Miracle-dz/UniFAR-FTUs huggingface dataset:
Mcl‐1–Bim complexes accommodate surprising point mutations via minor structural changes

Mcl‐1 is an antiapoptotic Bcl‐2‐family protein that protects cells against death. Structures of Mcl‐1, and of other anti‐apoptotic Bcl‐2 proteins, reveal a surface groove into which the α‐helical BH3 regions of certain proapoptotic proteins can bind. Despite high overall structural conservation, differences in this groove afford binding specificity that is important for the mechanism of Bcl‐2 family function. We report the crystal structure of human Mcl‐1 bound to a BH3 peptide derived from human Bim and the structures for three complexes that accommodate large physicochemical changes at conserved Bim sites. The mutations had surprisingly modest effects on complex stability, and the structures show that Mcl‐1 can undergo small changes to accommodate the mutant ligands. For example, a shift in a leucine side chain fills a hole left by an isoleucine‐to‐alanine mutation at the first hydrophobic buried position of Bim BH3. Larger changes are also observed, with shifting of helix α3 accommodating an isoleucine‐to‐tyrosine mutation at this same position. We surveyed the variation in available Mcl‐1 and Bcl‐xL structures and observed moderate flexibility that is likely critical for facilitating interactions of diverse BH3‐only proteins with Mcl‐1. With the antiapoptotic Bcl‐2 family members attracting significant attention as therapeutic targets, these structures contribute to our growing understanding of how specificity is achieved and can help to guide the design of novel inhibitors that target Mcl‐1.
Global Versus Local Consumer Culture: Theory, Measurement, and Future Research Directions

The last few decades have seen the emergence of global consumer culture (GCC) as an important force in the marketplace. Yet, in recent years, powerful political and economic forces suggest that globalization might be stalling, leading to renewed interest in local consumer culture (LCC). This article provides an overview of where the field of international marketing stands on GCC and LCC, and it presents new empirical insights. It elaborates on the roots of GCC and LCC in consumer culture theory, cultural globalization theory, and acculturation theory. This background information sets the context for an in-depth discussion of how international marketers have operationalized consumer attitudes toward GCC and LCC, and their individual-level and national-cultural correlates. The article addresses behavioral and managerial consequences of GCC and LCC and concludes with areas for future research.
Impaired Mast Cell Maturation and Degranulation and Attenuated Allergic Responses in Ndrg1-Deficient Mice1

We have previously reported that N-myc downstream regulated gene-1 (NDRG1) is an early inducible protein during the maturation of mouse bone marrow-derived mast cells (BMMCs) toward a connective tissue mast cell-like phenotype. To clarify the function of NDRG1 in mast cells and allergic responses, we herein analyzed mast cell-associated phenotypes of mice lacking the Ndrg1 gene. Allergic responses including IgE-mediated passive systemic and cutaneous anaphylactic reactions were markedly attenuated in Ndrg1-deficient mice as compared with those in wild-type mice. In Ndrg1-deficient mice, dermal and peritoneal mast cells were decreased in number and morphologically abnormal with impaired degranulating ability. Ex vivo, Ndrg1-deficient BMMCs cocultured with Swiss 3T3 fibroblasts in the presence of stem cell factor, a condition that facilitates the maturation of BMMCs toward a CTMC-like phenotype, displayed less exocytosis than replicate wild-type cells after the cross-linking of FcεRI or stimulation with compound 48/80, even though the exocytotic response of IL-3-maintained, immature BMMCs from both genotypes was comparable. Unlike degranulation, the production of leukotriene and cytokines by cocultured BMMCs was unaffected by NDRG1 deficiency. Taken together, the altered phenotypes of Ndrg1-deficient mast cells both in vivo and ex vivo suggest that NDRG1 has roles in the terminal maturation and effector function (degranulation) of mast cells.
Does the availability of hospital beds affect utilization patterns? The case of end-of-life care

Hospital downsizing in Canada during the 1990s raised public concern over the availability of hospital care, in addition to heightening administrative interest in improving or maximizing hospital utilization. One ongoing concern about hospital utilization is that a disproportionately large share of hospital resources is used by terminally ill and dying people. A research study using 1992/1993-1996/1997 in-patient abstracts data for the province of Alberta, Canada, was undertaken to explore and describe hospital utilization by dying in-patients. This investigation found only 48.2% of all deaths in Alberta over the five years studied involved hospital in-patients. An 18.5% reduction in the number of in-patient deaths and an 83.3% reduction in length of final stay occurred when 50% of acute care beds were closed, which was followed by an increase when beds began reopening - in terms of both the number of in-patient deaths (4.8%) and the average length of stay (2.6%). The ratio of men to women, the average age of dying in-patients, and the intensity of hospital care changed relatively little over those five years. Most in-patients were admitted for nursing care; in 51.3% of all cases, no diagnostic or therapeutic procedures were performed prior to death. These findings indicate hospital bed availability influences admission to hospital and length of stay, but not treatment decisions affecting seriously ill and dying patients. In addition, reduced length of stay appears to have been a widespread response to hospital downsizing, with this change substantially preserving individual access to hospitals.
Biological and immunological characterization of human luteinizing hormone discharged by the stimulation of synthetic luteinizing hormone-releasing hormone (LH-RH) in normal and anovulatory women.

Plasma samples were obtained by repeated venopunctures immediately before, and at 15, 30, 60, 120 and 180 min after intravenous bolus administration of 100 micrograms synthetic LH-RH in normal and various anovulatory women. Plasma hLH levels were determined by an in vitro bioassay and a radioimmunoassay with improved reagents. The LH-RH stimulation induced an abrupt elevation of both biological and immunological hLH activities in normal and anovulatory women, although the responsiveness to LH-RH differed from case to case. Both elevated biological and immunological hLH activities decreased gradually with a half disappearance time of 122.4 +/- 27.9 min and 112.5 +/- 25.4 min, respectively (Mean +/- S.D.). A transient and significant depression in the ratio of biological to immunological hLH activities (B/I ratio) was observed at 15 min after the LH-RH administration in normal subjects. This depression is attributable to the cross-contamination of an increased amount of hLH subunits induced by LH-RH stimulation. The B/I ratios were significantly elevated throughout the investigation period in the anovulatory patients when compared with those in the normal subjects. This elevation appears to indicate the increased discharge of special type(s) of hLH subpopulations of high biological potency in the anovulatory cases.
Allergic children have more numerous and severe respiratory infections than non‐allergic children

Allergic disorders are characterized by Th2‐polarization, and hence physiological Th1‐dependent mechanisms for fighting respiratory infections (RI) may be defective. This study aimed at evaluating the number and duration of RI in allergic and non‐allergic children suffering from recurrent RI. One hundred seventeen children (4.02 ± 1.0 yr, 72 males and 45 females) were studied during the spring, 46 were allergic. Allergic children showed a significantly higher number (mean 1.26 ± 0.73) and longer duration of RI (8.92 days) in comparison with non‐allergic group (0.94 ± 1.37 and 4.85 days) (p = 0.0001 and p = 0.009, respectively). In conclusion, this study provides the evidence that allergic children have more numerous and severe RI than non‐allergic children.
Families With Special Needs Children

There are 11.2 million children with special health care needs in the United States or one in five households caring for a special needs child. A small group of children who need continuous medical, nursing, therapeutic services that enable them to survive is growing in numbers. This study examined physical health (physical functioning), mental health (emotional, social, and cognitive functioning; communication; and worry), family functioning (daily activities, family relationships), and care burden (caregiver employment, caregiving time, travel time, health-related out-of-pocket expenditures) of parent caregivers for medically complex, medical technology–dependent children. Data were collected once a month for 5 months on 84 parents recruited in South Florida using the Pediatric Quality of Life Family Impact Module. Physically, parents were tired when they woke up: too tired to do the things they liked to do and with little energy for chores or social activities. Mentally, they were frustrated, anxious, and angry; felt helpless and hopeless; had cognitive problems remembering and focusing on tasks; were worried about the child’s medications, treatments, side effects; and were anxious about child’s future and effect of the child’s condition on other family members. Socially, they felt isolated and that people did not understand their family situation; they found it hard to talk with others including physicians and nurses. Average weekly hours of direct care was 33.0 (SD = 30.4 hours); average monthly out-of-pocket expenditures was $348.78 (SD = $623.34). It is essential to assess parents’ physical and mental health and functioning and to provide interventions to improve health and functioning for both the parents and the children for whom they are caring.
Modelling strategies for the reduction of fat dormice in northern Italian hazel groves

The production of hazelnuts represents an important resource for several Italian rural areas. Sicily and Piedmont, two of the most important producers of hazelnuts, are affected by the presence of the dormouse (Glis glis), that has considerably severely harmed the production of hazelnuts. This study aims to analyse the issue in the Province of Cuneo in Piedmont and to evaluate the sustainability of the policies implemented by using the system dynamics (SD) methodology. An SD predator-prey microworld was built to reproduce the main relevant cause and effect relationships between the development of the dormouse population and local hazelnut production. The results of the SD microworld simulation show the effects of reduction policies on hazelnut production over time. The findings and further research recommendations are briefly reported in the conclusion section.
The impact of sinus surgery on sleep outcomes

Functional endoscopic sinus surgery (FESS) is standard for patients who fail medical management of chronic sinusitis (CRS). The beneficial impact of surgery on CRS is well known. However, patients often note that their sleep is improved after FESS even without simultaneous correction of nasal obstruction. Sleep outcomes after FESS are significantly understudied. Hence in the current study we look to characterize patient sleep quality following sinus surgery.
Tumor-Suppressing Pathways in Cystic Pancreatic Tumors

Introduction and Aims Serous and mucinous cystic pancreatic tumors have different clinical behavior. We evaluated whether they also have genotypic differences by analyses of the tumor suppressor genes p16INK4a, p53, and DPC4. Methodology Seven serous cystadenomas (SCA) and seven malignant mucinous cystadenocarcinomas (MCC) were analyzed for alterations in the tumor suppressor genes p16INK4a, p53, and DPC4 by single-strand conformational variant analysis, direct sequencing, and immunohistochemical analysis. Methylation-specific polymerase chain reaction analysis was performed to identify p16INK4a promoter hypermethylation. Clinical data were compared with genetic data. Results None of the seven patients with SCAs but five of the seven patients with MCCs died of the tumor after a median follow-up of 44.5 months (range, 4–169 months). All seven MCCs had alterations in at least one tumor suppressor gene compared with none of the seven SCAs. Of the seven MCCs, three had inactivating p16INK4a promoter hypermethylation, five had p53 alterations, and three had DPC4 mutations. Conclusions The tumor suppressor genes p16INK4a, p53, and DPC4 appear to play an important role in the tumorigenesis of MCCs but not SCAs. These molecular data underscore the clinical and histologic differences of serous and mucinous cystic pancreatic tumors.
Screening for serious mental illness: methodological studies of the K6 screening scale

The K6 scale is a shortened version of the K10, a 10‐question scale originally developed to provide an efficient population‐level screen for serious mental disorders (SMI) in the USA. Evidence that the six‐item shortened version performed as well as the original 10‐item version, coupled with strong psychometric properties, led to rapid dissemination and replicated validation of the K6 in a number of other countries around the world. Based on these results, the K6 is now often included in large general‐purpose government health tracking surveys in a number of different countries. Until now, though, the scoring rules for the K6 in these surveys were inconsistent. The first paper in this special issue introduces the K6 scale and summarizes the results of a series of investigations to resolve these inconsistencies by providing optimal scoring rules for the K6 in 14 countries. Subsequent papers explore the usefulness of the K6 to screen for serious emotional disturbance among adolescents and report findings from validation efforts based on independent diagnostic assessments as well as of other measures of impairment and disability (World Health organization Disability Assessment Scale). Finally a highly innovative analysis using a Bayesian multilevel modeling approach is presented, designed to estimate the prevalence of SMI in small areas, such as cities, states, or schools, from surveys carried out in a larger population that includes only relatively small samples of respondents in each of the areas in which prevalence estimates are to be made. Taken together, these studies demonstrate that the K6 is an efficient and useful screening tool. The psychometric and methodological explorations will hopefully stimulate additional interest in the use of short screening scales in large‐scale general health surveys to supplement the more in‐depth information obtained in periodic psychiatric epidemiological surveys on the basis of diagnostic interviews. Copyright © 2010 John Wiley & Sons, Ltd.
A prospective neurosurgical registry evaluating the clinical care of traumatic brain injury patients presenting to Mulago National Referral Hospital in Uganda

Background Traumatic Brain Injury (TBI) is disproportionally concentrated in low- and middle-income countries (LMICs), with the odds of dying from TBI in Uganda more than 4 times higher than in high income countries (HICs). The objectives of this study are to describe the processes of care and determine risk factors predictive of poor outcomes for TBI patients presenting to Mulago National Referral Hospital (MNRH), Kampala, Uganda. Methods We used a prospective neurosurgical registry based on Research Electronic Data Capture (REDCap) to systematically collect variables spanning 8 categories. Univariate and multivariate analysis were conducted to determine significant predictors of mortality. Results 563 TBI patients were enrolled from 1 June– 30 November 2016. 102 patients (18%) received surgery, 29 patients (5.1%) intended for surgery failed to receive it, and 251 patients (45%) received non-operative management. Overall mortality was 9.6%, which ranged from 4.7% for mild and moderate TBI to 55% for severe TBI patients with GCS 3–5. Within each TBI severity category, mortality differed by management pathway. Variables predictive of mortality were TBI severity, more than one intracranial bleed, failure to receive surgery, high dependency unit admission, ventilator support outside of surgery, and hospital arrival delayed by more than 4 hours. Conclusions The overall mortality rate of 9.6% in Uganda for TBI is high, and likely underestimates the true TBI mortality. Furthermore, the wide-ranging mortality (3–82%), high ICU fatality, and negative impact of care delays suggest shortcomings with the current triaging practices. Lack of surgical intervention when needed was highly predictive of mortality in TBI patients. Further research into the determinants of surgical interventions, quality of step-up care, and prolonged care delays are needed to better understand the complex interplay of variables that affect patient outcome. These insights guide the development of future interventions and resource allocation to improve patient outcomes.
Interkinetic nuclear migration in the mouse embryonic ureteric epithelium: Possible implication for congenital anomalies of the kidney and urinary tract

Interkinetic nuclear migration (INM) is a phenomenon in which progenitor cell nuclei migrate along the apico‐basal axis of the pseudostratified epithelium, which is characterized by the presence of apical primary cilia, in synchrony with the cell cycle in a manner of apical mitosis. INM is suggested to regulate not only stem/progenitor cell proliferation/differentiation but also organ size and shape. INM has been reported in epithelia of both ectoderm and endoderm origin. We examined whether INM exists in the mesoderm‐derived ureteric epithelium. At embryonic day (E) 11.5, E12.5 and E13.5, C57BL/6J mouse dams were injected with 5‐bromo‐2’‐deoxyuridine (BrdU) and embryos were killed 1, 2, 4, 6, 8, 10 and 12 h later. We immunostained transverse sections of the ureter for BrdU, and measured the position of BrdU (+) nuclei in the ureteric epithelia along the apico‐basal axis at each time point. We analyzed the distribution patterns of BrdU (+) nuclei in histograms using the multidimensional scaling. Changes in the nucleus distribution patterns suggested nucleus movement characteristic of INM in the ureteric epithelia, and the mode of INM varied throughout the ureter development. While apical primary cilia are related with INM by providing a centrosome for the apical mitosis, congenital anomalies of the kidney and urinary tract (CAKUT) include syndromes linked to primary ciliary dysfunction affecting epithelial tubular organs such as kidney, ureter, and brain. The present study showed that INM exists in the ureteric epithelium and suggests that INM may be related with the CAKUT etiology via primary ciliary protein function.
Local Oscillations of On-Die Supply Voltage—A Reliability Issue

On-die measurements of <i>V</i> <sub>DD</sub> and <i>V</i> <sub>SS</sub> voltages inside a 90-nm VLSI technology chip are presented. The results show local fluctuations in the <i>V</i> <sub>DD</sub> and <i>V</i> <sub>SS</sub> voltages with amplitudes that can reach, in severe cases, more than 10% of <i>V</i> <sub>DD</sub>. These fluctuations can distort analog signals, cause immediate logic faults, and also aggravate other reliability wear-out mechanisms. Both measurements and simulations predict the aggravation of this phenomenon for future technologies.
Dietary changes of large herbivores in the Turkana Basin, Kenya from 4 to 1 Ma

Significance Stable carbon isotopes give diet information for both modern and fossil mammals and can be used to classify diets as C4 grazers, C3–C4 mixed, or C3 browsers. We show that diets of some major African herbivore lineages have significantly changed over the past 4 million years by comparing fossils from the Turkana Basin in Kenya with modern mammals from East and Central Africa. Some fossil assemblages have no modern analogues in East and Central Africa, suggesting different ecological functions for some mammals in the past as compared with their modern counterparts. The development of modern tropical grassland ecosystems are products of the coevolution of both grasses and herbivores. A large stable isotope dataset from East and Central Africa from ca. 30 regional collection sites that range from forest to grassland shows that most extant East and Central African large herbivore taxa have diets dominated by C4 grazing or C3 browsing. Comparison with the fossil record shows that faunal assemblages from ca. 4.1–2.35 Ma in the Turkana Basin had a greater diversity of C3–C4 mixed feeding taxa than is presently found in modern East and Central African environments. In contrast, the period from 2.35 to 1.0 Ma had more C4-grazing taxa, especially nonruminant C4-grazing taxa, than are found in modern environments in East and Central Africa. Many nonbovid C4 grazers became extinct in Africa, notably the suid Notochoerus, the hipparion equid Eurygnathohippus, the giraffid Sivatherium, and the elephantid Elephas. Other important nonruminant C4-grazing taxa switched to browsing, including suids in the lineage Kolpochoerus-Hylochoerus and the elephant Loxodonta. Many modern herbivore taxa in Africa have diets that differ significantly from their fossil relatives. Elephants and tragelaphin bovids are two groups often used for paleoecological insight, yet their fossil diets were very different from their modern closest relatives; therefore, their taxonomic presence in a fossil assemblage does not indicate they had a similar ecological function in the past as they do at present. Overall, we find ecological assemblages of C3-browsing, C3–C4-mixed feeding, and C4-grazing taxa in the Turkana Basin fossil record that are different from any modern ecosystem in East or Central Africa.
Endomysial antibody-negative coeliac disease: clinical characteristics and intestinal autoantibody deposits

Background: Some patients with untreated coeliac disease are negative for serum endomysial autoantibodies (EmA) targeted against transglutaminase 2 (TG2). Aims: To evaluate the clinical and histological features of EmA-negative coeliac disease, and to examine whether EmA-equivalent autoantibodies against TG2 can be seen in the small-bowel mucosa when absent in serum. Patients: Serum EmA was studied in 177 biopsy-proved specimens from adult patients with coeliac disease. 20 patients with intestinal diseases served as non-coeliac controls; three had autoimmune enteropathy with villous atrophy. Methods: Clinical manifestations, small-bowel mucosal morphology, intraepithelial inflammation and TG2-specific extracellular immunoglobulin A (IgA) deposits were investigated in both serum EmA-negative and EmA-positive patients. Results: 22 patients with IgA-competent coeliac disease were negative for serum EmA. Three of these had small-bowel lymphoma. Patients with EmA-negative coeliac disease were older, had abdominal symptoms more often, and the density of γδ+ intraepithelial lymphocytes in their intestinal mucosa was lower than in EmA-positive patients; otherwise the histology was similar. All serum EmA-negative patients with coeliac disease, but none of the disease controls, had gluten-dependent mucosal IgA deposits alongside TG2 in the small-bowel mucosal specimens. In vivo deposited IgA was shown to be TG2-specific by its ability to bind recombinant TG2. Conclusions: Negative serum EmA might be associated with advanced coeliac disease. TG2-targeted autoantibodies were deposited in the small-bowel mucosa even when absent in serum. This finding can be used in the diagnosis of seronegative coeliac disease when the histology is equivocal. It may also be helpful in the differential diagnosis between autoimmune enteropathy and coeliac disease.