Miracle-dz/UniFAR-FTUs huggingface dataset:
Endocytosis of beta-cyclodextrins is responsible for cholesterol reduction in Niemann-Pick type C mutant cells

Niemann-Pick type C disease (NPC) is a lysosomal storage disorder causing accumulation of unesterified cholesterol in lysosomal storage organelles. Recent studies have shown that hydroxypropyl-β-cyclodextrin injections in npc1−/− mice are partially effective in treating this disease. Using cultured fibroblasts, we have investigated the cellular mechanisms responsible for reduction of cholesterol accumulation. We show that decreased levels of cholesterol accumulation are maintained for several days after removal of cyclodextrin from the culture medium. This suggests that endocytosed cyclodextrin can reduce the cholesterol storage by acting from inside endocytic organelles rather than by removing cholesterol from the plasma membrane. To test this further, we incubated both NPC1 and NPC2 mutant cells with cholesterol-loaded cyclodextrin for 1 h, followed by chase in serum-containing medium. Although the cholesterol content of the treated cells increased after the 1-h incubation, the cholesterol levels in the storage organelles were later reduced significantly. We covalently coupled cyclodextrin to fluorescent dextran polymers. These cyclodextrin–dextran conjugates were delivered to cholesterol-enriched lysosomal storage organelles and were effective at reducing the cholesterol accumulation. We demonstrate that methyl-β-cyclodextrin is more potent than hydroxypropyl-β-cyclodextrin in reducing both cholesterol and bis(monoacylglycerol) phosphate accumulation in NPC mutant fibroblasts. Brief treatment of cells with cyclodextrins causes an increase in cholesterol esterification by acyl CoA:cholesterol acyl transferase, indicating increased cholesterol delivery to the endoplasmic reticulum. These findings suggest that cyclodextrin-mediated enhanced cholesterol transport from the endocytic system can reduce cholesterol accumulation in cells with defects in either NPC1 or NPC2.
HUNK suppresses metastasis of basal type breast cancers by disrupting the interaction between PP2A and cofilin-1

Metastasis leads to the death of most cancer patients, and basal breast cancer is the most aggressive breast tumor type. Metastasis involves a complex cell migration process dependent on cytoskeletal remodeling such that targeting such remodeling in tumor cells could be clinically beneficial. Here we show that Hormonally Up-regulated Neu-associated Kinase (HUNK) is dramatically down-regulated in tumor samples and cell lines derived from basal breast cancers. Reconstitution of HUNK expression in basal breast cancer cell lines blocked actin polymerization and reduced cell motility, resulting in decreased metastases in two in vivo murine cancer models. Mechanistically, HUNK overexpression sustained the constitutive phosphorylation and inactivation of cofilin-1 (CFL-1), thereby blocking the incorporation of new actin monomers into actin filaments. HUNK reconstitution in basal breast cancer cell lines prevented protein phosphatase 2-A (PP2A), a phosphatase putatively acting on CFL-1, from binding to CFL-1. Our investigation of HUNK suggests that the interaction between PP2A and CFL-1 may be a target for antimetastasis therapy, particularly for basal breast cancers.
Thin Films of Magnetically Doped Topological Insulator with Carrier‐Independent Long‐Range Ferromagnetic Order

Thin films of magnetically doped topological insulators Cr(0.22) (Bi(x) Sb(1-x) )(1.78) Te(3) are found to possess carrier-independent long-range ferromagnetic order with perpendicular magnetic anisotropy. The anomalous Hall resistance is greatly enhanced, up to one quarter of quantum Hall resistance, by depletion of the carriers. The results demonstrate this material as a promising system to realize the quantized anomalous Hall effect.
Genome-wide siRNA screen identifies SMCX, EP400, and Brd4 as E2-dependent regulators of human papillomavirus oncogene expression

An essential step in the pathogenesis of human papillomavirus (HPV)–associated cancers is the dysregulated expression of the viral oncogenes. The papillomavirus E2 protein can silence the long control region (LCR) promoter that controls viral E6 and E7 oncogene expression. The mechanisms by which E2 represses oncogene expression and the cellular factors through which E2 mediates this silencing are largely unknown. We conducted an unbiased, genome-wide siRNA screen and series of secondary screens that identified 96 cellular genes that contribute to the repression of the HPV LCR. In addition to confirming a role for the E2-binding bromodomain protein Brd4 in E2-mediated silencing, we identified a number of genes that have not previously been implicated in E2 repression, including the demethylase JARID1C/SMCX as well as EP400, a component of the NuA4/TIP60 histone acetyltransferase complex. Each of these genes contributes independently and additively to E2-mediated silencing, indicating that E2 functions through several distinct cellular complexes to repress E6 and E7 expression.
Homozygous DNA ligase IV R278H mutation in mice leads to leaky SCID and represents a model for human LIG4 syndrome

DNA ligase IV (LIG4) is an essential component of the nonhomologous end-joining (NHEJ) repair pathway and plays a key role in V(D)J recombination. Hypomorphic LIG4 mutations in humans are associated with increased cellular radiosensitivity, microcephaly, facial dysmorphisms, growth retardation, developmental delay, and a variable degree of immunodeficiency. We have generated a knock-in mouse model with a homozygous Lig4 R278H mutation that corresponds to the first LIG4 mutation reported in humans. The phenotype of homozygous mutant mice Lig4R278H/R278H (Lig4R/R) includes growth retardation, a decreased life span, a severe cellular sensitivity to ionizing radiation, and a very severe, but incomplete block in T and B cell development. Peripheral T lymphocytes show an activated and anergic phenotype, reduced viability, and a restricted repertoire, reminiscent of human leaky SCID. Genomic instability is associated with a high rate of thymic tumor development. Finally, Lig4R/R mice spontaneously produce low-affinity antibodies that include autoreactive specificities, but are unable to mount high-affinity antibody responses. These findings highlight the importance of LIG4 in lymphocyte development and function, and in genomic stability maintenance, and provide a model for the complex phenotype of LIG4 syndrome in humans.
Targeted disruption of the CREB coactivator Crtc2 increases insulin sensitivity

Under fasting conditions, increases in circulating concentrations of pancreatic glucagon maintain glucose homeostasis through induction of gluconeogenic genes by the CREB coactivator CRTC2. Hepatic CRTC2 activity is elevated in obesity, although the extent to which this cofactor contributes to attendant increases in insulin resistance is unclear. Here we show that mice with a knockout of the CRTC2 gene have decreased circulating glucose concentrations during fasting, due to attenuation of the gluconeogenic program. CRTC2 was found to stimulate hepatic gene expression in part through an N-terminal CREB binding domain that enhanced CREB occupancy over relevant promoters in response to glucagon. Deletion of sequences encoding the CREB binding domain in CRTC2 −/− mice lowered circulating blood glucose concentrations and improved insulin sensitivity in the context of diet-induced obesity. Our results suggest that small molecules that attenuate the CREB–CRTC2 pathway may provide therapeutic benefit to individuals with type 2 diabetes.
Plastic modifications induced by object recognition memory processing

Long-term potentiation (LTP) phenomenon is widely accepted as a cellular model of memory consolidation. Object recognition (OR) is a particularly useful way of studying declarative memory in rodents because it makes use of their innate preference for novel over familiar objects. In this study, mice had electrodes implanted in the hippocampal Schaffer collaterals–pyramidal CA1 pathway and were trained for OR. Field EPSPs evoked at the CA3-CA1 synapse were recorded at the moment of training and at different times thereafter. LTP-like synaptic enhancement was found 6 h posttraining. A testing session was conducted 24 h after training, in the presence of one familiar and one novel object. Hippocampal synaptic facilitation was observed during exploration of familiar and novel objects. A short depotentiation period was observed early after the test and was followed by a later phase of synaptic efficacy enhancement. Here, we show that OR memory consolidation is accompanied by transient potentiation in the hippocampal CA3-CA1 synapses, while reconsolidation of this memory requires a short-lasting phase of depotentiation that could account for its well described vulnerability. The late synaptic enhancement phase, on the other hand, would be a consequence of memory restabilization.
Supported housing in the community for persons with severe mental illness. Psychosocial environment, needs, quality of life and social network.

This study investigated psychosocial environment, needs, quality of life and social network for persons with severe mental illness in supported housing in the community. Eighty-three persons with severe mental illness living in three different types of housing setting accepted to participate in the interviews, which took place between December 1997 and April 2000. These settings were: inpatient settings (psychiatric rehabilitation units), small congregate residences and independent living with support from social services personnel. A majority of the subjects had a diagnosis of schizophrenia, were unmarried and unemployed. In the interviews the residents emphasized the importance of social interaction, Autonomy, Support and personal security as major constituents of the psychosocial environment of small congregate community residences. In a comparison of the psychosocial environment between psychiatric inpatient settings and congregate community residences both the residents and staff of the latter setting rated higher levels of Autonomy and lower levels of Practical Orientation, Anger and Aggression, and Order and Organization than their counterparts in from the former setting. In the study of quality of life greater satisfaction in four life domains, living situation, social relations, leisure activities and work as well as two global measures of quality of life was registered by individuals living in the two community settings as compared to those in inpatient settings. No differences in social network were found between those in inpatient settings and those in community settings. A greater number of total and met needs for care was associated with living in community settings in comparison to inpatient settings. This association was still valid after controlling for the influence of factors known to affect the level of needs, duration of illness and psychopathology. A greater proportion of the residents in supported community settings reported a need in the areas of psychotic symptoms, accommodation, food, daytime activities, asexual expression, and looking after the home than their counterparts in inpatient settings. No differences were found for quality of life, social network, and needs for care between the two community settings, congregate residences and independent living with support.
Self‐Healing Stretchable Wires for Reconfigurable Circuit Wiring and 3D Microfluidics

This article describes the fabrication of self-healing stretchable wires formed by embedding liquid metal wires in microchannels composed of self-healing polymer. These stretchable wires can be completely severed with scissors and rapidly self-heal both mechanically and electrically at ambient conditions. By cutting the channels strategically, the pieces can be re-assembled in a different order to form complex microfluidic networks in 2D or 3D space.
Frecuencia y pertinencia del perfil lipídico como examen inicial en vértigo periférico

Objetivos Determinar la prevalencia de la solicitud del perfil lipidico como ayuda diagnostica de primera linea en pacientes con impresion clinica de vertigo periferico, asi como un analisis de la relacion costo-beneficio de dicha solicitud. Metodos Estudio de tipo corte transversal retrospectivo. Revision de 201 historias de pacientes atendidos en la consulta externa tanto de especialistas como de medicos generales de la Clinica Universitaria Teleton y Casa chia, con diagnostico de vertigo periferico, en el periodo comprendido entre enero de 2005 y julio de 2008. Resultados Las edades de los pacientes oscilaron entre 6 y 87 anos, el 36 % de sexo masculino y el 64 % femenino. El perfil lipidico fue solicitado como prueba diagnostica inicial para el manejo de vertigo a un 76 % de los pacientes. Los perfiles lipidicos hallados fueron normales en el 80 % de los pacientes a quienes se les solicito. Se presenta el analisis de la relacion costo-beneficio de esta prueba. Conclusiones Existe una alta prevalencia de solicitud de perfil lipidico como estudio de primera linea en el abordaje de pacientes con vertigo periferico, aunque no existe evidencia que avale esta solicitud, se requiere retroalimentacion al cuerpo medico tanto de atencion primaria como especialistas.
Global Migration and Education: Schools, Children, and Families

Contents: Preface. L.D. Adams, A. Kirova, Introduction: Global Migration and the Education of Children. Part I: Multiple Global Issues for Immigrant Children and the Schools They Attend. Introduction to Part I. C. Horst, A. Holmen, Bringing Multicultural Education Into the Mainstream: Developing Schools for Minority and Majority Students. L. Herwartz-Emden, D. Kuffner, J. Landgraf, Acculturation and Educational Achievement of Children With an Immigrant BackGround in German Primary Schools. R. Blanco, Y. Takemoto, Inclusion in Schools in Latin America and the Caribbean: The Case of Children of Haitian Descent in the Dominican Republic. B. Kumar, M. Wandel, Nutritional Challenges Among Immigrant Children and Youth in Norway. Part II: They Are Here: Newcomers in the Schools. Introduction to Part II. L.D. Adams, K.M. Shambleau, Teachers', Children's, and Parents' Perspectives on Newly Arrived Children's Adjustment to Elementary School. D. Roer-Strier, R. Strier, The Role of Home and School in the Socialization of Immigrant Children in Israel: Fathers' Views. E.L. Vidali, L.D. Adams, A Challenge of Transnational Migration: Young Children Start School. Part III: Views and Voices of Immigrant Children. Introduction to Part III. N. Rao, M. Yuen, Listening to Children: Voices of Newly Arrived Immigrants From the Chinese Mainland to Hong Kong. A. Kirova, M. Emme, Immigrant Children's Understandings of Nonverbal Peer Interactions Through the Development of Visual Narratives. L. de Block, Talking Television Across Cultures: Negotiating Inclusion and Exclusion. A. Kirova, Moving Childhoods: Young Children's Lived Experiences of Being Between Languages and Cultures. Part IV: Far From Home With Fluctuating Hopes. Introduction to Part IV. A. Farrell, Transnational Displacement of Children: An Australian Perspective. J. Szente, J. Hoot, Exploring the Needs of Refugee Children in Our Schools. G. Li, Crossing Cultural Borders in the United States: A Case Study of a Sudanese Refugee Family's Experiences With Urban Schooling. D.M. Dachyshyn, Refugee Families With Preschool Children: Adjustment to Life in Canada. Part V: Searching for New Ways to Belong. Introduction to Part V. M. Ebbeck, V. Reus, The Experiences of Third-Culture Children. H. Fabian, C. Roberts, Children in Transition: Learning to Become Global Citizens. E. Omeroglu, A. Kandir, L.D. Adams, The Social Adaptation and Skills of Migrant Children Attending Primary School in Turkey. Z. Yan, W-X. Bing, Community-Based Education for Children of Migrant Peasant Workers. A. Kirova, L.D. Adams, Lessons Learned and Implications for the Future.
Medication‐related patient safety incidents in critical care: a review of reports to the UK National Patient Safety Agency *

We reviewed all patient safety incidents reported to the UK National Patient Safety Agency between 1st August 2006 and 28th February 2007 from intensive care or high dependency units. Incidents involving medications were then categorised. 12 084 incidents were submitted from 151 organisations (median 40, range 1–634/organisation). 2428 incidents were associated with medication use involving 355 different drugs, most commonly morphine (207 incidents), gentamicin (190 incidents) and noradrenaline (133 incidents). Noradrenaline (55 incidents of harm) and insulin (48 incidents of harm) were most commonly associated with patient harm. Sixty‐one percent of medication incidents were associated with drug administration and 26% with prescription. Two hundred and eighty‐seven medication incidents caused temporary harm and 43 more than temporary harm. Five per cent of medication incidents were associated with staff communication during transfer from theatre or recovery. Categorisation of medication‐associated incidents has allowed us to suggest changes to improve the reporting of incidents and to improve medication safety.
A Retrospective Study: The Relationship Between Health Care Costs, Absenteeism and Body Mass Index in a Group of Municipal Employees

This study evaluated the relationship of varying body mass index and average annual health care costs and absenteeism in a group of 524 municipal employees. The 269 employees with health care claims and the 487 employees with attendance records were categorized into five different BMI categories based on self-reported weight and height. Findings from the study suggest that as BMI increases, average annual health care costs and average annual absenteeism increase. However, BMI was only significantly related to absenteeism. The study also found significant relationships between education and health care costs and absenteeism. No significant differences for health care costs or absenteeism were found based on race, age, gender, wellness center membership, or smoking status.
Pore architecture of the ORAI1 store-operated calcium channel

ORAI1 is the pore-forming subunit of the calcium release-activated calcium (CRAC) channel, a store-operated channel that is central to Ca2+ signaling in mammalian cells. Electrophysiological data have shown that the acidic residues E106 in transmembrane helix 1 (TM1) and E190 in TM3 contribute to the high selectivity of ORAI1 channels for Ca2+. We have examined the pore architecture of the ORAI1 channel using ORAI1 proteins engineered to contain either one or two cysteine residues. Disulfide cross-linking shows that ORAI1 assembles as a tetramer or a higher oligomer with TM1 centrally located. Cysteine side chains projecting from TM1 at position 88, 95, 102, or 106 cross-link efficiently to the corresponding side chain in a second ORAI1 monomer. Cysteine residues at position 190 or at surrounding positions in TM3 do not cross-link. We conclude that E106 residues in wild-type ORAI1 are positioned to form a Ca2+ binding site in the channel pore and that E190 interacts less directly with ions traversing the pore. The cross-linking data further identify a relatively rigid segment of TM1 adjacent to E106 that is likely to contribute to the selectivity filter.
Unexpected Crystal and Domain Structures and Properties in Compositionally Graded PbZr1‐xTixO3 Thin Films

Synthesis of compositionally graded versions of PbZr(1-x)Ti(x)O3 thin films results in unprecedented strains (as large as ≈4.5 × 10(5) m(-1)) and correspondingly unexpected crystal structures, ferroelectric domain structures, and properties. This includes the observation of built-in electric fields in films as large as 200 kV/cm. Compositional and strain gradients could represent a new direction of strain-control of materials.
A procedure‐specific systematic review and consensus recommendations for postoperative analgesia following total knee arthroplasty

The PROSPECT Working Group, a collaboration of anaesthetists and surgeons, conducts systematic reviews of postoperative pain management for different surgical procedures (http://www.postoppain.org). Evidence‐based consensus recommendations for the effective management of postoperative pain are then developed from these systematic reviews, incorporating clinical practice observations, and transferable evidence from other relevant procedures. We present the results of a systematic review of pain and other outcomes following analgesic, anaesthetic and surgical interventions for total knee arthroplasty (TKA). The evidence from this review supports the use of general anaesthesia combined with a femoral nerve block for surgery and postoperative analgesia, or alternatively spinal anaesthesia with local anaesthetic plus spinal morphine. The primary technique, together with cooling and compression techniques, should be supplemented with paracetamol and conventional non‐steroidal anti‐inflammatory drugs or COX‐2‐selective inhibitors, plus intravenous strong opioids (high‐intensity pain) or weak opioids (moderate‐ to low‐intensity pain).
Induction of cortical endoplasmic reticulum by dimerization of a coatomer-binding peptide anchored to endoplasmic reticulum membranes

Cortical endoplasmic reticulum (cER) is a permanent feature of yeast cells but occurs transiently in most animal cell types. Ist2p is a transmembrane protein that permanently localizes to the cER in yeast. When Ist2 is expressed in mammalian cells, it induces abundant cER containing Ist2. Ist2 cytoplasmic C-terminal peptide is necessary and sufficient to induce cER. This peptide sequence resembles classic coat protein complex I (COPI) coatomer protein-binding KKXX signals, and indeed the dimerized peptide binds COPI in vitro. Controlled dimerization of this peptide induces cER in cells. RNA interference experiments confirm that coatomer is required for cER induction in vivo, as are microtubules and the microtubule plus-end binding protein EB1. We suggest that Ist2 dimerization triggers coatomer binding and clustering of this protein into domains that traffic at the microtubule growing plus-end to generate the cER beneath the plasma membrane. Sequences similar to the Ist2 lysine-rich tail are found in mammalian STIM proteins that reversibly induce the formation of cER under calcium control.
Dual stage synthesis and crucial role of cytoadherence-linked asexual gene 9 in the surface expression of malaria parasite var proteins

Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family members mediate the adherence of parasite-infected red blood cells (IRBCs) to various host receptors. A previous study has shown that the parasite protein, cytoadherence-linked asexual gene 9 (CLAG9), is also essential for IRBC adherence. However, how CLAG9 influences this process remains unknown. In this study, we show that CLAG9 interacts with VAR2CSA, a PfEMP1 that mediates IRBC adherence to chondroitin 4-sulfate in the placenta. Importantly, our results show that the adherent parasites synthesize CLAG9 at two stages—the early ring and late trophozoite stages. Localization studies revealed that a substantial level of CLAG9 is located mainly at or in close proximity of the IRBC membrane in association with VAR2CSA. Upon treatment of IRBCs with trypsin, a significant amount of CLAG9 (≈150 kDa) was converted into ≈142-kDa polypeptide. Together these data demonstrate that a considerable amount of CLAG9 is embedded in the IRBC membrane such that at least a portion of the polypeptide at either N or C terminus is exposed on the cell surface. In parasites lacking CLAG9, VAR2CSA failed to express on the IRBC surface and was located within the parasite. Based on these findings, we propose that CLAG9 plays a critical role in the trafficking of PfEMP1s onto the IRBC surface. These results have important implications for the development of therapeutics for cerebral, placental, and other cytoadherence-associated malaria illnesses.