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PubMed1995

Long loops in proteins.

In proteins, loop regions which connect secondary structures are generally short (80% are <10 amino acids long). However, long loops, defined here as > or = 10 residues, do occur. Two types of long loop may be distinguished: those which connect adjacent regions of secondary structure ('long-closed') and those which connect distant secondary structures ('long-open'). Only 5% of all loops in proteins fall into the long-open class. Inspection of these unusual long-open loops reveals a higher percentage of proline residues and more helix-helix linkages than expected. Exposure to solvent is similar for long-open and long-closed loops. The role of these loops in protein folding is discussed.

Amino Acid Sequence↗
PubMed2004

A new closed-loop control system for isoflurane using bispectral index outperforms manual control.

BACKGROUND: Automatic control of depth of hypnosis using the Bispectral Index (BIS) can help to reduce phases of inadequate control. Automated BIS control with propofol or isoflurane administration via an infusion system has recently been described, a comparable study with isoflurane administration via a vaporizer had not been conducted yet. Our hypothesis was that our new model based closed-loop control system can safely be applied clinically and maintains the BIS within a defined target range better than manual control. METHODS: Twenty-three patients, American Society of Anesthesiologists risk class I-III, scheduled for decompressive spinal surgery were randomized into groups with either closed-loop or manual control of BIS using isoflurane. An alfentanil target-controlled infusion was adjusted according to standard clinical practice. The BIS target was set to 50 during the operation. The necessity of human intervention in the control system and events of inadequate sedation (BIS <40 or BIS >60) were counted. The number of phases of inadequate control, defined as BIS >/=65 for more than 3 min, were recorded. The performance of the controller was assessed by several indicators (mean absolute deviation and median absolute performance error) and measured during the skin incision phase, the subsequent low flow phase, and the wound closure phase. Recovery profiles of both groups were compared. RESULTS: No human intervention was necessary in the closed-loop control group. The occurrence of inadequate BIS was quantified with the mean and median values of the area under the curve and amounted to 0.360 and 0.088 for the manual control group and 0.049 and 0.017 for the closed-loop control group, respectively. In the manual control group nine phases of inadequate control were recorded, compared with one in the closed-loop control group, 10.3% to 0.5% of all observed anesthesia time. During all phases the averages of the performance parameters (mean absolute deviation and median absolute performance error) were more than 30% smaller in closed-loop control than in manual control (P < 0.05 between groups). CONCLUSIONS: Closed-loop control with BIS using isoflurane can safely be applied clinically and performs significantly better than manual control, even in phases with abrupt changes of stimulation that cannot be foreseen by the control system.

Adolescent↗
PubMed2003

Hearing aid users benefit from induction loop when using digital cellular phones.

OBJECTIVE: Hearing aid users have recently been reported to experience problems with electromagnetic interference when using digital cellular phones. This study was undertaken to investigate the possible benefit of an induction loop system developed for use with some cellular phone models, and also to compare the possible benefit in two languages (Finnish and American English) as well as the benefit with two hearing aid technologies (analog versus digital). DESIGN: The study was performed in controlled laboratory conditions at two tertiary care hearing health care centers, one in Oulu, Finland and the other in Dallas, in the United States. The subjects were experienced users of behind-the-ear hearing aids and served as their own controls in three different listening conditions. Thirty-two eligible subjects (20 in Oulu and 12 in Dallas) participated in three test conditions: 1. call with a landline phone, 2. call with a digital cellular phone alone and 3. call with a digital cellular phone coupled to an induction loop. RESULTS: Sentence recognition scores and subjective judgments using a visual analog scale revealed the poorest results with the digital cellular phone alone. When the induction loop was used with the digital cellular phones, sentence recognition scores and the visual analog scale scores were comparable to the scores obtained with a landline phone. The mean sentence recognition score for analog hearing aids was 62.4% (95% confidence interval 50.2 to 74.6) with the landline phone, 12.6% (-1.6 to 26.9) with the digital cellular phone alone, and 63.3% (44.2 to 82.3) when using the digital cellular phone with the induction loop. For digital hearing aids, the sentence recognition scores were 62.4% (51.9 to 72.9), 37.4% (18.0 to 56.8) and 57.6% (39.0 to 76.2), respectively. There was no significant difference in performance between the two centers. However, when using the digital cellular phone alone, there was no drop in the sentence recognition scores with the few (N = 5) digital hearing aids in Dallas. The subjects ranked the digital cellular phone alone as the poorest test condition and the digital cellular phone with an induction loop as the best. CONCLUSIONS: Induction loops appear to offer one possible solution for the incompatibility problem between hearing aids and digital cellular phones. However, the generalizability of the results must be viewed cautiously, because testing included only one induction loop and two digital cellular phone models.

Adult↗
PubMed2004

A new technique for treating forgotten indwelling ureteral stents: silk loop assisted ureterorenoscopic lithotripsy.

PURPOSE: Treating forgotten indwelling ureteral stents is difficult because forgotten stents become encrusted and fragmented. Therefore, we developed a silk loop with which to loop the lower end of a forgotten ureteral stent during ureterorenoscopy to supply a counterforce, which fixed the stent while separating encrusted stones from the forgotten stent. We evaluated the success of the silk loop method. MATERIALS AND METHODS: Nine patients were enrolled in this study from 1997 to 2003. Each patient had a forgotten ureteral stent with renal stones on the tip of the proximal end. All consented to the procedure of silk loop assisted ureterorenoscopic lithotripsy (URSL) with a Lithoclast (Microvasive, Natick, Massachusetts) lithotriptor. RESULTS: We successfully removed the forgotten indwelling stent from all 9 patients with the silk loop assisted URSL method. CONCLUSIONS: Silk loop assisted URSL makes the removal of forgotten stents easier. While percutaneous nephrostolithotomy and open surgery produce successful results, the silk loop method is less invasive and expensive, and it minimizes hospital recovery time.

Adult↗
PubMed2006

Mutation of the Rev-binding loop in the human immunodeficiency virus 1 leader causes a replication defect characterized by altered RNA trafficking and packaging.

An internal RNA loop, located within the packaging signal of human immunodeficiency virus 1, that resembles the Rev-responsive element (RRE) closely was identified previously. Subsequent in vitro studies confirmed that the loop, termed loop A, could bind Rev protein specifically. Its proximity to the major splice donor has suggested a role for Rev-loop A interaction supplementary to or preceding that of the Rev-RRE interaction. To investigate this further in a replication-competent provirus, loop A was mutated to decrease its affinity for Rev. Impairing the Rev-loop A interaction led to reduced nuclear export of viral genomic RNA. RNA packaging decreased by approximately 30%. Viral protein production and export of virus particles appeared normal; however, the virus was severely replication-deficient. The loop A sequence, which is 98% conserved amongst viral isolates, is implicated in several cis-acting functions critical to virus viability.

Animals↗
PubMed2024

AAV-mediated genome editing is influenced by the formation of R-loops.

Recombinant adeno-associated viral vectors (rAAV) hold an intrinsic ability to stimulate homologous recombination (AAV-HR) and are the most used in clinical settings for in vivo gene therapy. However, rAAVs also integrate throughout the genome. Here, we describe DNA-RNA immunoprecipitation sequencing (DRIP-seq) in murine HEPA1-6 hepatoma cells and whole murine liver to establish the similarities and differences in genomic R-loop formation in a transformed cell line and intact tissue. We show enhanced AAV-HR in mice upon genetic and pharmacological upregulation of R-loops. Selecting the highly expressed Albumin gene as a model locus for genome editing in both in vitro and in vivo experiments showed that the R-loop prone, 3' end of Albumin was efficiently edited by AAV-HR, whereas the upstream R-loop-deficient region did not result in detectable vector integration. In addition, we found a positive correlation between previously reported off-target rAAV integration sites and R-loop enriched genomic regions. Thus, we conclude that high levels of R-loops, present in highly transcribed genes, promote rAAV vector genome integration. These findings may shed light on potential mechanisms for improving the safety and efficacy of genome editing by modulating R-loops and may enhance our ability to predict regions most susceptible to off-target insertional mutagenesis by rAAV vectors.

Preprint↗
PubMed2003

Reparametrizing the loop entropy weights: effect on DNA melting curves.

Recent advances in the understanding of the melting behavior of double-stranded DNA with statistical mechanics methods lead to improved estimates of the weight factors for the dissociation events of the chains, in particular for interior loop melting. So far, in the modeling of DNA melting, the entropy of denaturated loops has been estimated from the number of configurations of a closed self-avoiding walk. It is well understood now that a loop embedded in a chain is characterized by a loop closure exponent c which is higher than that of an isolated loop. Here we report an analysis of DNA melting curves for sequences of a broad range of lengths (from 10 to 10(6) base pairs) calculated with a program based on the algorithms underlying MELTSIM. Using the embedded loop exponent we find that the cooperativity parameter is one order of magnitude bigger than current estimates. We argue that in the melting region the double helix persistence length is greatly reduced compared to its room temperature value, so that the use of the embedded loop closure exponent for real DNA sequences is justified.

Algorithms↗
PubMed2006

Exposed loop domains of complexed 14-3-3 proteins contribute to structural diversity and functional specificity.

The 14-3-3 family of proteins functions through protein:phosphoprotein interactions, the nature of which has been elucidated using x-ray crystallography. However, some key structural features in nonconserved regions have yet to be fully resolved, leaving open questions regarding the functional selectivity of 14-3-3 family members for diverse clients. In an effort to study surface accessible structural features in 14-3-3 containing macromolecular complexes and to illuminate important structure/function variations among the 14-3-3 isoforms, we determined the epitopes for three unique monoclonal antibodies (mAbs) developed against the Arabidopsis (Arabidopsis thaliana) G-box DNA:protein complex. The epitopes mapped to different loops in a phylogenetically important subset of the 13 14-3-3 family members. All three epitopes were on a common exposed face of complexed 14-3-3s. Two of the mAbs recognized linear sequences within loops 5 and 6, while the third mAb recognized 14-3-3 residues surrounding the pivotal medial Gly in the divalent cation-binding domain of loop 8, together with distal residue(s) in the putative dynamic 10th helix that has yet to be determined by crystallography. Gly at this loop 8 position is unique to nonepsilon 14-3-3 isoforms of the plant kingdom, suggesting that this region constitutes a plant-specific key functional 14-3-3 feature and highlighting that the loop 8 region is functionally significant. Mutagenesis of the medial amino acid in the loop 8 domain changed the flexibility of the C terminus and altered client peptide-binding selectivity, demonstrating the functional significance of the surface accessible, evolutionarily distinct loop 8 domain.

14-3-3 Proteins↗
PubMed2000

An alternate binding site for the P1-P3 group of a class of potent HIV-1 protease inhibitors as a result of concerted structural change in the 80s loop of the protease.

Structures of the complexes of HIV protease inhibitor L--756,423 with the HIV-1 wild-type protease and of the inhibitors Indinavir, L-739,622 and Saquinavir with the mutant protease (9X) containing nine point mutations (Leu10Val, Lys20Met, Leu24Ile, Ser37Asp, Met46Ile, Ile54Val, Leu63Pro, Ala71Val, Val82Thr) have been determined. Comparative analysis of these structures reveals an alternate binding pocket for the P1-P3 group of Indinavir and L--756, 423. The alternate binding pocket is a result of concerted structural change in the 80s loop (residues 79-82) of the protease. The 80s loop is pulled away from the active site in order to accommodate the P1-P3 group, which is sandwiched between the flap and the 80s loop. This structural change is observed for the complexes of the wild type as well as the 9X mutant protease. The study reveals that the 80s loop is an intrinsically flexible loop in the wild-type HIV-1 protease and that mutations in this loop are not necessary to result in conformational changes. Conformation of this loop in the complex depends primarily upon the nature of the bound inhibitor and may be influenced by mutations in the protease. The results underscore the need to understand the intrinsic structural plasticity of the protease for the design of effective inhibitors against the wild-type and drug-resistant enzyme forms. In addition, the alternate binding pocket for the P1-P3 group of Indinavir and L--756,423 may be exploited for the design of potent inhibitors.

Amino Acid Substitution↗
PubMed2003

Cyclic coordinate descent: A robotics algorithm for protein loop closure.

In protein structure prediction, it is often the case that a protein segment must be adjusted to connect two fixed segments. This occurs during loop structure prediction in homology modeling as well as in ab initio structure prediction. Several algorithms for this purpose are based on the inverse Jacobian of the distance constraints with respect to dihedral angle degrees of freedom. These algorithms are sometimes unstable and fail to converge. We present an algorithm developed originally for inverse kinematics applications in robotics. In robotics, an end effector in the form of a robot hand must reach for an object in space by altering adjustable joint angles and arm lengths. In loop prediction, dihedral angles must be adjusted to move the C-terminal residue of a segment to superimpose on a fixed anchor residue in the protein structure. The algorithm, referred to as cyclic coordinate descent or CCD, involves adjusting one dihedral angle at a time to minimize the sum of the squared distances between three backbone atoms of the moving C-terminal anchor and the corresponding atoms in the fixed C-terminal anchor. The result is an equation in one variable for the proposed change in each dihedral. The algorithm proceeds iteratively through all of the adjustable dihedral angles from the N-terminal to the C-terminal end of the loop. CCD is suitable as a component of loop prediction methods that generate large numbers of trial structures. It succeeds in closing loops in a large test set 99.79% of the time, and fails occasionally only for short, highly extended loops. It is very fast, closing loops of length 8 in 0.037 sec on average.

Algorithms↗
PubMed1977

Ultrastructure of the capillary loops in the dermal papillae of psoriasis.

Electron microscopy was used to define the ultrastructure of the capillary loops in the dermal papillae of psoriatic lesions. Pustular psoriasis of von Zumbusch and psoriasis vulgaris were studied before and after treatment with the Goeckerman regimen. Capillary loops were reconstructed from 1-mum plastic-embedded sections. Ultrathin sections were taken at intervals for correlation with the 1-mum sections. There were no ultrastructural differences between the capillary loops in psoriasis vulgaris and pustular psoriasis. The intrapapillary portion of the loop was predominantly a venous capillary. Four basic ultrastructural loop patterns were recognized which can serve as markers in studying the responses of psoriatic loops in various experimental situations. Following 3 weeks of Goeckerman therapy, the morphology of psoriatic capillary loops changed from venous capillaries to arterial capillaries which are found in the papillae of normal skin. This transformation was observed to begin 48 to 72 hr after the initiation of therapy.

Biopsy↗
PubMed2004

Molecular mechanisms of DNA end-loop formation by TRF2.

In the telomere region of human chromosomes, the (TTAGGG)n sequence stretches over several kilobases and forms a distinct higher-order structure with various proteins. Telomere repeat binding factors (TRFs) bind specifically to this sequence and play critical roles in the maintenance of telomere structure and function. Here, we prepared a series of linear DNA carrying a stretch of telomeric sequence ((TTAGGG)n, approximately 1.8 (kb) with different end-structures and observed their higher-order complexes with TRFs by atomic force microscopy. TRF2 molecules exclusively bound to the telomeric DNA region at several different places simultaneously mainly as a dimer, and often mediated DNA loop formation by forming a tetramer at the root. These multiple-binding, multimerization and DNA loop formation by TRF2 were observed regardless of the DNA-end structure (blunt, 3'-overhanging, telomeric, non-telomeric). However, when the DNA end carried the telomeric-3'-overhanging region, the loop was frequently formed at the end of the DNA. Namely, the TRF2-mediated DNA loop formation is independent of the end-structure and the 3'-overhanging TTAGGG sequence is responsible for the stabilization of the loop. TRF1 also bound to the telomeric DNA as a dimer, but did not mediate DNA loop formation by itself. These results provide a new insight into the molecular mechanism of DNA end-loop formation by TRFs.

Binding Sites↗
PubMed2004

Effects of RNA polymerase modifications on transcription-induced negative supercoiling and associated R-loop formation.

Transcription in the absence of topoisomerase I, but in the presence of DNA gyrase, can result in the formation of hypernegatively supercoiled DNA and associated R-loops. In this paper, we have used several strategies to study the effects of elongation/termination properties of RNA polymerase on such transcription-induced supercoiling. Effects on R-loop formation were exacerbated when cells were exposed to translation inhibitors, a condition that stimulated the accumulation of R-loop-dependent hypernegative supercoiling. Translation inhibitors were not acting by decreasing (p)ppGpp levels as the absence of (p)ppGpp in spoT relA mutant strains had little effect on hypernegative supercoiling. However, an rpoB mutation leading to the accumulation of truncated RNAs considerably reduced R-loop-dependent hypernegative supercoiling. Transcription of an rrnB fragment preceded by a mutated and inactive boxA sequence to abolish the rrnB antitermination system also considerably reduced R-loop-dependent supercoiling. Taken together, our results indicate that RNA polymerase elongation/termination properties can have a major impact on R-loop-dependent supercoiling. We discuss different possibilities by which RNA polymerase directly or indirectly participates in R-loop formation in Escherichia coli. Finally, our results also indicate that what determines the steady-state level of hypernegatively supercoiled DNA in topA null mutants is likely to be complex and involves a multitude of factors, including the status of RNA polymerase, transcription-translation coupling, the cellular level of RNase HI, the status of DNA gyrase and the rate of relaxation of supercoiled DNA.

Bacterial Proteins↗
PubMed1982

R-loop mapping of calf-thymus RNA polymerase II. Transcripts in vitro on restriction fragments of adenovirus 2 DNA.

Nascent RNA, synthesized by calf thymus ENA polymerase II on the restriction endonuclease EcoRI fragment A and BamHI fragment B of adenovirus 2 DNA, was rehybridized to the template strand under conditions allowing transcription R-loop formation. Hybrids, visualized by electron microscopy, were found in looped and in branched configurations, the former being abundant, with an average loop number of roughly four per EcoRI fragment A and three per BamHI fragment B. Frequency distributions of transcription R-loops, synthesized on identical restriction fragments for different periods of time, showed similar patterns, thus pointing to a nonrandom type of transcription. A comparison of the frequency distribution of R-loops seen on the two overlapping restriction fragments reveals reasonable coincidence in the loop pattern in one out of the four possible fragment orientations, permitting correlation of the transcription R-loop pattern with the physical map of the adenovirus 2 DNA. Comparison of start sites tentatively mapped in vitro with the known promoters for RNA polymerase II in vivo suggests that a major transcription site in vitro is located in close proximity to, or identical with, two promoters in vivo at 16.1 and 16.5 map units.

Adenoviridae↗
PubMed1988

Socio-economic stratification generated by international migration loops.

This paper analyzes the migration phenomenon within a framework that treats migration movements as continuous loops, from the country of origin to the destination and back. Significant social-psychological factors at each step of the loop process contribute to the development of migration streams along a predictable pattern. The general model of the loop process shows that the migration stream is 1st sparked when labor is recruited from less developed countries for work in developed industrialized countries. Once the social process of migration has begun, it tends to acquire a self-feeding character. Social and economic change in sending and receiving societies brought about by migration make further migration more likely. The case of the Mexico-US-Mexico loop process is analyzed. This case illustrates the effects of socioeconomic stratification that occurs in communities where the migration loop process reaches a certain level of maturity. The majority of a town's population may become committed to migration as a way of life. Eventually, wealth becomes concentrated in the hands of those that are most able to migrate. Thus, migrants may become a new elite segment of rural populations that were once relatively homogenous societies. Further research of the migration loop process should be conducted. At least in the case of Mexico, the socioeconomic stratification in the villages and towns acting as sources of migration loops with destinations in the US have significant internal economic, social, and political implications.

Americas↗
PubMed2006

Ignoring distant genealogic loops leads to false-positives in homozygosity mapping.

Distant consanguineous loops are often unknown or ignored during homozygosity mapping analysis. This may potentially lead to an increased rate of false-positive linkage results. We show that failure to take into account the distant loops may seriously underestimate the degree of consanguinity, especially for people from genetically isolated populations; in 6 Alzheimer's disease (AD) patients the distant loops accounted for 57.7 % of inbreeding on average. Theoretical evaluation showed that ignoring distant loops, which account for 18-75% of inbreeding, inflates the frequency of false positive conclusions substantially in 2-point linkage analysis, up to several hundred times. In multipoint linkage analysis of the 6 AD patients a chromosome-wide "empirical" significance of 5% corresponded to a true false positive rate of 11.1%. We show that converting multiple loops to a hypothetical loop capturing all inbreeding may be a convenient solution to avoid false positive results. When extended genealogic data are not available a hypothetical loop may still be constructed based on genomic data.

Alzheimer Disease↗
PubMed1994

A new mock circulatory loop and its application to the study of chemical additive and aortic pressure effects on hemolysis in the Penn State electric ventricular assist device.

A new mock circulatory loop was developed for hemolysis studies associated with the Penn State electric ventricular assist device (EVAD). This flow loop has several advantages over previously designed loops. It is small enough to accommodate experiments in which only single units of blood are available, it is made out of biocompatible materials, it incorporates good geometry, and it provides normal physiological pressures and flows to both the aortic outlet and the venous inlet of the pumping device. Experiments with reduced aortic pressure but normal cardiac output showed that hemolysis in a loop with normal aortic blood pressure was significantly higher than that in a loop with lowered aortic pressure, thereby illustrating the importance of maintaining loop pressures as close as possible to those found in vivo. This data also imply that blood traveling through the left ventricle in an artificial heart may be subject to higher hemolysis rates than that traversing the right ventricle. Another set of experiments to determine the effects of 4 hemolysis or drag-reducing agents (Pluronic F-68, Dextran-40, Polyox WSR-301, and Praestol 2273TR) on blood trauma due to the EVAD and associated valves was performed. Results indicated that none of the additives significantly reduced hemolysis under the conditions found in the mock loop. Finally, a compilation of data gathered in these experiments showed that the index of hemolysis (IH) is dependent on hematocrit (HCT), which suggests that another parameter, IH/HCT, may be more suited to the quantification of hemolysis.

Acrylic Resins↗
PubMed2006

Roles of the human Rad51 L1 and L2 loops in DNA binding.

The human Rad51 protein, a eukaryotic ortholog of the bacterial RecA protein, is a key enzyme that functions in homologous recombination and recombinational repair of double strand breaks. The Rad51 protein contains two flexible loops, L1 and L2, which are proposed to be sites for DNA binding, based on a structural comparison with RecA. In the present study, we performed mutational and fluorescent spectroscopic analyses on the L1 and L2 loops to examine their role in DNA binding. Gel retardation and DNA-dependent ATP hydrolysis measurements revealed that the substitution of the tyrosine residue at position 232 (Tyr232) within the L1 loop with alanine, a short side chain amino acid, significantly decreased the DNA-binding ability of human Rad51, without affecting the protein folding or the salt-induced, DNA-independent ATP hydrolysis. Even the conservative replacement with tryptophan affected the DNA binding, indicating that Tyr232 is involved in DNA binding. The importance of the L1 loop was confirmed by the fluorescence change of a tryptophan residue, replacing the Asp231, Ser233, or Gly236 residue, upon DNA binding. The alanine replacement of phenylalanine at position 279 (Phe279) within the L2 loop did not affect the DNA-binding ability of human Rad51, unlike the Phe203 mutation of the RecA L2 loop. The Phe279 side chain may not be directly involved in the interaction with DNA. However, the fluorescence intensity of the tryptophan replacing the Rad51-Phe279 residue was strongly reduced upon DNA binding, indicating that the L2 loop is also close to the DNA-binding site.

Alanine↗