Cohesin biology meets the loop extrusion model

Extensive research has revealed that cohesin acts as a topological device, trapping chromosomal DNA within a large tripartite ring. In so doing, cohesin contributes to the formation of compact and organized genomes. How exactly the cohesin subunits interact, how it opens, closes, and translocates on chromatin, and how it actually tethers DNA strands together are still being elucidated. A comprehensive understanding of these questions will shed light on how cohesin performs its many functions, including its recently proposed role as a chromatid loop extruder. Here, we discuss this possibility in light of our understanding of the molecular properties of cohesin complexes

Interpretations of Presburger Arithmetic in Itself

Presburger arithmetic PrA is the true theory of natural numbers with addition. We study interpretations of PrA in itself. We prove that all one-dimensional self-interpretations are definably isomorphic to the identity self-interpretation. In order to prove the results we show that all linear orders that are interpretable in (N,+) are scattered orders with the finite Hausdorff rank and that the ranks are bounded in terms of the dimension of the respective interpretations. From our result about self-interpretations of PrA it follows that PrA isn't one-dimensionally interpretable in any of its finite subtheories. We note that the latter was conjectured by A. Visser.Comment: Published in proceedings of LFCS 201

Maximum tumor diameter is associated with event-free survival in PET-negative patients with stage I/IIA Hodgkin lymphoma.

Introduction: the high cure rates achieved in early-stage (ES) Hodgkin lymphoma (HL) are one of the great successes of hemato-oncology, but late treatment-related toxicity undermines long-term survival. Improving overall survival and quality of life further will require maintaining disease control while potentially de-escalating chemotherapy and/or omitting radiotherapy to reduce late toxicity. Accurate stratification of patients is required to facilitate individualized treatment approaches. Response assessment using 18F-fluorodeoxyglucose positron emission tomography (PET) is a powerful predictor of outcome in HL,1,2 and has been used in multiple studies, including the United Kingdom National Cancer Research Institute Randomised Phase III Trial to Determine the Role of FDG–PET Imaging in Clinical Stages IA/IIA Hodgkin’s Disease (UK NCRI RAPID) trial, to investigate whether patients achieving complete metabolic remission (CMR) can be treated with chemotherapy alone.3-5 These PET-adapted trials have demonstrated that omitting radiotherapy results in higher relapse rates, but without compromising overall survival.3-5 For the 75% of patients who achieved CMR in RAPID, neither baseline clinical risk stratification (favorable/unfavorable) nor PET (Deauville score 1/2) predicted disease relapse; additional biomarkers are needed.1 Tumor bulk has long been recognized as prognostic in HL,1,6 but there remains uncertainty about the significance and definition of bulk in the era of PET-adapted treatment.7 We performed a subsidiary analysis of RAPID to assess the prognostic value of baseline maximum tumor dimension (MTD) in patients achieving CMR. Methods: ee have previously reported the RAPID trial design, primary results, and outcomes according to pretreatment risk stratification and PET score.1,3 Patients were aged 16 to 75 years with untreated ES-HL and without B-symptoms or mediastinal bulk (mass > 1/3 internal mediastinal diameter at T5/6).6 Metabolic response after 3 cycles of ABVD chemotherapy (doxorubicin, bleomycin, vinblastine, and dacarbazine) was centrally assessed using PET (N = 562). Patients with CMR (ie, Deauville score 1-2) were randomly assigned to receive involved field radiotherapy (IFRT; n = 208) or no further therapy (NFT; n = 211). PET-positive patients (score, 3-5; n = 143) received a fourth cycle of ABVD and IFRT. Baseline disease assessment was performed by computed tomography, and bidimensional target lesion measurements were reported by local radiologists in millimeters. The association of baseline MTD with HL-related event-free survival (EFS: progression or HL-related death) and progression-free survival (PFS) (progression or any-cause death) was assessed using Kaplan-Meier and Cox regression analyses. Non-HL deaths were either related to primary treatment toxicity or occurred in HL remission.1 United Kingdom ethical approval for the RAPID trial was via the UK Multicentre Research ethics committee. Results and discussion: baseline patient characteristics have been previously described.1 Median age was 34 years (range, 16-75 years); 184 (37.4%) of 492 patients had unfavorable risk by European Organisation for Research and Treatment of Cancer criteria, and 155 (32.3%) of 480 by German Hodgkin Study Groupcriteria. Median MTD for patients achieving CMR was 3.0 cm (interquartile range, 2.0-4.0 cm) and 3.0 cm (interquartile range, 1.8-4.5 cm) in the NFT and IFRT groups, respectively, whereas PET-positive patients had a median MTD of 3.9 cm (interquartile range, 2.8-5.1 cm). After a median follow-up of 61.6 m, 44 HL progression events occurred: 21 NFT, 9 IFRT and 14 PET-positive. No patient received salvage treatment without documented progression. Only 5 HL-related deaths occurred (1 IFRT, 4 PET-positive), and 12 non-HL deaths (4 NFT, 6 IFRT, 2 PET-positive).1 For patients with CMR (N = 419), there was a strong association between MTD and EFS (hazard ratio [HR], 1.19; 95% confidence interval [CI], 1.02-1.39; P = .02), adjusting for treatment group, with an approximate 19% increase in HL risk per centimeter increase in MTD. The association was similar in both treatment groups (NFT HR, 1.20 [95% CI, 0.99-1.44; P = .06]; IFRT HR, 1.19 [95% CI, 0.92-1.55; P = .19]). The observed effect sizes did not markedly change after adjusting for baseline clinical risk factors, and similar results were observed for PFS (supplemental Table 1). In contrast, for PET-positive patients, there was no association between MTD and EFS (HR, 0.88; 95% CI, 0.70-1.11; P = .29) or PFS (HR, 0.87; 95% CI, 0.70-1.08; P = .21). In an exploratory analysis within the NFT group, MTD was dichotomized using increasing 1-cm intervals to investigate the relationship between MTD thresholds and EFS. The largest effect size was observed with an MTD threshold of ≥5 cm (Table 1). Similar results were observed for PFS; this threshold also performed best in time-dependent receiver operating characteristic curve analyses. It was not possible to assess MTD thresholds in the IFRT group with only 9 events. Among all randomized patients, 79 (18.9%) had MTD of ≥5 cm, the majority with mediastinal (n = 43), supraclavicular (n = 17), or cervical (n = 16) locations. Five-year EFS for patients with MTD of ≥5 cm randomly assigned to NFT and IFRT was 79.3% (n = 39; 95% CI, 66.6%-92.0%) and 94.9% (n = 40; 95% CI, 88.0%-100%), respectively (P = .03; Figure 1)

Randomisation and Derandomisation in Descriptive Complexity Theory

We study probabilistic complexity classes and questions of derandomisation from a logical point of view. For each logic L we introduce a new logic BPL, bounded error probabilistic L, which is defined from L in a similar way as the complexity class BPP, bounded error probabilistic polynomial time, is defined from PTIME. Our main focus lies on questions of derandomisation, and we prove that there is a query which is definable in BPFO, the probabilistic version of first-order logic, but not in Cinf, finite variable infinitary logic with counting. This implies that many of the standard logics of finite model theory, like transitive closure logic and fixed-point logic, both with and without counting, cannot be derandomised. Similarly, we present a query on ordered structures which is definable in BPFO but not in monadic second-order logic, and a query on additive structures which is definable in BPFO but not in FO. The latter of these queries shows that certain uniform variants of AC0 (bounded-depth polynomial sized circuits) cannot be derandomised. These results are in contrast to the general belief that most standard complexity classes can be derandomised. Finally, we note that BPIFP+C, the probabilistic version of fixed-point logic with counting, captures the complexity class BPP, even on unordered structures

Conserved noncoding sequences highlight shared components of regulatory networks in dicotyledonous plants

Conserved noncoding sequences (CNSs) in DNA are reliable pointers to regulatory elements controlling gene expression. Using a comparative genomics approach with four dicotyledonous plant species (Arabidopsis thaliana, papaya [Carica papaya], poplar [Populus trichocarpa], and grape [Vitis vinifera]), we detected hundreds of CNSs upstream of Arabidopsis genes. Distinct positioning, length, and enrichment for transcription factor binding sites suggest these CNSs play a functional role in transcriptional regulation. The enrichment of transcription factors within the set of genes associated with CNS is consistent with the hypothesis that together they form part of a conserved transcriptional network whose function is to regulate other transcription factors and control development. We identified a set of promoters where regulatory mechanisms are likely to be shared between the model organism Arabidopsis and other dicots, providing areas of focus for further research

Descriptive Complexity of Deterministic Polylogarithmic Time and Space

We propose logical characterizations of problems solvable in deterministic polylogarithmic time (PolylogTime) and polylogarithmic space (PolylogSpace). We introduce a novel two-sorted logic that separates the elements of the input domain from the bit positions needed to address these elements. We prove that the inflationary and partial fixed point vartiants of this logic capture PolylogTime and PolylogSpace, respectively. In the course of proving that our logic indeed captures PolylogTime on finite ordered structures, we introduce a variant of random-access Turing machines that can access the relations and functions of a structure directly. We investigate whether an explicit predicate for the ordering of the domain is needed in our PolylogTime logic. Finally, we present the open problem of finding an exact characterization of order-invariant queries in PolylogTime.Comment: Submitted to the Journal of Computer and System Science

Characterizing Polytobacco Use Trajectories and Their Associations With Substance Use and Mental Health Across Mid-Adolescence.

Background:Polytobacco product use is suspected to be common, dynamic across time, and increase risk for adverse behavioral outcomes. We statistically modeled characteristic types of polytobacco use trajectories during mid-adolescence and tested their prospective association with substance use and mental health problems. Methods:Adolescents (N = 3393) in Los Angeles, CA, were surveyed semiannually from 9th to 11th grade. Past 6-month combustible cigarette, e-cigarette, or hookah use (yes/no) over four assessments were analyzed using parallel growth mixture modeling to identify a parsimonious set of polytobacco use trajectories. A tobacco product use trajectory group was used to predict substance use and mental health at the fifth assessment. Results:Three profiles were identified: (1) tobacco nonusers (N = 2291, 67.5%) with the lowest use prevalence (<3%) of all products across all timepoints; (2) polyproduct users (N = 920, 27.1%) with moderate use prevalence of each product (8-35%) that escalated for combustible cigarettes but decreased for e-cigarettes and hookah across time; and (3) chronic polyproduct users (N = 182, 5.4%) with high prevalence of each product use (38-86%) that escalated for combustible cigarettes and e-cigarettes. Nonusers, polyproduct users, and chronic polyproduct users reported successively higher alcohol, marijuana, and illicit drug use and ADHD at the final follow-up, respectively. Both tobacco using groups (vs. nonusers) reported greater odds of depression and anxiety at the final follow-up but did not differ from each other. Conclusions:Adolescent polytobacco use may involve a common moderate risk trajectory and a less common high-risk chronic trajectory. Both trajectories predict substance use and mental health symptomology. Implications:Variation in use and co-use of combustible cigarette, e-cigarette, and hookah use in mid-adolescence can be parsimoniously characterized by a small set common trajectory profiles in which polyproduct use are predominant patterns of tobacco product use, which predict adverse behavioral outcomes. Prevention and policy addressing polytobacco use (relative to single product use) may be optimal tobacco control strategies for youth, which may in turn prevent other forms of substance use and mental health problems

On Second-Order Monadic Monoidal and Groupoidal Quantifiers

We study logics defined in terms of second-order monadic monoidal and groupoidal quantifiers. These are generalized quantifiers defined by monoid and groupoid word-problems, equivalently, by regular and context-free languages. We give a computational classification of the expressive power of these logics over strings with varying built-in predicates. In particular, we show that ATIME(n) can be logically characterized in terms of second-order monadic monoidal quantifiers

Investigation of initiation of gigantic jets connecting thunderclouds to the ionosphere

The initiation of giant electrical discharges called as "gigantic jets" connecting thunderclouds to the ionosphere is investigated by numerical simulation method in this paper. Using similarity relations, the triggering conditions of streamer formation in laboratory situations are extended to form a criterion of initiation of gigantic jets. The energy source causing a gigantic jet is considered due to the quasi-electrostatic field generated by thunderclouds. The electron dynamics from ionization threshold to streamer initiation are simulated by the Monte Carlo technique. It is found that gigantic jets are initiated at a height of ~18-24 km. This is in agreement with the observations. The method presented in this paper could be also applied to the analysis of the initiation of other discharges such as blue jets and red sprites.Comment: 12th International Congress on Plasma Physics, 25-29 October 2004, Nice (France

Credimus

We believe that economic design and computational complexity---while already important to each other---should become even more important to each other with each passing year. But for that to happen, experts in on the one hand such areas as social choice, economics, and political science and on the other hand computational complexity will have to better understand each other's worldviews. This article, written by two complexity theorists who also work in computational social choice theory, focuses on one direction of that process by presenting a brief overview of how most computational complexity theorists view the world. Although our immediate motivation is to make the lens through which complexity theorists see the world be better understood by those in the social sciences, we also feel that even within computer science it is very important for nontheoreticians to understand how theoreticians think, just as it is equally important within computer science for theoreticians to understand how nontheoreticians think