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PubMed2004

Clinical challenges of nosocomial infections caused by antibiotic-resistant pathogens in pediatrics.

Antibiotic resistance in nosocomial infections is an ever-increasing problem as health care institutions provide care for children with more complicated medical and surgical problems. Several mechanisms of antibiotic resistance are reviewed for both gram-negative and gram-positive nosocomial pathogens. These adaptive resistance mechanisms allow organisms to survive in an environment of extensive antibiotic use and result in clinically significant infections. Mobile genetic elements have facilitated the rapid spread of antibiotic resistance within and among species. The clinical challenge faced by many practitioners is to understand these mechanisms of antibiotic resistance and to develop strategies for successfully treating infection caused by resistant pathogens. Nosocomial outbreaks caused by resistant organisms are described, and an approach to empiric therapy based on presumed pathogens, site of infection, and local resistance patterns is discussed.

Adolescent↗
PubMed2001

The role of virulence factors in enterohemorrhagic Escherichia coli (EHEC)--associated hemolytic-uremic syndrome.

Enterohemorrhagic Escherichia coli (EHEC) are the most common cause of postdiarrheal hemolytic-uremic syndrome (HUS). The most important EHEC serotype implicated worldwide is O157:H7. However, several so-called non-O157 EHEC serotypes have emerged. After a mean incubation period of 3 days, patients develop watery diarrhea accompanied by cramping abdominal pain. During the next days, in most patients watery diarrhea changes to bloody diarrhea. One week after the onset of diarrhea, in about 15% of infected patients under 10 years of age EHEC infection results in a systemic complication, HUS. Shiga toxins (Stxs) are considered the major virulence factors of EHEC involved in the pathogenesis of HUS. It is generally believed that after intestinal infection with EHEC, Stxs cross the intestinal barrier and bind to endothelial cells. At this point they presumably injure the host cell by inhibition of protein synthesis, stimulation of prothrombotic messages, or induction of apoptosis. The B subunit of Stx binds to the membrane receptor globotriaosylceramide (Gb3). Gb3 facilitates the endocytosis and intracellular trafficking of the toxin. The Stx A subunit hydrolyzes a specific adenine residue of the 60S ribosomal subunit of mammalian cells. As a consequence, Stx shuts down the protein machinery of the susceptible cell. The HUS is the net effect of a variety of interacting factors, including background risk of acquisition, host factors (such as age), virulence characteristics of the infecting EHEC strain, and exogenous factors. All known EHEC virulence determinants are located on mobile genetic elements, and this has an important impact on the evolution of these pathogens. The evolution of EHEC has a dynamic component that includes different genetic mechanisms. The recent progress in understanding the pathogenesis and epidemiology of EHEC infections forms a basis for the development of future strategies to prevent EHEC infections in humans.

Endothelium, Vascular↗
PubMed2002

Integration of foreign DNA during natural transformation of Acinetobacter sp. by homology-facilitated illegitimate recombination.

The active uptake of extracellular DNA and its genomic integration is termed natural transformation and constitutes a major horizontal gene-transfer mechanism in prokaryotes. Chromosomal DNA transferred within a species can be integrated effectively by homologous recombination, whereas foreign DNA with low or no sequence homology would rely on illegitimate recombination events, which are rare. By using the nptII(+) gene (kanamycin resistance) as selectable marker, we found that the integration of foreign DNA into the genome of the Gram-negative Acinetobacter sp. BD413 during transformation indeed was at least 10(9)-fold lower than that of homologous DNA. However, integration of foreign DNA increased at least 10(5)-fold when it was linked on one side to a piece of DNA homologous to the recipient genome. Analysis of foreign DNA integration sites revealed short stretches of sequence identity (3-8 bp) between donor and recipient DNA, indicating illegitimate recombination events. These findings suggest that homologous DNA served as a recombinational anchor facilitating illegitimate recombination acting on the same molecule. Homologous stretches down to 183 nucleotides served as anchors. Transformation with heteroduplex DNA having different nucleotide sequence tags in the strands indicated that strands entered the cytoplasm 3' to 5' and that strands with either polarity were integrated by homologous recombination. The process led to the genomic integration of thousands of foreign nucleotides and often was accompanied by deletion of a roughly corresponding length of recipient DNA. Homology-facilitated illegitimate recombination would explain the introgression of DNA in prokaryotic genomes without the help of mobile genetic elements.

Acinetobacter↗
PubMed2005

Microarray-based detection of genetic heterogeneity, antimicrobial resistance, and the viable but nonculturable state in human pathogenic Vibrio spp.

The morbidity and mortality associated with Vibrio-mediated waterborne diseases necessitates the development of sensitive detection technologies that are able to elucidate the identity, potential pathogenicity, susceptibility, and viability of contaminating bacteria in a timely manner. For this purpose, we have designed a single multiplex PCR assay to simultaneously amplify 95 diagnostic regions (encompassing species/serogroup-specific, antimicrobial resistance, and known toxin markers) and combined it with a long oligonucleotide microarray to create a platform capable of rapidly detecting and discriminating the major human pathogenic species from the genus Vibrio: V. cholerae, V. parahaemolyticus, V. vulnificus, and V. mimicus. We were able to validate this strategy by testing 100 geographically and temporally distributed isolates and observed an excellent concordance between species- and serotype-level microarray-based identification and traditional typing methods. In addition to accurate identification, the microarray simultaneously provided evidence of antibiotic resistance genes and mobile genetic elements, such as sulfamethoxazole-trimethoprim constins and class I integrons, and common toxin (ctxAB, rtxA, hap, hlyA, tl, tdh, trh, vvhA, vlly, and vmhA) and pathogenicity (tcpA, type III secretion system) genes that are associated with pathogenic Vibrio. The versatility of this method was further underscored by its ability to detect the expression of known toxin and virulence genes from potentially harmful viable but nonculturable organisms. The results suggest that this molecular identification method provides rapid and definitive information that would be of value in epidemiological, environmental, and health risk assessment surveillance.

Anti-Infective Agents↗
PubMed2005

Probing conformational changes in T7 RNA polymerase during initiation and termination by using engineered disulfide linkages.

During the transition from an initiation complex to an elongation complex (EC), the single-subunit bacteriophage T7 RNA polymerase (RNAP) undergoes dramatic conformational changes. To explore the significance of these changes, we constructed mutant RNAPs that are able to form disulfide bonds that limit the mobility of elements that are involved in the transition (or its reversal) and examined the effects of the crosslinks on initiation and termination. A crosslink that is specific to the initiation complex conformation blocks transcription at 5-6 nt, presumably by preventing isomerization to an EC. A crosslink that is specific to the EC conformation has relatively little effect on elongation or on termination at a class I terminator (T), which involves the formation of a stable stem-loop structure in the RNA. Crosslinked ECs also pause and resume transcription normally at a class II pause site (concatamer junction) but are deficient in termination at a class II terminator (PTH, which is found in human preparathyroid hormone gene), both of which involve a specific recognition sequence. The crosslinked amino acids in the EC lie close to the upstream end of the RNA-DNA hybrid and may prevent a movement of the polymerase that would assist in displacing or releasing RNA from a relatively unstable DNA-RNA hybrid in the paused PTH complex.

Bacteriophage T7↗
PubMed2006

High-molecular-mass APOBEC3G complexes restrict Alu retrotransposition.

APOBEC3G (A3G) and related deoxycytidine deaminases are potent intrinsic antiretroviral factors. A3G is expressed either as an enzymatically active low-molecular-mass (LMM) form or as an enzymatically inactive high-molecular-mass (HMM) ribonucleoprotein complex. Resting CD4 T cells exclusively express LMM A3G, where it functions as a powerful postentry restriction factor for HIV-1. Activation of CD4 T cells promotes the recruitment of LMM A3G into 5- to 15-MDa HMM complexes whose function is unknown. Using tandem affinity purification techniques coupled with MS, we identified Staufen-containing RNA-transporting granules and Ro ribonucleoprotein complexes as specific components of HMM A3G complexes. Analysis of RNAs in these complexes revealed Alu and small Y RNAs, two of the most prominent nonautonomous mobile genetic elements in human cells. These retroelement RNAs are recruited into Staufen-containing RNA-transporting granules in the presence of A3G. Retrotransposition of Alu and hY RNAs depends on the reverse transcriptase machinery provided by long interspersed nucleotide elements 1 (L1). We now show that A3G greatly inhibits L1-dependent retrotransposition of marked Alu retroelements not by inhibiting L1 function but by sequestering Alu RNAs in cytoplasmic HMM A3G complexes away from the nuclear L1 enzymatic machinery. These findings identify nonautonomous Alu and hY retroelements as natural cellular targets of A3G and highlight how different forms of A3G uniquely protect cells from the threats posed by exogenous retroviruses (LMM A3G) and endogenous retroelements (HMM A3G).

APOBEC-3G Deaminase↗
PubMed2002

Genome sequence of Streptococcus mutans UA159, a cariogenic dental pathogen.

Streptococcus mutans is the leading cause of dental caries (tooth decay) worldwide and is considered to be the most cariogenic of all of the oral streptococci. The genome of S. mutans UA159, a serotype c strain, has been completely sequenced and is composed of 2,030,936 base pairs. It contains 1,963 ORFs, 63% of which have been assigned putative functions. The genome analysis provides further insight into how S. mutans has adapted to surviving the oral environment through resource acquisition, defense against host factors, and use of gene products that maintain its niche against microbial competitors. S. mutans metabolizes a wide variety of carbohydrates via nonoxidative pathways, and all of these pathways have been identified, along with the associated transport systems whose genes account for almost 15% of the genome. Virulence genes associated with extracellular adherent glucan production, adhesins, acid tolerance, proteases, and putative hemolysins have been identified. Strain UA159 is naturally competent and contains all of the genes essential for competence and quorum sensing. Mobile genetic elements in the form of IS elements and transposons are prominent in the genome and include a previously uncharacterized conjugative transposon and a composite transposon containing genes for the synthesis of antibiotics of the gramicidin/bacitracin family; however, no bacteriophage genomes are present.

Base Sequence↗
PubMed2026

Extreme climatic events drive consistent and predictable shifts in soil antibiotic resistance genes.

Antimicrobial resistance (AMR) is a growing One Health challenge, and as climate warming intensifies extreme events, it remains unclear how these disturbances affect soil antibiotic resistance genes (ARGs). Here we analyzed the data from a controlled experiment using soils from 30 grassland sites across ten European countries, which simulated drought, flooding, freeze-thaw, and heatwaves to explore ARG dynamics. Overall, ARGs exhibited relatively small but highly consistent shifts across treatments. Heatwaves caused the strongest reductions in ARG abundance and in their linkages with mobile genetic elements (MGEs), a pattern that may reflect a hypothesized metabolic-genetic trade-off, in which microbial investment may shift from core metabolism toward stress signaling and structural maintenance. ARG dynamics during and after disturbance were governed by distinct soil physicochemical properties, with temperature and nutrient status determining acute responses, whereas soil moisture and seasonal variability in temperature and precipitation shaped longer-term legacy effects. Cross-validated random-forest models showed positive predictive performance for Bray-Curtis-based compositional responses within the environmental range represented by the 30 grassland sites. Our findings enhance the understanding of how soil ARGs respond to extreme climatic events and provide a step toward predicting extreme-event impacts on soil resistomes with relevance to One Health.

Soil Microbiology↗
PubMed1988

Variable expression of extracellular polysaccharide in the marine bacterium Pseudomonas atlantica is controlled by genome rearrangement.

Production of extracellular polysaccharide by the marine bacterium Pseudomonas atlantica is a variable trait. Strains that produce extracellular polysaccharide (EPS(+)) have a mucoid colony phenotype, but during cultivation in the laboratory nonmucoid, EPS(-) variants arise that have a crenated colony morphology. This change is reversible since crenated variants rapidly switch to the original mucoid phenotype. We have cloned the locus (eps) controlling variable expression of EPS production by screening a recombinant cosmid library for clones that restore EPS production in the crenated variant. By using eps as a probe of genomic structure in variant strains, expression of EPS production was found to be controlled by a specific DNA rearrangement. Insertion of a 1.2-kilobase-pair DNA sequence in the eps locus results in EPS(-), whereas excision of the sequence restores the EPS(+) phenotype. Properties of the rearrangement suggest the involvement of a mobile genetic element. The possible significance of this DNA rearrangement to the survival of P. atlantica in the ocean is discussed.

Journal Article↗
PubMed1992

Interferon gamma rapidly induces in human monocytes a DNA-binding factor that recognizes the gamma response region within the promoter of the gene for the high-affinity Fc gamma receptor.

Interferon gamma (IFN-gamma) transcriptionally activates several early-response genes in monocytes that are important for the ultimate phenotype of the activated macrophage. One of these genes is the high-affinity Fc receptor for IgG (Fc gamma RI). Recently, Pearse et al. [Pearse, R.N., Feinman, R. & Ravetch, J. V. (1991) Proc. Natl. Acad. Sci. USA 88, 11305-11309] defined within the promoter region of the Fc gamma RI gene an element, the gamma response region, which was necessary for IFN-gamma-induced enhancement of Fc gamma RI. In this report we describe the induction by IFN-gamma of a DNA-binding factor, FcRF gamma (Fc gamma RI DNA-binding factor, IFN-gamma induced), that specifically recognizes the gamma response region element. Electrophoretic mobility shift assays (EMSAs) demonstrated the presence of FcRF gamma in human monocytes within 1 min after exposure to IFN-gamma. On EMSA, FcRF gamma consisted of two complexes termed FcRF gamma 1 and FcRF gamma 2. The nuclear concentration of FcRF gamma rapidly increased, peaked at 15 min, and then fell after 1-2 hr. Dose-response studies revealed (i) as little as 0.05 ng of IFN-gamma per ml induced FcRF gamma, (ii) maximum activation occurred at 1 ng/ml, and (iii) steady-state levels of Fc gamma RI mRNA closely paralleled that of FcRF gamma. Since FcRF gamma was activated in cells normally not expressing Fc gamma RI RNA, other regulatory mechanisms must control Fc gamma RI-restricted tissue expression. Activation of FcRF gamma by IFN-gamma was inhibited by pretreatment with 500 nM staurosporin and 25 microM phenyl arsine oxide. These data suggest that a kinase and possibly a phosphatase activity are required for IFN-gamma-induced signaling of FcRF gamma in monocytes.

Base Sequence↗
PubMed1992

Duplication-targeted DNA methylation and mutagenesis in the evolution of eukaryotic chromosomes.

Mammalian genomes are threatened with gene inactivation and chromosomal scrambling by recombination between repeated sequences such as mobile genetic elements and pseudogenes. We present and test a model for a defensive strategy based on the methylation and subsequent mutation of CpG dinucleotides in those DNA duplications that create uninterrupted homologous sequences longer than about 0.3 kilobases. The model helps to explain both the diversity of CpG frequencies in different genes and the persistence of gene fragmentation into exons and introns.

Animals↗
PubMed1993

Identification of human endogenous retroviruses with complex mRNA expression and particle formation.

Retroviruses comprise strains with considerable disease potential in animals and humans. In addition to exogenous strains transmitted horizontally, endogenous proviruses are transmitted through the germ line. Some of these endogenous retroviruses can be pathogenic in mice and possibly in other animal species. They may also be considered as mobile genetic elements with the potential to produce mutations. In humans, genomic DNA contains numerous endogenous retroviral sequences detected by their partial relatedness to animal retroviruses. However, all proviruses sequenced so far have been found to be defective. In this communication, we describe the expression of a family of human endogenous retrovirus sequences (HERV-K) in GH cells, a teratocarcinoma cell line producing the human teratocarcinoma-derived retrovirus (HTDV) particles previously described by us. Four viral mRNA species could be identified, including a full-length mRNA. The other three subgenomic mRNAs are generated by single or double splicing events. This expression pattern is reminiscent of the more complex control of virus gene regulation observed, for example, with lenti- or spumavirus strains, although HERV-K shows no sequence homology to human T-lymphotropic virus or human immunodeficiency virus. Sequence analysis of expressed HERV-K genomes revealed non-defective gag genes, a prerequisite for particle formation. Open reading frames were also observed in pol and env. Antisera raised against recombinant gag proteins of HERV-K stained HTDV particles in immunoelectron microscopy, linking them to the HERV-K family.

Base Sequence↗
PubMed1995

An intragenic tandem duplication of genomic DNA is responsible for the f3N mutation of Drosophila melanogaster.

Among the numerous X chromosome-linked forked bristle (f) mutations described in Drosophila melanogaster, one designated f3N exhibits the unusual property of reverting spontaneously to wild type at an inordinate frequency, a frequency that can be increased with x-ray irradiation. In contrast to the f mutants described thus far, all of which are associated with the insertion of mobile DNA elements, f3N is associated with an intragenic duplication of 2.8 kb of genomic DNA that resolves to the normal sequence when reversions occur. Consideration is given to intrachromosomal recombination as the mechanism of reversion and truncation of the forked protein as a cause for the mutant phenotype.

Amino Acid Sequence↗
PubMed1998

A substrate of the centisome 63 type III protein secretion system of Salmonella typhimurium is encoded by a cryptic bacteriophage.

Salmonella enterica has evolved a type III protein secretion system that allows these enteropathogens to translocate effector molecules directly into the host cell cytoplasm. These effectors mediate a variety of responses, including cytoskeletal rearrangements, cytokine production, and in certain cells, the induction of apoptosis. We report here the characterization of a substrate of this secretion system in S. enterica serovar typhimurium (Salmonella typhimurium) that is homologous to the SopE protein of Salmonella dublin implicated in bacterial entry into cultured epithelial cells. The sopE locus is located within a cluster of genes that encode tail and tail fiber proteins of a cryptic P2-like prophage, outside of the centisome 63 pathogenicity island that encodes the invasion-associated type III secretion system. Southern hybridization analysis revealed that sopE is present in only a subset of S. enterica serovars and that the flanking bacteriophage genes are also highly polymorphic. Encoding effector proteins that are delivered through type III secretion systems in highly mobile genetic elements may allow pathogens to adapt rapidly by facilitating the assembly of an appropriate set of effector proteins required for successful replication in a new environment.

Amino Acid Sequence↗
PubMed2000

The Pseudomonas syringae Hrp pathogenicity island has a tripartite mosaic structure composed of a cluster of type III secretion genes bounded by exchangeable effector and conserved effector loci that contribute to parasitic fitness and pathogenicity in plants.

The plant pathogenic bacterium Pseudomonas syringae is divided into pathovars differing in host specificity, with P. syringae pv. syringae (Psy) and P. syringae pv. tomato (Pto) representing particularly divergent pathovars. P. syringae hrp/hrc genes encode a type III protein secretion system that appears to translocate Avr and Hop effector proteins into plant cells. DNA sequence analysis of the hrp/hrc regions in Psy 61, Psy B728a, and Pto DC3000 has revealed a Hrp pathogenicity island (Pai) with a tripartite mosaic structure. The hrp/hrc gene cluster is conserved in all three strains and is flanked by a unique exchangeable effector locus (EEL) and a conserved effector locus (CEL). The EELs begin 3 nt downstream of the stop codon of hrpK and end, after 2.5-7.3 kb of dissimilar intervening DNA with tRNA(Leu)-queA-tgt sequences that are also found in Pseudomonas aeruginosa but without linkage to any Hrp Pai sequences. The EELs encode diverse putative effectors, including HopPsyA (HrmA) in Psy 61 and proteins similar to AvrPphE and the AvrB/AvrC/AvrPphC and AvrBsT/AvrRxv/YopJ protein families in Psy B728a. The EELs also contain mobile genetic element sequences and have a G + C content significantly lower than the rest of the Hrp Pai or the P. syringae genome. The CEL carries at least seven ORFs that are conserved between Psy B728a and Pto DC3000. Deletion of the Pto DC3000 EEL slightly reduces bacterial growth in tomato, whereas deletion of a large portion of the CEL strongly reduces growth and abolishes pathogenicity in tomato.

Bacterial Proteins↗
PubMed1995

Lock on/off disulfides identify the transmembrane signaling helix of the aspartate receptor.

The aspartate receptor of the bacterial chemotaxis pathway regulates the autophosphorylation rate of a cytoplasmic histidine kinase in response to ligand binding. The transmembrane signal, which is transmitted from the periplasmic aspartate-binding domain to the cytoplasmic regulatory domain, is carried by an intramolecular conformational change within the homodimeric receptor structure. The present work uses engineered cysteines and disulfide bonds to probe the nature of this conformational change, focusing in particular on the role of the second transmembrane alpha-helix. Altogether 26 modifications, consisting of 13 cysteine pairs and the corresponding disulfide bonds, have been introduced into the contacts between the second transmembrane helix and adjacent helices. The effects of these modifications on the transmembrane signal have been quantified by in vitro assays which measure (i) ligand binding, (ii) receptor-mediated regulation of kinase activity, and (iii) receptor methylation. All three parameters are observed to be highly sensitive to perturbations of the second transmembrane helix. In particular, 13 of the 26 modifications (6 cysteine pairs and 7 disulfides) significantly increase or decrease aspartate affinity, while 15 of the 26 modifications (6 cysteine pairs and 10 disulfides) destroy transmembrane kinase regulation. Importantly, 3 of the perturbing disulfides are found to lock the receptor in the "on" or "off" signaling state by covalently constraining the second transmembrane helix, demonstrating that it is possible to use engineered disulfides to lock the signaling function of a receptor protein. A separate aspect of the study probes the thermal motions of the second transmembrane helix: 4 disulfides designed to trap large amplitude twisting motions are observed to disrupt function but form readily, suggesting that the helix is mobile. Together the results support a model in which the second transmembrane helix is a mobile signaling element responsible for communicating the transmembrane signal.

Amino Acid Sequence↗
PubMed1997

Characterization of downstream Ras signals that induce alternative protease-dependent invasive phenotypes.

Invasive and metastatic cells require protease expression for migration through the extracellular matrix. Metastatic NIH 3T3 fibroblasts transformed by different activated ras genes showed two different protease phenotypes, rasuPA+/CL- and rasCL+/uPA- (Zhang, J-Y., and Schultz, R. M. (1992) Cancer Research 52, 6682-6689). Phenotype rasuPA+/CL- is dependent on expression of the serine-type protease urokinase plasminogen activator (uPA) and the phenotype rasCL+/uPA- on the cystine-type protease cathepsin L (CL) for lung colonization in experimental metastasis. The existence of multiple invasive phenotypes on ras-isoform transformation implied the activation of alternative pathways downstream from Ras. We now show that c-Raf-1, extracellular signal-regulated protein kinase (ERK)-1, and ERK-2 are hyperphosphorylated, and the ERK activity is high in both the uPA- and CL-dependent ras-transformed invasive phenotypes. Levels of c-Jun and c-Jun NH2-terminal kinase (JNK) activity are also high in the uPA-dependent phenotype, but they are almost undetectable in the CL-dependent phenotype. The uPA Ras-response element is a PEA3/URTF element, and mobility shift assays show a strong PEA3/URTF protein band in the uPA-dependent phenotype. This band is competed by a consensus AP-1 DNA sequence and by antibodies to PEA3 and c-Jun. Thus, the uPA-invasive phenotype appears to require the activation of Ets/PEA3 and c-Jun transcription factors activated by the ERK and JNK pathways, while the CL-invasive phenotype appears to require ERK activity with suppression of JNK and c-Jun activities. These postulates are supported by the introduction of a dominant negative c-Jun, TAM67, into cells of phenotype rasuPA+/CL-, which down-regulated the high uPA mRNA levels characteristic of this phenotype to basal levels and up-regulated basal levels of CL mRNA to levels similar to those observed in cells of phenotype rasCL+/uPA-. We conclude that the JNK pathway acts as a switch between two distinct protease phenotypes that are redundant in their abilities to grow tumors and metastasize.

3T3 Cells↗
PubMed2003

Lithostathine quadruple-helical filaments form proteinase K-resistant deposits in Creutzfeldt-Jakob disease.

Autocatalytic cleavage of lithostathine leads to the formation of quadruple-helical fibrils (QHF-litho) that are present in Alzheimer's disease. Here we show that such fibrils also occur in Creutzfeldt-Jakob and Gerstmann-Sträussler-Scheinker diseases, where they form protease-K-resistant deposits and co-localize with amyloid plaques formed from prion protein. Lithostathine does not appear to change its native-like, globular structure during fibril formation. However, we obtained evidence that a cluster of six conserved tryptophans, positioned around a surface loop, could act as a mobile structural element that can be swapped between adjacent protein molecules, thereby enabling the formation of higher order fibril bundles. Despite their association with these clinical amyloid deposits, QHF-litho differ from typical amyloid fibrils in several ways, for example they produce a different infrared spectrum and cannot bind Congo Red, suggesting that they may not represent amyloid structures themselves. Instead, we suggest that lithostathine constitutes a novel component decorating disease-associated amyloid fibrils. Interestingly, [6,6']bibenzothiazolyl-2,2'-diamine, an agent found previously to disrupt aggregates of huntingtin associated with Huntington's disease, can dissociate lithostathine bundles into individual protofilaments. Disrupting QHF-litho fibrils could therefore represent a novel therapeutic strategy to combat clinical amyloidoses.

Amino Acid Sequence↗