Miracle-dz/UniFAR-FTUs huggingface dataset:
Proteasomal Inhibition Restores Biological Function of Mis-sense Mutated Dysferlin in Patient-derived Muscle Cells*

Background: Dysferlin encoded by mis-sense alleles is rapidly degraded in skeletal muscle. Results: Proteasomal inhibitors increase dysferlin levels, restore membrane repair and myotube formation in patient-derived myoblasts harboring mis-sense mutated dysferlin. Conclusion: Proteasomal inhibition restores function of mis-sense mutated dysferlin. Significance: Inhibiting the degradation of mis-sense mutated dysferlin may be a therapeutic strategy for dysferlinopathies with certain mis-sense mutations. Dysferlin is a transmembrane protein implicated in surface membrane repair of muscle cells. Mutations in dysferlin cause the progressive muscular dystrophies Miyoshi myopathy, limb girdle muscular dystrophy 2B, and distal anterior compartment myopathy. Dysferlinopathies are inherited in an autosomal recessive manner, and many patients with this disease harbor mis-sense mutations in at least one of their two pathogenic DYSF alleles. These patients have significantly reduced or absent dysferlin levels in skeletal muscle, suggesting that dysferlin encoded by mis-sense alleles is rapidly degraded by the cellular quality control system. We reasoned that mis-sense mutated dysferlin, if salvaged from degradation, might be biologically functional. We used a dysferlin-deficient human myoblast culture harboring the common R555W mis-sense allele and a DYSF-null allele, as well as control human myoblast cultures harboring either two wild-type or two null alleles. We measured dysferlin protein and mRNA levels, resealing kinetics of laser-induced plasmalemmal wounds, myotube formation, and cellular viability after treatment of the human myoblast cultures with the proteasome inhibitors lactacystin or bortezomib (Velcade). We show that endogenous R555W mis-sense mutated dysferlin is degraded by the proteasomal system. Inhibition of the proteasome by lactacystin or Velcade increases the levels of R555W mis-sense mutated dysferlin. This salvaged protein is functional as it restores plasma membrane resealing in patient-derived myoblasts and reverses their deficit in myotube formation. Bortezomib and lactacystin did not cause cellular toxicity at the regimen used. Our results raise the possibility that inhibition of the degradation pathway of mis-sense mutated dysferlin could be used as a therapeutic strategy for patients harboring certain dysferlin mis-sense mutations.
Comparative molecular dynamics analysis of tapasin‐dependent and ‐independent MHC class I alleles

MHC class I molecules load antigenic peptides in the endoplasmic reticulum and present them at the cell surface. Efficiency of peptide loading depends on the class I allele and can involve interaction with tapasin and other proteins of the loading complex. Allele HLA‐B*4402 (Asp at position 116) depends on tapasin for efficient peptide loading, whereas HLA‐B*4405 (identical to B*4402 except for Tyr116) can efficiently load peptides in the absence of tapasin. Both alleles adopt very similar structures in the presence of the same peptide. Comparative unrestrained molecular dynamics simulations on the α1/α2 peptide binding domains performed in the presence of bound peptides resulted in structures in close agreement with experiments for both alleles. In the absence of peptides, allele‐specific conformational changes occurred in the first segment of the α2‐helix that flanks the peptide C‐terminal binding region (F‐pocket) and contacts residue 116. This segment is also close to the proposed tapasin contact region. For B*4402, a shift toward an altered F‐pocket structure deviating significantly from the bound form was observed. Subsequent free energy simulations on induced F‐pocket opening in B*4402 confirmed a conformation that deviated significantly from the bound structure. For B*4405, a free energy minimum close to the bound structure was found. The simulations suggest that B*4405 has a greater tendency to adopt a peptide receptive conformation in the absence of peptide, allowing tapasin‐independent peptide loading. A possible role of tapasin could be the stabilization of a peptide‐receptive class I conformation for HLA‐B*4402 and other tapasin‐dependent alleles.
Prognostic Factors Affecting the Clinical Outcome of Septic Arthritis of the Shoulder.

BACKGROUND The objective of this study was to determine prognostic factors affecting the clinical outcome of septic arthritis of the shoulder. METHODS We retrospectively reviewed 34 shoulders from 32 patients, two of which had bilateral involvement. Arthroscopic (22 shoulders) or open surgery (12 shoulders) was performed by a single surgeon. The mean follow-up period was 32.4 ± 17.0 months. Clinical outcomes according to the University of California at Los Angeles (UCLA) score, American Shoulder and Elbow Surgeons (ASES) score, and Subjective Shoulder Value (SSV) were assessed at the final follow-up period. Various factors were included for statistical analysis. RESULTS The mean UCLA, ASES scores, and SSV were 28.9 ± 7.2, 81.3 ± 21.0, 79.7 ± 2.5%, respectively. Positive culture was observed in only 13 shoulders (38.2%) and the most common organism was Staphylococcus aureus (seven shoulders). Five shoulders (14.7%) required two or three operations. Age and comorbidity were negatively correlated with the UCLA, ASES score, and/or SSV (p < 0.05). There was no correlation between clinical outcome and various parameters, including gender, location of lesion, history of previous steroid injection, interval between onset of symptoms and surgical intervention, bacterial organisms, operative method, and presence of rotator cuff tear and reoperation (p > 0.05). CONCLUSIONS Both arthroscopic and open surgery for septic shoulders showed satisfactory clinical outcomes. Old age and comorbidity were poor prognostic factors of clinical outcomes after treatment.
EFFECT OF SODIUM HYDROXIDE CONCENTRATION ON FRESH PROPERTIES AND COMPRESSIVE STRENGTH OF SELF-COMPACTING GEOPOLYMER CONCRETE

This paper reports the results of the laboratory tests conducted to investigate the effect of sodium hydroxide concentration on the fresh properties and compressive strength of self-compacting geopolymer concrete (SCGC). The experiments were conducted by varying the concentration of sodium hydroxide from 8 M to 14 M. Test methods such as Slump flow, V-Funnel, L-box and JRing were used to assess the workability characteristics of SCGC. The test specimens were cured at 70°C for a period of 48 hours and then kept in room temperature until the day of testing. Compressive strength test was carried out at the ages of 1, 3, 7 and 28 days. Test results indicate that concentration variation of sodium hydroxide had least effect on the fresh properties of SCGC. With the increase in sodium hydroxide concentration, the workability of fresh concrete was slightly reduced; however, the corresponding compressive strength was increased. Concrete samples with sodium hydroxide concentration of 12 M produced maximum compressive strength.
Satellite‐based estimates of Antarctic surface meltwater fluxes

This study generates novel satellite‐derived estimates of Antarctic‐wide annual (1999–2009) surface meltwater production using an empirical relationship between radar backscatter from the QuikSCAT (QSCAT) satellite and melt calculated from in situ energy balance observations. The resulting QSCAT‐derived melt fluxes significantly agree with output from the regional climate model RACMO2.1 and with independent ground‐based observations. The high‐resolution (4.45 km) QSCAT‐based melt fluxes uniquely detect interannually persistent and intense melt (>400 mm water equivalent (w.e.) year−1) on interior Larsen C Ice Shelf that is not simulated by RACMO2.1. This supports a growing understanding of the importance of a föhn effect in this region and quantifies the resulting locally enhanced melting that is spatially consistent with recently observed Larsen C thinning. These new results highlight important cryosphere‐climate interactions and processes that are presently not fully captured by the coarser‐resolution (27 km) regional climate model.
Contextual risk and parental attributions of children's behavior as factors that influence the acceptability of empirically supported treatments

This study examined the acceptability of several empirically supported treatments (child social skills training, parent training and medication) within a sample of low-income African American mothers of a preschooler exhibiting significant disruptive behavior. Contextual risk and causal and responsibility attributions were predicted to be associated with treatment acceptability. Eighty-seven participants completed an attributional-style measure of child misbehavior and considered hypothetically the acceptability of several empirically supported treatments. Social skills and parent training were highly accepted, while medication was not. Greater causal attributions (child's behavior viewed as global, stable and due to something within the child) were associated with higher acceptability of social skills training. The relationship between attributions and medication was moderated by risk. In the context of high risk, lower causal attributions were associated with higher acceptability of medication whereas in the context of low risk, lower causal attributions were associated with lower acceptability of medication. In contrast, in the context of high risk, higher responsibility attributions (child's behavior viewed as purposeful, selfish and deserving of blame) were associated with greater acceptability of medication, while in the context of low risk, higher responsibility attributions were associated with lower acceptability of medication. Implications for future research and the implementation of empirically supported treatments within communities of color and those with economic disadvantage are discussed.
Towards an Early Iron Age worldview: some ideas from KwaZulu-Natal

L'auteur presente les fouilles qu'il a mene sur deux sites de l'Age du Fer ancien, Nanda et KwaGandaganda, dans le KwaZulu-Natal, dans le but de determiner l'organisation spatiale de ces habitats et en particulier, des structures attestant des activites d'elevage et d'agriculture (etables et greniers). Il souhaite ainsi contribuer au debat sur l'organisation des habitats bantous en CCP (Central Cattle Pattern), qui serait represente selon T.N. Huffman, depuis le VIe s. apr J.-C. en Afrique australe. Dans la deuxieme partie de cette communication, l'auteur aborde la nature des depots d'objets decouverts sur ces sites et etudie leur importance pour l'analyse des rites de passage et des systemes politiques de l'Age du Fer Ancien dans les societes bantoues
Ethics requirements and impact factor

Do all clinical research publications show strong application of ethics principles and respect for biomedical law? We examined, for the year 2009, the ethics requirements displayed on the website of 30 leading medical journals with an impact factor (IF) >10, and 30 others with an IF <10. We carried out a short study looking at the relationship between the IF of a journal and the ethics requirements in its instructions to authors. We show that the IF of a biomedical journal bears a direct relationship to its ethics requirements. Such results should improve the ethics requirements of all biomedical journals, especially those with low IF, so that they are internationally standardised to the higher standard required by journals with higher IF.
Overcoming the barriers to patient-centred care: time, tools and training.

AIMS AND OBJECTIVES To investigate whether nurses experience barriers to delivering high quality care in areas that are of particular concern to patients and to describe which aspects of care are most affected when nurses lack the required resources, such as time, tools and training to do their job. BACKGROUND Patient surveys conducted in the National Health Service of the United Kingdom tend to show there is variation in the extent to which they are satisfied with care in a number of important areas, such as physical comfort, emotional support and the coordination of care. DESIGN A sample of nurses working in 20 acute London hospitals was asked to complete a postal questionnaire based on a prototype employee survey developed in the United States and adapted by the authors for use in the United Kingdom. METHOD Staff in the human resources departments of participating hospitals mailed the questionnaires to nurses' home addresses. After two reminders, 2880 (out of 6160) useable responses were returned, giving a response rate of 47%. RESULTS Nurses are aware that there are deficits in standards of care in areas that are particularly important to patients. The majority feel overworked (64%) and report that they do not have enough time to perform essential nursing tasks, such as addressing patients' anxieties, fears and concerns and giving patients and relatives information. Their work is often made more difficult by the lack of staff, space, equipment and cleanliness. They are often unable to control noise and temperature in clinical areas. Nurses in acute London hospitals are subject to high levels of aggressive behaviour, mainly from patients and their relatives, but also from other members of staff. More positively, high proportions of the nurses in our survey expressed the desire for further training, particularly in social and interpersonal aspects of care. RELEVANCE TO CLINICAL PRACTICE This paper goes beyond reporting problems with the quality and safety of care to try to understand why patients do not always receive optimum care in areas that are important to them. In many cases nurses lack the time, tools and training to deliver high quality care in acute London hospitals. We suggest a number of low-cost interventions that might remove some of the barriers to patient-centred care. The questionnaire we have developed could be a useful tool for improving quality locally.
Impact of the model‐building strategy on inference about nonlinear and time‐dependent covariate effects in survival analysis

Cox's proportional hazards (PH) model assumes constant‐over‐time covariate effects. Furthermore, most applications assume linear effects of continuous covariates on the logarithm of the hazard. Yet, many prognostic factors have time‐dependent (TD) and/or nonlinear (NL) effects, that is, violate these conventional assumptions. Detection of such complex effects could affect prognosis and clinical decisions. However, assessing the effects of each of the multiple, often correlated, covariates in flexible multivariable analyses is challenging. In simulations, we investigated the impact of the approach used to build the flexible multivariable model on inference about the TD and NL covariate effects. Results demonstrate that the conclusions regarding the statistical significance of the TD/NL effects depend heavily on the strategy used to decide which effects of the other covariates should be adjusted for. Both a failure to adjust for true TD and NL effects of relevant covariates and inclusion of spurious effects of covariates that conform to the PH and linearity assumptions increase the risk of incorrect conclusions regarding other covariates. In this context, iterative backward elimination of nonsignificant NL and TD effects from the multivariable model, which initially includes all these effects, may help discriminate between true and spurious effects. The practical importance of these issues was illustrated in an example that reassessed the predictive ability of selected biomarkers for survival in advanced non‐small‐cell lung cancer. In conclusion, a careful model‐building strategy and flexible modeling of multivariable survival data can yield new insights about predictors’ roles and improve the validity of analyses. Copyright © 2014 John Wiley & Sons, Ltd.
Antithrombin III and D-dimer levels as indicators of disease severity in patients with hyperlipidaemic or biliary acute pancreatitis

Objective To assess changes in anticoagulation and fibrinolytic systems between biliary and hyperlipidaemic acute pancreatitis (AP). Methods Patients with biliary or hyperlipidaemic AP were enrolled. Demographic and clinical data were collected, and antithrombin III (ATIII), protein C, protein S, and D-dimer levels were investigated. Results A total of 45 patients with biliary AP and 50 patients with hyperlipidaemic AP were included (68 with mild AP and 27 with moderately-severe AP). ATIII and protein C levels in the mild AP group were significantly higher, but prothrombin time and D-dimer were significantly lower, versus the moderately-severe AP group. ATIII and D-dimer were found to be risk factors for moderately-severe AP. ATIII could predict AP severity, particularly in patients with biliary AP. D-dimer was a sensitive and specific predictor for disease severity in patients with AP, particularly in patients with hyperlipidaemic AP. Conclusion ATIII and protein C levels decreased as severity of AP increased, particularly in cases of biliary AP. D-dimer levels increased with severity of AP, particularly in hyperlipidaemic AP. ATIII and D-dimer may be useful biomarkers for assessing AP severity in patients with biliary and hyperlipidaemic AP, respectively.
Maternal Mortality At Tertiary Care Hospital In Rajasthan : A 10-Year Review

Background: Maternal mortality in India continues to be unacceptably high. This study was done to evaluate the maternal mortality ratio (MMR) in our hospital, to assess the epidemiological aspects and causes of maternal mortality, and to suggest recommendations for improvement. Methods: This study was a 10 year retrospective study from year 2007 to 2016. Data was collected from the hospital record register, epidemiological factors and causes of maternal mortality were assessed. MMR was calculated. Results: Total 348 maternal deaths occurred in 10 years. The mean maternal mortality ratio in the study period was 253.13/100,000 live births. Most maternal deaths occurred in the age group of 21–25 years (47.4%), multiparous women (60.9%), women from rural areas (74.1%), unbooked patients (88.79%), and patients of low socioeconomic status (78.7%). Direct causes accounted for 66.95% of maternal deaths where as 33.045% of maternal deaths were due to indirect causes. Conclusion: Most of the causes of maternal deaths are preventable. Improvement in primary health care in rural areas, proper implementation of NRHM programs and up gradation of hospitals can bring down the number of maternal deaths.
Expression from a bacterial artificial chromosome containing the Dct gene locus

Keywords: melanocyte ; melanoblast ; dopachrome tautomerase ; transgenic ; pigment ; tyrosinase ; RPE ; BAC Reference GR-BEERMANN-ARTICLE-2008-003doi:10.1111/j.1755-148X.2008. 00449.xView record in Web of Science Record created on 2008-04-23, modified on 2017-05-12
p16 FISH Deletion in Surface Epithelial Mesothelial Proliferations Is Predictive of Underlying Invasive Mesothelioma

An atypical mesothelial proliferation along the pleural or peritoneal surface without evidence of invasive tumor poses a diagnostic challenge. Homozygous deletion of p16 (CDKN2A) by fluorescence in situ hybridization (FISH) has been shown to be a good marker of malignancy in mesothelial proliferations, but correlations of p16 status between atypical surface proliferations and underlying mesothelioma have not been described. We used p16 FISH to investigate 11 pleural and 7 peritoneal mesotheliomas that had both an invasive component and a separate surface mesothelial proliferation. In 5/11 pleural samples and 1/7 peritoneal samples, the invasive mesotheliomas showed homozygous deletion of p16 (all cases in excess of 90% of cells deleted); the surface proliferation in all 6 cases with deletion in the invasive tumor was also p16 deleted. Conversely, the 12 tumors that did not show p16 deletion in the invasive compartment also did not have deletion in the surface component. We conclude that (1) surface mesothelial proliferations near invasive mesotheliomas show the same pattern of p16 by FISH as the underlying tumor and may represent in situ disease or growth of the underlying mesothelioma along the serosal surface; (2) p16 deletion in mesothelial surface proliferations is strongly associated with p16 deletion in underlying mesotheliomas, and biopsies consisting of pure surface mesothelial proliferations that are p16 deleted allow a diagnosis of mesothelioma without an additional biopsy if there is clinical (thoracosopic/laparoscopic) or radiologic evidence of diffuse pleural or peritoneal tumor; (3) however, the absence of p16 deletion in surface proliferations does not rule out underlying invasive mesothelioma.
Theory and hardware implementation of an analog-to-Information Converter based on Compressive Sensing

In the practical application, Nyquist-Shannon sampling theorem has brought great challenges to high sampling rate, fast processing speed and hardware equipment. In the context, a new theory called Compressive Sensing (CS) has been proposed, which can break the restriction of the Nyquist theorem for sparse signal. The Analog-to-Information Converter(AIC) makes the CS theory into practical, which can replace the traditional Analog-to-Digital Converter (ADC) to sample the high rate signals at lower rate and solve the bottleneck of Shannon-Nyquist theorem. In this paper, we will analyze the mathematical model and architecture of AIC, Finally we proposed a hardware implementation for AIC.
The diagnostic accuracy of ruptures of the anterior cruciate ligament comparing the Lachman test, the anterior drawer sign, and the pivot shift test in acute and chronic knee injuries

Eighty-five patients with knee injuries were included in a 4 month retrospective study that compared the rela tive accuracy of the Lachman test, the anterior drawer sign, and the pivot shift test. All examinations were performed under anesthesia and followed by arthros copy, which confirmed 22 injuries. Of all ACL injuries occurring within 2 weeks of arthroscopy (N = 9), the pivot shift test was the most sensitive (88.8%), followed by the Lachman test with a 77.7% sensitivity. The anterior drawer sign was the least sensitive at 22.2%. All had specificities more than 95%. For all injuries of more than 2 weeks (N = 13), the Lachman and pivot shift tests were 84.6% sensitive, while the anterior drawer sign increased to a sensitivity of 53.8%. Again, all were specific to more than 95%. For all ACL injuries, irrespective of age, the Lachman test was 81.8% sen sitive and 96.8% specific; the anterior drawer sign was 40.9% sensitive and 95.2% specific; and the pivot shift was 81.8% sensitive and 98.4% specific. The data support an accurate preoperative diagnosis in ACL deficient knees when the Lachman and pivot shift tests are positive, and essentially rules out this type of injury when these tests are negative. The anterior drawer sign, although widely used, is a poor diagnostic indi cator of ACL injuries, especially in the acute setting.
GIGYF1/2 proteins use auxiliary sequences to selectively bind to 4EHP and repress target mRNA expression

In this study, Peter et al. present crystal structures of the 4EHP-binding regions of GIGYF1 and GIGYF2 in complex with 4EHP, which reveal the molecular basis for the selectivity of the GIGYF1/2 proteins for 4EHP. Their findings provide structural insights into the assembly of 4EHP–GIGYF1/2 repressor complexes and reveal that GIGYF1/2 proteins are required for repressive activity.
The Effect of Cilofungin (LY 121019) in Combination with Amphotericin B or Flucytosine AgainstCandidaSpecies

Summary: Cilofungin was combined with amphotericin B or flucytosine to determine if synergistic inhibition or killing occurred against 50 strains of various Candida species. Synergistic inhibition of growth occurred only once with amphotericin B and cilofungin and only 2 times with flucytosine and cilofungin. Synergistic killing occurred in 5 strains with the amphotericin B‐cilo‐fungin combination and in 7 strains with the flucytosine‐cilofungin combination. Antagonism occurred frequently with both the amphotericin B‐cilofungin and the flucytosine‐cilofungin combinations.