Similarity of ensembles of trajectories of reversible and irreversible growth processes

Models of bacterial growth tend to be “irreversible,” allowing for the number of bacteria in a colony to increase but not to decrease. By contrast, models of molecular self- assembly are usually “reversible,” allowing for the addition and removal of particles to a structure. Suc processes differ in a fundamental way because only reversible processes possess an equilibrium. Here we show at the mean-field level that dynamic trajectories of reversible and irreversible growth processes are similar in that both feel the influence of attractors, at which growth proceeds without limit but the intensive properties of the system are invariant. Attractors of both processes undergo nonequilibrium phase transitions as model parameters are varied, suggesting a unified way of describing typical properties of reversible and irreversible growth. We also establish a connection at the mean-field level between an irreversible model of growth (the magnetic Eden model) and the equilibrium Ising model, supporting the findings made by other authors using numerical simulations

Assessment of the response of pollinator abundance to environmental pressures using structured expert elicitation

Policy-makers often need to rely on experts with disparate fields of expertise when making policy choices in complex, multi-faceted, dynamic environments such as those dealing with ecosystem services. For policy-makers wishing to make evidence-based decisions which will best support pollinator abundance and pollination services, one of the problems faced is how to access the information and evidence they need, and how to combine it to formulate and evaluate candidate policies. This is even more complex when multiple factors provide influence in combination. The pressures affecting the survival and pollination capabilities of honey bees (Apis mellifera), wild bees, and other pollinators are well documented, but incomplete. In order to estimate the potential effectiveness of various candidate policy choices, there is an urgent need to quantify the effect of various combinations of factors on the pollination ecosystem service. Using high-quality experimental evidence is the most robust approach, but key aspects of the system may not be amenable to experimentation or may be prohibitive based on cost, time and effort. In such cases, it is possible to obtain the required evidence by using structured expert elicitation, a method for quantitatively characterizing the state of knowledge about an uncertain quantity. Here we report and discuss the outputs of the novel use of a structured expert elicitation, designed to quantify the probability of good pollinator abundance given a variety of weather, disease, and habitat scenarios

Contribution of retrotransposition to developmental disorders.

Mobile genetic Elements (MEs) are segments of DNA which can copy themselves and other transcribed sequences through the process of retrotransposition (RT). In humans several disorders have been attributed to RT, but the role of RT in severe developmental disorders (DD) has not yet been explored. Here we identify RT-derived events in 9738 exome sequenced trios with DD-affected probands. We ascertain 9 de novo MEs, 4 of which are likely causative of the patient's symptoms (0.04%), as well as 2 de novo gene retroduplications. Beyond identifying likely diagnostic RT events, we estimate genome-wide germline ME mutation rate and selective constraint and demonstrate that coding RT events have signatures of purifying selection equivalent to those of truncating mutations. Overall, our analysis represents a comprehensive interrogation of the impact of retrotransposition on protein coding genes and a framework for future evolutionary and disease studies

Evaluation of the feasibility, diagnostic yield, and clinical utility of rapid genome sequencing in infantile epilepsy (Gene-STEPS): an international, multicentre, pilot cohort study

BACKGROUND: Most neonatal and infantile-onset epilepsies have presumed genetic aetiologies, and early genetic diagnoses have the potential to inform clinical management and improve outcomes. We therefore aimed to determine the feasibility, diagnostic yield, and clinical utility of rapid genome sequencing in this population. METHODS: We conducted an international, multicentre, cohort study (Gene-STEPS), which is a pilot study of the International Precision Child Health Partnership (IPCHiP). IPCHiP is a consortium of four paediatric centres with tertiary-level subspecialty services in Australia, Canada, the UK, and the USA. We recruited infants with new-onset epilepsy or complex febrile seizures from IPCHiP centres, who were younger than 12 months at seizure onset. We excluded infants with simple febrile seizures, acute provoked seizures, known acquired cause, or known genetic cause. Blood samples were collected from probands and available biological parents. Clinical data were collected from medical records, treating clinicians, and parents. Trio genome sequencing was done when both parents were available, and duo or singleton genome sequencing was done when one or neither parent was available. Site-specific protocols were used for DNA extraction and library preparation. Rapid genome sequencing and analysis was done at clinically accredited laboratories, and results were returned to families. We analysed summary statistics for cohort demographic and clinical characteristics and the timing, diagnostic yield, and clinical impact of rapid genome sequencing. FINDINGS: Between Sept 1, 2021, and Aug 31, 2022, we enrolled 100 infants with new-onset epilepsy, of whom 41 (41%) were girls and 59 (59%) were boys. Median age of seizure onset was 128 days (IQR 46-192). For 43 (43% [binomial distribution 95% CI 33-53]) of 100 infants, we identified genetic diagnoses, with a median time from seizure onset to rapid genome sequencing result of 37 days (IQR 25-59). Genetic diagnosis was associated with neonatal seizure onset versus infantile seizure onset (14 [74%] of 19 vs 29 [36%] of 81; p=0·0027), referral setting (12 [71%] of 17 for intensive care, 19 [44%] of 43 non-intensive care inpatient, and 12 [28%] of 40 outpatient; p=0·0178), and epilepsy syndrome (13 [87%] of 15 for self-limited epilepsies, 18 [35%] of 51 for developmental and epileptic encephalopathies, 12 [35%] of 34 for other syndromes; p=0·001). Rapid genome sequencing revealed genetic heterogeneity, with 34 unique genes or genomic regions implicated. Genetic diagnoses had immediate clinical utility, informing treatment (24 [56%] of 43), additional evaluation (28 [65%]), prognosis (37 [86%]), and recurrence risk counselling (all cases). INTERPRETATION: Our findings support the feasibility of implementation of rapid genome sequencing in the clinical care of infants with new-onset epilepsy. Longitudinal follow-up is needed to further assess the role of rapid genetic diagnosis in improving clinical, quality-of-life, and economic outcomes. FUNDING: American Academy of Pediatrics, Boston Children's Hospital Children's Rare Disease Cohorts Initiative, Canadian Institutes of Health Research, Epilepsy Canada, Feiga Bresver Academic Foundation, Great Ormond Street Hospital Charity, Medical Research Council, Murdoch Children's Research Institute, National Institute of Child Health and Human Development, National Institute for Health and Care Research Great Ormond Street Hospital Biomedical Research Centre, One8 Foundation, Ontario Brain Institute, Robinson Family Initiative for Transformational Research, The Royal Children's Hospital Foundation, University of Toronto McLaughlin Centre

A Self-Assembling Lanthanide Molecular Nanoparticle for Optical Imaging

Chromophores that incorporate f-block elements have considerable potential for use in bioimaging applications because of their advantageous photophysical properties compared to organic dye, which are currently widely used. We are developing new classes of lanthanide-based self-assembling molecular nanoparticles as reporters for imaging and as multi-functional nanoprobes or nanosensors for use with biological samples. One class of these materials, which we call lanthanide "nano-drums", are homogeneous 4d-4f clusters approximately 25 to 30 angstrom in diameter. These are capable of emitting from the visible to near-infrared wavelengths. Here, we present the synthesis, crystal structure, photophysical properties and comparative cytotoxicity data for a 32 metal Eu-Cd nano-drum [Eu8Cd24L12(OAc)(48)] (1). We also explored the imaging capabilities of this nano-drum using epifluorescence, TIRF, and two-photon microscopy platforms.Welch Foundation F-816, F-1018, F1515Ministry of High Education (MOHE), Malaysia under High Impact Research (HIR) - MOHE project UM.C/625/1/HIR/MoE/CHAN/13/6 H-50001-00-A000034NIH/NIAID 1U01AI078008-3Centre for Blast Injury Study at Imperial College LondonCPRIT R1003NIH-NCI CA68682National Institutes of HealthNational Science FoundationCancer Prevention Research Institute of TexasNational Science Foundation CHE-0741973Chemistr

DNA Specificity Determinants Associate with Distinct Transcription Factor Functions

To elucidate how genomic sequences build transcriptional control networks, we need to understand the connection between DNA sequence and transcription factor binding and function. Binding predictions based solely on consensus predictions are limited, because a single factor can use degenerate sequence motifs and because related transcription factors often prefer identical sequences. The ETS family transcription factor, ETS1, exemplifies these challenges. Unexpected, redundant occupancy of ETS1 and other ETS proteins is observed at promoters of housekeeping genes in T cells due to common sequence preferences and the presence of strong consensus motifs. However, ETS1 exhibits a specific function in T cell activation; thus, unique transcriptional targets are predicted. To uncover the sequence motifs that mediate specific functions of ETS1, a genome-wide approach, chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq), identified both promoter and enhancer binding events in Jurkat T cells. A comparison with DNase I sensitivity both validated the dataset and also improved accuracy. Redundant occupancy of ETS1 with the ETS protein GABPA occurred primarily in promoters of housekeeping genes, whereas ETS1 specific occupancy occurred in the enhancers of T cell–specific genes. Two routes to ETS1 specificity were identified: an intrinsic preference of ETS1 for a variant of the ETS family consensus sequence and the presence of a composite sequence that can support cooperative binding with a RUNX transcription factor. Genome-wide occupancy of RUNX factors corroborated the importance of this partnership. Furthermore, genome-wide occupancy of co-activator CBP indicated tight co-localization with ETS1 at specific enhancers, but not redundant promoters. The distinct sequences associated with redundant versus specific ETS1 occupancy were predictive of promoter or enhancer location and the ontology of nearby genes. These findings demonstrate that diversity of DNA binding motifs may enable variable transcription factor function at different genomic sites

Dopaminergic Influences on Emotional Decision Making in Euthymic Bipolar Patients

We recently reported that the D2/D3 agonist pramipexole may have pro-cognitive effects in euthymic patients with bipolar disorder (BPD); however, the emergence of impulse-control disorders has been documented in Parkinson\u27s disease (PD) after pramipexole treatment. Performance on reward-based tasks is altered in healthy subjects after a single dose of pramipexole, but its potential to induce abnormalities in BPD patients is unknown. We assessed reward-dependent decision making in euthymic BPD patients pre- and post 8 weeks of treatment with pramipexole or placebo by using the Iowa Gambling Task (IGT). The IGT requires subjects to choose among four card decks (two risky and two conservative) and is designed to promote learning to make advantageous (conservative) choices over time. Thirty-four BPD patients completed both assessments (18 placebo and 16 pramipexole). Baseline performance did not differ by treatment group (F = 0.63; p = 0.64); however, at week 8, BPD patients on pramipexole demonstrated a significantly greater tendency to make increasingly high-risk, high-reward choices across the five blocks, whereas the placebo group\u27s pattern was similar to that reported in healthy individuals (treatment x time x block interaction,

Mass Assembly of Stellar Systems and Their Evolution With the Sma (Masses). Multiplicity and the Physical Environment in L1448n

We present continuum and molecular line observations at 230 and 345 GHz from the Submillimeter Array (SMA) toward three protostars in the Perseus L1448N region. The data are from the large project "Mass Assembly of Stellar Systems and their Evolution with the SMA." Three dust continuum sources, Source B, Source NW, and Source A, are detected at both frequencies. These sources have corresponding emission peaks in C18O ($J=2\to 1$), 13CO ($J=2\to 1$), and HCO+ ($J=4\to 3$), and have offsets with N2D+ ($J=3\to 2$) peaks. High angular resolution data from a complementary continuum survey with the Karl G. Jansky Very Large Array show that Source B is associated with three 8 mm continuum objects, Source NW with two, and Source A remains single. These results suggest that multiplicity in L1448N exists at different spatial scales from a few thousand AU to <100 AU. Velocity gradients in each source obtained from two-dimensional fits to the SMA C18O emission are found to be perpendicular to within 20° of the outflow directions as revealed by 12CO ($J=2\to 1$). We have observed that Sources B and NW with multiplicity have higher densities than Source A without multiplicity. This suggests that thermal Jeans fragmentation can be relevant in the fragmentation process. However, we have not observed a difference in the ratio between rotational and gravitational energy between sources with and without multiplicity. We also have not observed a trend between non-thermal velocity dispersions and the level of fragmentation. Our study has provided the first direct and comprehensive comparison between multiplicity and core properties in low-mass protostars, although based on small number statistics.Astronom