Miracle-dz/UniFAR-FTUs huggingface dataset:
More challenges for machine-learning protein interactions

MOTIVATION Machine learning may be the most popular computational tool in molecular biology. Providing sustained performance estimates is challenging. The standard cross-validation protocols usually fail in biology. Park and Marcotte found that even refined protocols fail for protein-protein interactions (PPIs). RESULTS Here, we sketch additional problems for the prediction of PPIs from sequence alone. First, it not only matters whether proteins A or B of a target interaction A-B are similar to proteins of training interactions (positives), but also whether A or B are similar to proteins of non-interactions (negatives). Second, training on multiple interaction partners per protein did not improve performance for new proteins (not used to train). In contrary, a strictly non-redundant training that ignored good data slightly improved the prediction of difficult cases. Third, which prediction method appears to be best crucially depends on the sequence similarity between the test and the training set, how many true interactions should be found and the expected ratio of negatives to positives. The correct assessment of performance is the most complicated task in the development of prediction methods. Our analyses suggest that PPIs square the challenge for this task.
Soluble Flt-1 release response to heparin use: implications for dialysis patients?

or results directly preceding dialysis. Ellam and his colleagues have to be congratulated for a thorough effort highlighting gender differences in nutritional burden by level of eGFR. Their study raises a number of important questions that should be investigated further, such as longitudinal changes in nutritional needs by gender and the important role of gender and societal context on how renal nutritional advice is being implemented.
Social Remittances: Migration Driven Local-Level Forms of Cultural Diffusion 1

Many studies highlight the macro-level dissemination of global culture and institutions. This article focuses on social remittances – a local-level, migration-driven form of cultural diffusion. Social remittances are the ideas, behaviors, identities, and social capital that flow from receiving- to sending-country communities. The role that these resources play in promoting immigrant entrepreneurship, community and family formation, and political integration is widely acknowledged. This article specifies how these same ideas and practices are remolded in receiving countries, the mechanisms by which they are sent back to sending communities, and the role they play in transforming sending-country social and political life.
Current Hypotheses on How Microsatellite Instability Leads to Enhanced Survival of Lynch Syndrome Patients

High levels of microsatellite instability (MSI-high) are a cardinal feature of colorectal tumors from patients with Lynch Syndrome. Other key characteristics of Lynch Syndrome are that these patients experience fewer metastases and have enhanced survival when compared to patients diagnosed with microsatellite stable (MSS) colorectal cancer. Many of the characteristics associated with Lynch Syndrome including enhanced survival are also observed in patients with sporadic MSI-high colorectal cancer. In this review we will present the current state of knowledge regarding the mechanisms that are utilized by the host to control colorectal cancer in Lynch Syndrome and why these same mechanisms fail in MSS colorectal cancers.
A trigonometric approach to quaternary code designs with application to one-eighth and one-sixteenth fractions

The study of good nonregular fractional factorial designs has received significant attention over the last two decades. Recent research indicates that designs constructed from quaternary codes (QC) are very promising in this regard. The present paper shows how a trigonometric approach can facilitate a systematic understanding of such QC designs and lead to new theoretical results covering hitherto unexplored situations. We focus attention on one-eighth and one-sixteenth fractions of two-level factorials and show that optimal QC designs often have larger generalized resolution and projectivity than comparable regular designs. Moreover, some of these designs are found to have maximum projectivity among all designs.
Establishing standards of orthostatic measurements in normovolemic adolescents.

OBJECTIVE To determine normal orthostatic heart rate and blood pressure changes in healthy adolescents. DESIGN Survey. SETTING General adolescent clinic at a military teaching medical center in Honolulu, Hawaii. PARTICIPANTS One hundred healthy normovolemic patients aged 12 to 19 years representing a cross section of individuals from a diverse military population during a 5-month study period. SELECTION PROCEDURE Convenience sample. INTERVENTIONS None. MEASUREMENTS/MAIN RESULTS The mean (+/- 2 SDs) orthostatic heart rate change in beats per minute was 21.5 +/- 21.2, with a range of 50 to -3 beats per minute. The mean (+/- 2 SDs) systolic blood pressure change was -0.9 +/- 15.7 mm Hg, with a range of 19 to -17 mm Hg. Orthostatic measurements in a normal adolescent population may result in a heart rate increase of 40 to 50 beats per minute and a systolic blood pressure decrease of 15 mm Hg. There were no significant differences between individuals with respect to age, race, sex, and body habitus. CONCLUSIONS Healthy adolescents display wide variation in orthostatic measurements that exceed previously accepted standards. Further study is required to determine if sensitivity and specificity values exist for orthostatic measurements that can identify individuals with intravascular volume depletion.
High energy variability of 3C 273 during the AGILE multiwavelength campaign of December 2007-January 2008

Context. We report the results of a 3-week multi-wavelength campaign targeting the flat spectrum radio quasar 3C 273 carried out with the AGILE gamma-ray mission, covering the 30 MeV–50 GeV and 18–60 keV, the REM observatory (covering the near-IR and optical), Swift (nearUV/Optical, 0.2–10 keV and 15–50 keV), INTEGRAL (3–200 keV) and Rossi XTE (2–12 keV). This is the first observational campaign including gamma-ray data, after the last EGRET observations, more than 8 years ago. Aims. This campaign has been organized by the AGILE team with the aim of observing, studying and modelling the broad band energy spectrum of the source, and its variability on a week timescale, testing the emission models describing the spectral energy distribution of this source. Methods. Our study was carried out using simultaneous light curves of the source flux from all the involved instruments, in the different energy ranges, to search for correlated variability. Then a time-resolved spectral energy distribution was used for a detailed physical modelling of the emission mechanisms. Results. The source was detected in gamma-rays only in the second week of our campaign, with a flux comparable to the level detected by EGRET in June 1991. We found an indication of a possible anti-correlation between the emission at gamma-rays and at soft and hard X-rays, supported by the complete set of instruments. Instead, optical data do not show short term variability, as expected for this source. Only in two preceding EGRET observations (in 1993 and 1997) 3C 273 showed intra-observation variability in gamma-rays. In the 1997 observation, flux variation in gamma-rays was associated with a synchrotron flare. The energy-density spectrum with almost simultaneous data partially covers the regions of synchrotron emission, the big blue bump, and the inverse-Compton. We adopted a leptonic model to explain the hard X/gamma-ray emissions, although from our analysis hadronic models cannot be ruled out. In the adopted model, the soft X-ray emission is consistent with combined synchrotron-self Compton and external Compton mechanisms, while hard X and gamma-ray emissions are compatible with external Compton from thermal photons of the disk. Under this model, the time evolution of the spectral energy distribution is well interpreted and modelled in terms of an acceleration episode of the electron population, leading to a shift in the inverse Compton peak towards higher energies.
Aspergillus fumigatus Strains with Mutations in the cyp51A Gene Do Not Always Show Phenotypic Resistance to Itraconazole, Voriconazole, or Posaconazole

ABSTRACT We performed molecular identification of 98 Aspergillus fumigatus complex isolates with MICs of 1 to 4 μg/ml for itraconazole and searched for the presence of mutations in cyp51A. Most of the isolates (91%) belonged to A. fumigatus sensu stricto. We found 14 different mutations in nine isolates at codons different from G54, M220, G138, G448, and L98. We report new mutations at positions 165, 262, 479, and 497 (silent). The role of these mutations should be analyzed.
Phospho-proteomic analyses of B-Raf protein complexes reveal new regulatory principles

B-Raf represents a critical physiological regulator of the Ras/RAF/MEK/ERK-pathway and a pharmacological target of growing clinical relevance, in particular in oncology. To understand how B-Raf itself is regulated, we combined mass spectrometry with genetic approaches to map its interactome in MCF-10A cells as well as in B-Raf deficient murine embryonic fibroblasts (MEFs) and B-Raf/Raf-1 double deficient DT40 lymphoma cells complemented with wildtype or mutant B-Raf expression vectors. Using a multi-protease digestion approach, we identified a novel ubiquitination site and provide a detailed B-Raf phospho-map. Importantly, we identify two evolutionary conserved phosphorylation clusters around T401 and S419 in the B-Raf hinge region. SILAC labelling and genetic/biochemical follow-up revealed that these clusters are phosphorylated in the contexts of oncogenic Ras, sorafenib induced Raf dimerization and in the background of the V600E mutation. We further show that the vemurafenib sensitive phosphorylation of the T401 cluster occurs in trans within a Raf dimer. Substitution of the Ser/Thr-residues of this cluster by alanine residues enhances the transforming potential of B-Raf, indicating that these phosphorylation sites suppress its signaling output. Moreover, several B-Raf phosphorylation sites, including T401 and S419, are somatically mutated in tumors, further illustrating the importance of phosphorylation for the regulation of this kinase.
Disturbed Follicular Architecture in B Cell A Disintegrin and Metalloproteinase (ADAM)10 Knockouts Is Mediated by Compensatory Increases in ADAM17 and TNF-α Shedding

B cell A disintegrin and metalloproteinase 10 (ADAM10) is required for the development and maintenance of proper secondary lymphoid tissue architecture; however, the underlying mechanism remains unclear. In this study, we show disturbances in naive lymph node architecture from B cell–specific ADAM10-deficient mice (ADAM10B−/−) including loss of B lymphocyte/T lymphocyte compartmentalization, attenuation of follicular dendritic cell reticula, excessive collagen deposition, and increased high endothelial venule formation. Because TNF-α signaling is critical for secondary lymphoid tissue architecture, we examined compensatory changes in ADAM17 and TNF-α in ADAM10B−/− B cells. Surprisingly, defective follicular development in these mice was associated with increased rather than decreased TNF-α expression. In this article, we describe an increase in TNF-α message, mRNA stability, soluble protein release, and membrane expression in ADAM10B−/− B cells compared with wild type (WT), which coincides with increased ADAM17 message and protein. To assess the mechanistic contribution of excessive TNF-α to abnormal lymphoid architecture in ADAM10B−/− mice, we performed a bone marrow reconstitution study. Rectification of WT architecture was noted only in irradiated WT mice reconstituted with ADAM10B−/− + TNF knockout bone marrow because of normalization of TNF-α levels not seen in ADAM10B−/− alone. We conclude that ADAM17 overcompensation causes excessive TNF-α shedding and further upregulation of TNF-α expression, creating an aberrant signaling environment within B cell cortical regions of ADAM10B−/− lymph nodes, highlighting a key interplay between B cell ADAM10 and ADAM17 with respect to TNF-α homeostasis.
Prediction of 1-year survival after thrombolysis for acute myocardial infarction in the global utilization of streptokinase and TPA for occluded coronary arteries trial.

BACKGROUND When a patient survives thrombolysis for acute myocardial infarction, little information from large studies exists from which to estimate prognosis during follow-up visits. METHODS AND RESULTS Baseline, in-hospital, and later survival data were collected from 41 021 patients enrolled in Global Utilization of Streptokinase and TPA for Occluded Coronary Arteries, a randomized trial of 4 thrombolytic-heparin regimens with standard aspirin and beta-blockade. Cox proportional hazards models were developed to predict 1-year survival in 30-day survivors (n=37 869) from baseline clinical and ECG factors and in-hospital factors; a combined model then was developed (C-index 0.800). The model was simplified into a nomogram to predict individual outcomes (C-index 0.754). Factors reflecting demographics (advanced age, lighter weight), larger infarctions (higher Killip class, lower blood pressure, faster heart rate, longer QRS duration), cardiac risk (smoking, hypertension, prior cerebrovascular disease), and arrhythmia were important predictors of death between 30 days and 1 year. Black race was associated with a substantial increase in risk after considering other factors. Revascularization was associated with reduced risk between 30 days and 1 year. CONCLUSIONS When evaluating a patient who has survived acute infarction treated with thrombolysis, clinicians can estimate the likelihood of survival from factors easily measured during admission. Although many risk factors clearly relate to age, left ventricular dysfunction, or clinical instability, black race is an unexplained risk factor requiring further examination.
Defeasible Inclusions in Low-Complexity DLs: Preliminary Notes

We analyze the complexity of reasoning with circumscribed low-complexity DLs such as DL-lite and the EL family, under suitable restrictions on the use of abnormality predicates. We prove that in circumscribed DL-liteR complexity drops from NExpNP to the second level of the polynomial hierarchy. In EL, reasoning remains ExpTime-hard, in general. However, by restricting the possible occurrences of existential restrictions, we obtain membership in Σ2p and Π2p for an extension of EL.
Targeting of the Hair Cell Proteins Cadherin 23, Harmonin, Myosin XVa, Espin, and Prestin in an Epithelial Cell Model

We have developed an advantageous epithelial cell transfection model for examining the targeting, interactions, and mutations of hair cell proteins. When expressed in LLC–PK1–CL4 epithelial cells (CL4 cells), the outer hair cell protein prestin showed faithful domain-specific targeting to the basolateral plasma membrane. We examined the consequences of mutations affecting prestin activity and assigned a targeting role to the cytoplasmic tail. The stereociliary link protein cadherin 23 (Cdh23) was targeted to the plasma membrane of CL4 cell microvilli, the topological equivalent of stereocilia. In cells coexpressing the Cdh23 cytoplasmic binding protein harmonin, a large fraction of harmonin became colocalized with Cdh23 in microvilli. Using this assay and in vitro protein binding assays, we formulated an alternative model for Cdh23-harmonin binding, in which the primary interaction is between the harmonin N-domain and a 35-residue internal peptide in the Cdh23 cytoplasmic tail. Contrary to a previous model, we found no role for the Cdh23 C-terminal PDZ (PSD-95/Dlg/ZO-1)-binding motif and observed that Cdh23 bound similar levels of harmonin with or without the exon 68 peptide. We also examined two proteins involved in stereocilium elongation. The stereociliary actin-bundling protein espin was targeted to CL4 cell microvilli and caused microvillar elongation, whereas espin with the c.2469delGTCA or c.1988delAGAG human deafness mutation showed defects in microvillar targeting and elongation. The unconventional myosin motor myosin XVa accumulated at the tips of espin-elongated microvilli, by analogy to its location in stereocilia, whereas myosin XVa with the c.4351G>A or c.4669A>G human deafness mutation did not, revealing functional deficits in motor activity.
Forecasting Financial Extremes: A Network Degree Measure of Super-Exponential Growth

Investors in stock market are usually greedy during bull markets and scared during bear markets. The greed or fear spreads across investors quickly. This is known as the herding effect, and often leads to a fast movement of stock prices. During such market regimes, stock prices change at a super-exponential rate and are normally followed by a trend reversal that corrects the previous overreaction. In this paper, we construct an indicator to measure the magnitude of the super-exponential growth of stock prices, by measuring the degree of the price network, generated from the price time series. Twelve major international stock indices have been investigated. Error diagram tests show that this new indicator has strong predictive power for financial extremes, both peaks and troughs. By varying the parameters used to construct the error diagram, we show the predictive power is very robust. The new indicator has a better performance than the LPPL pattern recognition indicator.
The relationships between communication, care and time are intertwined: a narrative inquiry exploring the impact of time on registered nurses' work.

AIM To report a qualitative study which explores registered nurses' views on the issue of time in the workplace. BACKGROUND There is a worldwide shortage of healthcare workers, subsequently time as a healthcare resource is both finite and scarce. As a result, increased attention is being paid to the restructuring of nursing work. However, the experience of time passing is a subjective one and there exists little research which, over a prolonged period of time, describes nurses' experiences of working in time-pressurized environments. DESIGN A narrative inquiry. METHOD Five registered nurses were individually interviewed a total of three times over a period of 12 months, amounting to a total of 15 interviews and 30 hours of data. Data were collected and analysed following a narrative enquiry approach during the period 2008-2010. FINDINGS Participants describe how attempts to work more effectively sometimes resulted in unintended negative consequences for patient care and how time pressure encourages collegiality amongst nurses. Furthermore, the registered nurses' account of how they opportunistically create time for communication with patients compels us to re-evaluate the nature of communication during procedural nursing care. CONCLUSION Increasingly nursing work is translated into quantitative data or metrics. This is an inescapable development which seeks to enhance understanding of nursing work. However, qualitative research may also offer a useful approach which captures the otherwise hidden, subjective experiences associated with time and work. Such data can exist alongside nursing metrics, and together these can build a better and more nuanced consideration of nursing practice.
Glutaraldehyde Cross-Linking of Tendon—Mechanical Effects at the Level of the Tendon Fascicle and Fibril

Conclusive insight into the microscopic principles that govern the strength of tendon and related connective tissues is lacking and the importance of collagen cross-linking has not been firmly established. The combined application of whole-tissue mechanical testing and atomic force spectroscopy allowed for a detailed characterization of the effect of cross-linking in rat-tail tendon. The cross-link inducing agent glutaraldehyde augmented the tensile strength of tendon fascicles. Stress at failure increased from ∼8 MPa to ∼39 MPa. The mechanical effects of glutaraldehyde at the tendon fibril level were examined by atomic force microscopy. Peak forces increased from ∼1379 to ∼2622 pN while an extended Hertz fit of force-indentation data showed a ∼24 fold increase in Young's modulus on indentation. The effect of glutaraldehyde cross-linking on the tensile properties of a single collagen fibril was investigated by a novel methodology based on atomic force spectroscopy. The Young's modulus of a secluded fibril increased from ∼407 MPa to ∼1.1 GPa with glutaraldehyde treatment. Collectively, the findings indicate that cross-linking at the level of the collagen fibril is of key importance for the mechanical strength of tendon tissue. However, when comparing the effects at the level of the tendon fascicle and fibril, respectively, further questions are prompted regarding the pathways of force through the tendon microstructure as fibril strength seems to surpass that of the tendon fascicle.
Variation in resistin gene promoter not associated with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a leading cause of anovulatory infertility and affects approximately 4-7% of reproductive age women in the U.S. It is characterized by hyperandrogenemia and chronic anovulation and is associated with insulin resistance, obesity, and increased risk for type 2 diabetes. In a screen of candidate genes, a region on chromosome 19p13.3 was identified that shows significant evidence for both linkage and association with PCOS. A promising candidate gene for PCOS, resistin, maps to exactly this region. Resistin is a protein hormone thought to modulate glucose tolerance and insulin action. We tested for association between a single nucleotide polymorphism in the promoter region of the resistin gene and three phenotypes: PCOS, obesity, and insulin resistance. We did not find evidence for association with any of the phenotypes. It is therefore unlikely that variation in the resistin gene accounts for the strong association that we observe between chromosome 19p13.3 and PCOS. Instead, this association is most likely due to a gene or genetic element in this region that has not been identified.
Dissection of Cell Division Processes in the One Cell Stage Caenorhabditis elegans Embryo by Mutational Analysis

To identify novel components required for cell division processes in complex eukaryotes, we have undertaken an extensive mutational analysis in the one cell stage Caenorhabditis elegans embryo. The large size and optical properties of this cell permit observation of cell division processes with great detail in live specimens by simple differential interference contrast (DIC) microscopy. We have screened an extensive collection of maternal-effect embryonic lethal mutations on chromosome III with time-lapse DIC video microscopy. Using this assay, we have identified 48 mutations in 34 loci which are required for specific cell division processes in the one cell stage embryo. We show that mutations fall into distinct phenotypic classes which correspond, among others, to the processes of pronuclear migration, rotation of centrosomes and associated pronuclei, spindle assembly, chromosome segregation, anaphase spindle positioning, and cytokinesis. We have further analyzed pronuclear migration mutants by indirect immunofluorescence microscopy using antibodies against tubulin and ZYG-9, a centrosomal marker. This analysis revealed that two pronuclear migration loci are required for generating normal microtubule arrays and four for centrosome separation. All 34 loci have been mapped by deficiencies to distinct regions of chromosome III, thus paving the way for their rapid molecular characterization. Our work contributes to establishing the one cell stage C. elegans embryo as a powerful metazoan model system for dissecting cell division processes.