Miracle-dz/UniFAR-FTUs huggingface dataset:
NF45 and NF90/NF110 coordinately regulate ESC pluripotency and differentiation

While years of investigation have elucidated many aspects of embryonic stem cell (ESC) regulation, the contributions of post-transcriptional and translational mechanisms to the pluripotency network remain largely unexplored. In particular, little is known in ESCs about the function of RNA binding proteins (RBPs), the protein agents of post-transcriptional regulation. We performed an unbiased RNAi screen of RBPs in an ESC differentiation assay and identified two related genes, NF45 (Ilf2) and NF90/NF110 (Ilf3), whose knockdown promoted differentiation to an epiblast-like state. Characterization of NF45 KO, NF90 + NF110 KO, and NF110 KO ESCs showed that loss of NF45 or NF90 + NF110 impaired ESC proliferation and led to dysregulated differentiation down embryonic lineages. Additionally, we found that NF45 and NF90/NF110 physically interact and influence the expression of each other at different levels of regulation. Globally across the transcriptome, NF45 KO ESCs and NF90 + NF110 KO ESCs show similar expression changes. Moreover, NF90 + NF110 RNA immunoprecipitation (RIP)-seq in ESCs suggested that NF90/NF110 directly regulate proliferation, differentiation, and RNA-processing genes. Our data support a model in which NF45, NF90, and NF110 operate in feedback loops that enable them, through both overlapping and independent targets, to help balance the push and pull of pluripotency and differentiation cues.
Medical history, lifestyle, family history, and occupational risk factors for mantle cell lymphoma: the InterLymph Non-Hodgkin Lymphoma Subtypes Project.

BACKGROUND The etiology of mantle cell lymphoma (MCL), a distinctive subtype accounting for 2%-10% of all non-Hodgkin lymphoma, is not known. METHODS We investigated associations with self-reported medical history, lifestyle, family history, and occupational risk factors in a pooled analysis of 557 patients with MCL and 13766 controls from 13 case-control studies in Europe, North America, and Australia. Odds ratios (ORs) and 95% confidence intervals (CIs) associated with each exposure were examined using multivariate logistic regression models. RESULTS The median age of the MCL patients was 62 years and 76% were men. Risk of MCL was inversely associated with history of hay fever (OR = 0.63, 95% CI = 0.48 to 0.82), and the association was independent of other atopic diseases and allergies. A hematological malignancy among first-degree relatives was associated with a twofold increased risk of MCL (OR = 1.99, 95% CI = 1.39 to 2.84), which was stronger in men (OR = 2.21, 95% CI = 1.44 to 3.38) than women (OR = 1.61, 95% CI = 0.82 to 3.19). A modestly increased risk of MCL was also observed in association with ever having lived on a farm (OR = 1.40, 95% CI = 1.03 to 1.90). Unlike some other non-Hodgkin lymphoma subtypes, MCL risk was not statistically significantly associated with autoimmune disorders, tobacco smoking, alcohol intake, body mass index, or ultraviolet radiation. CONCLUSIONS The novel observations of a possible role for atopy and allergy and farm life in risk of MCL, together with confirmatory evidence of a familial link, suggest a multifactorial etiology of immune-related environmental exposures and genetic susceptibility. These findings provide guidance for future research in MCL etiology.
The B56 Family of Protein Phosphatase 2A (PP2A) Regulatory Subunits Encodes Differentiation-induced Phosphoproteins That Target PP2A to Both Nucleus and Cytoplasm*

Protein phosphatase 2A is a heterotrimeric protein serine/threonine phosphatase consisting of a 36-kDa catalytic C subunit, a 65-kDa structural A subunit, and a variable regulatory B subunit. The B subunits determine the substrate specificity of the enzyme. There have been three families of cellular B subunits identified to date: B55, B56 (B′), and PR72/130. We have now cloned five genes encoding human B56 isoforms. Polypeptides encoded by all but one splice variant (B56γ1) are phosphoproteins, as shown by mobility shift after treatment with alkaline phosphatase and metabolic labeling with [32P]phosphate. All labeled isoforms contain solely phosphoserine. Indirect immunofluorescence microscopy demonstrates distinct patterns of intracellular targeting by different B56 isoforms. Specifically, B56α, B56β, and B56ϵ complexed with the protein phosphatase 2A A and C subunits localize to the cytoplasm, whereas B56δ, B56γ1, and B56γ3 are concentrated in the nucleus. Two isoforms (B56β and B56δ) are highly expressed in adult brain; here we show that mRNA for these isoforms increases severalfold when neuroblastoma cell lines are induced to differentiate by retinoic acid treatment. These studies demonstrate an increasing diversity of regulatory mechanisms to control the activity of this key intracellular protein phosphatase and suggest distinct functions for isoforms targeted to different intracellular locations.
Weight-training-induced attenuation of the circulatory response of older males to weight lifting.

We examined the effects of 12 wk of dynamic strength training on the heart rate (HR) and blood pressure of older male subjects during 10 repetitions of single-arm curl and single- and double-leg press at 60 and 80% of both the pre- and posttraining maximum capacities and during single maximum lifts (1 RM). The circulatory responses were greater at 80% of 1 RM than at 60% and increased with active muscle mass. After training, the 1 RMs increased by 24 (legs) to 54% (arms) and there was a marked attenuation of HR and arterial pressure during exercise when subjects lifted the same absolute load. Greatest reductions in HR (108 +/- 4 to 94 +/- 2 beats/min), systolic blood pressure (BPs, 247 +/- 14 to 206 +/- 9 Torr), diastolic pressure (156 +/- 9 to 116 +/- 5 Torr), mean arterial pressure (143 +/- 6 to 131 +/- 5 Torr), and rate-pressure product (268 +/- 22 to 196 +/- 12 HR.BPs/100) occurred during double-leg press at 80% of the pretraining 1 RM. After training, during lifting at 60, 80, and 100% of the posttraining 1 RMs, the HRs and arterial pressures were the same as those during pretraining testing when the same relative, but lighter, absolute loads were used. These observations are consistent with a significant part of the circulatory response to weight lifting being mediated by a feedforward "central command" mechanism coupled to the relative intensity rather than to the absolute level of force.
Promising SINEs in the Treatment of Pancreatic Cancer

Pancreatic cancer remains a deadly disease in urgent need of newer therapeutic modalities. Pancreatic tumors are very heterogeneous and carry alterations in many critical pathways (i.e. harboring a robust biological network) rendering the design of therapy against a single pathway unrealistic. The disease requires a broad form of therapy that can target the activation of multiple tumor suppressor proteins simultaneously. It has been consistently shown in pancreatic cancer biopsies that there is an over-expression of the nuclear exporter protein exportin 1 also known as Chromosome maintenance region 1. Nuclear exporter protein exportin 1 is recognized to export major nuclear residing tumor suppressor proteins causing their functional inactivation through their mislocalization to the cytoplasmic compartment. This makes exportin 1 an attractive therapeutic target in pancreatic cancer. Supporting this we have clearly demonstrated that targeted inhibition of exportin 1 by our specific inhibitors of nuclear export can restore the function of multiple tumor suppressor proteins leading the pancreatic cancer cell death and tumor inhibition in orthotopic models. Additionally, studies have demonstrated that specific inhibitors of nuclear export synergize with gemcitabine and nab-paclitaxel leading to enhanced pancreatic cancer growth inhibition, apoptosis, and disintegration of cancer stem cell mimicking spheroids. Collectively these studies have lead to a Phase Ib/II clinical evaluation of specific inhibitors of nuclear export with GEM and nab-paclitaxel in patients with metastatic pancreatic cancer (ClinicalTrials.gov Identifier: NCT02178436). In this mini-review we highlight the promising specific inhibitors of nuclear export in pancreatic cancer.
Analysis of effectiveness of human U-500 insulin in patients unresponsive to conventional insulin therapy.

OBJECTIVE To present a retrospective analysis of the effects of human U-500 insulin in 20 patients with type 2 diabetes and insulin resistance. METHODS Medical records of 20 patients with type 2 diabetes who had received U-500 insulin for at least 6 months were reviewed to determine glycemic control before and after this therapy. Human regular U-500 insulin therapy was initiated at a unit dosage equivalent to the previous standard insulin dosage. Comparisons of hemoglobin A1c levels, insulin doses, and body mass index at baseline and 6 months after changing to U-500 insulin therapy were analyzed. RESULTS In the 10 female and 10 male study subjects, the mean (+/-SD) hemoglobin A1c level was 9.59 +/- 1.37% initially, and it decreased to 8.53 +/- 1.11% at 3 months and to 7.83 +/- 1.26% at 6 months after initiation of U-500 insulin therapy. In comparison with baseline, these decreases were statistically significant. The amount of insulin used and the body mass index did not change significantly from baseline to 6 months after initiation of U-500 insulin treatment. CONCLUSION Analysis of data suggests that U-500 insulin therapy yields improved glycemic control in insulin-resistant patients who have poor control of blood glucose with use of standard insulin regimens. There is no proof, however, that improved glycemic control by this method decreases diabetes-related complications or improves survival. Further studies must be performed before U-500 insulin can be recommended as a standard therapy for patients with insulin resistance.
How effective is enteral nutrition in inducing clinical remission in active Crohn's disease? A meta-analysis of the randomized clinical trials.

BACKGROUND The purpose of the study was to evaluate, using meta-analysis techniques, whether enteral nutrition is effective in inducing clinical remission in active Crohn's disease. METHODS Randomized trials either comparing enteral nutrition with steroids or comparing elemental (amino acid-based) with nonelemental diets were selected using MEDLINE (1984 to 1994), reference lists from published articles, reviews, and abstracts from major gastrointestinal meetings. Sixteen studies fulfilled the inclusion criteria (four published as abstracts). Crude rates for induction of remission were collected on an intention-to-treat basis by three independent observers. Each study was given a quality score, based on predetermined criteria. RESULTS The pooled odds ratio (OR) for all type of enteral diets compared with steroid therapy was 0.35 (95% CI, 0.23 to 0.53). This result was similar for the best studies (by quality score) combined, for trials using tube feeding combined, and when noncompliant patients were withdrawn. Further subgroup analyses were conducted on the basis of the type of diet administered. Peptide-based diets were significantly inferior to steroids (pooled OR, 0.32; CI, 0.20 to 0.52). There was a trend to lower remission rate after elemental diets than after steroids (pooled OR, 0.44; CI 0.17 to 1.12). On the other hand, pooled OR for whole protein-based diets compared with elemental diets was 1.28 (CI, 0.40 to 4.02). CONCLUSIONS Data available to date show that steroids are better than enteral nutrition to induce remission in active Crohn's disease. These results are more evident when peptide-based diets are administered, but they are not conclusive when either elemental or whole protein-based diets are used.
The alignment of cyanogen bromide fragments from the flagellin of Salmonella adelaide.

The alignment of the polypeptide fragments obtained by digestion of flagellin with cyanogen bromide has been established from (a) the amino acid sequence of the methionine-containing, tryptic peptides and (b) the results of end group analyses on the cyanogen bromide fragments. A partial amino acid sequence of flagellin is presented.
A Strategy for Removing the Bias in the Graphical Analysis Method

The graphical analysis method, which transforms multiple time measurements of plasma and tissue uptake data into a linear plot, is a useful tool for rapidly obtaining information about the binding of radioligands used in PET studies. The strength of the method is that it does not require a particular model structure. However, a bias is introduced in the case of noisy data resulting in the underestimation of the distribution volume (DV), the slope obtained from the graphical method. To remove the bias, a modification of the method developed by Feng et al. (1993), the generalized linear least squares (GLLS) method, which provides unbiased estimates for compartment models was used. The one compartment GLLS method has a relatively simple form, which was used to estimate the DV directly and as a smoothing technique for more general classes of model structures. In the latter case, the GLLS method was applied to the data in two parts, that is, one set of parameters was determined for times 0 to T1 and a second set from T1 to the end time. The curve generated from these two sets of parameters then was used as input to the graphical method. This has been tested using simulations of data similar to that of the PET ligand [11C]-d-threo-methylphenidate (MP, DV = 35 mL/mL) and 11C raclopride (RAC, DV = 1.92 mL/mL) and compared with two examples from image data with the same tracers. The noise model was based on counting statistics through the half-life of the isotope and the scanning time. Five hundred data sets at each noise level were analyzed. Results (DV) for the graphical analysis (DV g ), the nonlinear least squares (NLS) method (DV nls ), the one-tissue compartment GLLS method (DV f ), and the two part GLLS followed by graphical analysis (DV fg ) were compared. DVFG was found to increase somewhat with increasing noise and in some data sets at high noise levels no estimate could be obtained. However, at intermediate levels it provided a good estimation of the true DV. This method was extended to use a reference tissue in place of the input function to generate the distribution volume ratio (DVR) to the reference region. A linearized form of the simplified reference tissue method of Lammertsma and Hume (1996) was used. The DVR generated directly from the model (DVR fl ) was compared with DVR fg (determined from a “smoothed” uptake curve as for DV fg ) using the graphical method.
An epidemic, toxin gene-variant strain of Clostridium difficile.

BACKGROUND Recent reports suggest that the rate and severity of Clostridium difficile-associated disease in the United States are increasing and that the increase may be associated with the emergence of a new strain of C. difficile with increased virulence, resistance, or both. METHODS A total of 187 C. difficile isolates were collected from eight health care facilities in six states (Georgia, Illinois, Maine, New Jersey, Oregon, and Pennsylvania) in which outbreaks of C. difficile-associated disease had occurred between 2000 and 2003. The isolates were characterized by restriction-endonuclease analysis (REA), pulsed-field gel electrophoresis (PFGE), and toxinotyping, and the results were compared with those from a database of more than 6000 isolates obtained before 2001. The polymerase chain reaction was used to detect the recently described binary toxin CDT and a deletion in the pathogenicity locus gene, tcdC, that might result in increased production of toxins A and B. RESULTS Isolates that belonged to one REA group (BI) and had the same PFGE type (NAP1) were identified in specimens collected from patients at all eight facilities and accounted for at least half of the isolates from five facilities. REA group BI, which was first identified in 1984, was uncommon among isolates from the historic database (14 cases). Both historic and current (obtained since 2001) BI/NAP1 isolates were of toxinotype III, were positive for the binary toxin CDT, and contained an 18-bp tcdC deletion. Resistance to gatifloxacin and moxifloxacin was more common in current BI/NAP1 isolates than in non-BI/NAP1 isolates (100 percent vs. 42 percent, P<0.001), whereas the rate of resistance to clindamycin was the same in the two groups (79 percent). All of the current but none of the historic BI/NAP1 isolates were resistant to gatifloxacin and moxifloxacin (P<0.001). CONCLUSIONS A previously uncommon strain of C. difficile with variations in toxin genes has become more resistant to fluoroquinolones and has emerged as a cause of geographically dispersed outbreaks of C. difficile-associated disease.
Selective inhibition of β2‐adrenergic receptor‐mediated cAMP generation by activation of the P2Y2 receptor in mouse pineal gland tumor cells

Rhythmic noradrenergic signaling from the hypothalamic clock in the suprachiasmatic nucleus to the pineal gland causes an increase in intracellular cAMP which regulates the circadian fluctuation of melatonin synthesis. The activation of phospholipase C (PLC)‐coupled P2Y2 receptors upon treatment with ATP and UTP exclusively inhibited the isoproterenol‐stimulated cAMP production in mouse pineal gland tumor cells. However, the activation of other PLC‐coupled receptors including P2Y1 and bombesin receptors had little or no effect on the isoproterenol‐stimulated cAMP production. Also, ATP did not inhibit cAMP production caused by forskolin, prostaglandin E2, or the adenosine analog NECA. These results suggest a selective coupling between signalings of P2Y2 and β2‐adrenergic receptors. The binding of [3H]CGP12177 to β2‐adrenergic receptors was not effected by the presence of ATP or UTP. Ionomycin decreased the isoproterenol‐stimulated cAMP production, whereas phorbol 12‐myristate 13‐acetate slightly potentiated the isoproterenol response. Chelation of intracellular Ca2+, however, had little effect on the ATP‐induced inhibition of cAMP production, while it completely reversed the ionomycin‐induced inhibition. Treatment of cells with pertussis toxin almost completely blocked the inhibitory effect of nucleotides. Pertussis toxin also inhibited the nucleotide‐induced increase in intracellular Ca2+ and inositol 1,4,5‐trisphosphate production by 30–40%, suggesting that the ATP‐mediated inhibition of the cAMP generation and the partial activation of PLC are mediated by pertussis toxin‐sensitive Gi‐protein. We conclude that one of the functions of P2Y2 receptors on the pineal gland is the selective inhibition of β‐adrenergic receptor‐mediated signaling pathways via the inhibitory G‐proteins.
Static dependency analysis of recursive structures for parallelisation

A new approach is presented for the analysis of dependencies in complex recursive data structures with pointer linkages that can be determined statically, at compile time. The pointer linkages in a data structure are initially described in the form of two-variable Finite State Automata (2FSA) which supplements the code that operates over the data structure. Some flexibility is possible in that the linkages can specify a number of possible target nodes for a pointer. An analysis method is described to extract data dependency information, also in the form of 2FSAs, from the recursive code that operates over these structures. For restricted, simple forms of recursion these data dependencies are exact; but, in general, heuristics are presented which provide approximate information. This method uses a novel technique that approximates the transitive closure of these 2FSA relations. In the context of dependency analysis, approxima¬ tions must be safe in that they are permitted to overestimate dependencies thereby including spurious ones, but none must be missed. A test is developed that permits the safety of these approximate solutions to be validated. When a recursive program is partitioned into a number of separate threads by the pro¬ grammer this dependency information can be used to synchronise the access to the recursive structure. This ensures that the threads execute correctly in parallel, enabling a multithreaded version of the code to be constructed. A multithreaded Micronet processor architecture was chosen as a target for this approach. Frontand back-ends of a compiler were developed to compile these multithreaded programs into executables for this architecture, which were then run on a simulation of the processor. The timing results for selected benchmarks are used to demonstrate that useful parallelism can be extracted.
Putting heterosynaptic plasticity in its place – as easy as PIE

Since Milner and Scoville published their observations of Henry Molaison's profound memory deficits following bilateral removal of the hippocampal formation (Scoville & Milner, 1957), generations of neuroscientists have sought to understand how the hippocampus executes its essential role in learning and memory. Central to that understanding is elaboration of the functions performed by the circuitry of the hippocampal CA3 region. A signature feature of CA3 is that its principal cells, the pyramidal cells (PCs), generate a highly recurrent network, by giving off and receiving excitatory collateral inputs to and from myriad other CA3 PCs. Inputs to this recurrent network come primarily from layer 2 neurons in nearby entorhinal cortex (EC) via the perforant pathway (PP), which bifurcates into two distinct excitatory pathways: a monosynaptic pathway onto the distal apical dendrites of the PCs; and a disynaptic pathway, where EC inputs synapse onto granule cells in the dentate gyrus, which, in turn, synapse onto the proximal apical dendrites of CA3 PCs via mossy fibre (MF) axons. Owing to their strength and location, the MF inputs strongly drive activity in the PCs despite there being only several dozen of these inputs per neuron (as opposed to thousands of inputs from the PP and recurrent collaterals).
Improved information gain feature selection method for Chinese text classification based on word embedding

Feature selection is a very important part of text categorization, which can reduce the dimensionality of the text representation by vector space model (VSM), and can avoid the problem of "curse of dimensionality". Information gain (IG) feature selection algorithm is one of the most effective feature selection algorithms, but it is easy to filter out the characteristic words which have a low IG score but have a strong ability of text type identification. Meanwhile, these words are often very similar to the words of high IG score. Aiming at this defect, we propose an improved feature selection method which uses word embedding to calculate the most similar words to the current dictionary selected by IG algorithm and expand the dictionary with these words under certain regulations. Finally we achieve good experimental results in Sogou Chinese text classification corpus and Fudan Chinese text classification corpus.