Miracle-dz/UniFAR-FTUs huggingface dataset:
The Protein Kinase Cβ–Selective Inhibitor, Enzastaurin (LY317615.HCl), Suppresses Signaling through the AKT Pathway, Induces Apoptosis, and Suppresses Growth of Human Colon Cancer and Glioblastoma Xenografts

Activation of protein kinase Cβ (PKCβ) has been repeatedly implicated in tumor-induced angiogenesis. The PKCβ-selective inhibitor, Enzastaurin (LY317615.HCl), suppresses angiogenesis and was advanced for clinical development based upon this antiangiogenic activity. Activation of PKCβ has now also been implicated in tumor cell proliferation, apoptosis, and tumor invasiveness. Herein, we show that Enzastaurin has a direct effect on human tumor cells, inducing apoptosis and suppressing the proliferation of cultured tumor cells. Enzastaurin treatment also suppresses the phosphorylation of GSK3β ser9 , ribosomal protein S6 S240/244 , and AKT Thr308 . Oral dosing with Enzastaurin to yield plasma concentrations similar to those achieved in clinical trials significantly suppresses the growth of human glioblastoma and colon carcinoma xenografts. As in cultured tumor cells, Enzastaurin treatment suppresses the phosphorylation of GSK3β in these xenograft tumor tissues. Enzastaurin treatment also suppresses GSK3β phosphorylation to a similar extent in peripheral blood mononuclear cells (PBMCs) from these treated mice. These data show that Enzastaurin has a direct antitumor effect and that Enzastaurin treatment suppresses GSK3β phosphorylation in both tumor tissue and in PBMCs, suggesting that GSK3β phosphorylation may serve as a reliable pharmacodynamic marker for Enzastaurin activity. With previously published reports, these data support the notion that Enzastaurin suppresses tumor growth through multiple mechanisms: direct suppression of tumor cell proliferation and the induction of tumor cell death coupled to the indirect effect of suppressing tumor-induced angiogenesis.
Mandibular implant-supported overdentures and oral function.

OBJECTIVES Oral rehabilitation by means of implant-retained mandibular overdentures is known to improve oral function. The aim of this study was to evaluate the long-term effects of mandibular implant treatment on oral function. We quantified maximum bite force and masticatory performance 10 years after implant treatment. It was hypothesized that these outcome measures would not change in this period. MATERIALS AND METHODS Eighteen edentulous patients were scheduled for re-evaluation of their oral function 10 years after they had participated in a randomized cross-over clinical trial. In that trial, they had received two mandibular implants and a new denture with successively magnet-, ball-socket, and bar-clip attachments. RESULTS At the 10-year follow-up, 14 of the initial 18 patients participated in the evaluation. As a result of the implant treatment, the average maximum bite force more than doubled, from 162 to 341 N, whereas the average number of chewing cycles to halve the initial particle size decreased from 55 to 27 cycles. No significant changes in maximum bite force and masticatory performance were observed after 10 years. However, the average maximum bite force obtained with implant-retained overdentures is still significantly lower than that of dentate subjects (569 N). CONCLUSION Maximum bite force and masticatory performance significantly increased after implant treatment and remained unaltered during the following 10-year period. Thus, implant treatment greatly improves oral function for a long period of time.
Covalent activation of retinal rod cGMP-gated channels reveals a functional heterogeneity in the ligand binding sites

Ion channels gated by the binding of multiple ligands play a critical role in synaptic transmission and sensory transduction. It has been difficult to resolve the contribution of individual binding events to channel gating because ligands are continuously binding and unbinding at each site. In examining the allosteric mechanism of retinal rod cGMP- gated channels, we have circumvented this problem by making use of a cGMP derivative, 8-p-azidophenacylthio-cGMP (APT-cGMP), that can be covalently tethered to the binding sites in the presence of long- wavelength UV light. In excised membrane patches, a population of channels was isolated that contained covalently-attached ligands at all but one site. Activation of these channels by cGMP revealed a previously unknown heterogeneity in the ligand-binding sites. The dose- response relations were much shallower than predicted by single-site activation models, but were well described by models in which there are two populations of sites, in roughly equal proportion, that bind cGMP with apparent affinities that differ by a factor of 25. The two apparent affinities, incorporated into a four-site model of the channel, provided an accurate description of the patch's original dose- response relation. A comparison of results on native and expressed channels suggests that the heterogeneity in the native channel arises at least in part from the presence of two different cGMP-binding subunits.
Cooperative signalling between opponents in fish fights

Cichlids of the species Nannacara anomala employ several colour displays during fights which do not seem to signal either fighting ability or motivation. How should these colour displays be interpreted when winning is reliably predicted by weight asymmetries? Medial Line colour displays were associated with, and predicted, tail-beating, while Vertical Bar colour displays were associated with mouth-wrestling. I suggest that these colour displays are used to facilitate the transmission of assessment information within a fight, and that they are an example of cooperative signalling between opponents. The results support the idea that the structure of fights contains strong cooperative aspects.Copyright 1997 The Association for the Study of Animal Behaviour1997The Association for the Study of Animal Behaviour
Functional activation of the human frontal cortex during the performance of verbal working memory tasks.

Regional cerebral blood flow was measured with positron emission tomography during the performance of verbal working memory tasks. The same type of verbal response (i.e., reciting numbers) was required in the control and the two experimental tasks. In the control task, the subjects were required to count aloud. In the two experimental tasks, the subjects were required to maintain within working memory the numbers they generated (self-ordered task) or the numbers generated by the experimenter (externally ordered task). Examination of the difference in activation between these conditions revealed strong bilateral activation within the mid-dorsolateral frontal cortex during both experimental tasks. There was, however, no evidence of additional activation within the mid-dorsolateral frontal cortex when monitoring self-generated responses as compared with the monitoring of externally generated responses. These results provide evidence regarding the role of the mid-dorsolateral frontal cortex in mnemonic processing that are in agreement with recent findings from work with non-human primates.
What predicts poor mother–infant interaction in schizophrenia?

Background. Poor clinician-rated parenting outcome and observed interactive deficits in mothers with schizophrenia admitted to a psychiatric mother and baby unit (MBU) reflect continuing concerns over the parenting capacity of this group. However, little is known about whether interaction deficits are accounted for by severity of illness or adverse social circumstances typically experienced by these mothers. Method. Thirty-eight women with severe perinatal illness (schizophrenia n=13; affective disorders n=25) and their infants were observed in play interaction a week prior to MBU discharge. Clinical and sociodemographic data were also obtained. Results. Mothers with schizophrenia and their infants were rated to have poorer interactive behaviour than the affective disorders group. Infant avoidance of the mother was associated with a lack of maternal sensitivity and responsiveness. The deficits in mother–infant interaction found in the schizophrenia group could not be accounted for by our measures of illness severity or factors relating to adverse social circumstances. Conclusions. The results replicate and extend previous findings showing poor interactive behaviours in mothers with schizophrenia, their infants, and in the dyad, in a range of areas following clinical recovery. The findings suggest that factors other than illness duration, dose of medication, marital status and occupational status are explanatory for the interactive deficits associated with maternal schizophrenia. Parenting interventions that aim to improve maternal sensitivity need to be developed specifically for this group.
Asymmetry of attentional set in rhesus monkeys learning colour and shape discriminations

We trained rhesus monkeys on six visual discrimination problems using stimuli that varied in both shape and colour. For one group of animals shape was always relevant in these six problems, and colour always irrelevant, and for the other animals vice versa. During these “intradimensional shifts” (ID) the problems were learned at equal rates by the two groups, shape-relevant and colour-relevant. We then trained three further problems in which the other dimension was now relevant (“extradimensional shifts”, ED). The animals showed slower learning when shifting from colour-relevant to shape-relevant, but not when shifting from shape-relevant to colour-relevant. These results show that monkeys’ ability to selectively attend to a relevant stimulus dimension and to ignore an irrelevant dimension depends on the experimenter's choice of relevant and irrelevant dimensions.
The complexity of genotypic alterations underlying HER2-positive breast cancer: an explanation for its clinical heterogeneity

Purpose of review We discuss recent findings on the genotypic alterations associated with HER2-positive breast cancer in an attempt to clarify the clinical heterogeneity observed among these tumors. Recent findings Molecular genetic analysis supports the distinctive nature of HER2-positive breast cancer, which is primarily driven by HER2 gene amplification. Depending on the amplicon size, a variety of genes can be coamplified and overexpressed together with HER2, some of which may contribute to tumorigenesis; the amplicon size may even predict response to trastuzumab therapy. HER2 gene amplification may further destabilize the tumor genome, facilitating the generation of additional genomic aberrations including aneuploidy. The latter might imply polysomy 17, a phenomenon that should be discriminated from true HER2 gene amplification: polysomy 17 in the absence of HER2 gene amplification is not associated with HER2 overexpression nor with the clinical characteristics of HER2-positive breast cancer. Summary HER2 gene amplification is a complex event: it includes coamplification of other, potentially oncogenic genes and facilitates the generation of additional genomic aberrations. Further studies on these genotypic findings will be helpful to better identify the patients that might benefit from trastuzumab therapy.
Current Methods for the Assessment of Oxygen Status and Biotissue Microcirculation Condition: Diffuse Optical Spectroscopy (Review)

V.V. Beschastnov, MD, DSc, Consulting Professor, Surgical Unit1; М. G. Ryabkov, MD, DSc, Consulting Professor, Surgical Unit1; I.V. Pavlenko, Resident, Surgical Unit1; М. V. Bagryantsev, Resident, Surgical Unit1; I.L. Dezortsev, MD, PhD, Head of the First Surgical Unit2; V.V. Kichin, Resident, Surgical Unit1; М. S. Baleyev, Resident, Surgical Unit1; А. V. Maslennikova, MD, DSc, Professor, Oncology Department3; А. G. Orlova, PhD, Senior Researcher, Department of Radiophysical Methods in Medicine4; М. S. Kleshnin, Researcher, Department of Radiophysical Methods in Medicine4; I.V. Turchin, PhD, Head of the Department of Radiophysical Methods in Medicine4
Comparisons of the Glycosylation of a Monoclonal Antibody Produced under Nominally Identical Cell Culture Conditions in Two Different Bioreactors

The murine B‐lymphocyte hybridoma cell line, CC9C10, was grown in serum‐free continuous culture at steady‐state dissolved oxygen (DO) concentrations of 10%, 50%, and 100% of air saturation in both LH Series 210 (LH) and New Brunswick Scientific (NBS) CelliGen bioreactors. All culture parameters were monitored and controlled and were nominally identical at steady state in the two bioreactors. The secreted monoclonal antibody (mAb), an immunoglobulin G1, was purified and subjected to enzymatic deglycosylation using peptide N‐glycosidase F (PNGase F). Asparagine‐linked (N‐linked) oligosaccharide pools released from mAb samples cultured in each bioreactor at each of the three DO setpoints were analyzed by high‐pH anion‐exchange chromatography with pulsed amperometric detection (HPAEC‐PAD). The predominant N‐linked structures were core‐fucosylated asialo biantennary chains with varying galactosylation. There were also minor amounts of monosialyl oligosaccharides and trace amounts of afucosyl oligosaccharides. The level of DO affects the glycosylation of this mAb. A definite reduction in the level of galactosylation of N‐glycan chains was observed at lower DO in both bioreactors, as evidenced by prominent increases in the relative amounts of agalactosyl chains and decreases in the relative amounts of digalactosyl chainswith the relative amounts of monogalactosyl chains being comparatively constant. However, the quantitative results are not precise matches between the two bioreactors. The effect of DO on galactosylation is less pronounced in the NBS bioreactor than in the LH bioreactor, particularly the shift between the relative amounts of agalactosyl and digalactosyl chains in 10% and 50% DO. There are also perceptibly higher levels of sialylation of the mAb glycans in the NBS bioreactor than in the LH bioreactor at all three DO setpoints. The results indicate that the DO effect is not bioreactor specific and that nominally identical steady‐state conditions in different chemostat bioreactors may still lead to some incongruities in glycosylation, possibly due to the particular architectures of the bioreactors and the design of their respective monitoring and control systems. The observed differences in N‐linked glycosylation of the mAb secreted by the hybridoma grown in the LH and NBS bioreactors may be explained by the differences in oxygen supply and control strategies between the two bioreactors.
Narrow-band pass filter array for integrated opto-electronic spectroscopy detectors to assess esophageal tissue

A strategy for spectroscopy tissue diagnosis using a small number of wavelengths is reported. The feasibility to accurately quantify tissue information using only 16 wavelengths is demonstrated with several wavelength reduction simulations of the existing esophageal data set. These results are an important step for the development of a miniaturized, robust and low-cost spectroscopy system. This system is based on a sub-millimeter high-selective filter array that offers prospects for a simplified miniature spectrographic detector for a future diagnostic tool to improve the diagnosis of dysplasia. Several thin-film optical filters are optimized and fabricated and its spectral performance is shown to be sufficient for the selection of specific wavelength bands.
MGUard versus bAre‐metal stents plus manual thRombectomy in ST‐elevation myocarDial infarction pAtieNts—(GUARDIAN) trial: Study design and rationale

Background: Distal embolization may decrease coronary and myocardial reperfusion after percutaneous coronary intervention (PCI) in ST‐elevation myocardial infarction (STEMI). In this setting, manual thrombectomy (MT) resulted in better perfusion and clinical outcomes when compared with “conventional” PCI (direct stenting or stenting after predilation). MGuard net protective stent (MGS, Inspire‐MD, Tel‐Aviv, Israel) is a new bare‐metal stent (BMS) with a polyethylene theraphthalate mesh coverage anchored to the external surface of the struts aiming to minimize distal embolization during PCI. Purpose: We intend to determine whether MGS implantation is comparable with a strategy of MT pretreatment followed by BMS deployment. Study design: The MGUard versus bAre‐metal stents plus manual thRombectomy in ST‐elevation myocarDial Infarction pAtieNts (GUARDIAN) is a multicentre, prospective, randomized, noninferiority, open‐label trial with a planned inclusion of 556 STEMI patients. Patients are assigned to treatment with MGS or MT pretreatment followed by BMS implantation in the infarct‐related artery. All patients are treated medically according to current international guidelines. Randomization is performed before coronary angiography. The primary endpoint is complete (≥70%) ST‐segment resolution at 60 min after PCI. Secondary endpoints are thrombolysis in myocardial infarction (TIMI) coronary flow grade ≥2, corrected TIMI frame count <23, myocardial blush grade of the infarct related area ≥2, and major adverse cardiac events rate at 30‐day, 6‐month, and 1‐year follow‐up. A cardiac magnetic resonance imaging substudy is planned to investigate microvascular obstruction and infarct size area reduction, at prespecified time‐points, among 80 consecutive patients enrolled. Conclusions: If MGS implantation is noninferior to a strategy of MT pretreatment followed by BMS deployment, it will lend support to the use of this treatment as another possible option for STEMI patients undergoing PCI. © 2012 Wiley Periodicals, Inc.
Antibiotics: Responding to a Global Challenge

The miracle of antibiotics is hard to exaggerate. Each day, in every corner of the world, antibiotics improve, or could be improving outcomes in the septic neonate, the child with pneumonia, the new mother after a complicated delivery, the patient undergoing surgery, the nursing home resident with a urinary tract infection, the patient being treated of cancer, or the trauma patient on life support. The miracle also keeps our animals healthy for effective food production. But the miracle of these 'wonder drugs' is under threat and may be short lived: antimicrobial resistance is relentlessly increasing, especially for Gram negative organisms, prompting the oft expressed concern that we are plummeting head-long back into the pre-antibiotics era where clinicians and families once again will have to stand by and watch patients and loved ones die from once easily-treated infections. [. ].
Great Lakes embryo mortality, edema, and deformities syndrome (GLEMEDS) in colonial fish-eating birds: similarity to chick-edema disease.

Several species of colonial fish-eating birds nesting in the Great Lakes basin, including herring gulls, common terns and double-crested cormorants, have exhibited chronic impairment of reproduction. In addition to eggshell thinning caused by high levels of DDT and metabolites, the reproductive impairment is characterized by high embryonic and chick mortality, edema, growth retardation, and deformities, hence the name Great Lakes embryo mortality, edema, and deformities syndrome (GLEMEDS). The hypothesis has been advanced that GLEMEDS in colonial fish-eating birds resembles chick-edema disease of poultry and has been caused by exposure to chick-edema active compounds that have a common mode of action through the cytochrome P-448 system. Detailed evidence has been collected from the following three groups of studies on herring gulls in the lower Great Lakes during the early 1970s; Forster's terns in Green Bay, Wisconsin in 1983; and double-crested cormorants and Caspian terns in various locations in the upper Great Lakes from 1986 onwards. It has proved difficult to establish not only the onset of the disease in the various species at various locations but also the period in which chick-edema active compounds were released. Anecdotal evidence suggested that serious egg mortality in Lake Ontario herring gulls first occurred in 1966, through the signs of chick-edema disease were not looked for until 1974. Only indirect evidence is available on the date of the release of one of the presumed causal agents, 2,3,7,8-tetrachlorodibenzo-p-dioxin, but highest levels may have occurred in the early to mid 1960s. More reliable data show that the onset of the improvement of reproduction of Lake Ontario herring gulls coincided with the declines in organochlorine compounds and particularly 2,3,7,8-TCDD and PCB. Similarly, information on the onset of the disease and exposures in the Forster's tern and double-crested cormorants in Green Bay is uncertain but bird banders did not observe deformities until the 1970s, which corresponds with the onset of high levels of PCB. If the disappearance of the Caspian tern from Saginaw Bay in the mid 1960s corresponds with the onset of GLEMEDS at that location, then there is a close temporal relationship to the onset of high PCB levels. Chick-edema disease is difficult to diagnose because there is no specific lesion, but rather there is a suite of lesions. (ABSTRACT TRUNCATED AT 400 WORDS)
RNA-Mediated Silencing in Algae: Biological Roles and Tools for Analysis of Gene Function

ABSTRACT Algae are a large group of aquatic, typically photosynthetic, eukaryotes that include species from very diverse phylogenetic lineages, from those similar to land plants to those related to protist parasites. The recent sequencing of several algal genomes has provided insights into the great complexity of these organisms. Genomic information has also emphasized our lack of knowledge of the functions of many predicted genes, as well as the gene regulatory mechanisms in algae. Core components of the machinery for RNA-mediated silencing show widespread distribution among algal lineages, but they also seem to have been lost entirely from several species with relatively small nuclear genomes. Complex sets of endogenous small RNAs, including candidate microRNAs and small interfering RNAs, have now been identified by high-throughput sequencing in green, red, and brown algae. However, the natural roles of RNA-mediated silencing in algal biology remain poorly understood. Limited evidence suggests that small RNAs may function, in different algae, in defense mechanisms against transposon mobilization, in responses to nutrient deprivation and, possibly, in the regulation of recently evolved developmental processes. From a practical perspective, RNA interference (RNAi) is becoming a promising tool for assessing gene function by sequence-specific knockdown. Transient gene silencing, triggered with exogenously synthesized nucleic acids, and/or stable gene repression, involving genome-integrated transgenes, have been achieved in green algae, diatoms, yellow-green algae, and euglenoids. The development of RNAi technology in conjunction with system level “omics” approaches may provide the tools needed to advance our understanding of algal physiological and metabolic processes.