bluuebunny/crossref_metadata_2025_split huggingface dataset:
Advances in biomolecular simulations: methodology and recent applications
Authors: Norberg Jan , Nilsson Lennart 
Published: January 2004

1. Introduction 2582. Set-up of MD simulations 2602.1 Constant-pressure dynamics 2602.2 Grand-canonical dynamics 2612.3 Boundary conditions 2613. Force fields 2623.1 Proteins 2623.2 Nucleic acids 2653.3 Carbohydrates 2663.4 Phospholipids 2663.5 Polarization 2674. Electrostatics 2674.1 Spherical truncation methods 2684.2 Ewald summation methods 2694.3 Fast multipole (FM) methods 2714.4 Reaction-field methods 2715. Implicit solvation models 2716. Speeding-up the simulation 2736.1 SHAKE and its relatives 2736.2 Multiple time-step algorithms 2746.3 Other algorithms 2757. Conformational space sampling 2757.1 Multiple copy simultaneous search (MCSS) and locally enhanced sampling (LES) 2757.2 Steered or targeted MD 2767.3 Self-guided MD 2767.4 Leaving the standard 3D Cartesian coordinate system: 4D MD and internal coordinate MD 2777.5 Temperature variations 2778. Thermodynamic calculations 2788.1 Lambda (λ) dynamics 2788.2 Extracting thermodynamic information from simulations 2798.3 Non-Boltzmann thermodynamic integration (NBTI) 2798.4 Other methods 2799. QM/MM calculations 28210. MD simulations of protein folding and unfolding 28310.1 High-temperature effects 28410.2 Co-solvent and polarization effects 28810.3 External force effects 28811. On the horizon 29112. Acknowledgements 29213. References 292Molecular dynamics simulations are widely used today to tackle problems in biochemistry and molecular biology. In the 25 years since the first simulation of a protein computers have become faster by many orders of magnitude, algorithms and force fields have been improved, and simulations can now be applied to very large systems, such as protein–nucleic acid complexes and multimeric proteins in aqueous solution. In this review we give a general background about molecular dynamics simulations, and then focus on some recent technical advances, with applications to biologically relevant problems.
Electron tunneling through proteins
Authors: Gray Harry B. , Winkler Jay R. 
Published: January 2004

1. History 3422. Activation barriers 3432.1 Redox potentials 3442.2 Reorganization energy 3443. Electronic coupling 3454. Ru-modified proteins 3484.1 Reorganization energy 3494.1.1 Cyt c 3494.1.2 Azurin 3504.2 Tunneling timetables 3525. Multistep tunneling 3576. Protein–protein reactions 3596.1 Hemoglobin (Hb) hybrids 3596.2 Cyt c/cyt b5 complexes 3606.3 Cyt c/cyt c peroxidase complexes 3606.4 Zn–cyt c/Fe–cyt c crystals 3617. Photosynthesis and respiration 3627.1 Photosynthetic reaction centers (PRCs) 3627.2 Cyt c oxidase (CcO) 3648. Concluding remarks 3659. Acknowledgments 36610. References 366Electron transfer processes are vital elements of energy transduction pathways in living cells. More than a half century of research has produced a remarkably detailed understanding of the factors that regulate these ‘currents of life’. We review investigations of Ru-modified proteins that have delineated the distance- and driving-force dependences of intra-protein electron-transfer rates. We also discuss electron transfer across protein–protein interfaces that has been probed both in solution and in structurally characterized crystals. It is now clear that electrons tunnel between sites in biological redox chains, and that protein structures tune thermodynamic properties and electronic coupling interactions to facilitate these reactions. Our work has produced an experimentally validated timetable for electron tunneling across specified distances in proteins. Many electron tunneling rates in cytochrome c oxidase and photosynthetic reaction centers agree well with timetable predictions, indicating that the natural reactions are highly optimized, both in terms of thermodynamics and electronic coupling. The rates of some reactions, however, significantly exceed timetable predictions; it is likely that multistep tunneling is responsible for these anomalously rapid charge transfer events.
Impairment of Hepatic Microcirculation in Fatty Liver
Authors: IJAZ SAMIA , YANG WENXUAN , WINSLET MARC C. , SEIFALIAN ALEXANDER M. 
Published: January 2004

ABSTRACTFatty liver or hepatic steatosis, which is the result of the abnormal accumulation of triacylglycerol within the cytoplasm of hepatocytes, is a common histological finding in human liver biopsy specimens that is attributed to the effects of alcohol excess, obesity, diabetes, or drugs. There is a general consensus that fatty liver compromises hepatic microcirculation, the common exchange network upon which hepatic arterial and portal inflows converge, regardless of underlying etiology. A significant reduction in hepatic microcirculation has been observed in human fatty donor livers and in experimental models of hepatic steatosis. There is an inverse correlation between the degree of fat infiltration and both total hepatic blood flow and flow in microcirculation. Fatty accumulation in the cytoplasm of the hepatocytes is associated with an increase in the cell volume that reduces the size of the hepatic sinusoid space by 50% compared with a normal liver and may result in partial or complete obstruction of the hepatic sinusoid space. As a result of impaired hepatic microcirculation, the hepatocytes of the fatty liver have reduced tolerance against ischemia‐reperfusion injury, which affects about 25% of the donors for liver transplantation because severe steatosis is associated with a high risk of primary nonfunction after liver transplantation.
A Model of Nitric Oxide Capillary Exchange
Authors: TSOUKIAS NIKOLAOS M. , POPEL ALEKSANDER S. 
Published: January 2004

ABSTRACTObjective: Our aim was to develop a mathematical model that describes the nitric oxide (NO) transport in and around capillaries. The model is used to make quantitative predictions for (1) the contribution of capillary endothelium to the nitric oxide flux into the parenchymal tissue cells; (2) the scavenging of arteriolar endothelium‐derived NO by capillaries in the surrounding tissue; and (3) the role of myoglobin in tissue cells and plasma‐based hemoglobin on NO diffusion in and around capillaries.Methods: We used a finite element model of a capillary and surrounding tissue with discrete parachute‐shape red blood cells (RBCs) moving inside the capillary to obtain the NO concentration distribution. An intravascular mass transfer coefficient is estimated as a function of RBC membrane permeability and capillary hematocrit. A continuum model of the capillary is also formulated, in which blood is treated as a homogeneous fluid; it uses the mass transfer coefficient and provides a closed‐form analytic solution for the average exchange rate of NO in a capillary‐perfused region.Results: The NO concentration in the parenchymal cells depends on parameters such as RBC membrane permeability and capillary hematocrit; the concentration is predicted for a wide range of parameters. In the absence of myoglobin or plasma‐based hemoglobin, the average tissue concentration generally ranges between 20 and 300 nM. In the presence of myoglobin or after transfusion of a hemoglobin‐based blood substitute, there is minimal NO penetration into the tissue from the capillary endothelium.Conclusions: The model suggests that NO originating from the capillary wall can diffuse toward the parenchymal cells and potentially sustain physiologically significant concentrations. The model provides estimates of NO exchange and concentration level in capillary‐perfused tissue, and it can be used in models of NO transport around arterioles or other NO sources.
Microvascular Abnormalities in Chronic Heart Failure: A Cross‐Sectional Analysis
Authors: HOUBEN ALPHONS J.H.M. , BELJAARS JEROEN H. , HOFSTRA LEO , KROON ABRAHAM A. , DE LEEUW PETER W. 
Published: January 2004

ABSTRACTObjectives: Similar to what has been found in hypertension, elevated peripheral resistance in chronic heart failure (CHF) might be related to microvascular constriction and rarefaction. Our objective was to evaluate both structural and functional microvascular changes in patients with CHF in relation to left ventricular function and neurohumoral activation.Methods: In 25 patients with mild and severe CHF (New York Heart Association class I‐II [n = 11] and class III‐IV [n = 14]) and 10 age‐matched healthy subjects, we studied microvascular density, diameters, and morphology of the bulbar conjunctiva and skin nailfold using intravital microscopy.Results: Total conjunctival microvascular density was higher in patients with mild heart failure compared with healthy controls, whereas it was lower in severe heart failure (medians, 6.75, 4.31, and 3.56 mm/mm2, respectively, p < 0.01). In patients with heart failure, venular density was correlated with left ventricular ejection fraction. Nailfold capillary recruitment during postocclusive reactive hyperemia, a measure of functional reserve capacity, was impaired in patients with severe CHF (p < 0.05). Furthermore, in severe CHF, more abnormal capillaries and enlarged diameters were found in the nailfold (p < 0.05).Conclusions: In heart failure, several microvascular abnormalities occur that differ, depending on the severity of this condition.
Blood—Brain Barrier Permeability Precedes Senile Plaque Formation in an Alzheimer Disease Model
Authors: UJIIE MAKI , DICKSTEIN DARA L. , CARLOW DOUGLAS A. , JEFFERIES WILFRED A. 
Published: January 2004

ABSTRACTObjective: To establish the generality of cerebrovascular pathology frequently observed with Alzheimer disease, we have assessed blood‐brain barrier (BBB) integrity using the Alzheimer disease model Tg2576 mice in which cognitive deficits and neuritic plaque formation develop around 10–12 months of age.Methods: We assessed BBB integrity using well‐established methods involving albumin and Evans blue uptake and introduce the use of a novel perfusion protocol using succinimidyl ester of carboxyfluorescein diacetate.Results: BBB permeability is increased in the cerebral cortex of 10‐month‐old Tg2576 mice preceding Alzheimer disease pathology presentation. Furthermore, when compared with their nontransgenic littermates, 4‐month‐old Tg2576 mice exhibit compromised BBB integrity in some areas of the cerebral cortex. An age‐related increase in albumin uptake by the brains of Tg2576 mice, compared with nontransgenic mice, was also observed. These findings were supported by quantitative Evans blue analysis (p = 0.07, two‐way analysis of variance).Conclusion: A breakdown of BBB was evident in young 4‐ to 10‐month‐old Tg2576 mice. Compromised barrier function could explain the mechanisms of Aβ entry into the brain observed in experimental Alzheimer disease vaccination models. Such structural changes to the BBB caused by elevated Aβ could play a central role in Alzheimer disease development and might define an early point of intervention for designing effective therapy against the disease.
Identification of a Novel Route of Iron Transcytosis across the Mammalian Blood‐Brain Barrier
Authors: MOROO IKU , UJIIE MAKI , WALKER BRANDIE L. , TIONG JACQUELINE W.C. , VITALIS TIMOTHY Z. , KARKAN DELARA , GABATHULER REINHARD , MOISE ALEXANDER R. , JEFFERIES WILFRED A. 
Published: January 2004

ABSTRACTObjective: This study was undertaken to assess the role of p97 (also known as melanotransferrin) in the transfer of iron into the brain, because the passage of most large molecules is limited by the presence of the blood‐brain barrier, including that of the serum iron transporter transferrin.Methods: To study the function of the soluble form of p97, we followed the uptake of radioiodinated and 55Fe loaded p97 and transferrin by the brain during a 24‐hour period.Results: We show that the soluble form of p97 has the ability to transcytose across the murine blood‐brain barrier, and its transcytosis can be inhibited in a specific manner. We also provide evidence that p97 transports iron into the brain more efficiently than transferrin.Conclusions: These data support the idea that p97 is an important iron transporter across the blood‐brain barrier in normal physiology and possibly in neurodegenerative diseases, such as Alzheimer disease, in which iron homeostasis in the brain becomes disrupted.
Hodgkin's lymphoma, Epstein–Barr virus reactivation and fatal haemophagocytic syndrome
Authors: Hasselblom S. , Linde A. , Ridell B. 
Published: January 2004

Abstract.Haemophagocytic syndrome is a serious disorder, often related to Epstein–Barr virus (EBV) or other infectious agents. Frequently an underlying immune abnormality or a T‐cell lymphoma is present. The combination of haemophagocytosis and Hodgkin's lymphoma seems to be rare. A 70‐year‐old female with rheumatoid arthritis was admitted with constitutional symptoms, persistent fever, pancytopenia, deranged liver enzymes, lymphadenopathy and splenomegaly. A fatal coagulopathy supervened. The clinical picture and the bone marrow findings indicated a haemophagocytic syndrome and a lymph node biopsy disclosed an EBV‐positive Hodgkin's lymphoma. EBV serology pointed at viral reactivation and a high EBV DNA content was detected in serum by real‐time quantitative PCR analysis (5.5 × 106 copies per mL). The case history is presented and the literature is reviewed.
Acute myocardial infarction: an unusual culmination of rheumatic pancarditis and antiphospholipid antibody syndrome
Authors: Izhevsky D. , Maple J. T. , Ommen S. R. 
Published: January 2004

Abstract.A 29‐year‐old man with history of antiphospholipid antibody syndrome (APS) and two prior episodes of acute rheumatic fever developed a third episode of acute rheumatic fever. This was complicated by acute myocardial infarction due to spontaneous arterial thrombosis of the left anterior descending and right coronary arteries. We postulate that rheumatic pancarditis created an inflammatory, thrombogenic environment that facilitated coronary artery thrombosis secondary to APS, a novel association. Our patient was left with significant left ventricular dysfunction at a young age, and cases such as this emphasize the need for early recognition and proper treatment of APS. Further, the pathogenesis of thrombosis in APS is incompletely understood, and the cellular and molecular basis for this, including the role of ‘second hits’, are areas needing further investigation.
Risk modifiers for peripheral sensory neuropathy in HIV infection/AIDS
Authors: Lopez O. L. , Becker J. T. , Dew M.‐A. , Caldararo R. 
Published: January 2004

The objective of this study is to examine the risk factors associated with the development of sensory neuropathy in human immunodeficiency virus (HIV)‐infected patients in 292 HIV+ patients recruited through a community‐based sentinel survey. We determined the clinical and treatment factors associated with the presence of peripheral sensory neuropathy in HIV+ subjects at baseline examination, and at 1‐year follow‐up. Baseline examination was assessed with a logistic regression analysis controlling for age, education level, history of drug/alcohol use, and anti‐retroviral treatment. The risk of developing new peripheral neuropathy at follow‐up was determined using a Cox proportional hazard model analysis. At study entry, neuropathy (n = 64) was associated with acquired immunodeficiency syndrome (AIDS), nucleoside analogue reverse transcriptase inhibitors (NRTI) (i.e. ddC), and history of alcohol abuse. After 1‐year follow‐up, the development of neuropathy was predicted by AIDS, age (older subjects), and NRTI use.These findings indicated that AIDS, age, alcohol abuse/dependence, and anti‐retroviral medication use are important predictors of motor/sensory peripheral neuropathy in the HIV infection. The peripheral neurotoxic effect of anti‐retroviral medication should be taken into account in the design of long‐term therapies.
The systemic amyloidoses: clearer understanding of the molecular mechanisms offers hope for more effective therapies
Authors: Merlini G , Westermark P 
Published: January 2004

Abstract.Knowledge about the systemic amyloidoses has increased considerably during the last few years. This group of diseases is characterized by great biochemical variability, including at least 11 different amyloid fibril proteins and a remarkable range of clinical manifestations. With the understanding that the pathogenesis is different in the various forms of amyloidosis, it is now being increasingly accepted that an early and accurate diagnosis, including that of the underlying biochemical nature, is crucial for a successful treatment. The elucidation of the molecular mechanisms involved in amyloidogenesis is at the basis of the recent blossoming of new, innovative and more effective therapeutic approaches.
Microalbuminuria and stroke in a British population: the European Prospective Investigation into Cancer in Norfolk (EPIC‐Norfolk) population study
Authors: Yuyun M. F. , Khaw K.‐T. , Luben R. , Welch A. , Bingham S. , Day N. E. , Wareham N. J. 
Published: January 2004

Abstract.Objectives. To examine the relationship between microalbuminuria and incident stroke in the general population.Design. Population‐based prospective cohort study.Setting. Participants were recruited in a primary care setting from 35 participating general practice units in Norfolk, UK.Subjects and main outcome measures. The study population consisted of 23 630 individuals aged 40–79 years recruited between 1993 and 1997 for the EPIC‐Norfolk Study and followed up for an average of 7.2 years. Random spot urine specimens were collected at baseline and albumin‐to‐creatinine ratio measured. Participants were categorized into normoalbuminuria, microalbuminuria and macroalbuminuria groups. During follow‐up, the main end point was stroke incidence (fatal and nonfatal), ascertained from the UK Office for National Statistics and from the National Health Service Health District database of all hospital admissions.Results. A total of 246 stroke events occurred during follow‐up [crude incidence rate of stroke, 1.5 per 1000 person years (pyrs)]. The age‐adjusted incidence of stroke increased significantly across categories of baseline albuminuria (0.9, 1.1 and 1.4/1000 pyrs for tertiles of normoalbuminuria, 2.6/1000 pyrs for microalbuminuria, and 6/1000 pyrs for macroalbuminuria in the total population,P < 0.001 for trend). In all women and men, the multivariate hazard ratio [95% confidence interval (CI)] for stroke associated with microalbuminuria was 1.49 (1.13–2.14) and macroalbuminuria 2.43 (1.11–6.26). After stratifying by stroke subtype, microalbuminuria was only independently predictive of ischaemic stroke, with hazard ratio (95% CI) of 2.01 (1.29–3.31).Conclusion. Microalbuminuria is independently associated with approximately 50% increased risk of stroke in the general population. Microalbuminuria may be useful in identifying those at increased risk of stroke in the general population.
QRS prolongation on surface ECG and brain natriuretic peptide as indicators of left ventricular systolic dysfunction
Authors: Krüger S. , Filzmaier K. , Graf J. , Kunz D. , Stickel T. , Hoffmann R. , Hanrath P. , Janssens U. 
Published: January 2004

Abstract.Objective.  To determine whether the combination of prolonged QRS duration and brain natriuretic peptide (BNP) levels predicts left ventricular systolic dysfunction (LVSD) with a higher accuracy compared with QRS duration or BNP alone.Setting.  University hospital.Methods.  We studied 128 consecutive patients with suspected cardiac disease. At rest the QRS duration on 12‐lead ECG and BNP levels were determined. A left ventricular ejection fraction (LVEF) <50% at echocardiography was defined as LVSD.Results.  QRS duration in the LVSD group (n = 66, LVEF 30 ± 8%) was longer than in the group without LVSD (n = 62, LVEF 60 ± 5%; QRS 129 ± 34 vs. 96 ± 20 ms, P < 0.001). BNP was higher in the LVSD group compared with controls (467 ± 397 vs. 169 ± 242 pg mL−1, P < 0.001). A QRS duration of >0.1, >0.11 or >0.12 s was highly specific (63, 90 and 98%) but less sensitive (84, 81 and 75%) for the prediction of LVSD. A QRS cut‐off value of 106 ms was moderately sensitive (65%) but very specific (87%) for the prediction of LVSD, whereas a BNP cut‐off value of >84 pg mL−1 was highly sensitive (89%) but only modestly specific (58%). The positive likelihood ratio for LVSD of abnormal BNP (2.0) and QRS prolongation >0.1 s (2.3) was improved by the combination of both criteria (5.1). In multivariate analysis, BNP and QRS duration were independent predictors of LVSD.Conclusions.  The combination of abnormal BNP and QRS prolongation yields a higher positive likelihood ratio for the detection of LVSD compared with the two criteria alone.
Is the relationship between type of alcohol and mortality influenced by socio‐economic status?
Authors: Nielsen N. R. , Schnohr P. , Jensen G. , Grønbæk M. 
Published: January 2004

Abstract.Objectives.  To assess the impact of socio‐economic status on the relationship between type of alcohol and all‐cause mortality.Design.  A prospective population study.Setting.  The Copenhagen City Heart Study, Denmark.Subjects.  A total of 14 223 men and women participated in the first examination of The Copenhagen City Heart Study in 1976–1978. The participants were followed up until 18th of September 2001 during which 7208 persons died. The effect of beer, wine and spirits on mortality was stratified according to levels of education, income and cohabitation, and the association was examined after controlling for intake of the other types of alcohol, and for sex, smoking, physical activity and body mass index.Main outcome measures.  Number and time of death from all causes.Results.  Consumers of wine were better educated and wealthier compared with beer and spirits drinkers. The association between type of beverage and mortality was noticed to differ according to socio‐economic level, especially where the apparent protective effect of wine consumption tended to be strongest in the lower income and educational groups.Conclusions.  This study finds the specific effects of beer, wine or spirits to moderately diverge in the socio‐economic groups. Future studies addressing the association between the type of beverage and mortality may need to more thoroughly take socio‐economic factors into account.
Metformin and lactic acidosis: cause or coincidence? A review of case reports
Authors: Stades A. M. E. , Heikens J. T. , Erkelens D. W. , Holleman F. , Hoekstra J. B. L. 
Published: January 2004

Abstract.Objective.  Metformin has been associated with the serious side‐effect lactic acidosis. However, it remains unclear whether the use of metformin was a cause or a coincidence in lactic acidosis.Design.  A literature search of the Index Medicus (1959–66) and of the databases Embase, Medline, Medline Express (1966–99) was performed using the keywords metformin, biguanides and lactic acidosis. All articles of cases with metformin‐induced lactic acidosis (MILA) were cross‐referenced.Subjects.  Cases were included for analysis if they met the following criteria: serum pH ≤7.35, lactate concentration ≥5 mmol L−1.Intervention.  A forum of six experts in intensive care medicine independently categorized the cases in MILA unlikely (score 0), possible MILA (score 1) or probable MILA (score 2).Main outcome measures.  Statistical analysis included the paired interobserver agreement (κ) and multivariate regression analysis.Results.  Of 80 reported cases, 33 were excluded because of insufficient quality. The forum scores of the remaining 47 cases were distributed normally with a mean score of 7 (range 2–10). The κ‐value was 0.041 (SD = 0.24, range −0.514, 0.427). Neither lactate concentration nor mortality correlated with serum metformin concentrations.Conclusions.  Given the low interobserver agreement and the lack of any relationship between metformin levels and outcome parameters, the concept that there is a simple, causal relationship between metformin use and lactic acidosis in diabetic patients has to be reconsidered.