Miracle-dz/UniFAR-FTUs huggingface dataset:
A Ruler Protein in a Complex for Antiviral Defense Determines the Length of Small Interfering CRISPR RNAs

Background: CRISPR immune systems protect prokaryotes from their viruses using small interfering RNAs (crRNAs), which require maturation events during their biogenesis. Results: In Staphylococcus epidermidis, crRNAs undergo maturation in a Cas10·Csm ribonucleoprotein complex; Csm3 modulates the extent of maturation. Conclusion: Csm3 acts as a ruler for crRNAs. Significance: Investigating CRISPR immunity is important to understand prokaryotic ecology and to develop biotechnological applications. Small RNAs undergo maturation events that precisely determine the length and structure required for their function. CRISPRs (clustered regularly interspaced short palindromic repeats) encode small RNAs (crRNAs) that together with CRISPR-associated (cas) genes constitute a sequence-specific prokaryotic immune system for anti-viral and anti-plasmid defense. crRNAs are subject to multiple processing events during their biogenesis, and little is known about the mechanism of the final maturation step. We show that in the Staphylococcus epidermidis type III CRISPR-Cas system, mature crRNAs are measured in a Cas10·Csm ribonucleoprotein complex to yield discrete lengths that differ by 6-nucleotide increments. We looked for mutants that impact this crRNA size pattern and found that an alanine substitution of a conserved aspartate residue of Csm3 eliminates the 6-nucleotide increments in the length of crRNAs. In vitro, recombinant Csm3 binds RNA molecules at multiple sites, producing gel-shift patterns that suggest that each protein binds 6 nucleotides of substrate. In vivo, changes in the levels of Csm3 modulate the crRNA size distribution without disrupting the 6-nucleotide periodicity. Our data support a model in which multiple Csm3 molecules within the Cas10·Csm complex bind the crRNA with a 6-nucleotide periodicity to function as a ruler that measures the extent of crRNA maturation.
Learning a graph-structured generative probabilistic grammar of linguistic experience

Learning a graph-structured generative probabilistic grammar of linguistic experience Oren Kolodny Tel Aviv University Arnon Lotem Tel Aviv University Shimon Edelman Cornell University Abstract: The mechanisms that allow situated, embodied learning systems employed by human babies or juvenile songbirds to distill their multimodal experience into a form that supports flexible and open-ended generation of behavior are still poorly understood. We describe an ongoing attempt to gain insight into those mechanisms, by developing a biologically motivated model capable of incremental unsupervised learning of a generative probabilistic grammar of behavior, focusing initially on language. The implemented model demonstrates learning from unanno- tated text corpora, including those of transcribed natural speech, while replicating the effect of variation sets on learning, an effect documented in a recent study with human subjects.
High prevalences of infection with Giardia intestinalis genotype B among children in urban and rural areas of Argentina

Abstract The protozoan parasite most frequently associated with diarrhoea worldwide is Giardia intestinalis. In 2005, a study was initiated to identify the genotypes of this parasite infecting children in the Argentinian provinces of Buenos Aires, Mendoza and Chaco, and to explore the associations between the genotype detected in a child, the characteristics of the child’s household and the child’s clinical presentation. Overall, 998 children (504 boys and 494 girls) aged between 2–14 years, with or without symptoms, were enrolled. The G. intestinalis in 94 of the 117 stool samples found positive for the parasite by microscopy were successfully genotyped by PCR. Seventy-seven of the children were found to be infected with genotype B only and 14 with genotype AII only, three children being found to have mixed (AII and B) infections. Only genotype B was detected in children from rural areas (P<0·05) and most Giardia detected in children from households with a piped water supply were also of this genotype (P<0·05). The other household characteristics investigated (quality of building, history of flooding, type of sanitation, level of overcrowding, and presence/absence of pet dogs) had no significant effect on the genotype distribution. Children infected with genotype AII were significantly younger than those infected with genotype B (P<0·05) and there was a significant positive association between infection with genotype B and abdominal pain (P<0·05). Diarrhoea was not, however, found to be significantly associated with genotype-AII or genotype-B infection. This is the first published report on the Giardia genotypes circulating in the provinces of Mendoza and Chaco. The results indicate the importance of asymptomatic children in the transmission of Giardia among the young.
Health-related quality of life in patients with major depression who are treated with moclobemide.

A total of 651 depressed patients completed self-administered health-related quality-of-life (HRQOL) questionnaires during treatment with moclobemide in order to evaluate whether general and psychopathology-specific HRQOL questionnaires could detect changes in depressed patients receiving treatment. Patients were treated with moclobemide on an outpatient basis over an 8-week period; questionnaires were completed at weeks 0, 2, 4, and 8. At each assessment, patients completed one of two HRQOL questionnaires: namely, the General Health Questionnaire (GHQ), a psychopathology-specific HRQOL questionnaire, or the Short-Form 36 (SF-36), a general HRQOL instrument. Physicians were randomized to one of the two HRQOL questionnaires for all of their patients. Because the French version of the SF-36 was not available in the public domain, the patients of all Francophone physicians completed the GHQ, whereas the patients enrolled by Anglophone physicians completed either the SF-36 or the GHQ. The GHQ provides an overall score that measures the emotional dimensions of HRQOL, whereas the SF-36 provides scores in the following eight domains: physical functioning (PF), physical role functioning (PRF), emotional role functioning (ERF), social functioning (SF), bodily pain (BP), mental health (MH), vitality (VT), and general health perceptions (GHP). The GHQ and seven domains of the SF-36 detected a statistically significant linear trend (improvement) over time (p < 0.05). The change in the BP domain of the SF-36 was not statistically significant (p = 0.29). (ABSTRACT TRUNCATED AT 250 WORDS)
Haar Wavelets for Efficient Similarity Search of Time-Series: With and Without Time Warping

We address the handling of time series search based on two important distance definitions: Euclidean distance and time warping distance. The conventional method reduces the dimensionality by means of a discrete Fourier transform. We apply the Haar wavelet transform technique and propose the use of a proper normalization so that the method can guarantee no false dismissal for Euclidean distance. We found that this method has competitive performance from our experiments. Euclidean distance measurement cannot handle the time shifts of patterns. It fails to match the same rise and fall patterns of sequences with different scales. A distance measure that handles this problem is the time warping distance. However, the complexity of computing the time warping distance function is high. Also, as time warping distance is not a metric, most indexing techniques would not guarantee any false dismissal. We propose efficient strategies to mitigate the problems of time warping. We suggest a Haar wavelet-based approximation function for time warping distance, called Low Resolution Time Warping, which results in less computation by trading off a small amount of accuracy. We apply our approximation function to similarity search in time series databases, and show by experiment that it is highly effective in suppressing the number of false alarms in similarity search.
Protein synthesis in vitro by Micrococcus luteus

Bacillus subtilis and related gram-positive bacteria which have low to moderate genomic G + C contents are unable to efficiently translate mRNA derived from gram-negative bacteria, whereas Escherichia coli and other gram-negative bacteria are able to translate mRNA from both types of organisms. This phenomenon has been termed translational species specificity. Ribosomes from the low-G + C-content group (low-G + C group) of gram-positive organisms (B. subtilis and relatives) lack an equivalent to Escherichia ribosomal protein S1. The requirement for S1 for translation in E. coli (G. van Dieijen, P. H. van Knippenberg, J. van Duin, B. Koekman, and P. H. Pouwels, Mol. Gen. Genet. 153:75-80, 1977) and its specific role (A.R. Subramanian, Trends Biochem. Sci. 9:491-494, 1984) have been proposed. The group of gram-positive bacteria characterized by high genomic G + C content (formerly Actinomyces species and relatives) contain S1, in contrast to the low-G + C group (K. Mikulik, J. Smardova, A. Jiranova, and P. Branny, Eur. J. Biochem. 155:557-563, 1986). It is not known whether members of the high-G + C group are translationally specific, although there is evidence that one genus, Streptomyces, can express Escherichia genes in vivo (M. J. Bibb and S. N. Cohen, Mol. Gen. Genet. 187:265-277, 1985; J. L. Schottel, M. J. Bibb, and S. N. Cohen, J. Bacteriol. 146:360-368, 1981). In order to determine whether the organisms of this group are translationally specific, we examined the in vitro translational characteristics of a member of the high-G + C group, Micrococcus luteus, whose genomic G + C content is 73%. A semipurified coupled transcription-translation system of M. luteus translates Escherichia mRNA as well as Bacillus and Micrococcus mRNA. Therefore, M. luteus is translationally nonspecific and resembles E. coli rather than B. subtilis in its translational characteristics.
Treatment of advanced non-small-cell lung cancer patients with ECOG performance status 2: results of an European Experts Panel.

BACKGROUND Platinum-based combination chemotherapy is currently recommended as the standard treatment for patients with advanced non-small-cell lung cancer (NSCLC), but its benefit seems limited to fit patients with a performance status (PS) of 0 or 1. For PS2 patients, there is no consensus on standard treatment. With the aims of reviewing the evidence supporting each of these therapeutic options, possibly reaching a consensus for treatment of PS2 patients affected by advanced NSCLC in clinical practice, and suggesting the priorities for clinical research in this field, an European Experts Panel took place in Avellino, Italy in April 2003. RESULTS and conclusions On the basis of current evidence, chemotherapy treatment appears justified for patients with advanced NSCLC and PS2. Single-agent chemotherapy (gemcitabine, vinorelbine, taxanes) could be the preferred option, although carboplatin-based or low-dose cisplatin-based doublets may represent alternative options. Stronger evidence is expected from new clinical research specifically focused on PS2 patients. Single-agent chemotherapy should be the standard arm against which experimental treatments are tested in randomised trials dedicated to PS2 patients. High priority should be given to the evaluation of tolerability and efficacy of platinum-based combinations, and to the testing of new biological agents. Another research priority is the improvement of supportive care. Patients strongly need symptomatic improvement: end points such as symptom relief, clinical benefit and quality of life should have a central position in trials dedicated to PS2 NSCLC patients.
Spell-Checking based on Syllabification and Character-level Graphs for a Peruvian Agglutinative Language

There are several native languages in Peru which are mostly agglutinative. These languages are transmitted from generation to generation mainly in oral form, causing different forms of writing across different communities. For this reason, there are recent efforts to standardize the spelling in the written texts, and it would be beneficial to support these tasks with an automatic tool such as an spell-checker. In this way, this spelling corrector is being developed based on two steps: an automatic rule-based syllabification method and a character-level graph to detect the degree of error in a misspelled word. The experiments were realized on Shipibo-konibo, a highly agglutinative and amazonian language, and the results obtained have been promising in a dataset built for the purpose.
c‐Jun NH2‐terminal kinase mediates interleukin‐1β‐induced inhibition of lacrimal gland secretion

Sjögren's syndrome, an inflammatory disease affecting the lacrimal and salivary glands, is the leading cause of aqueous tear‐deficient type of dry eye. We previously showed that interleukin‐1β (IL‐1β) protein is up regulated in the lacrimal gland of a murine model of Sjögren's syndrome and that exogenous addition of this cytokine inhibits neurotransmitter release and lacrimal gland protein secretion. In the present study we investigated the role of c‐Jun NH2‐terminal kinase (JNK) in IL‐1β‐mediated inhibition of lacrimal gland secretion and tear production. In vitro, IL‐1β induced a time‐dependent activation of JNK with a maximum 7.5‐fold at 30 min. SP600125, a JNK inhibitor, inhibited, in a concentration‐dependent manner, IL‐1β‐induced activation of JNK with a maximum of 87% at 10−4 m. In vivo, IL‐1β stimulated JNK and the expression of the inducible isoform of nitric oxide synthase (iNOS). IL‐1β inhibited high KCl and adrenergic agonist induced protein secretion by 85% and 66%, respectively. SP600125 alleviated the inhibitory effect of IL‐1β on KCl‐ and agonist‐induced protein secretion by 79% and 47%, respectively, and completely blocked the expression of iNOS. Treatment for 7 days with SP600125 increased tear production in a murine model of Sjögren's syndrome dry eye. We conclude that JNK plays a pivotal role in IL‐1β‐mediated inhibition of lacrimal gland secretion and subsequent dry eye.
Distinct Functional Surface Regions on Ubiquitin*

The characterized functions of the highly conserved polypeptide ubiquitin are to target proteins for proteasome degradation or endocytosis. The formation of a polyubiquitin chain of at least four units is required for efficient proteasome binding. By contrast, monoubiquitin serves as a signal for the endocytosis of plasma membrane proteins. We have defined surface residues that are important for ubiquitin's vital functions inSaccharomyces cerevisiae. Surprisingly, alanine scanning mutagenesis showed that only 16 of ubiquitin's 63 surface residues are essential for vegetative growth in yeast. Most of the essential residues localize to two hydrophobic clusters that participate in proteasome recognition and/or endocytosis. The others reside in or near the tail region, which is important for conjugation and deubiquitination. We also demonstrate that the essential residues comprise two distinct functional surfaces: residues surrounding Phe4 are required for endocytosis, whereas residues surrounding Ile44 are required for both endocytosis and proteasome degradation.
High Humidity Induces Abscisic Acid 8′-Hydroxylase in Stomata and Vasculature to Regulate Local and Systemic Abscisic Acid Responses in Arabidopsis1[OA]

Levels of endogenous abscisic acid (ABA) are changed dynamically in response to environmental conditions. The ABA 8′-hydroxylase is a key enzyme in ABA catabolism and is encoded by CYP707A genes. In this study, we examined physiological roles of Arabidopsis (Arabidopsis thaliana) CYP707As in the plant's response to changes in humidity. The cyp707a1 and cyp707a3 mutants displayed lower stomatal conductance under turgid conditions (relative humidity 60%) than the wild type. When wild-type plants were transferred to high-humidity conditions (relative humidity 90%), CYP707A1 and CYP707A3 transcript levels increased, followed by the reduction of ABA levels. The cyp707a3 mutant exhibited high ABA levels even after transferring to high-humidity conditions, whereas, under similar conditions, the cyp707a1 mutant exhibited low ABA levels comparable to the wild type. Analysis of spatial expression patterns by using transgenic plants harboring a promoter∷β-glucuronidase gene indicated that high-humidity-induced expression of CYP707A1 and CYP707A3 occurred primarily in guard cells and vascular tissues, respectively. Furthermore, stomatal closure of the cyp707a1 mutant, but not cyp707a3 mutant, was ABA hypersensitive when epidermal peel was treated with exogenous ABA, suggesting that CYP707A1 is essential for ABA catabolism inside the guard cells. These results implicate that CYP707A3 reduces the amount of mobile ABA in vascular tissues in response to high humidity, whereas CYP707A1 inactivates local ABA pools inside the guard cells. Taken together, ABA catabolism in both vascular tissues and guard cells participates in the systemic ABA action that controls stomatal movement in response to high humidity.
Association of the GPIa C807T and GPIIIa PlA1/A2 polymorphisms with premature myocardial infarction in men.

Aims Recent studies have reported an association between the platelet glycoprotein (GP) Ia C807T polymorphism and myocardial infarction, whereas other studies have reported contradictory results concerning the platelet GPIIIa PlA1/A2 polymorphism. In most of these studies the patients were older than 45 years. Thus we decided to examine both genotypes in 287 men who had their first myocardial infarction before age 45, and a group of 138 healthy controls. Methods and Results The frequency of T807 allele carriers was similar among myocardial infarction patients and among controls (54.6% vs 62.3%; odds ratio (OR) 0.73; 95% confidence interval (CI), 0.47-1.12). The frequency of PlA2 carriers was higher in cases than in controls (26.5% vs 15.2%; OR 1.65; CI, 1.09-2.54). After performing a logistic regression analysis, taking into account other cardiovascular risk factors, this difference did not remain significant. The combination of the risk alleles of both genotypes had no major effect on the myocardial infarction risk. Conclusions The GPIIIa PlA2 allele is not independently associated with the risk of premature myocardial infarction. The T807 allele of the GPIa gene alone or in combination with the PlA2 allele had no major effect on premature myocardial infarction risk.
Dose‐Response Model for 13 Strains of Salmonella

Data from a human feeding trial with healthy men were used to develop a dose‐response model for 13 strains of Salmonella and to determine the effects of strain variation on the shape of the dose‐response curve. Dose‐response data for individual strains were fit to a three‐phase linear model to determine minimum, median, and maximum illness doses, which were used to define Pert distributions in a computer simulation model. Pert distributions for illness dose of individual strains were combined in an Excel spreadsheet using a discrete distribution to model strain prevalence. In addition, a discrete distribution was used to model dose groups and thus create a model that simulated human feeding trials. During simulation of the model with @Risk, an illness dose and a dose consumed were randomly assigned to each consumption event in the simulated feeding trial and if the illness dose was greater than the dose consumed then the model predicted no illness, otherwise the model predicted that an illness would occur. To verify the dose‐response model predictions, the original feeding trial was simulated. The dose‐response model predicted a median of 69 (range of 43–101) illnesses compared to 74 in the original trial. Thus, its predictions were in agreement with the data used to develop it. However, predictions of the model are only valid for eggnog, healthy men, and the strains and doses of Salmonella used to develop it. When multiple strains of Salmonella were simulated together, the predicted dose‐response curves were irregular in shape. Thus, the sigmoid shape of dose‐response curves in feeding trials with one strain of Salmonella may not accurately reflect dose response in naturally contaminated food where multiple strains may be present.
Locally advanced breast cancer: MR imaging for prediction of response to neoadjuvant chemotherapy--results from ACRIN 6657/I-SPY TRIAL.

PURPOSE To compare magnetic resonance (MR) imaging findings and clinical assessment for prediction of pathologic response to neoadjuvant chemotherapy (NACT) in patients with stage II or III breast cancer. MATERIALS AND METHODS The HIPAA-compliant protocol and the informed consent process were approved by the American College of Radiology Institutional Review Board and local-site institutional review boards. Women with invasive breast cancer of 3 cm or greater undergoing NACT with an anthracycline-based regimen, with or without a taxane, were enrolled between May 2002 and March 2006. MR imaging was performed before NACT (first examination), after one cycle of anthracyline-based treatment (second examination), between the anthracycline-based regimen and taxane (third examination), and after all chemotherapy and prior to surgery (fourth examination). MR imaging assessment included measurements of tumor longest diameter and volume and peak signal enhancement ratio. Clinical size was also recorded at each time point. Change in clinical and MR imaging predictor variables were compared for the ability to predict pathologic complete response (pCR) and residual cancer burden (RCB). Univariate and multivariate random-effects logistic regression models were used to characterize the ability of tumor response measurements to predict pathologic outcome, with area under the receiver operating characteristic curve (AUC) used as a summary statistic. RESULTS Data in 216 women (age range, 26-68 years) with two or more imaging time points were analyzed. For prediction of both pCR and RCB, MR imaging size measurements were superior to clinical examination at all time points, with tumor volume change showing the greatest relative benefit at the second MR imaging examination. AUC differences between MR imaging volume and clinical size predictors at the early, mid-, and posttreatment time points, respectively, were 0.14, 0.09, and 0.02 for prediction of pCR and 0.09, 0.07, and 0.05 for prediction of RCB. In multivariate analysis, the AUC for predicting pCR at the second imaging examination increased from 0.70 for volume alone to 0.73 when all four predictor variables were used. Additional predictive value was gained with adjustments for age and race. CONCLUSION MR imaging findings are a stronger predictor of pathologic response to NACT than clinical assessment, with the greatest advantage observed with the use of volumetric measurement of tumor response early in treatment.
Analysis of frequency-dependent lossy transmission lines driven by CMOS gates

This paper introduces an accurate FDTD-based method for analysis of time domain response of frequency-dependent lossy transmission lines driven by CMOS gates. MOS transistors are modeled as the nonlinear alpha-power law model that includes the carriers' velocity saturation effect of short-channel devices. The dynamic behavior of CMOS gates during switching is defined in seven operation regions. Skin effects of lossy transmission line are included in the proposed method and analyzed with FDTD. The proposed method is accurate by comparison between the numerical results of the proposed method and the simulation results of SPICE.