Miracle-dz/UniFAR-FTUs huggingface dataset:
Addressing genetic tumor heterogeneity through computationally predictive combination therapy.

UNLABELLED Recent tumor sequencing data suggest an urgent need to develop a methodology to directly address intratumoral heterogeneity in the design of anticancer treatment regimens. We use RNA interference to model heterogeneous tumors, and demonstrate successful validation of computational predictions for how optimized drug combinations can yield superior effects on these tumors both in vitro and in vivo. Importantly, we discover here that for many such tumors knowledge of the predominant subpopulation is insufficient for determining the best drug combination. Surprisingly, in some cases, the optimal drug combination does not include drugs that would treat any particular subpopulation most effectively, challenging straightforward intuition. We confirm examples of such a case with survival studies in a murine preclinical lymphoma model. Altogether, our approach provides new insights about design principles for combination therapy in the context of intratumoral diversity, data that should inform the development of drug regimens superior for complex tumors. SIGNIFICANCE This study provides the first example of how combination drug regimens, using existing chemotherapies, can be rationally designed to maximize tumor cell death, while minimizing the outgrowth of clonal subpopulations.
Transglial transmission at the dorsal root ganglion sandwich synapse: glial cell to postsynaptic neuron communication

The dorsal root ganglion (DRG) contains a subset of closely‐apposed neuronal somata (NS) separated solely by a thin satellite glial cell (SGC) membrane septum to form an NS–glial cell–NS trimer. We recently reported that stimulation of one NS with an impulse train triggers a delayed, noisy and long‐lasting response in its NS pair via a transglial signaling pathway that we term a ‘sandwich synapse’ (SS). Transmission could be unidirectional or bidirectional and facilitated in response to a second stimulus train. We have shown that in chick or rat SS the NS‐to‐SGC leg of the two‐synapse pathway is purinergic via P2Y2 receptors but the second SGC‐to‐NS synapse mechanism remained unknown. A noisy evoked current in the target neuron, a reversal potential close to 0 mV, and insensitivity to calcium scavengers or G protein block favored an ionotropic postsynaptic receptor. Selective block by D‐2‐amino‐5‐phosphonopentanoate (AP5) implicated glutamatergic transmission via N‐methyl‐d‐aspartate receptors. This agent also blocked NS responses evoked by puff of UTP, a P2Y2 agonist, directly onto the SGC cell, confirming its action at the second synapse of the SS transmission pathway. The N‐methyl‐d‐aspartate receptor NR2B subunit was implicated by block of transmission with ifenprodil and by its immunocytochemical localization to the NS membrane, abutting the glial septum P2Y2 receptor. Isolated DRG cell clusters exhibited daisy‐chain and branching NS–glial cell–NS contacts, suggestive of a network organization within the ganglion. The identification of the glial‐to‐neuron transmitter and receptor combination provides further support for transglial transmission and completes the DRG SS molecular transmission pathway.
Synergistic Antitumor Activity of Cetuximab and Namitecan in Human Squamous Cell Carcinoma Models Relies on Cooperative Inhibition of EGFR Expression and Depends on High EGFR Gene Copy Number

Purpose: Despite the frequent overexpression of epidermal growth factor receptor (EGFR) in squamous cell carcinoma (SCC), the efficacy of cetuximab alone is limited. Given the marked activity of namitecan, a hydrophilic camptothecin, against SCC models, the present study was performed to explore the efficacy of the cetuximab–namitecan combination in a panel of SCC models. Experimental Design: We examined the antiproliferative and antitumor activities of the cetuximab–namitecan combination in four SCC models characterized by a different EGFR gene copy number/EGFR protein level. We also assessed the effects of the combination on EGFR expression at both mRNA and protein levels and investigated the molecular basis of the interaction between the two agents. Results: Cetuximab and namitecan exhibited synergistic effects, resulting in potentiation of cell growth inhibition and, most importantly, enhanced therapeutic efficacy, with high cure rates in three SCC models characterized by high EGFR gene copy number, without increasing toxicity. The synergistic antitumor effect was also observed with the cetuximab–irinotecan combination. At the molecular level, the two agents produced a cooperative effect resulting in complete downregulation of EGFR. Interestingly, when singly administered, the camptothecin was able to strongly decrease EGFR expression mainly by transcriptional inhibition. Conclusions: Our results (i) demonstrate a marked efficacy of the cetuximab–namitecan combination, which reflects a complete abrogation of EGFR expression as a critical determinant of the therapeutic improvement, in SCC preclinical models, and (ii) suggest EGFR gene copy number as a possible marker to be used for patient selection in the clinical setting. Clin Cancer Res; 20(4); 995–1006. ©2013 AACR.
Limited-area short-range ensemble predictions targeted for heavy rain in Europe

Abstract. Inherent uncertainties in short-range quantitative precipitation forecasts (QPF) from the high-resolution, limited-area numerical weather prediction model DMI-HIRLAM (LAM) are addressed using two different approaches to creating a small ensemble of LAM simulations, with focus on prediction of extreme rainfall events over European river basins. The first ensemble type is designed to represent uncertainty in the atmospheric state of the initial condition and at the lateral LAM boundaries. The global ensemble prediction system (EPS) from ECMWF serves as host model to the LAM and provides the state perturbations, from which a small set of significant members is selected. The significance is estimated on the basis of accumulated precipitation over a target area of interest, which contains the river basin(s) under consideration. The selected members provide the initial and boundary data for the ensemble integration in the LAM. A second ensemble approach tries to address a portion of the model-inherent uncertainty responsible for errors in the forecasted precipitation field by utilising different parameterisation schemes for condensation and convection in the LAM. Three periods around historical heavy rain events that caused or contributed to disastrous river flooding in Europe are used to study the performance of the LAM ensemble designs. The three cases exhibit different dynamic and synoptic characteristics and provide an indication of the ensemble qualities in different weather situations. Precipitation analyses from the Deutsche Wetterdienst (DWD) are used as the verifying reference and a comparison of daily rainfall amounts is referred to the respective river basins of the historical cases.
Terrestrial Laser Scanner Two-Face Measurements for Analyzing the Elevation-Dependent Deformation of the Onsala Space Observatory 20-m Radio Telescope’s Main Reflector in a Bundle Adjustment

For accurate astronomic and geodetic observations based on radio telescopes, the elevation-dependent deformation of the radio telescopes’ main reflectors should be known. Terrestrial laser scanning has been used for determining the corresponding changes of focal lengths and areal reflector deformations at several occasions before. New in this publication is the situation in which we minimize systematic measurement errors by an improved measurement and data-processing concept: Sampling the main reflector in both faces of the laser scanner and calibrating the laser scanner in situ in a bundle adjustment. This concept is applied to the Onsala Space Observatory 20-m radio telescope: The focal length of the main reflector decreases by 9.6 mm from 85∘ to 5∘ elevation angle. Further local deformations of the main reflector are not detected.
Multiple Outbreaks of Yersinia pseudotuberculosis Infections in Finland

ABSTRACT During 2001, 89 culture-confirmed cases of Yersinia pseudotuberculosis were reported in Finland; 55 (62%) were serotype O:1, and 34 (38%) were serotype O:3. Four major pulsed-field gel electrophoresis profiles were identified. A case-control study of 25 case patients and 71 healthy controls identified eating outside the home as a risk factor for infection.
Supramolecular Organization of the Repetitive Backbone Unit of the Streptococcus pneumoniae Pilus

Streptococcus pneumoniae, like many other Gram-positive bacteria, assembles long filamentous pili on their surface through which they adhere to host cells. Pneumococcal pili are formed by a backbone, consisting of the repetition of the major component RrgB, and two accessory proteins (RrgA and RrgC). Here we reconstruct by transmission electron microscopy and single particle image reconstruction method the three dimensional arrangement of two neighbouring RrgB molecules, which represent the minimal repetitive structural domain of the native pilus. The crystal structure of the D2-D4 domains of RrgB was solved at 1.6 Å resolution. Rigid-body fitting of the X-ray coordinates into the electron density map enabled us to define the arrangement of the backbone subunits into the S. pneumoniae native pilus. The quantitative fitting provide evidence that the pneumococcal pilus consists uniquely of RrgB monomers assembled in a head-to-tail organization. The presence of short intra-subunit linker regions connecting neighbouring domains provides the molecular basis for the intrinsic pilus flexibility.
Brain Injury-Induced Synaptic Reorganization in Hilar Inhibitory Neurons Is Differentially Suppressed by Rapamycin

Abstract Following traumatic brain injury (TBI), treatment with rapamycin suppresses mammalian (mechanistic) target of rapamycin (mTOR) activity and specific components of hippocampal synaptic reorganization associated with altered cortical excitability and seizure susceptibility. Reemergence of seizures after cessation of rapamycin treatment suggests, however, an incomplete suppression of epileptogenesis. Hilar inhibitory interneurons regulate dentate granule cell (DGC) activity, and de novo synaptic input from both DGCs and CA3 pyramidal cells after TBI increases their excitability but effects of rapamycin treatment on the injury-induced plasticity of interneurons is only partially described. Using transgenic mice in which enhanced green fluorescent protein (eGFP) is expressed in the somatostatinergic subset of hilar inhibitory interneurons, we tested the effect of daily systemic rapamycin treatment (3 mg/kg) on the excitability of hilar inhibitory interneurons after controlled cortical impact (CCI)-induced focal brain injury. Rapamycin treatment reduced, but did not normalize, the injury-induced increase in excitability of surviving eGFP+ hilar interneurons. The injury-induced increase in response to selective glutamate photostimulation of DGCs was reduced to normal levels after mTOR inhibition, but the postinjury increase in synaptic excitation arising from CA3 pyramidal cell activity was unaffected by rapamycin treatment. The incomplete suppression of synaptic reorganization in inhibitory circuits after brain injury could contribute to hippocampal hyperexcitability and the eventual reemergence of the epileptogenic process upon cessation of mTOR inhibition. Further, the cell-selective effect of mTOR inhibition on synaptic reorganization after CCI suggests possible mechanisms by which rapamycin treatment modifies epileptogenesis in some models but not others.
Two open states of P2X receptor channels

The occupancy of the orthosteric ligand binding sites of P2X receptor (P2XR) channels causes the rapid opening of a small cation-permeable pore, followed by a gradual dilation that renders the pore permeable to large organic cations. Electrophysiologically, this phenomenon was shown using whole-cell current recording on P2X2R-, P2X2/X5R-, P2X4R- and P2X7R-expressing cells that were bathed in N-methyl-D-glucamine (NMDG+)-containing buffers in the presence and/or absence of small monovalent and divalent cations. The pore dilation of P2X4R and P2X7R caused a secondary current growth, whereas that of P2X2R showed a sustained kinetic coupling of dilation and desensitization, leading to receptor channel closure. The pore size of the P2X7R open and dilated states was estimated to be approximately 0.85 nm and greater than 1 nm, respectively. The P2XR pore dilation was also observed in intact cells by measurement of fluorescent dye uptake/release, application of polyethylene glycols of different sizes, and atomic force microscopy. However, pore dilation was not observed at the single channel level. Structural data describing the dilated state are not available, and the relevance of orthosteric and allosteric ligand interactions to pore dilation was not studied.
Phonological encoding is not contingent on semantic feature retrieval: an electrophysiological study on object naming.

In the present study, the authors examined with event-related brain potentials whether phonological encoding in picture naming is mediated by basic semantic feature retrieval or proceeds independently. In a manual 2-choice go/no-go task the choice response depended on a semantic classification (animal vs. object) and the execution decision was contingent on a classification of name phonology (vowel vs. consonant). The introduction of a semantic task mixing procedure allowed for selectively manipulating the speed of semantic feature retrieval. Serial and parallel models were tested on the basis of their differential predictions for the effect of this manipulation on the lateralized readiness potential and N200 component. The findings indicate that phonological code retrieval is not strictly contingent on prior basic semantic feature processing.
Physiological Functions of the Cellular Prion Protein

The prion protein, PrPC, is a small, cell-surface glycoprotein notable primarily for its critical role in pathogenesis of the neurodegenerative disorders known as prion diseases. A hallmark of prion diseases is the conversion of PrPC into an abnormally folded isoform, which provides a template for further pathogenic conversion of PrPC, allowing disease to spread from cell to cell and, in some circumstances, to transfer to a new host. In addition to the putative neurotoxicity caused by the misfolded form(s), loss of normal PrPC function could be an integral part of the neurodegenerative processes and, consequently, significant research efforts have been directed toward determining the physiological functions of PrPC. In this review, we first summarise important aspects of the biochemistry of PrPC before moving on to address the current understanding of the various proposed functions of the protein, including details of the underlying molecular mechanisms potentially involved in these functions. Over years of study, PrPC has been associated with a wide array of different cellular processes and many interacting partners have been suggested. However, recent studies have cast doubt on the previously well-established links between PrPC and processes such as stress-protection, copper homeostasis and neuronal excitability. Instead, the functions best-supported by the current literature include regulation of myelin maintenance and of processes linked to cellular differentiation, including proliferation, adhesion, and control of cell morphology. Intriguing connections have also been made between PrPC and the modulation of circadian rhythm, glucose homeostasis, immune function and cellular iron uptake, all of which warrant further investigation.
Resistance to sodium sulfate attack of plain and blended cement containing corncob ash and ground granulated blast furnace slag

In this study blended cements containing corncob ash (CA) and ground granulated blast furnace slag (GGBFS) were investigated. The blended cements were prepared using a clinker, 5% gypsum by weight CA and GGBFS. Different amounts of additives (20 and 40%) were incorporated into these blends in equal amounts. Control cement, that is, plain Portland cement, without any additions, was also prepared and studied in order to establish the effects of additives to cement. Clinkers from Adana, Cimsa and Mardin were used. CA was obtained by burning corncob waste and had a 500 m²/kg Blaine value, and GGBFS was ground to give a Blaine value of 300 m²/kg for all cements. The compressive strengths were measured for 3, 7, 28, 90, and 180 days in tap water. Their sulfate resistance was determined by compressive strengths after 24 months under sulfate conditions. CA and GGBFS gave an activity index grades of 80 and 71%, respectively. The microstructures and morphology of plain and blended cements were studied by scanning electron microscopy. The micrographs showed that these additives provide more condense structures of cement hydration and excellent sulfate resistance. Thus, CA and GGBFS additives in cement production can contribute to the cement durability. Key words: Blended cements, corncob ash, ground granulated blast furnace slag, sulfate.
iPS Cells: Born-Again Stem Cells for Biomedical Applications

1.1 Stemness The fertilized egg, also known as the zygote, is a cell of total potential and plasticity and gives rise to the embryo and extra-embryonic tissues, and ultimately the whole adult organism. This property has since been termed totipotency, although the transition from fertilized egg to differentiated cells of the adult tissues (somatic cells) is not direct, progressing instead through lineages of successively more differentiated and committed intermediates towards the final cell type. Thus, the zygote gives rise to the trophoblast cells and inner cell mass (ICM) of the blastocyst stage embryo, the ICM gives rise to the primordial cells committed to the ectodermal, mesodermal and endodermal lineages. To give an example lineage, the ectoderm cells give rise to the neural crest stem cells, then neural stem cells, oligodendrocyte precursors, and finally oligodendrocytes which myelinate and form the white matter of the central nervous system. Each step is more specialized and less plastic than the base or ‘stem’ of the branch before it. Unlike the totipotent zygote, these ‘stem cells’ retain the ability to self-renew in addition to their plasticity. In addition to giving rise to somatic tissues during embryogenesis, the biological role of stem cells in an adult organism is to regenerate tissues lost to injury, disease or age.
Fatal Apnea in Piglets by way of Laryngeal Chemoreflex: Postmortem Findings as Anatomic Correlates of Sudden Infant Death Syndrome in the Human Infant

Objectives/Hypothesis: Intrathoracic petechiae are a prominent diagnostic finding in sudden infant death syndrome (SIDS) victims. In this study, the laryngeal chemoreflex (LCR) was elicited experimentally to discover whether intrathoracic petechiae would be produced by way of the LCR. The hypothesis was that water stimulation of the larynx in piglets, leading to death by prolonged apnea, would produce postmortem findings similar to those found in SIDS victims.
Transducer‐based evaluation of tremor

The International Parkinson and Movement Disorder Society established a task force on tremor that reviewed the use of transducer‐based measures in the quantification and characterization of tremor. Studies of accelerometry, electromyography, activity monitoring, gyroscopy, digitizing tablet‐based measures, vocal acoustic analysis, and several other transducer‐based methods were identified by searching PubMed.gov. The availability, use, acceptability, reliability, validity, and responsiveness were reviewed for each measure using the following criteria: (1) used in the assessment of tremor; (2) used in published studies by people other than the developers; and (3) adequate clinimetric testing. Accelerometry, gyroscopy, electromyography, and digitizing tablet‐based measures fulfilled all three criteria. Compared to rating scales, transducers are far more sensitive to changes in tremor amplitude and frequency, but they do not appear to be more capable of detecting a change that exceeds random variability in tremor amplitude (minimum detectable change). The use of transducer‐based measures requires careful attention to their limitations and validity in a particular clinical or research setting. © 2016 International Parkinson and Movement Disorder Society
“In-situ” Observation of Remelting Phenomenon after Solidification of Fe–B Alloy and B-bearing Commercial Steels

It is well known that boron (B) addition to steels can cause difficulties during continuous casting. The difficulty includes surface cracks, internal half-way cracks as well as centerline problems on the cast products. In severe cases, a breakout can occur during casting of B-bearing steels. According to the studies of the effect of boron on the pseudo-binary phase diagrams of Fe–B alloys at various carbon levels by the authors, it was found that the addition of boron introduces the possibility of steel initially completely solidifying followed by a retrograde melting phenomenon in all C contents below 1%. This retrograde melting phenomenon will most likely occur at interdendritic regions and grain boundaries at temperatures approaching 1350°C. The remelt liquid will be retained down to temperatures approaching 1100°C. The retention of this low melting point phase during casting is believed to be the primary cause of casting difficulties of the B-bearing commercial products.In order to confirm the modeling study of the phase diagrams and the finding of the remelting phenomenon, Confocal Scanning Laser Microscope (CSLM) studies were carried out for “in-situ” observation. These studies not only confirmed the existence of the retrograde-melting phenomenon at temperatures below 1200°C, but also revealed that severe segregation of B in steel could cause the existence of liquid phase down to at least 1350°C even in steels bearing as little as 10 ppm B. The present paper will summarize the observation results.
Leaf dynamics in growth and reproduction of Xanthium canadense as influenced by stand density

Background and Aims Leaf longevity is controlled by the light gradient in the canopy and also by the nitrogen (N) sink strength in the plant. Stand density may influence leaf dynamics through its effects on light gradient and on plant growth and reproduction. This study tests the hypothesis that the control by the light gradient is manifested more in the vegetative period, whereas the opposite is true when the plant becomes reproductive and develops a strong N sink. Methods Stands of Xanthium canadense were established at two densities. Emergence, growth and death of every leaf on the main stem and branches, and plant growth and N uptake were determined from germination to full senescence. Mean residence time and dry mass productivity were calculated per leaf number, leaf area, leaf mass and leaf N (collectively termed ‘leaf variables’) in order to analyse leaf dynamics and its effect on plant growth. Key Results Branching and reproductive activities were higher at low than at high density. Overall there was no significant difference in mean residence time of leaf variables between the two stands. However, early leaf cohorts on the main stem had a longer retention time at low density, whereas later cohorts had a longer retention time at high density. Branch leaves emerged earlier and tended to live longer at low than at high density. Leaf efficiencies, defined as carbon export per unit investment of leaf variables, were higher at low density in all leaf variables except for leaf number. Conclusions In the vegetative phase of plant growth, the light gradient strongly controls leaf longevity, whereas later the effects of branching and reproductive activities become stronger and over-rule the effect of light environment. As leaf N supports photosynthesis and also works as an N source for plant development, N use is pivotal in linking leaf dynamics with plant growth and reproduction.