Miracle-dz/UniFAR-FTUs huggingface dataset:
Proteolytic Dissection of Zab, the Z-DNA-binding Domain of Human ADAR1*

Zα is a peptide motif that binds to Z-DNA with high affinity. This motif binds to alternating dC-dG sequences stabilized in the Z-conformation by means of bromination or supercoiling, but not to B-DNA. Zα is part of the N-terminal region of double-stranded RNA adenosine deaminase (ADAR1) , a candidate enzyme for nuclear pre-mRNA editing in mammals. Zα is conserved in ADAR1 from many species; in each case, there is a second similar motif,Zβ, separated from Zα by a more divergent linker. To investigate the structure-function relationship ofZα, its domain structure was studied by limited proteolysis. Proteolytic profiles indicated that Zα is part of a domain, Zab, of 229 amino acids (residues 133–361 in human ADAR1). This domain contains both Zα and Zβas well as a tandem repeat of a 49-amino acid linker module. Prolonged proteolysis revealed a minimal core domain of 77 amino acids (positions 133–209), containing only Zα, which is sufficient to bind left-handed Z-DNA; however, the substrate binding is strikingly different from that of Zab. The second motif, Zβ, retains its structural integrity only in the context of Zab and does not bind Z-DNA as a separate entity. These results suggest that Zαand Zβ act as a single bipartite domain. In the presence of substrate DNA, Zab becomes more resistant to proteases, suggesting that it adopts a more rigid structure when bound to its substrate, possibly with conformational changes in parts of the protein.
The Mechanics of Creasing and Crease Recovery

The "blocking friction" model by Grosberg et al. has been applied to experimental results of loop bending recovery by Stuart et al. The failure is demonstrated and ex plained qualitatively. Then the "continuous" frictional-plasto-elastic model by Olofsson is applied together with a hypothesis of "form conservation" whose general importance is further discussed in the Appendix. The agreement with experiments is demonstrated to be most satisfactory.
Rapid Responses Information in Practice Kaiser Permanente's Experience of Implementing an Electronic Medical Record: a Qualitative Study

qualitative study implementing an electronic medical record: a Kaiser Permanente's experience of service Email alerting box at the top left of the article Receive free email alerts when new articles cite this article-sign up in the Topic collections (115 articles) Information in Practice (journal section) (1803 articles) Organization of health care (336 articles) Other Medical Informatics (340 articles) Sociology (301 articles) Other management Articles on similar topics can be found in the following collections Notes To order reprints follow the "Request Permissions" link in the navigation box Abstract Objective To examine users' attitudes to implementation of an electronic medical record system in Kaiser Permanente Hawaii. Design Qualitative study based on semistructured interviews. Setting Four primary healthcare teams in four clinics, and four specialty departments in one hospital, on Oahu, Hawaii. Shortly before the interviews, Kaiser Permanente stopped implementation of the initial system in favour of a competing one. Participants Twenty six senior clinicians, managers, and project team members. Results Seven key findings emerged: users perceived the decision to adopt the electronic medical record system as flawed; software design problems increased resistance; the system reduced doctors' productivity, especially during initial implementation, which fuelled resistance; the system required clarification of clinical roles and responsibilities, which was traumatic for some individuals; a cooperative culture created trade-offs at varying points in the implementation; no single leadership style was optimal—a participatory, consensus-building style may lead to more effective adoption decisions, whereas decisive leadership could help resolve barriers and resistance during implementation; the process fostered a counter climate of conflict, which was resolved by withdrawal of the initial system. Conclusions Implementation involved several critical components, including perceptions of the system selection, early testing, adaptation of the system to the larger organisation, and adaptation of the organisation to the new electronic environment. Throughout, organisational factors such as leadership, culture, and professional ideals played complex roles, each facilitating and hindering implementation at various points. A transient climate of conflict was associated with adoption of the system.
Hospital-based surveillance to estimate the burden of rotavirus gastroenteritis in children below five years of age in Romania.

INTRODUCTION Rotavirus (RV) is a leading cause of acute gastroenteritis (AGE), affecting 95% of children below five years of age. METHODS In this prospective, multi-center study, children below five years of age who were hospitalized or those who visited the emergency room (ER) due to AGE or who developed AGE at least 48 hours after hospitalization (nosocomial infection) and had a RV-positive stool sample were included (n=1,222). RV-positive samples were genotyped by reverse-transcriptase polymerase chain reaction. RESULTS RV test results were available for 1,212 children (hospitalizations [n=677], ER visits [n=398] and nosocomial AGE cases [n=137]). Proportions of rotavirus gastroenteritis (RVGE) hospitalizations and ER visits were 51.70% (350/677; 95%CI: 47.86-55.52) and 36.18% (144/398; 95%CI: 31.45-41.12), respectively. Overall, 45.95% (494/1075) of all community-acquired AGE cases were due to RV. High numbers of RVGE cases were recorded between January and March. Most common genotypes were G9P[8] (34.27%) followed by G4P[8] (25.83%) and G1P[8] (23.02%). Of all community-acquired RVGE cases, the highest number of cases was observed in children aged 12-23 months. Median duration of hospitalization among RV-positive subjects was six days (range: 2-31 days). Incidence of nosocomial RVGE was 0.52 (95%CI: 0.45-0.60) cases per 1,000 child-days hospitalization. Median duration for additional hospitalization due to nosocomial RVGE was five days (range: 1-10). The highest burden of nosocomial RVGE was observed in children aged 12-23 months (42.34%, 58/137). Our findings confirm a high burden of acute RVGE disease in Romania and provide useful data to support the implementation of RV vaccination in Romania. TRIAL REGISTRATION NCT01253967.
Evidence for a bladder cell glycolipid receptor for Escherichia coli and the effect of neuraminic acid and colominic acid on adherence

The rat bladder epithelial cell receptors involved in mannose-sensitive adherence of Escherichia coli strains were studied. Sodium metaperiodate and lipase pretreatment of epithelial cells significantly reduced bacterial adherence to cells whereas trypsin and phospholipase C had a marginal or insignificant effect on adherence. Neuraminidase and colominic acid significantly increased adherence, whereas N-acetylneuraminic acid significantly reduced adherence. These data suggest that the rat bladder epithelial cell receptors involved in mannose-sensitive adherence are glycolipids. In addition, the data suggested that sialic acid on bladder epithelial cells acts as a nonspecific inhibitor of adherence, whereas colominic acid, a component of some E. coli K1 capsules, may act as a promoter of adherence.
Coinhibitory Receptor Expression and Immune Checkpoint Blockade: Maintaining a Balance in CD8+ T Cell Responses to Chronic Viral Infections and Cancer

In cancer and chronic viral infections, T cells are exposed to persistent antigen stimulation. This results in expression of multiple inhibitory receptors also called “immune checkpoints” by T cells. Although these inhibitory receptors under normal conditions maintain self-tolerance and prevent immunopathology, their sustained expression deteriorates T cell function: a phenomenon called exhaustion. Recent advances in cancer immunotherapy involve blockade of cytotoxic T lymphocyte antigen-4 and programmed cell death 1 in order to reverse T cell exhaustion and reinvigorate immunity, which has translated to dramatic clinical remission in many cases of metastatic melanoma and lung cancer. With the paucity of therapeutic vaccines against chronic infections such as HIV, HPV, hepatitis B, and hepatitis C, such adjunct checkpoint blockade strategies are required including the blockade of other inhibitory receptors such as T cell immunoreceptor with immunoglobulin (Ig) and immunoreceptor tyrosine-based inhibitory motif domains, T cell Ig and mucin-domain containing-3, lymphocyte activation gene 3, and V-domain Ig-containing suppressor of T cell activation. The nature of different chronic viral infections and cancers is likely to influence the level, composition, and pattern of inhibitory receptors expressed by responding T cells. This will have implications for checkpoint antibody blockade strategies employed for treating tumors and chronic viral infections. Here, we review recent advances that provide a clearer insight into the role of coinhibitory receptor expression in T cell exhaustion and reveal novel antibody-blockade therapeutic targets for chronic viral infections and cancer. Understanding the mechanism of T cell exhaustion in response to chronic virus infections and cancer as well as the nature of restored T cell responses will contribute to further improvement of immune checkpoint blockade strategies.
Intravascular Extension of Wilms Tumor

ObjectiveTo define the incidence and manifestations of and optimal therapy for children with intravascular extension of Wilms tumor. MethodsChildren on a collaborative study of Wilms tumor who had intravascular extension into the inferior vena cava (IVC) or atrium were identified. Surgical checklists and surgical and pathology reports were reviewed. ResultsOne hundred sixty-five of 2,731 patients had intravascular extension of Wilms tumor. The level of extension was IVC in 134 and atrium in 31. Sixty-nine had received preoperative therapy (55 with IVC extension and 14 with atrial extension) for a median of 8 weeks. Complications during preoperative chemotherapy were seen in five patients (tumor embolism and tumor progression in one each, and three with adult respiratory distress syndrome, one of which was fatal). The intravascular extension of the tumor regressed in 39 of 49 children with comparable pre- and posttherapy radiographic studies, including 7 of 12 in whom the tumor regressed from an atrial location, thus obviating the need for cardiopulmonary bypass. Surgical complications occurred in 36.7% of the children in the atrial group and 17.2% in the IVC group. The frequency of surgical complications was 26% in the primary resection group versus 13.2% in children with preoperative therapy. When all the complications of therapy were considered, including those that occurred during the interval of preoperative chemotherapy (one of the five also had a surgical complication), the incidence of complications among those receiving preoperative therapy was not statistically different from the incidence among those who underwent primary resection. The difference in 3-year relapse-free survival (76.9% for 165 patients with intravascular extension, 80.3% for 1,622 patients with no extension) was not statistically significant whether or not it was adjusted for stage and histology. ConclusionsPreoperative treatment of these children may facilitate resection by decreasing the extent of the tumor thrombus, but the overall frequency of complications is similar in both groups.
Successful inhibition, unsuccessful retrieval: Manipulating time and success during retrieval practice

Retrieving an item or set of items from memory can cause the forgetting of other related items in memory; a phenomenon known as retrieval-induced forgetting. According to the inhibitory account of retrieval-induced forgetting, in searching for a particular item, other items that are related but incorrect can vie for access. Inhibition functions to decrease the accessibility of such interfering items, thereby facilitating access to the target item. Experiments 1 and 2 replicated recent work suggesting that retrieval success is not a necessary condition for retrieval-induced forgetting to occur. Interfering items were forgotten even when retrieval practice was designed to be impossible. Experiments 3 and 4 employed the impossible retrieval practice procedure to examine the time-course of forgetting across a single retrieval practice trial. Results support the inhibitory account of retrieval-induced forgetting and offer insight into the dynamics of how and when inhibition plays a role in retrieval.
Investigating the entire course of telithromycin binding to Escherichia coli ribosomes

Applying kinetics and footprinting analysis, we show that telithromycin, a ketolide antibiotic, binds to Escherichia coli ribosomes in a two-step process. During the first, rapidly equilibrated step, telithromycin binds to a low-affinity site (KT = 500 nM), in which the lactone ring is positioned at the upper portion of the peptide exit tunnel, while the alkyl–aryl side chain of the drug inserts a groove formed by nucleotides A789 and U790 of 23S rRNA. During the second step, telithromycin shifts slowly to a high-affinity site (KT* = 8.33 nM), in which the lactone ring remains essentially at the same position, while the side chain interacts with the base pair U2609:A752 and the extended loop of protein L22. Consistently, mutations perturbing either the base pair U2609:A752 or the L22-loop hinder shifting of telithromycin to the final position, without affecting the initial step of binding. In contrast, mutation Lys63Glu in protein L4 placed on the opposite side of the tunnel, exerts only a minor effect on telithromycin binding. Polyamines disfavor both sequential steps of binding. Our data correlate well with recent crystallographic data and rationalize the changes in the accessibility of ribosomes to telithromycin in response to ribosomal mutations and ionic changes.
Diffuse Continuum Gamma Rays from the Galaxy

A new study of the diffuse Galactic γ-ray continuum radiation is presented, using a cosmic-ray propagation model which includes nucleons, antiprotons, electrons, positrons, and synchrotron radiation. Our treatment of the inverse Compton scattering includes the effect of anisotropic scattering in the Galactic interstellar radiation field (ISRF) and a new evaluation of the ISRF itself. Models based on locally measured electron and nucleon spectra and synchrotron constraints are consistent with γ-ray measurements in the 30-500 MeV range, but outside this range excesses are apparent. A harder nucleon spectrum is considered but fitting to γ-rays causes it to violate limits from positrons and antiprotons. A harder interstellar electron spectrum allows the γ-ray spectrum to be fitted above 1 GeV as well, and this can be further improved when combined with a modified nucleon spectrum which still respects the limits imposed by antiprotons and positrons. A large electron/inverse Compton halo is proposed which reproduces well the high-latitude variation of γ-ray emission; this is taken as support for the halo size for nucleons deduced from studies of cosmic-ray composition. Halo sizes in the range 4-10 kpc are favored by both analyses. The halo contribution of Galactic emission to the high-latitude γ-ray intensity is large, with implications for the study of the diffuse extragalactic component and signatures of dark matter. The constraints provided by the radio synchrotron spectral index do not allow all of the γ-ray emission at less than 30 MeV to be explained in terms of a steep electron spectrum unless this takes the form of a sharp upturn below 200 MeV. This leads us to prefer a source population as the origin of the excess low-energy γ-rays, which can then be seen as a continuation of the hard X-ray continuum measured by OSSE, Ginga, and RXTE.
Turning 18 with congenital heart disease: prediction of infective endocarditis based on a large population.

AIMS The risk of infective endocarditis (IE) in adults with congenital heart disease is known to be increased, yet empirical risk estimates are lacking. We sought to predict the occurrence of IE in patients with congenital heart disease at the transition from childhood into adulthood. METHODS AND RESULTS We identified patients from the CONCOR national registry for adults with congenital heart disease. Potential predictors included patient characteristics, and complications and interventions in childhood. The outcome measure was the occurrence of IE up to the age of 40 and 60. A prediction model was derived using the Cox proportional hazards model and bootstrapping techniques. The model was transformed into a clinically applicable risk score. Of 10 210 patients, 233 (2.3%) developed adult-onset IE during 220 688 patient-years. Predictors of IE were gender, main congenital heart defect, multiple heart defects, and three types of complications in childhood. Up to the age of 40, patients with a low predicted risk (<3%) had an observed incidence of less than 1%; those with a high predicted risk (≥3%) had an observed incidence of 6%. The model also yielded accurate predictions up to the age of 60. CONCLUSION Among young adult patients with congenital heart disease, the use of six simple clinical parameters can accurately predict patients at relatively low or high risk of IE. After confirmation in other cohorts, application of the prediction model may lead to individually tailored medical surveillance and educational counselling, thus averting IE or enabling timely detection in adult patients with congenital heart disease.
Racial and Ethnic Disparities in Early Childhood Health and Health Care

Background. Racial/ethnic disparities in health care have received much national attention recently, but few studies have focused on disparities among children. We studied disparities in early childhood health and health care. Methods. We analyzed data for 2608 children, 4 to 35 months of age, from the 2000 National Survey of Early Childhood Health, a nationwide household survey. The overall response rate was 65.6%. Survey questions addressed health, health care, and interactions with health care providers. Results. Hispanic and black children were significantly less likely than whites to be in excellent/very good health (72%, 79%, and 90%, respectively) and were more likely to be uninsured (31%, 18%, and 9%, respectively). Only 60% of Hispanic and 77% of black parents would recommend their child's provider to others, compared with 84% of white parents. Minority parents more often reported that providers never or only sometimes understood their child-rearing preferences, and Hispanic parents most often reported that providers never or only sometimes understood their child's needs. Minority parents more often were asked about violence, smoking, drinking, and drug use. Hispanic and black parents averaged significantly fewer telephone calls to doctors' offices than did whites (2.0, 3.1, and 4.3 calls, respectively). Providers significantly less often referred Hispanic and black children to specialists (11% and 17%, respectively, compared with 22% for whites). Most disparities persisted in multivariate analyses, and several disparities were found between children with parents who completed surveys in Spanish and those with parents who completed surveys in English. Conclusion. Young minority children experience multiple disparities in health status, insurance coverage, topics discussed during pediatric visits, parents feeling understood by providers, parental satisfaction, and referrals to specialists.
Effects of trona on the redox status of cellular system of male rats

The effects of trona (Kaun), a food additive, on the redox status of the liver and kidney of male Wistar rats were investigated. A total of 60 male rats (145 ± 2.52 g) were grouped into four: A, B, C and D, where group A (the control) received 1 mL of distilled water orally while those in groups B, C and D (test groups) received orally, same volume of trona preparation corresponding to 100, 200 and 400 mg/kg body weight, respectively, for 28 days. Administration of trona significantly reduced (p < 0.05) alkaline phosphatase activity in the liver and kidney with corresponding increases in the serum enzyme. Acid phosphatase activity increased significantly (p < 0.05) in the liver and kidney with no significant change (p > 0.05) in the activity of the serum enzyme. The activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and the levels of reduced glutathione, vitamins C and E in the liver and kidney of the animals decreased significantly (p < 0.05). In contrast, malondialdehyde and lipid hydroperoxide of trona-treated animals increased significantly (p < 0.05) in liver and kidney. Overall, data from this study revealed that trona exhibited its toxic effect by suppressing or depleting the antioxidant systems and increasing the risk of attack by oxidants generated either from its metabolites or from other in vivo means on the rat cellular system.
ESCRTs regulate amyloid precursor protein sorting in multivesicular bodies and intracellular amyloid-β accumulation

ABSTRACT Intracellular amyloid-β (Aβ) accumulation is a key feature of early Alzheimer's disease and precedes the appearance of Aβ in extracellular plaques. Aβ is generated through proteolytic processing of amyloid precursor protein (APP), but the intracellular site of Aβ production is unclear. APP has been localized to multivesicular bodies (MVBs) where sorting of APP onto intraluminal vesicles (ILVs) could promote amyloidogenic processing, or reduce Aβ production or accumulation by sorting APP and processing products to lysosomes for degradation. Here, we show that APP localizes to the ILVs of a subset of MVBs that also traffic EGF receptor (EGFR), and that it is delivered to lysosomes for degradation. Depletion of the endosomal sorting complexes required for transport (ESCRT) components, Hrs (also known as Hgs) or Tsg101, inhibited targeting of APP to ILVs and the subsequent delivery to lysosomes, and led to increased intracellular Aβ accumulation. This was accompanied by dramatically decreased Aβ secretion. Thus, the early ESCRT machinery has a dual role in limiting intracellular Aβ accumulation through targeting of APP and processing products to the lysosome for degradation, and promoting Aβ secretion. Highlighted Article: The early ESCRT machinery has a dual role in limiting intracellular Aβ accumulation through targeting of APP and its processing products to lysosomes for degradation, and promoting Aβ secretion.
Antioxidant and Anti-cholinesterase Activity of Globularia meridionalis Extracts and Isolated Constituents

The antioxidant and anti-cholinesterase properties of Globularia meridional (Podp.) O. Schwarz (Globulariaceae) were investigated. G. meridionalis aerial parts and roots were extracted with methanol, and the total extract successively partitioned with n-hexane. The methanol fraction of the roots showed the highest antioxidant activity with IC50 values of 8.0 and 2.1 μg/mL in the DPPH and β-carotene bleaching tests, respectively. From this fraction, three flavonoids, namely pectolinarigenin 7-O-β-glucoside, apigenin 7-O-β-glucoside and luteolin, and two phenylethanoids, namely acteoside and isoacteoside, were isolated. Potential anti-cholinesterase effects were assessed through the acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes inhibition assay. The n-hexane fraction of the roots exhibited the highest activity against both AChE and BChE with IC50 values of 65.5 and 70.4 μg/mL, respectively.