Miracle-dz/UniFAR-FTUs huggingface dataset:
Effects of action potential duration on excitation-contraction coupling in rat ventricular myocytes. Action potential voltage-clamp measurements.

Although each of the fundamental processes involved in excitation-contraction coupling in mammalian heart has been identified, many quantitative details remain unclear. The initial goal of our experiments was to measure both the transmembrane Ca2+ current, which triggers contraction, and the Ca2+ extrusion due to Na(+)-Ca2+ exchange in a single ventricular myocyte. An action potential waveform was used as the command for the voltage-clamp circuit, and the membrane potential, membrane current, [Ca2+]i, and contraction (unloaded cell shortening) were monitored simultaneously. Ca(2+)-dependent membrane current during an action potential consists of two components: (1) Ca2+ influx through L-type Ca2+ channels (ICa-L) during the plateau of the action potential and (2) a slow inward tail current that develops during repolarization negative to approximately -25 mV and continues during diastole. This slow inward tail current can be abolished completely by replacement of extracellular Na+ with Li+, suggesting that it is due to electrogenic Na(+)-Ca2+ exchange. In agreement with this, the net charge movement corresponding to the inward component of the Ca(2+)-dependent current (ICa-L) was approximately twice that during the slow inward tail current, a finding that is predicted by a scheme in which the Ca2+ that enters during ICa is extruded during diastole by a 3 Na(+)-1 Ca2+ electrogenic exchanger. Action potential duration is known to be a significant inotropic variable, but the quantitative relation between changes in Ca2+ current, action potential duration, and developed tension has not been described in a single myocyte. We used the action potential voltage-clamp technique on ventricular myocytes loaded with indo 1 or rhod 2, both Ca2+ indicators, to study the relation between action potential duration, ICa-L, and cell shortening (inotropic effect). A rapid change from a "short" to a "long" action potential command waveform resulted in an immediate decrease in peak ICa-L and a marked slowing of its decline (inactivation). Prolongation of the action potential also resulted in slowly developing increases in the magnitude of Ca2+ transients (145 +/- 2%) and unloaded cell shortening (4.0 +/- 0.4 to 7.6 +/- 0.4 microns). The time-dependent nature of these effects suggests that a change in Ca2+ content (loading) of the sarcoplasmic reticulum is responsible. Measurement of [Ca2+]i by use of rhod 2 showed that changes in the rate of rise of the [Ca2+]i transient (which in rat ventricle is due to the rate of Ca2+ release from the sarcoplasmic reticulum) were closely correlated with changes in the magnitude and the time course of ICa-L. (ABSTRACT TRUNCATED AT 400 WORDS)
DNA Synthesis Generates Terminal Duplications That Seal End-to-End Chromosome Fusions

The fate of chromosomes that become catastrophically fused at their ends is revealed in the nematode worm. End-to-end chromosome fusions that occur in the context of telomerase deficiency can trigger genomic duplications. For more than 70 years, these duplications have been attributed solely to breakage-fusion-bridge cycles. To test this hypothesis, we examined end-to-end fusions isolated from Caenorhabditis elegans telomere replication mutants. Genome-level rearrangements revealed fused chromosome ends having interrupted terminal duplications accompanied by template-switching events. These features are very similar to disease-associated duplications of interstitial segments of the human genome. A model termed Fork Stalling and Template Switching has been proposed previously to explain such duplications, where promiscuous replication of large, noncontiguous segments of the genome occurs. Thus, a DNA synthesis–based process may create duplications that seal end-to-end fusions, in the absence of breakage-fusion-bridge cycles.
Opposing influences of protein kinase activities on neurite outgrowth in human neuroblastoma cells: Initiation by kinase A and restriction by kinase C

The respective roles of cAMP‐dependent protein kinase (protein kinase A [PKA]) and protein kinase C (PKC) in the early stages of neurite outgrowth were examined in SH‐SY‐5Y human neuroblastoma cells. Forskolin or dbcAMP, agents that increase intracellular cAMP levels, and intracellular delivery of PKA catalytic subunit induced neurite outgrowth. The PKA inhibitor, N‐(2‐guanidinoethyl)‐5‐isoquinolinesulfonamide (HA 1004), prevented the increases, and decreased further the percentage of cells possessing short, filopodia‐like neurites in the absence of inducers. In contrast to effects on PKA activation, PKC activation by 12‐0‐tetradecanoylphorbol‐13‐acetate (TPA) reduced the percentage of filopodia‐like neurites elaborated by otherwise untreated cells, and prevented neurite outgrowth induced by PKA activators. PKC inhibitors 1‐(5‐isoquinolinesulfonyl)‐2‐methylpiperazine dihydrochloride (H7), staurosporine, and sphingosine induced neurite outgrowth.
Rapid coastal spread of First Americans: Novel insights from South America's Southern Cone mitochondrial genomes

It is now widely agreed that the Native American founders originated from a Beringian source population ∼15–18 thousand years ago (kya) and rapidly populated all of the New World, probably mainly following the Pacific coastal route. However, details about the migration into the Americas and the routes pursued on the continent still remain unresolved, despite numerous genetic, archaeological, and linguistic investigations. To examine the pioneering peopling phase of the South American continent, we screened literature and mtDNA databases and identified two novel mitochondrial DNA (mtDNA) clades, here named D1g and D1j, within the pan-American haplogroup D1. They both show overall rare occurrences but local high frequencies, and are essentially restricted to populations from the Southern Cone of South America (Chile and Argentina). We selected and completely sequenced 43 D1g and D1j mtDNA genomes applying highest quality standards. Molecular and phylogeographic analyses revealed extensive variation within each of the two clades and possibly distinct dispersal patterns. Their age estimates agree with the dating of the earliest archaeological sites in South America and indicate that the Paleo-Indian spread along the entire longitude of the American double continent might have taken even <2000 yr. This study confirms that major sampling and sequencing efforts are mandatory for uncovering all of the most basal variation in the Native American mtDNA haplogroups and for clarification of Paleo-Indian migrations, by targeting, if possible, both the general mixed population of national states and autochthonous Native American groups, especially in South America.
Study on Location and Route Optimization of Distribution Center of a Digital Company Based on Clustering Algorithm and Ant Colony Algorithm Method

Aiming at the complex problem of logistics distribution, in order to achieve the shortest path and the least total cost, this paper analyzes and designs the logistics distribution network from the two aspects of distribution center location and path optimization. Firstly, the improved clustering algorithm is used to determine the distribution center, the corresponding supply point and distribution point of each distribution center, then the ant colony algorithm is used to optimize the path, and finally the distribution center and the corresponding distribution path are determined. In the end of this paper, the case analysis is carried out to find out the best distribution center and the shortest path, which gets an optimized distribution network, so as to achieve the purpose of the lowest cost.
Dynamic Output Feedback Control of Switched Linear Systems

This paper is devoted to stability analysis and control design of switched linear systems in both continuous and discrete-time domains. A particular class of matrix inequalities, the so-called Lyapunov--Metzler inequalities, provides conditions for open-loop stability analysis and closed-loop switching control using state and output feedback. Switched linear systems are analyzed in a general framework by introducing a quadratic in the state cost determined from a series of impulse perturbations. Lower bounds on the cost associated with the optimal switching control strategy are derived from the determination of a feasible solution to the Hamilton--Jacobi--Bellman inequality. An upper bound on the optimal cost associated with a closed-loop stabilizing switching strategy is provided as well. The solution of the output feedback problem is based on the construction of a full-order linear switched filter whose state variable is used by the mechanism for the determination of the switching rule. Throughout, the theoretical results are illustrated by means of academic examples. A realistic practical application related to the optimal control of semiactive suspensions in road vehicles is reported.
Evaluation of Disaggregation Methods for Downscaling MODIS Land Surface Temperature to Landsat Spatial Resolution in Barrax Test Site

Thermal infrared (TIR) data are usually acquired at a coarser spatial resolution (CR) than visible and near infrared (VNIR). Several disaggregation methods have been recently developed to enhance the TIR spatial resolution using VNIR data. These approaches are based on the retrieval of a relation between TIR and VNIR data at CR, or training of a neural network, to be applied at the fine resolution afterward. In this work, different disaggregation methods are applied to the combination of two different sensors in the experimental test site of Barrax, Spain. The main objective is to test the feasibility of these techniques when applied to satellites provided with no TIR bands. Landsat and moderate imaging spectroradiometer (MODIS) images were used for this work. Land surface temperature (LST) from MODIS images was disaggregated to the Landsat spatial resolution using Landsat VNIR data. Landsat LST was used for the validation and comparison of the different techniques. Best results were obtained by the method based on a linear regression between normalized difference vegetation index (NDVI) and LST. An average RMSE = ±1.9 K was observed between disaggregated and Landsat LST from four different dates in a study area of 120 km2.
Imaging of Acute Stroke

The utility of diagnostic imaging during the critical first few hours after stroke onset has many important applications. First and foremost, imaging technologies that can reliably detect and quantify the location of acute stroke will greatly enhance the clinician’s ability to accurately diagnose individual stroke patients. Secondly, if imaging technology could provide information about the likely severity of the ischemic injury, patient prognosis and management would be enhanced. The possibility of potentially distinguishing severely injured and likely irreversible ischemic brain tissue from ischemic tissue likely not yet irreversibly injured may soon be attainable. The ability of imaging technology to reliably distinguish the status of focally ischemic brain will presumably dramatically impact upon patient management. This information, along with the data about the severity and extent of blood flow and tissue perfusion abnormalities, will help acute stroke care evolve beyond rigid time windows to individualized, pathophysiologically based treatment decisions. Not only will decisions to treat or not be made based upon imaging-derived status, but also the most appropriate type of therapy to be employed, i.e. thrombolysis, neuroprotection, therapy to reduce secondary reperfusion-related injury or combinations of these modalities. In this brief and necessarily incomplete overview of acute stroke imaging, the focus will be on new developments in CT and MRI.
Clinical evaluation of a polymerase chain reaction assay to detect Aspergillus species in bronchoalveolar lavage samples of neutropenic patients

Summary. The increasing incidence of invasive aspergillosis, a life‐threatening infection in immunocompromised patients, emphasizes the need to improve the currently limited diagnostic tools. Using a recently developed two‐step polymerase chain reaction (PCR) assay to detect 10 fg of Aspergillus DNA, corresponding to 1–5 colony‐forming units (CFU)/ml of spiked samples in vitro, we prospectively examined 197 bronchoalveolar lavage (BAL) samples from 176 subjects, including 141 neutropenic, febrile patients with lung infiltrates, at risk for invasive fungal disease. Underlying diseases of these patients were haematological malignancies; 93 patients suffered from acute leukaemias. Thirty‐one of these immunocompromised patients (17·6%) were PCR positive, correlating with positive BAL culture, positive histology from lung surgery or from autopsy, positive computerized tomography scans or positive galactomannan enzyme‐linked immunosorbent assay. Six patients (4·3%) of this group had positive PCR results without any correlation to clinical or other diagnostic data, probably owing to contamination of the samples by ubiquitous Aspergillus spores. The samples of two patients (1·4%) with a subsequent histologically proven mould infection were PCR negative. All 102 immunocompromised patients (72·3%) with a negative PCR showed no evidence of invasive fungal disease. From 35 patients without immunodeficiency, four (11·4%) showed positive results, without evidence of invasive or non‐invasive pulmonary aspergillosis. In this haematological population, the sensitivity and specificity values of the test reached 93·9% and 94·4%, the positive predictive value 83·8%, the negative predictive value 98·1%. Our data support the considerable clinical value of this PCR assay for confirming and improving diagnosis of pulmonary aspergillosis in high‐risk patients.
Functional Subdivisions in the Left Angular Gyrus Where the Semantic System Meets and Diverges from the Default Network

The left angular gyrus (AG) is reliably activated across a wide range of semantic tasks, and is also a consistently reported component of the so-called default network that it is deactivated during all goal-directed tasks. We show here that there is only partial overlap between the semantic system and the default network in left AG and the overlap defines a reliable functional landmark that can be used to segregate functional subdivisions within AG. In 94 healthy human subjects, we collected functional magnetic resonance imaging (fMRI) data during fixation and eight goal directed tasks that involved semantic matching, perceptual matching or speech production in response to familiar or unfamiliar stimuli presented in either verbal (letters) or nonverbal (pictures) formats. Our results segregated three different left AG regions that were all activated by semantic relative to perceptual matching: (1) a midregion (mAG) that overlapped with the default network because it was deactivated during all tasks relative to fixation; (2) a dorsomesial region (dAG) that was more activated by all tasks relative to fixation; and (3) a ventrolateral region (vAG) that was only activated above fixation during semantic matching. By examining the effects of task and stimuli in each AG subdivision, we propose that mAG is involved in semantic associations regardless of the presence or absence of a stimulus; dAG is involved in searching for semantics in all visual stimuli, and vAG is involved in the conceptual identification of visual inputs. Our findings provide a framework for reporting and interpreting AG activations with greater definition.
Membrane Proteome Analysis of Glioblastoma Cell Invasion

Abstract Glioblastoma multiforme (GBM) tumor invasion is facilitated by cell migration and degradation of the extracellular matrix. Invadopodia are actin-rich structures that protrude from the plasma membrane in direct contact with the extracellular matrix and are proposed to participate in epithelial-mesenchymal transition. We characterized the invasiveness of 9 established GBM cell lines using an invadopodia assay and performed quantitative mass spectrometry–based proteomic analyses on enriched membrane fractions. All GBM cells produced invadopodia, with a 65% difference between the most invasive cell line (U87MG) and the least invasive cell line (LN229) (p = 0.0001). Overall, 1,141 proteins were identified in the GBM membrane proteome; the levels of 49 proteins correlated with cell invasiveness. Ingenuity Pathway Analysis predicted activation “cell movement” (z-score = 2.608, p = 3.94E−04) in more invasive cells and generated a network of invasion-associated proteins with direct links to key regulators of invadopodia formation. Gene expression data relating to the invasion-associated proteins ITGA5 (integrin &agr;5), CD97, and ANXA1 (annexin A1) showed prognostic significance in independent GBM cohorts. Fluorescence microscopy demonstrated ITGA5, CD97, and ANXA1 localization in invadopodia assays, and small interfering RNA knockdown of ITGA5 reduced invadopodia formation in U87MG cells. Thus, invasion-associated proteins, including ITGA5, may prove to be useful anti-invasive targets; volociximab, a therapeutic antibody against integrin &agr;5&bgr;1, may be useful for treatment of patients with GBM.
Defects in cholesterol synthesis genes in mouse and in humans: lessons for drug development and safer treatments

This review describes the mouse knockout models of cholesterol synthesis, together with human malformations and drugs that target cholesterogenic enzymes. Generally, the sooner a gene acts in cholesterol synthesis, the earlier the phenotype occurs. Humans with loss of function of early cholesterogenic enzymes have not yet been described, and in the mouse, loss of Hmgcr is preimplantation lethal. Together, these results indicate that the widely prescribed cholesterol-lowering statins are potentially teratogenic. The Mvk knockout is early embryonic lethal in the mouse, the absence of Fdft1 is lethal at E9.5–12.5 dpc, while the Cyp51 knockouts die at 15.0 dpc. Fungal CYP51 inhibitor azoles are teratogenic in humans, potentially leading to symptoms of Antley-Bixler syndrome. The X-linked mutations in Nsdhl and Ebp are embryonic lethal in male mice, while heterozygous females are also affected. Consequently, the anticancer drugs, tamoxifen and toremifene, inhibiting human EBP, may be harmful in early pregnancy. The Dhcr7 and Dhcr24 knockout mice die shortly after birth, while humans survive with Smith-Lemli-Opitz syndrome or desmosterolosis. Since cholesterol is essential for hedgehog signaling, disturbance of this pathway by antipsychotics and -depressants explains some drug side effects. In conclusion, defects in cholesterol synthesis are generally lethal in mice, while humans with impaired later steps of the pathway can survive with severe malformations. Evidence shows that drugs targeting or, by coincidence, inhibiting human cholesterol synthesis are better avoided in early pregnancy. Since some drugs with teratogenic potential still stay on the market, this should be avoided in new cholesterol-related drug development.
Lung Adenocarcinoma With Mixed Bronchioloalveolar and Invasive Components: Clinicopathological Features, Subclassification by Extent of Invasive Foci, and Immunohistochemical Characterization

A significant proportion of small lung adenocarcinomas consists of two components: bronchioloalveolar carcinoma (BAC) and invasive carcinoma. The purpose of this study was to compare their clinicopathologic features with those of BAC and those of invasive cancer without BAC, and to define “early invasive” lesions based on the extent of invasive foci. We reviewed 484 lesions of resected lung adenocarcinoma and classified them into three groups according to tumor growth pattern: group 1 (n = 102, BAC), group 2 (n = 216, adenocarcinoma consisting of BAC and invasive carcinoma), and group 3 (n = 166, invasive adenocarcinoma without BAC component). Group 2 was further subdivided according to the extent of the invasive area: group 2a (n = 54), BAC with invasive foci ≤5 mm; group 2b (n = 162), BAC with invasive foci >5 mm. These groups were compared with regard to their clinicopathologic features, expression of Ki-67 and p53, and expression of laminin-5, a putative marker for tumor invasion. The positivity rates of vascular, lymphatic, and pleural invasion in each group were as follows: 0%, 0%, and 0% in group 1; 5.5%, 14.8%, and 1.9% in group 2a; 45.7%, 41.4%, and 25.9% in group 2b; and 84.9%, 61.4%, and 60.8% in group 3. Notably, no lymph node metastasis occurred in either group 2a or group 1, but it was observed in 24.1% of group 2b and 47.0% of group 3. The mean Ki-67 labeling index, the frequency of p53 overexpression, and the frequency of laminin-5 overexpression increased from group 1 (11%, 4%, and 0%) to group 2a (16%, 20%, and 7%) to group 2b (24%, 41%, and 23%) to group 3 (35%, 38%, and 38%). In contrast, no clear differences were observed when lesions were subdivided according to size. Based on the distribution pattern of Ki-67-positive tumor cells, lesions were classified into two groups: marginal type (63%) and nonmarginal type (37%). The latter showed a significantly higher labeling index than the former. Moreover, the proportion of the marginal type clearly decreased from group 1 (85%) and group 2a (87%) to group 2b (55%) to group 3 (19%). Group 2 lesions showed characteristics intermediate between the BAC and invasive adenocarcinoma. According to the extent of the invasive area, we were able to define a subgroup of mixed-type adenocarcinomas (group 2a) that could be regarded as early invasive cancer because they showed low rates of vascular, lymphatic, and pleural invasion, and no nodal involvement.
A Creative Computing Based Inspiration Assistant to Poem Generation

This paper presents a process of poem generation for users who need creative inspiration. Rather than enumerating existing poems, users are able to discover possible creative changes of existing poems, and then develop their own poems through our App. Creativity can re-shape the way that people look at things, which has already been studied in many disciplines. When collaborating with most widely used facility, computers, as a joining force of innovation, can be formed by researching creative computing. In order to explain how computers can enhance human creativity, a general framework of creative computing has been proposed. For the purpose of evaluating creative computing in practice, this paper proposes a creative approach to inspiring users and a supplemental poem modification case will be presented to show how knowledge combination can contribute and help the inspiration process in the form of software development. In order to achieve this purpose, the intrinsic motivation and external stimulation for creativity from psychology will be abstracted to a word linking algorithm in the proposed research and the semantic web techniques will be used to make software understand the context of input. Then a feedback loop will be constructed to make software adaption.