Miracle-dz/UniFAR-FTUs huggingface dataset:
Replication is required for the RecA localization response to DNA damage in Bacillus subtilis

In both prokaryotes and eukaryotes, proteins involved in DNA repair often organize into multicomponent complexes that can be visualized as foci in living cells. We used a RecA-GFP fusion to examine the subcellular cues that direct RecA-GFP to assemble as foci in response to DNA damage. We used two different methods to inhibit initiation of DNA replication and determined that DNA replication is required for the cell to establish RecA-GFP foci after exposure to DNA-damaging agents. Furthermore, use of endonuclease cleavage to generate a site-specific double-strand break demonstrated that the replication machinery (replisome) and DNA synthesis are required for assembly of RecA-GFP foci during repair of a double-strand break. We monitored the cellular levels of RecA and found that focus formation does not require further induction of protein levels, suggesting that foci result from a redistribution of existing protein to sites of damage encountered by the replisome. Taken together, our results support the model that existing RecA protein is recruited to ssDNA generated by the replisome at sites of DNA damage. These results provide insight into the mechanisms that the cell uses to recruit repair proteins to damaged DNA in living cells.
Design, development and analysis of a haptic-enabled modular flexure-based manipulator

The design, computational analysis, and experimental study of a modular flexure-based micro/nano manipulator is presented. The system combines a novel, compact, modular flexure-based mechanism with a haptic device, and a bilateral control architecture to enable rapid haptically-guided micromanipulation tasks. In principle the modular design allows manipulators to be constructed according to task-specific requirements. These mechanisms are designed for minimal mass, to maximize the transient response time of the system. Theoretical modelling and computational analysis of the one degree of freedom (DOF) flexure-based mechanism is performed. Modal analysis, mode shapes, maximum stresses generated within the mechanism and the maximum workspace of the mechanism are investigated. The modular mechanism has a measured range of translational motion of approximately 38. 9μm in one DOF, with the capability to be grouped together to create two or three DOF of motion. The first natural frequency of the prototype mechanism is measured at 417Hz, indicating a response time rapid enough to be undetectable to a human user. An experimental research facility is established as a proof of concept. The teleoperated control scheme is shown to track motions with accuracy of approximately 104nm, in a stable and transparent manner.
Antimicrobials, Stress and Mutagenesis

Cationic antimicrobial peptides are ancient and ubiquitous immune effectors that multicellular organisms use to kill and police microbes whereas antibiotics are mostly employed by microorganisms. As antimicrobial peptides (AMPs) mostly target the cell wall, a microbial ‘Achilles heel’, it has been proposed that bacterial resistance evolution is very unlikely and hence AMPs are ancient ‘weapons’ of multicellular organisms. Here we provide a new hypothesis to explain the widespread distribution of AMPs amongst multicellular organism. Studying five antimicrobial peptides from vertebrates and insects, we show, using a classic Luria-Delbrück fluctuation assay, that cationic antimicrobial peptides (AMPs) do not increase bacterial mutation rates. Moreover, using rtPCR and disc diffusion assays we find that AMPs do not elicit SOS or rpoS bacterial stress pathways. This is in contrast to the main classes of antibiotics that elevate mutagenesis via eliciting the SOS and rpoS pathways. The notion of the ‘Achilles heel’ has been challenged by experimental selection for AMP-resistance, but our findings offer a new perspective on the evolutionary success of AMPs. Employing AMPs seems advantageous for multicellular organisms, as it does not fuel the adaptation of bacteria to their immune defenses. This has important consequences for our understanding of host-microbe interactions, the evolution of innate immune defenses, and also sheds new light on antimicrobial resistance evolution and the use of AMPs as drugs.
EXTRAHEPATIC FIRST‐PASS METABOLISM OF NIFEDIPINE IN THE RAT

The peroral (po) bioavailability of nifedipine is reported to range from about 45 to 58% in the rat; this compares favourably to human beings. The metabolism of nifedipine is similar in rats and humans (oxidation of the dihydropyridine ring), with the liver believed to be solely responsible for the systemic clearance of the drug and the observed first‐pass effect after po dosing. The purpose of this study was to determine whether intestinal metabolism also contributes to the first‐pass elimination of nifedipine in the rat. The systemic availabilities of nifedipine doses given by po, intracolonic (ic), and intraperitoneal (ip) routes of administration were compared to that for an intravenous (iv) dose (in each case a dose of 6 mg kg−1 was given) using adult male Sprague–Dawley rats (249–311 g, n =6 or 7/group). The geometric mean of systemic nifedipine plasma clearance after iv dosing was 10·3 mL min−1 kg−1. The nifedipine blood‐to‐plasma ratio was found to be about 0·59. Therefore, the systemic blood clearance of nifedipine was about 17·5 mL min−1 kg−1; which, compared to the hepatic blood flow of rats (55 to 80 mL min−1 kg−1) showed that nifedipine is poorly extracted by the liver (0·22≤EH≤0·32). The mean absolute bioavailabilities of the po, ip, and ic doses were 61, 90, and 100%, respectively. Assuming complete absorption of the extravascular nifedipine doses these results indicate that, in addition to hepatic extraction, substantial first‐pass elimination of nifedipine occurs within the wall of the small intestine but not the colon of the rat. © 1997 John Wiley & Sons, Ltd.
On the Evolutionary Optimization of Many Conflicting Objectives

This study explores the utility of multiobjective evolutionary algorithms (using standard Pareto ranking and diversity-promoting selection mechanisms) for solving optimization tasks with many conflicting objectives. Optimizer behavior is assessed for a grid of mutation and recombination operator configurations. Performance maps are obtained for the dual aims of proximity to, and distribution across, the optimal tradeoff surface. Performance sweet-spots for both variation operators are observed to contract as the number of objectives is increased. Classical settings for recombination are shown to be suitable for small numbers of objectives but correspond to very poor performance for higher numbers of objectives, even when large population sizes are used. Explanations for this behavior are offered via the concepts of dominance resistance and active diversity promotion.
The Latency-Associated UL138 Gene Product of Human Cytomegalovirus Sensitizes Cells to Tumor Necrosis Factor Alpha (TNF-α) Signaling by Upregulating TNF-α Receptor 1 Cell Surface Expression

ABSTRACT Many viruses antagonize tumor necrosis factor alpha (TNF-α) signaling in order to counteract its antiviral properties. One way viruses achieve this goal is to reduce TNF-α receptor 1 (TNFR1) on the surface of infected cells. Such a mechanism is also employed by human cytomegalovirus (HCMV), as recently reported by others and us. On the other hand, TNF-α has also been shown to foster reactivation of HCMV from latency. By characterizing a new variant of HCMV AD169, we show here that TNFR1 downregulation by HCMV only becomes apparent upon infection of cells with HCMV strains lacking the so-called ULb′ region. This region contains genes involved in regulating viral immune escape, cell tropism, or latency and is typically lost from laboratory strains but present in low-passage strains and clinical isolates. We further show that although ULb′-positive viruses also contain the TNFR1-antagonizing function, this activity is masked by a dominant TNFR1 upregulation mediated by the ULb′ gene product UL138. Isolated expression of UL138 in the absence of viral infection upregulates TNFR1 surface expression and can rescue both TNFR1 reexpression and TNF-α responsiveness of cells infected with an HCMV mutant lacking the UL138-containing transcription unit. Given that the UL138 gene product is one of the few genes recognized to be expressed during HCMV latency and the known positive effects of TNF-α on viral reactivation, we suggest that via upregulating TNFR1 surface expression UL138 may sensitize latently infected cells to TNF-α-mediated reactivation of HCMV.
Using Tags To Bootstrap Stereotypes And Trust ( Extended Abstract )

Agents joining multi-agent systems (MAS) face two significant problems: they do not know who to trust and others do not know if they are trustworthy. Our contribution extends trust and stereotype approaches to use a comparison of agents’ observable features, called tags, as an initial indication of expected behaviour. The results show an improvement in agents’ rewards in the early stages of their lifetimes, prior to having sufficient information to use trust or stereotype methods.
Temperament, personality, and quality of life in pediatric cancer patients.

OBJECTIVE The developmental psychology literature shows that children with higher levels of effortful control (EC) and ego-resilience (ER) display greater social competence and better emotional adjustment. This study examined whether these dispositional attributes contribute to positive quality of life (QOL) in pediatric cancer patients. METHOD Participants were 103 pediatric cancer patients (and their parents) who were part of a larger parent study. At study entry, parents reported their own anxiety and depression and their children's EC and ER. At 3-month follow-up, parents reported children's QOL. RESULTS ER was positively correlated with children's QOL. EC showed a positive indirect effect on QOL through ER. Inclusion of potential correlates of pediatric QOL (e.g., parent neuroticism) did not change these relationships. CONCLUSIONS Temperament and personality play significant roles in pediatric cancer patients' QOL. Assessing dispositional attributes early in treatment may help identify children at risk for poor QOL during and after treatment.
The influence of different erythrocyte lysing procedures on flow cytometric determination of CD34+ cells in umbilical cord blood transplants

Since the correct determination of CD34+ cells is of great clinical importance for successful transplantation with haematopoietic progenitor cells (HPCs) from cord blood, we investigated the influence of different erythrocyte lysing techniques on the quantification of CD34+ cells in umbilical cord blood.
Angiogenesis , Metastasis , and the Cellular Microenvironment Oxidative Stress and Prostate Cancer Progression Are Elicited by Membrane-Type 1 Matrix Metalloproteinase

Oxidative stress caused by high levels of reactive oxygen species (ROS) has been correlated with prostate cancer aggressiveness. Expression of membrane-type 1 matrix metalloproteinase (MT1-MMP), which has been implicated in cancer invasion and metastasis, is associated with advanced prostate cancer. We show here that MT1-MMP plays a key role in eliciting oxidative stress in prostate cancer cells. Stable MT1-MMP expression in less invasive LNCaP prostate cancer cells with low endogenous MT1-MMP increased activity of ROS, whereas MT1-MMP knockdown in DU145 cells with high endogenous MT1-MMP decreased activity of ROS. Expression of MT1-MMP increased oxidative DNA damage in LNCaP and in DU145 cells, indicating that MT1-MMP–mediated induction of ROS caused oxidative stress. MT1-MMP expression promoted a more aggressive phenotype in LNCaP cells that was dependent on elaboration of ROS. Blocking ROS activity using the ROS scavenger N-acetylcysteine abrogated MT1-MMP–mediated increase in cell migration and invasion. MT1MMP–expressing LNCaP cells displayed an enhanced ability to grow in soft agar that required increased ROS. Using cells expressing MT1-MMP mutant cDNAs, we showed that ROS activation entails cell surface MT1MMP proteolytic activity. Induction of ROS in prostate cancer cells expressing MT1-MMP required adhesion to extracellular matrix proteins and was impeded by anti-b1 integrin antibodies. These results highlight a novel mechanism of malignant progression in prostate cancer cells that involves b1 integrin–mediated adhesion, in concert withMT1-MMP proteolytic activity, to elicit oxidative stress and induction of a more invasive phenotype. Mol Cancer Res; 9(10); 1305–18. 2011 AACR.
Comparative MR study of hepatic fat quantification using single‐voxel proton spectroscopy, two‐point dixon and three‐point IDEAL

Hepatic fat fraction (HFF) was measured in 28 lean/obese humans by single‐voxel proton spectroscopy (MRS), a two‐point Dixon (2PD), and a three‐point iterative decomposition of water and fat with echo asymmetry and least‐squares estimation (IDEAL) method (3PI). For the lean, obese, and total subject groups, the range of HFF measured by MRS was 0.3–3.5% (1.1 ± 1.4%), 0.3–41.5% (11.7 ± 12.1), and 0.3–41.5% (10.1 ± 11.6%), respectively. For the same groups, the HFF measured by 2PD was −6.3–2.2% (−2.0 ± 3.7%), −2.4–42.9% (12.9 ± 13.8%), and −6.3–42.9% (10.5 ± 13.7%), respectively, and for 3PI they were 7.9–12.8% (10.1 ± 2.0%), 11.1–49.3% (22.0 ± 12.2%), and 7.9–49.3% (20.0 ± 11.8%), respectively. The HFF measured by MRS was highly correlated with those measured by 2PD (r = 0.954, P < 0.001) and 3PI (r = 0.973, P < 0.001). With the MRS data as a reference, the percentages of correct differentiation between normal and fatty liver with the MRI methods ranged from 68–93% for 2PD and 64–89% for 3PI. Our study demonstrates that the apparent HFF measured by the MRI methods can significantly vary depending on the choice of water–fat separation methods and sequences. Such variability may limit the clinical application of the MRI methods, particularly when a diagnosis of early fatty liver needs to be performed. Therefore, protocol‐specific establishment of cutoffs for liver fat content may be necessary. Magn Reson Med 59:521–527, 2008. © 2008 Wiley‐Liss, Inc.
Metabolic control of beta-cell function.

Glucose-induced insulin secretion is pulsatile. Glucose metabolism generates oscillations in the ATP/ADP ratio which lead to opening and closing of ATP-sensitive K(+)-channels producing subsequent oscillations in membrane potential, cytoplasmic calcium and insulin release. Metabolic signals derived from glucose can also stimulate insulin release independent of their effects on ATP-sensitive K(+)-channels. The ATP/ADP ratio may mediate both ATP-sensitive K(+)-channel-dependent and -independent pathways of secretion. Glucose metabolism also results in an increase in long-chain acyl-CoA, which is proposed to act as an effector molecule in the beta -cell. Long-chain acyl-CoA has a variety of effects in the beta -cell that may effect insulin secretion including opening ATP-sensitive K(+)-channels, activating endoplasmic reticulum Ca(2+)-ATPases and stimulating classical protein kinase C activity. In addition to stimulating insulin release, nutrients also effect gene expression, protein synthesis and beta -cell proliferation. Gene expression is effected by nutrient induction of a variety of immediate early response genes. Glucose stimulates proinsulin biosynthesis both at the translational and transcriptional level. beta -cell proliferation, as a result of insulin-like growth factor and growth hormone mitogenic pathways, is also glucose dependent. Thus, many beta -cell functions in addition to secretion are controlled by nutrient metabolism.
Function‐Focused Care and Changes in Physical Function in Chinese American and Non‐Chinese American Hospitalized Older Adults

&NA; Function‐focused care (FFC) is a rehabilitative philosophy of care with which nurses help patients engage in activities of daily living and physical activity with the goal of preventing avoidable functional decline. This prospective, observational study described the degree of FFC provided by nursing staff to Chinese American (n= 32) and non‐Chinese American (n = 43) older adults in medical‐surgical units of an urban hospital. In both groups, only a few ADLs were a focus of FFC. Loss of physical function occurred, and physical function did not return to baseline by discharge in both groups; however, FFC was associated with less decline. Results suggest that hospitalized elders, both Chinese American and non‐Chinese American, can benefit from nurse‐led FFC. FFC may help minimize functional decline and decrease the use of postacute care rehabilitation. The gerontological rehabilitation nurse can play an essential role, guiding a function‐focused approach throughout the hospital stay, including with the transitional care plan.
A Novel, Low-Voltage, Current Reused, Quadrature VCO and Divide-by-4 Frequency Divider Circuit

A low-voltage, current-reused, quadrature voltage controlled oscillator (QVCO) and divide-by-4 frequency divider (FD4) architecture is presented for the first time. The proposed architecture features compact and low voltage operation by the proper stacking of a ring-type injection locked FD4 and a back-gate coupled QVCO. This design lowers the power consumption and eliminates the need of high frequency divider as well as buffering stage. The circuit has been implemented in 0.18-μm triple-well CMOS process. Experimental results show a phase noise level of -114.1 dBc/Hz at 1 MHz offset from carrier (2.2 GHz). This chip occupies a core area of 0.9×0.35 mm2 and consumes 2.7 mA from a 1.3 V power supply.
Potential Limitations of E-mail and Text Messaging in Improving Adherence in Glaucoma and Ocular Hypertension

Purpose:To determine how receptive patients are to the use of e-mail and text message reminders for appointments and medications. Methods:We conducted a consecutive cross-sectional survey of eligible patients with glaucoma or ocular hypertension at a private glaucoma subspecialty practice with 3 locations from February 2011 to January 2012. Main outcome measures were answers to survey questions regarding how receptive patients are to e-mail and text messaging reminders for appointments and medications. Results:Of 989 patients, 404 (40.8%) patients reported that e-mail reminders would help remember appointments and 185 (18.7%) reported that they would help for medications. Among those with access to text messaging, 280 (68.9%) reported text messaging would help them remember appointments and 193 (47.5%) reported it would help with medications. Patients who reported e-mail would help them remember medications were more likely to live in an urban location [P=0.05, odds ratio (OR)=1.84], check the internet at least daily (P⩽0.001, OR=1.04), check e-mail when not at home or the office (P=0.02, OR=1.62), and know how to open attachments (P=0.03, OR=1.87). Patients who reported that text messaging would help them remember their medications were more likely to be 40 or less (P⩽0.001, OR=8.54) and African American (P<0.001, OR=2.59). Conclusions:E-mail and text messaging reminders currently may have a limited utility in improving adherence in the general glaucoma population but may be useful in younger patients with glaucoma.
Coordinated Regulation of Transcription Factor Bcl11b Activity in Thymocytes by the Mitogen-activated Protein Kinase (MAPK) Pathways and Protein Sumoylation*

Background: The transcription factor Bcl11b plays essential roles during T-cell development. Results: Bcl11b activity in thymocytes is regulated by MAPK-mediated phosphorylation and subsequent sumoylation and ubiquitination. Conclusion: A regulatory pathway links thymocyte stimulation, MAPK activation, and Bcl11b-dependent regulation of gene expression during late T-cell development. Significance: This work has implications for the role of Bcl11b in T-cell development and leukemogenesis. The transcriptional regulatory protein Bcl11b is essential for T-cell development. We have discovered a dynamic, MAPK-regulated pathway involving sequential, linked, and reversible post-translational modifications of Bcl11b in thymocytes. MAPK-mediated phosphorylation of Bcl11b was coupled to its rapid desumoylation, which was followed by a subsequent cycle of dephosphorylation and resumoylation. Additionally and notably, we report the first instance of direct identification by mass spectrometry of a site of small ubiquitin-like modifier (SUMO) adduction, Lys-679 of Bcl11b, in a protein isolated from a native, mammalian cell. Sumoylation of Bcl11b resulted in recruitment of the transcriptional co-activator p300 to a Bcl11b-repressed promoter with subsequent induction of transcription. Prolonged treatment of native thymocytes with phorbol 12,13-dibutyrate together with the calcium ionophore A23187 also promoted ubiquitination and proteasomal degradation of Bcl11b, providing a mechanism for signal termination. A Bcl11b phospho-deSUMO switch was identified, the basis of which was phosphorylation-dependent recruitment of the SUMO hydrolase SENP1 to phospho-Bcl11b, coupled to hydrolysis of SUMO-Bcl11b. These results define a regulatory pathway in thymocytes that includes the MAPK pathways and upstream signaling components, Bcl11b and the associated nucleosome remodeling and deacetylation (NuRD) complex, SENP proteins, the Bcl11b protein phosphatase 6, the sumoylation machinery, the histone acetyltransferase p300, and downstream transcriptional machinery. This pathway appears to facilitate derepression of repressed Bcl11b target genes as immature thymocytes initiate differentiation programs, biochemically linking MAPK signaling with the latter stages of T-cell development.
Microbial network, phylogenetic diversity and community membership in the active layer across a permafrost thaw gradient

Biogenic production and release of methane (CH4) from thawing permafrost has the potential to be a strong source of radiative forcing. We investigated changes in the active layer microbial community of three sites representative of distinct permafrost thaw stages at a palsa mire in northern Sweden. The palsa sites with intact permafrost, and low radiative forcing signature had a phylogenetically clustered community dominated by Acidobacteria and Proteobacteria. The bog with thawing permafrost and low radiative forcing signature was dominated by hydrogenotrophic methanogens and Acidobacteria, had lower alpha diversity, and midrange phylogenetic clustering, characteristic of ecosystem disturbance affecting habitat filtering, shifting from palsa-like to fen-like at the waterline. The fen had no underlying permafrost, and the highest alpha, beta and phylogenetic diversity, was dominated by Proteobacteria and Euryarchaeota, and was significantly enriched in methanogens. The mire microbial network was modular with module cores consisting of clusters of Acidobacteria, Euryarchaeota, or Xanthomonodales. Loss of underlying permafrost with associated hydrological shifts correlated to changes in microbial composition, alpha, beta, and phylogenetic diversity associated with a higher radiative forcing signature. These results support the complex role of microbial interactions in mediating carbon budget changes and climate feedback in response to climate forcing.