Miracle-dz/UniFAR-FTUs huggingface dataset:
Induction of caspase‐mediated apoptosis and cell‐cycle G1 arrest by selenium metabolite methylselenol

Previous work based on mono‐methyl selenium compounds that are putative precursors of methylselenol has strongly implicated this metabolite in the induction of caspase‐mediated apoptosis of human prostate carcinoma and leukemia cells and G1 arrest in human vascular endothelial and cancer epithelial cells. To test the hypothesis that methylselenol itself is responsible for exerting these cellular effects, we examined the apoptotic action on DU145 human prostate cancer cells and the G1 arrest effect on the human umbilical vein endothelial cells (HUVECs) of methylselenol generated with seleno‐L‐methionine as a substrate for L‐methionine‐α‐deamino‐γ‐mercaptomethane lyase (EC4.4.1.11, also known as methioninase). Exposure of DU145 cells to methylselenol so generated in the sub‐micromolar range led to caspase‐mediated cleavage of poly(ADP‐ribose) polymerase, nucleosomal DNA fragmentation, and morphologic apoptosis and resulted in a profile of biochemical effects similar to that of methylseleninic acid (MSeA) exposure as exemplified by the inhibition of phosphorylation of protein kinase AKT and extracellularly regulated kinases 1/2. In HUVEC, methylselenol exposure recapitulated the G1 arrest action of MSeA in mitogen‐stimulated G1progression during mid‐G1 to late G1. This stage specificity was mimicked by inhibitors of phosphatidylinositol 3‐kinase. The results support methylselenol as an active selenium metabolite for inducing caspase‐mediated apoptosis and cell‐cycle G1 arrest. This cell‐free methylselenol‐generation system is expected to have significant usefulness for studying the biochemical and molecular targeting mechanisms of this critical metabolite and may constitute the basis of a novel therapeutic approach for cancer, using seleno‐L‐methionine as a prodrug. © 2002 Wiley‐Liss, Inc.
Neurophysiological and neurochemical basis of modern pruritus treatment

Abstract: Chronic pruritus of any origin is a frequent discomfort in daily medical practice, and its therapy is challenging. Frequently, the underlying origin may not be identified and symptomatic therapy is necessary. Conventional treatment modalities such as antihistamines often lack efficacy, and hence new therapeutic strategies are necessary. The neuronal mechanisms underlying chronic pruritus have been partly identified during the past years and offer new therapeutic strategies. For example, mast cell degranulation, activation of neuroreceptors on sensory nerve fibres and neurogenic inflammation have been identified to be involved in induction and chronification of the symptom. Accordingly, controlling neuroreceptors such as cannabinoid receptors by agonists or antagonists showed high antipruritic efficacy. Pruritus is transmitted to the central nervous system by specialized nerve fibres and sensory receptors. It has been demonstrated that pruritus and pain have their own neuronal pathways with broad interactions. Accordingly, classical analgesics for neuropathic pain (gabapentin, antidepressants) also exhibit antipruritic efficacy upon clinical use. In summary, these recent developments show that highlighting the basis of pruritus offers modern neurophysiological and neurochemical therapeutic models and the possibility to treat patients with refractory itching of different origin.
The Relationship of Premature Mitosis to Cytotoxicity in Response to Checkpoint Abrogation and Antimetabolite Treatment

Inhibition of one or both of the checkpoint kinases, Chk1 and Chk2, has been proposed as a strategy for improving the efficacy of cytotoxic chemotherapeutic agents in tumor cells. Previous studies have demonstrated that Chk1 inhibition potentiates the cytotoxicity of chemotherapeutic agents in a variety of systems. We designed a study to test whether the simultaneous depletion of Chk1 and Chk2 would sensitize cells to FdUrd- and gemcitabine-induced cytotoxicity to a greater extent than Chk1 depletion alone and to determine the contribution of premature mitosis to cytotoxicity. We found that RNAi-mediated Chk1 depletion enhanced FdUrd- and gemcitabine-mediated cytotoxicity (2- to 3-fold) in Panc-1 and SW620 cells. Furthermore enhanced cytotoxicity by Chk1 depletion was accompanied by inhibition of FdUrd- or gemcitabine-induced Cdc25A degradation and induction of premature mitotic entry in drug-treated cells. The simultaneous depletion of Chk1 and Chk2 inhibited Cdc25A degradation, induced premature mitotic entry and enhanced cytotoxicity in response to FdUrd and gemcitabine to a similar extent as Chk1 depletion alone. These results imply that Chk2 inhibition has no immediate consequence on survival or cell cycle progression in tumor cells treated with antimetabolites, regardless of their Chk1 status. In addition, these results suggest that premature mitotic entry is a qualitative marker for enhanced antimetabolite-induced cytotoxicity by Chk1 inhibition. The finding that Chk1 inhibition significantly enhanced antimetabolite-induced cytotoxicity supports further investigation and the development of more specific Chk1 inhibitors for use in the clinic.
Molecular Cloning and Functional Characterization of a Novel Mammalian Sphingosine Kinase Type 2 Isoform*

Sphingosine-1-phosphate (SPP) has diverse biological functions acting inside cells as a second messenger to regulate proliferation and survival, and extracellularly, as a ligand for G protein-coupled receptors of the endothelial differentiation gene-1 subfamily. Based on sequence homology to murine and human sphingosine kinase-1 (SPHK1), which we recently cloned (Kohama, T., Oliver, A., Edsall, L., Nagiec, M. M., Dickson, R., and Spiegel, S. (1998) J. Biol. Chem. 273, 23722–23728), we have now cloned a second type of mouse and human sphingosine kinase (mSPHK2 and hSPHK2). mSPHK2 and hSPHK2 encode proteins of 617 and 618 amino acids, respectively, both much larger than SPHK1, and though diverging considerably, both contain the conserved domains found in all SPHK1s. Northern blot analysis revealed that SPHK2 mRNA expression had a strikingly different tissue distribution from that of SPHK1 and appeared later in embryonic development. Expression of SPHK2 in HEK 293 cells resulted in elevated SPP levels. d-erythro-dihydrosphingosine was a better substrate than d-erythro-sphingosine for SPHK2. Surprisingly, d,l-threo-dihydrosphingosine was also phosphorylated by SPHK2. In contrast to the inhibitory effects on SPHK1, high salt concentrations markedly stimulated SPHK2. Triton X-100 inhibited SPHK2 and stimulated SPHK1, whereas phosphatidylserine stimulated both type 1 and type 2 SPHK. Thus, SPHK2 is another member of a growing class of sphingolipid kinases that may have novel functions.
Terminal attack trajectories of peregrine falcons are described by the proportional navigation guidance law of missiles

Significance Renowned as nature’s fastest predators, peregrines are famous for their high-speed stooping and swooping attack behaviors. We used miniature GPS receivers to track peregrines attacking dummy targets thrown by a falconer or towed by a drone and fitted a simulation describing the dynamics of the guidance system used in interception. We collected onboard video giving a falcon’s-eye view of the attacks and used this to validate our conclusions for attacks on live targets. Remarkably, we find that the terminal attack trajectories of peregrines are described by the same feedback law used by visually guided missiles, but with a tuning appropriate to their lower flight speed. Our findings have application to drones designed to remove other drones from protected airspace. The ability to intercept uncooperative targets is key to many diverse flight behaviors, from courtship to predation. Previous research has looked for simple geometric rules describing the attack trajectories of animals, but the underlying feedback laws have remained obscure. Here, we use GPS loggers and onboard video cameras to study peregrine falcons, Falco peregrinus, attacking stationary targets, maneuvering targets, and live prey. We show that the terminal attack trajectories of peregrines are not described by any simple geometric rule as previously claimed, and instead use system identification techniques to fit a phenomenological model of the dynamical system generating the observed trajectories. We find that these trajectories are best—and exceedingly well—modeled by the proportional navigation (PN) guidance law used by most guided missiles. Under this guidance law, turning is commanded at a rate proportional to the angular rate of the line-of-sight between the attacker and its target, with a constant of proportionality (i.e., feedback gain) called the navigation constant (N). Whereas most guided missiles use navigation constants falling on the interval 3 ≤ N ≤ 5, peregrine attack trajectories are best fitted by lower navigation constants (median N < 3). This lower feedback gain is appropriate at the lower flight speed of a biological system, given its presumably higher error and longer delay. This same guidance law could find use in small visually guided drones designed to remove other drones from protected airspace.
Heat-Shock Protein 60-Reactive CD4+CD28null T Cells in Patients With Acute Coronary Syndromes

Background—CD4+CD28null T cells are present in increased numbers in the peripheral blood of patients with acute coronary syndrome (ACS) compared with patients with chronic stable angina (CSA). The triggers of activation and expansion of these cells to date remain unclear. Methods and Results—Twenty-one patients with ACS and 12 CSA patients with angiographically confirmed coronary artery disease and 9 healthy volunteers were investigated. Peripheral blood leukocytes were stimulated with human cytomegalovirus (HCMV), Chlamydia pneumoniae, human heat-shock protein 60 (hHSP60), or oxidized LDL (ox-LDL). CD4+CD28null cells were separated by flow cytometry and assessed for antigen recognition using upregulation of interferon-&ggr; and perforin mRNA transcription as criteria for activation. CD4+CD28null cells from 12 of 21 patients with ACS reacted with hHSP60. No response was detected to HCMV, C pneumoniae, or ox-LDL. Incubation of the cells with anti-MHC class II and anti-CD4 antibodies but not anti-class I antibodies blocked antigen presentation, confirming recognition of the hHSP60 to be via the MHC class II pathway. Patients with CSA had low numbers of CD4+CD28null cells. These cells were nonreactive to any of the antigens used. Circulating CD4+CD28null cells were present in 5 of the 9 healthy controls. None reacted with hHSP60. Conclusions—We have shown that hHSP60 is an antigen recognized by CD4+CD28null T cells of ACS patients. Endothelial cells express hHSP60 either constitutively or under stress conditions. Circulating hHSP60-specific CD4+CD28null cells may, along other inflammatory mechanisms, contribute to vascular damage in these patients.
MIMO radar moving target detection in compound-Gaussian clutter

This paper considers moving target detection for multiple-input multiple-output (MIMO) radar in compound-Gaussian clutter. A new detector is devised according to a centralized processing scheme for MIMO radar system based on the generalized likelihood ratio test (GLRT) design criterion. Then, an adaptive version of the derived detector is investigated. The fixed point estimation (FPE) strategy is introduced to make the proposed detector fully adaptive. Finally, several numerical simulations of the derived detectors with typical parameters are obtained and discussed.
The epidemiology of maternal overweight in Dane County, Wisconsin.

BACKGROUND Research shows that maternal obesity leads not only to adverse pregnancy outcomes but also can act as a predictor of poor health of future generations. The Public Health Madison & Dane County Fetal and Infant Mortality Review Board observed poor health associated with prepregnancy BMI > or = 25, prompting further exploration of this issue in the Dane County, Wisconsin population. OBJECTIVE This is a descriptive epidemiologic study of the problem of maternal overweight defined as prepregnancy BMI > or = 25 in Dane County. METHODS Data were abstracted from the Secure Public Health Electronic Records Environment (SPHERE) on births in Dane County in 2011. Risk ratios were used to determine associations between race, education, parity, gravidity, and place of residence and maternal overweight. A t test was completed to determine differences in mean age of overweight and healthy weight mothers. RESULTS Approximately half (50.6%) of Dane County mothers in 2011 were overweight or obese prepregnancy. Results showed increased risk of overweight for black mothers and multiparous/multigravidous mothers. There was no difference in mean age of overweight and healthy weight mothers. Overweight rates varied considerably by ZIP code of residence. CONCLUSION Rates of maternal overweight vary significantly in Dane County by social and demographic factors. This information can be used to design and target interventions and monitor trends over time.
Functional T cells targeting NY-ESO-1 or Melan-A are predictive for survival of patients with distant melanoma metastasis.

PURPOSE To analyze the prognostic relevance of circulating T cells responding to NY-ESO-1, Melan-A, MAGE-3, and survivin in patients with melanoma with distant metastasis. PATIENTS AND METHODS We examined 84 patients with follow-up after analysis (cohort A), 18 long-term survivors with an extraordinarily favorable course of disease before analysis (> 24 months survival after first occurrence of distant metastases; cohort B), and 14 healthy controls. Circulating antigen-reactive T cells were characterized by intracellular cytokine staining after in vitro stimulation. RESULTS In cohort A patients, the presence of T cells responding to peptides from NY-ESO-1, Melan-A, or MAGE-3 and the M category according to the American Joint Committee on Cancer classification were significantly associated with survival. T cells responding to NY-ESO-1 and Melan-A (hazard ratios, 0.29 and 0.18, respectively) remained independent prognostic factors in Cox regression analysis and were superior to the M category in predicting outcome. Median survival of patients possessing T cells responding to NY-ESO-1, Melan-A, or both was 21 months, compared with 6 months for all others. NY-ESO-1-responsive T cells were detected in 70% of cohort A patients surviving > 18 months and in 50% of cohort B patients. Melan-A responses were found in 42% and 47% of patients in cohorts A and B, respectively. In contrast, the proportion was only 22% for NY-ESO-1 and 23% for Melan-A in those who died within 6 months. CONCLUSION The presence of circulating T cells responding to Melan-A or NY-ESO-1 had strong independent prognostic impact on survival in advanced melanoma. Our findings support the therapeutic relevance of Melan-A and NY-ESO-1 as targets for immunotherapy.
Genes Associated with Desiccation and Osmotic Stress in Listeria monocytogenes as Revealed by Insertional Mutagenesis

ABSTRACT Listeria monocytogenes is a foodborne pathogen whose survival in food processing environments may be associated with its tolerance to desiccation. To probe the molecular mechanisms used by this bacterium to adapt to desiccation stress, a transposon library of 11,700 L. monocytogenes mutants was screened, using a microplate assay, for strains displaying increased or decreased desiccation survival (43% relative humidity, 15°C) in tryptic soy broth (TSB). The desiccation phenotypes of selected mutants were subsequently assessed on food-grade stainless steel (SS) coupons in TSB plus 1% glucose (TSB-glu). Single transposon insertions in mutants exhibiting a change in desiccation survival of >0.5 log CFU/cm2 relative to that of the wild type were determined by sequencing arbitrary PCR products. Strain morphology, motility, and osmotic stress survival (in TSB-glu plus 20% NaCl) were also analyzed. The initial screen selected 129 desiccation-sensitive (DS) and 61 desiccation-tolerant (DT) mutants, out of which secondary screening on SS confirmed 15 DT and 15 DS mutants. Among the DT mutants, seven immotile and flagellum-less strains contained transposons in genes involved in flagellum biosynthesis (fliP, flhB, flgD, flgL) and motor control (motB, fliM, fliY), while others harbored transposons in genes involved in membrane lipid biosynthesis, energy production, potassium uptake, and virulence. The genes that were interrupted in the 15 DS mutants included those involved in energy production, membrane transport, protein metabolism, lipid biosynthesis, oxidative damage control, and putative virulence. Five DT and 14 DS mutants also demonstrated similar significantly (P < 0.05) different survival relative to that of the wild type when exposed to osmotic stress, demonstrating that some genes likely have similar roles in allowing the organism to survive the two water stresses.
Experimental Demonstration of Symmetric 100-Gb/s DML-Based TWDM-PON System

In this letter, first, the symmetric 100-Gb/s time and wavelength-division-multiplexed passive optical network system is experimentally demonstrated, based on the directly modulated lasers (DMLs) modulated by 25-Gb/s none-return-to-zero signals. A bypass delay interferometer (DI) is deployed in the optical line terminal to mitigate the signal distortion caused by the DML chirp and fiber chromatic dispersion. The experimental results show that with the DI, error free transmission is achieved over 25-km single mode fiber with a power budget of 42 dB, which could support 1:1024 splitting ratio. Moreover, the transmission performance of differential fiber length and burst-mode operation is also investigated.
Identification of a Novel GC-Rich 113-Nucleotide Region To Complete the Circular, Single-Stranded DNA Genome of TT Virus, the First Human Circovirus

ABSTRACT The sequence data (H. Okamoto et al., Hepatol. Res. 10:1–16, 1998) of a newly discovered single-stranded DNA virus, TT virus (TTV), showed that it did not have the terminal structure typical of a parvovirus. Elucidation of the complete genome structure was necessary to understand the nature of TTV. We obtained a 1.0-kb amplified product from serum samples of four TTV carriers by an inverted, nested long PCR targeted for nucleotides (nt) 3025 to 3739 and 1 to 216 of TTV. The sequence of a clone obtained from serum sample TA278 was compared with those registered in GenBank. The complete circular TTV genome contained a novel sequence of 113 nt (nt 3740 to 3852 [=0]) in between the known 3′- and 5′-end arms, forming a 117-nt GC-rich stretch (GC content, 90.6% at nt 3736 to 3852). We found a 36-nt stretch (nt 3816 to 3851) with an 80.6% similarity to chicken anemia virus (CAV) (nt 2237 to 2272 of M55918), a vertebrate circovirus. A putative SP-1 site was located at nt 3834 to 3839, followed by a TATA box at nt 85 to 90, the first initiation codon of a putative VP2 at nt 107 to 109, the termination codon of a putative VP1 at nt 2899 to 2901, and a poly(A) signal at nt 3073 to 3078. The arrangement was similar to that of CAV. Furthermore, several AP-2 and ATF/CREB binding sites and an NF-κB site were arranged around the GC-rich region in both TTV and CAV. The data suggested that TTV is circular and similar to CAV in its genomic organization, implying that TTV is the first human circovirus.
Dietary restriction attenuates age‐associated muscle atrophy by lowering oxidative stress in mice even in complete absence of CuZnSOD

Age‐related loss of muscle mass and function, sarcopenia, has a major impact on the quality of life in the elderly. Among the proposed causes of sarcopenia are mitochondrial dysfunction and accumulated oxidative damage during aging. Dietary restriction (DR), a robust dietary intervention that extends lifespan and modulates age‐related pathology in a variety of species, has been shown to protect from sarcopenia in rodents. Although the mechanism(s) by which DR modulates aging are still not defined, one potential mechanism is through modulation of oxidative stress and mitochondrial dysfunction. To directly test the protective effect of DR against oxidative stress–induced muscle atrophy in vivo, we subjected mice lacking a key antioxidant enzyme, CuZnSOD (Sod1) to DR (60% of ad libitum fed diet). We have previously shown that the Sod1−/− mice exhibit an acceleration of sarcopenia associated with high oxidative stress, mitochondrial dysfunction, and severe neuromuscular innervation defects. Despite the dramatic atrophy phenotype in the Sod1−/− mice, DR led to a reversal or attenuation of reduced muscle function, loss of innervation, and muscle atrophy in these mice. DR improves mitochondrial function as evidenced by enhanced Ca2+ regulation and reduction of mitochondrial reactive oxygen species (ROS). Furthermore, we show upregulation of SIRT3 and MnSOD in DR animals, consistent with reduced mitochondrial oxidative stress and reduced oxidative damage in muscle tissue measured as F2‐isoprostanes. Collectively, our results demonstrate that DR is a powerful mediator of mitochondrial function, mitochondrial ROS production, and oxidative damage, providing a solid protection against oxidative stress–induced neuromuscular defects and muscle atrophy in vivo even under conditions of high oxidative stress.
A robust algorithm based on nonstationary degree for ultrasonic data enhancement

Compared with other medical imaging modalities, ultrasound imaging has its own advantages. The three-dimensional (3-D) ultrasound stereo visualization technique has a broad promising future for its ability superior to traditional two-dimensional (2-D) ultrasound image, and it helps to understand the complex structures of tissues as well as to measure tissular volumes. However, it is often difficult to interpret the 3-D structure from acoustic data because of the speckle noise. To solve this problem, we propose a new enhancement algorithm which is based on calculating nonstationary degree of ultrasound data to improve the image quality. We observe data within a finite length window and then map them to an N-dimensional space where every point represents the observed data. According to the data features, we divide this space into two parts: the stationary subspace constituted by the stationary points, which represent a line in the space, and the nonstationary subspace is formed by the points out of the line. Then the nonstationary degree of a set of observed data is defined as the distance from the correspondent point to the stationary line. Thus, we can enhance the image since the nonstationary degree is larger on tissular border where features vary rapidly. Finally, the application of the proposed algorithm to real data of the liver of a rabbit is described. The results are shown by means of 3-D ultrasound stereo visualization, and the results demonstrate a significant improvement compared with the original image.