Miracle-dz/UniFAR-FTUs huggingface dataset:
Intrauterine transmission of cytomegalovirus to infants of women with preconceptional immunity

BACKGROUND Preconceptional immunity against cytomegalovirus (CMV) provides only partial protection against intrauterine transmission of the virus. Whether congenital CMV infection in the offspring of women who are seropositive for CMV can occur after maternal reinfection with a different strain of CMV is unknown. METHODS Serum specimens from 46 women with preconceptional immunity against CMV that were obtained during the previous pregnancy and the current pregnancy were analyzed for antibodies against the strain-specific epitopes of CMV glycoprotein H. Virus-neutralizing activity in maternal serum samples was measured against the AD169 laboratory strain of CMV and the CMV isolates available from seven infected infants. In addition, the nucleotide sequences of the glycoprotein H gene from the seven CMV isolates were determined. RESULTS Eleven of the 16 mothers with infected infants (69 percent) had antibodies against the glycoprotein H epitopes present on two laboratory strains of CMV, AD169 and Towne. Ten of the 16 mothers with infected children (62 percent) acquired new antibody specificities against glycoprotein H, as compared with only 4 of the 30 mothers of uninfected infants (13 percent, P<0.001). The samples obtained at the time of the current delivery from four of the seven mothers contained at least twice as many neutralizing antibodies against the CMV isolated from their infants as were present in the samples obtained at the previous delivery. The specificity of the newly acquired maternal antibodies reflected the amino acid sequence of the glycoprotein H epitope of CMV from these four infants. CONCLUSIONS In women who are seropositive for CMV, reinfection with a different strain of CMV can lead to intrauterine transmission and symptomatic congenital infection.
Apolipoprotein E4 Produced in GABAergic Interneurons Causes Learning and Memory Deficits in Mice

Apolipoprotein (apo) E4 is expressed in many types of brain cells, is associated with age-dependent decline of learning and memory in humans, and is the major genetic risk factor for AD. To determine whether the detrimental effects of apoE4 depend on its cellular sources, we generated human apoE knock-in mouse models in which the human APOE gene is conditionally deleted in astrocytes, neurons, or GABAergic interneurons. Here we report that deletion of apoE4 in astrocytes does not protect aged mice from apoE4-induced GABAergic interneuron loss and learning and memory deficits. In contrast, deletion of apoE4 in neurons does protect aged mice from both deficits. Furthermore, deletion of apoE4 in GABAergic interneurons is sufficient to gain similar protection. This study demonstrates a detrimental effect of endogenously produced apoE4 on GABAergic interneurons that leads to learning and memory deficits in mice and provides a novel target for drug development for AD related to apoE4.
Tumor Necrosis Factor Receptor-associated Factor 6 Is an Intranuclear Transcriptional Coactivator in Osteoclasts*

Tumor necrosis factor receptor-associated factor 6 (TRAF6) associates with the cytoplasmic domain of receptor activator of NF-κB (RANK) and is an essential component of the signaling complex mediating osteoclastogenesis. However, the osteoclastic activity of TRAF6 is blunted by its association with four and half LIM domain 2 (FHL2), which functions as an adaptor protein in the cytoplasm and transcriptional regulator in the nucleus. We find that TRAF6 also localizes in the nuclei of osteoclasts but not their bone marrow macrophage precursors and that osteoclast intranuclear abundance is specifically increased by RANK ligand (RANKL). TRAF6 nuclear localization requires FHL2 and is diminished in fhl2-/- osteoclasts. Suggesting transcriptional activity, TRAF6 interacts with the transcription factor RUNX1 in the osteoclast nucleus. FHL2 also associates with RUNX1 but does so only in the presence of TRAF6. Importantly, TRAF6 recognizes FHL2 and RUNX1 in osteoclast nuclei, and the three molecules form a DNA-binding complex that recognizes and transactivates the RUNX1 response element in the fhl2 promoter. Finally, TRAF6 and its proximal activator, RANKL, polyubiquitinate FHL2, prompting its proteasomal degradation. These observations suggest a feedback mechanism whereby TRAF6 negatively regulates osteoclast formation by intracytoplasmic sequestration of FHL2 to blunt RANK activation and as a component of a transcription complex promoting FHL2 expression.
Shall we crosstalk? – The relationship between DNA methylation and histone H3 lysine 27 trimethylation (comment on DOI 10.1002/bies.201300130)

Cancer cells usurp silencing mechanisms to extinguish functional pathways by epigenetic processes. There are two important epigenetic silencing mechanisms, polycomb repressive complex 2 (PRC2)-based histone H3 lysine 27 trimethylation (H3K27me3), and DNA methylation, which are associated with a variety of cellular functions. Studies have shown that these two epigenetic marks seem to be dependent on one another, although the precise mechanistic link between them remains to be fully characterized [1]. This crosstalk between DNA methylation and PRC2H3K27me3 has implications for understanding stem cell differentiation, somatic cell reprogramming, and tumorigenesis as well: dysregulation of these two epigenetic mechanisms has frequently been observed in many types of cancers. It is well appreciated that stem cell PRC2 targets – which are generally associated with embryonic development – are more likely to have cancerspecific promoter DNA methylation than non-targets [1]. During tumorigenesis, these vulnerable genes undergo
Human fibroblasts show expression of the leukotriene-A4-hydrolase gene, which is increased after simian-virus-40 transformation.

Human fibroblasts in cell culture converted the epoxide intermediate leukotriene A4 into the potent chemotaxin leukotriene B4. The identity of leukotriene B4 was ascertained by its mobility in reverse-phase high performance liquid chromatography, ultraviolet spectroscopy and gas chromatography/mass spectrometry. The presence of the enzyme responsible for the conversion (i.e. leukotriene A4 hydrolase), as well as the corresponding mRNA, were demonstrated by Western and Northern blot analyses. Leukotriene-A4-hydrolase enzyme activity, protein and mRNA were all enhanced (approximately threefold) in human fibroblasts that had been transformed by simian virus 40.
On the Role of Maximum Demand Charges in the Presence of Distributed Generation Resources

We examine the role that maximum demand charges (MDCs) can play in avoiding the death spiral that some utilities may otherwise face as the distributed generation (DG) of electricity proliferates. We find that MDCs generally secure gains for consumers that do not undertake DG, and often secure gains for consumers that undertake DG. However, the welfare gains tend to be modest in plausible settings. Furthermore, time-of-use pricing often secures larger welfare gains than do MDCs.
Bevacizumab combined with two-weekly paclitaxel as first-line therapy for metastatic breast cancer.

BACKGROUND Metastatic breast cancer remains a major clinical issue despite progress achieved in recent years. Three randomised trials have demonstrated the benefit of combining bevacizumab with various taxane schedules. Herein, this study sought to investigate an alternative bevacizumab-taxane regimen as first-line treatment for metastatic breast cancer. PATIENTS AND METHODS Patients with metastatic breast cancer and who received first-line bevacizumab 10 mg/kg with paclitaxel 135 mg/m(2) every 2 weeks were studied. RESULTS All 43 enrolled patients were evaluable for efficacy and safety. The response rate was 58%; a further 40% achieved stable disease. After a median follow-up of 16 months, disease had progressed in 9 patients (21%). Treatment was well tolerated: grade 4 toxicities were absent; grade 3 adverse events comprised neutropenia (5%; no febrile neutropenia), hypertension (2%) and neuropathy (2%). CONCLUSION This regimen may provide improved patient acceptability, quality of life and pharmacoeconomic benefits over a weekly paclitaxel schedule, and deserves further evaluation.
Technological Wealth and the Evaluation of Information Poverty

'Technological wealth' and 'information poverty' have obvious relevance to social equity and quality of life, but there is no methodology for evaluating their impact. Universal diffusion of, and access to, new on-line multimedia services has obvious advantages to commercial players because money can be made, and to community players because social equity objectives can be met. Public interest and commercial needs often converge in electronic markets. This paper outlines a framework for evaluating technological wealth and information poverty in the context of Gungahlin, a new residential community in Canberra. This community has the essential characteristics for diffusion of on-line services, but it is yet to be seen whether such 'model' communities which desire those services actually experience an increased quality of life as a result of receiving them.
Effects of immobilization, three forms of remobilization, and subsequent deconditioning on bone mineral content and density in rat femora

Disuse is associated with bone loss, which may not be recoverable. It is not known whether intensified remobilization is beneficial in restoring disuse‐related bone loss nor if any such benefit would depend upon continuing mobilization for its maintenance. After an immobilization period of 3 weeks, the effects of free remobilization (11 weeks), and low‐ and high‐intensity treadmill running (11 weeks) with and without subsequent deconditioning (18 weeks) on the bone mineral content (BMC) and density (BMD) of the hindlimb femora of Sprague‐Dawley rats (n = 98) were studied using a dual‐energy X‐ray absorptiometric (DXA) scanner. Our hypothesis was that intensified remobilization is beneficial in restoring the BMC and BMD from disuse to normal while subsequent deconditioning is deleterious to these parameters. Immobilization for 3 weeks produced a significant BMC and BMD loss in the immobilized left femur (range −4.4 to −12.8%; p < 0.05‐0.001). In the groups with free remobilization (free cage activity), the body weight‐adjusted BMCs and BMDs always remained below those in the controls (range −2.3 to −12.1%; p values ranging from NS to <0.01). Both low‐ and high‐intensity running restored BMC and BMD in the immobilized limb, the effect being better in the latter group. In both of these groups, the values of the immobilized left limbs and those of the free right limbs exclusively exceeded the corresponding values of the age‐matched control rats (left limb values 3.0‐21.1% higher with p values ranging from NS to <0.01; right limb values 7.9‐21.4% higher with p < 0.05‐0.01). However, after the deconditioning period of 18 weeks, the above described beneficial effects of low‐ and high‐intensity running were lost, the left and right limb BMC and BMD values being lower than those in the age‐matched controls (range −3.8 to −8.7%; p values ranging from NS to <0.05). In conclusion, this study clearly indicates the need for greater than normal activity to restore the BMC and BMD after disuse to normal levels. However, the benefits of intensified remobilization are lost if the activity is terminated, and therefore, after immobilization and disuse, bone loading activities should be continued, perhaps indefinitely.
Phosphorylation of AKT(Ser473) serves as an independent prognostic marker for radiosensitivity in advanced head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC) is frequently characterized by high resistance to radiotherapy, which critically depends on both altered signaling pathways within tumor cells and their dynamic interaction with the tumor microenvironment. This study evaluated the prognostic value of the phosphorylation status of AKT on Ser473 and Thr308 for the clinical outcome of patients with advanced HNSCC on radiotherapy. Furthermore, we investigated the impact of AKT(Ser473) phosphorylation [p‐AKT(Ser473)] in the context of radioresistance using ex vivo tissue cultures that resemble the complex tissue architecture and paracrine interaction with the tumor microenvironment. In a cohort of 120 patients with advanced HNSCC, who were treated with primary or adjuvant radiotherapy, a significant association was found between relative p‐AKT(Ser473) levels and overall survival (p = 0.006) as well as progression‐free survival (p = 0.021), while no significant correlation was revealed for relative p‐AKT(Thr308) levels. In ex vivo tissue cultures p‐AKT(Ser473) levels were increased upon irradiation and treatment with the PI3K inhibitor LY294002 inhibited both basal and irradiation induced AKT(Ser473) phosphorylation. Strikingly, pretreatment with LY294002 sensitized tissue cultures derived from primary and recurrent tumors to radiotherapy as determined by impaired tumor cell proliferation and enhanced DNA damage. In conclusion, phosphorylation status of AKT(Ser473) in tumor specimens serves as a novel biomarker to identify patients with advanced HNSCC at high risk for treatment failure following radiotherapy, and our data from ex vivo tissue cultures support the assumption that pharmacological inhibition of AKT(Ser473) phosphorylation might circumvent radioresistance to improve efficiency and reduce toxicity of current treatment modalities.
Decline in titin content in rat skeletal muscle after denervation

Titin, an elastic and giant myofibrillar protein, is responsible for generating passive tension and maintaining sarcomere structure in striated muscles. Several studies have reported attenuation of passive tension and disorganization of sarcomere in atrophic muscles, but the changes of titin have not been investigated after denervation. For this purpose, we used sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS‐PAGE) and immunofluorescent staining to examine titin in innervated and denervated tibialis anterior (TA) muscles of the rat. With increasing denervation time, we found a greater loss of titin than myosin heavy chain (MHC) and actin contents in atrophic TA muscle. The ratios of titin/MHC and titin/actin gradually decreased following denervation. In contrast, ratios of MHC/actin in the denervated groups showed no significant differences with the controls even at 56 days postdenervation. The ultrastructure of myofibrils also showed disturbed arrangements of myofilaments and a disorganized contractile apparatus in denervated muscle. Immunofluorescent staining displayed translocation of the titin epitope from the Z‐line to the I‐band, suggesting that the apparent cleavage of titin occurred near the Z‐line region during the atrophying process. Our study provides evidence that titin is more sensitive to degradation than MHC and actin after denervation. Moreover, the titin decline results in the loss of titin‐based sarcomeric integrity in atrophic muscle. Muscle Nerve, 2005
Restructuring the English Working Class for Global Competitiveness

This paper considers the latest developments in an ongoing attempt to restructure the English working class. It divides this project into two distinct phases. The first is associated with destructive policies to undermine the political, social and institutional structures of the working class embedded in the post- War social democratic and compromise. The paper then goes on to show how New Labour initially sought to rebuild the working class in the image of global competitiveness, at the outset of the second phase to restructure the English working class. The paper argues that the present moment in policy development represents a watershed in this second-phase. The aim now is to contain and overcome some of the contradictions thrown up by New Labour’s early policies and to raise the raise the workforce in terms of its position in the Global Division of Labour. To do so, there is a need to move up those sections of the working class currently working in, and competing for, low-value and low paid ‘entry-level’ work, in order to create space for largely inactive elements of the latent workforce to move into. The project is pre-figured by a wholesale acceptance of the politics of global competitiveness. The discussion is undertaken via an analysis of three key sets of policy documents associated with the Harker Review of Child Poverty, the Leitch Review of Skills and the Freud Review of Welfare.
Molecular Characterization of Ypi1, a Novel Saccharomyces cerevisiae Type 1 Protein Phosphatase Inhibitor*

The Saccharomyces cerevisiae open reading frame YFR003c encodes a small (155-amino acid) hydrophilic protein that we identified as a novel, heat-stable inhibitor of type 1 protein phosphatase (Ypi1). Ypi1 interacts physically in vitro with both Glc7 and Ppz1 phosphatase catalytic subunits, as shown by pull-down assays. Ypi1 inhibits Glc7 but appears to be less effective toward Ppz1 phosphatase activity under the conditions tested. Ypi1 contains a 48RHNVRW53 sequence, which resembles the characteristic consensus PP1 phosphatase binding motif. A W53A mutation within this motif abolishes both binding to and inhibition of Glc7 and Ppz1 phosphatases. Deletion of YPI1 is lethal, suggesting a relevant role of the inhibitor in yeast physiology. Cells overexpressing Ypi1 display a number of phenotypes consistent with an inhibitory role of this protein on Glc7, such as decreased glycogen content and an increased growth defect in a slt2/mpk1 mitogen-activated protein kinase-deficient background. Taking together, these results define Ypi1 as the first inhibitory subunit of Glc7 identified in budding yeast.
Molecular modeling and dynamics study of nonsynonymous SNP in bread wheat HSP16.9B gene

An ubiquitous molecular chaperon, small heat shock proteins (sHSP) maintain protein homeostasis under stress conditions. Single nucleotide polymorphism was predicted in HSP16.9B gene but so far its impact on protein structure has not been extensively studied. Keeping this point in mind, we applied computational methods and performed molecular dynamics simulation to examine the effect of aspartic acid substitution for asparagine at 11th position (D11N) in HSP16.9B. Furthermore, the secondary structural analysis revealed an addition of beta sheet before the mutation point in the mutant protein. Three dimensional protein structure modeling, validation of structures and molecular dynamics were performed to study the mechanism of the non-synonymous single nucleotide polymorphism on structural changes. The root mean square deviation (RMSD) result showed the stability of the mutated structure throughout simulations. Moreover, root mean square fluctuation (RMSF) of atoms and Hydrogen-bond patterns further supported our results.
Novel high efficiency low ripple charge pump using variable frequency modulation

A novel charge pump with variable frequency modulation (VFM) is proposed in this paper. To provide base for its design and improvement, detailed models for VFM charge pump are derived. And it is successfully implemented for the charge pump to introduce a voltage controlled oscillator (VCO) to control the switching frequency, which results in its high efficiency and low ripple output both at high load and light load. The chip is designed and fabricated in TSMC 0.35um mixed signal process. The simulation and test results show that high efficiency (up to 75%) and very low ripple output ( around 10 mV) is realized as expected. Besides, the accuracy of the model's prediction is proved.
Identification of a minimal domain of 5 S ribosomal RNA sufficient for high affinity interactions with the RNA-specific zinc fingers of transcription factor IIIA.

Transcription factor IIIA of Xenopuslaevis serves a dual function during oogenesis and early development: this zinc finger protein binds to the internal promoter element of the 5 S ribosomal RNA genes and acts as a positive transcription factor; additionally, the protein functions in 5 S RNA storage. The central four zinc fingers (zf4-7) of the nine-finger protein have been shown to bind 5 S rRNA with comparable or higher affinity than the full-length protein. The role of finger seven in binding affinity has been examined by deletion analysis. A zf4-6 protein binds 5 S RNA with about a sevenfold reduction in binding affinity, compared to zf4-7. The effect of non-specific competitor DNA on binding affinities of the zinc finger peptides was examined and found to have a significant effect on the measured affinities of these peptides for full-length and truncated versions of 5 S RNA. The interaction of zf4-6 with full-length 5 S RNA was far more sensitive to non-specific competitor concentration than was the zf4-7:5 S RNA interaction, suggesting that finger seven contributes to both affinity and specificity in this protein:RNA interaction. In order to map zinc finger binding sites on the 5 S RNA molecule, we generated truncated versions of the RNA and tested these molecules for their binding affinities with zf4-7 and zf4-6. Previous studies showed that a 75 nucleotide long RNA, comprising loop A, helix II, helix V, region E and helix IV, bound zf4-7 with high affinity. Selection and amplification binding assays (selex) have now been used to generate smaller high-affinity binding RNAs. We find that a 55 nucleotide long RNA, comprising loop A, helix V, region E and helix IV, but lacking helix II, retains high affinity for zf4-6. These data are consistent with the proposal that fingers 4-6 bind this central core of 5 S RNA and that finger seven binds the helix II region.
Focused Shrinkage Estimators for the Global Minimum Variance Portfolio

We propose a shrinkage estimator for covariance matrices designed to minimize estimation error of the Global Minimum Variance (GMV) portfolio. Implementing the GMV portfolio requires estimating the asset covariance matrix and using this to obtain variance-minimizing portfolio weights. Standard estimation approaches for this application utilize shrinkage. These estimators use shrinkage weights that are not designed to directly minimize estimation error of the final object of interest: GMV portfolio weights. We develop a focused shrinkage approach to the problem. This method utilizes the form of the trading rule to derive a shrinkage estimator that directly controls estimation error of GMV portfolio weights. Extensive simulations are conducted to compare performance with nine standard competitors. Our estimator uniformly outperformed all competitors across portfolios of various sizes. The methods are applied to several standard portfolios of US and international assets. Similar improvements are found. Our estimator achieves the smallest out-of-sample portfolio variance in 25 of 28 data sets considered.