bluuebunny/crossref_metadata_2025_split huggingface dataset:
The E23K Variant of KCNJ11 Encoding the Pancreatic β-Cell Adenosine 5′-Triphosphate-Sensitive Potassium Channel Subunit Kir6.2 Is Associated with an Increased Risk of Secondary Failure to Sulfonylurea in Patients with Type 2 Diabetes
Authors: Sesti Giorgio , Laratta Emanuela , Cardellini Marina , Andreozzi Francesco , Del Guerra Silvia , Irace Concetta , Gnasso Agostino , Grupillo Maria , Lauro Renato , Hribal Marta Letizia , Perticone Francesco , Marchetti Piero 
Published: April 2006

Abstract
Context: Several studies suggest that genetic factors may play a role in the different responses to antidiabetic therapy; however, conclusive evidence is still lacking.
Objective: The objective of the study was to investigate whether diabetic patients carrying the E23K variant in KCNJ11 are at increased risk for secondary sulfonylurea failure.
Design: Secondary sulfonylurea failure was defined as fasting plasma glucose greater than 300 mg/dl despite sulfonylurea-metformin combined therapy and appropriate diet, in the absence of other conditions causing hyperglycemia.
Setting: The study was conducted in an ambulatory care facility.
Patients: A total of 525 Caucasian type 2 diabetic patients were enrolled in the study.
Intervention: Sulfonylurea treatment was followed by sulfonylurea-metformin combined therapy and then insulin treatment.
Main Outcome Measure: Secondary failure was the main outcome measure.
Results: Of the diabetic patients enrolled in the study, 38.5% were E23E homozygous, 51.4% were E23K heterozygous, and 10.1% were K23K homozygous. The frequency of carriers of the K allele was 58 and 66.8% among patients treated with oral therapy or secondary sulfonylurea failure, respectively (odds ratio, 1.45; 95% confidence interval, 1.01–2.09; P = 0.04). Adjustment for age, gender, fasting glycemia, glycosylated hemoglobin, age at diagnosis, and duration of diabetes in a logistic regression analysis did not change this association (odds ratio, 1.69; 95% confidence interval, 1.02–2.78; P = 0.04). Islets isolated from carriers of the K allele showed no differences in glucose-stimulated insulin secretion and a tendency toward reduced response upon glibenclamide stimulation (P = 0.09). After 24-h exposure to high (16.7 mmol/liter) glucose concentration, impairment of glibenclamide-induced insulin release was significantly (P = 0.01) worse with the E23K variant.
Conclusions: These data suggest that the E23K variant in KCNJ11 may influence the variability in the response of patients to sulfonylureas, thus representing an example of pharmacogenetics in type 2 diabetes.
Larger Testes and Higher Inhibin B Levels in Finnish than in Danish Newborn Boys
Authors: Main Katharina M. , Toppari Jorma , Suomi Anne-Maarit , Kaleva Marko , Chellakooty Marla , Schmidt Ida M. , Virtanen Helena E. , Boisen Kirsten A. , Kai Claudia M. , Damgaard Ida N. , Skakkebæk Niels E. 
Published: April 2006

AbstractContext: Recent studies showed that male reproductive health problems, such as cryptorchidism, hypospadias, testicular cancer, and low sperm quality, are more prevalent in Denmark than in Finland.Objectives: We hypothesized that, if fetal testicular dysgenesis contributed to these observations, differences in gonadal development and the hypothalamus-pituitary-testis axis would already be detectable perinatally. Thus, we investigated healthy newborn boys in both countries.Design: This was a prospective, longitudinal population-based study.Setting: Two primary obstetric centers were included at the University Hospitals of Copenhagen, Denmark, and Turku, Finland.Participants: The participants of the study included 633 Danish and 1044 Finnish boys, born at term with appropriate weight for gestational age.Interventions: Ultrasound determination of testis size at 0, 3, and 18 months and blood sampling (n = 727) at 3 months were analyzed.Main Outcome Measures: Testicular volume and reproductive hormones were measured.Results: Testis volume was significantly higher at all ages in Finnish than in Danish boys (medians, 98 vs. 95, 185 vs. 119, and 188 vs. 136 mm3, respectively; P &lt; 0.00001). Testis growth from birth to 3 months was larger in Finnish than in Danish boys (mean, 75 vs. 26 mm3; P &lt; 0.0001). Serum hormone levels were higher in Finnish than Danish boys for inhibin B (median, 456 vs. 385 pg/ml; P &lt; 0.0001), FSH (1.33 vs. 1.21 IU/liter; P &lt; 0.036), and SHBG (143 vs. 136 nmol/liter; P &lt; 0.022). Inhibin B was significantly positively correlated to testicular volume (r = 0.25; P &lt; 0.006).Conclusions: The larger testes and higher inhibin B levels most likely represent a bigger volume of seminiferous tubules in Finnish compared with Danish boys. Although this phenomenon may be attributable to a genetic difference between the two countries, it may also reflect environmental factors influencing testicular development.
Dramatic Effects of d-Electron Configurations on Vibrational Circular Dichroism Spectra of Tris(acetylacetonato)metal(III)
Authors: Sato Hisako , Taniguchi Tohru , Monde Kenji , Nishimura Shin-Ichiro , Yamagishi Akihiko 
Published: April 2006

Abstract
The VCD spectra of a series of tris(acetylacetonato)metal(III) ([M(acac)3] with M = Co, Cr, Ru, and Rh) have revealed a new aspect concerning the effects of a central metal ion on the vibrational energy levels split by the inter-ligand interactions. Our present view is that the correlated vibrational motions of vicinal ligands are affected by the d-electron configuration of a central metal ion.
Screening Tests for Intended Medication Adherence Among the Elderly
Authors: Raehl Cynthia L , Bond CA , Woods Tresa J , Patry Roland A , Sleeper Rebecca B 
Published: April 2006

Background: Medication nonadherence is increasingly recognized as a cause of preventable adverse events, hospitalizations, and poor healthcare outcomes. While comprehensive medication adherence assessment for the elderly is likely to identify and prevent drug-related problems, it is time consuming for patient and healthcare providers alike. Objective: To identify screening tools to predict elderly patients' intended medication adherence that are suitable for primary-care settings and community pharmacies. Methods: This study evaluated 57 English-speaking persons aged 65 years and older who were from diverse socioeconomic backgrounds. Intended adherence was quantified, and the relationships to demographic, medical history, socioeconomic, and literacy variables were determined. Results: In a multivariate analysis with the composite MedTake Test (a quantitative measure of each subject's intent to adhere to prescribed oral medications) as the dependent variable, independent predictors of intended adherence included: age, car ownership in the last 10 years, receipt of food assistance in the last 10 years, number of over-the-counter (OTC) medicines, and REALM (Rapid Estimate of Adult Literacy in Medicine). The strongest predictor was the REALM word-recognition pronunciation test (β = 0.666; R2 = 0.271; p < 0.001). Conclusions: We observed that the REALM word-recognition pronunciation test, along with age, number of OTC drugs, and 2 socioeconomic questions, predicted the intent of seniors to correctly take their own prescribed oral medications.
Atenolol-Induced Breast Pain in a Woman with Hypertension
Authors: Kelleher Julia A 
Published: April 2006

Objective: To describe a case of atenolol-induced breast pain and swelling in a patient receiving atenolol. Case Summary: A 54-year-old woman was diagnosed with hypertension with no existing comorbidity. The patient was not taking any prescription medications, but was using an herbal supplement and several other over-the-counter supplements. After diet and exercise failed to control the woman's blood pressure, atenolol 25 mg daily was initiated. She reported symptoms of insomnia 9 days after starting the medication. During a follow-up visit 5 weeks later, the patient reported continued insomnia, as well as a 6 day history of breast pain, swelling, and tenderness. Atenolol was quickly titrated to discontinuation, and a thiazide diuretic was prescribed. Subsequently, the pain and swelling gradually resolved. Discussion: Assessment using the Naranjo probability scale revealed that the adverse reaction was probably associated with atenolol. While rare cases of hyperprolactinemia and galactorrhea have been reported with β-blocker use, no reports of breast pain caused by this drug class were identified in the literature. Conclusions: Atenolol has many reported adverse reactions, both common and rare; however, until this report, breast pain and swelling had not been documented adverse reactions. Clinicians should be aware that atenolol may be a cause of nonorganic breast pain and swelling in women.
Zn‐Dependent Medium‐Chain Dehydrogenases/Reductases
Authors: Meijers Rob , Cedergren‐Zeppezauer Eila S 
Published: April 2006

AbstractMedium‐chain dehydrogenases/reductases (MDRs) have about 350 to 390 amino acids and belong to a large superfamily of proteins including the Zn‐dependent alcohol dehydrogenases (ADHs) and several other Zn‐dependent activities. They are dimers or tetramers and utilize either NADH or NADPH as electron carriers referred to as cofactors. The oxidation/reduction process is a 2‐electron/1‐proton (hydride ion, H−) transfer between substrate and cofactor. The compounds oxidized or reduced by these enzymes vary considerably in structure ranging from small primary and secondary alcohols/aldehydes/ketones (aliphatic and aromatic), sugars (sorbitol/fructose, glucose) to large substances like fatty acids, steroids, and retinoids. ADHs are widely distributed in nature and some MDR members are found in all species. An essential Zn ion at the active site is common to all MDRs but some members have two zinc ions per subunit.The 3D Structures of Zn‐dependent MDRs are highly similar and they essentially have the same polypeptide fold. The low sequence identity found sometimes could not immediately reveal this close structural relationship. Now numerous structures have been examined indicating that the evolutionary strategy for MDRs has been to vary amino acids preferably at the reaction center and further away in the substrate binding area. Thus, the size and shape of the substrate channel is adapted for small or large substrates, hydrophilic or hydrophobic substances, modifications attained via few mutations, or significant deletions/additions of amino acids. A further opportunity to create multiplicity has been to vary the control mechanism for the protein conformation change and the oligomeric state. Some enzymes undergo significant structural changes upon cofactor binding, while others do not.A transition state intermediate of NADH in complex with horse liver alcohol dehydrogenase, resolved to atomic resolution (≈1 Å), has revealed structural modifications of the cofactor associated with the activation process for hydride transfer. This involves an OH−pyridine ring adduct, connected to the zinc center. The distortion of the nicotinamide at the enzyme site, affected by the presence of the negatively charged oxygen ligand, influences three parameters: (i) the puckering of the ring, (ii) a deviation from a standard carbon–carbon double bond length, and (iii) accumulation of negative charge at the C4 atom promoting hydride transfer. The active site Zn‐center of this large enzyme group shows great flexibility with respect to metal–ligand geometry and dynamics. Structural and spectroscopic evidence suggest that Zn‐dependent MDRs should be included in the general family of Zn‐enzymes, which require water and hydroxide ion as reactants during catalysis.
6‐Pyruvoyl‐Tetrahydropterin Synthase
Authors: Nar Herbert 
Published: April 2006

AbstractThe 6‐pyruvoyl‐tetrahydropterin synthase (PTPS), a zinc‐dependent, heat‐stable, homohexameric protein complex of approximately 90 kDa molecular weight catalyzes the conversion of dihydroneopterin triphosphate to 6‐pyruvoyl‐tetrahydropterin, the second of three enzymatic steps in the synthesis of tetrahydrobiopterin from GTP.The 6‐pyruvoyl‐tetrahydropterin synthetase monomer forms a compact, single‐domain α + β structure containing a sequential, four‐stranded, antiparallel β‐sheet. Oligomerization occurs through association of monomers via their β‐sheets that form a 12‐stranded β‐barrel structure that is duplicated in the functional hexameric form via a head‐to‐head association of two trimers.The PTPS active site is a 12‐Å deep cavity that is located on the interface of three monomers, two from one trimer and one subunit from the other trimer. The Zn(II) binding site is located at the center of the cavity. The transition metal is bound to the NE2 atoms of the three histidine residues. The role of the catalytic metal is to correctly position the substrate, to polarize the carbon–oxygen bonds for facile proton release from the substrate, and to prevent cleavage of the C1′‐C2′ substrate side‐chain bond.In addition, PTPS contains an intersubunit catalytic triad motif composed of the amino acid residues CysA42, HisB89, and AspB88 from two neighboring monomers (A and B) that putatively function as a relay system for proton abstraction from substrate and reaction intermediate. Residue GluA133 may represent the key residue for the stereospecificity of the catalyzed reaction.
Cys2His2Zinc Finger Proteins
Authors: Laity John H 
Published: April 2006

AbstractThe Cys2His2(C2H2) zinc finger is one of the simplest independently folded structural domains known, yet the number of proteins with distinct and complex functions that contain the motif is too large to count. The domain consists of a small antiparallel β‐sheet and a single helix that contribute two cysteine and two histidine ligands respectively to coordinate a central Zn(II) ion in a nearly perfect tetrahedral geometry. The C2H2 zinc finger is one of the major DNA binding motifs in eukaryotic transcription factors, and probably the most common protein motif in the human genome. DNA sequence specificity is achieved through residue side‐chain contacts to DNA bases that occur at preferential residue positions located in the N‐terminal region of the zinc finger helix (‘fingertip’) that reside primarily on one surface of the domain. Functional specificity and diversity of C2H2 zinc finger proteins are, paradoxically, both achieved through tandem repeats of the motif separated by short, conserved peptide linkers, where each individual finger is capable of recognizing a distinct DNA subsite. Diversity of the C2H2 motif extends beyond DNA recognition to protein–RNA and protein–protein interactions, although these functions are not well understood. Since the first reported structure of a single finger almost 15 years ago, over 40 C2H2 zinc finger structures have been reported both free and bound to DNA. Detailed molecular aspects of C2H2 zinc finger structure, function, and metal binding are examined.
Leishmanolysin
Authors: Metcalf Peter , Etges Robert 
Published: April 2006

AbstractLeishmanolysin is a major surface antigen of the promastigote insect form of the parasitic protozoanLeishmania, and is thought to play a role preventing complement‐mediated lysis after infection of the mammalian host by the sand fly vector. Leishmanolysin is a ∼52 kDa membrane‐bound neutral zinc proteinase of the metzincin class, with some resemblance to collagenase in the active site region. Leishmanolysin can be inhibited by collagenase inhibitors but it does not cleave native collagen. Thein vivosubstrates have not been determined. The crystal structure, determined using protein purified fromLeishmania majorpromastigotes, revealed three domains where the N‐terminal domain has a similar fold to the catalytic domains of zinc proteinases and the central and cysteine‐rich C‐terminal domains have novel folds. The active site is located in a cleft between the N‐terminal and central domains. The molecule is attached to the outer membrane of the promastigote via a C‐terminal‐linked GPI anchor.
3
D
Structures of the Calcium and Zinc Binding
S
100 Proteins
Authors: Fritz Günter , Heizmann Claus W 
Published: April 2006

Abstract

S100 proteins are involved in many cellular processes such as cell growth and motility, cell cycle regulation, transcription, and differentiation. Twenty members have been discovered so far, and altogether, S100 proteins represent the largest subgroup within the EF‐hand Ca
2+
‐protein family. In resting cells, S100 proteins are localized in specific cellular compartments from which they relocate upon activation, hereby transducing the Ca
2+
/Zn
2+
signals by interacting with various target proteins. Some members are even secreted from cells exerting extracellular, cytokine‐like activities by interacting with the surface receptor RAGE.
Dockerin Domains
Authors: Volkman Brian F , Lytle Betsy L , David Wu J H 
Published: April 2006

Abstract
Bacterial protein domains known as dockerins serve as anchoring or tethering modules for the assembly of large extracellular cellulase complexes called cellulosomes. Dockerins function through interactions with another class of protein‐interaction module, the cohesins, and both domain families are currently divided into two subclasses (type I and type II) originally based on binding specificity. Dockerin sequences contain a pair of 22‐residue motifs with homology to calcium‐binding loops of the EF‐hand family. When exposed to calcium, the dockerin adopts a novel fold distinct from EF‐hand proteins that binds its cognate cohesin with high affinity. Conversely, in the absence of calcium, the dockerin domain is unfolded and does not bind cohesin. Thus, dockerin domains serve as calcium‐regulated mediators of protein complex formation. Analysis of conserved sequence features in the context of the three‐dimensional dockerin structure may identify elements that confer class and species specificity of dockerin–cohesin binding reactions.
Calsequestrin
Authors: Kang ChulHee 
Published: April 2006

Abstract

The contraction/relaxation of the muscle cell is controlled by the transient increase/decrease of Ca
2+
concentration. A large fraction of this Ca
2+
is stored in and released from the sarcoplasmic reticulum (SR) by the presence of high concentrations of an acidic protein, calsequestrin, in the lumen of the junctional terminal cisternae of SR. Calsequestrin binds and releases large quantities of Ca
2+
ion rapidly: about 40 to 50 ions per molecule with a binding constant of approximately 1 mM under physiological conditions. The cation binding by calsequestrin is nonspecific and the Ca
2+
binding sites incorporate the numerous acidic residues that comprise over one‐third of the total residues. The crystal structure of calsequestrin shows that it is made up of three domains, each with a thioredoxin fold. Ca
2+
ions are bound on the protein surface and between domains. Two distinct dimerization contacts in calsequestrin crystals suggested a mechanism for Ca
2+
regulation resulting from the occurrence of coupled Ca
2+
binding and protein polymerization. Ca
2+
‐induced formation of one contact was proposed to lead to dimerization followed by Ca
2+
‐induced formation of the second contact to bring about polymerization. Strong cooperative calcium binding accompanies the polymerization of calsequestrin into insoluble, extended, and often needle‐like structures. The polymerization of calsequestrin also provides a highly charged surface onto which calcium is adsorbed. A sparingly soluble ion such as Ca
2+
would tend to spread over the surface of the polymer, forming a readily exchangeable film. The propensity of Ca
2+
‐bound calsequestrin to form linear structures would make Ca
2+
dissociation and diffusion a more rapid event.
The Superfamily of Cadherins: Calcium‐Dependent Cell Adhesion Receptors
Authors: Ahrens Thomas , Stetefeld Jörg , Häussinger Daniel , Engel Jürgen 
Published: April 2006

AbstractSpecific cell–cell contacts are important in tissue morphogenesis, development, and during signal transduction of vertebrates as well as invertebrates. Cadherins are cell‐surface transmembrane receptors that mediate such specific, homotypic cell–cell adhesion. The adhesive activity of cadherins requires calcium binding by the ectodomain of the protein. The extracellular part of cadherins is composed of different numbers of individually folding cadherin repeats (CAD). Calcium binding pockets are located in the interdomain sections and conserved peptide sequences in consecutive domains are involved in coordination of three calcium ions per binding pocket. Low‐ and high‐affinity calcium binding sites have been detected and binding constants in the micromolar (Kd = 30–330 µM) to millimolar (Kd = 2 mM) range were determined. When calcium is added to purified cadherin ectodomains, rigidification and conformational changes are observed, exposing interaction surfaces that are involved in homoassociation of cadherins. This review summarizes electron micrographic, crystallographic, and recent NMR data analyzing the molecular details and functional consequences of calcium binding by cadherins.
Mitochondrial Cytochrome

c

Oxidase
Authors: Yoshikawa Shinya , Shinzawa‐Itoh Kyoko , Yamashita Eiki , Tsukihara Tomitake 
Published: April 2006

Abstract

Cytochrome
c
oxidase reduces molecular oxygen (O
2
) to water (coupled with proton pumping) at its O
2
reduction site composed of an iron ion (heme
a
3
) and a copper ion (Cu
B
) by electrons transferred from cytochrome
c
in the intermembrane space by Cu
A
and heme
a
in the enzyme protein and by protons from the matrix space. Mitochondrial cytochrome
c
oxidase, isolated from bovine heart muscle as early as in 1941, was crystallized to determine the X‐ray structure at 2.3/2.35 Å resolutions in the fully oxidized/reduced states in 1998, showing 13 different subunits and Cu
B
, liganded with three histidine imidazole groups in a trigonal‐planer coordination in the fully reduced state. A tyrosine phenol group is fixed close to the O
2
reduction site with a covalent link with one of the three imidazole groups. This O
2
reduction site structure suggests that Fe

a
3

O
2
and Fe

a
3

OOH are stable and unstable, respectively, to form FeO as the second intermediate in the O
2
reduction process, consistent with the resonance Raman results for the process. A fairly big redox‐coupled X‐ray structural change in an aspartate (Asp51) located near the intermembrane surface of the enzyme molecule suggesting a large redox‐coupled pKa change in Asp51 and a hydrogen bond network connecting Asp51 with the matrix surface indicate that Asp51 is the site for proton pumping. A peptide bond in the hydrogen bond network facilitates the unidirectional proton transfer through the hydrogen bond network up to Asp51.
ba3‐CytochromecOxidase FromThermus Thermophilus
Authors: Than Manuel E , Soulimane Tewfik 
Published: April 2006

Abstractba3‐Cytochromecoxidase fromThermus thermophilusis a terminal enzyme of respiration that catalyzes the reduction of dioxygen to water. It is produced at low oxygen tension and is one of the most divergent members of the heme–copper oxidase superfamily.ba3‐Oxidase has been isolated fromT. thermophilusmembranes, purified and characterized using several biochemical and biophysical techniques. Its crystal structure has been solved at high resolution. The current review summarizes the results on structure and function relationship ofba3‐oxidase that have been elucidated during the last decade.