Bat pluripotent stem cells reveal unusual entanglement between host and viruses.

Bats are distinctive among mammals due to their ability to fly, use laryngeal echolocation, and tolerate viruses. However, there are currently no reliable cellular models for studying bat biology or their response to viral infections. Here, we created induced pluripotent stem cells (iPSCs) from two species of bats: the wild greater horseshoe bat (Rhinolophus ferrumequinum) and the greater mouse-eared bat (Myotis myotis). The iPSCs from both bat species showed similar characteristics and had a gene expression profile resembling that of cells attacked by viruses. They also had a high number of endogenous viral sequences, particularly retroviruses. These results suggest that bats have evolved mechanisms to tolerate a large load of viral sequences and may have a more intertwined relationship with viruses than previously thought. Further study of bat iPSCs and their differentiated progeny will provide insights into bat biology, virus host relationships, and the molecular basis of bats' special traits.

Call detail record aggregation methodology impacts infectious disease models informed by human mobility.

This paper demonstrates how two different methods used to calculate population-level mobility from Call Detail Records (CDR) produce varying predictions of the spread of epidemics informed by these data. Our findings are based on one CDR dataset describing inter-district movement in Ghana in 2021, produced using two different aggregation methodologies. One methodology, "all pairs," is designed to retain long distance network connections while the other, "sequential" methodology is designed to accurately reflect the volume of travel between locations. We show how the choice of methodology feeds through models of human mobility to the predictions of a metapopulation SEIR model of disease transmission. We also show that this impact varies depending on the location of pathogen introduction and the transmissibility of infections. For central locations or highly transmissible diseases, we do not observe significant differences between aggregation methodologies on the predicted spread of disease. For less transmissible diseases or those introduced into remote locations, we find that the choice of aggregation methodology influences the speed of spatial spread as well as the size of the peak number of infections in individual districts. Our findings can help researchers and users of epidemiological models to understand how methodological choices at the level of model inputs may influence the results of models of infectious disease transmission, as well as the circumstances in which these choices do not alter model predictions.

Sun protection education for adolescents: a feasibility study of a wait-list controlled trial of an intervention involving a presentation, action planning, and SMS messages and using objective measurement of sun exposure.

BACKGROUND: People increase their risk of melanoma unless they are protected from the harmful effects of sun exposure during childhood and adolescence. We aimed to assess the feasibility of a three-component sun protection intervention- presentation, action planning, and SMS messages - and trial parameters. METHODS: This feasibility wait-list trial was conducted in the United Kingdom in 2018. Students aged 13-15 years were eligible. Feasibility outcomes were collected for recruitment rates; data availability rates for objective measurements of melanin and erythema using a Mexameter and self-reported sunburn occurrences, severity and body location, tanning, sun protection behaviours and Skin Self-Examination (SSE) collected before (baseline) and after the school summer holidays (follow-up); intervention reach, adherence, perceived impact and acceptability. Quantitative data were analysed using descriptive statistics; qualitative data were analysed thematically. RESULTS: Five out of eight schools expressing an interest in participating with four allocated to act as intervention and one control. Four parents/carers opted their child out of the study. Four hundred and eighty-seven out of 724 students on the school register consented to the study at baseline (67%). Three hundred and eighty-five were in intervention group schools. Objective skin measurements were available for 255 (66%) of the intervention group at baseline and 237 (61%) of the group at follow up. Melanin increased; erythema decreased. Complete self-report data were available for 247 (64%) students in the intervention group. The number of students on the school register who attended the presentation and given the booklet was 379 (98%) and gave their mobile phone number was 155 (40%). No intervention component was perceived as more impactful on sun protection behaviours. Adolescents did not see the relevance of sun protection in the UK or for their age group. CONCLUSIONS: This is the first study to use a Mexameter to measure skin colour in adolescents. Erythema (visible redness) lasts no more than three days and its measurement before and after a six week summer holiday may not yield relevant or meaningful data. A major challenge is that adolescents do not see the relevance of sun protection and SSE. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number ISRCTN11141528. Date registered 0/2/03/2018; last edited 31/05/2018. Retrospectively registered.

Increasing participation of people with learning disabilities in bowel screening.

Learning disability nurses have a key role in addressing the health inequalities experienced by people with learning disabilities. People with learning disabilities are less likely to participate in bowel screening than other sectors of the population, despite there being evidence of this population being at an increased risk of developing bowel cancer. There are a range of barriers at individual and systemic levels that impact on participation in bowel screening by people with learning disabilities. Actions to address these barriers have been identified in the literature and learning disability nurses are a key agent of change in enabling people with learning disabilities to participate in the national screening programmes.

Choosing the choice: Reflections on modelling decisions and behaviour in demographic agent-based models.

This paper investigates the issues associated with choosing appropriate models of choice for demographic agent-based models. In particular, we discuss the importance of context, time preference, and dealing with uncertainty in decision modelling, as well as the heterogeneity between agents in their decision-making strategies. The paper concludes by advocating empirically driven, modular, and multi-model approaches to designing simulations of human decision-making, given the lack of an agreed strategy for dealing with any of these issues. Furthermore, we suggest that an iterative process of data collection and simulation experiments, with the latter informing future empirical data collection, should form the basis of such an endeavour. The discussion is illustrated with reference to selected demographic agent-based models, with a focus on migration.

Rb regulates proliferation and rod photoreceptor development in the mouse retina.

The retinoblastoma protein (Rb) regulates proliferation, cell fate specification and differentiation in the developing central nervous system (CNS), but the role of Rb in the developing mouse retina has not been studied, because Rb-deficient embryos die before the retinas are fully formed. We combined several genetic approaches to explore the role of Rb in the mouse retina. During postnatal development, Rb is expressed in proliferating retinal progenitor cells and differentiating rod photoreceptors. In the absence of Rb, progenitor cells continue to divide, and rods do not mature. To determine whether Rb functions in these processes in a cell-autonomous manner, we used a replication-incompetent retrovirus encoding Cre recombinase to inactivate the Rb1(lox) allele in individual retinal progenitor cells in vivo. Combined with data from studies of conditional inactivation of Rb1 using a combination of Cre transgenic mouse lines, these results show that Rb is required in a cell-autonomous manner for appropriate exit from the cell cycle of retinal progenitor cells and for rod development.

The genome sequence of Molossusnigricans (Chiroptera, Molossidae; Miller, 1902).

We present a genome assembly from an individual male Molossus nigricans (Chordata; Mammalia; Chiroptera; Molossidae). The genome sequence is 2.41 gigabases in span. The majority of the assembly is scaffolded into 24 chromosomal pseudomolecules, with the X sex chromosome assembled.

A pilot study of electrocortical activity in dysfunctional anger: decreased frontocortical activation, impaired attention control, and diminished behavioral inhibition.

Dysfunctional anger, though not a primary clinical diagnosis per se, does present clinically as a pathological mood for which treatment is sought. Few studies have probed the neurocortical correlates of dysfunctional anger or assessed if cognitive processes, such as attention, are altered in dysfunctional anger. Though dysfunctional and high trait anger appears to be associated with biased processing of anger-eliciting information, few studies have examined if dysfunctional anger modulates attention more generally. This is a notable gap as volitional attention control is associated with effective emotive regulation, which is impaired in dysfunctional anger and in associated acts of aggression. In this pilot study, we examined performance and electroencephalographic (EEG) profiles during a 12-min continuous performance task (CPT) of sustained attention in 15 adults with dysfunctional anger (Anger group) and 14 controls (control group). The Anger group had fewer hits at the end of the CPT, which correlated with decreased frontocortical activation, suggesting decreased engagement of frontal circuits when attention is taxed. The Anger group had more false alarms overall indicating impaired response inhibition. Increased right cortical activation during the initial portion of CPT existed in the Anger group, perhaps reflecting greater engagement of frontal circuits (i.e. effort) during initial stages of the task compared to controls. Finally, increased overall beta1 power, suggesting increased cortical activation, was noted in the Anger group. These EEG patterns suggest a hypervigilant state in dysfunctional anger, which may interfere with effective attention control and decrease inhibition. Such impairments likely extend beyond the laboratory setting, and may associate with aggressive acts in real life.

Staying with the trouble of networks.

Networks have risen to prominence as intellectual technologies and graphical representations, not only in science, but also in journalism, activism, policy, and online visual cultures. Inspired by approaches taking trouble as occasion to (re)consider and reflect on otherwise implicit knowledge practices, in this article we explore how problems with network practices can be taken as invitations to attend to the diverse settings and situations in which network graphs and maps are created and used in society. In doing so, we draw on cases from our research, engagement and teaching activities involving making networks, making sense of networks, making networks public, and making network tools. As a contribution to "critical data practice," we conclude with some approaches for slowing down and caring for network practices and their associated troubles to elicit a richer picture of what is involved in making networks work as well as reconsidering their role in collective forms of inquiry.

Human-level play in the game of Diplomacy by combining language models with strategic reasoning.

Despite much progress in training artificial intelligence (AI) systems to imitate human language, building agents that use language to communicate intentionally with humans in interactive environments remains a major challenge. We introduce Cicero, the first AI agent to achieve human-level performance in Diplomacy, a strategy game involving both cooperation and competition that emphasizes natural language negotiation and tactical coordination between seven players. Cicero integrates a language model with planning and reinforcement learning algorithms by inferring players' beliefs and intentions from its conversations and generating dialogue in pursuit of its plans. Across 40 games of an anonymous online Diplomacy league, Cicero achieved more than double the average score of the human players and ranked in the top 10% of participants who played more than one game.

Hypoxic preconditioning failure in aging hippocampal neurons: impaired gene expression and rescue with intracellular calcium chelation.

Hypoxic preconditioning in the brain (HPC), a phenomenon whereby noninjurious hypoxia induces resistance to cell death following ischemia, requires the expression of specific genes. Declines in signal transduction pathway activity with aging may decrease the genomic response to HPC and limit its neuroprotective efficacy. To test this, we determined how signal transduction gene expression, intracellular Ca(2+) levels, and phosphorylation of the survival-associated kinase Akt differ in hippocampal slice cultures (HSCs) made from postnatal day 7-10 (P7-10) and 2-year-old rats following HPC. HPC neuroprotection decreased with increasing source animal age, and HPC could not be demonstrated in HCSs made from animals >6 months of age, despite adjusting the duration of hypoxic exposure. Preconditioning protection required the survival kinase Akt in P10 hippocampal slices cultures. In P9 cultures, HPC increased Akt phosphorylation and the expression of prosurvival genes, including Bcl-2, heat shock proteins, protein kinases, c-jun, and NfκB. Lack of increased Akt phosphorylation and a greatly diminished signaling pathway gene response were found in HSCs from aging animals. Moderate and transient increases in [Ca(2+) ](i) during HPC occurred in P7-10 HSCs, but [Ca(2+) ](i) was persistently increased at 1 and 24 hr after preconditioning in HSCs from 2-year-old rats. The intracellular Ca(2+) chelator BAPTA-AM facilitated HPC neuroprotection in 2-year-old HSCs and restored the pattern of post-HPC gene expression seen in immature animals. We conclude that age-related loss of preconditioning may be due to altered intracellular Ca(2+) homeostasis (excess and sustained increase in [Ca(2+) ](i) ) and is a lesion that prevents critical elements of neuroprotective signal transduction.

Insight into the effects of electrochemical factors on host-guest interaction induced signature events in a biological nanopore.

The signature events caused by host-guest interactions in the nanopore system can be used as a novel and characteristic signal in quantitative detection and analysis of various molecules. However, the effect of several electrochemical factors on the host-guest interactions in nanopore still remains unknown. Here, we systematically studied host-guest interactions, especially oscillation of DNA-azide adamantane@cucurbit[6] in α-Hemolysin nanopore under varying pH, concentration of electrolytes and counterions (Li+, Na+, K+). Our results indicate correlations between the change of pH and the duration of the oscillation signal. In addition, the asymmetric electrolyte concentration and the charge of the counterions affects the frequency of signature events in oscillation signals, and even the integrity of the protein nanopore. This study provides insight into the design of a future biosensing platform based on signature oscillation signals of the host-guest interaction within a nanopore.

N-Terminal Derivatization-Assisted Identification of Individual Amino Acids Using a Biological Nanopore Sensor.

Nanopore technology has been employed as a powerful tool for DNA sequencing and analysis. To extend this method to peptide sequencing, a necessary step is to profile individual amino acids (AAs) through their nanopore stochastic signals, which remains a great challenge because of the low signal-to-noise ratio and unpredictable conformational changes of AAs during their translocation through nanopores. We showed that the combination of an N-terminal derivatization strategy of AAs with nanopore technology could lead to effective in situ differentiation of AAs. Four different derivatization reactions have been tested with five selected AAs: Ala, Phe, Tyr, His, and Asp. Using an α-hemolysin nanopore, we demonstrated the feasibility of derivatization-assisted identification of AAs regardless of their charge composition and polarity. The method was further applied to discriminate each individual AA in testing data sets using their established nanopore profiles from training data sets. We envision that this proof-of-concept study will not only pave a way for identification of individual AAs but also lead to future applications in protein/peptide sequencing using the nanopore technology.

Treatment planning and delivery of external beam radiotherapy for pediatric sarcoma: the St. Jude Children's Research Hospital experience.

PURPOSE: To describe and review the radiotherapy (RT) treatment planning and delivery techniques used for pediatric sarcoma patients at St. Jude Children's Research Hospital. The treatment characteristics serve as a baseline for future comparison with developing treatment modalities. PATIENTS AND METHODS: Since January 2003, we have prospectively treated pediatric and young-adult patients with soft-tissue and bone sarcomas on an institutional Phase II protocol evaluating local control and RT-related treatment effects from external-beam RT (conformal or intensity-modulated RT; 83.4%), low-dose-rate brachytherapy (8.3%), or both (8.3%). Here we describe the treatment dosimetry and delivery parameters of the initial 72 patients (median, 11.6 years; range, 1.4-21.6 years). RESULTS: Cumulative doses from all RT modalities ranged from 41.4 to 70.2 Gy (median, 50.4 Gy). Median D(95) and V(95) of the planning target volume of external-beam RT plans were, respectively, 93.4% of the prescribed dose and 94.6% of the target volume for the primary phase and 97.8% and 99.2% for the cone-down/boost phase. The dose-volume histogram statistics for 27 critical organs varied greatly. The spinal cord in 13 of 36 patients received dose >45 Gy (up to 52 Gy in 1 cc) because of tumor proximity. CONCLUSIONS: Planning and delivery of complex multifield external beam RT is feasible in pediatric patients with sarcomas. Improvements on conformity and dose gradients are still desired in many cases with sensitive adjacent critical structures. Long-term follow-up will determine the risk of local failure and the benefit of normal tissue avoidance for this population.

High resolution mapping of soil organic carbon stocks using remote sensing variables in the semi-arid rangelands of eastern Australia.

Efficient and effective modelling methods to assess soil organic carbon (SOC) stock are central in understanding the global carbon cycle and informing related land management decisions. However, mapping SOC stocks in semi-arid rangelands is challenging due to the lack of data and poor spatial coverage. The use of remote sensing data to provide an indirect measurement of SOC to inform digital soil mapping has the potential to provide more reliable and cost-effective estimates of SOC compared with field-based, direct measurement. Despite this potential, the role of remote sensing data in improving the knowledge of soil information in semi-arid rangelands has not been fully explored. This study firstly investigated the use of high spatial resolution satellite data (seasonal fractional cover data; SFC) together with elevation, lithology, climatic data and observed soil data to map the spatial distribution of SOC at two soil depths (0-5cm and 0-30cm) in semi-arid rangelands of eastern Australia. Overall, model performance statistics showed that random forest (RF) and boosted regression trees (BRT) models performed better than support vector machine (SVM). The models obtained moderate results with R2 of 0.32 for SOC stock at 0-5cm and 0.44 at 0-30cm, RMSE of 3.51MgCha-1 at 0-5cm and 9.16MgCha-1 at 0-30cm without considering SFC covariates. In contrast, by including SFC, the model accuracy for predicting SOC stock improved by 7.4-12.7% at 0-5cm, and by 2.8-5.9% at 0-30cm, highlighting the importance of including SFC to enhance the performance of the three modelling techniques. Furthermore, our models produced a more accurate and higher resolution digital SOC stock map compared with other available mapping products for the region. The data and high-resolution maps from this study can be used for future soil carbon assessment and monitoring.

Topotecan combination chemotherapy in two new rodent models of retinoblastoma.

Chemotherapy combined with laser therapy and cryotherapy has improved the ocular salvage rate for children with bilateral retinoblastoma. However, children with late-stage disease often experience recurrence shortly after treatment. To improve the vision salvage rate in advanced bilateral retinoblastoma, we have developed and characterized two new rodent models of retinoblastoma for screening chemotherapeutic drug combinations. The first model is an orthotopic xenograft model in which green fluorescent protein- or luciferase-labeled human retinoblastoma cells are injected into the eyes of newborn rats. The second model uses a replication-incompetent retrovirus (LIA-E(E1A)) encoding the E1A oncogene. Clonal, focal tumors arise from mouse retinal progenitor cells when LIA-E(E1A) is injected into the eyes of newborn p53-/- mice. Using these two models combined with pharmacokinetic studies and cell culture experiments, we have tested the efficacy of topotecan combined with carboplatin and of topotecan combined with vincristine for the treatment of retinoblastoma. The combination of topotecan and carboplatin most effectively halted retinoblastoma progression in our rodent models and was superior to the current triple drug therapy using vincristine, carboplatin, and etoposide. Vincristine had the lowest LC50 in culture but did not reduce tumor growth in our preclinical retinoblastoma models. Taken together, these data suggest that topotecan may be a suitable replacement for etoposide in combination chemotherapy for the treatment of retinoblastoma.

OpenTrials: towards a collaborative open database of all available information on all clinical trials.

OpenTrials is a collaborative and open database for all available structured data and documents on all clinical trials, threaded together by individual trial. With a versatile and expandable data schema, it is initially designed to host and match the following documents and data for each trial: registry entries; links, abstracts, or texts of academic journal papers; portions of regulatory documents describing individual trials; structured data on methods and results extracted by systematic reviewers or other researchers; clinical study reports; and additional documents such as blank consent forms, blank case report forms, and protocols. The intention is to create an open, freely re-usable index of all such information and to increase discoverability, facilitate research, identify inconsistent data, enable audits on the availability and completeness of this information, support advocacy for better data and drive up standards around open data in evidence-based medicine. The project has phase I funding. This will allow us to create a practical data schema and populate the database initially through web-scraping, basic record linkage techniques, crowd-sourced curation around selected drug areas, and import of existing sources of structured and documents. It will also allow us to create user-friendly web interfaces onto the data and conduct user engagement workshops to optimise the database and interface designs. Where other projects have set out to manually and perfectly curate a narrow range of information on a smaller number of trials, we aim to use a broader range of techniques and attempt to match a very large quantity of information on all trials. We are currently seeking feedback and additional sources of structured data.

Reliability and validity of the DSM-IV-TR and proposed DSM-5 criteria for pedophilia: Implications for the ICD-11 and the next DSM.

We tested the inter-rater reliability and criterion-related validity of the DSM-IV-TR pedophilia diagnosis and proposed DSM-5 pedohebephilia diagnosis in a sample of 79 men who had committed child pornography offenses, contact sexual offenses against children, or who were referred because of concerns about whether they had a sexual interest in children. Participants were evaluated by two independent psychiatrists with an interview and questionnaire regarding demographic characteristics, sexual history, and self-reported sexual interests; they also completed phallometric and visual reaction time testing. Kappa was .59 for ever meeting DSM-IV-TR criteria for pedophilia and .52 for ever meeting the proposed DSM-5 criteria for pedohebephilia. Ever meeting DSM-IV-TR diagnosis was significantly related to self-reported index of sexual interest in children (highest AUC=.81, 95% CI=.70-.91, p<.001) and to indices of sexual interest in children from phallometric testing (AUC=.70; 95% CI=.52-.89; p<.05) or a computerized assessment based on visual reaction time and self-report (AUC=.75; 95% CI=.62-.88; p<.005). Ever meeting the proposed DSM-5 "diagnosis" was similarly related to self-report (AUC=.84, 95% CI=.74-.94, p<.001) and to the two objective indices, with AUCs of .69 (95% CI=.53-.85; p<.05) and .77 (95% CI=.64-.89; p<.001), respectively. Because the pDSM-5 criteria did not produce significantly better reliability or validity results and users are more familiar with the current DSM-5 criteria, we believe these results suggest the revision of DSM-5 and development of ICD-11 could benefit from drawing on the current DSM-5 criteria, which are essentially the same as DSM-IV-TR except for a distinction between having a paraphilia (the interest) and a paraphilic disorder (the paraphilia plus clinically significant distress or impairment).