Miracle-dz/UniFAR-FTUs huggingface dataset:
Molecular modelling of the immunoglobulin‐like domains of the neural cell adhesion molecule (NCAM): Implications for the positioning of functionally important sugar side chains

The neural cell adhesion molecule (NCAM) is thought to mediate cell–cell adhesion by a homophilic mechanism involving binding sites located in the N‐terminal region of the protein. This region of the molecule consists of five domains that are homologous to each other and share conserved residues with immunoglobulin domains. We report here secondary structure predictions for the five NCAM domains and three‐dimensional models for two of them. The results are entirely consistent with an immunoglobulin‐like folding of the NCAM domains into seven strands forming two b̃‐sheets. NCAM–NCAM binding may thus be analogous to the pairwise associations of immunoglobulin constant domains, which are involved in dimer formation. Insertions and deletions are located mostly in b̃‐turn regions. Two α‐helical regions in the third and fourth domain are predicted with high probability. NCAM bears two kinds of functionally important sugar side chains, sialic acid polymers in the fifth domain, which modulate NCAM binding, and the L2 moiety, which is involved in cell adhesion and can be assigned to the third domain. Three‐dimensional modelling of the corresponding domains indicates that two of the three sites for N‐linked glycosylation in the fifth and the single site in the third domain are located on he face of the domain, which in immunoglobulin contant regions engages in intermolecular interactions.
The lipid A palmitoyltransferase PagP: molecular mechanisms and role in bacterial pathogenesis

Palmitoylated lipid A can both protect pathogenic bacteria from host immune defences and attenuate the activation of those same defences through the TLR4 signal transduction pathway. A palmitate chain from a phospholipid is incorporated into lipid A by an outer membrane enzyme PagP, which is an 8‐stranded antiparallel β‐barrel preceded by an amino‐terminal amphipathic α‐helix. The PagP barrel axis is tilted by 25° with respect to the membrane normal. An interior hydrophobic pocket in the outer leaflet‐exposed half of the molecule functions as a hydrocarbon ruler that allows the enzyme to distinguish palmitate from other acyl chains found in phospholipids. Internalization of a phospholipid palmitoyl group within the barrel appears to occur by lateral diffusion from the outer leaflet through non‐hydrogen‐bonded regions between β‐strands. The MsbA‐dependent trafficking of lipids from the inner membrane to the outer membrane outer leaflet is necessary for lipid A palmitoylation in vivo. The mechanisms by which bacteria regulate pagP gene expression strikingly reflect the corresponding pathogenic lifestyle of the bacterium. Variations on PagP structure and function can be illustrated with the known homologues from Gram‐negative bacteria, which include pathogens of humans and other mammals in addition to pathogens of insects and plants. The PagP enzyme is potentially a target for the development of anti‐infective agents, a probe of outer membrane lipid asymmetry, and a tool for the synthesis of lipid A‐based vaccine adjuvants and endotoxin antagonists.
PHYSIOLOGIC RESPONSES OF GRIZZLY BEARS TO DIFFERENT METHODS OF CAPTURE

The physiologic effects of two methods of capture, chemical immobilization of free-ranging (FR) bears by remote injection from a helicopter and physical restraint (PR) by leg-hold snare prior to chemical immobilization, were compared in 46 grizzly bears (Ursus arctos) handled during 90 captures between 1999 and 2001. Induction dosages and times were greater for FR bears than PR bears, a finding consistent with depletion of, or decreased sensitivity to, catecholamines. Free-ranging bears also had higher rectal temperatures 15 min following immobilization and temperatures throughout handling that correlated positively with induction time. Physically restrained bears had higher white blood cell counts, with more neutrophils and fewer lymphocytes and eosinophils, than did FR bears. This white blood cell profile was consistent with a stress leukogram, possibly affected by elevated levels of serum cortisol. Serum concentrations of alanine aminotransferase, aspartate aminotransferase, and creatine kinase were higher in PR bears that suggested muscle injury. Serum concentrations of sodium and chloride also were higher in PR bears and attributed to reduced body water volume through water deprivation and increased insensible water loss. Overall, different methods of capture resulted in different patterns of physiologic disturbance. Reducing pursuit and drug induction times should help to minimize increase in body temperature and alteration of acid-base balance in bears immobilized by remote injection. Minimizing restraint time and ensuring snare-anchoring cables are short should help to minimize loss of body water and prevent serious muscle injury in bears captured by leg-hold snare.
Oil Wealth, Post-conflict Elections, and Postwar Peace Failure

New research has emerged that suggests there is a troubling relationship between elections and civil wars; primarily, elections increase the risk of civil war recurrence. I investigate this relationship further by examining the economic factors associated with the connection between postwar elections and peace failure. Specifically, how does the presence of oil wealth impact the risk posed by postwar elections. Drawing on previous findings in the democratization literature, I suggest the immobility of oil wealth dramatically increases the stakes associated with postwar elections. As postwar elites use irregular electioneering to consolidate their control of oil revenue, it increases the incentives for postwar opposition to use violence as a means to achieve their objectives. Using post-civil war data from 1945 to 2005, I demonstrate that postwar elections that occur in oil-rich economies dramatically decrease the durability of postwar peace. Once controlling for petro elections, though, I demonstrate that subsequent postwar elections actually increase the durability of postwar peace.
Human papillomavirus infection and lymphoma incidence using cervical conization as a surrogate marker: a Danish nationwide cohort study

Persistent human papillomavirus (HPV) infection may promote carcinogenesis by hyperactivation of the immune system. We, therefore, explored the associations between HPV infection and risk of Hodgkin and non‐Hodgkin lymphoma in a nationwide cohort study using conization as a surrogate marker. We identified all Danish women who underwent conization between 1978 and 2011. We computed standardized incidence ratios and 95% confidence intervals for Hodgkin and non‐Hodgkin lymphoma based on national cancer incidence rates. Among 87 435 women who underwent conization, we noted an increased incidence of Hodgkin (standardized incidence ratio 1.48, 95% confidence interval 1.05–2.02) but only a slight increase for non‐Hodgkin lymphoma (standardized incidence ratio 1.10, 95% confidence interval 0.97–1.25). As measured by conization, HPV infection is associated with an increased risk of lymphoma. This association may be attributable to a chronic immune activation induced by persistent HPV infection and/or failure of the immune system both to clear HPV infection and to control lymphoma development. Copyright © 2015 John Wiley & Sons, Ltd.
Effects of prior contractions on muscle microvascular oxygen pressure at onset of subsequent contractions

In humans, pulmonary oxygen uptake (V̇O2) kinetics may be speeded by prior exercise in the heavy domain. This ‘speeding’ arises potentially as the result of an increased muscle O2 delivery (Q̇O2) and/or a more rapid elevation of oxidative phosphorylation. We adapted phosphorescence quenching techniques to determine the QO2‐to‐O2 utilization (Q̇O2/V̇O2) characteristics via microvascular O2 pressure (PO2,m) measurements across sequential bouts of contractions in rat spinotrapezius muscle. Spinotrapezius muscles from female Sprague‐Dawley rats (n= 6) were electrically stimulated (1 Hz twitch, 3–5 V) for two 3 min bouts (ST1 and ST2) separated by 10 min rest. PO2,m responses were analysed using an exponential + time delay (TD) model. There was no significant difference in baseline and ΔPO2,m between ST1 and ST2 (28.5 ± 2.6 vs. 27.9 ± 2.4 mmHg, and 13.9 ± 1.8 vs. 14.1 ± 1.3 mmHg, respectively). The TD was reduced significantly in the second contraction bout (ST1, 12.2 ± 1.9; ST2, 5.7 ± 2.2 s, P < 0.05), whereas the time constant of the exponential PO2,m decrease was unchanged (ST1, 16.3 ± 2.6; ST2, 17.6 ± 2.7 s, P > 0.1). The shortened TD found in ST2 led to a reduced time to reach 63 % of the final response of ST2 compared to ST1 (ST1, 28.3 ± 3.0; ST2, 20.2 ± 1.8 s, P < 0.05). The speeding of the overall response in the absence of an elevated PO2,m baseline (which had it occurred would indicate an elevated QO2/V̇O2) or muscle blood flow suggests that some intracellular process(es) (e.g. more rapid increase in oxidative phosphorylation) may be responsible for the increased speed of PO2,m kinetics after prior contractions under these conditions.
The Danish Medical Birth Registry.

BACKGROUND The Danish Medical Birth Registry (MBR) was established in 1968 and has been computerized since 1973. The primary purpose of the registration is to monitor the health of the newborns and of the quality of the antenatal and delivery care services, but the registry is increasingly being used in research. Major changes in registration have taken place in 1978 and 1991. The paper describes the content and usage of the MBR over time and suggests research topics for the future. RESULTS A broad scope of studies illustrates how the MBR has been used, either as single data source, linked with data from other registries or with data from interviews or self-completed questionnaires. Validations have shown variations in the quality of data, depending on source, and have underlined the need for constant quality control. Any access to data at the individual level is subjected to special provisions laid down by the Data Surveillance Authority and also requires a permission from the National Board of Health. CONCLUSIONS The time from conception to early childhood is an important period concerning future health for the individual. The Danish Medical Birth Registry is a valuable tool in this respect, which has not yet been used to its full potential in research or monitoring. Experience indicates that the quality of the registry depends upon having a close link to the staff responsible for delivery services and thus having the necessary specialised skills and interest.
Pancreatic and Extrapancreatic Effects of Gastric Inhibitory Polypeptide

The hormonal factor(s) implicated as transmitters of signals from the gut to pancreatic β-cells is referred to as incretin, and gastric inhibitory polypeptide (GIP) is identified as one of the incretins. GIP is a gastrointestinal peptide hormone of 42 amino acids that is released from duodenal endocrine K-cells after absorption of glucose or fat and exerts its effects by binding to its specific receptor, the GIP receptor. By generating and characterizing mice with a targeted mutation of the GIP receptor gene, we have shown that GIP has not only an insulinotropic role, but also physiological roles on fat accumulation into adipose tissues and calcium accumulation into bone. We here propose a new acronym, GIP, for gut-derived nutrient-intake polypeptide.
Rawlsian Land Reform with Human Capital An empirical investigation taking into account the gender

It is argued that land reform, consisting on the transformation of latifundia to mesofundia or microfundia , can be welfare improving, from a Rawlsian point of view, as it generates a superior situation, in terms of equity. Having this in mind, this (short) paper intends to be an empirical investigation of the possession rights and, in particular the agricultural holdings, of the land, differentiated by gender. This unveils that, even if land reform is put in practice, it generally remains a problem of inequality, in terms of land rights (ownership and/or holding), by gender.
Transcriptional Activity of Serum Amyloid A-activating Factor-1 Is Regulated by Distinct Functional Modules*

Serum amyloid A-activating transcription factor-1 (SAF-1) plays a major role in regulating transcription of several inflammation-responsive genes, including SAA and matrix metalloproteinase-1, that are implicated in the pathogenesis of reactive secondary amyloidosis, atherosclerosis, and arthritis. SAF-1 is a 477-amino acid protein with six zinc fingers. Its activation during inflammatory condition by a phosphorylation event that leads to an altered structure suggested possible structural modification of this protein as a leading cause of higher activity. However, no information is available regarding structural features that might regulate its activity. Here, we have characterized its functional domains, delineating activation and repression modules, DNA binding, and nuclear localization activities. Using GAL4AD chimeras and a DNA-binding assay with proteins prepared from various deletion constructs, the core DNA-binding domain of SAF-1 is mapped between amino acids 282 and 361, which contain second, third, and fourth zinc fingers. Results from several deletion and point mutants using green fluorescent protein reporter show that SAF-1 contains two independent nuclear localization signals; one is composed of a stretch of basic amino acids, and the other is a bipartite signal located within the core DNA-binding domain. SAF-1 contains several negative and positively functioning transactivation modules clustered at the two ends of this protein. Removal of any one of the terminal negative modules renders the SAF-1 protein functionally very active. These findings suggest that the terminal repression modules act in conjunction to regulate the functional activity of this protein.
Cell lineage of primary and secondary enamel knots

Recent research indicates that control of cusp morphology involves a signalling center at the heart of the developing tooth germ, known as the enamel knot. The primary enamel knot forms in both incisors and molar tooth germs at the cap stage of tooth development. Secondary and tertiary enamel knots only develop in molar tooth germs. These sit at the sites of future cusp tips from the early bell stage of tooth development. In studies describing the relationship between the primary and secondary enamel knots, it is often assumed that there is a cellular continuity between these structures, such that cells from the primary enamel knot physically contribute to the secondary enamel knots. We have devised a method whereby the developing tooth germ can be cultured in frontal slices with the enamel knot visible. The fate of the primary enamel knot cells can then be followed by 1,1′, di‐octadecyl‐3,3,3′,3′,‐tetramethylindo‐carbocyanine perchlorate (DiI) labeling. Using this method, no cells of the primary enamel knot were seen to move toward the developing secondary enamel knots. Thus, although the primary and secondary enamel knots have a close molecular and functional relationship in molar development, they are not actually derived from the same cells. Developmental Dynamics 233:754–759, 2005 © 2005 Wiley‐Liss, Inc.
A randomized comparison of modified intermediate-dose Ara-C versus high-dose ara-c in post-remission therapy for acute myeloid leukemia.

BACKGROUND We conducted a prospective, multicenter cooperative study to compare two courses of modified intermediate-dose cytarabine (Ara-C) (mIDAC; Ara-C at a dose of 1.0 g/m(2) every 12 hours for 5 days) versus high-dose Ara-C (HDAC; Ara-C at a dose of 2.0 g/m(2) every 12 hours for 5 days) in post-remission therapy for acute myeloid leukemia (AML) to confirm the post-remission antileukemic efficacy and safety of mIDAC. PATIENTS AND METHODS Twenty-six newly diagnosed patients with AML underwent remission induction therapy consisted of behenoyl Ara-C, mitoxantrone, etoposide, and 6-mercaptopurine. Post-remission therapy included four courses of consolidation and four courses of intensification. Patients who achieved complete remission (CR) were randomly assigned to mIDAC or HDAC for the second course of consolidation. The third course of intensification was the same as the second course of consolidation. Other post-remission therapies were the same in each group. RESULTS Twenty-two patients (84.6%) achieved CR and 21 patients were randomly assigned to receive either mIDAC (n=11) or HDAC (n=10). The predicted 4-year relapse-free survival for the mIDAC group and for the HDAC group were 49% and 56%, respectively (p=0.86). Although HDAC developed severe leukocytopenia compared to mIDAC, there were no significant differences between HDAC and mIDAC in the incidence of ≥grade 3 and ≥grade 4 documented infections. The mean lowest white blood cell count (WBC) after HDAC was significantly lower than that after mIDAC (0.208±0.120×10(3)/mm(3) and 0.459±0.333×10(3)/mm(3), respectively, p<0.05). The time to WBC recovery to 2.0×10(3)/mm(3) after HDAC was significantly longer than that after mIDAC (34.3±12.1 days and 27.1±9.5 days, respectively, p<0.05). CONCLUSION This study suggests that mIDAC may have an equivalent post-remission antileukemic efficacy to HDAC with less myelosuppression for AML patients.
Modern multidisciplinary perioperative management of rectal cancer.

IMPORTANCE The management of care for rectal cancer has undergone many changes and improvements in recent decades. A multidisciplinary approach to this complex disease is essential to ensure high-quality treatment and outcomes. OBJECTIVE To present a current, evidence-based approach to the multidisciplinary team management of rectal cancer with a review of the diagnosis, staging, and treatment of the disease by radiologists, oncologists, surgeons, and pathologists. EVIDENCE REVIEW The literature review was conducted through online searches of MEDLINE and PubMed. Articles published between January 1, 2000, and June 2014 and pertaining to staging modalities, surgical approaches, pathologic assessment, and medical treatments of rectal cancer were considered. All studies were reviewed, with preferential inclusion of larger or randomized trials. The review focused on changing paradigms and current controversies in rectal cancer management. FINDINGS A multidisciplinary approach to the patient with rectal cancer includes many health care professionals. Although treatments continue to evolve and improve, clear evidence-based principles have been well studied. The important roles of various specialists must be acknowledged and utilized. Within each role, new and emerging treatment approaches require critical review by experts in their fields. CONCLUSIONS AND RELEVANCE Many new technologies and treatment options will continue to advance the treatment of rectal cancer, further emphasizing the need for a multidisciplinary approach to achieve optimal care.
Analysis of Conserved Active Site Residues in Monoamine Oxidase A and B and Their Three-dimensional Molecular Modeling*

Monoamine oxidase (MAO) is a key enzyme responsible for the degradation of serotonin, norepinephrine, dopamine, and phenylethylamine. It is an outer membrane mitochondrial enzyme existing in two isoforms, A and B. We have recently generated 14 site-directed mutants of human MAO A and B, and we found that four key amino acids, Lys-305, Trp-397, Tyr-407, and Tyr-444, in MAO A and their corresponding amino acids in MAO B, Lys-296, Trp-388, Tyr-398, and Tyr-435, play important roles in MAO catalytic activity. Based on the polyamine oxidase three-dimensional crystal structure, it is suggested that Lys-305, Trp-397, and Tyr-407 in MAO A and Lys-296, Trp-388, and Tyr-398 in MAO B may be involved in the non-covalent binding to FAD. Tyr-407 and Tyr-444 in MAO A (Tyr-398 and Tyr-435 in MAO B) may form an aromatic sandwich that stabilizes the substrate binding. Asp-132 in MAO A (Asp-123 in MAO B) located at the entrance of the U-shaped substrate-binding site has no effect on MAO A nor MAO B catalytic activity. The similar impact of analogous mutants in MAO A and MAO B suggests that these amino acids have the same function in both isoenzymes. Three-dimensional modeling of MAO A and B using polyamine oxidase as template suggests that the overall tertiary structure and the active sites of MAO A and B may be similar.
Research on the ecology of ticks and tick-borne pathogens—methodological principles and caveats

Interest in tick-transmitted pathogens has experienced an upsurge in the past few decades. Routine application of tools for the detection of fragments of foreign DNA in ticks, together with a high degree of interest in the quantification of disease risk for humans, has led to a marked increase in the number of reports on the eco-epidemiology of tick-borne diseases. However, procedural errors continue to accumulate in the scientific literature, resulting in misleading information. For example, unreliable identification of ticks and pathogens, erroneous interpretations of short-term field studies, and the hasty acceptance of some tick species as vectors have led to ambiguities regarding the vector role of these arthropods. In this review, we focus on the ecological features driving the life cycle of ticks and the resulting effects on the eco-epidemiology of tick-transmitted pathogens. We review the factors affecting field collections of ticks, and we describe the biologically and ecologically appropriate procedures for describing tick host-seeking activity and its correlation with environmental traits. We detail the climatic variables that have biological importance on ticks and explain how they should be properly measured and analyzed. We also provide evidence to critically reject the use of some environmental traits that are being increasingly reported as the drivers of the behavior of ticks. With the aim of standardization, we propose unambiguous definitions of the status of hosts and ticks regarding their ability to maintain and spread a given pathogen. We also describe laboratory procedures and standards for evaluating the vectorial capacity of a tick or the reservoir role of a host. This approach should provide a coherent framework for the reporting of research findings concerning ticks and tick-borne diseases.
Can Developing Economies Benefit from WTO negotiations on Binding Disciplines for Hard Core Cartels

At the next WTO Ministerial Conference, to be held in Cancun 10-14 September 2003, Ministers will decide by explicit consensus on modalities of negotiations on competition issues. In addition to the decision on whether to proceed with negotiations, an agreement will have to be reached on what type of provisions should be included in a multilateral framework on competition, and of particular interest here is the desirability of including possible provisions on so-called hard core cartels. Many developing countries have actively participated in discussions on competition-policy-related matters in the WTO and they can be expected to play a full part in the deliberations in Cancun . This paper assesses the potential costs and benefits of negotiations on potential provisions for hard core cartels for developing economies and begins by reviewing the factual record in this regard. Estimates are presented here on the likely damage done to developing countries by the 40 or more private international cartels that were prosecuted by government agencies in the industrial economies in the 1990s. In the case of the international vitamins cartel, which was worldwide in scope and lasted 10 years, there is robust evidence that cartel members targeted those jurisdictions with little or no cartel enforcement for greater price rises and larger overcharges to customers. This evidence, as well as other evidence, raises the question of what measures, if any, are being taken to protect developing economies' interests against this form of international anti-competitive practice.