Miracle-dz/UniFAR-FTUs huggingface dataset:
Sequence, Stability, and Structure of G‐Quadruplexes and Their Interactions with Drugs

Although DNA is most widely known for its ability to store and pass along genetic information, the discovery of G‐quadruplex structures has illuminated a new role for DNA in biology. DNA G‐quadruplexes are four‐stranded globular nucleic acid secondary structures formed in specific G‐rich sequences with biological significance, such as human telomeres and oncogene promoters. This review focuses on the unimolecular DNA G‐quadruplexes, which can readily form in solution under physiological conditions and are considered to be the most biologically relevant. Available structural data show a great conformational diversity of unimolecular G‐quadruplexes, which are amenable to small‐molecule drug targeting. The relationships between sequence, structure, and stability of unimolecular DNA G‐quadruplexes, as well as the recent progress on interactions with small‐molecule compounds and insights into rational design of G‐quadruplex‐interactive molecules, will be discussed. Curr. Protoc. Nucleic Acid Chem. 50:17.5. 1‐17.5. 17. © 2012 by John Wiley & Sons, Inc.
Rapid improvement of acute pulmonary edema with sublingual captopril.

OBJECTIVE To test the hypothesis that sublingual captopril produces a more rapid improvement of acute pulmonary edema (APE) than does placebo, when added to a standard regimen of O2, nitrates, morphine, and furosemide. METHODS Prospective, randomized, double-blind, placebo-controlled clinical trial in an urban teaching hospital ED. Adults brought to the ED with APE were given captopril or placebo sublingually. Every 5 minutes a clinical APE distress score (APEX) was obtained. RESULTS Over the first 40 minutes of treatment, the mean APEXs were significantly better for the patients given captopril [p < 0.001, F = 14.5, one-way (repeated-measures) analysis of variance (ANOVA)]. At 30 minutes, the patients given captopril had a mean APEX improvement of 43% (i.e., to 57% of initial distress); the group given the current standard regimen plus placebo improved only 25% (i.e., to 75% of initial distress; p = 0.03, multiway ANOVA). In addition, there was less respiratory failure necessitating mechanical ventilation in the captopril patients (9%) vs the placebo patients (20%), which did not achieve significance (p = 0.10, Fisher's exact test). CONCLUSION In APE, the addition of sublingual captopril to the standard regimen of O2, nitrates, morphine, and furosemide produces more rapid clinical improvement than does the standard regimen alone.
Dos and don’ts for hospital cleaning

Purpose of review More evidence is emerging on the role of cleaning and decontamination for reducing hospital-acquired infection. Timely and adequate removal of environmental pathogens leads to measurable clinical benefits for patients. This article considers studies published from 2013 examining hospital decontamination technologies and evidence for cost-effectiveness. Recent findings Novel biocides and cleaning products, antimicrobial coatings, monitoring practices and automated equipment are widely accessible. They do not necessarily remove all environmental pathogens, however, and most have yet to be comprehensively assessed against patient outcome. Some studies are confounded by concurrent infection control and/or antimicrobial stewardship initiatives. Few contain data on costs. Summary As automated dirt removal is assumed to be superior to human effort, there is a danger that traditional cleaning methods are devalued or ignored. Fear of infection encourages use of powerful disinfectants for eliminating real or imagined pathogens in hospitals without appreciating toxicity or cost benefit. Furthermore, efficacy of these agents is compromised without prior removal of organic soil. Microbiocidal activity should be compared and contrasted against physical removal of soil in standardized and controlled studies to understand how best to manage contaminated healthcare environments.
A Kinome-Wide siRNA Screen Identifies Multiple Roles for Protein Kinases in Hypoxic Stress Adaptation, Including Roles for IRAK4 and GAK in Protection against Apoptosis in VHL−/− Renal Carcinoma Cells, Despite Activation of the NF-κB Pathway

Hypoxia induces changes to cancer cells that make them more resistant to treatment. We have looked at signaling pathways that facilitate these changes by screening the human kinome for effects on hypoxic responses in SW480 colon cancer cells. Hits identified in the screen were examined for effects on multiple molecular responses to hypoxia, including the endoplasmic reticulum stress and DNA damage responses in colon, melanoma, and renal cancer lines. To validate the hits from the small interfering RNA studies, we developed cell lines expressing stable short hairpin RNAs (shRNAs) in the A498 renal carcinoma cell line. Several lines, including those expressing shRNAs against DYRK1B, GAK, IHPK2, IRAK4, and MATK, showed an inability to form spheroid cultures. In addition, shRNAs targeting IRAK4 and GAK were incapable of 2D growth under anoxia. In the GAK shRNA-expressing line, nuclear factor–κB (NF-κB) was localized to the nucleus, but in the IRAK4 shRNA line, NF-κB levels were increased but the extent of nuclear localization was unchanged. Dominant negative mutants of IRAK4 and GAK also showed strong apoptotic effects in A498 cells under anoxia, supporting a direct link between these kinases and survival of the VHL−/− RCC line, which is typically highly resistant to hypoxic stress as a result of high and constitutive levels of Hif-1α.
Origins of protein denatured state compactness and hydrophobic clustering in aqueous urea: Inferences from nonpolar potentials of mean force

Free energies of pairwise hydrophobic association are simulated in aqueous solutions of urea at concentrations ranging from 0–8 M. Consistent with the expectation that hydrophobic interactions are weakened by urea, the association of relatively large nonpolar solutes is destabilized by urea. However, the association of two small methane‐sized nonpolar solutes in water has the opposite tendency of being slightly strengthened by the addition of urea. Such size effects and the dependence of urea‐induced stability changes on the configuration of nonpolar solutes are not predicted by solvent accessible surface area approaches based on energetic parameters derived from bulk‐phase solubilities of model compounds. Thus, to understand hydrophobic interactions in proteins, it is not sufficient to rely solely on transfer experiment data that effectively characterize a single nonpolar solute in an aqueous environment but not the solvent‐mediated interactions among two or more nonpolar solutes. We find that the m‐values for the rate of change of two‐methane association free energy with respect to urea concentration is a dramatically nonmonotonic function of the spatial separation between the two methanes, with a distance‐dependent profile similar to the corresponding two‐methane heat capacity of association in pure water. Our results rationalize the persistence of residual hydrophobic contacts in some proteins at high urea concentrations and explain why the heat capacity signature (ΔCP) of a compact denatured state can be similar to ΔCP values calculated by assuming an open random‐coil‐like unfolded state. Proteins 2002;49:560–566. © 2002 Wiley‐Liss, Inc.
Effect of total body irradiation, busulfan-cyclophosphamide, or cyclophosphamide conditioning on inflammatory cytokine release and development of acute and chronic graft-versus-host disease in H-2-incompatible transplanted SCID mice.

In a previous study, we found that total body irradiation (TBI) was essential to induce acute graft-versus-host disease (GVHD) after allogeneic H-2-incompatible splenocyte (SP) transplantation in SCID mice. SCID mice (H-2d) conditioned with cyclophosphamide and transplanted intravenously (IV) with 5 x 10(7) C57BL/6 (H-2b) SP developed chronic GVHD within 3 months posttransplant without any evidence of preceding acute GVHD. In this study, SCID mice were conditioned with 4 Gy TBI or non-TBI regimens, either BuCy2 (busulfan 4 mg/kg/d + cyclophosphamide 100 mg/kg/d for 2 days) or Cy5 (cyclophosphamide 100 mg/kg/d for 5 days), and then transplanted IV with 5 x 10(7) SP. The TBI-conditioned mice were further divided into tree transplant groups: (1) TBI and SP administered the same day (TBI + D0 SP), (2) SP administered 4 days post-TBI (TBI + D4 SP), and (3) SP administered 7 days post-TBI (TBI + D7 SP). The severity of GVHD was compared among these groups by clinical and histologic grading. Twenty-eight of 28 mice treated with TBI + D0 SP died of acute GVHD, with overwhelming diarrhea by day 15 posttransplantation. Sixteen mice treated with either TBI + D4 SP or TBI + D7 SP developed acute GVHD, but none of them died of this disorder during 30 days posttransplantation. The mice conditioned with non-TBI regimens developed chronic GVHD within 3 months without showing any detectable signs of acute GVHD. Serum and in situ colonic cytokines were determined by enzyme-linked immunosorbent assay and immunohistology respectively. TBI itself significantly increased both serum and colonic tumor necrosis factor-alpha (TNF-alpha), interleukin-1 alpha (IL-1 alpha), and IL-6 when compared with non-TBI regimens and normal controls. TNF-alpha appeared in the serum and colon 4 hours post-TBI and peaked in 24 hours, followed by increasing IL-1 alpha and then IL-6 levels. TNF-alpha and IL-1 alpha decreased rapidly within 3 to 5 days post-TBI if no allogeneic cells were transplanted. Histoincompatible transplantation augmented cytokine release, which remained elevated on day 10 in these animals. Mice treated with TBI + D0 SP developed the most severe acute GVHD and had the highest levels of TNF-alpha, IL-1 alpha, and IL-6. The BuCy2-conditioned mice had the lowest cytokine levels and developed no acute GVHD. When the mice transplanted with TBI + D0 SP were treated immediately with recombinant soluble human TNF receptor (rhuTNFR:Fc) 100 micrograms/d intraperitoneally and for the subsequent 15 days acute GVHD mortality was significantly reduced from 100% to 50% (P < .001). (ABSTRACT TRUNCATED AT 400 WORDS)
FGF4 and FGF8 comprise the wavefront activity that controls somitogenesis

Somites form along the embryonic axis by sequential segmentation from the presomitic mesoderm (PSM) and differentiate into the segmented vertebral column as well as other unsegmented tissues. Somites are thought to form via the intersection of two activities known as the clock and the wavefront. Previous work has suggested that fibroblast growth factor (FGF) activity may be the wavefront signal, which maintains the PSM in an undifferentiated state. However, it is unclear which (if any) of the FGFs expressed in the PSM comprise this activity, as removal of any one gene is insufficient to disrupt early somitogenesis. Here we show that when both Fgf4 and Fgf8 are deleted in the PSM, expression of most PSM genes is absent, including cycling genes, WNT pathway genes, and markers of undifferentiated PSM. Significantly, markers of nascent somite cell fate expand throughout the PSM, demonstrating the premature differentiation of this entire tissue, a highly unusual phenotype indicative of the loss of wavefront activity. When WNT signaling is restored in mutants, PSM progenitor markers are partially restored but premature differentiation of the PSM still occurs, demonstrating that FGF signaling operates independently of WNT signaling. This study provides genetic evidence that FGFs are the wavefront signal and identifies the specific FGF ligands that encode this activity. Furthermore, these data show that FGF action maintains WNT signaling, and that both signaling pathways are required in parallel to maintain PSM progenitor tissue.
The Comprehensive Psychopathological Rating Scale in patients with dementia of Alzheimer type and multiinfarct dementia

ABSTRACT– Eighteen patients with the clinical diagnosis dementia of Alzheimer type (AD/SDAT) and 20 patients with the clinical diagnosis multiinfarct dementia (MID) were interviewed using a subscale to the Comprehensive Psychopathological Rating Scale (CPRS), consisting of items measuring psychopathological symptoms and signs commonly seen in patients with dementia. The aim of the investigation was to evaluate whether a difference in psychopathology between AD/SDAT and MID could be observed during a semistructured psychiatric interview using the CPRS. In both groups the duration of illness was similar and the dementia mild to moderate. All patients were subjected to somatic, psychiatric, laboratory, neurophysiologic and neuroradiologic examinations in order to obtain the correct clinical diagnoses. The results show that patients with AD/SDAT have a more variable psychopathology than patients with MID. Patients with MID were rated lower on all items used, especially those concerning verbal and personal contact. This might explain the generally accepted opinion that patients with MID have better contact with their surroundings and better preservation of their personality, even though they have the same degree of dementia as patients with AD/SDAT.
Towards an explicative model of human cognitive process in a hidden hazardous situation and a cognitive ergonomics intervention in railway environment

Over the recent decades, situation awareness errors and human errors are always considered among primary factors contributing to railway incidents and accidents. Hence, the need to focus research efforts on approaches centered on human factors rather than absolute technical solutions is becoming greater. In this paper, we firstly present the rail human factors context and cognitive ergonomics as a field of research in ergonomics. Then we state a brief overview of human errors contributing to rail accidents and that have major impact on railway safety. Secondly, we review models related to human cognitive behaviour in working environment. Then, we base our research on the Endesley model in order to propose an explicative model of cognitive processes involved in hidden hazardous situations. Through this model, we introduce the human cognitive processes with emphasis on situation awareness errors and complacency which are considered among causal factors of accidents including railway ones. In relation to the proposed model, we will proceed to human behaviour analysis and a cognitive ergonomic intervention in railway environment. This latter will allow to understand human behaviour in hazardous or hidden hazardous situation, to design the human cognitive processes involved, and then to reduce the resulting accidents and incidents.
Advancing maternal age: the actual risks.

A growing number of US women are delaying childbirth until their late 30s. Pregnant women 35 years old face various risks including genetic disorders, prenatal medical and obstetric complications, intrapartum complications, and perinatal and neonatal morbidity and mortality. With each passing year, the risk of chromosomal abnormality such as Down's syndrome increases. Physicians perform chorionic villus sampling (CVS) between 9-11 weeks gestation and amniocentesis between 16-18 weeks to detect chromosomal abnormalities. CVS carries the higher risk of spontaneous abortion (1-2%). 35-year old pregnant women are more likely to suffer from hypertension and gestational diabetes than younger women. Yet their incidence remains at an acceptable level. Older pregnant women tend to also be at risk of several antepartum obstetric complications such as gestational bleeding, abruptio placentae, and placenta previa. The likelihood of cesarean section and dysfunctional labor is greater among 35-year old pregnant women. Between 1974 and 1978, older mothers were 4 times more likely to die than young mothers, but by 1982 the overall maternal mortality rate fell by 50%. The main causes of death among older mothers were hemorrhage, embolism, and hypertensive conditions. Positive effects of advanced maternal age were less worry about and better adjustment to pregnancy, cautiousness, and more likely to consult their physicians. Advanced maternal age tends not to effect neonatal outcome other than chromosomal anomalies. Physicians should not allow the pregnancy of 35-year old mothers to go beyond 42 weeks' gestation. Despite the minimal increased risks, 35-year old women should not allow their advanced age to be an absolute barrier to reproductive decisions. Obstetricians should conduct thorough and appropriate antepartum testing and surveillance, however.
E2A-HLF-mediated cell transformation requires both the trans-activation domains of E2A and the leucine zipper dimerization domain of HLF

The E2A-HLF fusion gene, formed by the t(17;19)(q22;p13) translocation in childhood acute pro-B-cell leukemia, encodes a hybrid protein that contains the paired trans-activation domains of E2A (E12/E47) linked to the basic region/leucine zipper DNA-binding and dimerization domain of hepatic leukemia factor (HLF). To assess the transforming potential of this novel gene, we introduced it into NIH 3T3 murine fibroblasts by using an expression vector that also contained the neomycin resistance gene. Cells selected for resistance to the neomycin analog G418 formed aberrant colonies in monolayer cultures, marked by increased cell density and altered morphology. Transfected cells also grew readily in soft agar, producing colonies whose sizes correlated with E2A-HLF expression levels. Subclones expanded from colonies with high levels of the protein reproducibly formed tumors in nude mice and grew to higher plateau-phase cell densities in reduced-serum conditions than did parental NIH 3T3 cells. By contrast, NIH 3T3 cells expressing mutant E2A-HLF proteins that lacked either of the bipartite E2A trans-activation domains or the HLF leucine zipper domain failed to show oncogenic properties, including anchorage-independent cell growth. Thus, both of the E2A trans-activation motifs and the HLF leucine zipper dimerization domain are essential for the transforming potential of the chimeric E2A-HLF protein, suggesting a model in which aberrant regulation of the expression pattern of downstream target genes contributes to leukemogenesis.
Preserved Prolactin Fluctuations and Response to Metoclopramide in Ovulatory, Infertile, Hyperprolactinemic Women

Abstract. The study included 18 infertile, hyperprolacti‐nemic women with preserved menstrual cycles. Among 13 women with consistently elevated prolactin (PRL) levels, 6 had either anovulatory cycles or luteal insufficiency, whereas 7 had apparently normal ovulatory cycles. Comparisons of these two groups showed that basal levels were similar but the PRL response to metoclopramide (MTC) and the day‐to‐day fluctuations were significantly lower in the group with altered oyulatory function. In this group the PRL response to MTC was significantly greater than in control patients with hyperprolactinemic amenorrhea (n = 12), but lower than in normal women (n = 10). The PRL response to MTC in hyperprolactinemic women with normal ovulatory function did not differ significantly from that of normal women, irrespective of whether hyperprolactinemia was sustained (n = 7) or intermittent (n = 5).
Filipino American women's perceptions and experiences with breast cancer screening.

PURPOSE/OBJECTIVES To determine information about Filipino American women's perceptions of breast cancer, the most frequently diagnosed cancer and number-one killer of Asian American women, and their experiences with screening. DESIGN A qualitative, exploratory approach with focus groups. SETTING Suburban Filipino American communities in the midwestern United States. SAMPLE 11 Filipino American women aged 45-80 years who shared their experiences with breast cancer screening. METHODS Focus groups were conducted, and the meetings were recorded on audiotape, transcribed, and analyzed using constant comparison techniques. MAIN RESEARCH VARIABLES Breast cancer screening, experiences, motivators, and barriers. FINDINGS Avoidance was the main theme for Filipino American women in dealing with a cancer diagnosis in the Filipino American culture. Facilitators of Filipino American women's screening practices were support from family members, recommendations from familiar physicians, health insurance reinforcement, and personal attributes of physical symptoms, family history, past diagnosis, and health literacy. Barriers identified were different mind-sets and healthcare systems in the Philippines in regard to early detection, unpleasant experiences with mammography, cultural beliefs, and difficulties accessing services. CONCLUSIONS Results of the focus group discussions provide useful information about facilitators and barriers that affect Filipino American women's screening practices. IMPLICATIONS FOR NURSING The findings of the study can be used to develop tailored interventions for addressing culturally specific barriers and promoting screening practices in the Filipino American community.
Acute effects of cannabinoids on symptoms of obsessive-compulsive disorder: A human laboratory study.

BACKGROUND Preclinical data implicate the endocannabinoid system in the pathology underlying obsessive-compulsive disorder (OCD), while survey data have linked OCD symptoms to increased cannabis use. Cannabis products are increasingly marketed as treatments for anxiety and other OCD-related symptoms. Yet, few studies have tested the acute effects of cannabis on psychiatric symptoms in humans. METHODS We recruited 14 adults with OCD and prior experience using cannabis to enter a randomized, placebo-controlled, human laboratory study to compare the effects on OCD symptoms of cannabis containing varying concentrations of Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) on OCD symptoms to placebo. We used a within-subjects design to increase statistical power. Across three laboratory sessions, participants smoked three cannabis varietals in random order: placebo (0% THC/0% CBD); THC (7.0% THC/0.18% CBD); and CBD (0.4% THC/10.4% CBD). We analyzed acute changes in OCD symptoms, state anxiety, cardiovascular measures, and drug-related effects (e.g., euphoria) as a function of varietal. RESULTS Twelve participants completed the study. THC increased heart rate, blood pressure, and intoxication compared with CBD and placebo. Self-reported OCD symptoms and anxiety decreased over time in all three conditions. Although OCD symptoms did not vary as a function of cannabis varietal, state anxiety was significantly lower immediately after placebo administration relative to both THC and CBD. CONCLUSIONS This is the first placebo-controlled investigation of cannabis in adults with OCD. The data suggest that smoked cannabis, whether containing primarily THC or CBD, has little acute impact on OCD symptoms and yields smaller reductions in anxiety compared to placebo.