Miracle-dz/UniFAR-FTUs huggingface dataset:
Identification of tyrosine residues involved in ligand recognition by the phosphatidylinositol 3-kinase Src homology 3 domain: circular dichroism and UV resonance Raman studies.

Src homology 3 (SH3) domains are small noncatalytic protein modules capable of mediating protein-protein interactions. We previously demonstrated that the association of a ligand peptide RLP1 (RKLPPRPSK) causes environmental and structural changes of Trp55 and some of seven Tyr residues in the phosphatidylinositol 3-kinase (PI3K) SH3 domain by circular dichroism (CD) and 235-nm excited UV resonance Raman (UVRR) spectroscopies [Okishio, N. , et al. (2000) Biopolymers 57, 208-217]. In this work, the affected Tyr residues were identified as Tyr12, Tyr14, and Tyr73 by the CD analysis of a series of mutants, in which every single Tyr residue was replaced by a Phe residue. Among these three residues, Tyr14 was found to be a main contributor to the UVRR spectral change upon the RLP1 binding. Interestingly, CD and UVRR analyses revealed that RLP1 associates with the Y14F and Y14H mutants in different ways. These results suggest that Tyr14 plays a crucial role in the ligand recognition, and the amino acid substitution at Tyr14 affects the mode of PI3K SH3-ligand interaction. Our findings give an insight into how SH3 domains can produce diversity and specificity to transduce signaling within cells.
Avoidable mortality in Lithuania.

STUDY OBJECTIVE--The study aimed to analyse avoidable mortality in Lithuania as an index of the quality of health care and to assess trends in avoidable mortality from 1970-90. SETTING AND PARTICIPANTS--All deaths of Lithuanian residents aged between 0 and 64 years between 1970 and 1990 were analysed. MEASUREMENTS AND MAIN RESULTS--Twenty seven per cent of all deaths in this age group were avoidable. Avoidable deaths were grouped into preventable and treatable ones. Treatable causes of death accounted for 54%, and preventable, 46% of avoidable mortality. Time trends showed that general mortality and mortality from avoidable causes of death in this age group were almost stable between 1970 and 1990. Mortality from treatable causes of death fell, while deaths from preventable causes increased. The results in the preventable group were greatly affected by deaths from malignant neoplasms of trachea, bronchus, and lungs. Differences were noted between the sexes in total mortality as well as in avoidable mortality. CONCLUSIONS--Avoidable causes of death are relatively common and, consequently, they are of practical importance for public health and studies of the health care quality in Lithuania. Reorganisation of health care is to be carried out and considerable emphasis will be placed on health education, promotion, and prevention, as primary prevention measures have not been effective thus far.
Crystal Structure of the Minor Pilin FctB Reveals Determinants of Group A Streptococcal Pilus Anchoring*

Cell surface pili are polymeric protein assemblies that enable bacteria to adhere to surfaces and to specific host tissues. The pili expressed by Gram-positive bacteria constitute a unique paradigm in which sortase-mediated covalent linkages join successive pilin subunits like beads on a string. These pili are formed from two or three distinct types of pilin subunit, typically encoded in small gene clusters, often with their cognate sortases. In Group A streptococci (GAS), a major pilin forms the polymeric backbone, whereas two minor pilins are located at the tip and the base. Here, we report the 1.9-Å resolution crystal structure of the GAS basal pilin FctB, revealing an immunoglobulin (Ig)-like N-terminal domain with an extended proline-rich tail. Unexpected structural homology between the FctB Ig-like domain and the N-terminal domain of the GAS shaft pilin helps explain the use of the same sortase for polymerization of the shaft and its attachment to FctB. It also enabled the identification, from mass spectral data, of the lysine residue involved in the covalent linkage of FctB to the shaft. The proline-rich tail forms a polyproline-II helix that appears to be a common feature of the basal (cell wall-anchoring) pilins. Together, our results indicate distinct structural elements in the pilin proteins that play a role in selecting for the appropriate sortases and thereby help orchestrate the ordered assembly of the pilus.
Serum antibody response to outer membrane proteins of Moraxella (Branhamella) catarrhalis in patients with bronchopulmonary infection

A Western blot (immunoblot) method for detecting antibodies against outer membrane protein (OMP) epitopes of Moraxella (Branhamella) catarrhalis was evaluated. Paired serum samples from patients suspected of M. catarrhalis (n = 38) and non-M. catarrhalis (n = 25) bronchopulmonary infection were examined for the presence of antibodies of the immunoglobulin M (IgM), IgG, and IgA classes to OMPs from M. catarrhalis by a gel electrophoresis-immunoperoxidase technique (Western blotting); sera from 40 healthy adult blood donors were also included. A significantly (P = 0.004) more frequent occurrence of IgM-class antibodies and/or an increase in the number of IgG-class antibodies against different M. catarrhalis OMPs from acute- to convalescent-phase serum samples was found for patients with M. catarrhalis (79%) than for patients without M. catarrhalis (40%). IgM-class antibodies against OMPs of M. catarrhalis were found in acute- and/or convalescent-phase serum samples form 58% of patients with M. catarrhalis and 32% of patients without M. catarrhalis. Fifty percent of patients with M. catarrhalis and 16% of patients without M. catarrhalis had, from acute- to convalescent-phase serum samples, an increased number of IgG-class antibodies directed against different OMPs. A total of 34% of patients with M. catarrhalis and 4% of patients without M. catarrhalis had, from acute- to convalescent-phase serum samples, an increased number of IgA-class antibodies directed against different OMPs. The present study indicates that M. catarrhalis is one of the bacteria involved in acute exacerbations of chronic bronchitis.
Manganese ion enhances T1‐weighted MRI during brain activation: An approach to direct imaging of brain function

Present techniques for functional MRI rely on detecting changes in hemodynamics that result as a consequence of brain activation. It would be useful if MRI techniques could be developed that enable imaging of a parameter directly related to neuronal activity. Influx of calcium into neurons is necessary for release of neurotransmitters. Divalent manganese ions (Mn2+) can enter cells through voltage‐gated calcium channels and Mn2+ is paramagnetic. Mn2+ accumulation in brain due to activation should alter relaxation times offering an approach to sensitize MRI to calcium influx in the brain. To test this idea, T1‐weighted MRI was obtained from the rat brain in the presence of a continuous intravenous infusion of 3.6 μmol/min MnCl2. In the anesthetized rat brain, signal enhancement was detected in regions corresponding to ventricles. Activation of the brain with glutamate led to increase in MRI signal intensity in the brain to 238 ± 23% of the original. This increase in signal was dependent on the presence of MnCl2 and was not due to changes in blood flow. It was necessary to break the blood brain barrier with mannitol to make Mn2 accessible to the active sites for efficient detection. Enhancement of MRI signal in the brain was also detected with decreasing anesthesia and with somatosensory stimulation. Due to the slow clearance of Mn2+ from the stimulated region of the brain, MRI enhancement could also be detected after stimulation that occurred on awake, behaving rats outside the magnet. These data indicate that MnCl2 shows potential as a MRI contrast agent that is directly sensitive to brain activation.
Adenovirus E1A reverses the resistance of normal primary human lung fibroblast cells to TRAIL through DR5 upregulation and caspase 8-dependent pathway

Expression of the adenovirus serotype 5 (Ad5) E1A enhances tumor cells to apoptosis by TNF-α, Fas-ligand and TNF-related apoptosis-inducing ligand (TRAIL). In this study, we found that E1A expression reversed the resistance of normal primary human lung fibroblast cells (P-HLF) to TRAIL-induced apoptosis. Furthermore, TRAIL dramatically induced apoptosis of P-HLF cells that expressed E1A following either infection with Ad-E1A or transfection with pcDNA3-E1A. Further results demonstrated that E1A specifically up-regulated DR5 levels but had nearly no effect on the levels of DR4. E1A dramatically up-regulated the exogenous TRAIL, and then increased a substantial amount of TRAIL on the surface of P-HLF cells treated with the expression vectors, both Ad-TRAIL and pIRES-EGFP-TRAIL. The dominant negative FADD mutation (FADD-DN) results revealed that the apoptosis in Ad-E1A and Ad-TRAIL co-infected P-HLF cells was completely blocked following inhibition of the death receptors-associated apoptosis-inducing molecules FADD. Moreover, the caspase 8 inhibitor (Z-IETD-FMK) could efficiently block caspase 8 activation and resulted in inhibition of caspase 3 activation and cleavage. However, The caspase 9 specific inhibitor (Z-LEHD-FMK) could not counteract the synergistic effect of TRAIL-induced apoptosis in combination with E1A, and caspase 3 activation and cleavage were not inhibited by Z-LEHD-FMK. Thus, our results suggest that adenovirus E1A sensitizes P-HLF cells to TRAIL-induced apoptosis involving DR5 upregulation and the caspase 8-dependent pathway. These findings provide the first direct evidence for molecular mechanisms of adenovirus E1A gene products to sensitize normal cells to TRAIL-mediated apoptosis.
Early Introduction of Complementary Foods in Preterm Infants

Objectives: The aim of the present study was to determine the odds of early introduction of solid foods in a nationally representative sample of preterm infants when compared with term infants and to examine whether factors associated with early introduction are the same for preterm and term infants. Methods: Our sample of 7650 came from the first wave of the Early Childhood Longitudinal Study, Birth Cohort (2001–2002). We performed multivariable logistic regression to determine whether preterm infants were introduced to solid foods more frequently before 4 months than term infants using adjusted age for preterm infants and chronological age for term infants. In a separate analysis in preterm infants, we used multivariable logistic regression to determine whether the factors associated with early introduction in term infants were the same in the preterm sample. Results: Infants born 22 to 32 weeks’ gestation had a 9.90 (95% confidence interval 5.54–18.0) odds of being fed solid food before 4 months compared with term infants, and infants born 33 to 36 weeks’ gestation had a 6.19 (95% confidence interval 4.58–8.36) odds. Race/ethnicity and maternal smoking were the only factors that predicted early solid feeding in both preterm and term infants; the remaining predictors differed. Conclusions: Preterm infants are significantly more likely to be introduced to complementary foods early compared with term infants. The predictors of early solid feeding differ for preterm infants. Given the health implications, specific guidelines for preterm infants should be developed and future research should examine predictors of early introduction in preterm infants.
An Illustrated Consensus on the Classification of Pancreatic Intraepithelial Neoplasia and Intraductal Papillary Mucinous Neoplasms

Invasive pancreatic ductal adenocarcinoma is an almost uniformly fatal disease. Several distinct noninvasive precursor lesions can give rise to invasive adenocarcinoma of the pancreas, and the prevention, detection, and treatment of these noninvasive lesions offers the potential to cure early pancreatic cancers. Noninvasive precursors of invasive ductal adenocarcinoma of the pancreas include pancreatic intraepithelial neoplasias (PanINs), intraductal papillary mucinous neoplasms (IPMNs), and mucinous cystic neoplasms. Diagnostic criteria, including a distinct ovarian-type stroma, and a consistent nomenclature are well established for mucinous cystic neoplasms. By contrast, consistent nomenclatures and diagnostic criteria have been more difficult to establish for PanINs and IPMNs. Because both PanINs and IPMNs consist of intraductal neoplastic proliferations of columnar, mucin-containing cells with a variable degree of papilla formation, the distinction between these two classes of precursor lesions remains problematic. Thus, considerable ambiguities still exist in the classification of noninvasive neoplasms in the pancreatic ducts. A meeting of international experts on precursor lesions of pancreatic cancer was held at The Johns Hopkins Hospital from August 18 to 19, 2003. The purpose of this meeting was to define an international acceptable set of diagnostic criteria for PanINs and IPMNs and to address a number of ambiguities that exist in the previously reported classification systems for these neoplasms. We present a consensus classification of the precursor lesions in the pancreatic ducts, PanINs and IPMNs.
Role of the carboxy‐termini of tubulin on its chaperone‐like activity

Mutational analysis and the enzymatic digestion of many chaperones indicate the importance of both hydrophobic and hydrophilic residues for their unique property. Thus, the chaperone activity of α‐crystallin is lost due to the substitution of hydrophobic residues or upon enzymatic digestion of the negatively charged residues. Tubulin, an eukaryotic cytoskeletal protein, exhibits chaperone‐like activity as demonstrated by prevention of DTT‐induced aggregation of insulin, thermal aggregation of alcohol dehydrogenase, βγ‐crystallin, and other proteins. We have shown that the tubulin lost its chaperone‐like activity upon digestion of its negatively charged C‐termini. In this article, the role of the C‐terminus of individual subunits has been investigated. We observe that the digestion of C‐terminus of β‐subunit with subtilisin causes loss of chaperone‐like activity of tubulin. The contribution of C‐terminus of α‐subunit is difficult to establish directly as subtilisin cleaves C‐terminus of β‐subunit first. This has been ascertained indirectly using a 14‐residue peptide P2 having the sequence corresponding to a conserved region of MHC class I molecules and that binds tightly to the C‐terminus of α‐subunit. We have shown that the binding of P2 peptide to αβ‐tubulin causes complete loss of its chaperone‐like activity. NMR and gel‐electrophoresis studies indicate that the P2 peptide has a significant higher binding affinity for the C‐terminus of α‐subunit compared to that of β‐subunit. Thus, we conclude that both the C‐termini are necessary for the chaperone‐like activity of tubulin. Implications for the chaperone functions in vivo have been discussed. Proteins 2001;44:262–269. © 2001 Wiley‐Liss, Inc.
Inositol trisphosphate activates a voltage-dependent calcium influx in Xenopus oocytes

Injection of inositol trisphosphate (IP3) into oocytes of Xenopus laevis induces the appearance of a transient inward (Tin) current on hyperpolarization of the membrane. This current is carried largely by chloride ions, but is shown to depend on extracellular calcium, because it is abolished by removal of calcium in the bathing fluid or by addition of manganese. Recordings with aequorin as an intracellular calcium indicator show that a calcium influx is activated by hyperpolarization after intracellular injection of IP3 as well as after activation of neurotransmitter receptors thought to mediate a rise in IP3. Furthermore, by substituting barium for calcium in the bathing solution, inward barium currents can be recorded during hyperpolarization. We conclude that intracellular IP3 modulates the activity of a class of calcium channels, so as to allow an influx of calcium on hyperpolarization. In normal Ringer solution this then leads to the generation of a chloride current, because of the large numbers of calcium-dependent chloride channels in the oocyte membrane.
Favorable long-term survival in patients undergoing multivessel-PCI compared to predicted prognosis of CABG estimated by EuroSCORE: procedural and clinical determinants of long-term outcome.

AIMS/METHODS Treatment of patients with multivessel coronary artery disease (CAD) has been an ongoing focus of recent clinical studies, questioning the ideal treatment. Randomized trials comparing coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) have so far only included a minority of screened patients. Therefore, we analyzed data from 679 consecutive "all-comer" patients, who underwent PCI in at least two main vessels. Expected in-hospital mortality for CABG was calculated using the EuroSCORE and compared to the observed mortality rate during in-hospital as well as long-term follow-up. RESULTS The patients were suffering from 2.5 +/- 0.6 diseased vessels, and 2.8 +/- 1.0 lesions were stented (32% of patients received at least one drug-eluting stent [DES]; 20% of lesions were treated with DES). Forty-seven percent of patients were treated for acute coronary syndrome (ACS) (N = 176 ST-elevation myocardial infarction [STEMI]; N = 140 non-ST-elevation myocardial infarction [NSTEMI]). The EuroSCORE was significantly higher in ACS patients compared to stable patients (logistic: STEMI 16.3 +/- 17.2; NSTEMI 13.6 +/- 13.0; stable CAD 3.9 +/- 4.2). The observed in-hospital mortality (STEMI 13.0%; NSTEMI 2.9%; stable CAD 1.7%, P < 0.001) was far lower than the estimated 30-day mortality. Cox regression analysis identified an elevated logistic EuroSCORE (HR per quartile 2.7, P = 0.003), severely reduced left ventricular ejection fraction (HR 2.7, P < 0.001), elevated C-reactive protein (HR 1.8, P = 0.012), and chronic renal failure (HR 2.8, P = 0.001) as independent predictors of long-term mortality. CONCLUSIONS The EuroSCORE, which is routinely used to estimate the perioperative risk of patients undergoing CABG, also predicts short- and long-term prognosis of patients undergoing MV-PCI. The observed mortality of patients undergoing MV-PCI seems to be much lower than the estimated mortality of CABG.
Regulatory Reform in Ontario: Machine Learning and Regulation

Government regulation of individual and business activity is part and parcel of modern society. But many businesses face difficulties in understanding and navigating the legal hurdles, rules, and uncertainty that come with modern regulation. Many governments in Canada have taken steps to reduce this burden by streamlining regulation and cutting unnecessary red tape. In this Commentary, I explore how regulators can continue this trend toward more efficient and effective regulation: by embracing data analytics and machine-learning tools. Big data, analytics and machine learning offer new and difficult challenges for regulators who oversee how many businesses make decisions. But regulators can also benefit from effective use of data science. Some of these benefits can be realized almost immediately by using data that the regulators already have. First, regulators can better predict who should and should not be investigated. A regulator needs to make choices about how to allocate and prioritize scarce resources. With the right data and appropriate data analytics, predictions can be made about where to best place investigation resources. Second, regulators must make choices over which cases to prosecute. Regulators should not waste resources litigating cases they are likely to lose. Instead, regulators should put resources only toward cases that they are likely to win. Regulators can turn to the data and use machine learning to predict how a court would resolve a particular problem. Moving further into the future, big data and machine learning will change the way that laws and regulations will be consumed and produced. Lawmakers will have greater ability to provide relevant information before the individual or business acts, rather than waiting to adjudicate after they have acted. Businesses will seek prior authorization for many more regulated actions. Furthermore, the time and cost for regulators to respond to the queries will fall drastically. Instead of relying primarily on vague guidelines, regulators will be able to offer more expedient and personalized responses. There are enormous benefits to regulators making decisions before individuals and business act. Advance rulings, given before investments are made, provide certain outcomes and reduce the likelihood of wasted investments. There are, of course, a number of potential barriers and issues that may arise. These include: the quality of the data, accountability and due process, the need for transparency, privacy and the reluctance to share data, the benefits of uncertainty, and the stability of social views and goals.
Phylogenetic interrelationships among baculoviruses: evolutionary rates and host associations.

The phylogenetic relationship of several baculovirus polyhedrin genes was investigated. Alignments of 18 polyhedrin gene amino acid sequences from which 12 were also available as DNA sequences were constructed based on positional homology and trees were calculated using character state and distance methods. Our results indicate that the Hymenopteran NsSNPV diverged from the Lepidopteran baculovirus before the separation of the NPV from the GV and subsequent radiation of these Lepidopteran groups. Moreover, this analysis indicates that lepidopteran NPV are clustered in at least two groups with distinct evolutionary rates. Group I includes the AcMNPV, BmMNPV, BmSNPV, OpMNPV, AgMNPV, and possibly the GmMNPV and AsMNPV. Group II includes the MbMNPV, PfMNPV, SfMNPV, SeMNPV, and possibly the OpSNPV. This grouping is also supported by a tree constructed from sequence data from the 5' untranslated leader region of the polyhedrin gene. Furthermore, the polyhedrin-based phylogeny was analyzed for its congruence to the genomic organization and other biological characteristics of the baculoviruses. This study shows that the SNPV and MNPV morphotypes have to be taken with caution as classificatory traits since they appear to be unpolarized. In addition, the comparison of the baculovirus phylogeny with the Lepidoptera phylogeny confirms the assumption that the evolutionary history of the baculoviruses is not entirely in agreement with the taxonomic organization of the Lepidoptera, implying that the common designation of baculoviruses based on the hosts may not be adequate for baculovirus classification since it does not reflect the genetic relatedness of the viruses. (ABSTRACT TRUNCATED AT 250 WORDS)
Class II Alloantibody and Mortality in Simultaneous Liver‐Kidney Transplantation

Hyperacute kidney rejection is unusual in crossmatch positive recipients of simultaneous liver–kidney transplants (SLKT). However, recent data suggest that these patients remain at risk for antibody‐mediated kidney rejection. To further investigate the risk associated with donor‐specific alloantibodies (DSA) in SLKT, we studied 86 consecutive SLKT patients with an available pre‐SLKT serum sample. Serum samples were analyzed in a blinded fashion for HLA DSA using single antigen beads (median florescence intensity ≥ 2,000 = positive). Post‐SLKT samples were analyzed when available (76%). Thirty patients had preformed DSA, and nine developed de novo DSA. Preformed class I DSA did not change the risk of rejection, patient or allograft survival. In contrast, preformed class II DSA was associated with a markedly increased risk of renal antibody mediated rejection (AMR) (p = 0.006), liver allograft rejection (p = 0.002), patient death (p = 0.02), liver allograft loss (p = 0.02) and renal allograft loss (p = 0.045). Multivariable modeling showed class II DSA (preformed or de novo) to be an independent predictor of patient death (HR = 2.2; p = 0.043) and liver allograft loss (HR = 2.2; p = 0.044). These data warrant reconsideration of the approach to DSA in SLKT.