pinecone/core-2020-05-10-deduplication huggingface dataset:
Protein secretion in gram-positive bacteria: from multiple pathways to biotechnology

A number of Gram-positive bacteria are important players in industry as producers of a diverse array of economically interesting metabolites and proteins. As discussed in this overview, several Gram-positive bacteria are valuable hosts for the production of heterologous proteins. In contrast to Gram-negative bacteria, proteins secreted by Gram-positive bacteria are released into the culture medium where conditions for correct folding are more appropriate, thus facilitating the isolation and purification of active proteins. Although seven different protein secretion pathways have been identified in Gram-positive bacteria, the majority of heterologous proteins are produced via the general secretion or Sec pathway. Not all proteins are equally well secreted, because heterologous protein production often faces bottlenecks including hampered secretion, susceptibility to proteases, secretion stress, and metabolic burden. These bottlenecks are associated with reduced yields leading to non-marketable products. In this chapter, besides a general overview of the different protein secretion pathways, possible hurdles that may hinder efficient protein secretion are described and attempts to improve yield are discussed including modification of components of the Sec pathway. Attention is also paid to omics-based approaches that may offer a more rational approach to optimize production of heterologous proteins.status: publishe
Validation of a Light Aspiration device for in vivo Soft TIssue Characterization (LASTIC)

International audienceIn-vivo characterization of soft tissue is a key step towards accurate biomechanical simulation enabling planning and intra-operative assisted surgery. This chapter presents the new version of LASTIC, a device measuring soft tissue deformations using a negative pressure. Its capabilities are compared with standard tensile tests on five samples with different elastic properties, i.e Young modu-lus, from 10 kPa to 1 MPa, in order to estimate its accuracy and define the functional measurement range. Results show that LASTIC overestimates Young modulus by an average of 24 % compared to the tensile devices. This error, although rather large, allows a first estimation of the elastic modulus of different materials, especially living tissues, even during surgery. Directions for improve-ments are given that will allow for better patient-specific biomechanical simula-tions of soft tissues
SOFA: A Multi-Model Framework for Interactive Physical Simulation

International audienceSOFA (Simulation Open Framework Architecture) is an open-source C++ library primarily targeted at interactive computational medical simulation. SOFA facilitates collaborations between specialists from various domains, by decomposing complex simulators into components designed independently and organized in a scenegraph data structure. Each component encapsulates one of the aspects of a simulation, such as the degrees of freedom, the forces and constraints, the differential equations, the main loop algorithms, the linear solvers, the collision detection algorithms or the interaction devices. The simulated objects can be represented using several models, each of them optimized for a different task such as the computation of internal forces, collision detection, haptics or visual display. These models are synchronized during the simulation using a mapping mechanism. CPU and GPU implementations can be transparently combined to exploit the computational power of modern hardware architectures. Thanks to this flexible yet efficient architecture, \sofa{} can be used as a test-bed to compare models and algorithms, or as a basis for the development of complex, high-performance simulators
Analysis of lipids and polycyclic aromatic hydrocarbons as indicators of past and present (micro)biological activity

Analysis of lipids and hydrocarbons is performed frequently in recent and ancient plant tissues, soils, sediments, peat deposits, oil, rocks, anthropogenic artifacts (archeological samples), and other materials to trace the contribution of different biological and anthropogenic sources of organic matter as well as environmental changes and the fate of organic matter like degradation. The approaches for the analysis of lipids and hydrocarbons strongly vary from traditional methodologies like thin-layer chromatography to universal approaches like pyrolysis, whereas the preparative separation of lipid fractions based on their polarity enables gas-chromatographic analyses of single fractions and compound-specific analysis of stable (2H/1H, 13C/12C) and radioactive (14C) isotope compositions. Often, lipid extraction operationally defines a subfraction of total lipids. On the one hand, free extractable lipids are obtained by extraction with organic solvents, whereas on the other hand, total samples or extraction residues are extracted for more polar lipid fractions using highly polar organic solvents and water, to release bound lipids. Procedures for extraction of free extractable lipids are diverse and mainly defined by the target of research and availability of instrumentation. In the current protocol, state-of-the-art techniques for the investigation of free extract- able lipids in various materials are explained, which can be applied even in laboratory environments with limited technical equipment. The protocols cover sample preparation, extraction, purification, analysis, as well as a brief overview of the data evaluation using lipid molecular proxies and compound-specific isotopes
Kinetic theory models for the distribution of wealth: power law from
  overlap of exponentials

Various multi-agent models of wealth distributions defined by microscopic
laws regulating the trades, with or without a saving criterion, are reviewed.
We discuss and clarify the equilibrium properties of the model with constant
global saving propensity, resulting in Gamma distributions, and their
equivalence to the Maxwell-Boltzmann kinetic energy distribution for a system
of molecules in an effective number of dimensions $D_\lambda$, related to the
saving propensity $\lambda$ [M. Patriarca, A. Chakraborti, and K. Kaski, Phys.
Rev. E 70 (2004) 016104]. We use these results to analyze the model in which
the individual saving propensities of the agents are quenched random variables,
and the tail of the equilibrium wealth distribution exhibits a Pareto law $f(x)
\propto x^{-\alpha -1}$ with an exponent $\alpha=1$ [A. Chatterjee, B. K.
Chakrabarti, and S. S. Manna, Physica Scripta T106 (2003) 367]. Here, we show
that the observed Pareto power law can be explained as arising from the overlap
of the Maxwell-Boltzmann distributions associated to the various agents, which
reach an equilibrium state characterized by their individual Gamma
distributions. We also consider the influence of different types of saving
propensity distributions on the equilibrium state.Comment: 18 pages, 9 figures, Springer style. Submitted to the Proc. Vol. for
  the International Workshop on the "Econophysics of Wealth Distributions
Blockbusters, Bombs and Sleepers: The income distribution of movies

The distribution of gross earnings of movies released each year show a
distribution having a power-law tail with Pareto exponent $\alpha \simeq 2$.
While this offers interesting parallels with income distributions of
individuals, it is also clear that it cannot be explained by simple asset
exchange models, as movies do not interact with each other directly. In fact,
movies (because of the large quantity of data available on their earnings)
provide the best entry-point for studying the dynamics of how ``a hit is born''
and the resulting distribution of popularity (of products or ideas). In this
paper, we show evidence of Pareto law for movie income, as well as, an analysis
of the time-evolution of income.Comment: 5 pages, 3 figures, to appear in Proceedings of International
  Workshop on Econophysics of Wealth Distributions (Econophys-Kolkata I), March
  15-19, 200
Methionine Adenosyltransferase I/III Deficiency in Portugal: High Frequency of a Dominantly Inherited Form in a Small Area of Douro High Lands

Methionine adenosyltransferase deficienc(MAT I/III deficiency) is an inborn error of metabolism resulting in isolated hypermethioninemia, and usually inherited as an autosomal recessive trait, although a dominant form has been reported in several families. During the last 6 years, approximately 520,000 newborns were screened in the Portuguese Newborn Screening Laboratory by MS/MS, and 21 cases of persistent hypermethioninemia were found. One case was confirmed to be a deficiency of cystathionine b-synthase and 20 cases were confirmed by MAT1A gene analysis to have an elevation of methionine due to MAT I/III deficiency, which indicates an incidence for this condition of 1/26,000. Twelve of the MAT I/III deficient newborns, belonging to 11 families, were identified in the northern region of Portugal and sent to the same treatment center, where they are under follow-up. Clinical, biochemical, and genetic characteristics of individuals from these 11 families are presented. Plasma methionine and homocysteine concentrations were found to be moderately increased in all
newborns, and molecular analysis revealed that they all were heterozygous for R264H mutation. Normal growth,development, and neurological examination were observed in all cases, and cerebral MRI performed in six cases revealed myelination abnormalities in one case. Plasma methionine concentration for all 12 cases was always below 300 mM, and they are all on a normal diet for their age
Deficiency of Subunit 6 of the Conserved Oligomeric Golgi Complex (COG6-CDG): Second Patient, Different Phenotype

We describe a 27-month-old girl with COG6 deficiency. She is the first child of healthy consanguineous Moroccan parents. She presented at birth with dysmorphic features including microcephaly, post-axial polydactyly, broad palpebral fissures, retrognathia, and anal anteposition. The clinical phenotype was further characterised by multiorgan involvement including mild psychomotor retardation, and microcephaly, chronic inflammatory bowel disease, micronodular liver cirrhosis, associated with life-threatening and recurrent infections due to combined T- and B-cell dysfunction and neutrophil dysfunction.Mutation analysis showed the patient to be homozygous for the c.G1646T mutation in the COG6 gene. She is the second reported patient with a deficiency of subunit 6 of the COG complex. Although both patients are homozygous for the same mutation, they present a markedly different clinical picture. Indeed immunodeficiency as well as inflammatory bowel disease has not been described previously in patients with any COG-CDG
Alu-Alu Recombination Underlying the First Large Genomic Deletion in GlcNAc-Phosphotransferase Alpha/Beta (GNPTAB) Gene in a MLII Alpha/Beta Patient

Mucolipidosis type II α/β is a severe, autosomal recessive lysosomal storage disorder, caused by a defect in the GNPTAB gene that codes for the α/β subunits of the GlcNAc-phosphotransferase. To date, over 100 different mutations have been identified in MLII α/β patients, but no large deletions have been reported. Here we present the first case of a large homozygous intragenic GNPTAB gene deletion (c.3435-386_3602 + 343del897) encompassing exon 19, identified in a ML II α/β patient. Long-range PCR and sequencing methodologies were used to refine the characterization of this rearrangement, leading to the identification of a 21 bp repetitive motif in introns 18 and 19. Further analysis revealed that both the 5' and 3' breakpoints were located within highly homologous Alu elements (Alu-Sz in intron 18 and Alu-Sq2, in intron 19), suggesting that this deletion has probably resulted from Alu-Alu unequal homologous recombination. RT-PCR methods were used to further evaluate the consequences of the alteration for the processing of the mutant pre mRNA GNPTAB, revealing the production of three abnormal transcripts: one without exon 19 (p.Lys1146_Trp1201del); another with an additional loss of exon 20 (p.Arg1145Serfs*2), and a third in which exon 19 was substituted by a pseudoexon inclusion consisting of a 62 bp fragment from intron 18 (p.Arg1145Serfs*16). Interestingly, this 62 bp fragment corresponds to the Alu-Sz element integrated in intron 18.This represents the first description of a large deletion identified in the GNPTAB gene and contributes to enrich the knowledge on the molecular mechanisms underlying causative mutations in ML II.This work was supported by FCT - project PIC/IC/83252/2007 (http://alfa.fct.mctes.pt/). Coutinho MF and Quental S received grants from the FCT (SFRH/BD/48103/2008; SFRH/BPD/64025/2009)
5-Oxoprolinuria in Heterozygous Patients for 5-Oxoprolinase (OPLAH) Missense Changes

6 páginas, 1 figura. PAGS: 123-128The inherited 5-oxoprolinuria is primarily suggestive of genetic defects in two enzymes belonging to the gamma-glutamyl cycle in the glutathione (GSH) metabolism: the glutathione synthetase (GSS) and the 5-oxoprolinase (OPLAH). The GSS deficiency is the best characterized of the inborn errors of GSH metabolism, whereas the OPLAH deficiency is questioned whether it is a disorder or just a biochemical condition with no adverse clinical effects. Recently, the first human OPLAH mutation (p.H870Pfs) was reported in homozygosis in two siblings who suffered from 5-oxoprolinuria with a benign clinical course. We report two unrelated patients who manifested massive excretion of 5-oxoproline in urine. In both probands, the blood GSH levels were normal and no mutations were found in the GSS gene. The mutational screening of the OPLAH gene, which included the codified sequences, the intronic flanking sequences, the promoter sequence, and a genetic analysis in order to detect large deletions and/or duplications, showed that each patient only harbors one missense mutation in heterozygosis. The in silico analyses revealed that each one of these OPLAH mutations, p.S323R and p.V1089I, could alter the proper function of this homodimeric enzyme. In addition, clinical symptoms manifest in these two probands were not related to GSH cycle defects and, therefore, this study provides further evidence that oxoprolinuria may present as epiphenomenon in several pathological conditions and confound the final diagnosis.C.E. has a “Miguel Servet” contract funded by the Institutode Salud Carlos III(ISCIII). Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) is an initiative from the ISCIII.Peer reviewe
THERAPEUTIC EFFICACY OF MAGNESIUM VALPROATE IN SUCCINIC SEMIALDEHYDE DEHYDROGENASE DEFICIENCY

Succinic semialdehyde dehydrogenase deficiency (SSADHD), a disorder of γ-aminobutyric acid (GABA) metabolism, manifests typically as a nonprogressive neurodevelopmental disorder with cognitive deficiency, neuropsychiatric morbidity and epilepsy. Therapy targets symptomatic seizures and neurobehavioral disturbances. We report an adolescent female with SSADHD whose unresponsiveness to a broad spectrum of antiepileptics was circumvented with magnesium valproate (MgVPA). Epilepsy remains well controlled in our patient, with concomitant improvements in behavioral symptoms and an absence of adverse symptoms. MgVPA intervention may have utility in SSADHD
Non-syndromic Hearing Impairment in a Hungarian Family with the m.7510T>C Mutation of Mitochondrial tRNA^^Ser(UCN)^^^ and Review of Published Cases

The m.7510T>C mitochondrial DNA (mtDNA) mutation is a tRNA(Ser(UCN)) alteration leading to matrilineal isolated hearing impairment. The current paper reviews the available reports on the m.7510T>C mtDNA mutation, with special attention to phenotypic variations and haplogroup background. A Hungarian family, the fourth family reported in the literature, is presented, in which analysis of three generations with bilateral isolated hearing loss revealed the m.7510T>C tRNA(Ser(UCN)) mutation in homoplasmic form in the affected members. Haplogroup analysis verified an unnamed subgroup of mitochondrial haplogroup H. Previously reported Spanish and North American Caucasian families belong to different subgroups of haplogroup H. Analyzing our biobank of Hungarian patients with sensorineural hearing loss, we did not detect this mutation in any other patient, nor was it found in Caucasian haplogroup H control samples. Comparing the cases reported so far, there is interfamilial variablity in the age of onset, accompanying symptoms, and haplogroup background. Our case adds further genetic evidence for the pathogenicity of the m.7510T>C mutation and underlines the need to include full mtDNA sequencing in the screening for unexplained hearing loss
Liver transplantation prevents progressive neurological impairment in argininemia

Argininemia is a rare hereditary disease due to a deficiency of hepatic arginase, which is the last enzyme of the urea cycle and hydrolyzes arginine to ornithine and urea. The onset of the disease is usually in childhood, and clinical manifestations include progressive spastic paraparesis and mental retardation. Liver involvement is less frequent and usually not as severe as observed in other UCDs. For this reason, and because usually there is a major neurological disease at diagnosis, patients with argininemia are rarely considered as candidates for OLT despite its capacity to replace the deficient enzyme by an active one. We report on long-term follow-up of two patients with argininemia. Patient 1 was diagnosed by the age of 20 months and despite appropriate conventional treatment progressed to spastic paraparesis with marked limp. OLT was performed at10 years of age with normalization of plasmatic arginine levels and guanidino compounds. Ten years post-OLT, under free diet, there is no progression of neurological lesions. The second patient (previously reported by our group) was diagnosed at 2 months of age, during a neonatal cholestasis workup study. OLT was performed at the age of 7 years, due to liver cirrhosis with portal hypertension, in the absence of neurological lesions and an almost-normal brain MRI. After OLT, under free diet, there was normalization of plasmatic arginine levels and guanidino compounds. Twelve years post-OLT, she presents a normal neurological exami- nation. We conclude that OLT prevents progressive neuro- logical impairment in argininemia and should be considered when appropriate conventional treatment fails
Evaluation of Implementation, Adaptation and Use of the Recently Proposed Urea Cycle Disorders Guidelines

BACKGROUND  Implementation of guidelines and assessment of their adaptation is not an extensively investigated process in the field of rare diseases. However, whether targeted recipients are reached and willing and able to follow the recommendations has significant impact on the efficacy of guidelines. In 2012, a guideline for the management of urea cycle disorders (UCDs) has been published. We evaluate the efficacy of implementation, adaptation, and use of the UCD guidelines by applying different strategies.  METHODS  (i) Download statistics from online sources were recorded. (ii) Facilities relevant for the implementation of the guidelines were assessed in pediatric units in Germany and Austria. (iii) The guidelines were evaluated by targeted recipients using the AGREE instrument. (iv) A regional networking-based implementation process was evaluated.  RESULTS  (i) Download statistics revealed high access with an increase in downloads over time. (ii) In 18% of hospitals ammonia testing was not available 24/7, and emergency drugs were often not available. (iii) Recipient criticism expressed in the AGREE instrument focused on incomplete inclusion of patients' perspectives. (iv) The implementation process improved the availability of ammonia measurements and access to emergency medication, patient care processes, and cooperation between nonspecialists and specialists.  CONCLUSION  Interest in the UCD guidelines is high and sustained, but more precise targeting of the guidelines is advisable. Surprisingly, many hospitals do not possess all facilities necessary to apply the guidelines. Regional network and awareness campaigns result in the improvement of both facilities and knowledge
Newborn Screening for Homocystinuria Revealed a High Frequency of MAT I/III Deficiency in Iberian Peninsula

Acessível em: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4375120/Homocystinuria due to cystathionine β-synthase deficiency or "classical homocystinuria" is a rare autosomal recessive condition resulting in altered sulfur metabolism with elevated methionine and homocysteine in plasma and homocystine in urine. This condition is characterized by a high clinical heterogeneity, which contributes to late clinical diagnosis, usually only made after irreversible damage has occurred. Treatment is effective if started before clinical symptoms. The analysis of methionine levels by tandem mass spectrometry (MS/MS) allows the newborn screening for homocystinuria, but false-positive results can be frequently obtained and lead to the unwanted identification of methionine adenosyl transferase (MAT I/III) deficiency. This latter condition is biochemically characterized by isolated persistent hypermethioninemia, accompanied in some individuals with slightly elevated levels of homocysteine in plasma. A dominant form of MAT I/III deficiency, associated with mutation p.R264H, seems to be very frequent in the Iberian Peninsula and usually has a clinically benign course. Both these metabolic disorders are screened in Galicia and Portugal since the introduction of the MS/MS technology, in 2000 and 2004, respectively, resulting in the identification of three patients with classical homocystinuria and 44 patients with MAT I/III deficiency. All but one heterozygous parent of MAT I/III patients, identified with the p.R264H mutation, are healthy adults around the age of 30/40. The implementation of a second-tier test for homocysteine in dried blood spots would considerably reduce the number of MAT I/III-deficient patients identified and improve the specificity and positive predictive value for classical homocystinuria screening
Clinical Severity of PGK1 Deficiency Due To a Novel p.E120K Substitution Is Exacerbated by Co-inheritance of a Subclinical Translocation t(3;14)(q26.33;q12), Disrupting NUBPL Gene

Acessível em: www.ncbi.nlm.nih.gov/pmc/articles/pmid/25814383/Carriers of cytogenetically similar, apparentlybalanced familial chromosome translocations not alwaysexhibit the putative translocation-associated disease phenotype.Additional genetic defects, such as genomic imbalanceat breakpoint regions or elsewhere in the genome,have been reported as the most plausible explanation.By means of comprehensive molecular and functionalanalyses, additional to careful dissection of the t(3;14)(q26.33;q12) breakpoints, we unveil a novel X-linkedPGK1 mutation and examine the contribution of these tothe extremely severe clinical phenotype characterized byhemolytic anemia and neuromyopathy.The 3q26.33 breakpoint is 40 kb from the 50 region oftetratricopeptide repeat domain 14 gene (TTC14), whereasthe 14q12 breakpoint is within IVS6 of nucleotide-bindingprotein-like gene (NUBPL) that encodes a mitochondrialcomplex I assembly factor. Disruption of NUBPL intranslocation carriers leads to a decrease in thecorresponding mRNA accompanied by a decrease inprotein level. Exclusion of pathogenic genomic imbalanceand reassessment of familial clinical history indicate theexistence of an additional causal genetic defect. Consequently,by WES a novel mutation, c.358G>A, p.E120K,in the X-linked phosphoglycerate kinase 1 (PGK1) wasidentified that segregates with the phenotype. Specificactivity, kinetic properties, and thermal stability of thisenzyme variant were severely affected. The novel PGK1mutation is the primary genetic alteration underlying thereported phenotype as the translocation per se only resultsin a subclinical phenotype. Nevertheless, its co-inheritancepresumably exacerbates PGK1-deficient phenotype, mostlikely due to a synergistic interaction of the affected genesboth involved in cell energy supply