Miracle-dz/UniFAR-FTUs huggingface dataset:
In Vivo Base Editing of PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) as a Therapeutic Alternative to Genome Editing

Objective— High-efficiency genome editing to disrupt therapeutic target genes, such as PCSK9 (proprotein convertase subtilisin/kexin type 9), has been demonstrated in preclinical animal models, but there are safety concerns because of the unpredictable nature of cellular repair of double-strand breaks, as well as off-target mutagenesis. Moreover, precise knock-in of specific nucleotide changes—whether to introduce or to correct gene mutations—has proven to be inefficient in nonproliferating cells in vivo. Base editors comprising CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats [CRISPR]-CRISPR-associated 9) fused to a cytosine deaminase domain can effect the alteration of cytosine bases to thymine bases in genomic DNA in a sequence-specific fashion, without the need for double-strand DNA breaks. The efficacy of base editing has not been established in vivo. The goal of this study was to assess whether in vivo base editing could be used to modify the mouse Pcsk9 gene in a sequence-specific fashion in the liver in adult mice. Approach and Results— We screened base editors for activity in cultured cells, including human-induced pluripotent stem cells. We then delivered a base editor into the livers of adult mice to assess whether it could introduce site-specific nonsense mutations into the Pcsk9 gene. In adult mice, this resulted in substantially reduced plasma PCSK9 protein levels (>50%), as well as reduced plasma cholesterol levels (≈30%). There was no evidence of off-target mutagenesis, either cytosine-to-thymine edits or indels. Conclusions— These results demonstrate the ability to precisely introduce therapeutically relevant nucleotide variants into the genome in somatic tissues in adult mammals, as well as highlighting a potentially safer alternative to therapeutic genome editing.
Estrategia empresarial e innovación como concluyentes de la intensidad exportadora: un análisis empírico

El ambito de trabajo de la presente tesis se centra en el analisis del resultado exportador de las pequenas y medianas empresas -en un territorio concreto- desde una perspectiva empresarial y tratando de integrar un modelo que recoja los principales aspectos destacados por la literatura como factores de competitividad. Inicialmente se ha efectuado una revision de las diferentes teorias sobre la internacionalizacion empresarial, asi como las proposiciones metodologicas y conclusiones de los estudios empiricos mas trascendentales que se han publicado en los ultimos anos. En este sentido, lo anterior ha sido el fundamento para el posterior desarrollo de un marco de trabajo teorico que tuviera en cuenta los principales factores que afectan dicho cometido. El esquema teorico que se presenta, relaciona el desempeno exportador con los principales factores identificados. A continuacion, se formulan las hipotesis a partir de dichos factores y las preguntas que sugiere la investigacion. Inmediatamente se muestra el ambito del estudio y los criterios de seleccion de las empresas y la muestra resultante del trabajo de campo. La muestra utilizada se ha compuesto de 164 empresas (extraidas de una poblacion de 640). Finalmente, se ha explicado, de manera resumida, los metodos y las tecnicas de analisis de los datos utilizados en la presente investigacion. En una primera parte empirica del estudio se presenta un analisis descriptivo de la informacion que se propuso investigar sobre como es la empresa exportadora. Despues, en una segunda, igualmente empirica, se realiza un analisis comparativo entre aquellas empresas con mayor exito exportador (con una intensidad exportadora superior a la media) y aquellas otras empresas con resultados exteriores mas reducidos. Finalmente, en la tercera parte, se presenta un analisis sobre cuales de las variables utilizadas anteriormente producen un efecto positivo sobre la intensidad exportadora de las empresas. En este sentido, se utiliza como principal herramienta estadistica para el estudio de la informacion el analisis de regresion lineal -complementado con el analisis factorial- para ver que efecto tienen las mencionadas variables sobre la intensidad exportadora. El estudio acaba definiendo aquellas areas en las que pueden mejorar las empresas, asi como unas futuras lineas de investigacion propuestas.
Identification of antigenically important domains in the glycoproteins of Sindbis virus by analysis of antibody escape variants

To study important epitopes on glycoprotein E2 of Sindbis virus, eight variants selected to be singly or multiply resistant to six neutralizing monoclonal antibodies reactive against E2, as well as four revertants which had regained sensitivity to neutralization, were sequenced throughout the E2 region. To study antigenic determinants in glycoprotein E1, four variants selected for resistance to a neutralizing monoclonal antibody reactive with E1 were sequenced throughout the E2 and E1 regions. All of the salient changes in E2 occurred within a relatively small region between amino acids 181 and 216, a domain that encompasses a glycosylation site at residue 196 and that is rich in charged amino acids. Almost all variants had a change in charge, suggesting that the charged nature of this domain is important for interaction with antibodies. Variants independently isolated for resistance to the same antibody were usually altered in the same amino acid, and reversion to sensitivity occurred at the sites of the original mutations, but did not always restore the parental amino acid. The characteristics of this region suggest that this domain is found on the surface of E2 and constitutes a prominent antigenic domain that interacts directly with neutralizing antibodies. Previous studies have shown that this domain is also important for penetration of cells and for virulence of the virus. Resistance to the single E1-specific neutralizing monoclonal antibody resulted from changes of Gly-132 of E1 to either Arg or Glu. Analogous to the findings with E2, these changes result in a change in charge and are found near a glycosylation site at residue 139. This domain of E1 may therefore be found near the 181 to 216 domain of E2 on the surface of the E1-E2 heterodimer; together, they could form a domain important in virus penetration and neutralization.
Titi Livi Ab urbe condita

This is the sixth volume in the Oxford Classical Texts series of Livy and contains a Latin text (without translation), together with full apparatus criticus and Latin introduction, of Books 36-40, which cover the period from 192 to 179 BC. This momentous era in the history of Republican Rome begins with the war with Antiochus, which resulted in Rome's indirect control of Greece and Asia, and concludes with the death of Philip V of Macedon, foreshadowing the Third Macedonian War. During these years Rome also struggled for the increasing dominance of northern Italy and Spain. On the domestic front, Livy depicts this period as the beginning of Roman moral decline, as reflected in such events as the trials of the Scipios, the censorship of Cato, and the Bacchanalia. Since much of the account by Polybius is fragmentary, Livy's narrative is the main source for the history of the period.
Association analysis of cysteinyl-leukotriene receptor 2 (CYSLTR2) polymorphisms with aspirin intolerance in asthmatics

Objectives and methods The cysteinyl leukotriene receptor 2 (CYSLTR2) gene on chromosome 13q14.12–q21.1 encodes a receptor for CYSLTs, potent biological mediators in the pathogenesis of asthma, particularly that associated with aspirin intolerance (AIA). In an effort to discover additional polymorphism(s), the variant(s) of which have been implicated in asthma and aspirin intolerance, we scrutinized genetic polymorphisms of the CYSLTR2 gene, and evaluated this locus as a potential candidate for asthma. Results DNA sequencing in 24 Koreans of the 5-kb region of the CYSLTR2 gene, including the ∼1500-bp promoter region, revealed four sequence variants: one in the 5′-flanking region (c.−819T>G), two in the 3′-flanking region (c.2078C>T and c.2534A>G), and one downstream of the gene (c.2545+297A>G). The SNP frequencies were 0.499 (c.−819T>G), 0.351 (c.2078C>T), 0.429 (c.2534A>G), and 0.088 (c.2545+297A>G), and five haplotypes were constructed. The SNPs and haplotypes were not associated with risk of asthma development, but were significantly associated with aspirin intolerance. The frequencies of rare alleles on c. −819T>G, c.2078C>T, and c.2534A>G were higher in subjects with AIA than in subjects with aspirin-tolerant asthma (P=0.013–0.031). Asthmatics who had rare alleles for c. −819T>G, c.2078C>T or c.2534A>G exhibited a more pronounced fall in FEV1 after aspirin provocation than did those who carried the common allele (P=0.03–0.009). Asthmatics carrying ht2 (TTGA) also showed a more pronounced decrease in FEV1% after aspirin provocation than those carrying ht1 (GCGA) (P=0.006). These associations were even stronger when combined with LTC4S polymorphisms (−444A>C [c.−444A>C]) gene. Conclusion CYSLTR2 polymorphisms are associated with aspirin intolerance in asthmatics.
Influência dos padrões alimentares na síndrome metabólica em adultos

Oliveira MSR. Influencia dos padroes alimentares na sindrome metabolica em adultos. / Influence of dietary patterns on metabolic syndrome in adults. [dissertation] Sao Paulo (BR): Faculdade de Saude Publica da Universidade de Sao Paulo; 2013. Background: Metabolic Syndrome (MetS) is a complex disorder represented by a combination of cardiometabolic risk factors related to central obesity and insulin resistance, which directly increase the risk of cardiovascular disease. The growth in the prevalence of MetS follows the increase in consumption of foods whose nutrient combinations are potentially adipogenic (diets high in saturated fats and sugar and low in whole grains, fruits and vegetables). This new pattern of food consumption in the world follows the modern western lifestyle that is characterized by excessive consumption of calories and low energy expenditure. Objective: To investigate the association between dietary patterns, MetS and some of its main components in adults of both sexes carriers and non-carriers of the syndrome. Methods: Crosssectional study conducted with 267 adults of both sexes. Were evaluated the following data previously collected: demographic (age and sex), anthropometric and body composition (body mass index and waist circumference), dietary (food patterns detected from analysis of a 24-hour recall), clinical and biochemical (blood pressure measurement, blood sampling after 12h of fasting for evaluation of serum triglycerides, total cholesterol, LDL-c, HDL-c and fasting glucose). Dietary patterns (DPs) were obtained by principal component analysis and subsequent statistical analyzes of correlation and mean comparison were performed to further investigate the relationship between the dietary patterns identified by this method and the characteristics of the population. Results: Three distinct dietary patterns were identified from the principal component factor analysis, explaining 25.59% of the dietary intake variance: (i) “Traditional Dietary Pattern”, represented by the high intake of rice, beans, fresh spice, vegetables, white meat, juices, coffee & teas and sugar, and low intake of pasta; (ii) “Healthy Dietary Pattern”, characterized by high
Characterization of lipopolysaccharide heterogeneity in Salmonella enteritidis by an improved gel electrophoresis method

Salmonella enteritidis field isolates of different phage types and pathogenicities were assessed for changes in lipopolysaccharide (LPS) structure, using an improved method of polyacrylamide gel electrophoresis (PAGE) that revealed the same degree of structural detail as mass spectroscopy. The method allowed characterization of an LPS chemotype that may be associated, regardless of phage type, with increased virulence of S. enteritidis. The virulent variant SE6-E21, which efficiently contaminates eggs and yields high numbers of organisms from chick spleens, had an O-antigen/core ratio of 2.8, as determined from gels by densitometry, and 1.67 micrograms of mannose per microgram of 2-keto-3-deoxy-octulosonic acid (KDO), while the avirulent variant SE6-E5 had O-antigen/core ratios of 1.2 and 1.00. The association between O antigen and virulence was also seen on analysis of five new field isolates. One of the new field isolates generated a mixed population of smooth and semismooth variants in agreement with its mixed virulence in chicks. When LPS was purified from large-volume cultures, only the most virulent isolate yielded high amounts of O antigen (1.6 micrograms of mannose per microgram of KDO), while the other isolates had ratios characteristic of semismooth variants (< or = 1.0 microgram of mannose per microgram of KDO), including the isolate of mixed virulence. These results indicate that the improved PAGE method might provide a rapid, sensitive, in vitro assessment of field isolate virulence prior to the performance of definitive infectivity trials.
Endoloop technique for laparoscopic cornuectomy: A safe and effective approach for the treatment of interstitial pregnancy

Interstitial pregnancy (IP) occurs within the intramural portion of the tube and accounts for 2% of ectopic pregnancies. Surgery is considered the most definitive treatment for IPs, although there is no clear consensus regarding the optimal approach. In this paper we describe the advantages of cornual resection performed using the Endoloop technique and present three patients who were successfully treated using this approach. IP diagnosis was confirmed at two and three‐dimensional ultrasound and laparoscopy in all cases. Fertility sparing surgery with cornuectomy by Endoloop ligature technique demonstrated low mean operating time and blood loss, and allowed the quick recovery and discharge of all patients. Laparoscopy has become the gold standard surgical approach for IP. Cornual resection or excision is the most commonly performed procedure. In our case series, the Endoloop technique showed excellent treatment outcomes in terms of effectiveness, blood loss, operative time, recovery and post‐procedure fertility. Because of these features, Endoloop appears to be a suitable option for the laparoscopic management of IPs, both in elective and emergency settings.
A Theory of Ambiguity, Credibility, and Inflation under Discretion and Asymmetric Information

This paper develops a positive theory of credibility, ambiguity, and inflation under discretion and asymmetric information. The monetary policymaker maximizes his own (politically motivated) objective function that is positively related to economic stimulation through monetary surprises and negatively related to monetary growth. The relative importance he assigns to each target shifts stochastically through time. His current preference trade-off is known to him but not to the public. When choosing the (state contingent) path of money growth for the present and the future, the policymaker compares the benefits from current stimulation with the costs associated with higher future inflation expectations. Current monetary growth conveys information to the public about future money growth because there is persistence in the policymaker's objectives. Although expectations are rational, information is imperfect because monetary control procedures are imprecise. As a result the public cannot correctly distinguish persistent changes of emphasis on different policy objectives from transitory monetary control errors. The public becomes aware of changes gradually by observing past monetary growth. Credibility is defined in terms of the speed with which the public recognizes changes in the objectives of the policymaker. Credibility is lower the noisier monetary control and the more stable the objectives of the policymaker. Looser monetary control and a higher degree of time preference on the part of the policymaker induce him to produce higher and more variable monetary growth. When the policymaker is free to determine the accuracy of monetary control he does not always choose the most effective control available in spite of the fact that monetary surprises always have an expected value of zero. The reason is that ambiguous control procedures enable the policymaker to generate positive surprises when he cares more than on average about economic stimulation. He leaves the inevitable negative surprises for periods in which he cares more about inflation prevention. This result provides an explanation for the Fed's preference for ambiguity, recently documented by Goodfriend (1986). The policymaker is more likely to pick more ambiguous control procedures the more uncertain his objectives and the higher his time preference. The paper also provides a theoretical underpinning for the well documented crosscountry positive correlation between the level and the variability of inflation.
VARIATION IN OFFSPRING SIZE WITH BIRTH ORDER IN PLACENTAL FISH: A ROLE FOR ASYMMETRIC SIBLING COMPETITION?

Asymmetric sibling competition arises when siblings with different competitive abilities share a limited resource. Such competition occurs in species with postnatal parental care and may also occur when mothers provision embryos between fertilization and birth (matrotrophy). We hypothesized that the combination of matrotrophy and the simultaneous provisioning of embryos in different stages of development (superfetation) leads to asymmetric competition between sibling embryos. Moreover, we expect the intensity of this competition to increase with the level of superfetation as high levels of superfetation result in greater temporal overlap between broods. This hypothesis predicts that offspring from early broods, which predominantly compete with less‐developed siblings, will be larger at birth than offspring from later broods, which experience competition from more and less‐developed siblings. Data on offspring size at birth from two populations of the highly matrotrophic fish, Heterandria formosa, and similar studies of poeciliid fish spanning a range of life histories are consistent with our hypothesis. Together these results suggest that sibling competition is a direct consequence of the evolution of matrotrophy and superfetation in poeciliid fish.
Analysis of the effects of all‐trans retinoic acid on human melanocytes and melanoblasts in vitro

All-trans retinoic acid (ATRA), a group of chemically related molecules derived from vitamin A, has been used clinically to treat photoaged skin and pigmentary disorders such as melasma and senile pigment freckles. However, the basic mechanisms of action of the effects of ATRA in topical treatment have not been elucidated. In this study, we examined the in vitro effects of ATRA on human melanocytes and on human melanoblasts following treatment with various concentrations of ATRA and/or an antagonist of the endothelin B receptor (EDNRB) (bosentan). All experiments were repeated at least four times. Data were assessed by the Mann–Whitney U-test and the level of significance was set at P < 0.05 in all cases. Normal human adult epidermal melanocytes (HEMa-LP cells) were purchased from Invitrogen Gibco (Carlsbad, CA, USA). Human undifferentiated epidermal melanoblasts were established in melanoblast proliferation medium supplemented with basic fibroblast growth factor as described previously. Melanocytes and melanoblasts were plated at 2000 cells per well in 96-well plates and were incubated at 37°C in a humidified atmosphere. The following day, various concentrations of ATRA were added to the medium (day 0). On day 3, the cells were incubated with Alamar blue dye (Trek Diagnostic Systems, Westlake, OH, USA) for 4 h and fluorescence was measured using a Fluoroskan II microplate reader (Labsystems, Helsinki, Finland). The addition of ATRA to the medium (a)
Biological Approaches to Therapy of Pancreatic Cancer

Pancreatic cancer is a lethal disease and notoriously difficult to treat. Only a small proportion is curative by surgical resection, whilst standard chemotherapy for patients with advanced disease has only modest effect with substantial toxicity. Clearly there is a need for the continual development of novel therapeutic agents to improve the current situation. Improvement of our understanding of the disease has generated a large number of studies on biological approaches targeting the molecular abnormalities of pancreatic cancer, including gene therapy and signal transduction inhibition, antiangiogenic and matrix metalloproteinase inhibition, oncolytic viral therapy and immunotherapy. This article provides a review of these approaches, both investigated in the laboratories and in subsequent clinical trials.
Neuronal migration and glial remodeling in degenerating retinas of aged rats and in nonneovascular AMD.

PURPOSE To demonstrate structural and immunocytochemical changes associated with light-induced degeneration in albino rat retinas and human AMD retinas. METHODS Retinas from Wistar rats aged 3, 6, or 10 months were examined by immunocytochemistry, with antibodies to neuronal and glial markers. Results were compared with human nonneovascular AMD retinas. RESULTS In aging rat retinas, many photoreceptors were lost in response to normal ambient light exposure. Photoreceptor loss was preceded by loss of RPE cells. Müller cells extended processes through gaps in Bruch's membrane, into the choroid. immunolabeling for gamma-aminobutyric acid (GABA), the glycine transporter Glyt-1, and the rod bipolar cell marker PKC revealed the presence of numerous neuronal somata and processes that appeared to have migrated into the choroidal region. Processes of presumptive ganglion cells remodeled and stratified in the choroid, where strong labeling for synaptic vesicle antigens was present. Myelination of retinal ganglion cell axons was also observed, especially in the peripheral retina. In AMD retinas, glial rearrangement and displacement of neurons suggestive of their migration were also observed. CONCLUSIONS In response to loss of RPE and photoreceptor cells, adult retinal neurons migrate out of the retina along remodeled processes of Müller cells. The presence of synaptic vesicle antigens suggests the formation of new synapses between migrating neurons. The myelination is probably due to the ingress of Schwann cells from the sclera. The presence of some similar changes in human AMD retinas suggests that these findings are of broad significance for determining the likely events in transplantation of neurons in the human retina and elsewhere.
Convexity inequalities for estimating generalized conditional entropies from below

Generalized entropic functionals are in an active area of research. Hence lower and upper bounds on these functionals are of interest. Lower bounds for estimating Renyi conditional $\alpha$-entropy and two kinds of non-extensive conditional $\alpha$-entropy are obtained. These bounds are expressed in terms of error probability of the standard decision and extend the inequalities known for the regular conditional entropy. The presented inequalities are mainly based on the convexity of some functions. In a certain sense, they are complementary to generalized inequalities of Fano type.
The lateral compartmentation of the yeast plasma membrane

The plasma membrane of Saccharomyces cerevisiae contains large microdomains enriched in ergosterol, which house at least nine integral proteins, including proton symporters. The domains adopt a characteristic structure of furrow‐like invaginations typically seen in freeze‐fracture pictures of fungal cells. Being stable for the time comparable with the cell cycle duration, they might be considered as fixed islands (rafts) in an otherwise fluid yeast plasma membrane. Rapidly moving endocytic marker proteins avoid the microdomains; the domain‐accumulated proton symporters consequently show a reduced rate of substrate‐induced endocytosis and turnover. Copyright © 2010 John Wiley & Sons, Ltd.