bluuebunny/crossref_metadata_2025 huggingface dataset:
Eukaryotic cells are dynamically ordered or critical but not chaotic
Authors: Shmulevich Ilya , Kauffman Stuart A. , Aldana Maximino
Published: September 2005

Two important theoretical approaches have been developed to generically characterize the relationship between the structure and function of large genetic networks: The continuous approach, based on reaction-kinetics differential equations, and the Boolean approach, based on difference equations and discrete logical rules. These two approaches do not always coincide in their predictions for the same system. Nonetheless, both of them predict that the highly nonlinear dynamics exhibited by genetic regulatory systems can be characterized into two broad regimes, to wit, an ordered regime where the system is robust against perturbations, and a chaotic regime where the system is extremely sensitive to perturbations. It has been a plausible and long-standing hypothesis that genomic regulatory networks of real cells operate in the ordered regime or at the border between order and chaos. This hypothesis is indirectly supported by the robustness and stability observed in the phenotypic traits of living organisms under genetic perturbations. However, there has been no systematic study to determine whether the gene-expression patterns of real cells are compatible with the dynamically ordered regimes predicted by theoretical models. Using the Boolean approach, here we show what we believe to be the first direct evidence that the underlying genetic network of HeLa cells appears to operate either in the ordered regime or at the border between order and chaos but does not appear to be chaotic.
Expression of the immunoregulatory molecule FcRH4 defines a distinctive tissue-based population of memory B cells
Authors: Ehrhardt Götz R.A. , Hsu Joyce T. , Gartland Lanier , Leu Chuen-Miin , Zhang Shuangyin , Davis Randall S. , Cooper Max D.
Published: September 2005

The FcRH4 transmembrane molecule, a member of the Fc receptor homologue family, can potently inhibit B cell receptor (BCR) signaling. We show that cell surface expression of this immunoregulatory molecule is restricted to a subpopulation of memory B cells, most of which lack the classical CD27 marker for memory B cells in humans. The FcRH4+ and FcRH4− memory B cells have undergone comparable levels of immunoglobulin isotype switching and somatic hypermutation, while neither subpopulation expresses the transcription factors involved in plasma cell differentiation. The FcRH4+ memory cells are morphologically distinctive large lymphocytes that express the CD69, CD80, and CD86 cell activation markers. They are also shown to be poised to secrete high levels of immunoglobulins in response to stimulation with T cell cytokines, but they fail to proliferate in response either to BCR ligation or Staphylococcus aureus stimulation. A heightened expression of the CCR1 and CCR5 chemokine receptors may facilitate their preferential localization in lymphoid tissues near epithelial surfaces. Cell surface FcRH4 expression thus marks a unique population of memory B cells with distinctive morphology, functional capabilities, and tissue localization.
Does the 23‐Valent Pneumococcal Vaccine Protect Cochlear Implant Recipients?
Authors: Hey Christiane , Rose Markus A. , Kujumdshiev Sandy , Gstoettner Wolfgang , Schubert Ralf , Zielen Stefan
Published: September 2005

Objectives/Hypothesis: The incidence of meningitis is increased in cochlear implant (CI) recipients. Besides malformations, immunological deficiencies are predisposing factors. Therefore, the immunological background of CI recipients and the immunogenicity of the recommended 23‐valent pneumococcal polysaccharide vaccine (PPV‐23) were investigated.

Study Design: Prospective study in a tertiary care referral center.

Methods: One hundred twenty CI recipients who were at least 5 years of age were vaccinated with PPV‐23. Levels of immunoglobulins G, A, and M (IgG, IgA, and IgM, respectively) and IgG subclasses IgG1–IgG4 before vaccination and serum concentrations of antibodies against seven pneumococcal serotypes before and 4 weeks after vaccination were determined. The cohort was subdivided by patient age into groups A1 (5–8 y), A2 (8–12 y), and A3 (>12 y).

Results: Geometric mean concentrations of pneumococcal antibodies before vaccination were remarkably low in all three groups, emphasizing the importance of vaccination in this risk group. All groups showed a statistically significant increase in geometric mean concentrations after immunization. For group A1 compared with groups A2 and A3, response was limited, especially for serotypes 6B (geometric mean concentration, 1.71 μg/mL; P = .0007), 23F (geometric mean concentration, 2.28 μg/mL; P = .04), and 14 (geometric mean concentration, 3.98 μg/mL; P = .0004). The percentages of patients reaching the presumed protective threshold of at least 1 μg/mL pneumococcal antibody concentration were at least 71.1% in group A1, 93.8% in group A2, and 90.5% in group A3. This raises the question of whether PPV‐23 evokes satisfying seroprotection in CI recipients younger than 8 years of age.

Conclusion: With regard to the increased risk for bacterial meningitis, the authors recommend priming CI recipients younger than 8 years of age with pneumococcal conjugate vaccine followed by a PPV‐23 booster.
MED‐EL Combi40+ Cochlear Implantation in Adults
Authors: Bassim Marc K. , Buss Emily , Clark Marcia S. , Kolln Karen A. , Pillsbury Carol H. , Pillsbury Harold C. , Buchman Craig A.
Published: September 2005

Objective/Hypothesis: Cochlear implantation is currently the treatment of choice for severe to profound sensorineural hearing loss. The MED‐EL Combi40+ (Innsbruck, Austria) cochlear implant system was approved for use in the United States in 2001. This device employs a 31‐mm‐long electrode array, ceramic case, and continuous interleaved sampling with Hilbert transformation for envelope extraction. A single institution's experience with the Combi40+ implant in adult patients was reviewed.

Study Design: Retrospective chart review.

Methods: Medical‐surgical and audiological data were collected from 112 patients who received a MED‐EL Combi40+ cochlear implant between December 1998 and April 2004.

Results: The rate of surgical complications and speech perception testing results compared favorably with those of other cochlear implant systems. For postlingually deafened adults, mean CNC word, HINTQ, CUNY, and HINT + 10 dB signal‐to‐noise ratio scores after 1 year of implant usage were 54%, 87%, 96%, and 64%, respectively. Prelingually deafened adults also derived significant benefit, but plateau performance for these patients was well below that for patients with later onset of deafness and significant variability was seen in this group. Repeat implantation for suspected device malfunction was undertaken in seven cases (6% of devices) (mean duration of use, 28 ± 12 mo) with ultimate resolution of the presenting problem.

Conclusion: The study results support the safety and efficacy of cochlear implantation with the MED‐EL Combi40+ cochlear implant system.
Dilatation for Assisted Ventilation‐Induced Laryngotracheal Stenosis
Authors: Clément Philippe , Hans Stéphane , de Mones Erwan , Sigston Elizabeth , Laccourreye Ollivier , Brasnu Daniel
Published: September 2005

Objective: To assess the long‐term results of dilatation and our experience with dilatation for assisted ventilation‐induced laryngotracheal stenosis.

Design: A retrospective study of 32 patients primarily treated with dilatation for assisted ventilation‐induced laryngotracheal stenosis between 1977 and 2002.

Setting: A tertiary care center and university teaching hospital.

Patients: There were 19 men and 13 women aged 15 to 76 years. The stenosis was cicatricial with some inflammatory process in 27 patients and completely mature in 5 patients. The stenosis involved the cricoid and the trachea in four patients. In 28 patients, the stenosis involved only the trachea.

Methods: Dilatation was performed with serially sized rigid bronchoscopes. Endoscopic laser vaporization was never performed in this series. Six patients were treated with only one dilatation. The 26 remaining patients were treated with successively 2 to 10 dilatations (mean, 3.3 dilatations). The dilatation success rate was analyzed using the Kaplan‐Meier method.

Results: Median duration of follow‐up was 1.8 years. Mortality rate was 9.4%. The overall failure rate was 71.8%. Twenty patients presented with recurrent stenosis. The treatment of recurrent stenosis consisted of tracheal resection with end‐to‐end anastomosis (11 patients, 55%), cricotracheal anastomosis (5 patients, 25%), tracheal endoprosthesis (2 patients, 10%), and tracheotomy (1 patient, 5%). All patients who underwent tracheal or cricotracheal anastomosis were successfully treated. None of the variables under analysis (sex, age, medical history, cause for intubation, intubation type and duration, delay from initial injury, degree of stenosis, length of trachea involved, number of dilatations) were statistically related to the incidence of complications and the success rate of dilatations.

Conclusions: We do not recommend dilatation technique as the sole treatment for assisted ventilation‐induced laryngotracheal stenosis. This technique is helpful in case of emergency to restore an airway and useful for the assessment of stenosis.
Ligasure versus Cold Knife Tonsillectomy
Authors: Lachanas Vassilios A. , Prokopakis Emmanuel P. , Bourolias Constantinos A. , Karatzanis Alexander D. , Malandrakis Stylianos G. , Helidonis Emmanuel S. , Velegrakis George A.
Published: September 2005

Objective: To assess parameters related to ligasure tonsillectomy (LT) versus cold knife tonsillectomy (CKT) procedure.

Study Design: Prospective randomized study.

Methods: A prospective study was conducted on 200 consecutive adult patients undergoing tonsillectomy. Indications included chronic tonsillitis and obstructive sleep apnea syndrome. Patients undergoing adenoidectomy, or any procedure together with tonsillectomy, and patients with peritonsillar abscess history or bleeding disorders were excluded. Patients were randomly assigned to either the LT or CKT group. Intraoperative bleeding, operative time, postoperative pain using a visual analogue scale, and complication rates were evaluated.

Results: The LT and CDT groups consisted of 108 and 92 individuals, respectively. In the LT group, there was no measurable intraoperative bleeding, whereas mean bleeding for CKT group was 125 mL. The mean operative time was 15 ± 1.43 minutes for the LT group and 21 ± 1.09 minutes for the CKT group (P < .001). The overall mean pain score for the LT group was 3.63, whereas for the CKT group it was 5.09 (P < .001). Primary hemorrhage occurred in one subject of the CKT group. Secondary postoperative hemorrhage was noticed two subjects of the LT group and two subjects of the CKT group. In 21 subjects of the LT group, limited peritonsillar edema was noticed. No other complication occurred in both groups.

Conclusion: LT procedure provides sufficient hemostasis, lower postoperative pain, and reduced operative time, as well as safety against Creutzfeld Jakob disease transmission.
Lymph Node Metastases from Cutaneous Squamous Cell Carcinoma of the Head and Neck
Authors: Moore Brian A. , Weber Randal S. , Prieto Victor , El‐Naggar Adel , Holsinger F Christopher , Zhou Xian , Lee J Jack , Lippman Scott , Clayman Gary L.
Published: September 2005

Objective/Hypothesis: Cutaneous squamous cell carcinoma (CSCC) has been reported to metastasize to parotid and cervical lymph nodes. Few prospective investigations of associated clinical and histopathologic findings and their effect on patient outcomes exist. We seek to identify risk factors for nodal metastases in CSCC and determine the impact of lymphatic spread on survival and recurrence.

Study Design: Subset analysis of a prospective, longitudinal database of patients with CSCC at a comprehensive cancer center.

Methods: Eligible patients with nonmelanoma skin cancer were consecutively enrolled in a prospective database from July 1996 through June 2001; this cohort was then followed to the key endpoints of recurrence and mortality.

Results: Two hundred ten patients were enrolled, and 193 patients with CSCC of the head and neck are included in this analysis. The incidence of nodal metastases in this population was 20.7% at study entry. Median follow‐up was 20 months in patients with lymph node metastases and 24 months in patients without metastases. Nodal metastases were significantly associated with recurrent lesions (P = .002) and the following histopathologic features: lymphovascular invasion (P < .0001), inflammation (P = .010), poorly differentiated histology (P = .001), invasion into the subcutaneous tissues (P = .0001), perineural invasion (P = .005), and larger size (P = .0007). Metastases to the cervical nodes were not clinically apparent in 42% of patients with parotid metastases. Combination surgery and radiation therapy resulted in regional control rates of 95%, although local recurrence and distant metastases, along with second primary tumors, were the most frequent recurrent events. Kaplan‐Meier survival analysis demonstrates a decrease in overall survival (P = .005), disease‐free survival (P = .015), disease‐specific survival (P = 0002), and time to recurrence (P = .012) in patients with nodal metastases compared with controls.

Conclusions: Lymph node metastases from CSCC are common in our population and are associated with diminished survival. The presence of nodal spread occurs with other adverse histopathologic findings, and we recommend surgery and postoperative radiation therapy to control regional disease in the presence of nodal metastases and perineural invasion. New approaches in early identification of nodal metastases, treatment, and prevention of local recurrences and second primary malignancies are warranted.
Microdebriders Used in Functional Endoscopic Sinus Surgery: Secondary Analysis and Validation of a New Tissue Model
Authors: Dave Sandeep P. , Polak Marek , Casiano Roy R.
Published: September 2005

Objectives/Hypothesis: To validate a previously reported in vitro tissue model for microdebrider comparison and determine which microdebrider, tissue type, blade type, and suction strength is most efficient. Specifically, the goal of the secondary analysis is to expand on the results of the preliminary analy‐sis by increasing the sample size, and introduce an aspiration efficiency score (AES) to facilitate microdebrider comparison.

Study Design: Prospective randomized comparison.

Methods: A prospective randomized comparison of the Diego Powered Dissector and XPS 3000 Powered ENT System was conducted using a soft tissue and a firm tissue model. In addition to evaluating tissue aspiration with straight and angled blades, clogging rates and clearance times were measured. Both standard wall suction and liposuction were used. Basic statistical analysis, a one‐way analysis of variance, and a post hoc Student's t test were performed to compare outcomes.

Results: With standard wall suction, the microdebriders were equivalent for the overall microdebrider comparison. For the “head to head” comparison with standard wall suction, the devices were also equivalent when using the straight blades, but the XPS 3000 aspirated more tissue when using the angled blades. With liposuction, the XPS 3000 and liposuction independently aspirated more tissue but clogged more often compared with the Diego PD and regular suction. The aspiration efficiency of soft tissue (oysters) and straight blades was superior compared with firm tissue (scallops) and angled blades. For the “head to head” comparison with liposuction, the XPS 3000 aspirated more tissue regardless of tissue type, but the Diego PD clogged less with firm tissue (scallops). Overall, the AES favored the XPS 3000, soft tissue (oysters), straight blades, and liposuction.

Conclusion: Our tissue model represents a reliable and reproducible means of microdebrider comparison. Statistically significant differences between the Diego PD and XPS 3000, as well as between tissue types, blade types, and suction strengths, are reported. Using these results, microdebrider manufacturers can adopt similar tissue models, expand on the current AES, and include other commercially available microdebrider devices to test and report product performance to the consumer. Perhaps an optimal open to closed ratio or liposuction pressure can be determined that yields the greatest tissue aspiration with the fewest number of clogs.
Clinical Features of Sudden Sensorineural Hearing Loss in Diabetic Patients
Authors: Weng Shuen‐Fu , Chen Yuh‐Shyang , Hsu Chuan‐Jen , Tseng Fen‐Yu
Published: September 2005

Objectives: Clinical studies of sudden sensorineural hearing loss (SSNHL) rarely focus on diabetic patients. We attempted to elucidate the clinical features of SSNHL in diabetic patients and to evaluate the factors influencing hearing deficits.

Study Design: Retrospective.

Methods: A retrospective review of diabetic patients with SSNHL was conducted at National Taiwan University Hospital from 1984 to 2003. The demographic and clinical characteristics, audiometries, and course of hearing recovery were reviewed.

Results: Sixty‐seven patients (38 men and 29 women) with a mean age of 60.1 ±11.9 years were recruited. The mean duration of diabetes was 7. 5 ± 7.7 years. The mean fasting plasma glucose (FPG), postprandial plasma glucose (PPG), and glycosylated hemoglobin (HbA1C) at admission were 12.4 ± 5.3 mmol/L, 14.5 ± 5.4 mmol/L, and 9.9 ± 2.9 mmol/L, respectively. Profound hearing loss was very common in this series (44.8%). Hearing impairment was also noted in the opposite ear, especially in the high frequencies. Presenting symptoms, the duration of diabetes, the FPG, and the HbA1C had no significant correlations with the severity of hearing loss. After adjusting for sex and age, a high PPG level was significantly associated with opposite‐ear hearing deficits in the middle frequencies. In follow‐up, the low and middle tone hearing thresholds in the lesion ears improved more than that at high frequencies, but they still did not return to baseline. Hearing consistently improved within 2 months after disease onset, but improvements were rare thereafter. With suitable treatment, optimal glycemic control could be achieved even under high‐dose steroid regimens.

Conclusions: In diabetic patients with SSNHL, hearing loss in the contralateral ear and the profound type hearing loss in the lesion ear were commonly noted. The age and PPG level had significant correlations to contra‐ear hearing loss. The poor prognosis of sudden deafness in diabetes patients may be caused by preexisting microvascular lesions in the inner ear, and the PPG level could be a risk factor indicator for cochlear dysfunction in diabetic patients. High‐dose glucocorticoid should not be contraindicant in diabetic patients with SSNHL. Whether a longer duration of treatment will result in more hearing improvement is worthy of further study.
Management of Contralateral N0 Neck in Tonsillar Squamous Cell Carcinoma
Authors: Lim Young Chang , Lee Sei Young , Lim Jae‐Yol , Shin Hyang Ae , Lee Jin Seok , Koo Bon Seok , Kim Se‐Heon , Choi Eun Chang
Published: September 2005

Objectives: It is well established that tonsillar squamous cell carcinomas have a high probability of disseminating to the neck. An ipsilateral neck treatment is mandatory during initial treatment of stages II to IV tonsillar carcinomas. However, as of yet, no consensus exists whether to perform elective contralateral neck management.

Materials and Methods: A retrospective analysis of 43 N0‐3 tonsillar cancer patients with contralateral clinically negative necks from 1992 to 2002 was performed. All patients had a contralateral elective neck dissection. Surgical treatment was followed by postoperative radiotherapy in 33 patients. The follow‐up period ranged from 2 to 120 (mean 38) months. The Kaplan‐Meier method and log‐rank test were used to calculate the disease‐specific survival rates and prognostic significance of contralateral occult lymph node metastasis.

Results: Clinically negative, but pathologically positive, contralateral lymph nodes occurred in 16% (7 of 43). Of the 33 cases with an ipsilateral node positive neck, contralateral occult lymph node metastases developed in 21% (7 of 33), in contrast with 0% in ipsilateral N0 necks. On the basis of the clinical staging of the tumor, 5% (1 of 22) of the cases showed lymph node metastases in T2 tumors, 36% (5 of 14) in T3, and 25% (1 of 4) in T4. None of the T1 tumors (3 cases) had pathologically positive lymph nodes (T1 + T2 vs. T3 + T4, P < .05). Patients with no evidence of contralateral nodal cancer had significantly improved disease‐specific survival over patients with any pathologically positive nodes (5 year disease‐specific survival rate 92% vs. 28%, P = < .05).

Conclusion: The risk of contralateral occult neck involvement in above T3 staged tonsillar squamous cell carcinomas with unilateral metastases was high (approximately 21%), and patients who present with a contralateral metastatic neck have a worse prognosis than those who are staged as N0. Therefore, we advocate an elective contralateral neck treatment in tonsillar squamous cell carcinoma patients with ipsilateral node metastases.
Psb29, a Conserved 22-kD Protein, Functions in the Biogenesis of Photosystem II Complexes in Synechocystis and Arabidopsis
Authors: Keren Nir , Ohkawa Hiroshi , Welsh Eric A. , Liberton Michelle , Pakrasi Himadri B.
Published: September 2005

Photosystem II (PSII), the enzyme responsible for photosynthetic oxygen evolution, is a rapidly turned over membrane protein complex. However, the factors that regulate biogenesis of PSII are poorly defined. Previous proteomic analysis of the PSII preparations from the cyanobacterium Synechocystis sp PCC 6803 detected a novel protein, Psb29 (Sll1414), homologs of which are found in all cyanobacteria and vascular plants with sequenced genomes. Deletion of psb29 in Synechocystis 6803 results in slower growth rates under high light intensities, increased light sensitivity, and lower PSII efficiency, without affecting the PSII core electron transfer activities. A T-DNA insertion line in the PSB29 gene in Arabidopsis thaliana displays a phenotype similar to that of the Synechocystis mutant. This plant mutant grows slowly and exhibits variegated leaves, and its PSII activity is light sensitive. Low temperature fluorescence emission spectroscopy of both cyanobacterial and plant mutants shows an increase in the proportion of uncoupled proximal antennae in PSII as a function of increasing growth light intensities. The similar phenotypes observed in both plant and cyanobacterial mutants demonstrate that the function of Psb29 has been conserved throughout the evolution of oxygenic photosynthetic organisms and suggest a role for the Psb29 protein in the biogenesis of PSII.
SUPPRESSOR OF FRIGIDA3Encodes a Nuclear ACTIN-RELATED PROTEIN6 Required for Floral Repression inArabidopsis w⃞
Authors: Choi Kyuha , Kim Sanghee , Kim Sang Yeol , Kim Minsoo , Hyun Youbong , Lee Horim , Choe Sunghwa , Kim Sang-Gu , Michaels Scott , Lee Ilha
Published: September 2005

Flowering traits in winter annual Arabidopsis thaliana are conferred mainly by two genes, FRIGIDA (FRI) and FLOWERING LOCUS C (FLC). FLC acts as a flowering repressor and is regulated by multiple flowering pathways. We isolated an early-flowering mutant, suppressor of FRIGIDA3 (suf3), which also shows leaf serration, weak apical dominance, and infrequent conversion of the inflorescence shoot to a terminal flower. The suf3 mutation caused a decrease in the transcript level of FLC in both a FRI-containing line and autonomous pathway mutants. However, suf3 showed only a partial reduction of FLC transcript level, although it largely suppressed the late-flowering phenotype. In addition, the suf3 mutation caused acceleration of flowering in both 35S-FLC and a flc null mutant, indicating that SUF3 regulates additional factor(s) for the repression of flowering. SUF3 is highly expressed in the shoot apex, but the expression is not regulated by FRI, autonomous pathway genes, or vernalization. SUF3 encodes the nuclear ACTIN-RELATED PROTEIN6 (ARP6), the homolog of which in yeast is a component of an ATP-dependent chromatin-remodeling SWR1 complex. Our analyses showed that SUF3 regulates FLC expression independent of vernalization, FRI, and an autonomous pathway gene, all of which affect the histone modification of FLC chromatin. Subcellular localization using a green fluorescent protein fusion showed that Arabidopsis ARP6 is located at distinct regions of the nuclear periphery.
The Flowering Integrator FT RegulatesSEPALLATA3andFRUITFULLAccumulation inArabidopsisLeaves
Authors: Teper-Bamnolker Paula , Samach Alon
Published: September 2005

The transition to flowering involves major changes in the shoot apical meristem and in the fate of existing leaf primordia. Transcripts of the Arabidopsis thaliana flowering-promoting gene FLOWERING LOCUS T (FT) are present in leaf tissue but can also promote flowering when artificially introduced into the meristem. FT may normally act in the leaf and/or the meristem, initiating or constituting a mobile flower-promoting signal. We studied FT-dependent events in the rosette leaf, some of which might precede or mimic events in the meristem and its primordia. We show FT-dependent transcript accumulation of the MADS box transcription factors FRUITFULL (FUL) and SEPALLATA3 (SEP3) in leaves. Abnormally high levels of FT further increase the expression of these genes, leading to morphological changes in the leaves. Loss of the flowering-time gene FD, as well as environmental conditions that delay flowering, reduce FT's effect on leaves via reduced activation of its targets. FUL, SEP3, and APETALA1 accumulation in the meristem is associated with and contributes to the transition to flowering. We propose that FT functions through partner-dependent transcriptional activation of these and as-yet-unknown genes and that this occurs at several sites. Organ fate may depend on both degree of activation and the developmental stage reached by the organ before activation occurs.
Prediction of protein thermostability with a direction‐ and distance‐dependent knowledge‐based potential
Authors: Hoppe Christian , Schomburg Dietmar
Published: September 2005

The increasing use of enzymes in industrial processes and the importance of understanding protein folding and stability have led to several attempts to predict and quantify the effect of every possible amino acid exchange (mutation) on the thermostability of proteins. In this article we describe a knowledge‐based discrimination function that acts as a fast and reliable guide in protein engineering and optimization. The function used consists of two parts, a pairwise energy function based on a distance‐ and direction‐dependent atomic description of the amino acid environment, and a torsion angle energy function. In a first step a training set of 11 proteins including 646 mutant proteins with experimentally determined thermostability was used to optimize the knowledge‐based energy functions. The resulting potential function was then tested using a test mutant database consisting of 918 various point mutations introduced in 27 proteins. The best correlation coefficient obtained for the experimental data and the predicted thermostability for the training set is r = 0.81 (561 data points). A total of 76% of the mutations could be predicted correctly as being either stabilizing or destabilizing. The results for the test set are r = 0.74 (747 data points) and 72%, respectively. The global correlation over the combined data (1308 mutants) obtained is 0.78.
Three‐state protein folding: Experimental determination of free‐energy profile
Authors: Baryshnikova Ekaterina N. , Melnik Bogdan S. , Finkelstein Alexei V. , Semisotnov Gennady V. , Bychkova Valentina E.
Published: September 2005

When considering protein folding with a transient intermediate, a difficulty arises as to determination of the rates of separate transitions. Here we overcome this problem, using the kinetic studies of the unfolding/refolding reactions of the three‐state protein apomyoglobin as a model. Amplitudes of the protein refolding kinetic burst phase corresponding to the transition from the unfolded (U) to intermediate (I) state, that occurs prior to the native state (N) formation, allow us to estimate relative populations of the rapidly converting states at various final urea concentrations. On the basis of these proportions, a complicated experimental chevron plot has been deconvolved into the urea‐dependent rates of the I↔N and U↔N transitions to give the dependence of free energies of the main transition state and of all three (N, I, and U) stable states on urea concentration.
Effect of hexafluoroisopropanol alcohol on the structure of melittin: A molecular dynamics simulation study
Authors: Roccatano Danilo , Fioroni Marco , Zacharias Martin , Colombo Giorgio
Published: September 2005

The molecular mechanism by which HFIP stabilizes the α‐helical structure of peptides is not well understood. In the present study, we use melittin as a model to gain insight into the details of the atomistic interactions of HFIP with the peptide. We have performed extensive comparative molecular dynamics simulations (up to 100 nsec) in the absence and in the presence of HFIP. In agreement with recent NMR experiments, the simulations show rapid loss of tertiary structure in water at pH 2 but much higher helicity in 35% HFIP. The MD simulations also indicate that melittin adopts a highly dynamic global structure in 35% HFIP solution with two α‐helical segments sampling a wide range of angular orientations. The analysis of the HFIP distribution shows the tendency of HFIP to aggregate around the peptide, increasing the local cosolvent concentration to more than two times that in the bulk concentration. The correlation of local peptide structure with HFIP coating suggests that displacement of water at the peptide surface is the main contribution of HFIP in stabilizing the secondary structure of melittin. Finally, a stabilizing effect promoted by the presence of counter‐ions was also observed in the simulations.
Organism complexity anti‐correlates with proteomic β‐aggregation propensity
Authors: Tartaglia Gian Gaetano , Pellarin Riccardo , Cavalli Andrea , Caflisch Amedeo
Published: September 2005

We introduce a novel approach to estimate differences in the β‐aggregation potential of eukaryotic proteomes. The approach is based on a statistical analysis of the β‐aggregation propensity of polypeptide segments, which is calculated by an equation derived from first principles using the physicochemical properties of the natural amino acids. Our analysis reveals a significant decreasing trend of the overall β‐aggregation tendency with increasing organism complexity and longevity. A comparison with randomized proteomes shows that natural proteomes have a higher degree of polarization in both low and high β‐aggregation prone sequences. The former originates from the requirement of intrinsically disordered proteins, whereas the latter originates from the necessity of proteins with a stable folded structure.
Crystal lattice as biological phenotype for insect viruses
Authors: Anduleit Karin , Sutton Geoff , Diprose Jonathan M. , Mertens Peter P.C. , Grimes Jonathan M. , Stuart David I.
Published: September 2005

Many insect viruses survive for long periods by occlusion within robust crystalline polyhedra composed primarily of a single polyhedrin protein. We show that two different virus families form polyhedra which, despite lack of sequence similarity in the virally encoded polyhedrin protein, have identical cell constants and a body‐centered cubic lattice. It is almost inconceivable that this could have arisen by chance, suggesting that the crystal lattice has been preserved because it is particularly well‐suited to its function of packaging and protecting viruses.
Structural characterization of Lyn‐SH3 domain in complex with a herpesviral protein reveals an extended recognition motif that enhances binding affinity
Authors: Bauer Finn , Schweimer Kristian , Meiselbach Heike , Hoffmann Silke , Rösch Paul , Sticht Heinrich
Published: September 2005

The Src homology 3 (SH3) domain of the Src family kinase Lyn binds to the herpesviral tyrosine kinase interacting protein (Tip) more than one order of magnitude stronger than other closely related members of the Src family. In order to identify the molecular basis for high‐affinity binding, the structure of free and Tip‐bound Lyn‐SH3 was determined by NMR spectroscopy. Tip forms additional contacts outside its classical proline‐rich recognition motif and, in particular, a strictly conserved leucine (L186) of the C‐terminally adjacent sequence stretch packs into a hydrophobic pocket on the Lyn surface. Although the existence of this pocket is no unique property of Lyn‐SH3, Lyn is the only Src family kinase that contains an additional aromatic residue (H41) in the n‐Src loop as part of this pocket. H41 covers L186 of Tip by forming tight hydrophobic contacts, and model calculations suggest that the increase in binding affinity compared with other SH3 domains can mainly be attributed to these additional interactions. These findings indicate that this pocket can mediate specificity even between otherwise closely related SH3 domains.
Solution structure of a late embryogenesis abundant protein (LEA14) from Arabidopsis thaliana, a cellular stress‐related protein
Authors: Singh Shanteri , Cornilescu Claudia C. , Tyler Robert C. , Cornilescu Gabriel , Tonelli Marco , Lee Min S. , Markley John L.
Published: September 2005

We report the three‐dimensional structure of a late embryogenesis abundant (LEA) protein from Arabidopsis thaliana gene At1g01470.1. This protein is a member of Pfam cluster PF03168, and has been classified as a LEA14 protein. LEA proteins are expressed under conditions of cellular stress, such as desiccation, cold, osmotic stress, and heat. The structure, which was determined by NMR spectroscopy, revealed that the At1g01470.1 protein has an αβ‐fold consisting of one α‐helix and seven β‐strands that form two antiparallel β‐sheets. The closest structural homologs were discovered to be fibronectin Type III domains, which have <7% sequence identity. Because fibronectins from animal cells have been shown to be involved in cell adhesion, cell motility, wound healing, and maintenance of cell shape, it is interesting to note that in plants wounding or stress results in the overexpression of a protein with fibronectin Type III structural features.
In vitro study of stability and amyloid‐fibril formation of two mutants of human stefin B (cystatin B) occurring in patients with EPM1
Authors: Rabzelj Sabina , Turk Vito , Žerovnik Eva
Published: September 2005

Myoclonus epilepsy of type 1 (EPM1) is a rare monogenic progressive and degenerative epilepsy, also known under the name Unverricht‐Lundborg disease. With the aim of comparing their behavior in vitro, wild‐type (wt) human stefin B (cystatin B) and the G4R and the R68X mutants observed in EPM1 were expressed and isolated from the Escherichia coli lysate. The R68X mutant (Arg68Stop) is a peptide of 67 amino acids from the N terminus of stefin B. CD spectra have shown that the R68X peptide is not folded, in contrast to the G4R mutant, which folds like wild type. The wild type and the G4R mutant were unfolded by urea and by trifluoroethanol (TFE). It has been shown that both proteins have closely similar stability and that at pH 4.8, where a native‐like intermediate was demonstrated, TFE induces unfolding intermediates prior to the major transition to the all‐α‐helical state. Kinetics of fibril formation were followed by Thioflavin T fluorescence while the accompanying changes of morphology were followed by the transmission electron microscopy (TEM). For the two folded proteins the optimal concentration of TFE producing extensive lag phases and high fibril yields was predenaturational, 9% (v/v). The unfolded R68X peptide, which is highly prone to aggregate, formed amyloid fibrils in aqueous solution and in predenaturing 3% TFE. The G4R mutant exhibited a much longer lag phase than the wild type, with the accumulation of prefibrillar aggregates. Implications for pathology in view of the higher toxicity of prefibrillar aggregates to cells are discussed.
COG3926 and COG5526: A tale of two new lysozyme‐like protein families
Authors: Pei Jimin , Grishin Nick V.
Published: September 2005

We have identified two new lysozyme‐like protein families by using a combination of sequence similarity searches, domain architecture analysis, and structural predictions. First, the P5 protein from bacteriophage ϕ8, which belongs to COG3926 and Pfam family DUF847, is predicted to have a new lysozyme‐like domain. This assignment is consistent with the lytic function of P5 proteins observed in several related double‐stranded RNA bacteriophages. Domain architecture analysis reveals two lysozyme‐associated transmembrane modules (LATM1 and LATM2) in a few COG3926/DUF847 members. LATM2 is also present in two proteins containing a peptidoglycan binding domain (PGB) and an N‐terminal region that corresponds to COG5526 with uncharacterized function. Second, structure prediction and sequence analysis suggest that COG5526 represents another new lysozyme‐like family. Our analysis offers fold and active‐site assignments for COG3926/DUF847 and COG5526. The predicted enzymatic activity is consistent with an experimental study on the zliS gene product from Zymomonas mobilis, suggesting that bacterial COG3926/DUF847 members might be activators of macromolecular secretion.
Structure of the nuclease domain of ribonuclease III from M. tuberculosis at 2.1 Å
Authors: Akey David L. , Berger James M.
Published: September 2005

RNase III enzymes are a highly conserved family of proteins that specifically cleave double‐stranded (ds)RNA. These proteins are involved in a diverse group of functions, including ribosomal RNA processing, mRNA maturation and decay, snRNA and snoRNA processing, and RNA interference. Here we report the crystal structure of the nuclease domain of RNase III from the pathogen Mycobacterium tuberculosis. Although globally similar to other RNase III folds, this structure has some features not observed in previously reported models. These include the presence of an additional metal ion near the catalytic site, as well as conserved secondary structural elements that are proposed to have functional roles in the recognition of dsRNAs.
Systematic review: treatment of chronic hepatitis B virus infection by pegylated interferon
Authors: HUI A. Y. , CHAN H. L.‐Y. , CHEUNG A. Y.‐K. , COOKSLEY G. , SUNG J. J.‐Y.
Published: September 2005

Background:  Pegylated interferon‐α has been shown to be more efficacious than conventional interferon in treating chronic hepatitis C. The use of peginterferon in chronic hepatitis B virus infection with positive hepatitis B e antigen has also been tested in a number of trials since 2003.

Aim:  To systematically summarize and compare the results of these studies.

Methods:  Four studies were identified from PubMed, Medline and reference lists. Data from the trials were extracted and analysed. Where appropriate, combined odds ratio of different trials was calculated. Safety data including serious adverse events and emergence of drug‐resistant mutants were recorded.

Results:  Three of the four trials contained predominantly Asian patients. Peginterferon is found to be superior to lamivudine monotherapy and induced sustained biochemical and virological responses in about one‐thirds of patients after 12 months of therapy. Coadministration of lamivudine did not result in improvement in viral suppression. Peginterferon appears to reduce the emergence of YMDD mutation in the combination treatment groups. It was well tolerated with serious adverse events reported in <10% of patients in most trials.

Conclusions:  Peginterferon‐α treatment of at least 6 months should be considered as one of the first‐line therapeutic options for hepatitis B virus infection.
Variation in practice of ileal intubation among diverse endoscopy settings: results from a national endoscopic database
Authors: HAREWOOD G. C. , MATTEK N. C. , HOLUB J. L. , PETERS D. , LIEBERMAN D. A.
Published: September 2005

Background:  Terminal ileum intubation rates at colonoscopy are variable. One of the major indications for terminal ileum intubation is to identify Crohn's disease. Signs and symptoms which raise a suspicion of Crohn's include abdominal pain/bloating, anaemia and diarrhoea.

Aim:  To determine the proportion of terminal ileal intubation in patients undergoing evaluation of abdominal pain/bloating, anaemia or diarrhoea with normal endoscopic findings at colonoscopy.

Methods:  The Clinical Outcomes Research Initiative national endoscopic database was analysed to determine the proportion of terminal ileum intubation in patients undergoing evaluation of either abdominal pain/bloating, anaemia or diarrhoea with normal endoscopic findings at colonoscopy and to characterize this population of patients. Patients with known or suspected inflammatory bowel disease were excluded from the analysis.

Results:  Between January 2000 and December 2003, 21 638 patients underwent complete colonoscopy for evaluation of either abdominal pain/bloating, anaemia or diarrhoea with normal colon findings. Overall, 3858 patients (18%) underwent terminal ileum evaluation. Intubation rates differed according to procedure indication: abdominal pain (13%), anaemia (13%), diarrhoea (28%). Terminal ileum assessment declined with advancing patient age and was least frequent in Black patients (12% vs. 18% in non‐Blacks, P < 0.0001). Ileal intubation rates also varied among endoscopy site types: community (17%), academic (21%), Veterans Affairs Medical Centres (17%), P < 0.0001. Multiple logistic regression identified patients with the indication of diarrhoea (OR: 2.58) as more likely to undergo terminal ileum intubation when compared with those with abdominal pain/bloating. Patients in Veterans Affairs (OR: 1.26) and academic (OR: 1.29) sites were more likely to undergo terminal ileum intubation compared with community sites.

Conclusion:  Less than one‐fifth of patients with either abdominal pain/bloating, anaemia or diarrhoea underwent ileal intubation in the setting of a normal colonoscopy. Significant practice variation was observed in rates of terminal ileum evaluation. Further study is required to determine whether terminal ileum examination impacts patient management or outcome.
Socioeconomic gradient in use of statins among Danish patients: population‐based cross‐sectional study
Authors: Thomsen Reimar W. , Johnsen Søren P. , Olesen Anne V. , Mortensen Jens T. , Bøggild Henrik , Olsen Jørn , Sørensen Henrik T.
Published: September 2005

Aims

Socioeconomic inequalities in statin use are a public health concern but they may also confound observational studies of statins’ effectiveness. We conducted a population‐based cross‐sectional study in Denmark to examine the association between socioeconomic status (SES) and statin use.

Methods

We obtained data on socioeconomic status of all persons in North Jutland County, Denmark, between 1995 and 1999 from the Prevention Registry at Statistics Denmark. Data on filled statin prescriptions were identified through the County Prescription Database. We compared the 1‐year prevalence proportions of statin use for different socioeconomic groups, adjusted for age and urbanization. Separate analyses were done for patients with a history of cardiovascular disease as recorded in the County Hospital Discharge Registry.

Results

Among men with cardiovascular disease, statin use in 1995 was higher in those with the highest socioeconomic status (adjusted relative prevalence proportion (RPP) among top managers 1.86, 95% CI: 1.17–2.96), and lower among retired men (RPP (95% CI) 0.63 [0.43–0.93] in old‐age pensioners, and 0.66 [0.45–0.98] in the early retired), when compared with basic‐level workers. The socioeconomic differences in statin use among men decreased in magnitude over time but remained throughout the study period. We found no clear social gradient in statin use among women.

Conclusions

Even in a health care system that claims to ensure a high degree of equity in medical care, we found clear indications of a socioeconomic gradient in statin use among men in the years after the launching of these drugs.
Treatment‐related death in childhood acute lymphoblastic leukaemia in the Nordic countries: 1992–2001
Authors: Christensen Merete Stubkjaer , Heyman Mats , Möttönen Merja , Zeller Bernward , Jonmundsson Gudmundur , Hasle Henrik ,   on behalf of the Nordic Society of Paediatric Haematology and Oncology (NOPHO)
Published: September 2005

Despite continuously more successful treatment of childhood acute lymphoblastic leukaemia (ALL), 2–5% of children still die of other causes than relapse. The Nordic Society of Paediatric Haematology and Oncology‐ALL92 protocol included 1652 patients ≤15 years of age with precursor B‐ and T‐cell ALL diagnosed between 1992 and 2001. Induction deaths and deaths in first complete remission (CR1) were included in the study. A total of 56 deaths (3%) were identified: 19 died during induction (1%) and 37 in CR1 (2%). Infection was the major cause of death in 38 cases. Five patients died of early death before initiation of cytotoxic therapy. Five patients died because of toxicity of inner organs and one of accidental procedure failures. Seven patients died of complications following allogenic haematopoietic stem cell transplantation (HSCT) in CR1. Girls were at higher risk of treatment‐related death (TRD) [relative risk (RR) = 2·2; 95% confidence interval (CI95%): 1·2–4·0, P < 0·01], mostly because of infections. Risk of TRD was also higher in children with Down syndrome (RR = 4·5; CI95%: 2·0–10·2, P < 0·00). In conclusion, 3% of children with ALL died of TRD, with bacterial infections as the most common cause of death. Girls and Down syndrome patients had a higher risk of TRD. Infections still remain a major challenge in childhood ALL.
The interactions between inflammation and coagulation
Authors: Esmon Charles T.
Published: September 2005

Inflammation initiates clotting, decreases the activity of natural anticoagulant mechanisms and impairs the fibrinolytic system. Inflammatory cytokines are the major mediators involved in coagulation activation. The natural anticoagulants function to dampen elevation of cytokine levels. Furthermore, components of the natural anticoagulant cascades, like thrombomodulin, minimise endothelial cell dysfunction by rendering the cells less responsive to inflammatory mediators, facilitate the neutralisation of some inflammatory mediators and decrease loss of endothelial barrier function. Hence, downregulation of anticoagulant pathways not only promotes thrombosis but also amplifies the inflammatory process. When the inflammation–coagulation interactions overwhelm the natural defence systems, catastrophic events occur, such as manifested in severe sepsis or inflammatory bowel disease.