition and general cell cycle regulation is discussed.
A Class of Methods for Solving Nonlinear Simultaneous Equations

solution. The functions that require zeroing are real functions of real variables and it will be assumed that they are continuous and differentiable with respect to these variables. In many practical examples they are extremely complicated anld hence laborious to compute, an-d this fact has two important immediate consequences. The first is that it is impracticable to compute any derivative that may be required by the evaluation of the algebraic expression of this derivative. If derivatives are needed they must be obtained by differencing. The second is that during any iterative solution process the bulk of the computing time will be spent in evaluating the functions. Thus, the most efficient process will tenid to be that which requires the smallest number of function evaluations. This paper discusses certain modificatioins to Newton's method designed to reduce the number of function evaluations required. Results of various numerical experiments are given and conditions under which the modified versions are superior to the original are tentatively suggested.
Mapping Epitope Structure and Activity: From One-Dimensional Prediction to Four-Dimensional Description of Antigenic Specificity

Our knowledge of antigenic specificity has greatly increased in recent years mainly through X-ray crystallographic studies of proteins and peptides complexed with monoclonal antibodies. However, our ability to predict the location of antigenic sites in proteins remains limited partly because prediction algorithms reduce the complexity of epitopes to one-dimensional, linear peptide models. Epitopes and paratopes are relational entities definable by their mutual complementarity and adaptation potential as well as by their activity. A complete account of antigenic specificity demands the integration of both structural and binding activity data that can be achieved only through a spatiotemporal four-dimensional analysis. Failure to include the fourth dimension, i.e., time, in the analysis of antigen-antibody complementarity amounts to considering proteins as rigid bodies and ignores the mutual adaptation that occurs when the two partners interact. Reducing four-dimensional protein systems to three-dimensional or two-dimensional representations inevitably distorts our perception of the dynamic nature of epitopes.
A multiple-perspective analysis of doctoral interdisciplinarity

Interdisciplinary and assessment initiatives are two parallel educational paradigms that are being increasingly implemented in higher education institutions. Our study combines these two paradigms in order to assess the significance and performance of factors and processes that facilitate interdisci-plinarity at the doctoral level. Using the 360-degree feedback methodology, we integrate the perspectives of different academic stakeholders in the assessment, namely students, post-doctoral researchers, professors, directors, visiting professors and research funding agencies. Therefore, this study not only provides a global assessment but also informative intermediate results, such as analyses on the alignment and discrepancies of stakeholders as well as the identification of priorities for improvement. This paper presents the development and implementation of this multiple-perspective assessment within an academic context and discusses the results of its application in a European faculty of computer science where several doctoral programs with different approaches to interdisciplinarity co-exist.
Non-Rigid Graph Registration Using Active Testing Search

We present a new approach for matching sets of branching curvilinear structures that form graphs embedded in <inline-formula><tex-math notation="LaTeX">${\mathbb {R}}^2$</tex-math><alternatives> <inline-graphic xlink:type="simple" xlink:href="sznitman-ieq1-2343235.gif"/></alternatives></inline-formula> or <inline-formula> <tex-math notation="LaTeX">${\mathbb {R}}^3$</tex-math><alternatives> <inline-graphic xlink:type="simple" xlink:href="sznitman-ieq2-2343235.gif"/></alternatives></inline-formula> and may be subject to deformations. Unlike earlier methods, ours does not rely on local appearance similarity nor does require a good initial alignment. Furthermore, it can cope with non-linear deformations, topological differences, and partial graphs. To handle arbitrary non-linear deformations, we use Gaussian process regressions to represent the geometrical mapping relating the two graphs. In the absence of appearance information, we iteratively establish correspondences between points, update the mapping accordingly, and use it to estimate where to find the most likely correspondences that will be used in the next step. To make the computation tractable for large graphs, the set of new potential matches considered at each iteration is not selected at random as with many RANSAC-based algorithms. Instead, we introduce a so-called <italic>Active Testing Search</italic> strategy that performs a priority search to favor the most likely matches and speed-up the process. We demonstrate the effectiveness of our approach first on synthetic cases and then on angiography data, retinal fundus images, and microscopy image stacks acquired at very different resolutions.
Survival of Patients With Spinal Muscular Atrophy Type 1

BACKGROUND: Spinal muscular atrophy type 1 (SMA1) is a progressive disease and is usually fatal in the first year of life. METHODS: A retrospective chart review was performed of SMA1 patients and their outcomes according to the following choices: letting nature take its course (NT); tracheostomy and invasive mechanical ventilation (TV); continuous noninvasive respiratory muscle aid (NRA), including noninvasive ventilation; and mechanically assisted cough. RESULTS: Of 194 consecutively referred patients enrolled in this study (103 males, 91 females), NT, TV, and NRA were chosen for 121 (62.3%), 42 (21.7%), and 31 (16%) patients, respectively. Survival at ages 24 and 48 months was higher in TV than NRA users: 95% (95% confidence interval: 81.8%–98.8%) and 67.7% (95% confidence interval: 46.7%–82%) at age 24 months (P < .001) and 89.43% and 45% at age 48 months in the TV and NRA groups, respectively (P < .001). The choice of TV decreased from 50% (1992–1998) to 12.7% (2005–2010) (P < .005) with a nonstatistically significant increase for NT from 50% to 65%. The choice of NRA increased from 8.1% (1999–2004) to 22.7% (2005–2010) (P < .001). CONCLUSIONS: Long-term survival outcome is determined by the choice of the treatment. NRA and TV can prolong survival, with NRA showing a lower survival probability at ages 24 and 48 months.