tbuckley/cabot-search huggingface dataset:
The magical number 4 in short-term memory: A reconsideration of mental storage capacity
Authors: Nelson Cowan
Journal: Behavioral and Brain Sciences (2001)

Miller (1956) summarized evidence that people can remember about seven chunks in short-term memory (STM) tasks. However, that number was meant more as a rough estimate and a rhetorical device than as a real capacity limit. Others have since suggested that there is a more precise capacity limit, but that it is only three to five chunks. The present target article brings together a wide variety of data on capacity limits suggesting that the smaller capacity limit is real. Capacity limits will be useful in analyses of information processing only if the boundary conditions for observing them can be carefully described. Four basic conditions in which chunks can be identified and capacity limits can accordingly be observed are: (1) when information overload limits chunks to individual stimulus items, (2) when other steps are taken specifically to block the recoding of stimulus items into larger chunks, (3) in performance discontinuities caused by the capacity limit, and (4) in various indirect effects of the capacity limit. Under these conditions, rehearsal and long-term memory cannot be used to combine stimulus items into chunks of an unknown size; nor can storage mechanisms that are not capacity-limited, such as sensory memory, allow the capacity-limited storage mechanism to be refilled during recall. A single, central capacity limit averaging about four chunks is implicated along with other, noncapacity-limited sources. The pure STM capacity limit expressed in chunks is distinguished from compound STM limits obtained when the number of separately held chunks is unclear. Reasons why pure capacity estimates fall within a narrow range are discussed and a capacity limit for the focus of attention is proposed.
ERJ Open Research: FAQs
Authors: Anita K. Simonds, Elin L. Reeves
Journal: European Respiratory Journal (2015)

ERJ Open Research launched in May 2015. It has been an exciting and busy couple of months since the launch and we've been pleased with the response from readers and authors that we've received so far. The editorial board has already had several teleconferences and a face-to-face meeting, and we are looking forward to our first official editorial board meeting taking place at the European Respiratory Society (ERS) International Congress in Amsterdam in September 2015, where we hope to discuss new ideas for evolving our young journal. Introducing ERJ Open Research: everything you need to know about the new open access journal from the ERS <http://ow.ly/OnBXf>
Eosinophilic airway inflammation and exacerbations of COPD: a randomised controlled trial
Authors: R. Siva, R. H. Green, C. E. Brightling, M. Shelley, B. Hargadon, S. McKenna, W. Monteiro, M. Berry, D. Parker, A. J. Wardlaw, I. D. Pavord
Journal: European Respiratory Journal (2007)

Evidence suggests that eosinophilic airway inflammation is important in the pathogenesis of severe chronic obstructive pulmonary disease (COPD) exacerbations. The present authors tested the hypothesis that a management strategy that aims to reduce sputum eosinophil counts is associated with a reduction in exacerbations of COPD. A total of 82 patients with COPD were randomised into two groups. One group was treated according to traditional guidelines (British Thoracic Society (BTS) group) and the other (sputum group) was treated with the additional aim of minimising eosinophilic airway inflammation, assessed using the induced sputum eosinophil count. The primary outcome was exacerbations, which were categorised as mild, moderate or severe. The frequency of severe exacerbations per patient per year was 0.5 and 0.2 in the BTS and sputum groups, respectively (mean reduction 62%). The majority of this benefit was confined to patients with eosinophilic airway inflammation. There was no difference in the frequency of mild and moderate exacerbations. The average daily dose of inhaled or oral corticosteroids during the trial did not differ between the groups. Out of 42 patients in the sputum group, 17 required regular oral corticosteroids to minimise eosinophilic airway inflammation. A management strategy that aims to minimise eosinophilic airway inflammation, as well as symptoms, is associated with a reduction in severe exacerbations of chronic obstructive pulmonary disease.
Ki-67 as a Molecular Target for Therapy in an <i>In vitro</i> Three-Dimensional Model for Ovarian Cancer
Authors: Ramtin Rahmanzadeh, Prakash Rai, Jonathan P. Celli, Imran Rizvi, Bettina Baron-Lühr, Johannes Gerdes, Tayyaba Hasan
Journal: Cancer Research (2010)

Targeting molecular markers and pathways implicated in cancer cell growth is a promising avenue for developing effective therapies. Although the Ki-67 protein (pKi-67) is a key marker associated with aggressively proliferating cancer cells and poor prognosis, its full potential as a therapeutic target has never before been successfully shown. In this regard, its nuclear localization presents a major hurdle because of the need for intracellular and intranuclear delivery of targeting and therapeutic moieties. Using a liposomally encapsulated construct, we show for the first time the specific delivery of a Ki-67-directed antibody and subsequent light-triggered death in the human ovarian cancer cell line OVCAR-5. Photoimmunoconjugate-encapsulating liposomes (PICEL) were constructed from anti-pKi-67 antibodies conjugated to fluorescein 5(6)-isothiocyanate, as a photoactivatable agent, followed by encapsulation in noncationic liposomes. Nucleolar localization of the PICELs was confirmed by confocal imaging. Photodynamic activation with PICELs specifically killed pKi-67-positive cancer cells both in monolayer and in three-dimensional (3D) cultures of OVCAR-5 cells, with the antibody TuBB-9 targeting a physiologically active form of pKi-67 but not with MIB-1, directed to a different epitope. This is the first demonstration of (a) the exploitation of Ki-67 as a molecular target for therapy and (b) specific delivery of an antibody to the nucleolus in monolayer cancer cells and in an in vitro 3D model system. In view of the ubiquity of pKi-67 in proliferating cells in cancer and the specificity of targeting in 3D multicellular acini, these findings are promising and the approach merits further investigation.
Comparison of the Systemic and Intratumoral Effects of Tamoxifen and the Aromatase Inhibitor Vorozole in Postmenopausal Patients With Primary Breast Cancer
Authors: C. L. Harper-Wynne
Journal: Journal of Clinical Oncology (2002)

PURPOSE: To determine biologic differences, if any, between presurgical endocrine treatment with an aromatase inhibitor (vorozole) and tamoxifen in patients with postmenopausal primary breast cancer. PATIENTS AND METHODS: Randomization was to 12 weeks of 2.5 mg of vorozole per day or 20 mg of tamoxifen per day, both orally. Clinical response was assessed monthly together with serum sex hormone binding globulin (SHBG), luteinizing hormone (LH), follicle-stimulating hormone (FSH), estrogens (E1, E2, and E1S), lipids, insulin-like growth factor-1 (IGF-1), and bone metabolites (CrossLaps CTx). Tissue samples for Ki67, apoptotic index (AI), estrogen receptor, and progesterone receptor were collected at 0, 2, and 12 weeks. RESULTS: Ki67 fell by 58% and 43% (means) at 2 weeks in the vorozole and tamoxifen patients, respectively (P = .13). In the vorozole group, the correlations of proportional changes in Ki67 at 2 weeks with tumor volume changes and clinical response at 12 weeks were not significant (P = .09) and marginally significant (P = .04), respectively. Serum lipids did not differ between groups. Serum levels of EI, E2, and E1S were suppressed markedly by vorozole, whereas levels of SHBG increased and LH and FSH fell significantly with tamoxifen. IGF-1 levels fell significantly with tamoxifen (P = .001) compared with the nonsignificant rise with vorozole. Twelve-week CTx values fell by 19% with tamoxifen (P = .006) and rose by 11% with vorozole (P = .15). CONCLUSION: The correlation with vorozole of Ki67 with volume and clinical response supports this as an intermediate marker. The nonsignificant effects on bone and lipid metabolism by the aromatase inhibitor may be important to consider for adjuvant and potential prevention strategies.
Cognitive Dysfunction Is Associated With Poor Socioeconomic Status in Patients With Cirrhosis: An International Multicenter Study
Authors: Jasmohan S. Bajaj, Oliviero Riggio, Sanath Allampati, Ravi Prakash, Stefania Gioia, Eugenia Onori, Nicole Piazza, Nicole A. Noble, Melanie B. White, Kevin D. Mullen
Journal: Clinical Gastroenterology and Hepatology (2013)
Targeted p16Ink4a epimutation causes tumorigenesis and reduces survival in mice
Authors: Da-Hai Yu, Robert A. Waterland, Pumin Zhang, Deborah Schady, Miao-Hsueh Chen, Yongtao Guan, Manasi Gadkari, Lanlan Shen
Journal: Journal of Clinical Investigation (2014)

Cancer has long been viewed as a genetic disease; however, epigenetic silencing as the result of aberrant promoter DNA methylation is frequently associated with cancer development, suggesting an epigenetic component to the disease. Nonetheless, it has remained unclear whether an epimutation (an aberrant change in epigenetic regulation) can induce tumorigenesis. Here, we exploited a functionally validated cis-acting regulatory element and devised a strategy to induce developmentally regulated genomic targeting of DNA methylation. We used this system to target DNA methylation within the p16(Ink4a) promoter in mice in vivo. Engineered p16(Ink4a) promoter hypermethylation led to transcriptional suppression in somatic tissues during aging and increased the incidence of spontaneous cancers in these mice. Further, mice carrying a germline p16(Ink4a) mutation in one allele and a somatic epimutation in the other had accelerated tumor onset and substantially shortened tumor-free survival. Taken together, these results provide direct functional evidence that p16(Ink4a) epimutation drives tumor formation and malignant progression and validate a targeted methylation approach to epigenetic engineering.
Rhabdoid Tumor of the Kidney in The National Wilms' Tumor Study: Age at Diagnosis As a Prognostic Factor
Authors: Gail E. Tomlinson, Norman E. Breslow, Jeffrey Dome, Katherine Adams Guthrie, Pat Norkool, Sierra Li, Patrick R.M. Thomas, Elizabeth Perlman, J. Bruce Beckwith, Giulio J. D'Angio, Daniel M. Green
Journal: Journal of Clinical Oncology (2005)

The objective of this study is to determine prognostic factors in rhabdoid tumor of the kidney (RTK), including both demographic and treatment variables.A total of 142 patients studied on National Wilms' Tumor Studies 1, 2, 3, 4, and 5 were analyzed. Patients were enrolled between the years 1969 and 2002. Variables examined included sex, age of diagnosis, tumor stage, presence of CNS lesions, as well as treatment variables, including the use of doxorubicin and/or radiotherapy (RT).No survival differences were observed between males and females, between those treated with or without doxorubicin, or with or without RT. Patients with tumors of lower stage had an overall survival rate of 41.8%, whereas, tumors of higher stage were associated with a 15.9% survival (P < .001). A highly significant difference in survival was noted when patients were stratified according to age of diagnosis. Survival at 4 years in infants under 6 months of age at diagnosis was 8.8%, whereas, survival in patients 2 years of age or older was 41.1% (P < .0001). Stratification into intermediate age brackets demonstrated a strong correlation of increasing survival with increasing age at diagnosis. All patients with a CNS lesion, except one, died.Age at diagnosis is a highly significant prognostic factor for survival of children with RTK. Infants have a dismal prognosis, whereas, older children have a more favorable outcome. Higher tumor stage and presence of a CNS lesion were both factors predictive of a poor survival rate.
Molecular Evolution of Cytochrome c Oxidase Underlies High-Altitude Adaptation in the Bar-Headed Goose
Authors: G. R. Scott, P. M. Schulte, S. Egginton, A. L. M. Scott, J. G. Richards, W. K. Milsom
Journal: Molecular Biology and Evolution (2010)

Bar-headed geese (Anser indicus) fly at up to 9,000 m elevation during their migration over the Himalayas, sustaining high metabolic rates in the severe hypoxia at these altitudes. We investigated the evolution of cardiac energy metabolism and O2 transport in this species to better understand the molecular and physiological mechanisms of high-altitude adaptation. Compared with low-altitude geese (pink-footed geese and barnacle geese), bar-headed geese had larger lungs and higher capillary densities in the left ventricle of the heart, both of which should improve O2 diffusion during hypoxia. Although myoglobin abundance and the activities of many metabolic enzymes (carnitine palmitoyltransferase, citrate synthase, 3-hydroxyacyl-coA dehydrogenase, lactate dehydrogenase, and pyruvate kinase) showed only minor variation between species, bar-headed geese had a striking alteration in the kinetics of cytochrome c oxidase (COX), the heteromeric enzyme that catalyzes O2 reduction in oxidative phosphorylation. This was reflected by a lower maximum catalytic activity and a higher affinity for reduced cytochrome c. There were small differences between species in messenger RNA and protein expression of COX subunits 3 and 4, but these were inconsistent with the divergence in enzyme kinetics. However, the COX3 gene of bar-headed geese contained a nonsynonymous substitution at a site that is otherwise conserved across vertebrates and resulted in a major functional change of amino acid class (Trp-116 → Arg). This mutation was predicted by structural modeling to alter the interaction between COX3 and COX1. Adaptations in mitochondrial enzyme kinetics and O2 transport capacity may therefore contribute to the exceptional ability of bar-headed geese to fly high.
DIFFERENTIAL OUTCOMES WITH CHELATION THERAPY AMONG PATIENTS WITH ANTERIOR VERSUS NON-ANTERIOR MYOCARDIAL INFARCTION: A TACT SUBSTUDY
Authors: Eldrin F. Lewis, Gervasio Lamas, Daniel Mark, Yves Rosenberg, Robin Boineau, Rhonda S. Roberts, Christine Goertz, Mario Stylianou, Lauren Lindblad, Kerry Lee
Journal: Journal of the American College of Cardiology (2014)
Polyvinyl alcohol and amino acids as substitutes for bovine serum albumin in culture media for mouse preimplantation embryos
Authors: J. Biggers
Journal: Human Reproduction Update (1997)

The effect of replacing bovine serum albumin (BSA) in a simple defined medium (KSOM) with polyvinyl alcohol (PVA) and/or amino acids on the percentages of mouse zygotes that develop to at least the blastocyst stage and that hatch at least partially or completely is reported. Blastocysts could form when BSA was replaced with only PVA, but at a moderately reduced rate; however, partial hatching, and hence complete hatching, were severely impaired when BSA was replaced with only PVA. The substitution of BSA with amino acids alone resulted in a high rate of blastocyst formation and moderate impairment of hatching. The addition of PVA to BSA-free DSOM supplemented with amino acids had no extra effect. BSA had significant effects when added to BSA-free KSOM supplemented with amino acids. The BSA caused a significant increase in the rate of partial hatching, and may even have had a small effect on the rate of blastocyst formation. The results also showed that glucose, at a high concentration of 5.56 mM, does not inhibit the development of mouse zygotes to hatched blastocysts when cultured in KSOM supplemented with amino acids.
PEGylated Polyplex With Optimized PEG Shielding Enhances Gene Introduction in Lungs by Minimizing Inflammatory Responses
Authors: Satoshi Uchida, Keiji Itaka, Qixian Chen, Kensuke Osada, Takehiko Ishii, Masa-Aki Shibata, Mariko Harada-Shiba, Kazunori Kataoka
Journal: Molecular Therapy (2012)

Safety is a critical issue in clinical applications of nonviral gene delivery systems. Safe and effective gene introduction into the lungs was previously achieved using polyplexes from poly(ethyleneglycol) (PEG)-block-polycation [PEG-block-PAsp(DET)] and plasmid DNA (pDNA). Although PEGylated polyplexes appeared to be safe, an excess ratio of polycation to pDNA was needed to obtain sufficient transgene expression, which may cause toxicities shortly after gene introduction. In the present study, we investigated the combined use of two polymers, PEG-block-PAsp(DET) (B) and homo PAsp(DET) (H) across a range of mixing ratios to construct polyplexes. Although transgene expressions following in vitro transfections increased in parallel with increased proportions of H, polyplexes with B/H = 50/50 formulation produced the highest expression level following in vivo intratracheal administration. Higher proportions of H elicited high levels of cytokine induction with significant inflammation as assessed by histopathological examinations. Based on the aggregation behavior of polyplexes in bronchoalveolar lavage fluids (BALFs), we suggested that rapid aggregation of polyplexes in the lung induced acute inflammatory responses, resulting in reduced transgene expression. B/H formulation of polyplex can help to improve gene therapy for the respiratory system because it achieves both effective PEG shielding of polyplexes and functioning of PAsp(DET) polycations to enhance endosomal escape.
Krüppel-like factor 4 regulates genetic stability in mouse embryonic fibroblasts
Authors: Enas A El-Karim, Engda G Hagos, Amr M Ghaleb, Bing Yu, Vincent W Yang
Journal: Molecular Cancer (2013)

Abstract Background Krüppel-like factor 4 (KLF4) is a member of the KLF family of transcription factors and regulates proliferation, differentiation, apoptosis and somatic cell reprogramming. Evidence also suggests that KLF4 is a tumor suppressor in certain cancers including colorectal cancer. We previously showed that KLF4 inhibits cell cycle progression following DNA damage and that mouse embryonic fibroblasts (MEFs) null for Klf4 are genetically unstable, as evidenced by increased rates of cell proliferation, and the presence of DNA double strand breaks (DSBs), centrosome amplification, chromosome aberrations and aneuploidy. Methods To determine whether re-expression of Klf4 corrects the observed genetic instability in MEFs null for Klf4 ( Klf4 −/− ), we transfected Klf4 −/− MEFs with Klf4-expressing plasmids and compared the results to wild type ( Klf4 +/+ ) and untransfected or mock-transfected Klf4 −/− MEFs. Results We show that overexpression of Klf4 in Klf4 −/− MEFs reduced cell proliferation rates and the proportion of cells with DSBs, abnormal centrosome numbers, aneuploidy and micronuclei. In addition, Klf4-transfected Klf4 −/− MEFs exhibited a more robust DNA damage repair response as demonstrated by the greater rate in disappearance of γ-H2AX and 53BP1 foci following γ-irradiation. Conclusion Taken together these findings provide evidence that KLF4 plays a crucial role in the maintenance of genetic stability by modulating the DNA damage response and repair processes.
Flexible Intensive Insulin Therapy in Adults With Type 1 Diabetes and High Risk for Severe Hypoglycemia and Diabetic Ketoacidosis
Authors: Alexander Sämann, Ingrid Mühlhauser, Ralf Bender, Wilgard Hunger-Dathe, Christof Kloos, Ulrich A. Müller
Journal: Diabetes Care (2006)

OBJECTIVE—Diabetes treatment and teaching programs (DTTPs) for type 1 diabetes, which teach flexible intensive insulin therapy to enable dietary freedom, have proven to be safe and effective in routine care. This study evaluates DTTP outcomes in patients at high risk for severe hypoglycemia and severe ketoacidosis. RESEARCH DESIGN AND METHODS—There were 96 diabetes centers that participated between 1992 and 2004. A total of 9,583 routine-care patients with type 1 diabetes were examined before and 1 year after a DTTP. History of repeated severe hypoglycemia/severe ketoacidosis was an indication for DTTP participation. Before-after analyses were performed for subgroups of patients with three or more episodes of severe hypoglycemia or two or more episodes of severe ketoacidosis during the year before a DTTP. Main outcome measures were GHb, severe hypoglycemia, severe ketoacidosis, and hospitalization. RESULTS—A total of 341 participants had three or more episodes of severe hypoglycemia the year before a DTTP. Mean baseline GHb was 7.4 vs. 7.2% after the DTTP, incidence of severe hypoglycemia was 6.1 vs. 1.4 events · patient−1 · year−1, and hospitalization was 8.6 vs. 3.9 days · patient−1 · year−1. In mixed-effects models taking effects of centers and diabetes duration into account, mean difference was −0.3% (95% CI −0.5 to −0.1%; P = 0.0006) for GHb and −4.7 events · patient−1 · year−1 (−5.4 to −4; P &amp;lt; 0.0001) for severe hypoglycemia. A total of 95 patients had two or more episodes of severe ketoacidosis. GHb was 9.4% at baseline versus 8.7% after DTTP; incidence of severe ketoacidosis was 3.3 vs. 0.6 events · patient−1 · year−1, and hospitalization was 19.4 vs. 10.2 days · patient−1 · year−1. In linear models with diabetes duration as the fixed effect, the adjusted mean difference was −2.7 events · patient−1 · year−1 (95% CI −3.3 to −2.1; P &amp;lt; 0.0001) for severe ketoacidosis and −8.1 days (−12.9 to −3.2; P = 0.0014) for hospitalization. CONCLUSIONS—Patients at high risk for severe hypoglycemia or severe ketoacidosis may benefit from participation in a standard DTTP for intensive insulin therapy and dietary freedom.
Direct Measurement of Superficial and Deep Venous Flow in the Cat Kidney
Authors: OLE I. NISSEN, Åge GALSKOV
Journal: Circulation Research (1972)

In an excised cat kidney, the subcapsular veins were clipped near their connections with the renal vein and cut open distal to the clamps. The kidney was then placed in an oil-filled lucite chamber and perfused from a donor cat via tubes entering the chamber through its close-fitting lid. The blood leaking from the cut subcapsular veins was led to one flowmeter; that leaving via the cannulated renal vein (supplied now only by the arcuate vein system) was led to another flowmeter. Catecholamines and stimulation of the renal nerves reduced the arcuate blood flow more than the subcapsular blood flow, the two average reductions being 28% and 20% with epinephrine and 22% and 14% with stimulation of the renal nerves. Angiotensin reduced both flows equally. Microspheres reduced the subcapsular flow more than the arcuate flow, the two average reductions being 42% and 25% of the control flows. This effect was probably caused by trapping of the microspheres in the distal ends of the interlobular arteries beyond the inlets to the afferent arterioles, since these vessels are too narrow to allow free entrance of the microspheres. The preferential effect of epinephrine and nerve stimulation on the deep circulation is thought to be the result of the special structure of the juxtamedullary glomerular units.