Miracle-dz/UniFAR-FTUs huggingface dataset:
Lentiviral vectors that express UGT1A1 in liver and contain miR-142 target sequences normalize hyperbilirubinemia in Gunn rats.

BACKGROUND & AIMS Crigler-Najjar type 1 (CN-I) is an inherited liver disease caused by an absence of bilirubin-uridine 5'-diphosphate-glucuronosyltransferase (UGT1A1) activity. It results in life-threatening levels of unconjugated bilirubin, and therapeutic options are limited. We used adult Gunn rats (an animal model of the disease) to evaluate the efficiency of lentiviral-based gene therapy to express UGT1A1 in liver. METHODS Gunn rats were given intraportal injections of VSVG-pseudotyped lentiviral vectors that encode UGT1A1 under the control of a liver-specific transthyretin promoter (mTTR.hUGT1A1); this vector does not contain target sequences for miR-142, a microRNA that is expressed specifically in hematopoietic cells. Rats were also injected with the vector mTTR.hUGT1A1.142T, which contains 4 copies of the miR-142 target sequences; its messenger RNA should be degraded in antigen-presenting cells. Bilirubinemia was monitored, and the presence of transduced hepatocytes was analyzed by quantitative polymerase chain reaction. Vector expression was tested in vitro in rat hematopoietic cells. RESULTS In Gunn rats, bilirubin levels normalized 2 weeks after administration of mTTR.hUGT1A1. However, hyperbilirubinemia resumed 8 weeks after vector administration, concomitant with the induction of an immune response. In contrast, in rats injected with mTTR-UGT1A1.142T, bilirubin levels normalized for up to 6 months and transduced cells were not eliminated. CONCLUSIONS Lentiviral vectors that express UGT1A1 reduce hyperbilirubinemia in immunocompetent Gunn rats for at least 6 months. The immune response against virally expressed UGT1A1 can be circumvented by inclusion of miR-142 target sequences, which reduce vector expression in antigen-presenting cells. This lentiviral-based gene therapy approach might be developed to treat patients with CN-I.
New Human Immunodeficiency Virus, Type 1 Reverse Transcriptase (HIV-1 RT) Mutants with Increased Fidelity of DNA Synthesis

Infidelity of DNA synthesis by human immunodeficiency virus, type 1 reverse transcriptase (HIV-1 RT) is a presumptive determinant of HIV-1 hypervariability and is incompletely understood at the mechanistic and structural levels. Amino acid substitution at only three residues, including Asp-76 (Kim, B., Hathaway, T. R., and Loeb, L. A. (1996)Biochemistry 37, 5831–5839), is known to increase fidelity. We report here that substitution at Arg-78 can also increase accuracy. Mutant R78A RT showed reduced primer extension in misincorporation assays lacking a complementary dNTP and exhibited a 9-fold decrease in mutation frequency in the M13mp2 lacZforward mutation assay. Previous structural studies indicate that Arg-78 and Asp-76 lie in a region that interacts with template nucleotides. Interestingly, R78A RT exhibited 6- to 8-fold decreases in binding affinity (K d ) for RNA and DNA templates relative to wild type RT. In contrast, D76V RT, which also increases fidelity (Kim et al., 1996), showed a 6- to 7-fold increased affinity. The processivity of R78A RT on both RNA and DNA templates was substantially reduced relative to wild type RT, whereas the processivity of D76V RT was increased. We discuss relationships of fidelity, template binding, and processivity in these and other HIV RT mutants.
Evaluating Crossdating Accuracy: A Manual and Tutorial for the Computer Program COFECHA

COFECHA is a computer program that assesses the quality of crossdating and measurement accuracy of tree -ring series. Written by Richard L. Holmes in 1982, the program has evolved into one of the most important and widely used in dendrochronology. It is important to note that COFECHA does not perform all the necessary steps in crossdating. Rather, the program is a tool that helps the dendrochronologist assess the quality of crossdating and measurement accuracy. The ultimate decision whether or not a tree -ring series is successfully crossdated must lie with the dendrochronologist and not with the software. Therefore, the program is most useful after initial crossdating is accomplished using visual or graphical techniques (such as skeleton plots), and the rings have been measured. The proper use of COFECHA adds a high degree of confidence that tree -ring samples have been crossdated correctly and measured accurately, ensuring that the environmental signal is maximized. In this paper, I describe the use of COFECHA through all necessary steps, and discuss the meaning of the initial questions posed at program start -up, the various options available in the main menu, the various sections of the output from COFECHA, and interpretation of the diagnostics of crossdating and measurement accuracy. I demonstrate methods used to help crossdate undated series, and offer tips on taking full advantage of the various options available in the program.
Synovial fluid recruits human mesenchymal progenitors from subchondral spongious bone marrow

Microfracture is a frequently used reparative technique that induces a healing response in articular cartilage defects. Penetration of the subchondral bone leads to blood clot formation, allows multipotent mesenchymal cells to access the defect and, subsequently, leads to cartilaginous repair tissue. The aim of our study was to analyze the chemotactic recruitment of human subchondral spongious bone marrow‐derived cells by synovial fluid (SF) from normal donors (ND), patients with osteoarthritis (OA) and rheumatoid arthritis (RA). Subchondral spongious bone marrow‐derived mesenchymal progenitors were isolated from bone cylinders after high tibial osteotomy and analyzed for the presence of stem cell‐related cell surface antigens by flowcytometry. Recruitment of subchondral progenitors by normal SF and SF from donors with degenerated joint diseases was documented by using a modified Boyden chamber chemotaxis assay. The chemotaxis assay demonstrated that synovial fluid has the potential to recruit mesenchymal progenitors in vitro. SF from normal donors and patients with OA showed no difference in the potential to stimulate cell migration. SF obtained from RA donors showed significantly reduced cell recruitment compared to SF derived from OA patients (p = 0.0054) and normal donors (p < 0.0001). The chemotactic activity of SF obtained from normal donors and from patients with degenerative joint diseases suggests that SF may be actively involved in the migration of progenitors in cartilage defects after microfracture. © 2007 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 25:1299–1307, 2007
Mobile push personalization and user experience

With the advances in and popularity of mobile devices, mobile service providers have a direct channel for transferring information to their subscribers, i.e., short messaging service (SMS) and multimedia messaging service (MMS). Mobile service operators can recommend new content and information to users who opt in to receive such information directly through push messages at any time or place. However, as mobile push messages sent to users can cause interruptions, such as alarms, users who receive irrelevant push messages may become dissatisfied with their mobile Web service and even their service provider. In this paper, we propose a mobile content recommender system for sending personalized mobile push messages with content that users are likely to find relevant. This system learns users' preferences from contents and keywords in their usage logs and recommends items that match these preferences or those of similar users. We analyzed (a) customer feedback on personalized content dissemination, and (b) the relationship between customer feedback and mobile Web usage of customers subscribing to a Korean mobile service provider. Push messages with personalized recommendations resulted in more positive feedback from customers, and the mobile Web usage of these customers increased.
Humidor : Microbial Community Classification of the 16 S Gene by Training CIGAR Strings with Convolutional Neural Networks

We propose a new model for classifying microbiota based on CIGAR strings depicting indels and mismatches for 16S gene sequences. To test this model, we used the sequences found in the Green Genes database consisting of 23,662 aligned sequences and 237,880 unaligned sequences. We aligned the target sequences against consensus sequences generated by selecting the mode base pairs at each position for all aligned sequences under each of the 207 unique Orders. This resulted in 209,587 successfully aligned sequences against 180 of the 207 consensus sequences with on average 1322 alignments per reference. The resulting SAM files generated, on average, a 1433 dimensional feature set for each of the sequences with 39 non-null descriptors defining an insertion, deletion, or mismatch. These features defined the input for a Convolutional Neural Network following an architecture of 3 convolutional layers, a final deeply connected layer, and ReLu activation functions. The resulting model demonstrated similar accuracy to the RDP classifier with area of 0.719, 0.733, and 0.825 under the ROC curves for predicted Order, Family, and Genus respectively. Moreover, the model produced a likelihood for unclassifed sequences’ taxonomic rank and was robust against incorrect alignments. We demonstrated that a new type of algorithm using CIGAR string information held up against the RDP classifier while offering a mechanism for determining the taxonomic rank of unknown sequences by taking advantage of the advances made in Deep Learning and Machine Vision. ∗University of California Davis, Mathematics and Computer Science Department
SNP Variants in Major Histocompatibility Complex Are Associated with Sarcoidosis Susceptibility—A Joint Analysis in Four European Populations

Sarcoidosis is a multiorgan inflammatory disorder with heritability estimates up to 66%. Previous studies have shown the major histocompatibility complex (MHC) region to be associated with sarcoidosis, suggesting a functional role for antigen-presenting molecules and immune mediators in the disease pathogenesis. To detect variants predisposing to sarcoidosis and to identify genetic differences between patient subgroups, we studied four genes in the MHC Class III region (LTA, TNF, AGER, BTNL2) and HLA-DRA with tag-SNPs and their relation to HLA-DRB1 alleles. We present results from a joint analysis of four study populations (Finnish, Swedish, Dutch, and Czech). Patients with sarcoidosis (n = 805) were further subdivided based on the disease activity and the presence of Löfgren’s syndrome. In a joint analysis, seven SNPs were associated with non-Löfgren sarcoidosis (NL; the strongest association with rs3177928, P = 1.79E−07, OR = 1.9) and eight with Löfgren’s syndrome [Löfgren syndrome (LS); the strongest association with rs3129843, P = 3.44E−12, OR = 3.4] when compared with healthy controls (n = 870). Five SNPs were associated with sarcoidosis disease course (the strongest association with rs3177928, P = 0.003, OR = 1.9). The high linkage disequilibrium (LD) between SNPs and an HLA-DRB1 challenged the result interpretation. When the SNPs and HLA-DRB1 alleles were analyzed together, independent association was observed for four SNPs in the HLA-DRA/BTNL2 region: rs3135365 (NL; P = 0.015), rs3177928 (NL; P < 0.001), rs6937545 (LS; P = 0.012), and rs5007259 (disease activity; P = 0.002). These SNPs act as expression quantitative trait loci (eQTL) for HLA-DRB1 and/or HLA-DRB5. In conclusion, we found novel SNPs in BTNL2 and HLA-DRA regions associating with sarcoidosis. Our finding further establishes that polymorphisms in the HLA-DRA and BTNL2 have a role in sarcoidosis susceptibility. This multi-population study demonstrates that at least a part of these associations are HLA-DRB1 independent (e.g., not due to LD) and shared across ancestral origins. The variants that were independent of HLA-DRB1 associations acted as eQTL for HLA-DRB1 and/or -DRB5, suggesting a role in regulating gene expression.
Biology, risk stratification, and therapy of pediatric acute leukemias: an update.

PURPOSE We review recent advances in the biologic understanding and treatment of childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), identify therapeutically challenging subgroups, and suggest future directions of research. METHODS A review of English literature on childhood acute leukemias from the past 5 years was performed. RESULTS Contemporary treatments have resulted in 5-year event-free survival rates of approximately 80% for childhood ALL and almost 60% for pediatric AML. The advent of high-resolution genome-wide analyses has provided new insights into leukemogenesis and identified many novel subtypes of leukemia. Virtually all ALL and the vast majority of AML cases can be classified according to specific genetic abnormalities. Cooperative mutations involved in cell differentiation, cell cycle regulation, tumor suppression, drug responsiveness, and apoptosis have also been identified in many cases. The development of new formulations of existing drugs, molecularly targeted therapy, and immunotherapies promises to further advance the cure rates and improve quality of life of patients. CONCLUSION The application of new high-throughput sequencing techniques to define the complete DNA sequence of leukemia and host normal cells and the development of new agents targeted to leukemogenic pathways promise to further improve outcome in the coming decade.
Information extraction from pharmaceutical literature

With the constantly growing amount of biomedical literature, methods for automatically distilling information from unstructured data, collectively known as information extraction, have become indispensable. Whilst most biomedical information extraction efforts in the last decade have focussed on the identification of gene products and interactions between them, the biomedical text mining community has recently extended their scope to capture associations between biomedical and chemical entities with the aim of supporting applications in drug discovery. This thesis is the first comprehensive study focussing on information extraction from pharmaceutical chemistry literature. In this research, we describe our work on (1) recognising names of chemical compounds and drugs, facilitated by the incorporation of domain knowledge; (2) exploring different coreference resolution paradigms in order to recognise co-referring expressions given a full-text article; and (3) defining drug-target interactions as events and distilling them from pharmaceutical chemistry literature using event extraction methods.
Inadequate Budgets and Salaries as Instruments for Institutionalizing Public Sector Corruption in Indonesia

Soeharto used the Indonesian bureaucracy to generate rents that could be harvested by ‘insider’ firms, while also encouraging it to extort money from ‘outsider’ firms and individuals. This necessitated incentives that would ensure strong loyalty and minimize internal opposition. Government entities were provided with insufficient budget funding to cover their costs, and their officials were expected to generate cash from illegal activities, making public sector employees financially dependent on corruption. Any employee who opposed this system could expect to be restricted to earning no more than the pitifully low formal salary entitlement. The system therefore became strongly self-reinforcing.
Accumulation of B Lymphocytes with a Naive, Resting Phenotype in a Subset of Hepatitis C Patients 1

Chronic infection with hepatitis C virus (HCV) is associated with disturbances of B lymphocyte activation and function: autoantibody production, mixed cryoglobulinemia, and B cell lymphomas. It has been proposed that these abnormalities reflect chronic antigenic stimulation or aberrant signaling through the B cell coreceptor, the latter mediated by binding of the HCV E2 glycoprotein to CD81. To test this hypothesis, we measured expression of activation and differentiation markers on peripheral blood B cells from patients with chronic HCV infection. Thirty-six HCV patients with and without mixed cryoglobulinemia were compared with 18 healthy control volunteers and 17 sustained virologic responders who had cleared HCV infection. Ten of the 36 HCV patient samples showed increased B cell frequencies; B cell frequency was higher in patients with more severe hepatic fibrosis. However, these samples lacked evidence of Ag-driven activation or proliferation. The expanded cells were low in the activation markers CD25, CD69, CD71, CD80, and CD86. Proliferation of circulating B cells was unchanged in HCV patients. These cells did not express the differentiation marker CD27, suggesting that they were not enriched in memory B cells. Furthermore, the expanded B cells expressed both IgD and IgM, suggesting that they were antigenically naive. Together, these results indicate that B cell expansion in the peripheral blood of HCV patients is not associated with Ag-mediated activation and differentiation. Instead, factors other than antigenic stimulation may promote the accumulation of peripheral blood B cells with a naive phenotype in a subset of HCV patients.
Crystal structure of the TM1442 protein from Thermotoga maritima, a homolog of the Bacillus subtilis general stress response anti‐anti‐sigma factor RsbV

Introduction. In Bacillus subtilis, the activities of several sigma ( ) factors and their cognate antifactors regulate important cellular processes such as sporulation and stress response. Sporulation in B. subtilis requires four factors: , , , and . The activities of F and G are controlled by the regulatory proteins SpoIIAB (antifactor and serine kinase), SpoIIAA (anti-antifactor), and SpoIIE (phosphatase). The antifactor SpoIIAB inhibits F and G by direct interaction. It has also kinase activity that inactivates the anti-antifactor SpoIIAA by phosphorylation at Ser58. SpoIIAB is regulated in turn by unphosphorylated SpoIIAA, which releases F and G from the SpoIIABF and SpoIIABG complexes. The solution structure of B. subtilis SpoIIAA revealed that it is a monomeric protein with a novel fold consisting of a four-stranded -sheet and four -helices. Subsequently, the crystal structures of SpoIIAA from B. sphaericus in both phosphorylated and unphosphorylated forms were determined. A comparison of these structures shows that phosphorylation has no significant effect on the global structure of the protein. Regulation of gene expression in response to the metabolic stress due to starvation and the environmental stress such as elevated temperatures, high salt concentrations, and high manganese ion concentrations is essential for bacterial survival. The general stress responses of B. subtilis involve an estimated 200 genes, which are regulated by , an alternative factor. The activity of B itself is tightly controlled by a regulatory module consisting of RsbU or RsbP (phosphatase)-RsbV (antagonist)RsbW (kinase). RsbV plays an important role in both the environmental stress and the energy stress. Likewise, -dependent expression of sporulation genes is controlled by the module comprising SpoIIE (phosphatase)-SpoIIAA (antagonist)-SpoIIAB (kinase). Significant homology was noted between the RsbU, RsbP, and SpoIIE phosphatases; between the RsbV and SpoIIAA antagonists; between RsbW and SpoIIAB kinases; and between the F and B transcription factors. It was concluded that the higher affinity of RsbW for RsbV than for B is the driving force that is responsible for the switch of RsbW to unphosphorylated RsbV. The TM1442 gene of T. maritima encodes a 110-residue polypeptide chain of 12,300 Da. Its gene product shows significant levels (between 36 and 31%) of amino acid sequence identity to RsbV-like anti-antifactors. The level of sequence identity to B. subtilis SpoIIAA and its homologs is lower (between 29 and 17%). In order to provide further structural data on anti-antifactors necessary for a better understanding of their mechanism of action and functional differences, we have determined the three-dimensional structure of the TM1442 protein from T. maritima, a homolog of RsbV-like anti-antifactors.
The Tycho Brahe Corpus of Historical Portuguese

This article introduces the Tycho Brahe Corpus (TBC), a parsed corpus of Historical Portuguese built on the model of the Penn-York Corpora of English. As an illustration of the usefulness of the TBC, the article presents research on the evolution of the position and interpretation of subjects in Portuguese from the 16th to the 19th century. Two main claims emerge, in response to questions that have largely remained unanswered until now, due to the paucity of available data. One is that the texts of the classical period instantiate verb-movement to Comp in matrix clauses, reflecting a V2 grammar. The other is that quantitative and qualitative changes appearing in the texts of the authors born from the beginning of the 18th century on indicate that, at this period, verb-movement to Comp was lost and the modern SVO grammar emerged.
Ischaemia and reperfusion effects on skeletal muscle tissue: morphological and histochemical studies

This was a study on the oxidative stress due to ischaemia (I) and reperfusion (R) in skeletal muscle tissue. Using a tourniquet, groups of rats were submitted to ischaemia for 4 h, followed by different reperfusion periods. The animals were divided in four groups: control; 4 h of ischaemia (IR); 4 h of ischaemia plus 1 h reperfusion (IR‐1 h); 4 h of ischaemia plus 24 h reperfusion (IR‐24 h); and 4 h of ischaemia plus 72 h reperfusion (IR‐72 h). At the end of the procedures, samples of soleus muscle were collected and frozen in n‐hexane at −70 °C. Cryostat sections were submitted to haematoxylin–eosin, succinate dehydrogenase (SDH) and nicotinamide adenine dinucleotide‐tetrazolium reductase (NADH‐TR) stains. An additional muscle sample was processed for electron microscopy. No alterations were found in control animals. IR group showed fibres had normal aspect besides some round, acidophilic and hypertrophic fibres. There were several fibres with angular outlines and smaller diameters in this group compared with control group. NADH‐TR/SDH reaction was moderately intense in most fibres. In some fibres, cytoplasm showed areas without activity and other fibres had very intense reactivity. IR‐1 h group showed oedema hypercontracted fibres with disorganized myofibrils, mitochondria with focal lesions and dilated sarcoplasmic reticulum. NADH‐TR/SDH reaction was moderate to weak. IR‐24 h showed intense inflammatory infiltrate in the endomysium and perimysium. NADH‐TR/SDH reaction was similar to IR‐1 h. IR‐72 h showed necrotic fibres, areas with inflammatory infiltrate, reduced muscle fibres at different stages of necrosis and phagocytosis, and many small round and basophilic fibres characterizing a regeneration process. NADH‐TR/SDH reaction was weak to negative. Our results suggest that ischaemia and the subsequent 1‐, 24‐ and 72‐h reperfusions induced progressive histological damage. Although progressive, it may be reversible because there were ultrastructural signs of recovery after 72‐h reperfusion. This recovery could in part be due to the low oxidative stress identified by the morphological and histochemical analysis.