Miracle-dz/UniFAR-FTUs huggingface dataset:
Computed Tomography Screening for Lung Cancer

TO THE EDITOR: Henschke and colleagues (1) suggest that a threshold of 7.0 or 8.0 mm to define positive results in the baseline round of computed tomography (CT) screening for lung cancer could decrease further work-up and a delay in diagnosis in some patients. Although nodule size is important, it is not the sole predictor of risk for cancer (2). In our experience, 70% of the pleural surface is accessible by transthoracic ultrasonography when the lung comes up to the pleura or is reachable via a sound window. Contrast-enhanced ultrasonography provides further information. In patients with lung cancer, we observed intralesional enhancement consistent with tumor neovascularization on contrast-enhanced ultrasonography (3). Some cases had unenhanced areas consistent with zones of necrosis, and these areas were avoided during fineneedle aspiration (FNA) biopsy (3–5). Thoracic ultrasonographic elastography (MyLab-ElaXto Biomedica, Genoa, Italy) is a novel approach used to estimate the stiffness or elasticity of tissues, allowing a reliable preliminary differentiation between cancerous and noncancerous consolidations. It is followed by a focused and guided FNA biopsy to diagnose and stage lung cancer. Thoracic ultrasonographic elastography and FNA biopsy were performed after chest radiography and CT in 91 patients (67 men and 24 women, aged 62.84 7.51 years) with lung consolidation. Tissue stiffness was scored from 1 (greatest elasticity) to 5 (no elasticity) by using a convex multifrequency 2to 8-mHz probe. Elasticity of nodules was significantly lower (P 0.001) in all patients with lung cancer (n 67; stiffness score, 4.19 0.55) than in those with pneumonitis (n 24; stiffness score, 2.35 0.48). The size of the consolidation is larger in pneumonitis versus lung cancer (4.03 0.82 cm vs. 3.06 0.88 cm; P 0.001), which is a further argument against using nodule size as a discriminant between cancerous and noncancerous consolidations. Although neither transthoracic ultrasonography (nor CT) is widely valuated for this use, either approach could contribute to a more efficient work-up, at least in some patients. Both ultrasonography procedures provide diagnostically useful information on peripheral lung lesions and increase the diagnostic yield of transthoracic FNA biopsy by reducing the risk for inadequate tissue sampling.
Crime, Inequality, and Unemployment

There has been much discussion of the relationships between crime, inequality and unemployment. We construct a model where all three are endogenous. Introducing crime into otherwise standard models affects the labor market in several interesting ways. For example, we show how the crime rate affects the unemployment rate and vice-versa; how the possibility of criminal activity can lead to wage inequality among homogeneous workers; and how the possibility of crime can generate multiple equilibria in natural but previously unexplored ways. In particular, two fundamentally identical neighborhoods may easily end up with different levels of unemployment, inequality, and crime. The model can be used to study the equilibrium effects of anti-crime policies, such as changes in apprehension rates or jail sentences, as well as more traditional labor market policies such as unemployment insurance.
The Eukaryotic Elongation Factor 1 Alpha (eEF1α) from the Parasite Leishmania infantum Is Modified with the Immunomodulatory Substituent Phosphorylcholine (PC)

Proteins and glycolipids have been found to be decorated with phosphorylcholine (PC) both in protozoa and nematodes that parasitize humans and animals. PC epitopes can provoke various effects on immune cells leading to an immunomodulation of the host’s immune system that allows long-term persistence of the parasites. So far, only a limited number of PC-modified proteins, mainly from nematodes, have been identified. Infections caused by Leishmania spp. (e.g., L. infantum in southern Europe) affect about 12 million people worldwide and are characterized by a wide spectrum of clinical forms in humans, ranging from cutaneous to fatal visceral leishmaniasis. To establish and maintain the infection, these protozoa are dependent on the secretion of effector molecules into the host for modulating their immune system. In this project, we analyzed the PC modification of L. infantum promastigotes by 2D-gel based proteomics. Western blot analysis with the PC-specific antibody TEPC-15 revealed one PC-substituted protein in this organism, identified as eEF1α. We could demonstrate that the binding of eEF1α to one of its downstream effectors is dependent on its PC-modification. In this study we provide evidence that in this parasite the modification of eEF1α with PC may be essential for its function as an important virulence factor.
Homologous Transcription Factors DUX4 and DUX4c Associate with Cytoplasmic Proteins during Muscle Differentiation

Hundreds of double homeobox (DUX) genes map within 3.3-kb repeated elements dispersed in the human genome and encode DNA-binding proteins. Among these, we identified DUX4, a potent transcription factor that causes facioscapulohumeral muscular dystrophy (FSHD). In the present study, we performed yeast two-hybrid screens and protein co-purifications with HaloTag-DUX fusions or GST-DUX4 pull-down to identify protein partners of DUX4, DUX4c (which is identical to DUX4 except for the end of the carboxyl terminal domain) and DUX1 (which is limited to the double homeodomain). Unexpectedly, we identified and validated (by co-immunoprecipitation, GST pull-down, co-immunofluorescence and in situ Proximal Ligation Assay) the interaction of DUX4, DUX4c and DUX1 with type III intermediate filament protein desmin in the cytoplasm and at the nuclear periphery. Desmin filaments link adjacent sarcomere at the Z-discs, connect them to sarcolemma proteins and interact with mitochondria. These intermediate filament also contact the nuclear lamina and contribute to positioning of the nuclei. Another Z-disc protein, LMCD1 that contains a LIM domain was also validated as a DUX4 partner. The functionality of DUX4 or DUX4c interactions with cytoplasmic proteins is underscored by the cytoplasmic detection of DUX4/DUX4c upon myoblast fusion. In addition, we identified and validated (by co-immunoprecipitation, co-immunofluorescence and in situ Proximal Ligation Assay) as DUX4/4c partners several RNA-binding proteins such as C1QBP, SRSF9, RBM3, FUS/TLS and SFPQ that are involved in mRNA splicing and translation. FUS and SFPQ are nuclear proteins, however their cytoplasmic translocation was reported in neuronal cells where they associated with ribonucleoparticles (RNPs). Several other validated or identified DUX4/DUX4c partners are also contained in mRNP granules, and the co-localizations with cytoplasmic DAPI-positive spots is in keeping with such an association. Large muscle RNPs were recently shown to exit the nucleus via a novel mechanism of nuclear envelope budding. Following DUX4 or DUX4c overexpression in muscle cell cultures, we observed their association with similar nuclear buds. In conclusion, our study demonstrated unexpected interactions of DUX4/4c with cytoplasmic proteins playing major roles during muscle differentiation. Further investigations are on-going to evaluate whether these interactions play roles during muscle regeneration as previously suggested for DUX4c.
Thyrotropin-Releasing Hormone Increases Behavioral Arousal through Modulation of Hypocretin/Orexin Neurons

Thyrotropin-releasing hormone (TRH) has previously been shown to promote wakefulness and to induce arousal from hibernation. Expression of TRH-R1 (TRH receptor 1) is enriched in the tuberal and lateral hypothalamic area (LHA), brain regions in which the hypocretin/orexin (Hcrt) cells are located. Because the Hcrt system is implicated in sleep/wake control, we hypothesized that TRH provides modulatory input to the Hcrt cells. In vitro electrophysiological studies showed that bath application of TRH caused concentration-dependent membrane depolarization, decreased input resistance, and increased firing rate of identified Hcrt neurons. In the presence of tetrodotoxin, TRH induced inward currents that were associated with a decrease in frequency, but not amplitude, of miniature postsynaptic currents (PSCs). Ion substitution experiments suggested that the TRH-induced inward current was mediated in part by Ca2+ influx. Although TRH did not significantly alter either the frequency or amplitude of spontaneous excitatory PSCs, TRH (100 nm) increased the frequency of spontaneous inhibitory PSCs by twofold without affecting the amplitude of these events, indicating increased presynaptic GABA release onto Hcrt neurons. In contrast, TRH significantly reduced the frequency, but not amplitude, of miniature excitatory PSCs without affecting miniature inhibitory PSC frequency or amplitude, indicating that TRH also reduces the probability of glutamate release onto Hcrt neurons. When injected into the LHA, TRH increased locomotor activity in wild-type mice but not in orexin/ataxin-3 mice in which the Hcrt neurons degenerate postnatally. Together, these results are consistent with the hypothesis that TRH modulates behavioral arousal, in part, through the Hcrt system.
The Calcium Sensitivity of Individual Secretory Vesicles Is Invariant with the Rate of Calcium Delivery

Differences in the calcium sensitivity of individual secretory vesicles can explain a defining feature of calcium-regulated exocytosis, a graded response to calcium. The role of the time dependence of calcium delivery in defining the observed differences in the calcium sensitivity of sea urchin egg secretory vesicles in vitro was examined. The calcium sensitivity of individual secretory vesicles (i.e., the distribution of calcium thresholds) is invariant over a range of calcium delivery rates from faster than micromolar per millisecond to slower than micromolar per second. Any specific calcium concentration above threshold triggers subpopulations of vesicles to fuse, and the size of these subpopulations is independent of the time course required to reach that calcium concentration. All evidence supports the hypothesis that the magnitude of the free calcium is the single controlling variable that determines the fraction of vesicles that fuse, and that this fraction is established before the application of calcium. Submaximal responses to calcium cannot be attributed to alterations in the calcium sensitivity of individual secretory vesicles arising from the temporal properties of the calcium delivery. Models that attempt to explain the cessation of fusion using changes in the distribution of calcium thresholds arising from the rate of calcium delivery and/or adaptation are not applicable to this system, and thus cannot be general.
Shadow Insurance

Life insurers use reinsurance to move liabilities from regulated and rated companies that sell policies to shadow reinsurers, which are less regulated and unrated off-balance-sheet entities within the same insurance group. U.S. life insurance and annuity liabilities ceded to shadow reinsurers grew from $11 billion in 2002 to $364 billion in 2012. Life insurers using shadow insurance, which capture half of the market share, ceded 25 cents of every dollar insured to shadow reinsurers in 2012, up from 2 cents in 2002. By relaxing capital requirements, shadow insurance could reduce the marginal cost of issuing policies and thereby improve retail market efficiency. However, shadow insurance could also reduce risk-based capital and increase expected loss for the industry. We model and quantify these effects based on publicly available data and plausible assumptions.
Muscarinic modulation of voltage-dependent Ca2+ channels in insulin-secreting HIT-T15 cells.

Potentiation of insulin secretion from pancreatic β-cells by acetylcholine requires ongoing cyclic electrical activity initiated by other depolarizing secretagogues. Patch-clamp recordings in glucose-free solutions were made from the clonal β-cell line HIT-T15 to determine whether the muscarinic agonist bethanechol (BCh) modulated voltage-dependent Ca2+ channels independent of effects on membrane potential. Only high-threshold, dihydropyridine-sensitive (L-type) Ca2+ channels with a mean conductance of 26 pS were observed in cell-attached patches. BCh (100 μM) caused a two- to threefold increase in both fractional open time and mean current of single Ca2+channels. These changes resulted from a 44% decrease in the longer of two apparent mean closed times and a 25% increase in the mean open time. Similar BCh-stimulated increases in macroscopic Ca2+ currents were recorded in whole cell, perforated-patch recordings. The role of protein kinase C (PKC) in the muscarinic activation of Ca2+ channels was tested using a variety of PKC activators and inhibitors. Acute application of either the active phorbol ester phorbol 12-myristate 13-acetate (PMA) or the membrane-permeable diacylglycerol analog 1,2-didecanoyl- rac-glycerol mimicked the effects of BCh, whereas an inactive phorbol (4α) had no effect. Depletion of PKC activity by chronic exposure to PMA or acute application of the PKC inhibitor staurosporine greatly reduced or abolished muscarinic activation of Ca2+ channels. These results are consistent with muscarinic activation of L-type, voltage-dependent Ca2+ channels mediated in large part by PKC.
Recent Advances in Translational Magnetic Resonance Imaging in Animal Models of Stress and Depression

Magnetic resonance imaging (MRI) is a valuable translational tool that can be used to investigate alterations in brain structure and function in both patients and animal models of disease. Regional changes in brain structure, functional connectivity, and metabolite concentrations have been reported in depressed patients, giving insight into the networks and brain regions involved, however preclinical models are less well characterized. The development of more effective treatments depends upon animal models that best translate to the human condition and animal models may be exploited to assess the molecular and cellular alterations that accompany neuroimaging changes. Recent advances in preclinical imaging have facilitated significant developments within the field, particularly relating to high resolution structural imaging and resting-state functional imaging which are emerging techniques in clinical research. This review aims to bring together the current literature on preclinical neuroimaging in animal models of stress and depression, highlighting promising avenues of research toward understanding the pathological basis of this hugely prevalent disorder.
Reservoir Computing optimization with a hybrid method

Reservoir Computing (RC) is a paradigm of artificial neural networks with important applications in the real world. RC uses similar architecture to recurrent networks without the difficulty of training the network hidden layer (reservoir). However, RC can be computationally expensive and various parameters influence its efficiency, making it necessary to search for alternatives to increase its capacity. This work aims to use a hybrid algorithm between a PSO (Particle Swarm Optimization) extension and Simulated Annealing for optimize the global parameters, architecture and weights of RC, in time series forecasting. The results showed that the Reservoir Computing optimization with the hybrid algorithm achieved satisfactory performance in all databases investigated and outperformed original APSO (Adaptive Particle Swarm Optimization) in some of them.
On destructive superposition of shaping pulses in band-limited linear modulation systems

We analyze pulse-shaped transmit signals with correlated input sequences in the framework of band-limited liner modulations. These signals are formed by superposition (convolution) of the shaping pulses and may have different amplitude statistics depending on the correlation properties of the input sequences. Hence, even if the sequences have a unit average power in discrete-time domain, the resulting transmit signals exhibit smaller (or larger) average power if there are many destructive (or constructive) superpositions produced by the correlated source. Since such a reduction of average transmit power does not change the amplitude of the underlying discrete-time sequence, one may expect the so-called shaping gain. We comprehensively analyze the shaping gain achieved by the correlation of the input sequences, and show that the use of a pulse shape, which convolves the sequence destructively, is capable of increasing the achievable information rate of the system.
Sensor System for High Throughput Fluorescent Bio-assays

This thesis presents consolidated research results of a low-cost, high efficiency, high throughput detection system for fluorescence-based bioassays. Such high throughput screening process is an invaluable tool for the multifaceted field of Systems Biology, where it is widely used in genomics and proteomics for drug and gene discovery applications. The thesis is divided into three parts: addressing the feasibility of using hydrogenated amorphous silicon photodiodes as the sensor, the development of an associated compact model suitable for circuit-level simulations, and integration of the sensors and switches to realize the array. Requirements of fluorescent bio-assays demand low sensor dark current densities in the order of 10 ̄11A/cm2 at room temperature. Fabrication of high quality segmented a–Si:H n–i–p photodiodes with such specification is achieved by tailoring defects at photodiode junction sidewalls, where both the dry etching and passivation conditions play important roles. Measurements of the fabricated photodiodes at different temperatures allowed the extraction of reverse current components, which are necessary in modeling such sensors in Verilog-A. Two prototype array designs are fabricated with pixel dimensions matching ANSI standard microwell plates. The functionalities of the small arrays are demonstrated with green LEDs to simulate fluorescent dyes that are commonly used in the high throughput bio-assay processes.
Speed-Accuracy Tradeoff Operator Characteristics of Endogenous and Exogenous Covert Orienting of Attention

There is debate over the mechanisms that govern the orienting of attention. Some argue that the enhanced performance observed at a cued location is the result of increased perceptual sensitivity or preferential access to decision-making processes. It has also been suggested that these effects may be the result of trades in speed for accuracy on the part of the observers. In the present study, observers performed either an exogenous or an endogenous orienting of attention task under both normal instructions (respond as quickly and as accurately as possible) and speeded instructions that used a deadline procedure to limit the amount of time observers had to complete a choice reaction time (CRT) task. An examination of the speed-accuracy operating characteristics (SAOCs) yielded evidence against the notion that CRT precuing effects are due primarily to a tradeoff of accuracy for speed.
Isospectral deformations for Sturm-Liouville and Dirac-type operators and associated nonlinear evolution equations

We give a systematic account of isospectral deformations for Sturm-Liouville and Dirac-type operators and associated hierarchies of nonlinear evolution equations. In particular, we study generalized KdV and modified KdV-hierarchies and their reduction to the standard (m)KdV-hierarchy. As an example we study the Harry Dym equation in some detail and relate its solutions to KdV-solutions and to Hirota’s τ -functions.
Assessment of a Micropatterned Hepatocyte Coculture System to Generate Major Human Excretory and Circulating Drug Metabolites

Metabolism is one of the important determinants of the overall disposition of drugs, and the profile of metabolites can have an impact on efficacy and safety. Predicting which drug metabolites will be quantitatively predominant in humans has become increasingly important in the research and development of new drugs. In this study, a novel micropatterned hepatocyte coculture system was evaluated for its ability to generate human in vivo metabolites. Twenty-seven compounds of diverse chemical structure and subject to a range of drug biotransformation reactions were assessed for metabolite profiles in the micropatterned coculture system using pooled cryopreserved human hepatocytes. The ability of this system to generate metabolites that are >10% of dose in excreta or >10% of total drug-related material in circulation was assessed and compared to previously reported data obtained in human hepatocyte suspensions, liver S-9 fraction, and liver microsomes. The micropatterned coculture system was incubated for up to 7 days without a change in medium, which offered an ability to generate metabolites for slowly metabolized compounds. The micropatterned coculture system generated 82% of the excretory metabolites that exceed 10% of dose and 75% of the circulating metabolites that exceed 10% of total circulating drug-related material, exceeds the performance of hepatocyte suspension incubations and other in vitro systems. Phase 1 and phase 2 metabolites were generated, as well as metabolites that arise via two or more sequential reactions. These results suggest that this in vitro system offers the highest performance among in vitro metabolism systems to predict major human in vivo metabolites.
Regional Specialization in Pyramidal Cell Structure in the Visual Cortex of the Galago: An Intracellular Injection Study of Striate and Extrastriate Areas with Comparative Notes on New World and Old World Monkeys

Recent studies have revealed marked differences in the basal dendritic structure of layer III pyramidal cells in the cerebral cortex of adult simian primates. In particular, there is a consistent trend for pyramidal cells of increasing complexity with anterior progression through occipitotemporal cortical visual areas. These differences in pyramidal cell structure, and their systematic nature, are believed to be important for specialized aspects of visual processing within, and between, cortical areas. However, it remains unknown whether this regional specialization in the pyramidal cell phenotype is unique to simians, is unique to primates in general or is widespread amongst mammalian species. In the present study we investigated pyramidal cell structure in the prosimian galago (Otolemur garnetti). We found, as in simians, that the basal dendritic arbors of pyramidal cells differed between cortical areas. More specifically, pyramidal cells became progressively more spinous through the primary (V1), second (V2), dorsolateral (DL) and inferotemporal (IT) visual areas. Moreover, pyramidal neurons in V1 of the galago are remarkably similar to those in other primate species, in spite of large differences in the sizes of this area. In contrast, pyramidal cells in inferotemporal cortex are quite variable among primate species. These data suggest that regional specialization in pyramidal cell phenotype was a likely feature of cortex in a common ancestor of simian and prosimian primates, but the degree of specialization varies between species.