Miracle-dz/UniFAR-FTUs huggingface dataset:
Adenylyl cyclase-dependent axonal targeting in the olfactory system

The vertebrate olfactory bulb is a remarkably organized neuronal structure, in which hundreds of functionally different sensory inputs are organized into a highly stereotyped topographical map. How this wiring is achieved is not yet understood. Here, we show that the olfactory bulb topographical map is modified in adenylyl cyclase 3 (adenylate cyclase 3)-deficient mice. In these mutants, axonal projection targets corresponding to specific odorant receptors are disorganized, are no longer exclusively innervated by functionally identical axonal projections and shift dramatically along the anteroposterior axis of the olfactory bulb. Moreover, the cyclase depletion leads to the prevention of neuropilin 1 (Nrp1) expression in olfactory sensory neuron axonal projections. Taken together, our data point to a major role played by a crucial element of the odorant-induced transduction cascade, adenylyl cyclase 3, in the targeting of olfactory sensory neuron axons towards the brain. This mechanism probably involves the regulation of receptor genes known to be crucial in axonal guidance processes.
Dynamics of [Ca2+] in the Endoplasmic Reticulum and Cytoplasm of Intact HeLa Cells

We have measured the [Ca2+] in the endoplasmic reticulum ([Ca2+]er) of intact HeLa cells at both 22 °C and 37 °C using endoplamsic reticulum-targeted, low Ca2+ affinity aequorin reconstituted with coelenterazine n. Aequorin consumption was much slower at 22 °C, and this allowed performing a much longer study of the dynamics of [Ca2+]er. The steady-state [Ca2+]er (500–600 μm) was not modified by the temperature, although both the rates of pumping and leak were decreased at 22 °C. The behavior of both [Ca2+]er and cytoplasmic [Ca2+] ([Ca2+]c) after the addition of increasing concentrations of agonists and/or Ca2+-ATPase inhibitors, or following incubation in Ca2+-free medium were compared. We show that agonists induce a fast but relatively small decrease in [Ca2+]er, which is enough to produce a sharp increase in [Ca2+]c. Termination of Ca2+ release is controlled by feedback inhibition of the inositol 1,4,5-trisphosphate receptors by [Ca2+]c, a mechanism that appears to be designed to release the minimum amount of Ca2+ necessary to produced the required [Ca2+]c signal. We also show that Ca2+ release is inhibited progressively when [Ca2+]er decreases below a threshold of about 150 μm, even in the absence of Ca2+ pumping or [Ca2+]c increase. This effect is consistent with a regulation of the inositol 1,4,5-trisphosphate-gated channels by [Ca2+]er.
Temporal repolarization lability in hypertrophic cardiomyopathy caused by beta-myosin heavy-chain gene mutations.

BACKGROUND Certain genetic mutations associated with hypertrophic cardiomyopathy (HCM) carry an increased risk of sudden death. QT variability identifies patients at a high risk for sudden death from ventricular arrhythmias. We tested whether patients with HCM caused by beta-myosin heavy-chain (beta-MHC) gene mutations exhibit labile ventricular repolarization using beat-to-beat QT variability analysis. METHODS AND RESULTS We measured the QT variability index and heart rate-QT interval coherence from Holter monitor recordings in 36 patients with HCM caused by known beta-MHC gene mutations and in 26 age- and sex-matched controls. There were 7 distinct beta-MHC gene mutations in these 36 patients; 9 patients had HCM caused by the malignant Arg(403)Gln mutation and 8 patients had HCM caused by the more benign Leu(908)Val mutation. The QT variability index was higher in HCM patients than in controls (-1.24+/-0.17 versus -1. 58+/-0.38, P<0.01), and the greatest abnormality was detected in patients with the Arg(403)Gln mutation (-0.99+/-0.49 versus -1. 46+/-0.43 in controls, P<0.05). In keeping with this finding, coherence was lower for the entire HCM group than for controls (P<0. 001). Coherence was also significantly lower in patients with the Arg(403)Gln mutation compared with controls (P<0.05). CONCLUSIONS These findings suggest that (1) patients with HCM caused by beta-MHC gene mutations exhibit labile repolarization quantified by QT variability analysis and, hence, may be more at risk for sudden death from ventricular arrhythmias, and (2) indices of QT variability may be particularly abnormal in patients with beta-MHC gene mutations that are associated with a poor prognosis.
Linear time-invariant feedback operator for mobile robot trajectory tracking

In this paper we propose a linear time-invariant (LTI) state feedback operator for nonholonomic mobile robots to track a pre-defined trajectory on a 2D planar region. Designing an on-line smooth state feedback control law is still among the major challenges for solving the trajectory tracking problem of nonholonomic systems including differential drive mobile robots. To address this problem, numerous nonlinear feedback control laws have been proposed to date. Most of these feedback control laws yield online solutions to the trajectory tracking problem with satisfactory tracking errors asymptotically. In most cases, they suffer from an overwhelming degree of computational complexity even to track a 2D trajectory using a simple unicycle-like nonholonomic system. The proposed control law offers an advantage of being smooth and LTI state-feedback in addition to its capability to address problems of partially observed systems. The shortcoming of the proposed control law is that the LTI feedback operator is computed off-line before the robot applies its control signal into the left and right wheels through their actuators. The theoretical results are supported by computer simulations followed by experiments with an e-puck mobile robot.
Uniform tissue distribution of tRNALys mutation in mitochondrial DNA in MERRF patients

We documented the presence of a point mutation in the tRNALys gene of mitochondrial DNA (mtDNA) in various postmortem tissues from two patients with myoclonus epilepsy associated with ragged-red fibers (MERRF). The percentages of the mutant mtDNA were similar (93 to 99%) in both clinically affected and unaffected tissues, suggesting that preferential clinical involvement of certain tissues in MERRF is based not only on the variation of distribution of the mutant mtDNA, but also on other factors such as differences in the threshold in various CNS regions and organs.
Crystal Structure of the Human BRD2 Bromodomain

The BET (bromodomains and extra terminal domain) family proteins recognize acetylated chromatin through their bromodomain and act as transcriptional activators. One of the BET proteins, BRD2, associates with the transcription factor E2F, the mediator components CDK8 and TRAP220, and RNA polymerase II, as well as with acetylated chromatin during mitosis. BRD2 contains two bromodomains (BD1 and BD2), which are considered to be responsible for binding to acetylated chromatin. The BRD2 protein specifically recognizes the histone H4 tail acetylated at Lys12. Here, we report the crystal structure of the N-terminal bromodomain (BD1, residues 74-194) of human BRD2. Strikingly, the BRD2 BD1 protein forms an intact dimer in the crystal. This is the first observation of a homodimer among the known bromodomain structures, through the buried hydrophobic core region at the interface. Biochemical studies also demonstrated BRD2 BD1 dimer formation in solution. The two acetyllysine-binding pockets and a negatively charged secondary binding pocket, produced at the dimer interface in BRD2 BD1, may be the unique features that allow BRD2 BD1 to selectively bind to the acetylated H4 tail.
The Type VI Secretion System Spike Protein VgrG5 Mediates Membrane Fusion during Intercellular Spread by Pseudomallei Group Burkholderia Species

ABSTRACT Pseudomallei group Burkholderia species are facultative intracellular parasites that spread efficiently from cell to cell by a mechanism involving the fusion of adjacent cell membranes. Intercellular fusion requires the function of the cluster 5 type VI secretion system (T6SS-5) and its associated valine-glycine repeat protein, VgrG5. Here we show that VgrG5 alleles are conserved and functionally interchangeable between Burkholderia pseudomallei and its relatives B. mallei, B. oklahomensis, and B. thailandensis. We also demonstrate that the integrity of the VgrG5 C-terminal domain is required for fusogenic activity, and we identify sequence motifs, including two hydrophobic segments, that are important for fusion. Mutagenesis and secretion experiments using B. pseudomallei strains engineered to express T6SS-5 in vitro show that the VgrG5 C-terminal domain is dispensable for T6SS-mediated secretion of Hcp5, demonstrating that the ability of VgrG5 to mediate membrane fusion can be uncoupled from its essential role in type VI secretion. We propose a model in which a unique fusogenic activity at the C terminus of VgrG5 facilitates intercellular spread by B. pseudomallei and related species following injection across the plasma membranes of infected cells.
The role of sunlight and DNA repair in melanoma and nonmelanoma skin cancer. The xeroderma pigmentosum paradigm.

BACKGROUND AND DESIGN The frequency of melanoma and nonmelanoma skin cancer is increasing rapidly in the United States. However, the linkage of these cancers to sun exposure has been questioned because of differences in anatomic site distribution. To obtain insights into the development of these skin cancers, we examined reports of 132 patients with xeroderma pigmentosum (XP), an inherited cancer-prone, DNA repair-deficient disorder with marked clinical and laboratory UV hypersensitivity. RESULTS Malignant skin neoplasms were present in 70% of the patients with XP at a median age of 8 years, which is 50 years earlier than in the US white population. Fifty-seven percent of the patients had basal cell or squamous cell carcinoma, and 22% had melanoma. The frequency of melanomas, like the frequency of nonmelanoma skin cancers (basal cell and squamous cell carcinomas), anterior eye cancers, and tongue cancers, but unlike that of internal neoplasms, was increased 1000-fold or more in patients with XP who were younger than 20 years. As in the general population, the anatomic distribution of melanomas was different from that of nonmelanomas in the patients with XP. CONCLUSIONS These data suggest that (1) DNA repair plays a major role in the prevention of cutaneous cancers in the general population and (2) sunlight exposure is responsible for the induction of melanoma as well as nonmelanoma skin cancer in patients with XP, although acting by different mechanisms for the two types of skin cancer.
A Web-Based Mindfulness Stress Management Program in a Corporate Call Center

Objective: The objective of this study is to determine the effectiveness of an 8-week web-based, mindfulness stress management program (WSM) in a corporate call center and added benefit of group support. Methods: One hundred sixty-one participants were randomized to WSM, WSM with group support, WSM with group and expert clinical support, or wait-list control. Perceived stress, burnout, emotional and psychological well-being, mindfulness, and productivity were measured at baseline, weeks 8 and 16, and 1 year. Results: Online usage was low with participants favoring CD use and group practice. All active groups demonstrated significant reductions in perceived stress and increases in emotional and psychological well-being compared with control. Group support improved participation, engagement, and outcomes. Conclusion: A self-directed mindfulness program with group practice and support can provide an affordable, effective, and scalable workplace stress management solution. Engagement may also benefit from combining web-based and traditional CD delivery.
[Left ventricular functional parameters using ECG-gated multidetector spiral CT in comparison with invasive ventriculography].

PURPOSE To evaluate the accuracy of left ventricular function using a multidetector CT (MDCT) with retrospective ECG-gating and to compare the results with conventional ventriculography. MATERIALS AND METHODS In 26 patients, retrospectively ECG-gated MDCT of the heart (Volume Zoom, Siemens, Germany) as well as conventional coronary angiography including ventriculography was performed to exclude or follow coronary artery disease. CT examination (120 KV, 400 mAs) was carried out with 4 x 1 mm collimation (500 ms gantry rotation time). For CT angiography, 150 ml of contrast media was injected intravenously at a flow rate of 4 ml/s. All data sets of the functional cardiac parameters were reconstructed in end-systolic and end-diastolic phase. End-systolic volume (ESV), end-diastolic volume (EDV) and ejection fraction (EF) were determined from multiplanar reformations orthogonally through the cardiac short axis and analyzed using special evaluation software (ARGUS, Siemens). The results were compared with ESV, EDV and EF obtained from invasive ventriculography. RESULTS In all cases, a sufficient quality of the MDCT images was achieved. EDV (150.1 +/- 16.2 ml MDCT vs. 138.7 +/- 16.9 ml ventriculography; mean difference 11.4 +/- 12.7 ml; r = 0.51) had an acceptable correlation to conventional ventriculography, and ESV (58.1 +/- 14.6 ml vs. 50.2 +/- 13.4 ml; mean difference 7.9 +/- 8.8 ml; r = 0.81) and EF (60.9 +/- 13.6 % vs. 64.9 +/- 12.7 %; mean difference 4.0 +/- 6.2 %; r = 0.79) showed a good correlation. In comparison with invasive ventriculography, MDCT tended to overestimate significantly EDV (p = 0.008) and ESV (p = 0.003) and to underestimate EF (p = 0.001). CONCLUSION MDCT of the heart with retrospective ECG-gating enables efficient estimation of left ventricular function, providing important additional information of non-invasive cardiac imaging using MDCT. However, EDV and EVS were significantly overestimated and EF was underestimated in MDCT compared to ventriculography.
A Single LED Photoplethysmography-Based Noninvasive Glucose Monitoring Prototype System

Continuous glucose monitoring is essential for patients to avoid complications of both hypoglycemia and hyperglycemia. This paper presents a novel non-invasive continuous blood glucose monitoring system based on a single wavelength near-infrared (NIR) spectroscopy. The analog frontend of the system is designed with a single NIR LED to record the Photoplethysmographic (PPG) signal from the fingertip with motion artifacts removal and a bias current rejection up to 20uA. The proposed digital backend extracts 10 discriminating features from the PPG signal to predict the blood glucose level using (Exponential Gaussian Process) machine learning regression. To realize the feature extraction on FPGA, a novel two-dimensional structure of 256-point Fast Fourier Transform (FFT) is implemented which achieves a 47% reduction in complex multiplications compared to the conventional Radix-2 algorithm. The performance of the proposed system is validated using 200 patients PPG recordings and glucose levels measured via a commercial glucometer. It successfully predicts the glucose level with a mean absolute relative difference (mARD) of 8.97%.
Localization of collagen types in regional segments of the fetal bovine aorta.

Types I, III, and IV collagens were localized immunocytochemically in muscular and small arteries of fetal bovine tissues and in different regional segments of the aorta. The distribution of these collagens was found to be unique, not only with respect to collagen type and fiber orientation but also to the specific region of the vessel being examined. Collagen types I, III, and IV often codistribute in the intimal and medial regions of blood vessels, whereas types I and III show selective association in fibers with varied morphology in the adventitial layer. Specific segments of the aorta (proximal thoracic versus distal abdominal) were examined to determine the relative distribution and morphologic presentation of the collagens. In the ascending region of the aorta proximal to the heart, the types I, III, and IV collagen colocalized in the intimal and medial layers. Types I and III collagen predominated in the relatively small adventitial layer, whereas type IV collagen was found only in association with the media of small blood vessels and capillaries in this layer. In the descending thoracic region of the aorta distal to the arch, types I and IV collagens were distributed throughout the intimal and medial layers, whereas type III collagen localization was variable depending on the antibody used for detection. The adventitia stained predominantly for type III collagen that was distinctly organized in folded arrays of fibers. These same fibers stained less intensely with antibody to type I collagen. The abdominal aorta near the common iliacs stained in a fashion similar to that of muscular arteries of the organs and tissues examined, i.e., types I and IV collagen were found in the intimal and medial layers, whereas type III collagen localized heavily to the adventitial layer, with differential staining in the intima and media depending on the antibody used. Additional staining of the adventitial region of the abdominal aorta with type I and type IV collagen antibodies was the same as in the proximal and descending regions. Since the abdominal aorta sustains decreased levels of pulsatile distension compared with the ascending thoracic aorta, type III collagen distribution and its association with other matrix components may be important in regulating the range of distensibility of the vessel wall.
Molecular analysis of neurogenic placode development in a basal ray‐finned fish

Neurogenic placodes are transient, thickened patches of embryonic vertebrate head ectoderm that give rise to the paired peripheral sense organs and most neurons in cranial sensory ganglia. We present the first analysis of gene expression during neurogenic placode development in a basal actinopterygian (ray‐finned fish), the North American paddlefish (Polyodon spathula). Pax3 expression in the profundal placode confirms its homology with the ophthalmic trigeminal placode of amniotes. We report the conservation of expression of Pax2 and Pax8 in the otic and/or epibranchial placodes, Phox2b in epibranchial placode‐derived neurons, Sox3 during epibranchial and lateral line placode development, and NeuroD in developing cranial sensory ganglia. We identify Sox3 as a novel marker for developing fields of electrosensory ampullary organs and for ampullary organs themselves. Sox3 is also the first molecular marker for actinopterygian ampullary organs. This is consistent with, though does not prove, a lateral line placode origin for actinopterygian ampullary organs. genesis 49:278–294, 2011. © 2011 Wiley‐Liss, Inc.
Anxiety and Adverse Health Outcomes Among Cardiac Patients: A Biobehavioral Model

Background:Anxiety is a common experience among patients with acute coronary syndrome (ACS) that can have a negative impact on health outcomes. Nonetheless, the negative role of anxiety remains underappreciated, as reflected by clinicians’ underrecognition and undertreatment of anxious hospitalized and nonhospitalized patients with ACS. Underappreciation of the role of anxiety is possibly related to inadequate understanding of the mechanisms whereby anxiety may adversely affect health outcomes. Purpose:The aim of this study was to synthesize the evidence about potential mechanisms by which anxiety and adverse health outcomes are related. Conclusions:A biobehavioral model links anxiety to the development of thrombogenic and arrhythmic events in patients with ACS. Biologically, anxiety may interfere with the immune system, lipid profile, automatic nervous system balance, and the coagulation cascade, whereas behaviorally, anxiety may adversely affect adoption of healthy habits and cardiac risk–reducing behaviors. The biological and behavioral pathways complement each other in the production of poor outcomes. Clinical Implications:Anxiety requires more attention from clinical cardiology. The adverse impact of anxiety on health outcomes could be avoided by efficient assessment and treatment of anxiety.
Considerations in the evaluation of haemophilia patients for short‐term prophylactic therapy: a paediatric and adult case study

Summary. The long‐term prophylactic administration of clotting factor concentrate in patients with haemophilia reduces bleeding events, slows joint deterioration, and improves quality of life. Prophylaxis can also be effective when used short‐term to prevent or reduce bleeding associated with trauma, surgery, and athletic activities. While clinical trials are needed to establish the optimal length of prophylaxis following injury, several weeks and possibly months of treatment may be needed. Discontinuing therapy prematurely can result in rebleeding in the injured area.
Analysis and elimination of protein perturbation in infrared difference spectra of acyl-chymotrypsin ester carbonyl groups by using 13C isotopic substitution.

I.r. spectroscopy has been applied to the study of hydrogen-bonding of the unique ester carbonyl group of acylchymotrypsins in the oxyanion hole of the enzyme. This catalytic device provides electrophilic stabilization of negative charge in the transition states and tetrahedral intermediates along the reaction pathway. The use of 13C isotope substitution of the ester carbonyl group reinforces the previous observation [White & Wharton (1990) Biochem. J. 270, 627-637] that the ester carbonyl group is significantly polarized in the ground state by hydrogen bonding in the oxyanion hole. I.r. difference spectra of [carbonyl-12C]-minus [carbonyl-13C]-cinnamoyl-chymotrypsin as well as each of these acylenzymes minus free enzyme are reported. These spectra show that the contribution of protein perturbation (i.e. spectral features that arise from the enzyme which is distorted on acylation) in [carbonyl-12C]cinnamoyl-chymotrypsin minus free enzyme spectra is significant. The contribution of the perturbation components of the spectra is pH-dependent and can represent up to 50% of the total absorbance in the spectral region from 1690 to 1740 cm-1. Use of the isotopic difference method has allowed problems associated with protein perturbation to be eliminated. Similar difference spectra are presented for dihydrocinnamoyl-chymotrypsin. In this case the effect of perturbation is very marked and leads to the cancellation of the band assigned to the non-bonded conformation of the acyl group which has previously only been observed at higher pH. The isotopic difference method again proves reliable and shows that the frequency difference previously used to calculate the ground-state electronic strain induced by the oxyanion-hole catalytic device is not affected by the perturbation, although the amplitudes of the spectral features are different. A study of the deacylation of cinnamoyl-chymotrypsin in water and deuterium oxide using both u.v. and i.r. spectroscopies has confirmed that the use of deuterium oxide as solvent has no serious effect on the deacylation behaviour of the enzyme. I.r. bands assigned to nonproductive and productive conformers decline identically during deacylation, which shows that the conformers are in dynamic exchange on the reaction time-scale.