Miracle-dz/UniFAR-FTUs huggingface dataset:
Kinetic study and numerical reconstruction of A-type current in granule cells of rat cerebellar slices.

1. Whole-cell voltage-clamp techniques were used to study voltage-activated transient potassium currents in a large sample (n = 143) of granule cells (GrC) from rat cerebellar slices. Tetrodotoxin (TTX; 0.1 microM) was used to block sodium currents, while calcium current was too small to be seen under ordinary conditions. 2. Depolarizing pulses from -50 mV evoked a slow, sustained outward current, developing with a time constant of 10 ms, inactivating over a time scale of seconds and which could be suppressed by 20 mM tetraethylammonium (TEA). By preventing the Ca2+ inflow, this slow outward current could be further separated into a Ca(2+)-dependent and a Ca(2+)-independent component. 3. After conditioning hyperpolarizations to potentials negative to -60 mV, depolarizations elicited transient outward current, peaking in 1-2 ms and inactivating rapidly (approximately 10 ms at 20 degrees C), showing the overall kinetic characteristics of the A-current (IA). The current activated following third-order kinetics and showed a maximal conductance of 12 nS per cell, corresponding to a normalized conductance of 3.8 nS/pF. 4. IA was insensitive to TEA and to the Ca(2+)-channel blockers. 4-Aminopyridine (4-AP) reduced the A-current amplitude by approximately 20%, and the delayed outward currents by > 80%. 5. Voltage-dependent steady-state inactivation of peak IA was described by a Boltzmann function with a slope factor of 8.4 mV and half-inactivation occurring at -78.8 mV. Activation of IA was characterized by a Boltzmann curve with the midpoint at -46.7 mV and with a slope factor of 19.8 mV. 6. IA activation and inactivation was best fitted by the Hodgkin-Huxley m3h formalism. The rate of activation, tau a, was voltage-dependent, and had values ranging from 0.55 ms at -40 mV to 0.2 ms at +50 mV. Double-pulse experiment showed that development and removal of inactivation followed a single-exponential time course; the inactivation time constant, tau ha, was markedly voltage-dependent and ranged from approximately 10 ms at -40 and -100 mV and 70 ms at -70 mV. 7. A set of continuous equations has been developed describing the voltage-dependence of both the steady-state and time constant of activation and inactivation processes, allowing a satisfactory numerical reconstruction of the A-current over the physiologically significant membrane voltage range. (ABSTRACT TRUNCATED AT 400 WORDS)
Prolactin regulation of beta‐casein gene expression and of a cytosolic 120‐kd protein in a cloned mouse mammary epithelial cell line.

In order to study the hormonal regulation of gene expression in mammary epithelial cells, we isolated a prolactin‐responsive cell clone, HC11, from the COMMA‐1D mouse mammary epithelial cell line. Clone HC11 was selected as a unique example of a cloned mouse mammary epithelial cell which has no requirement for complex, exogenously added, extracellular matrix or co‐cultivation with other cell types for the prolactin‐dependent in vitro induction of the endogenous beta‐casein gene by lactogenic hormones. Induction of beta‐casein mRNA is rapid and was detected 3 h after hormone stimulation. A prolactin‐dependent increase in the rate of transcription of the beta‐casein gene was shown in an in vitro nuclear transcription assay. beta‐Casein protein was detected in an immunoblot assay after 24 h, and further accumulated during 5 days of hormone treatment. To identify low‐abundance proteins induced directly after prolactin stimulation, mRNA was accumulated during 5 h of stimulation of HC11 cells with prolactin in the presence of cycloheximide. Following cycloheximide removal, the mRNA was translated into protein during a 60‐min [35S]methionine pulse and the proteins were resolved by DEAE ion exchange HPLC and SDS‐PAGE. A strong induction of a 120‐kd cytosolic protein was detected which was maximally expressed within 6 h of hormone stimulation.
A tissue reconstitution model to study cancer cell‐intrinsic and ‐extrinsic factors in mammary tumourigenesis

The contribution of cancer cell‐intrinsic and ‐extrinsic factors to metastatic breast cancer is still poorly understood, hampering development of novel therapeutic strategies that decrease breast cancer mortality. Cre/loxP‐based conditional mouse models of breast cancer present unique opportunities to study sporadic tumour formation and progression in a controlled setting. Unfortunately, the generation of mouse strains carrying multiple mutant alleles needed for such studies is very time‐consuming. Moreover, conditional mouse tumour models do not permit independent manipulation of tumour cell‐intrinsic and ‐extrinsic factors. Although the latter can be achieved by cleared fat‐pad transplantation of mouse mammary epithelial cells (MMECs) from tumour suppressor gene (TSG) knockouts into wild‐type or mutant recipients, this procedure is not possible for mutations that cause embryonic lethality or preclude mammary gland development. Here we show that cleared fat‐pad transplantations with MMECs isolated from K14cre;Cdh1F/F; Trp53F/F mice expressing Cre recombinase under control of the cytokeratin‐14 promoter and carrying conditional null alleles for p53 and E‐cadherin (Cdh1) first resulted in the formation of phenotypically normal mammary glands, followed by the development of invasive metastatic mammary tumours. Tumour formation in the recipients mimicked tumour latency, spectrum, morphology, immunophenotype, and metastatic characteristics of the original mammary tumour model. This transplantation system, which can be expanded to other conditional TSG knockouts, permits independent genetic analysis of stromal factors and testing of additional cancer cell‐intrinsic mutations that would otherwise be embryonic lethal or require intensive breeding. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Generation of a Collection of Mutant Tomato Lines Using Pooled CRISPR Libraries1

Plant transformation with pooled CRISPR libraries enables the rapid production of mutant lines for functional screens. The high efficiency of clustered regularly interspaced short palindromic repeats (CRISPR)-mediated mutagenesis in plants enables the development of high-throughput mutagenesis strategies. By transforming pooled CRISPR libraries into tomato (Solanum lycopersicum), collections of mutant lines were generated with minimal transformation attempts and in a relatively short period of time. Identification of the targeted gene(s) was easily determined by sequencing the incorporated guide RNA(s) in the primary transgenic events. From a single transformation with a CRISPR library targeting the immunity-associated leucine-rich repeat subfamily XII genes, heritable mutations were recovered in 15 of the 54 genes targeted. To increase throughput, a second CRISPR library was made containing three guide RNAs per construct to target 18 putative transporter genes. This resulted in stable mutations in 15 of the 18 targeted genes, with some primary transgenic plants having as many as five mutated genes. Furthermore, the redundancy in this collection of plants allowed for the association of aberrant T0 phenotypes with the underlying targeted genes. Plants with mutations in a homolog of an Arabidopsis (Arabidopsis thaliana) boron efflux transporter displayed boron deficiency phenotypes. The strategy described here provides a technically simple yet high-throughput approach for generating a collection of lines with targeted mutations and should be applicable to any plant transformation system.
Congenital Zika virus infection in twin pregnancies

Dear Editor, The publication on “Congenital Zika virus infection in twin pregnancies” is very interesting1. Linden et al. reported on “two cases of twin pregnancies exposed to the Zika virus, but with only one of the fetuses affected with microcephaly and brain damage1. ” Indeed, the transplacental transmission of the Zika virus has been confirmed and direct cytopathology due to the virus is possible2. Nevertheless, not all cases of infection will result in symptomatic clinical manifestation and most cases are usually asymptomatic3. In the case of identical twins exposed to the virus, if there is discordance of susceptibility, it might imply that there may be little or no role of the genetic background on susceptibility or resistance to the virus. Nevertheless, there can also be some other explanations for the discordance. Firstly, there might be some variant in the placenta and umbilical cord, or in the infant, and this might act as a preventive barrier to infection. In the report by Linden et al.1, there is no data on the placenta and umbilical cord, hence we cannot draw a final conclusion on this issue. Secondly, the disorder in the abnormal fetus might be due to another cause, such as a somatic mutation, which might occur sporadically. Since there is no complete genetic workup comparing the normal and abnormal twin fetuses, and there is also no proof of viral infection in both fetuses, the conclusion also cannot be reached. Finally, although the mother might get the infection, and as transplacental transmission is possible, virus identification in both fetal brain and umbilical cord is required for confirmation of actual vertical transmission4. Beuy Joob1, Viroj Wiwanitkit2
Prostaglandin-independent anovulatory mechanism of indomethacin action: inhibition of tumor necrosis factor alpha-induced sheep ovarian cell apoptosis.

Indomethacin, a nonsteroidal anti-inflammatory agent, is a potent inhibitor of ovulation in vertebrates. The presumptive obligate anovulatory mode of indomethacin action is via suppression of ovarian prostaglandin production. We report that a very high systemic dose of indomethacin (800 mg i.m.) is required to block ovulation in gonadotropin-treated anestrous ewes. A lower dose of indomethacin (200 mg), which negated the preovulatory rise in follicular prostaglandin (PGF(2alpha)) biosynthesis, did not prevent ovulation. Endothelial secretion of tumor necrosis factor (TNF)-alpha within the apical follicular wall (prospective site of rupture) was not altered by indomethacin; notwithstanding, the apoptosis (DNA-fragmentation)-inducing effect of TNF-alpha (a determinant of ovulatory stigma formation) was attenuated by 800 (but not 200) mg indomethacin. A suprapharmacological concentration of indomethacin also was necessary to protect ovarian surface epithelial cells from a (prostaglandin-independent) cytotoxic effect of TNF-alpha in vitro. It is concluded that indomethacin inhibits ovulation by anti-apoptotic mechanisms that can be dissociated from the paradigm of prostanoid down-regulation.
A C++ research and development environment for speech and audio processing applications

Speech and audio processing algorithms, which are based on the processing of the features and signals, are often written using poor programming styles. Understanding the existing source code and extending it is thus a time-consuming process that forces researchers to deal with programming problems instead of speech and audio processing innovations. We have developed a new system in C++ to overcome these problems. The programming techniques used in this environment allow a researcher to concentrate on innovations in an environment that still allows the rapid implementation of efficient real-time speech and audio processing applications.
Intra- and postoperative electrode impedance of the straight and Contour arrays of the Nucleus 24 cochlear implant: Relation to T and C levels

The objective of this study was to investigate electrode impedance in cochlear implant recipients in relation to electrically evoked stapedius reflex measurements during surgery, and to electrode design, stimulation mode, and T and C levels over a nine month period after surgery. Seventy-five implant recipients, implanted with a Nucleus straight electrode array or a Contour array, were included. The results show that: (1) during surgery electrode impedance decreases markedly after electrically evoked stapedius reflex measurements, (2) after surgery, during the period without stimulation until speech processor switch-on, impedance increases, (3) after processor switch-on impedance decreases. The lower impedance values after a period of stimulation are found at the higher T and C levels. Impedances of the straight array electrodes are lower than those of the Contour array. The difference corresponds mainly to their respective surface areas. In addition, the straight array shows a larger increase of impedance in the apical direction than the Contour array, probably because of the larger fluid environment around the basal electrodes of the straight array. Sumario El objetivo de este estudio fue investigar la impedancia de los electrodos en implantados cocleares en relación con medidas de reflejo estapedial evocado eléctricamente durante la cirugía, con el diseño del electrodo, el modo de estimulación, y los niveles T y C durante los 9 meses siguientes a la cirugía. Se incluyeron setenta y cinco sujetos implantados con un electrodo Nucleus recto o con uno Contour. Los resultados muestran que, 1) la impedancia de los electrodos disminuye marcadamente después de las mediciones del reflejo estapedial evocado eléctricamente, durante la cirugía, 2) la impedancia aumenta después de la cirugía, durante el período sin estimulación y hasta la activación de procesador de lenguaje, 3) después de la activación del procesador la impedancia disminuye. Se encontró que los menores valores de impedancia después de un periodo de estimulación se encuentran en los niveles T y C más altos. Las impedancias de los electrodos rectos son más bajas que aquellas del Contour. La diferencia corresponde a sus respectivas áreas de superficie. Además, los electrodos rectos muestran un incremento mayor de la impendacia en la dirección apical que los electrodos Contour, probablemente debida al ambiente con más líquido alrededor de los electrodos basales de los electrodos rectos.
Child Fatalities in Dammam: A Call for Child Fatality Reviews in Arab Countries

Identifying children's risk exposure is the first step toward mortality prevention. This retrospective study determined the causes of child fatalities in Dammam, Saudi Arabia. Death reports of children and adolescents from 1999 to 2015 (N = 157) were analyzed. Boys represented most cases (69%) and there were two age peaks (1–5 years and 16–18 years). Accidents (typically immersion) defined the main death circumstance (51%) followed by homicide (25%). Only 33% of cases underwent autopsy, and the most common cause of death was head injury (27%) followed by firearm injury. Only one immersion death underwent autopsy. This study revealed important data about the risk exposure of children in Dammam and emphasizes deficient investigative procedures. Child fatality reviews comprise systematic data collection by multidisciplinary teams to determine the true risks toward children in a community. Such teams do not exist in Arab countries; therefore, strategies should be implemented to initiate them.
Research on 2D Variable Learning Controller and Application in Pneumatic Servo System

In this paper a novel learning control law is proposed which can obtain learning gain matrices from a recursive identifier along the learning axis. This algorithm convergence is proved with random noise disturbance. The control law can online regulate learning gain matrices along the learning axis by using RLS technique and doesnpsilat need system accurate model. Finally it is applied in pneumatic servo control system, the simulation and experimentpsilas results show its validity, and then receive the idea results.
Two-Level Response and Parameter Mapping Optimization for Magnetic Shielding

We present a new technique for reducing computation time of numerical solutions to optimal design problems. We incorporate in the optimization procedure a coarse model. Our technique, the two-level response and parameter mapping (RPM) algorithm, is based on space mapping and manifold mapping. Space mapping (SM) performs a mapping between the parameter spaces of the coarse and fine models, while manifold mapping (MM) makes a mapping between the response spaces of the coarse and fine models through the use of response correction. Here, we use and compare the three two-level optimization procedures, SM, MM, and RPM, for the optimization of passive and active shields in induction heating. The results demonstrate accurate and time-efficient optimization of magnetic shields by the RPM algorithm.
Liposomes targeting tumour stromal cells

Abstract Liposomes have found clinical application in cancer therapy in the delivery of cytostatic agents. As a result of the targeted delivery of these toxic molecules to the tumour cells coupled to avoidance of toxicity-sensitive tissues, the therapeutic window is widened. Over the past years the focus of cancer therapy has shifted towards the stromal cells that are present in the tumour. It appears that clinically relevant tumours have acquired the ability to modulate the microenvironment in such a way that a chronic pro-inflammatory and pro-angiogenic state is achieved that contributes to invasion and metastasis and continued proliferation. Over the past years, liposomal formulations have been designed that target key stromal cell types that contribute to tumour growth. At the same time, many promising cell types have not been targeted yet and most of the studies employ drugs that aim at depleting stromal cells rather than modulating their activity towards an anti-tumour phenotype. In this review these target cell types will be addressed. Complementing these targeted formulations with the appropriate drugs to optimally suppress tumour-promoting signals while preserving anti-tumour action will be the challenge for the future.
Clinical whole‐body skin examination reduces the incidence of thick melanomas

Survival from melanoma is strongly related to tumour thickness, thus earlier diagnosis has the potential to reduce mortality from this disease. However, in the absence of conclusive evidence that clinical skin examination reduces mortality, evidence‐based assessments do not recommend population screening. We aimed to assess whether clinical whole‐body skin examination is associated with a reduced incidence of thick melanoma and also whether screening is associated with an increased incidence of thin lesions (possible overdiagnosis). We conducted a population‐based case‐control study of all Queensland residents aged 20–75 years with a histologically confirmed first primary invasive cutaneous melanoma diagnosed between January 2000 and December 2003. Telephone interviews were completed by 3,762 eligible cases (78.0%) and 3,824 eligible controls (50.4%). Whole‐body clinical skin examination in the three years before diagnosis was associated with a 14% lower risk of being diagnosed with a thick melanoma (>0.75 mm) (OR = 0.86, 95% CI = 0.75, 0.98). Risk decreased for melanomas of increasing thickness: the risk of being diagnosed with a melanoma 0.76–1.49 mm was reduced by 7% (OR = 0.93, 95% CI 0.79, 1.10), by 17% for melanomas 1.50–2.99 mm (OR = 0.83, 95% CI = 0.65, 1.05) and by 40% for melanomas ≥3 mm (OR = 0.60, 95% CI = 0.43, 0.83). Screening was associated with a 38% higher risk of being diagnosed with a thin invasive melanoma (≤0.75 mm) (OR = 1.38, 95% CI = 1.22, 1.56). This is the strongest evidence to date that whole‐body clinical skin examination reduces the incidence of thick melanoma. Because survival from melanoma is strongly related to tumour thickness, these results suggest that screening would reduce melanoma mortality.
A new functional parameter measured at the time of ablation that can be used to predict differentiated thyroid cancer recurrence during follow-up.

BACKGROUND This study addresses the questions whether patients with a high risk for recurrent thyroid cancer can be identified at initial stage, i.e. at the time of ablation. METHODS We evaluated tumor recurrence in consecutive patients treated for differentiated thyroid cancer (DTC). Prognostic factors were statistically analyzed. We defined prognostic parameters based on thyroglobulin (Tg) levels, 24-h I-131 uptake rates and TSH values: (a) Tg/TSH, (b) Tg/24-h I-131 uptake value, and (c) Tg/(TSHx24-h I-131 uptake). RESULTS We included 190 patients (50 male, 140 female; mean age 47 years) with DTC for analysis, 146 without distant metastases and 44 with M1 tumor stage at initial presentation. The mean period of follow-up was 10.4 years (s.d. +/- 3.7 years). In 18 out of the 146 DTC patients with M0 disease (12.4%), tumor recurrence was found during follow-up. Although tumor stage, age, and standard biochemical values significantly differ between patients with and without recurrent disease or between patients with M0 and M1 tumor stage, the newly defined parameter Tg/(TSHx24-h I-131 uptake) was the best independent significant prognostic parameter in the assessment whether patients will develop a tumor recurrence during follow-up or not. CONCLUSION High Tg/(TSHx24-h I-131 uptake) ratios justify an adjustment of the I-131 activity for ablation therapy. To assess the optimal cut-off value for a dose adjustment, however, further studies are required in more patients, but the initial results are encouraging with respect to improving outcome in DTC patients.
NF 2 is a “ gatekeeper ” during tissue repair normal tissue repair cell-cell contact stimulation of repair in NF 2 signaling deficient cell

Malignant pleural mesothelioma (MPM) is molecularly characterized by loss of function or mutations in the neurofibromin 2 (NF2) and the cyclin-dependent kinase inhibitor 2 genes. NF2 activates a cascade of kinases, called Hippo pathway, which downregulates Yes associated protein (YAP) function as transcription co-activator for TEA domain transcription factors (TEAD). In the absence of functional NF2, the expression of genes essential for cell cycling such as survivin is increased. New therapeutic strategies aimed at interfering with YAP activity include inhibition of hedgehog pathway, which downregulates the YAP protein, verteporfin, which inhibits the assembly of a functional YAPTEAD transcription factor, and interference with thrombin and lysophosphatidic acid (LPA) receptors downstream signalling, since upon agonist binding they activate YAP. DOI: 10.3978/j.issn. 2218-6751.2014. 02.03 Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: http://doi.org/10.5167/uzh-112748 Published Version Originally published at: Felley-Bosco, Emanuela; Stahel, Rolf (2014). Hippo/YAP pathway for targeted therapy. Translational Lung Cancer Research, 3(2):75-83. DOI: 10.3978/j.issn. 2218-6751.2014. 02.03