Miracle-dz/UniFAR-FTUs huggingface dataset:
“I Will Not Be Discriminated Against”: Older Lesbians Creating New Communities

Lesbian, gay, bisexual, and transgender (LGBT) older adults fear discrimination in long-term care and voice a preference for LGBT-specific services. The purpose of this study was to describe, through the eyes of 10 socially interconnected older lesbians (>55 years), the roles that life experiences, social ties, and expectations for aging play in their decision to live in an LGBT continuous-care setting. Nursing has been largely inattentive to older lesbians' unique health and care issues. Reforms in nursing research, education, and practice are suggested to make this population more visible and better understood.
High-Throughput Screening Platform for Engineered Nanoparticle-Mediated Genotoxicity Using CometChip Technology

The likelihood of intentional and unintentional engineered nanoparticle (ENP) exposure has dramatically increased due to the use of nanoenabled products. Indeed, ENPs have been incorporated in many useful products and have enhanced our way of life. However, there are many unanswered questions about the consequences of nanoparticle exposures, in particular, with regard to their potential to damage the genome and thus potentially promote cancer. In this study, we present a high-throughput screening assay based upon the recently developed CometChip technology, which enables evaluation of single-stranded DNA breaks, abasic sites, and alkali-sensitive sites in cells exposed to ENPs. The strategic microfabricated, 96-well design and automated processing improves efficiency, reduces processing time, and suppresses user bias in comparison to the standard comet assay. We evaluated the versatility of this assay by screening five industrially relevant ENP exposures (SiO2, ZnO, Fe2O3, Ag, and CeO2) on both suspension human lymphoblastoid (TK6) and adherent Chinese hamster ovary (H9T3) cell lines. MTT and CyQuant NF assays were employed to assess cellular viability and proliferation after ENP exposure. Exposure to ENPs at a dose range of 5, 10, and 20 μg/mL induced dose-dependent increases in DNA damage and cytotoxicity. Genotoxicity profiles of ZnO > Ag > Fe2O3 > CeO2 > SiO2 in TK6 cells at 4 h and Ag > Fe2O3 > ZnO > CeO2 > SiO2 in H9T3 cells at 24 h were observed. The presented CometChip platform enabled efficient and reliable measurement of ENP-mediated DNA damage, therefore demonstrating the efficacy of this powerful tool in nanogenotoxicity studies.
Isothiazolones as inhibitors of PCAF and p300 histone acetyltransferase activity

Histone acetylation plays an important role in regulating the chromatin structure and is tightly regulated by two classes of enzyme, histone acetyltransferases (HAT) and histone deacetylases (HDAC). Deregulated HAT and HDAC activity plays a role in the development of a range of cancers. Consequently, inhibitors of these enzymes have potential as anticancer agents. Several HDAC inhibitors have been described; however, few inhibitors of HATs have been disclosed. Following a FlashPlate high-throughput screen, we identified a series of isothiazolone-based HAT inhibitors. Thirty-five N-substituted analogues inhibited both p300/cyclic AMP–responsive element binding protein–binding protein–associated factor (PCAF) and p300 (1 to >50 μmol/L, respectively) and the growth of a panel of human tumor cell lines (50% growth inhibition, 0.8 to >50 μmol/L). CCT077791 and CCT077792 decreased cellular acetylation in a time-dependent manner (2–48 hours of exposure) and a concentration-dependent manner (one to five times, 72 hours, 50% growth inhibition) in HCT116 and HT29 human colon tumor cell lines. CCT077791 reduced total acetylation of histones H3 and H4, levels of specific acetylated lysine marks, and acetylation of α-tubulin. Four and 24 hours of exposure to the compounds produced the same extent of growth inhibition as 72 hours of continuous exposure, suggesting that growth arrest was an early event. Chemical reactivity of these compounds, as measured by covalent protein binding and loss of HAT inhibition in the presence of DTT, indicated that reaction with thiol groups might be important in their mechanism of action. As one of the first series of small-molecule inhibitors of HAT activity, further analogue synthesis is being pursued to examine the potential scope for reducing chemical reactivity while maintaining HAT inhibition.
Mutagenic Mapping Suggests a Novel Binding Mode for Selective Agonists of M1 Muscarinic Acetylcholine Receptors

Point mutations and molecular modeling have been used to study the activation of the M1 muscarinic acetylcholine receptor (mAChR) by the functionally selective agonists 4-n-butyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl]-piperidine (AC-42), and 1-[3-(4-butyl-1-piperidinyl)propyl]-3,4-dihydro-2(1H)-quinolinone (77-LH-28-1), comparing them with N-desmethylclozapine (NDMC) and acetylcholine (ACh). Unlike NDMC and ACh, the activities of AC-42 and 77-LH-28-1 were undiminished by mutations of Tyr404 and Cys407 (transmembrane helix 7), although they were reduced by mutations of Tyr408. Signaling by AC-42, 77-LH-28-1, and NDMC was reduced by L102A and abolished by D105E, suggesting that all three may interact with transmembrane helix 3 at or near the binding site Asp105 to activate the M1 mAChR. In striking contrast to NDMC and ACh, the affinities of AC-42 and 77-LH-28-1 were increased 100-fold by W101A, and their signaling activities were abolished by Y82A. Tyr82 and Leu102 contact the indole ring of Trp101 in a structural model of the M1 mAChR. We suggest the hypothesis that the side chain of Trp101 undergoes conformational isomerization, opening a novel binding site for the aromatic side chain of the AC-42 analogs. This may allow the positively charged piperidine nitrogen of the ligands to access the neighboring Asp105 carboxylate to activate signaling following a vector within the binding site that is distinct from that of acetylcholine. NDMC does not seem to use this mechanism. Subtype-specific differences in the free energy of rotation of the side chain and indole ring of Trp101 might underlie the M1 selectivity of the AC-42 analogs. Tryptophan conformational isomerization may open up new avenues in selective muscarinic receptor drug design.
Early Experience With Implantable Collamer Lens in the Management of Hyperopia After Radial Keratotomy

Purpose: To report the initial experience of the use of implantable collamer lens (ICL) in the management of hyperopia after radial keratotomy (RK). Methods: Single-center, retrospective chart review. Four eyes of 3 patients with secondary hyperopic shift after myopic RK had a mean spherical equivalent of 5.31 D (range, 3.25-9 D) on presentation. All of them underwent ICL implantation to correct the refractive error. Results: There were no intraoperative complications. At a mean follow-up of 5.5 months (range, 3-7 months), the mean uncorrected visual acuity improved from 20/130 preoperatively to 20/24 postoperatively, and the mean spherical equivalent decreased from 5.31 D preoperatively to 0.08 D postoperatively. At 1-month follow-up, all eyes had an uncorrected visual acuity better than or equal to preoperative best spectacle-corrected visual acuity. Two eyes were within 0.25 D and all were within 0.5 D of the predicted refractive target. Conclusions: ICL implantation is an effective surgical option to consider in the management of hyperopia after RK. However, a large cohort and longer follow-up are needed to determine the long-term efficacy and safety of this procedure in this clinical setting.
Examining technology, structure and identity during an Enterprise System implementation

Abstract. This paper presents a longitudinal study of an Enterprise System (ES) implementation by critically examining the discursive context in which an ES implementation unfolds. The findings show that users strongly supported the ES in the earlier stage of implementation when the technology was an imaginary phenomenon. However, in later stages, when the technology is in use, user support was not consistent. In this phase, the ES produces loss of control and an inability to function as an arbiter of fairness (in allocating resources associated with the system), thereby directly challenging existing professional identities and roles. These outcomes, in turn, generate acts of resistance on the part of workers. Users reach inside the technology and reshape it by devising creative workarounds that produce a sense of reskilling to counter the deskilling produced by the loss of control and power. The analysis also shows that an ES is a complex social phenomenon that is intricately linked to and complicit in shaping organizational structure and identity. In particular, this study shows how technology, structure and identity are in a mutually constitutive relationship.
Cortex and Memory: Emergence of a New Paradigm

Converging evidence from humans and nonhuman primates is obliging us to abandon conventional models in favor of a radically different, distributed-network paradigm of cortical memory. Central to the new paradigm is the concept of memory network or cognit—that is, a memory or an item of knowledge defined by a pattern of connections between neuron populations associated by experience. Cognits are hierarchically organized in terms of semantic abstraction and complexity. Complex cognits link neurons in noncontiguous cortical areas of prefrontal and posterior association cortex. Cognits overlap and interconnect profusely, even across hierarchical levels (heterarchically), whereby a neuron can be part of many memory networks and thus many memories or items of knowledge.
Plasma Nesfatin-1 Is Not Affected by Long-Term Food Restriction and Does Not Predict Rematuration among Iteroparous Female Rainbow Trout (Oncorhynchus mykiss)

The metabolic peptide hormone nesfatin-1 has been linked to the reproductive axis in fishes. The purpose of this study was to determine how energy availability after spawning affects plasma levels of nesfatin-1, the metabolic peptide hormone ghrelin, and sex steroid hormones in rematuring female rainbow trout (Oncorhynchus mykiss). To limit reproductive maturation, a group of female trout was food-restricted after spawning and compared with a control group that was fed a standard broodstock ration. The experiment was conducted twice, once using two-year-old trout (second-time spawners) and once using three-year-old trout (third-time spawners). During monthly sampling, blood was collected from all fish, and a subset of fish from each treatment was sacrificed for pituitaries. Pituitary follicle-stimulating hormone-beta (fsh-β) mRNA expression was analyzed with q-RT-PCR; plasma hormone levels were quantified by radioimmunoassay (17β-estradiol and ghrelin) and enzyme-linked immunosorbent assay (11-keto-testosterone and nesfatin-1). Although plasma nesfatin-1 levels increased significantly in the months immediately after spawning within both feeding treatments, plasma nesfatin-1 did not differ significantly between the two treatments at any point. Similarly, plasma ghrelin levels did not differ significantly between the two treatments at any point. Food restriction arrested ovarian development by 15–20 weeks after spawning, shown by significantly lower plasma E2 levels among restricted-ration fish. Pituitary fsh-β mRNA levels were higher among control-ration fish than restricted-ration fish starting at 20 weeks, but did not differ significantly between treatment groups until 30 weeks after spawning. Within both treatment groups, plasma 11-KT was elevated immediately after spawning and rapidly decreased to and persisted at low levels; starting between 20 and 25 weeks after spawning, plasma 11-KT was higher among control-ration fish than restricted-ration fish. The results from these experiments do not provide support for plasma nesfatin-1 as a signal for the initiation of reproductive development in rematuring female rainbow trout.
Gene Expression Analysis of Biological Systems Driving an Organotypic Model of Endometrial Carcinogenesis and Chemoprevention

An organotypic model of endometrial carcinogenesis and chemoprevention was developed in which normal endometrial organotypic cultures exposed to the carcinogen, DMBA (7,12-dimethylbenz[a]anthracene), developed a cancerous phenotype in the absence, but not presence of subsequent treatment with a flexible heteroarotinoid (Flex-Het), called SHetA2. A discriminant function based on karyometric features of cellular nuclei and an agar clonogenic assay confirmed these histologic changes. Interpretation of microarray data using an internal standard approach identified major pathways associated with carcinogenesis and chemoprevention governed by c-myc, p53, TNFα and Jun genes. Cluster analysis of functional associations of hypervariable genes demonstrated that carcinogenesis is accompanied by a stimulating association between a module of genes that includes tumor necrosis factor α (TNFα), c-myc, and epidermal growth factor-receptor (EGF-R) and a module that includes insulin-like growth factor I-receptor (IGF-IR), p53, and Jun genes. Two secreted proteins involved in these systems, tenascin C and inhibin A, were validated at the protein level. Tenascin C is an EGF-R ligand, and therefore may contribute to the increased EGF-R involvement in carcinogenesis. The known roles of the identified molecular systems in DMBA and endometrial carcinogenesis and chemoprevention supports the validity of this model and the potential clinical utility of SHetA2 in chemoprevention.
Effect of the Number of Involved Spinal Cord Segments on Gait Function in Patients with Cervical Spondylotic Myelopathy

Study Design Retrospective. Purpose To determine the effect of severity of cervical spondylotic myelopathy (CSM) on gait parameters according to the number of involved spinal cord segments. Overview of Literature Although there are a large number of studies on CSM, almost all studies have focused on hand function and only a few studies have examined the gait function in patients with CSM. Methods Twenty-three patients with CSM underwent magnetic resonance imaging and gait analysis. The subjects were divided into 2 groups; group I consisted of 9 patients with a single-level stenotic lesion and group II comprised 14 patients with multi-level stenotic lesions. Gait parameters were compared between the 2 groups and the normal control group. Results There was no significant difference in the Japanese Orthopaedic Association score between the 2 groups. Cadence, walking speed, stride length, and step length were decreased in group II compared to group I and normal control group. Peak ankle plantar flexion moments during the stance phase and peak knee flexion angle during the swing phase were decreased in group II. Peak ankle, knee, and hi p power generation during the stance phase were decreased in group II; in addition, the peak ankle power generation was decreased in group II than in the normal control group. Conclusions Patients with multi-level stenotic lesions had decreased gait ability compared to that in patients with a single-level stenotic lesion. The number of involved spinal cord segments can be one cause of gait deterioration in patients with CSM. Performing a gait analysis is useful for accurate evaluation of the patient.
Activation in the VTA and Nucleus Accumbens Increases in Anticipation of Both Gains and Losses

To represent value for learning and decision making, the brain must encode information about both the motivational relevance and affective valence of anticipated outcomes. The nucleus accumbens (NAcc) and ventral tegmental area (VTA) are thought to play key roles in representing these and other aspects of valuation. Here, we manipulated the valence (i.e., monetary gain or loss) and personal relevance (i.e., self-directed or charity-directed) of anticipated outcomes within a variant of the monetary incentive delay task. We scanned young-adult participants using functional magnetic resonance imaging (fMRI), utilizing imaging parameters targeted for the NAcc and VTA. For both self-directed and charity-directed trials, activation in the NAcc and VTA increased to anticipated gains, as predicted by prior work, but also increased to anticipated losses. Moreover, the magnitude of responses in both regions was positively correlated for gains and losses, across participants, while an independent reward-sensitivity covariate predicted the relative difference between and gain- and loss-related activation on self-directed trials. These results are inconsistent with the interpretation that these regions reflect anticipation of only positive-valence events. Instead, they indicate that anticipatory activation in reward-related regions largely reflects the motivational relevance of an upcoming event.
Transcription factor ATF4 directs basal and stress-induced gene expression in the unfolded protein response and cholesterol metabolism in the liver

Whole-body and liver-specific ATF4–knockout mice are used to evaluate the role of ATF4 transcription factor in the unfolded protein response (UPR). ATF4 directs a small subset of UPR gene expression, and deletion of ATF4 in the liver triggers enhanced oxidative stress, disrupts cholesterol metabolism, and enhances cell death.
Social-Support, Self-Esteem and Depression as Determinants of Quality of Life among Sickle Cell Patients

This study examined the influence of social support, self-esteem and depression on the quality of life among sickle cell patients in Benin City. A total of 52 sickle cell patients made up of 29 males and 23 females participated in the study. Questionnaire was used in collecting data. The questionnaire consisted of the demographic variables, as well as Quality of Life, Depression, Self-esteem, and Social Support scales. Results of the simple multiple regression analysis revealed a significant joint influence of self-esteem, social support and depression [R2 = 0.32F (7,527); p . 05]. The findings have implication for understanding quality of life among sickle cell patients. Again, the findings are useful for the development of intervention that will enhance social support and self-efficacy among sickle cell patient as well as decrease their negative mood.
HIV-positive migrants’ encounters with the Swedish health care system

Background There is limited knowledge about human immunodeficiency virus (HIV)-positive migrants and their experiences in the Swedish health care system. It is necessary to increase our knowledge in this field to improve the quality of care and social support for this vulnerable group of patients. Objective The aim of this study was to describe the experiences of HIV-positive migrants and their encounters with the health care system in Sweden. Design This is a Grounded Theory study based on qualitative interviews with 14 HIV-positive migrants living in Sweden, aged 29–55 years. Results ‘A hybrid of access and adversity’ was identified as the core category of the study. Three additional categories were ‘appreciation of free access to treatment’, ‘the impact of the Swedish Disease Act on everyday life’, and ‘encountering discrimination in the general health care system’. The main finding indicated that participants experienced frustration and discrimination because they were required to provide sexual partners with information about their HIV status, which is compulsory under the Swedish Disease Act. The study also showed that the bias or fear regarding HIV infection among general health care professionals outside of the infectious diseases clinics limited the access to the general health care system for HIV-positive migrants. Conclusions The HIV-positive migrants appreciated the free access to antiviral therapy, but wished to have more time for patient–physician communications. The participants of this study felt discrimination in health care settings outside of the infectious diseases clinics. There is a need to reduce the discrimination in general health care services and to optimize the social support system and social network of this vulnerable group.
Small interfering RNA library screen of human kinases and phosphatases identifies polo-like kinase 1 as a promising new target for the treatment of pediatric rhabdomyosarcomas

Rhabdomyosarcoma, consisting of alveolar (aRMS) and embryonal (eRMS) subtypes, is the most common type of sarcoma in children. Currently, there are no targeted drug therapies available for rhabdomyosarcoma. In searching for new molecular therapeutic targets, we carried out genome-wide small interfering RNA (siRNA) library screens targeting human phosphatases (n = 206) and kinases (n = 691) initially against an aRMS cell line, RH30. Sixteen phosphatases and 50 kinases were identified based on growth inhibition after 72 hours. Inhibiting polo-like kinase 1 (PLK1) had the most remarkable impact on growth inhibition (∼80%) and apoptosis on all three rhabdomyosarcoma cell lines tested, namely, RH30, CW9019 (aRMS), and RD (eRMS), whereas there was no effect on normal muscle cells. The loss of PLK1 expression and subsequent growth inhibition correlated with decreased p-CDC25C and Cyclin B1. Increased expression of WEE 1 was also noted. The induction of apoptosis after PLK1 silencing was confirmed by increased p-H2AX, propidium iodide uptake, and chromatin condensation, as well as caspase-3 and poly(ADP-ribose) polymerase cleavage. Pediatric Ewing's sarcoma (TC-32), neuroblastoma (IMR32 and KCNR), and glioblastoma (SF188) models were also highly sensitive to PLK1 inhibition. Finally, based on cDNA microarray analyses, PLK1 mRNA was overexpressed (>1.5 fold) in 10 of 10 rhabdomyosarcoma cell lines and in 47% and 51% of primary aRMS (17 of 36 samples) and eRMS (21 of 41 samples) tumors, respectively, compared with normal muscles. Similarly, pediatric Ewing's sarcoma, neuroblastoma, and osteosarcoma tumors expressed high PLK1. We conclude that PLK1 could be a promising therapeutic target for the treatment of a wide range of pediatric solid tumors including rhabdomyosarcoma. [Mol Cancer Ther 2009;8(11):3024–35]
Neuropeptide Y selectively inhibits slow synaptic potentials in rat dorsal raphe nucleus in vitro by a presynaptic action

Neuropeptide Y (NPY) has been shown to modulate synaptic transmission in both peripheral and central tissues via both pre- and postsynaptic mechanisms. In this study, we examined the effect of NPY and its analog, peptide YY (PYY), on slow synaptic potentials in the dorsal raphe nucleus in vitro using intracellular recording and single- microelectrode voltage-clamp techniques. NPY and PYY inhibited both the slow 5-HT1A receptor-mediated IPSP and the alpha 1-adrenoceptor- mediated slow EPSP while not affecting the fast, amino acid-mediated synaptic responses. PYY also inhibited pharmacologically isolated slow synaptic responses. NPY/PYY appear to mediate the observed inhibitions via a presynaptic mechanism, as the postsynaptic conductances mediated by activation of 5-HT1A receptors or alpha 1-adrenoceptors were unaffected by the peptides. NPY/PYY act via a different mechanism than presynaptic 5-HT1B receptors. NPY/PYY probably act via presynaptic Y2 receptors, as the C-terminal fragment NPY 13–36 and the Y2-selective agonist C2-NPY are effective. Since NPY and its receptors are present in the dorsal raphe nucleus, this peptide may act as an endogenous modulator of the state of activity of neurons in this region and may thus have a role in the modulation of neuronal output from this nucleus.