Miracle-dz/UniFAR-FTUs huggingface dataset:
HOXB13 Induces Growth Suppression of Prostate Cancer Cells as a Repressor of Hormone-Activated Androgen Receptor Signaling

Androgen receptor (AR) signals play a decisive role in regulating the growth and differentiation of both normal and cancerous prostate cells by triggering the regulation of target genes, in a process in which AR cofactors have critical functions. Because of the highly prostate-specific expression pattern of HOXB13, we studied the role of this homeodomain protein in prostate cells. Expression of HOXB13 was limited to AR-expressing prostate cells. Reporter transcription assay demonstrated that HOXB13 significantly suppressed hormone-mediated AR activity in a dose-responsive manner, and suppression was specific to AR with which HOXB13 physically interacts. Overexpression of HOXB13 further down-regulated the androgen-stimulated expression of prostate-specific antigen, and suppression of endogenous HOXB13 stimulated transactivation of AR. Functionally, HOXB13 suppressed growth of LNCaP prostate cancer cells, which could be counteracted by additional hormone-activated AR. On the other hand, the growth-suppressive function of HOXB13 in AR-negative CV-1 cells was not affected by AR. These results suggest that HOXB13 functions as an AR repressor to modulate the complex AR signaling and subsequent growth regulation of prostate cancer cells. In addition to the loss of HOXB13 expression, maintaining AR may be an important step for prostate cancer cells to tolerate the suppressor function of HOXB13. Altogether, our data present a novel mechanism for the HOXB13-mediated repression of AR signaling, which can be interpreted to a growth-suppressive event.
Telomerase Activity is Downregulated Early During Human Brain Development

Changes in hTERT splice variant expression have been proposed to facilitate the decrease of telomerase activity during fetal development in various human tissues. Here, we analyzed the expression of telomerase RNA (hTR), wild type and α-spliced hTERT in developing human fetal brain (post conception weeks, pcw, 6–19) and in young and old cortices using qPCR and correlated it to telomerase activity measured by TRAP assay. Decrease of telomerase activity occurred early during brain development and correlated strongest to decreased hTR expression. The expression of α-spliced hTERT increased between pcw 10 and 19, while that of wild type hTERT remained unchanged. Lack of expression differences between young and old cortices suggests that most changes seem to occur early during human brain development. Using in vitro differentiation of neural precursor stem cells (NPSCs) derived at pcw 6 we found a decrease in telomerase activity but no major expression changes in telomerase associated genes. Thus, they do not seem to model the mechanisms for the decrease in telomerase activity in fetal brains. Our results suggest that decreased hTR levels, as well as transient increase in α-spliced hTERT, might both contribute to downregulation of telomerase activity during early human brain development between 6 and 17 pcw.
Postural control before and after cochlear implantation: Standard cochleostomy versus round window approach

Conclusion: The approach to the cochlea did not influence postural control after cochlear implantation (CI) surgery. Most patients already have impaired vestibular function before surgery. These balance deficits did not change after CI surgery in the majority of patients but static balance might be improved by CI surgery. Objectives: To determine whether the technique used to insert the CI electrode has an influence on vestibular function. Methods: Static and dynamic postural control and caloric vestibular function were measured prospectively before and after CI surgery in 36 CI patients with standard cochleostomy (SC) insertion and 16 patients with insertion across the round window (RW). The test battery consisted of the modified clinical test of sensory interaction on balance (mCTSIB), the Rhythmic Weight Shift (RWS), the Walk Across (WA), and the Tandem Walk (TW) test. Results: Caloric testing was normal in the majority of CI candidates and remained normal after surgery. mCTSIB results were not significantly different before and after CI surgery between the SC and RW groups. Within both subgroups, the mCTSIB composite value improved within 6 weeks after surgery compared with the values obtained before surgery. Dynamic standing balance showed no postoperative change in RWS.
Massively Parallel Sequencing Reveals an Accumulation of De Novo Mutations and an Activating Mutation of LPAR1 in a Patient with Metastatic Neuroblastoma

Neuroblastoma is one of the most genomically heterogeneous childhood malignances studied to date, and the molecular events that occur during the course of the disease are not fully understood. Genomic studies in neuroblastoma have showed only a few recurrent mutations and a low somatic mutation burden. However, none of these studies has examined the mutations arising during the course of disease, nor have they systemically examined the expression of mutant genes. Here we performed genomic analyses on tumors taken during a 3.5 years disease course from a neuroblastoma patient (bone marrow biopsy at diagnosis, adrenal primary tumor taken at surgical resection, and a liver metastasis at autopsy). Whole genome sequencing of the index liver metastasis identified 44 non-synonymous somatic mutations in 42 genes (0.85 mutation/MB) and a large hemizygous deletion in the ATRX gene which has been recently reported in neuroblastoma. Of these 45 somatic alterations, 15 were also detected in the primary tumor and bone marrow biopsy, while the other 30 were unique to the index tumor, indicating accumulation of de novo mutations during therapy. Furthermore, transcriptome sequencing on the 3 tumors demonstrated only 3 out of the 15 commonly mutated genes (LPAR1, GATA2, and NUFIP1) had high level of expression of the mutant alleles, suggesting potential oncogenic driver roles of these mutated genes. Among them, the druggable G-protein coupled receptor LPAR1 was highly expressed in all tumors. Cells expressing the LPAR1 R163W mutant demonstrated a significantly increased motility through elevated Rho signaling, but had no effect on growth. Therefore, this study highlights the need for multiple biopsies and sequencing during progression of a cancer and combinatorial DNA and RNA sequencing approach for systematic identification of expressed driver mutations.
Parallel Profiling of Fission Yeast Deletion Mutants for Proliferation and for Lifespan During Long-Term Quiescence

Genetic factors underlying aging are remarkably conserved from yeast to human. The fission yeast Schizosaccharomyces pombe is an emerging genetic model to analyze cellular aging. Chronological lifespan (CLS) has been studied in stationary-phase yeast cells depleted for glucose, which only survive for a few days. Here, we analyzed CLS in quiescent S. pombe cells deprived of nitrogen, which arrest in a differentiated, G0-like state and survive for more than 2 months. We applied parallel mutant phenotyping by barcode sequencing (Bar-seq) to assay pooled haploid deletion mutants as they aged together during long-term quiescence. As expected, mutants with defects in autophagy or quiescence were under-represented or not detected. Lifespan scores could be calculated for 1199 mutants. We focus the discussion on the 48 most long-lived mutants, including both known aging genes in other model systems and genes not previously implicated in aging. Genes encoding membrane proteins were particularly prominent as pro-aging factors. We independently verified the extended CLS in individual assays for 30 selected mutants, showing the efficacy of the screen. We also applied Bar-seq to profile all pooled deletion mutants for proliferation under a standard growth condition. Unlike for stationary-phase cells, no inverse correlation between growth and CLS of quiescent cells was evident. These screens provide a rich resource for further studies, and they suggest that the quiescence model can provide unique, complementary insights into cellular aging.
Perspective of Cyclin-dependent kinase 9 (CDK9) as a Drug Target

Deregulation of cyclin-dependent kinases (CDKs) has been associated with many cancer types and has evoked an interest in chemical inhibitors with possible therapeutic benefit. While most known inhibitors display broad selectivity towards multiple CDKs, recent work highlights CDK9 as the critical target responsible for the anticancer activity of clinically evaluated drugs. In this review, we discuss recent findings provided by structural biologists that may allow further development of highly specific inhibitors of CDK9 towards applications in cancer therapy. We also highlight the role of CDK9 in inflammatory processes and diseases.
Eliminating Carcinogenic Acetaldehyde By Cysteine From Saliva During Smoking

Tobacco smoking is one of the strongest risk factors not only for lung cancer but also for cancers of the upper gastrointestinal tract. Acetaldehyde has been shown to dissolve into the saliva during smoking and to be a local carcinogen in the human upper digestive tract. Cysteine can bind to acetaldehyde and eliminate its toxicity. We developed a tablet that releases cysteine into the oral cavity during smoking and could therefore be a potential chemopreventive agent against toxicity of tobacco smoke. In this study, the efficacy of l-cysteine–containing tablets to reduce the carcinogenic acetaldehyde in the saliva during tobacco smoking was examined. Seven volunteers smoked five cigarettes. During every smoking period, each volunteer sucked a blinded tablet containing 0, 1.25, 2.5, 5, or 10 mg of l-cysteine. Acetaldehyde was analyzed from salivary samples gas chromatographically at 0, 5, and 10 minutes from the beginning of the smoking. All tablets containing l-cysteine reduced highly significantly the salivary acetaldehyde; 5 mg of l-cysteine was the minimum concentration to totally eliminate the acetaldehyde from saliva. The mean salivary acetaldehyde concentrations in samples collected immediately after smoking with 0, 1.25, 2.5, 5, or 10 mg of l-cysteine were 228 ± 115 μmol/L, 85 ± 42 μmol/L (P = 0.007), 9 ± 7 μmol/L, 0.09 ± 0.2 μmol/L, 0 ± 0 μmol/L (P < 0.001), respectively. In conclusion, carcinogenic acetaldehyde could be totally inactivated in the saliva during smoking by sucking tablet containing 5 mg of l-cysteine. Even a small reduction of the carcinogenicity of cigarette smoke could gain benefit at the population level. Hence, this finding warrants for further clinical trials for l-cysteine tablet in the prevention of upper digestive tract cancers in smokers. (Cancer Epidemiol Biomarkers Prev 2006;15(1):146–9)
Dilated convolution neural network with LeakyReLU for environmental sound classification

Environmental sound classification task (ESC) is still open and challenging. In contrast to speech, sounds of a specific acoustic event may be produced by a wide variety of sources. Thus for one class, feature spectrums of acoustic events are much more transformative than human speech. In order to learn better high-level feature representations from these transformative feature spectrums, convolution neural network (CNN) has been applied to ESC tasks and achieved state-of-the-art results. However, it is noted that existing CNN-based ESC systems only use small convolution filters (typically 2×2 or 3×3) in CNN model which results in deep CNN model for learning long contextual information of sound events. Besides, to our knowledge, there is no work of evaluating the effect of activation functions on the performance of CNN-based ESC systems, which is actually very critical for improving the performance. Motivated by these findings, in this study, we propose a dilated CNN-based ESC (D-CNN-ESC) system where dilated filters and LeakyReLU activation function are adopted. The main ideas behind our research are that the dilated filters will increase receptive field of convolution layers to incorporate more contextual information. Moreover, the LeakyReLU function brings the tradeoff between the network sparsity and the performance. To evaluate the effectiveness of our proposed D-CNN-ESC system, we conduct several experiments on three sound event datasets. It is encouraged to see that our proposed D-CNN-ESC system outperforms the state-of-the-art ESC results obtained by very deep CNN-ESC system on UrbanSound8K dataset, the absolute error of our method is about 10% less than that of compared method.
Rat blood neutrophils express very late antigen 4 and it mediates migration to arthritic joint and dermal inflammation

Blood neutrophils contribute to joint injury in human and experimental models of arthritis. Neutrophil migration out of the blood in joint inflammation involves both the CD18 (beta2) integrins and a CD18 integrin-independent pathway. To investigate this migration, radiolabeled rat blood neutrophils were used to measure neutrophil accumulation in the inflamed joints of rats with adjuvant arthritis and the role of leukocyte integrins in migration to these joints and to dermal inflammation was determined. Neutrophils migrated rapidly (<2 h) to the inflamed joints 14-18 d after immunization with adjuvant. Blocking monoclonal antibodies (mAbs) to both LFA-1 and Mac-1 together, as well as a mAb to CD18, inhibited neutrophil accumulation in the inflamed joints by 50-75%. However, migration to dermal inflammation induced by C5a(des Arg)' tumor necrosis factor alpha, lipopolysaccharide, and poly-inosine:cytosine was inhibited by approximately 90%. Flow cytometry revealed the expression of low levels of very late antigen 4 (VLA-4) on nearly all rat blood neutrophils. Treatment with anti-VLA-4 plus anti-LFA-1 but neither mAb alone, strongly (60-75%) inhibited neutrophil accumulation in arthritic joints. This mAb combination also inhibited neutrophil migration to dermal inflammatory reactions by 30-70%. Blocking VLA-4 together with the CD18 integrins inhibited neutrophil accumulation by 95-99%, virtually abolishing neutrophil accumulation in cutaneous inflammation. A similar blockade of VLA-4 and CD18 decreased neutrophil accumulation in the inflamed joints by 70-83%, but a significant portion of the neutrophil accumulation to these joints still remained. In conclusion, rat blood neutrophils express functional VLA-4 that can mediate neutrophil migration to both inflamed joints and dermal inflammatory sites. VLA-4 appears to be able to substitute for LFA-1 in this migration and is particularly important for accumulation in inflamed joints. However, there exists an additional CD18- and VLA-4-independent pathway of neutrophil migration to arthritic joints that is not involved in acute dermal inflammation.
Development and Organization of the Lamprey Telencephalon with Special Reference to the GABAergic System

Lampreys, together with hagfishes, represent the sister group of gnathostome vertebrates. There is an increasing interest for comparing the forebrain organization observed in lampreys and gnathostomes to shed light on vertebrate brain evolution. Within the prosencephalon, there is now a general agreement on the major subdivisions of the lamprey diencephalon; however, the organization of the telencephalon, and particularly its pallial subdivisions, is still a matter of controversy. In this study, recent progress on the development and organization of the lamprey telencephalon is reviewed, with particular emphasis on the GABA immunoreactive cell populations trying to understand their putative origin. First, we describe some early general cytoarchitectonic events by searching the classical literature as well as our collection of embryonic and prolarval series of hematoxylin-stained sections. Then, we comment on the cell proliferation activity throughout the larval period, followed by a detailed description of the early events on the development of the telencephalic GABAergic system. In this context, lampreys apparently do not possess the same molecularly distinct subdivisions of the gnathostome basal telencephalon because of the absence of a Nkx2.1-expressing domain in the developing subpallium; a fact that has been related to the absence of a medial ganglionic eminence as well as of its derived nucleus in gnathostomes, the pallidum. Therefore, these data raise interesting questions such as whether or not a different mechanism to specify telencephalic GABAergic neurons exists in lampreys or what are their migration pathways. Finally, we summarize the organization of the adult lamprey telencephalon by analyzing the main proposed conceptions, including the available data on the expression pattern of some developmental regulatory genes which are of importance for building its adult shape.
Recent developments and future challenges in fatigue strength assessment of welded joints

Fatigue is an important design criterion for welded structures subjected to cyclic loading. Several approaches for fatigue strength assessment have been developed which are either based on Woehler S–N curves and damage accumulation rule or on crack propagation law. The paper briefly reviews the different approaches, highlighting their advantages and limitations. In this connection, the problematic distinction between crack initiation and propagation phases is discussed, followed by considerations about some parameters which have large influence on the fatigue behaviour of welded joints but are considered differently in the approaches, such as plate thickness and stress gradient effects, multiaxial stress states, welding-induced distortions and residual stresses. Finally, ways of improving the fatigue behaviour of welded structures, either during design by reducing the stress concentration or during fabrication by improved quality or post-weld treatment or else by special material characteristics, are addressed. Emphasis will be placed on recent developments and challenges for the future from a personal perspective of the author.
Evidence-based practice models for organizational change: overview and practical applications.

AIM To provide an overview, summary of key features and evaluation of usefulness of six evidence-based practice models frequently discussed in the literature. BACKGROUND The variety of evidence-based practice models and frameworks, complex terminology and organizational culture challenges nurses in selecting the model that best fits their practice setting. DATA SOURCES The authors: (1) initially identified models described in a predominant nursing text; (2) searched the literature through CINAHL from 1998 to current year, using combinations of 'evidence', 'evidence-based practice', 'models', 'nursing' and 'research'; (3) refined the list of selected models based on the initial literature review; and (4) conducted a second search of the literature on the selected models for all available years to locate both historical and recent articles on their use in nursing practice. DISCUSSION Authors described model key features and provided an evaluation of model usefulness based on specific criteria, which focused on facilitating the evidence-based practice process and guiding practice change. IMPLICATIONS FOR NURSING The evaluation of model usefulness can be used to determine the best fit of the models to the practice setting. CONCLUSION The Johns Hopkins Model and the Academic Center for Evidence-Based Practice Star Model emphasize the processes of finding and evaluating evidence that is likely to appeal to nursing educators. Organizations may prefer the Promoting Action on Research Implementation in Health Services Framework, Advancing Research and Clinical Practice Through Close Collaboration, or Iowa models for their emphasis on team decision-making. An evidence-based practice model that is clear to the clinician and fits the organization will guide a systematic approach to evidence review and practice change.
Prior Knowledge Integration for Neural Machine Translation using Posterior Regularization

Although neural machine translation has made significant progress recently, how to integrate multiple overlapping, arbitrary prior knowledge sources remains a challenge. In this work, we propose to use posterior regularization to provide a general framework for integrating prior knowledge into neural machine translation. We represent prior knowledge sources as features in a log-linear model, which guides the learning processing of the neural translation model. Experiments on Chinese-English dataset show that our approach leads to significant improvements.
Topology and Geometry of Online Social Networks

In this paper, we study certain geometric and topological properties of online social networks using the concept of density and geometric vector spaces. "Moi Krug" ("My Circle"), a Russian social network that promotes the principle of the "six degrees of separation" and is positioning itself as a vehicle for professionals and recruiters seeking each others' services, is used as a test vehicle.
Nevirapine versus ritonavir-boosted lopinavir for HIV-infected children.

BACKGROUND Nevirapine-based antiretroviral therapy is the predominant (and often the only) regimen available for children in resource-limited settings. Nevirapine resistance after exposure to the drug for prevention of maternal-to-child human immunodeficiency virus (HIV) transmission is common, a problem that has led to the recommendation of ritonavir-boosted lopinavir in such settings. Regardless of whether there has been prior exposure to nevirapine, the performance of nevirapine versus ritonavir-boosted lopinavir in young children has not been rigorously established. METHODS In a randomized trial conducted in six African countries and India, we compared the initiation of HIV treatment with zidovudine, lamivudine, and either nevirapine or ritonavir-boosted lopinavir in HIV-infected children 2 to 36 months of age who had no prior exposure to nevirapine. The primary end point was virologic failure or discontinuation of treatment by study week 24. RESULTS A total of 288 children were enrolled; the median percentage of CD4+ T cells was 15%, and the median plasma HIV type 1 (HIV-1) RNA level was 5.7 log(10) copies per milliliter. The percentage of children who reached the primary end point was significantly higher in the nevirapine group than in the ritonavir-boosted lopinavir group (40.8% vs. 19.3%; P<0.001). Among the nevirapine-treated children with virologic failure for whom data on resistance were available, more than half (19 of 32) had resistance at the time of virologic failure. In addition, the time to a protocol-defined toxicity end point was shorter in the nevirapine group (P=0.04), as was the time to death (P=0.06). CONCLUSIONS Outcomes were superior with ritonavir-boosted lopinavir among young children with no prior exposure to nevirapine. Factors that may have contributed to the suboptimal results with nevirapine include elevated viral load at baseline, selection for nevirapine resistance, background regimen of nucleoside reverse-transcriptase inhibitors, and the standard ramp-up dosing strategy. The results of this trial present policymakers with difficult choices. (Funded by the National Institute of Allergy and Infectious Diseases and others; P1060 ClinicalTrials.gov number, NCT00307151.).