Statistical mechanics of transcription-factor binding site discovery using Hidden Markov Models

Hidden Markov Models (HMMs) are a commonly used tool for inference of transcription factor (TF) binding sites from DNA sequence data. We exploit the mathematical equivalence between HMMs for TF binding and the "inverse" statistical mechanics of hard rods in a one-dimensional disordered potential to investigate learning in HMMs. We derive analytic expressions for the Fisher information, a commonly employed measure of confidence in learned parameters, in the biologically relevant limit where the density of binding sites is low. We then use techniques from statistical mechanics to derive a scaling principle relating the specificity (binding energy) of a TF to the minimum amount of training data necessary to learn it.Comment: 25 pages, 2 figures, 1 table V2 - typos fixed and new references adde

Effectiveness of targeted enhanced terminal room disinfection on hospital-wide acquisition and infection with multidrug-resistant organisms and Clostridium difficile: a secondary analysis of a multicentre cluster randomised controlled trial with crossover design (BETR Disinfection)

Background: The hospital environment is a source of pathogen transmission. The effect of enhanced disinfection strategies on the hospital-wide incidence of infection has not been investigated in a multicentre, randomised controlled trial. We aimed to assess the effectiveness of four disinfection strategies on hospital-wide incidence of multidrug-resistant organisms and Clostridium difficile in the Benefits of Enhanced Terminal Room (BETR) Disinfection study. Methods: We did a prespecified secondary analysis of the results from the BETR Disinfection study, a pragmatic, multicentre, crossover cluster-randomised trial that assessed four different strategies for terminal room disinfection in nine hospitals in the southeastern USA. Rooms from which a patient with a specific infection or colonisation (due to the target organisms C difficile, meticillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci (VRE), or multidrug-resistant Acinetobacter spp) was discharged were terminally disinfected with one of four strategies: standard disinfection (quaternary ammonium disinfectant, except for C difficile, for which 10% hypochlorite [bleach] was used; reference); standard disinfection and disinfecting ultraviolet light (UV-C), except for C difficile, for which bleach and UV-C was used (UV strategy); 10% hypochlorite (bleach strategy); and bleach and UV-C (bleach and UV strategy). We randomly assigned the sequence of strategies for each hospital (1:1:1:1), and each strategy was used for 7 months, including a 1-month wash-in period and 6 months of data collection. The prespecified secondary outcomes were hospital-wide, hospital-acquired incidence of all target organisms (calculated as number of patients with hospital-acquired infection with a target organism per 10 000 patient days), and hospital-wide, hospital-acquired incidence of each target organism separately. BETR Disinfection is registered with ClinicalTrials.gov, number NCT01579370. Findings: Between April, 2012, and July, 2014, there were 271 740 unique patients with 375 918 admissions. 314 610 admissions met all inclusion criteria (n=73 071 in the reference study period, n=81 621 in the UV study period, n=78 760 in the bleach study period, and n=81 158 in the bleach and UV study period). 2681 incidenct cases of hospital-acquired infection or colonisation occurred during the study. There was no significant difference in the hospital-wide risk of target organism acquisition between standard disinfection and the three enhanced terminal disinfection strategies for all target multidrug-resistant organisms (UV study period relative risk [RR] 0·89, 95% CI 0·79–1·00; p=0·052; bleach study period 0·92, 0·79–1·08; p=0·32; bleach and UV study period 0·99, 0·89–1·11; p=0·89). The decrease in risk in the UV study period was driven by decreases in risk of acquisition of C difficile (RR 0·89, 95% CI 0·80–0·99; p=0·031) and VRE (0·56, 0·31–0·996; p=0·048). Interpretation: Enhanced terminal room disinfection with UV in a targeted subset of high-risk rooms led to a decrease in hospital-wide incidence of C difficile and VRE. Enhanced disinfection overcomes limitations of standard disinfection strategies and is a potential strategy to reduce the risk of acquisition of multidrug-resistant organisms and C difficile. Funding: US Centers for Disease Control and Prevention

Enhanced terminal room disinfection and acquisition and infection caused by multidrug-resistant organisms and Clostridium difficile (the Benefits of Enhanced Terminal Room Disinfection study): a cluster-randomised, multicentre, crossover study

Background Patients admitted to hospital can acquire multidrug-resistant organisms and Clostridium difficile from inadequately disinfected environmental surfaces. We determined the effect of three enhanced strategies for terminal room disinfection (disinfection of a room between occupying patients) on acquisition and infection due to meticillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, C difficile, and multidrug-resistant Acinetobacter. Methods We did a pragmatic, cluster-randomised, crossover trial at nine hospitals in the southeastern USA. Rooms from which a patient with infection or colonisation with a target organism was discharged were terminally disinfected with one of four strategies: reference (quaternary ammonium disinfectant except for C difficile, for which bleach was used); UV (quaternary ammonium disinfectant and disinfecting ultraviolet [UV-C] light except for C difficile, for which bleach and UV-C were used); bleach; and bleach and UV-C. The next patient admitted to the targeted room was considered exposed. Every strategy was used at each hospital in four consecutive 7-month periods. We randomly assigned the sequence of strategies for each hospital (1:1:1:1). The primary outcomes were the incidence of infection or colonisation with all target organisms among exposed patients and the incidence of C difficile infection among exposed patients in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT01579370. Findings 31 226 patients were exposed; 21 395 (69%) met all inclusion criteria, including 4916 in the reference group, 5178 in the UV group, 5438 in the bleach group, and 5863 in the bleach and UV group. 115 patients had the primary outcome during 22 426 exposure days in the reference group (51·3 per 10 000 exposure days). The incidence of target organisms among exposed patients was significantly lower after adding UV to standard cleaning strategies (n=76; 33·9 cases per 10 000 exposure days; relative risk [RR] 0·70, 95% CI 0·50–0·98; p=0·036). The primary outcome was not statistically lower with bleach (n=101; 41·6 cases per 10 000 exposure days; RR 0·85, 95% CI 0·69–1·04; p=0·116), or bleach and UV (n=131; 45·6 cases per 10 000 exposure days; RR 0·91, 95% CI 0·76–1·09; p=0·303) among exposed patients. Similarly, the incidence of C difficile infection among exposed patients was not changed after adding UV to cleaning with bleach (n=38 vs 36; 30·4 cases vs 31·6 cases per 10 000 exposure days; RR 1·0, 95% CI 0·57–1·75; p=0·997). Interpretation A contaminated health-care environment is an important source for acquisition of pathogens; enhanced terminal room disinfection decreases this risk. Funding US Centers for Disease Control and Prevention

Quantum Measurement of a Coupled Nanomechanical Resonator -- Cooper-Pair Box System

We show two effects as a result of considering the second-order correction to the spectrum of a nanomechanical resonator electrostatically coupled to a Cooper-pair box. The spectrum of the Cooper-pair box is modified in a way which depends on the Fock state of the resonator. Similarly, the frequency of the resonator becomes dependent on the state of the Cooper-pair box. We consider whether these frequency shifts could be utilized to prepare the nanomechanical resonator in a Fock state, to perform a quantum non-demolition measurement of the resonator Fock state, and to distinguish the phase states of the Cooper-pair box

Luminescence spectra and kinetics of disordered solid solutions

We have studied both theoretically and experimentally the luminescence spectra and kinetics of crystalline, disordered solid solutions after pulsed excitation. First, we present the model calculations of the steady-state luminescence band shape caused by recombination of excitons localized in the wells of random potential induced by disorder. Classification of optically active tail states of the main exciton band into two groups is proposed. The majority of the states responsible for the optical absorption corresponds to the group of extended states belonging to the percolation cluster, whereas only a relatively small group of “radiative” states forms the steady-state luminescence band. The continuum percolation theory is applied to distinguish the “radiative” localized states, which are isolated in space and have no ways for nonradiative transitions along the tail states. It is found that the analysis of the exciton-phonon interaction gives the information about the character of the localization of excitons. We have shown that the model used describes quite well the experimental cw spectra of CdS(1−c)Sec and ZnSe(1−c)Tec solid solutions. Further, the experimental results are presented for the temporal evolution of the luminescence band. It is shown that the changes of band shape with time come from the interplay of population dynamics of extended states and spatially isolated “radiative” states. Finally, the measurements of the decay of the spectrally integrated luminescence intensity at long delay times are presented. It is shown that the observed temporal behavior can be described in terms of relaxation of separated pairs followed by subsequent exciton formation and radiative recombination. Electron tunneling processes are supposed to be responsible for the luminescence in the long-time limit at excitation below the exciton mobility edge. At excitation by photons with higher energies the diffusion of electrons can account for the observed behavior of the luminescence

Nucleosomes in gene regulation: theoretical approaches

This work reviews current theoretical approaches of biophysics and bioinformatics for the description of nucleosome arrangements in chromatin and transcription factor binding to nucleosomal organized DNA. The role of nucleosomes in gene regulation is discussed from molecular-mechanistic and biological point of view. In addition to classical problems of this field, actual questions of epigenetic regulation are discussed. The authors selected for discussion what seem to be the most interesting concepts and hypotheses. Mathematical approaches are described in a simplified language to attract attention to the most important directions of this field

Age at first birth in women is genetically associated with increased risk of schizophrenia

Prof. Paunio on PGC:n jäsenPrevious studies have shown an increased risk for mental health problems in children born to both younger and older parents compared to children of average-aged parents. We previously used a novel design to reveal a latent mechanism of genetic association between schizophrenia and age at first birth in women (AFB). Here, we use independent data from the UK Biobank (N = 38,892) to replicate the finding of an association between predicted genetic risk of schizophrenia and AFB in women, and to estimate the genetic correlation between schizophrenia and AFB in women stratified into younger and older groups. We find evidence for an association between predicted genetic risk of schizophrenia and AFB in women (P-value = 1.12E-05), and we show genetic heterogeneity between younger and older AFB groups (P-value = 3.45E-03). The genetic correlation between schizophrenia and AFB in the younger AFB group is -0.16 (SE = 0.04) while that between schizophrenia and AFB in the older AFB group is 0.14 (SE = 0.08). Our results suggest that early, and perhaps also late, age at first birth in women is associated with increased genetic risk for schizophrenia in the UK Biobank sample. These findings contribute new insights into factors contributing to the complex bio-social risk architecture underpinning the association between parental age and offspring mental health.Peer reviewe