103 research outputs found
On the size of knots in ring polymers
We give two different, statistically consistent definitions of the length l
of a prime knot tied into a polymer ring. In the good solvent regime the
polymer is modelled by a self avoiding polygon of N steps on cubic lattice and
l is the number of steps over which the knot ``spreads'' in a given
configuration. An analysis of extensive Monte Carlo data in equilibrium shows
that the probability distribution of l as a function of N obeys a scaling of
the form p(l,N) ~ l^(-c) f(l/N^D), with c ~ 1.25 and D ~ 1. Both D and c could
be independent of knot type. As a consequence, the knot is weakly localized,
i.e. ~ N^t, with t=2-c ~ 0.75. For a ring with fixed knot type, weak
localization implies the existence of a peculiar characteristic length l^(nu) ~
N^(t nu). In the scaling ~ N^(nu) (nu ~0.58) of the radius of gyration of the
whole ring, this length determines a leading power law correction which is much
stronger than that found in the case of unrestricted topology. The existence of
such correction is confirmed by an analysis of extensive Monte Carlo data for
the radius of gyration. The collapsed regime is studied by introducing in the
model sufficiently strong attractive interactions for nearest neighbor sites
visited by the self-avoiding polygon. In this regime knot length determinations
can be based on the entropic competition between two knotted loops separated by
a slip link. These measurements enable us to conclude that each knot is
delocalized (t ~ 1).Comment: 29 pages, 14 figure
Equilibrium shapes of flat knots
We study the equilibrium shapes of prime and composite knots confined to two
dimensions. Using rigorous scaling arguments we show that, due to self-avoiding
effects, the topological details of prime knots are localised on a small
portion of the larger ring polymer. Within this region, the original knot
configuration can assume a hierarchy of contracted shapes, the dominating one
given by just one small loop. This hierarchy is investigated in detail for the
flat trefoil knot, and corroborated by Monte Carlo simulations.Comment: 4 pages, 3 figure
Type II enteropathy-associated T-cell lymphoma features a unique genomic profile with highly recurrent SETD2 alterations.
Enteropathy-associated T-cell lymphoma (EATL), a rare and aggressive intestinal malignancy of intraepithelial T lymphocytes, comprises two disease variants (EATL-I and EATL-II) differing in clinical characteristics and pathological features. Here we report findings derived from whole-exome sequencing of 15 EATL-II tumour-normal tissue pairs. The tumour suppressor gene SETD2 encoding a non-redundant H3K36-specific trimethyltransferase is altered in 14/15 cases (93%), mainly by loss-of-function mutations and/or loss of the corresponding locus (3p21.31). These alterations consistently correlate with defective H3K36 trimethylation. The JAK/STAT pathway comprises recurrent STAT5B (60%), JAK3 (46%) and SH2B3 (20%) mutations, including a STAT5B V712E activating variant. In addition, frequent mutations in TP53, BRAF and KRAS are observed. Conversely, in EATL-I, no SETD2, STAT5B or JAK3 mutations are found, and H3K36 trimethylation is preserved. This study describes SETD2 inactivation as EATL-II molecular hallmark, supports EATL-I and -II being two distinct entities, and defines potential new targets for therapeutic intervention
Activating mutations in genes related to TCR signaling in angioimmunoblastic and other follicular helper T-cell-derived lymphomas.
Angioimmunoblastic T-cell lymphoma (AITL) and other lymphomas derived from follicular T-helper cells (TFH) represent a large proportion of peripheral T-cell lymphomas (PTCLs) with poorly understood pathogenesis and unfavorable treatment results. We investigated a series of 85 patients with AITL (n = 72) or other TFH-derived PTCL (n = 13) by targeted deep sequencing of a gene panel enriched in T-cell receptor (TCR) signaling elements. RHOA mutations were identified in 51 of 85 cases (60%) consisting of the highly recurrent dominant negative G17V variant in most cases and a novel K18N in 3 cases, the latter showing activating properties in in vitro assays. Moreover, half of the patients carried virtually mutually exclusive mutations in other TCR-related genes, most frequently in PLCG1 (14.1%), CD28 (9.4%, exclusively in AITL), PI3K elements (7%), CTNNB1 (6%), and GTF2I (6%). Using in vitro assays in transfected cells, we demonstrated that 9 of 10 PLCG1 and 3 of 3 CARD11 variants induced MALT1 protease activity and increased transcription from NFAT or NF-κB response element reporters, respectively. Collectively, the vast majority of variants in TCR-related genes could be classified as gain-of-function. Accordingly, the samples with mutations in TCR-related genes other than RHOA had transcriptomic profiles enriched in signatures reflecting higher T-cell activation. Although no correlation with presenting clinical features nor significant impact on survival was observed, the presence of TCR-related mutations correlated with early disease progression. Thus, targeting of TCR-related events may hold promise for the treatment of TFH-derived lymphomas
Abundance of unknots in various models of polymer loops
A veritable zoo of different knots is seen in the ensemble of looped polymer
chains, whether created computationally or observed in vitro. At short loop
lengths, the spectrum of knots is dominated by the trivial knot (unknot). The
fractional abundance of this topological state in the ensemble of all
conformations of the loop of segments follows a decaying exponential form,
, where marks the crossover from a mostly unknotted
(ie topologically simple) to a mostly knotted (ie topologically complex)
ensemble. In the present work we use computational simulation to look closer
into the variation of for a variety of polymer models. Among models
examined, is smallest (about 240) for the model with all segments of the
same length, it is somewhat larger (305) for Gaussian distributed segments, and
can be very large (up to many thousands) when the segment length distribution
has a fat power law tail.Comment: 13 pages, 6 color figure
Bicarbonate Evokes Reciprocal Changes in Intracellular Cyclic di-GMP and Cyclic AMP Levels in Pseudomonas aeruginosa
The formation of Pseudomonas aeruginosa biofilms in cystic fibrosis (CF) is one of the most common causes of morbidity and mortality in CF patients. Cyclic di-GMP and cyclic AMP are second messengers regulating the bacterial lifestyle transition in response to environmental signals. We aimed to investigate the effects of extracellular pH and bicarbonate on intracellular c-di-GMP and cAMP levels, and on biofilm formation. P. aeruginosa was inoculated in a brain–heart infusion medium supplemented with 25 and 50 mM NaCl in ambient air (pH adjusted to 7.4 and 7.7 respectively), or with 25 and 50 mM NaHCO3 in 5% CO2 (pH 7.4 and 7.7). After 16 h incubation, c-di-GMP and cAMP were extracted and their concentrations determined. Biofilm formation was investigated using an xCelligence real-time cell analyzer and by crystal violet assay. Our results show that HCO3− exposure decreased c-di-GMP and increased cAMP levels in a dose-dependent manner. Biofilm formation was also reduced after 48 h exposure to HCO3−. The reciprocal changes in second messenger concentrations were not influenced by changes in medium pH or osmolality. These findings indicate that HCO3− per se modulates the levels of c-di-GMP and cAMP, thereby inhibiting biofilm formation and promoting the planktonic lifestyle of the bacteria
When increasing population density can promote the evolution of metabolic cooperation.
This is the author accepted manuscript. The final version is available from Nature Publishing Group via the DOI in this record.Microbial cooperation drives ecological and epidemiological processes and is affected by the ecology and demography of populations. Population density influences the selection for cooperation, with spatial structure and the type of social dilemma, namely public-goods production or self-restraint, shaping the outcome. While existing theories predict that in spatially structured environments increasing population density can select either for or against cooperation, experimental studies with both public-goods production and self-restraint systems have only ever shown that increasing population density favours cheats. We suggest that the disparity between theory and empirical studies results from experimental procedures not capturing environmental conditions predicted by existing theories to influence the outcome. Our study resolves this issue and provides the first experimental evidence that high population density can favour cooperation in spatially structured environments for both self-restraint and public-goods production systems. Moreover, using a multi-trait mathematical model supported by laboratory experiments we extend this result to systems where the self-restraint and public-goods social dilemmas interact. We thus provide a systematic understanding of how the strength of interaction between the two social dilemmas and the degree of spatial structure within an environment affect selection for cooperation. These findings help to close the current gap between theory and experiments.RJL and IG: European Research Council No. 647292
MathModExp. BJP: Engineering and Physical Sciences Research
Council Doctoral training grant studentship
Ex vivo drug response profiling detects recurrent sensitivity patterns in drug-resistant acute lymphoblastic leukemia
Drug sensitivity and resistance testing on diagnostic leukemia samples should provide important functional information to guide actionable target and biomarker discovery. We provide proof of concept data by profiling 60 drugs on 68 acute lymphoblastic leukemia (ALL) samples mostly from resistant disease in cocultures of bone marrow stromal cells. Patient-derived xenografts retained the original pattern of mutations found in the matched patient material. Stromal coculture did not prevent leukemia cell cycle activity, but a specific sensitivity profile to cell cycle-related drugs identified samples with higher cell proliferation both in vitro and in vivo as leukemia xenografts. In patients with refractory relapses, individual patterns of marked drug resistance and exceptional responses to new agents of immediate clinical relevance were detected. The BCL2inhibitor venetoclax was highly active below 10 nM in B-cell precursor ALL (BCP-ALL) subsets, including MLL-AF4 and TCF3-HLF ALL, and in some T-cell ALLs (T-ALLs), predicting in vivo activity as a single agent and in combination with dexamethasone and vincristine. Unexpected sensitivity to dasatinib with half maximal inhibitory concentration values below 20 nM was detected in 2 independent T-ALL cohorts, which correlated with similar cytotoxic activity of the SRC inhibitor KX2-391 and inhibition of SRC phosphorylation. A patient with refractory T-ALL was treated with dasatinib on the basis of drug profiling information and achieved a 5-month remission. Thus, drug profiling captures disease-relevant features and unexpected sensitivity to relevant drugs, which warrants further exploration of this functional assay in the context of clinical trials to develop drug repurposing strategies for patients with urgent medical needs.Peer reviewe
Genomics and drug profiling of fatal TCF3-HLF-positive acute lymphoblastic leukemia identifies recurrent mutation patterns and therapeutic options.
TCF3-HLF-positive acute lymphoblastic leukemia (ALL) is currently incurable. Using an integrated approach, we uncovered distinct mutation, gene expression and drug response profiles in TCF3-HLF-positive and treatment-responsive TCF3-PBX1-positive ALL. We identified recurrent intragenic deletions of PAX5 or VPREB1 in constellation with the fusion of TCF3 and HLF. Moreover somatic mutations in the non-translocated allele of TCF3 and a reduction of PAX5 gene dosage in TCF3-HLF ALL suggest cooperation within a restricted genetic context. The enrichment for stem cell and myeloid features in the TCF3-HLF signature may reflect reprogramming by TCF3-HLF of a lymphoid-committed cell of origin toward a hybrid, drug-resistant hematopoietic state. Drug response profiling of matched patient-derived xenografts revealed a distinct profile for TCF3-HLF ALL with resistance to conventional chemotherapeutics but sensitivity to glucocorticoids, anthracyclines and agents in clinical development. Striking on-target sensitivity was achieved with the BCL2-specific inhibitor venetoclax (ABT-199). This integrated approach thus provides alternative treatment options for this deadly disease
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