Measuring the knot of non-Hermitian degeneracies and non-commuting braids.

Any system of coupled oscillators may be characterized by its spectrum of resonance frequencies (or eigenfrequencies), which can be tuned by varying the system's parameters. The relationship between control parameters and the eigenfrequency spectrum is central to a range of applications1-3. However, fundamental aspects of this relationship remain poorly understood. For example, if the controls are varied along a path that returns to its starting point (that is, around a 'loop'), the system's spectrum must return to itself. In systems that are Hermitian (that is, lossless and reciprocal), this process is trivial and each resonance frequency returns to its original value. However, in non-Hermitian systems, where the eigenfrequencies are complex, the spectrum may return to itself in a topologically non-trivial manner, a phenomenon known as spectral flow. The spectral flow is determined by how the control loop encircles degeneracies, and this relationship is well understood for [Formula: see text] (where [Formula: see text] is the number of oscillators in the system)4,5. Here we extend this description to arbitrary [Formula: see text]. We show that control loops generically produce braids of eigenfrequencies, and for [Formula: see text] these braids form a non-Abelian group that reflects the non-trivial geometry of the space of degeneracies. We demonstrate these features experimentally for [Formula: see text] using a cavity optomechanical system.

Chromosome segregation in Archaea: SegA- and SegB-DNA complex structures provide insights into segrosome assembly.

Genome segregation is a vital process in all organisms. Chromosome partitioning remains obscure in Archaea, the third domain of life. Here, we investigated the SegAB system from Sulfolobus solfataricus. SegA is a ParA Walker-type ATPase and SegB is a site-specific DNA-binding protein. We determined the structures of both proteins and those of SegA-DNA and SegB-DNA complexes. The SegA structure revealed an atypical, novel non-sandwich dimer that binds DNA either in the presence or in the absence of ATP. The SegB structure disclosed a ribbon-helix-helix motif through which the protein binds DNA site specifically. The association of multiple interacting SegB dimers with the DNA results in a higher order chromatin-like structure. The unstructured SegB N-terminus plays an essential catalytic role in stimulating SegA ATPase activity and an architectural regulatory role in segrosome (SegA-SegB-DNA) formation. Electron microscopy results also provide a compact ring-like segrosome structure related to chromosome organization. These findings contribute a novel mechanistic perspective on archaeal chromosome segregation.

Attachment and antibiotic response of early-stage biofilms studied using resonant hyperspectral imaging.

Many bacterial species readily develop biofilms that act as a protective matrix against external challenge, e.g., from antimicrobial treatment. Therefore, biofilms are often responsible for persistent and recurring infections. Established methods for studying biofilms are either destructive or focus on the biofilm's surface. A non-destructive method that is sensitive to the underside of the biofilm is highly desirable, as it allows studying the penetration of antibiotics through the film. Here, we demonstrate that the high surface sensitivity of resonant hyperspectral imaging provides this capability. The method allows us to monitor the early stages of Escherichia coli biofilm formation, cell attachment and microcolony formation, in-situ and in real-time. We study the response of the biofilm to a number of different antibiotics and verify our observations using confocal microscopy. Based on this ability to closely monitor the surface-bound cells, resonant hyperspectral imaging gives new insights into the antimicrobial resistance of biofilms.

An operon encoding enzymes for synthesis of a putative extracellular carbohydrate attenuates acquired vancomycin resistance in Streptomyces coelicolor.

Actinomycete bacteria use polyprenol phosphate mannose as a lipid-linked sugar donor for extra-cytoplasmic glycosyl transferases that transfer mannose to cell envelope polymers, including glycoproteins and glycolipids. Strains of Streptomyces coelicolor with mutations in the gene ppm1, encoding polyprenol phosphate mannose synthase, and in pmt, encoding a protein O-mannosyltransferase, are resistant to phage ϕC31 and have greatly increased susceptibility to some antibiotics, including vancomycin. In this work, second-site suppressors of the vancomycin susceptibility were isolated. The suppressor strains fell into two groups. Group 1 strains had increased resistance to vancomycin, teicoplanin and ß-lactams, and had mutations in the two-component sensor regulator system encoded by vanSR, leading to upegulation of the vanSRJKHAX cluster. Group 2 strains only had increased resistance to vancomycin and these mostly had mutations in sco2592 or sco2593, genes that are derepressed in the presence of phosphate and are likely to be required for the synthesis of a phosphate-containing extracellular polymer. In some suppressor strains the increased resistance was only observed in media with limited phosphate (mimicking the phenotype of wild-type S. coelicolor), but two strains, DT3017_R21 (ppm1-vanR-) and DT3017_R15 (ppm1- sco2593-), retained resistance on media with high phosphate content. These results support the view that vancomycin resistance in S. coelicolor is a trade-off between mechanisms that confer resistance and at least one that interferes with resistance mediated through the sco2594-sco2593-sco2592 operon.

Disruption of the GDP-mannose synthesis pathway in Streptomyces coelicolor results in antibiotic hyper-susceptible phenotypes.

Actinomycete bacteria use polyprenol phosphate mannose as a lipid linked sugar donor for extra-cytoplasmic glycosyl transferases that transfer mannose to cell envelope polymers, including glycoproteins and glycolipids. We showed recently that strains of Streptomyces coelicolor with mutations in the gene ppm1 encoding polyprenol phosphate mannose synthase were both resistant to phage φC31 and have greatly increased susceptibility to antibiotics that mostly act on cell wall biogenesis. Here we show that mutations in the genes encoding enzymes that act upstream of Ppm1 in the polyprenol phosphate mannose synthesis pathway can also confer phage resistance and antibiotic hyper-susceptibility. GDP-mannose is a substrate for Ppm1 and is synthesised by GDP-mannose pyrophosphorylase (GMP; ManC) which uses GTP and mannose-1-phosphate as substrates. Phosphomannomutase (PMM; ManB) converts mannose-6-phosphate to mannose-1-phosphate. S. coelicolor strains with knocked down GMP activity or with a mutation in sco3028 encoding PMM acquire phenotypes that resemble those of the ppm1- mutants i.e. φC31 resistant and susceptible to antibiotics. Differences in the phenotypes of the strains were observed, however. While the ppm1- strains have a small colony phenotype, the sco3028 :: Tn5062 mutants had an extremely small colony phenotype indicative of an even greater growth defect. Moreover we were unable to generate a strain in which GMP activity encoded by sco3039 and sco4238 is completely knocked out, indicating that GMP is also an important enzyme for growth. Possibly GDP-mannose is at a metabolic branch point that supplies alternative nucleotide sugar donors.

Streptomyces coelicolor strains lacking polyprenol phosphate mannose synthase and protein O-mannosyl transferase are hyper-susceptible to multiple antibiotics.

Polyprenol phosphate mannose (PPM) is a lipid-linked sugar donor used by extra-cytoplasmic glycosyl tranferases in bacteria. PPM is synthesized by polyprenol phosphate mannose synthase, Ppm1, and in most Actinobacteria is used as the sugar donor for protein O-mannosyl transferase, Pmt, in protein glycosylation. Ppm1 and Pmt have homologues in yeasts and humans, where they are required for protein O-mannosylation. Actinobacteria also use PPM for lipoglycan biosynthesis. Here we show that ppm1 mutants of Streptomyces coelicolor have increased susceptibility to a number of antibiotics that target cell wall biosynthesis. The pmt mutants also have mildly increased antibiotic susceptibilities, in particular to ß-lactams and vancomycin. Despite normal induction of the vancomycin gene cluster, vanSRJKHAX, the pmt and ppm1 mutants remained highly vancomycin sensitive indicating that the mechanism of resistance is blocked post-transcriptionally. Differential RNA expression analysis indicated that catabolic pathways were downregulated and anabolic ones upregulated in the ppm1 mutant compared to the parent or complemented strains. Of note was the increase in expression of fatty acid biosynthetic genes in the ppm1- mutant. A change in lipid composition was confirmed using Raman spectroscopy, which showed that the ppm1- mutant had a greater relative proportion of unsaturated fatty acids compared to the parent or the complemented mutant. Taken together, these data suggest that an inability to synthesize PPM (ppm1) and loss of the glycoproteome (pmt- mutant) can detrimentally affect membrane or cell envelope functions leading to loss of intrinsic and, in the case of vancomycin, acquired antibiotic resistance.

Devosia nitraria sp. nov., a novel species isolated from the roots of Nitraria sibirica in China.

An aerobic, Gram-stain negative, short rod-shaped and motile strain, 36-5-1T, was isolated from the roots of Nitraria sibirica in Zhangye city, Gansu province, north-west of China. Phylogenetic analysis based on the 16S rRNA gene sequence and two housekeeping genes (glnA and atpD) indicated that the strain represents a novel species closely related to the Devosia, Rhizobium and Devosia genera with 98.3, 96.2 and 91.1% similarities, respectively. The strain 36-5-1T contained Q-10 as the predominant ubiquinone and 16:0 (36.8%) as the major fatty acid; a large amount of unidentified glycolipid, diphosphatidylglycerol, phosphatidylglycerol and a small amount of unidentified polar lipids were present as polar lipids. In addition, the G+C content of the genomic DNA was 61.7 mol% and the DNA-DNA hybridization with type strains Devosia geojensis BD-c194T and Devosia pacifica NH131T 44.1 ± 1.1 and 40.2 ± 1.7, respectively. Based on chemotaxonomic data and molecular properties, strain 36-5-1T represents a novel species within the genus Devosia, for which the name Devosia nitraria sp. nov. is proposed. The type strain is 36-5-1T (=CGMCC1.15704T=NBRC112416T).

The relationship between somatisation and outcome in patients with severe irritable bowel syndrome.

OBJECTIVE: This study aimed to assess the relationship between somatisation and outcome in patients with severe irritable bowel syndrome (IBS). METHOD: Two hundred fifty-seven patients with severe IBS included in a randomised controlled trial were assessed at baseline and divided into four quartiles on the basis of their somatisation score. The patients were randomised to receive the following over 3 months: brief interpersonal psychotherapy, 20 mg daily of the SSRI antidepressant paroxetine, or treatment as usual. Outcome 1 year after treatment was assessed using the Short Form-36 physical component summary (PCS) score and total costs for posttreatment year. RESULTS: The patients in the quartile with the highest baseline somatisation score had the most severe IBS, the most concurrent psychiatric disorders, and the highest total costs for the year prior to baseline. At 1 year after the end of treatment, however, the patients with marked somatisation, who received psychotherapy or antidepressant, had improved health status compared to those who received usual care: mean (S.E.) PCS scores at 15 months were 36.6 (2.2), 35.5 (1.9), and 26.4 (2.7) for psychotherapy, antidepressant, and treatment-as-usual groups, respectively (adjusted P=.014). Corresponding data for total costs over the year following the trial, adjusted for baseline costs, were pound 1092 (487), pound 1394 (443), and pound 2949 (593) (adjusted P=.050). CONCLUSIONS: Patients with severe IBS who have marked somatisation improve with treatment like other IBS patients and show a greater reduction of costs. Antidepressants and psychotherapy are cost-effective treatments in severe IBS accompanied by marked somatisation.

Nanoscale visualization of a fibrillar array in the cell wall of filamentous cyanobacteria and its implications for gliding motility.

Many filamentous cyanobacteria are motile by gliding, which requires attachment to a surface. There are two main theories to explain the mechanism of gliding. According to the first, the filament is pushed forward by small waves that pass along the cell surface. In the second, gliding is powered by the extrusion of slime through pores surrounding each cell septum. We have previously shown that the cell walls of several motile cyanobacteria possess an array of parallel fibrils between the peptidoglycan and the outer membrane and have speculated that the function of this array may be to generate surface waves to power gliding. Here, we report on a study of the cell surface topography of two morphologically different filamentous cyanobacteria, using field emission gun scanning electron microscopy (FEGSEM) and atomic force microscopy (AFM). FEGSEM and AFM images of Oscillatoria sp. strain A2 confirmed the presence of an array of fibrils, visible as parallel corrugations on the cell surface. These corrugations were also visualized by AFM scanning of fully hydrated filaments under liquid; this has not been achieved before for filamentous bacteria. FEGSEM images of Nostoc punctiforme revealed a highly convoluted, not parallel, fibrillar array. We conclude that an array of parallel fibrils, beneath the outer membrane of Oscillatoria, may function in the generation of thrust in gliding motility. The array of convoluted fibrils in N. punctiforme may have an alternative function, perhaps connected with the increase in outer membrane surface area resulting from the presence of the fibrils.

Does psychological treatment help only those patients with severe irritable bowel syndrome who also have a concurrent psychiatric disorder?

OBJECTIVE: We have previously reported improved health-related quality of life in patients with severe irritable bowel syndrome (IBS) following psychological treatments. In this paper, we examine whether this improvement was associated with improvement in psychological symptoms and was confined to those patients who had concurrent psychiatric disorder. METHOD: Two hundred and fifty-seven patients with severe IBS entering a psychological treatment trial were interviewed using the Schedules for Clinical Assessment in Neuropsychiatry. At entry to the trial and 15 months later, patients were also assessed using the Hamilton Depression Rating Scale, Symptom Cheecklist-90 (SCL-90) and Short Form-36 (SF36) physical component summary score as the main outcome measure. Partial correlation was used to compare changes in SF36 score and changes in psychological scores while controlling for possible confounders, treatment group and baseline scores. Multiple regression analysis was used to examine whether changes in psychological scores, changes in pain and a history of abuse could account for most of the variance of change in SF36 physical component score. RESULTS: Of 257 patients with severe IBS, 107 (42%) had a depressive, panic or generalized anxiety disorder at trial entry. There were moderate but significant correlations (0.21-0.47) between change in the psychological scores and the change in SF36 physical component scores. The correlation coefficients were similar in the groups with and without psychiatric disorder. The superiority of psychotherapy and antidepressant groups over treatment as usual was similar in those with and without psychiatric disorder. Multiple regression found significant independent effects of change in depression, anxiety, somatization and abdominal pain but there was still variance explained by treatment group. CONCLUSIONS: In severe IBS improvement in health-related quality of life following psychotherapy or antidepressants is correlated with, but not explained fully by reduction of psychological scores. A more complete understanding of how these treatments help patients with medically unexplained symptoms will enable us to refine them further.

Outcome in severe irritable bowel syndrome with and without accompanying depressive, panic and neurasthenic disorders.

BACKGROUND: Irritable bowel syndrome often leads to impaired functioning. AIMS: To assess the contribution of psychiatric disorders to impaired outcome in severe irritable bowel syndrome. METHOD: Patients with severe irritable bowel syndrome entering a psychological treatment trial (n=257) were interviewed using the Schedules for Clinical Assessment in Neuropsychiatry. Outcomes were number of days of restricted activity, role limitation (physical) score of the Short Form Health Survey and costs. RESULTS: At baseline, depressive disorder (29% of patients), panic (12%) and neurasthenia (35%) were associated with impairment; number of psychiatric disorders was associated in a dose-response fashion (P=0.005). At follow-up, depressive disorder and neurasthenia were associated with role limitation score. Improved depression was associated with improved role functioning. CONCLUSIONS: Depressive, panic and neurasthenic disorders contribute to poor outcomes in severe irritable bowel syndrome, and appropriate treatment should be available to these patients.

Reported sexual abuse predicts impaired functioning but a good response to psychological treatments in patients with severe irritable bowel syndrome.

OBJECTIVE: We assessed the effect of reported sexual abuse on symptom severity and health-related quality of life in patients with severe irritable bowel syndrome (IBS) undergoing psychological treatments. METHODS: IBS patients entering a treatment trial who reported prior sexual abuse were compared with the remainder in terms of symptom severity and health-related quality of life (SF-36) at trial entry and 15 months later. Analyses used ANCOVA with age, sex, marital status, and treatment group as covariates. We assessed possible mediators using multiple regression analysis. RESULTS: Of 257 patients with severe IBS, 31 (12.1%) reported a history of rape and 28 (10.9%) reported forced, unwanted touching. People who reported abuse were more impaired than the remainder on the SF-36 scales for pain (adjusted p = .023) and physical function (p = .029); these relationships followed a "dose-response" relationship and were mediated by SCL-90 somatization score. At 15 months follow-up, the associations between reported abuse and SF-36 scores were lost because people with reported abuse, especially rape, improved more than the remainder when treated with psychotherapy or paroxetine (selective serotonin reuptake inhibitor antidepressant); this improvement was mediated by change in SCL-90 somatization score. CONCLUSIONS: In severe IBS, the association between self-reported sexual abuse and impaired functioning is mediated by a general tendency to report numerous bodily symptoms. A reported history of abuse is associated with a marked improvement following psychological treatment.

Changes in tolerance to rectal distension correlate with changes in psychological state in patients with severe irritable bowel syndrome.

OBJECTIVE: Reduced tolerance to rectal distension has been regarded as a biological marker for irritable bowel syndrome (IBS), but longitudinal studies are few. This study determined whether change in tolerance to rectal distension after psychological treatments was associated with: 1) change in abdominal pain; 2) change in psychological symptoms; 3) a reported history of sexual abuse. METHODS: Participants completed a visual analogue scale of abdominal pain, SCL-90 and Hamilton rating scale of depression; discomfort threshold to rectal distension was determined using a double random staircase protocol. These were measured at entry to a trial of psychotherapy or paroxetine (selective serotonin reuptake inhibitor antidepressant) and 3 months later (N = 52). Analysis of change scores were adjusted for treatment group and baseline values. RESULTS: Increased tolerance to distension after treatment was associated with reduction in depression (r = -0.37, p =.008) but not abdominal pain. Patients who reported prior sexual abuse showed greater increase in tolerance than the remainder (changes in volume threshold: -24.7 ml [SEM = 12.1] vs. 3.6 ml [SEM = 6.2], adjusted p =.045; changes in pressure threshold: -4.7 [SEM = 1.7] mm Hg vs. 0.96 [SEM=0.9], adjusted p =.005). Multiple regression indicated that reduction in depression score and a reported history of sexual abuse were independently associated with improved tolerance to distension. CONCLUSIONS: In patients with severe IBS, increased tolerance to rectal distension after psychological treatment is significantly associated with improved depression and reported sexual abuse. These results suggest that in some patients with severe IBS psychological rather than biological processes are primarily responsible for reduced tolerance to rectal distension.

The cost-effectiveness of psychotherapy and paroxetine for severe irritable bowel syndrome.

BACKGROUND & AIMS: Psychotherapy and antidepressants are effective in patients with severe irritable bowel syndrome (IBS), but the cost-effectiveness of either treatment in routine practice has not been established. METHODS: Patients with severe IBS were randomly allocated to receive 8 sessions of individual psychotherapy, 20 mg daily of the specific serotonin reuptake inhibitor (SSRI) antidepressant, paroxetine, or routine care by a gastroenterologist and general practitioner. Primary outcome measures of abdominal pain, health-related quality of life, and health care costs were determined after 3 months of treatment and 1 year later. RESULTS: A total of 257 subjects (81% response rate) from 7 hospitals were recruited; 59 of 85 patients (69%) randomized to psychotherapy and 43 of 86 (50%) of the paroxetine group completed the full course of treatment. Both psychotherapy and paroxetine were superior to treatment as usual in improving the physical aspects of health-related quality of life (SF-36 physical component score improvement, 5.2 [SEM, 1.26], 5.8 [SEM, 1.0], and -0.3 [SEM, 1.17]; P < 0.001), but there was no difference in the psychological component. During the follow-up year, psychotherapy but not paroxetine was associated with a significant reduction in health care costs compared with treatment as usual (psychotherapy, $976 [SD, $984]; paroxetine, $1252 [SD, $1616]; and treatment as usual, $1663 [SD, $3177]). CONCLUSIONS: For patients with severe IBS, both psychotherapy and paroxetine improve health-related quality of life at no additional cost.