Miracle-dz/UniFAR-FTUs huggingface dataset:
CDK12 regulates alternative last exon mRNA splicing and promotes breast cancer cell invasion

Abstract CDK12 (cyclin-dependent kinase 12) is a regulatory kinase with evolutionarily conserved roles in modulating transcription elongation. Recent tumor genome studies of breast and ovarian cancers highlighted recurrent CDK12 mutations, which have been shown to disrupt DNA repair in cell-based assays. In breast cancers, CDK12 is also frequently co-amplified with the HER2 (ERBB2) oncogene. The mechanisms underlying functions of CDK12 in general and in cancer remain poorly defined. Based on global analysis of mRNA transcripts in normal and breast cancer cell lines with and without CDK12 amplification, we demonstrate that CDK12 primarily regulates alternative last exon (ALE) splicing, a specialized subtype of alternative mRNA splicing, that is both gene- and cell type-specific. These are unusual properties for spliceosome regulatory factors, which typically regulate multiple forms of alternative splicing in a global manner. In breast cancer cells, regulation by CDK12 modulates ALE splicing of the DNA damage response activator ATM and a DNAJB6 isoform that influences cell invasion and tumorigenesis in xenografts. We found that there is a direct correlation between CDK12 levels, DNAJB6 isoform levels and the migration capacity and invasiveness of breast tumor cells. This suggests that CDK12 gene amplification can contribute to the pathogenesis of the cancer.
Endothelial Cell Transplantation for Gene Therapy in Experimental Gliomas

OBJECTIVE: Malignant gliomas are prominent targets for cancer gene therapy approaches because of their poor prognosis despite all available therapies. Endothelial cells (ECs) are considered attractive vehicles for cell-based gene therapy because of their tropism to the tumor vasculature. In this study, we investigated the potential of ECs to incorporate into glioma vessels after intra-arterial or local application to establish whether ECs can be used as cellular vectors for gene therapy in gliomas. METHODS: Immortalized rat brain endothelial cells (BECs) were modified to express either β-galactosidase or green fluorescent protein (GFP). The ability of transduced BECs to integrate into tumor vessels after interstitial implantation was evaluated in C6 and 9L glioma models. The fate of GFP-BECs was investigated after selective intracarotid injection into C6 tumor-bearing animals. RESULTS: The interstitially grafted BECs organized themselves into vascular-like structures and integrated into the tumor vasculature. Transgene expression was limited to 10 days after injection. After selective intra-arterial injection, numerous GFP-BECs were adherent to the vascular lumen at least 7 days after injection. These cells were evenly distributed within small vessels and capillaries of the injected hemisphere and did not home selectively to the tumor vessels. CONCLUSION: Cell-based therapy approaches to brain tumor treatment using BECs as cellular vectors might be hampered by the rapid downregulation of transgene expression and by the fact that these cells do not home specifically to tumor vessels after intra-arterial injection. Nevertheless, locoregional administration of BECs might be an interesting approach for delivering molecules to brain tumors when short-term expression of transgene in the perivascular space is desirable.
On the Quantification Accuracy, Homogeneity, and Stability of Simultaneous Positron Emission Tomography/Magnetic Resonance Imaging Systems

ObjectiveA potential major application of simultaneous avalanche photodiode–based positron emission tomography (PET)/magnetic resonance imaging (MRI) systems are quantitative brain studies for cerebral blood flow measurements in combination with blood-oxygen-level–dependent or perfusion MRI, requiring a high performance for both modalities. Thus, we evaluated PET quantification accuracy and homogeneity for 2 different simultaneous PET/MRI systems (whole–body and brain scanner) compared with those of a state-of-the-art PET detector (PET/computed tomography) using phantom studies. In addition, we investigated the long-term stability of PET and quality of functional MRI measurements of a clinical whole-body PET/MRI scanner. Materials and MethodsPhantom measurements were conducted using spheres filled with [18F]-fluoride distributed in a homogeneous cylinder phantom at different positions inside the PET field of view. Recovery values and standard deviations were extracted from resulting PET images. The influence of magnetic resonance–based attenuation correction and that of activity outside the PET field of view on the recovery values of these spheres was evaluated. Furthermore, long-term PET stability of the whole-body PET/MRI system was assessed by evaluating position profiles, energy spectra, count rates, and recovery values from [68Ge]-phantom scans. Functional MRI applicability was tested in accordance with the functional Biomedical Information Research Network procedure. ResultsThe BrainPET system showed high recovery values (up to 99%) but also increased variability (up to 7.4%). Significant underestimations in PET quantification near activity outside the PET field of view were found (up to 80%). Using magnetic resonance–based attenuation correction led to an underestimation in PET activity of approximately 7%. In distinction, the whole-body PET/MRI system revealed performance similar to the PET/computed tomographic scanner (recovery values up to approximately 60% with a variability of approximately 4%). Long-term stability and fMRI performance of the whole-body PET/MRI scanner showed no degradation compared with stand-alone systems. ConclusionsHomogeneity and accuracy of avalanche photodiode-based PET detectors is comparable with those of the state-of-the-art detectors based on photomultiplier tubes. However, attenuation correction on PET/MRI systems has to be adapted carefully for quantitative PET measurements. The BrainPET system needs improved scatter correction to perform quantitative brain studies. The whole-body PET/MRI scanner, however, is applicable for quantitative brain studies.
Vascular Access in Critically Ill Pediatric Patients With Obesity*

Objectives: Pediatric obesity is highly prevalent and has been associated with poor outcomes for hospitalized children. Vascular access is essential in critically ill patients. The aim of this study was to evaluate whether critically ill children with obesity are more likely to undergo vascular device insertion (excluding peripheral IV catheters) and develop related complications. Design: Multi-institutional retrospective observational cohort study. Setting: Ninety-four U.S. PICUs included in the Virtual Pediatric Systems, LLC database. Patients: 120,272 unique patients 2 to less than 18 years old admitted between January 2009 and December 2014. Interventions: None. Measurements and Main Results: Patients were categorized into normal weight, overweight, and obese (class 1, 2, or 3); underweight patients were excluded. We used mixed-effects multivariable logistic regression to test body mass index category as an independent predictor of vascular device placement and associated complications, adjusted for age, sex, severity of illness, primary diagnosis, presence of a complex chronic condition, and admission related to trauma or surgery. A total of 73,964 devices were placed in 45,409 patients (37.8% of the total cohort received a vascular device). Most device types placed differed significantly by weight status. Subjects with class 3 obesity were less likely (odds ratio, 0.74; 95% CI, 0.67–0.81) to undergo placement of any device compared with normal weight patients. Patients with all classes of obesity were more likely to undergo placement of a peripherally inserted central catheter, with the strongest association in those with class 2 obesity (odds ratio, 1.26; 95% CI, 1.14–1.40). Class 1 and class 3 obesity were independent risk factors for developing a complication, with odds ratio of 1.31 (95% CI, 1.11–1.53) and 1.45 (95% CI, 1.07–1.99), respectively. Conclusions: Severe obesity is associated with decreased overall likelihood of placement of a vascular access device but increased likelihood of peripherally inserted central catheter placement and of device-related complications.
Age-related macular degeneration and low-vision rehabilitation: a systematic review.

BACKGROUND Because of the prevalence and devastating consequences of age-related macular degeneration (AMD), a systematic review devoted to low-vision rehabilitation and AMD seems timely and appropriate. METHODS Several electronic databases were searched for studies from 1980 to 2006 involving individuals with low vision or visual impairment and rehabilitation interventions. Studies were assessed for quality and level of evidence. RESULTS The findings indicate that standard low-vision rehabilitation programs, conventional in-clinic assessments, and optical devices are effective ways of managing and living with vision loss. Areas of unmet need include determining which types of orientation and mobility programs and devices are most effective and developing methods of matching assistive technologies with the individual's visual and environmental requirements. INTERPRETATION Additional randomized controlled trials with similar intervention comparisons and outcome measures are needed to form stronger conclusions for the most effective low-vision rehabilitation interventions for individuals with AMD.
Improvement of radar signal phase extraction using All Phase FFT spectrum analysis

The purpose of this work is the extraction of signal phase by improving the input data truncating based on spectrum analysis. The method of All Phase Fast Fourier Transform (APFFT) has perfect characteristic of phase estimation and analysis. The phase in this case does not need to be corrected and the error between the exact phase and the estimated one by the APFFT is extremely small. In this paper, we present an algorithm for sinusoidal signal's phase estimation based on APFFT and intrapulse modulation extraction (Barker code as example). Simulations show that the APFFT is more accurate and practicable than traditional FFT algorithm. The obtained results are presented and discussed.
Breast size and risk of type 2 diabetes mellitus

Background: Elevated waist circumference and body mass index (BMI), both traditional measures of obesity, are accepted risk factors for type 2 diabetes mellitus. Girls who are obese experience earlier onset of puberty and possibly greater breast development. We sought to evaluate whether a woman's breast size in late adolescence is associated with an increased risk of type 2 diabetes mellitus in adulthood. Methods: In conjunction with the ongoing Nurses' Health Study II, which began to study risk factors for breast cancer among women in 1989, we conducted a prospective cohort study involving 92 106 of the participants. We assessed the risk of type 2 diabetes mellitus in relation to self-reported bra cup sizes, categorized as ≤ A, B, C and ≥ D cups, among participants at age 20. Results: The mean age of participants at baseline was 38.1 years. A total of 1844 new cases of type 2 diabetes mellitus arose at a mean age of 44.9 years during 886 443 person-years of follow-up. Relative to bra cup size ≤ A, the respective age-adjusted hazard ratios (and 95% confidence intervals [CIs]) were 2.30 (1.99–2.66) for B cup, 4.32 (3.71–5.04) for C cup and 4.99 (4.12–6.05) for ≥ D cup. Upon further adjustments for age at menarche, parity, physical activity, smoking status, diet, multivitamin use, family history of diabetes mellitus, BMI at age 18 and current BMI, the corresponding hazard ratios (and 95% CIs) were 1.37 (1.18–1.59) for B cup, 1.80 (1.53- 2.11) for C cup and 1.64 (1.34–2.01) for ≥ D cup. The addition of waist circumference to this model minimally changed the hazard ratios (and 95% CIs): 1.32 (1.14–1.53) for B cup, 1.71 (1.46–2.01) for C cup and 1.58 (1.29–1.94) for ≥ D cup. Interpretation: A large bra cup size at age 20 may be a predictor of type 2 diabetes mellitus in middle-aged women. Whether this relation is independent of traditional indicators of obesity remains to be determined.
Using Caenorhabditis elegans for antimicrobial drug discovery

Introduction: The number of microorganism strains with resistance to known antimicrobials is increasing. Therefore, there is a high demand for new, non-toxic and efficient antimicrobial agents. Research with the microscopic nematode Caenorhabditis elegans can address this high demand for the discovery of new antimicrobial compounds. In particular, C. elegans can be used as a model host for in vivo drug discovery through high-throughput screens of chemical libraries. Areas covered: This review introduces the use of substitute model hosts and especially C. elegans in the study of microbial pathogenesis. The authors also highlight recently published literature on the role of C. elegans in drug discovery and outline its use as a promising host with unique advantages in the discovery of new antimicrobial drugs. Expert opinion: Caenorhabditis elegans can be used, as a model host, to research many diseases, including fungal infections and Alzheimer's disease. In addition, high-throughput techniques for screening chemical libraries can also be facilitated. Nevertheless, C. elegans and mammals have significant differences that both limit the use of the nematode in research and the degree by which results can be interpreted. That being said, the use of C. elegans in drug discovery still holds promise and the field continues to grow, with attempts to improve the methodology already underway.
Rotating night shift work and polymorphism of genes important for the regulation of circadian rhythm.

OBJECTIVE People living in industrialized societies have developed specific working schedules during the day and at night, including permanent night shifts and rotating night shifts. The aim of this study was to examine the association between circadian polymorphisms and rotating night shift work. METHODS This cross-sectional study comprised 709 nurses and midwives (348 current rotating and 361 current day workers). Genetic polymorphism of selected clock genes BMAL1 (rs2279287), CLOCK (rs1801260), PER1 (rs2735611), PER2 (rs2304672), PER3 (rs10462020), CRY1 (rs8192440), CRY2 (rs10838527, rs10838527) was determined using real-time polymerase chain reaction (PCR) assays. RESULTS There were no differences in BMAL1, CLOCK, CRY2, PER1, PER2, and PER3 genotypes among nurses and midwives working rotating night and day shifts. The frequency of women with rare CRY1 TT genotype was higher in the group of rotating night shift than day workers (17.0% versus 13.9%, P=0.06). Moreover, CRY1 TT genotype was associated with the total rotating shift-work duration, compared to women rarely working night shifts. CONCLUSIONS These results suggest that CRY1 (rs8192440) polymorphism may influence the adaptation to the rotating night shift work among nurses and midwives.
shinyheatmap: Ultra fast low memory heatmap web interface for big data genomics

Background Transcriptomics, metabolomics, metagenomics, and other various next-generation sequencing (-omics) fields are known for their production of large datasets, especially across single-cell sequencing studies. Visualizing such big data has posed technical challenges in biology, both in terms of available computational resources as well as programming acumen. Since heatmaps are used to depict high-dimensional numerical data as a colored grid of cells, efficiency and speed have often proven to be critical considerations in the process of successfully converting data into graphics. For example, rendering interactive heatmaps from large input datasets (e.g., 100k+ rows) has been computationally infeasible on both desktop computers and web browsers. In addition to memory requirements, programming skills and knowledge have frequently been barriers-to-entry for creating highly customizable heatmaps. Results We propose shinyheatmap: an advanced user-friendly heatmap software suite capable of efficiently creating highly customizable static and interactive biological heatmaps in a web browser. shinyheatmap is a low memory footprint program, making it particularly well-suited for the interactive visualization of extremely large datasets that cannot typically be computed in-memory due to size restrictions. Also, shinyheatmap features a built-in high performance web plug-in, fastheatmap, for rapidly plotting interactive heatmaps of datasets as large as 105 − 107 rows within seconds, effectively shattering previous performance benchmarks of heatmap rendering speed. Conclusions shinyheatmap is hosted online as a freely available web server with an intuitive graphical user interface: http://shinyheatmap.com. The methods are implemented in R, and are available as part of the shinyheatmap project at: https://github.com/Bohdan-Khomtchouk/shinyheatmap. Users can access fastheatmap directly from within the shinyheatmap web interface, and all source code has been made publicly available on Github: https://github.com/Bohdan-Khomtchouk/fastheatmap.
Preferred sequences for DNA recognition by the TAL1 helix-loop-helix proteins

Tumor-specific activation of the TAL1 gene is the most common genetic alteration seen in patients with T-cell acute lymphoblastic leukemia. The TAL1 gene products contain the basic helix-loop-helix (bHLH) domain, a protein dimerization and DNA-binding motif common to several known transcription factors. A binding-site selection procedure has now been used to evaluate the DNA recognition properties of TAL1. These studies demonstrate that TAL1 polypeptides do not have intrinsic DNA-binding activity, presumably because of their inability to form bHLH homodimers. However, TAL1 readily interacts with any of the known class A bHLH proteins (E12, E47, E2-2, and HEB) to form heterodimers that bind DNA in a sequence-specific manner. The TAL1 heterodimers preferentially recognize a subset of E-box elements (CANNTG) that can be represented by the consensus sequence AACAGATGGT. This consensus is composed of half-sites for recognition by the participating class A bHLH polypeptide (AACAG) and the TAL1 polypeptide (ATGGT). TAL1 heterodimers with DNA-binding activity are readily detected in nuclear extracts of Jurkat, a leukemic cell line derived from a patient with T-cell acute lymphoblastic leukemia. Hence, TAL1 is likely to bind and regulate the transcription of a unique subset of subordinate target genes, some of which may mediate the malignant function of TAL1 during T-cell leukemogenesis.
The Epstein-Barr Virus Major Latent Promoter Qp Is Constitutively Active, Hypomethylated, and Methylation Sensitive

ABSTRACT Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1) is indispensable for viral DNA replication and episome maintenance in latency. Four promoters, Cp, Wp, Qp, and Fp, are known to drive EBNA1 expression. Here we show that the TATA-less Qp is constitutively active in a variety of EBV-positive [EBV(+)] tumors and cell lines, irrespective of the activities of other EBNA1 promoters, the type of viral latency, and the cell type. The transcription of highly regulated promoters such as the EBV Cp is known to be directly regulated by CpG methylation. To characterize the role of CpG methylation in the regulation of the constitutively active Qp, we performed bisulfite genomic sequencing and functional analyses using a methylation cassette transcriptional reporter assay. Twenty consecutive CpG sites (16 proximal to the Qp initiation site and 4 upstream of the adjacent Fp initiation site) were studied by bisulfite sequencing of DNA extracted from EBV(+) tumors and cell lines. Eighteen EBV(+) tumors of lymphoid (B, T, and NK cell) or epithelial origin and five Burkitt’s lymphoma cell lines were studied. The 16 CpG sites proximal to Qp were virtually all unmethylated, but the 4 CpG sites upstream of the Fp initiation site were variably methylated. The methylation cassette assay showed that in vitro methylation of the Qp cassette (−172 to +32) resulted in strong repression of Qp activity in transient transfection. Thus, Qp is susceptible to repression by methylation but was found to be consistently hypomethylated and expressed in all tumors and tumor-derived cell lines studied.
Nerolidol-loaded nanospheres prevent hepatic oxidative stress of mice infected by Trypanosoma evansi

SUMMARY The aim of this study was to evaluate the effect of nerolidol free (N-F) and nerolidol-loaded in nanospheres (N-NS) on the hepatic antioxidant/oxidant status of mice experimentally infected by Trypanosoma evansi. In the liver it was measured: reactive oxygen species (ROS), thiobarbituric reactive acid substances (TBARS) and non-protein thiols (NPSH), catalase (CAT), superoxide dismutase (SOD) and glutathione-S-transferase (GST) and performed histopathological examination. In addition, seric levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured. Liver samples from mice infected by T. evansi showed increased (P < 0·05) ROS, TBARS, AST and ALT levels and SOD activity, and decreased NPSH levels and CAT activity (P < 0·05) compared with uninfected animals. N-NS treatment prevented (P < 0·05) ROS and TBARS increase, and increased NPSH levels, and ameliorate CAT and SOD activities on liver of infected mice. Moreover, N-NS treatment reduced (P < 0·05) AST and ALT levels, and prevented histopathological changes caused by the parasite. N-NS protected the liver from the oxidative stress caused by T. evansi, which might be due to its antioxidant properties. Nerolidol might be considered a promising therapeutic agent against oxidative stress, and nanotechnology is an encouraging approach to be explored.
Regulation of T cell dependent immune responses by TIM family members

The T cell immunoglobulin mucin (TIM) proteins are type I membrane glycoproteins expressed on T cells and containing common structural motifs. While our understanding on the distribution and functions of TIM family members is still incomplete, data from several recent reports indicate that these proteins, together with T cell receptor and costimulatory signals, regulate the expansion and effector functions of T helper cells. In the current review, we provide evidences indicating that TIM-3 is capable of modulating the function of CD4+CD25+ regulatory T cells and inhibiting aggressive Th1 mediated auto- and allo-immune responses. Similarly, additional data suggest that TIM-2 molecules function by negatively regulating Th2 immune responses. In contrast, TIM-1 appears to be an activation molecule for all T cells, although the mechanisms through which TIM-1 activates T cells remain to be elicited.
Fully Integrated ASK Receiver MMIC for Terahertz Communications at 300 GHz

An ASK receiver MMIC operating at 300 GHz for future terahertz communications is presented. In the receiver IC, we fully integrated all necessary components-a receiving dipole antenna, high gain RF amplifier, envelop detector for demodulating ASK signal and output differential data amplifier-in a 1000×2500 μm2 area. A silicon lens was used to compensate for the small gain of the on-chip antenna. To ensure reliable and stable operation, we designed the MMIC with a thin-film microstrip line, which is expected to suppress crosstalk between the on-chip antenna and the RF amplifier through the substrate and silicon lens. The packaged receiver module with the silicon lens is expected to provide approximately 24-dBi beam directivity. Measured RF and baseband bandwidths are around 30 and 15 GHz, respectively, when a single bias of 3.3 V and total current of around 86 mA are applied. With the receiver module, simple wireless data transmission was conducted for up to 24 Gbps in the 300-GHz band. At 12.5 Gbps, error-free data transmission (bit error rate <; 10-9) over 0.3 m was achieved with the transmission power of - 16-dBm and a 25-dBi transmitting antenna. With -10-dBm transmission power, measured Q-factors of the received eye patterns were larger than 6 for up to 20 Gbps, which implies that the bit error rate will be less than 10-9.