Search

Exploratory analyses were conducted on more than two dozen measures to assess the claims of the DARPA program in Artificial Social Intelligence for Successful Teams (ASIST). These claims (see Figure 1) were that social science implemented in Analytic Components (AC) (i.e., measurement agents) informs a Machine Theory of Teams (MToT) implemented in Artificial Social Intelligence (ASI), which generates interventions to influence team state, team processes, and mission effects. In this document, we describe measures and analysis strategy, then turn to inferential, descriptive, and qualitative exploratory analyses of the measurement data for each element of the storyline above. Additional information concerning the survey instruments, AC measures, and the study are available in the ASIST Study-3 Pre-Registration document on OSF (https://osf.io/jwyvf).

Pediatric brain tumors are the leading cause of cancer-related death in children in the United States and contribute a disproportionate number of potential years of life lost compared to adult cancers. Moreover, survivors frequently suffer long-term side effects, including secondary cancers. The Children’s Brain Tumor Network (CBTN) is a multi-institutional international clinical research consortium created to advance therapeutic development through the collection and rapid distribution of biospecimens and data via open-science research platforms for real-time access and use by the global research community. The CBTN’s 32 member institutions utilize a shared regulatory governance architecture at the Children’s Hospital of Philadelphia to accelerate and maximize the use of biospecimens and data. As of August 2022, CBTN has enrolled over 4,700 subjects, over 1,500 parents, and collected over 65,000 biospecimen aliquots for research. Additionally, over 80 preclinical models have been developed from collected tumors. Multi-omic data for over 1,000 tumors and germline material is currently available with data generation for > 5,000 samples underway. To our knowledge, CBTN provides the largest open-access pediatric brain tumor multi-omic dataset annotated with longitudinal clinical and outcome data, imaging, associated biospecimens, child-parent genomic pedigrees, andin vivoandin vitropreclinical models. Empowered by NIH-supported platforms such as the Kids First Data Resource and the Childhood Cancer Data Initiative, the CBTN continues to expand the resources needed for scientists to accelerate translational impact for improved outcomes and quality of life for children with brain and spinal cord tumors.

The data formats for gamma-ray astronomy contain high-level data format specifications, ranging from event lists and instrument response formats to maps, spectra and lightcurves. This version 0.3 describes the formats currently in use and under development by various instruments (e.g. CTA, HESS, MAGIC, VERITAS, FACT, Fermi-LAT) and science tools (e.g. Gammapy and Gammalib). The data formats for gamma-ray astronomy are also available athttps://gamma-astro-data-formats.readthedocs.io/ and are written and discussed athttps://github.com/open-gamma-ray-astro/gamma-astro-data-formats .

In amyloid-positive individuals at risk for Alzheimer's disease (AD), high soluble 42-amino acid amyloid-β (Aβ42) levels are associated with normal cognition. It is unknown if this relationship applies longitudinally in a genetic cohort.To test the hypothesis that high Aβ42 preserves normal cognition in amyloid-positive individuals with Alzheimer's disease (AD)-causing mutations (APP, PSEN1, or PSEN2) to a greater extent than lower levels of brain amyloid, cerebrospinal fluid (CSF) phosphorylated tau (p-tau), or total tau (t-tau).Cognitive progression was defined as any increase in Clinical Dementia Rating (CDR = 0, normal cognition; 0.5, very mild dementia; 1, mild dementia) over 3 years. Amyloid-positivity was defined as a standard uptake value ratio (SUVR) ≥1.42 by Pittsburgh compound-B positron emission tomography (PiB-PET). We used modified Poisson regression models to estimate relative risk (RR), adjusted for age at onset, sex, education, APOE4 status, and duration of follow-up. The results were confirmed with multiple sensitivity analyses, including Cox regression.Of 232 mutation carriers, 108 were PiB-PET-positive at baseline, with 43 (39.8% ) meeting criteria for progression after 3.3±2.0 years. Soluble Aβ42 levels were higher among CDR non-progressors than CDR progressors. Higher Aβ42 predicted a lower risk of progression (adjusted RR, 0.36; 95% confidence interval [CI], 0.19-0.67; p = 0.002) better than lower SUVR (RR, 0.81; 95% CI, 0.68-0.96; p = 0.018). CSF Aβ42 levels predicting lower risk of progression increased with higher SUVR levels.High CSF Aβ42 levels predict normal cognition in amyloid-positive individuals with AD-causing genetic mutations.

Participants will engage in a ~10-min screening session to check their capability to play Minecraft via the Parsec platform. Once determined that they are eligible, they will be given an intake survey of about 20 minutes to finish on their own. Submission of the survey will enable them to sign up for the Session 2 Minecraft experiment. Then, teams of three qualified participants will be scheduled to participate in a 2-hour experiment that involves searching for victims and rescuing them in a Minecraft task environment. During that experiment, participants will receive training videos that introduces the rules of the game and provides some hands-on experience with the environment before two 17-min missions. A survey of training knowledge will occur after the training video, and then a survey to gather reflections about the missions will occur after each mission. In the search and rescue task environment, the three participants on each team will be assigned by the experimenter to one of three roles: Medic, Transporter, and Engineer. The participants cannot change roles during the missions. ○ The Minecraft environment will simulate a collapsed building. Participants will be asked to search the building and rescue victims. They will be given a map that depicts the building’s floor layout prior to the collapse. Participants will need to remove rubble to clear paths in their search, stabilize victims, and transport victims from rubble to specific locations. Completion of these tasks produces rewards that vary in size. Victims stabilized and delivered to the correct zones count toward the team points: regular victims are 10 points each and critical victims are 50 points each. Participants will be able to view their accumulated team score, which is the sum of point rewards for all stabilized victims that are delivered to the correct zones by all team members. ○ In addition, any participant may enter a threat room whose entryway will then collapse into rubble when the participant steps on a hidden collapse plate. The plate is the same color as the rest of the floor. The Engineer, only, can free the occupant or herself. A threat room entry can collapse repeatedly (with an interval of 40s since the last collapse was triggered, upon every subsequent trigger of the collapse plate). ○ All participants will conduct two missions of 17 minutes at equivalent mission complexity levels in a fixed order. The complexity of the mission is a function of the complexity of the SAR environment (the building), number of victims, victims’ location by region and by room, the number and location of blockages and threat rooms (see Appendix Z: Map Design of Victim and Rubble Layout). Perturbations may be introduced into missions, such as elimination or falsification of some or all comms (e.g., marker blocks, and/or maps), and rubble falls. ○ The three roles have a unique set of capabilities and knowledge. Specifically: i. The Medic (Red suit) 1. Walks at a normal speed of 4.317 m/s 2. Can stabilize victims using a medic kit 3. Can diagnose victim injury type when stabilizing victims using an injury diagnose device (unique knowledge) 4. Can transport victims at the normal speed using a stretcher 5. Has unique knowledge of one's own location (but not the location of others) through a dynamic map 6. Receives information in the Knowledge Integration Task (KIT, described below) about the location of some (not all) of the planned meetings for the day at the time of the collapse through a text field below the dynamic map. 7. Has unique knowledge of any chat messages from ASI that are delivered solely to them through chat ii. The Transporter (Green suit) 1. Can move at the fastest speed of 5.18 m/s (20% faster than normal 2. Can detect whether there is a victim (at least one regular or a critical before being moved, awakened, or stabilized) in a room at each door without entering the room (unique knowledge); this is done through a victim-detection plate at the door. 3. Can transport victims of all types using a stretcher at the fastest speed 4. Can help the medic to wake up a critical victim 5. Has unique knowledge of one's own location (but not the location of others) through a dynamic map. 6. Receives KIT information about the number of attendees for some (not all) of the planned meetings for the day at the time of the collapse through a text field below the dynamic map. 7. Has unique knowledge of any chat messages from ASI that are delivered solely to them through chat iii. The Engineer (Blue suit) 1. Can move at a slow speed of 3.669 m/s (15% slower than normal) 2. Can remove rubble using a hammer 3. Can transport victims at a slow speed 4. Can see the threat rooms on the dynamic map (unique knowledge) 5. Has unique knowledge of one's own location (but not the location of others) through a dynamic map 6. Receives KIT information about the severity of some (but not all) rooms where injuries have happened through the text field below the dynamic map. 7. Has unique knowledge of any chat messages from ASI that are delivered solely to them through chat. ○ The tools of all roles are impervious to wear4. ○ The three members of a team will each have a dynamic map of the mission space (i.e., the map is updated automatically in real time). These maps depict some information in common to all participants, specifically building structure, and the location and type of marker blocks (but not rubble location or victim location). ○ Knowledge Integration Task (KIT): Each mission has one KIT. Each member receives part of the KIT information that, when combined, rewards teamwork, specifically information sharing. Successfully solving the KIT will enable participants to identify all three rooms that have critical victims, especially one of them that has 3 critical victims. Participants will be given 1 minute to read a mission brief slide containing KIT information before the mission starts. After the roles are selected and a mission starts, the KIT information will also be displayed below the dynamic map for the entire mission. That information is as follows: i. Only the Medic receives information about the location of some (not all) of the planned meetings for the day at the time of the collapse. ii. Only the Transporter receives information about the number of attendees for some (not all) of the planned meetings for the day at the time of the collapse. iii. Only the Engineer receives information about the severity of some (not all) rooms where injuries have happened. ○ The three participants have the same set of marker blocks, which are designed to communicate information about the game and indicate the identity (Medic-Red, Transporter-Green, or Engineer-Blue) of the author. Marker blocks laid in the game will appear on the maps of all players dynamically. These marker blocks indicate: Regular victim here, Critical victim here, No victim here, Victim injury type A, Victim injury type B, Victim injury type C, Rubble here, Threat room here, and help me here5. ○ The program evaluation team (TA3) will apply approximately 30 measures that provide quantitative or qualitative evidence concerning these claims for the ASIST program: that social science implemented in Analytic Components drives ASI MToT, which in turn drives ASI interventions, which influence team process, and potentially influence mission effects. That evaluation will contrast the eight between-teams experimental conditions (the no-advisor baseline, human advisor benchmark, and each of the six ASI advisors). See the Evaluation section of this document for detail.

Participants will participate in a 1-hour session to install required software appropriately and fill out independent surveys. Then, teams of three qualified participants will participate in a 2.5-hour session to complete an experiment in which they search for victims and rescue them in a Minecraft task environment. Participants will receive training that introduces the rules of the game and provides some hands-on experience with the environment. In the search and rescue task environment, the three participants on each team may choose one of three roles -- Medical Specialist (medic), Search Specialist (searcher), or Heavy Equipment Specialist (engineer) -- and change those roles during the mission.

This registration contains the preregistered study information for Experiment 1 conducted as part of the DARPA ASIST program.

Participants will participate in a 1-hour session to install required software appropriately and fill out independent surveys. Then, teams of three qualified participants will participate in a 2.5-hour session to complete an experiment in which they search for victims and rescue them in a Minecraft task environment. Participants will receive training that introduces the rules of the game and provides some hands-on experience with the environment. In the search and rescue task environment, the three participants on each team may choose one of three roles -- Medical Specialist (medic), Search Specialist (searcher), or Heavy Equipment Specialist (engineer) -- and change those roles during the mission.

Additional file 2: Supplementary Table 1. Mouse primers used for quantitative real-time PCR.

Supplemental Material, sj-pdf-1-ppa-10.1177_09520767221098292 for Public sector accountability styles in Europe comparing accountability and control of agencies in the Netherlands, Norway, Switzerland and the UK by Thomas Schillemans, Sjors Overman, Matthew Flinders, Per Laegreid, Martino Maggetti, Yannis Papadopoulos and Matthew Wood in Public Policy and Administration

Japan, a country dependent on science and technology for economic gains, is faced with a shrinking workforce in science-related fields due to an aging population, reduced interest in science and falling enrolments in university science courses. There is a growing need to increase young people's involvement in science and to encourage them to follow a science -related career path. Students' perceptions of science and scientists are said to influence their choices regarding study and career paths. This study investigated the perceptions of science and scientists held by Japanese year ten high school students. Four hundred and four students answered questions on their opinions of science, scientists and themselves, as well as their school science results, and their intention to enrol in a university science course and follow a science -related career. Students also completed the Draw-A-Scientist Test (DAST) to identify the presence of "stereotypical" images of scientists. The results indicated that students felt science is somewhat difficult, but also slightly exciting, practical, good, constructive, and somewhat useful. Students also felt that scientists are very intelligent, somewhat imaginative and diligent, slightly moral and open-minded, but also slightly selfish and somewhat introverted. The so-called stereotypical image of a scientist, found to be present among students of various countries, ages and backgrounds, was also present among the students in this study. The study also found that there are differences in how students perceive science and scientists, depending on the student's gender, school, and whether or not they imagine their own character to be similar to, or different from that of a scientist. Most notably, the likelihood of a student pursuing science at university or as a career is strongly dependent on the student's gender, with far more males than females showing a desire to be involved in science.

Supplemental Material, sj-pdf-1-ppa-10.1177_09520767221098292 for Public sector accountability styles in Europe comparing accountability and control of agencies in the Netherlands, Norway, Switzerland and the UK by Thomas Schillemans, Sjors Overman, Matthew Flinders, Per Laegreid, Martino Maggetti, Yannis Papadopoulos and Matthew Wood in Public Policy and Administration

Extracellular vesicles (EVs) form an endogenous transport system for intercellular transfer of biological cargo, including RNA, that plays a pivotal role in physiological and pathological processes. Unfortunately, whereas biological effects of EV-mediated RNA transfer are abundantly studied, regulatory pathways and mechanisms remain poorly defined due to a lack of suitable readout systems. Here, we describe a highly-sensitive CRISPR-Cas9-based reporter system that allows direct functional study of EV-mediated transfer of small non-coding RNA molecules at single-cell resolution. Using this CRISPR operated stoplight system for functional intercellular RNA exchange (CROSS-FIRE) we uncover various genes involved in EV subtype biogenesis that play a regulatory role in RNA transfer. Moreover we identify multiple genes involved in endocytosis and intracellular membrane trafficking that strongly regulate EV-mediated functional RNA delivery. Altogether, this approach allows the elucidation of regulatory mechanisms in EV-mediated RNA transfer at the level of EV biogenesis, endocytosis, intracellular trafficking, and RNA delivery., Extracellular vesicles (EV) facilitate intercellular transfer of biological material including RNA, but the regulatory mechanisms for their formation and transfer are incompletely known. Here the authors develop a CRISPR-based reporting system to detect the transfer of guide RNAs and identify genes not previously linked to EV-mediated RNA delivery.

Bott et al. here reports that de novo and biallelic variants in ATP6V0A1 gene affect the ability of the V-ATPase complex to translocate protons and acidify the endolysosomal compartment in neurons, causing a severe neurological phenotype ranging from developmental and epileptic encephalopathy to progressive myoclonus epilepsy. The vacuolar H+-ATPase is a large multi-subunit proton pump, composed of an integral membrane V0 domain, involved in proton translocation, and a peripheral V1 domain, catalysing ATP hydrolysis. This complex is widely distributed on the membrane of various subcellular organelles, such as endosomes and lysosomes, and plays a critical role in cellular processes ranging from autophagy to protein trafficking and endocytosis. Variants in ATP6V0A1, the brain-enriched isoform in the V0 domain, have been recently associated with developmental delay and epilepsy in four individuals. Here, we identified 17 individuals from 14 unrelated families with both with new and previously characterized variants in this gene, representing the largest cohort to date. Five affected subjects with biallelic variants in this gene presented with a phenotype of early-onset progressive myoclonus epilepsy with ataxia, while 12 individuals carried de novo missense variants and showed severe developmental and epileptic encephalopathy. The R740Q mutation, which alone accounts for almost 50% of the mutations identified among our cases, leads to failure of lysosomal hydrolysis by directly impairing acidification of the endolysosomal compartment, causing autophagic dysfunction and severe developmental defect in Caenorhabditis elegans. Altogether, our findings further expand the neurological phenotype associated with variants in this gene and provide a direct link with endolysosomal acidification in the pathophysiology of ATP6V0A1-related conditions.

The aim was to investigate the kinematic factors associated with successful performance in the initial acceleration phase of a sprint in the best male athletes in the World at the 2018 World Indoor Athletics Championships. High speed video (150 Hz) was captured for eight sprinters in the men’s 60 m final. Spatio-temporal and joint kinematic variables were calculated from the set position to the end of the first ground contact post-block exit (GC1). Normalised average horizontal external power (NAHEP) defined performance and was the dependent variable for a series of regression analyses. Clear relationships were found between GC1 NAHEP and 10-m time, 60-m time, change in velocity, acceleration and contact time in the first ground contact (r = -0.74, -0.64, 0.96, 0.91 and -0.56, respectively). Stepwise multiple linear regression of joint kinematic variables in the first ground contact revealed that trunk angle at take-off and thigh separation angle at take-off explained nearly 90% of variation in GC1 NAHEP (R2 = 0.89). The athletes’ projection at take-off with a forward leaning trunk and large thigh separation is characteristic therefore of excellent initial acceleration performance and this will be a good visual guide for technical coaching instruction. This was the first study of its kind to adopt such a research design in a World-class sample in a representative environment. Future studies that combine detailed kinematic and kinetic data capture and analysis in such a setting will add further insight to the findings of this investigation.

Supplemental material, sj-pdf-1-han-10.1177_1558944721998022 for Beyond the Cubital Tunnel: Use of Adjunctive Procedures in the Management of Cubital Tunnel Syndrome by Adam Evans, William M. Padovano, J. Megan M. Patterson, Matthew D. Wood, Warangkana Fongsri, Carie R. Kennedy and Susan E. Mackinnon in HAND

Supplemental material, sj-docx-1-han-10.1177_15589447211003175 for Acellular Nerve Allografts in Major Peripheral Nerve Repairs: An Analysis of Cases Presenting With Limited Recovery by Blair R. Peters, Matthew D. Wood, Daniel A. Hunter and Susan E. Mackinnon in HAND

Supplemental material, sj-pdf-1-han-10.1177_1558944721998022 for Beyond the Cubital Tunnel: Use of Adjunctive Procedures in the Management of Cubital Tunnel Syndrome by Adam Evans, William M. Padovano, J. Megan M. Patterson, Matthew D. Wood, Warangkana Fongsri, Carie R. Kennedy and Susan E. Mackinnon in HAND

Supplemental material, sj-docx-1-aas-10.1177_00953997211004606 for Conflictual Accountability: Behavioral Responses to Conflictual Accountability of Agencies by Thomas Schillemans, Sjors Overman, Paul Fawcett, Matthew Flinders, Magnus Fredriksson, Per Laegreid, Martino Maggetti, Yannis Papadopoulos, Kristin Rubecksen, Lise H. Rykkja, Heidi H. Salomonsen, Amanda Smullen, Koen Verhoest and Matthew Wood in Administration & Society

Supplemental material, sj-pdf-1-han-10.1177_15589447211003175 for Acellular Nerve Allografts in Major Peripheral Nerve Repairs: An Analysis of Cases Presenting With Limited Recovery by Blair R. Peters, Matthew D. Wood, Daniel A. Hunter and Susan E. Mackinnon in HAND

In contemporary public governance, leaders of public organizations are faced with multiple, and oftentimes conflictual, accountability claims. Drawing upon a survey of CEO’s of agencies in seven countries, we explore whether and how conflictual accountability regimes relate to strategic behaviors by agency-CEO’s and their political principals. The presence of conflictual accountability is experienced as a major challenge and is associated with important behavioral responses by those CEO’s. This article demonstrates empirically how conflictual accountability is related to (a) controlling behaviors by principals, (b) constituency building behaviors by agencies, and (c) a general pattern of intensified contacts and information processing by both parties.

HIV-exposed uninfected (HEU) infants exhibit altered vaccine responses and an increased mortality compared with HIV-unexposed infants. Here, vaccine responses in HEU and HIV-unexposed cord blood monocytes (CBMs) were assessed following Bacillus Calmette--Guerín (BCG) treatment.Innate responses to in-vitro BCG treatment were assessed through transcriptional profiling using CBMs obtained from a Nigerian cohort of HIV-infected and uninfected women.HIV-unexposed (n = 9) and HEU (n = 10) infant CBMs were treated with BCG and transcriptionally profiled with the Nanostring nCounter platform. Differential expression and pathway enrichment analyses were performed, and transcripts were identified with enhanced or dampened BCG responses.Following BCG stimulation, several pathways associated with inflammatory gene expression were upregulated irrespective of HIV exposure status. Both HIV-unexposed and HEU monocytes increased expression of several cytokines characteristic of innate BCG responses, including IL1β, TNFα, and IL-6. Using differential expression analysis, we identified genes significantly upregulated in HEU compared with HIV-unexposed monocytes including monocyte chemokine CCL7 and anti-inflammatory cytokine TNFAIP6. In contrast, genes significantly upregulated in HIV-unexposed compared with HEU monocytes include chemokine CCL3 and cytokine IL23A, both of which influence anti-mycobacterial T-cell responses. Finally, two genes, which regulate prostaglandin production, CSF2 and PTGS2, were also more significantly upregulated in the HIV-unexposed cord blood indicating that inflammatory mediators are suppressed in the HEU infants.HEU monocytes exhibit altered induction of several key innate immune responses, providing mechanistic insights into dysregulated innate response pathways that can be therapeutically targeted to improve vaccine responses in HEU infants.

We present the results of a census of the Manx Shearwaters Puffinus puffinus nesting on the three Pembrokeshire islands of Skomer, Skokholm and Midland (formerly Middleholm), Pembrokeshire, undertaken in 2018. The breeding population estimates were largely in line with those made in 2011–2013, but differed markedly from 1998; this difference seems to be due to the different methods used in 1998 rather than any marked change in population size. Despite attempts to refine the estimation of response rate to call playback, the error of the population estimates remains large, illustrating the logistical and analytical challenges of making seabird censuses using call playback. Nonetheless, the population estimates are large and the spatial distribution of occupied burrows is consistent between censuses, and thus Wales may hold more than half of the world’s breeding population of Manx Shearwaters.

International audience; TAR DNA-binding protein 43 (TDP-43; also known as TARDBP) is an RNA-binding protein whose aggregation is a hallmark of the neurodegenerative disorders amyotrophic lateral sclerosis and frontotemporal dementia. TDP-43 loss increases DNA damage and compromises cell viability, but the actual function of TDP-43 in preventing genome instability remains unclear. Here, we show that loss of TDP-43 increases R-loop formation in a transcription-dependent manner and results in DNA replication stress. TDP-43 nucleic-acid-binding and self-assembly activities are important in inhibiting R-loop accumulation and preserving normal DNA replication. We also found that TDP-43 cytoplasmic aggregation impairs TDP-43 function in R-loop regulation. Furthermore, increased R-loop accumulation and DNA damage is observed in neurons upon loss of TDP-43. Together, our findings indicate that TDP-43 function and normal protein homeostasis are crucial in maintaining genomic stability through a co-transcriptional process that prevents aberrant R-loop accumulation. We propose that the increased R-loop formation and genomic instability associated with TDP-43 loss are linked to the pathogenesis of TDP-43 proteinopathies.This article has an associated First Person interview with the first author of the paper.

Additional file 1. The Robotic Gynaecological Surgery Training Curriculum

Supplemental material, Supplemental_material for Incidence of Nerve Injury After Extremity Trauma in the United States by William M. Padovano, Jana Dengler, Megan M. Patterson, Andrew Yee, Alison K. Snyder-Warwick, Matthew D. Wood, Amy M. Moore and Susan E. Mackinnon in HAND

Rosette-forming glioneuronal tumor (RGNT) most commonly occurs adjacent to the fourth ventricle and therefore rarely presents with epilepsy. Recent reports describe RGNT occurrence in other anatomical locations with considerable morphologic and genetic overlap with the epilepsy-associated dysembryoplastic neuroepithelial tumor (DNET). Examples of RGNT or DNET with anaplastic change are rare, and typically occur in the setting of radiation treatment. We present the case of a 5-year-old girl with seizures, who underwent near total resection of a cystic temporal lobe lesion. Pathology showed morphologic and immunohistochemical features of RGNT, albeit with focally overlapping DNET-like patterns. Resections of residual or recurrent tumor were performed 1 year and 5 years after the initial resection, but no adjuvant radiation or chemotherapy was given. Ten years after the initial resection, surveillance imaging identified new and enhancing nodules, leading to another gross total resection. This specimen showed areas similar to the original tumor, but also high-grade foci with oligodendroglial morphology, increased cellularity, palisading necrosis, microvascular proliferation, and up to 13 mitotic figures per 10 high power fields. Ancillary studies the status by sequencing showed wild-type of the isocitrate dehydrogenase 1 (IDH1), IDH2, and human histone 3.3 (H3F3A) genes, and BRAF studies were negative for mutation or rearrangement. Fluorescence in situ hybridization (FISH) showed codeletion of 1p and 19q limited to the high-grade regions. By immunohistochemistry there was loss of nuclear alpha-thalassemia mental retardation syndrome, X-linked (ATRX) expression only in the high-grade region. Next-generation sequencing showed an fibroblast growth factor receptor receptor 1 (FGFR1) kinase domain internal tandem duplication in three resection specimens. ATRX mutation in the high-grade tumor was confirmed by sequencing which showed a frameshift mutation (p.R1427fs), while the apparent 1p/19q-codeletion by FISH was due to loss of chromosome arm 1p and only partial loss of 19q. Exceptional features of this case include the temporal lobe location, 1p/19q loss by FISH without true whole-arm codeletion, and anaplastic transformation associated with ATRX mutation without radiation or chemotherapy.

Millisecond pulsars (MSPs) are old neutron stars that spin hundreds of times per second and appear to pulsate as their emission beams cross our line of sight. To date, radio pulsations have been detected from all rotation-powered MSPs. In an attempt to discover radio-quiet gamma-ray MSPs, we used the aggregated power from the computers of tens of thousands of volunteers participating in the Einstein@Home distributed computing project to search for pulsations from unidentified gamma-ray sources in Fermi Large Area Telescope data. This survey discovered two isolated MSPs, one of which is the only known rotation-powered MSP to remain undetected in radio observations. These gamma-ray MSPs were discovered in completely blind searches without prior constraints from other observations, raising hopes for detecting MSPs from a predicted Galactic bulge population., This work was supported by the Max-Planck-Gesellschaft, the Deutsche Forschungsgemeinschaft through an Emmy Noether Research Grant [no. PL 710/1-1 (H.J.P.)], and NSF award 1104902. C.J.C. acknowledges support from the European Research Council under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 715051; Spiders). W.M. was partially supported by the Thailand Research Fund (grants TRG5880173 and RTA5980003). M.R. was funded by the Italian Ministry of Education, University and Research (contract no. FIRB-2012-RBFR12PM1F). Work at the Naval Research Laboratory is supported by NASA. The Parkes Observatory is part of the Australia Telescope, funded by the Commonwealth of Australia for operation as a National Facility managed by the Commonwealth Scientific and Industrial Research Organisation (CSIRO). The Fermi LAT Collaboration acknowledges generous ongoing support from a number of agencies and institutes that have supported both the development and the operation of the LAT, as well as scientific data analysis. These include the National Aeronautics and Space Administration and the Department of Energy in the United States, the Commissariat à l’Energie Atomique and the Centre National de la Recherche Scientifique/Institut National de Physique Nucléaire et de Physique des Particules in France; the Agenzia Spaziale Italiana and the Istituto Nazionale di Fisica Nucleare in Italy, the Ministry of Education, Culture, Sports, Science and Technology (MEXT), High Energy Accelerator Research Organization (KEK), and Japan Aerospace Exploration Agency (JAXA) in Japan; and the K. A. Wallenberg Foundation, the Swedish Research Council, and the Swedish National Space Board in Sweden. Additional support for science analysis during the operations phase is gratefully acknowledged from the Istituto Nazionale di Astrofisica in Italy and the Centre National d’Études Spatiales in France. This work performed in part under DOE Contract DE-AC02-76SF00515.

This study aims to gain a deeper understanding of the relationship between parental resilience and parenting styles and the impact of these characteristics on children’s eating behaviors and weight. Through a quantitative examination, we found parental concerns about their child’s weight positively relate to family attitudes toward fruits and vegetables but negatively relate to actual consumption of fruits and vegetables. Contrarily, advance planning of healthy meals among parents is negatively associated with family attitudes toward fruits and vegetables but positively associated with children’s consumption of fruits and vegetables. Family attitudes toward fruits and vegetables have a significant influence on children’s consumption of fruits and vegetables. The personal competence component of parental resilience has a significant moderating influence on the relationship between parental concerns about their child’s weight and his or her consumption of fruits and vegetables. The “acceptance of self and life” component of parental resilience has a significant moderating influence on the relationship between advance planning of healthy meals among parents and children’s consumption of fruits and vegetables.

Multiple studies have described extracellular microRNAs (ex-miRNAs) as being remarkably stable despite the hostile extracellular environment, when stored at 4oC or lower. Here we show that many ex-miRNAs are rapidly degraded when incubated at 37oC in the presence of serum (thereby simulating physiologically relevant conditions). Stability varied widely between miRNAs, with half-lives ranging from similar to 1.5 hours to more than 13 hours. Notably, ex-miRNA half-lives calculated in two different biofluids (murine serum and C2C12 mouse myotube conditioned medium) were highly similar, suggesting that intrinsic sequence properties are a determining factor in miRNA stability. By contrast, ex-miRNAs associated with extracellular vesicles (isolated by size exclusion chromatography) were highly stable. The release of ex-miRNAs from C2C12 myotubes was measured over time, and mathematical modelling revealed miRNA-specific release kinetics. While some ex-miRNAs reached the steady state in cell culture medium within 24 hours, the extracellular level of miR-16 did not reach equilibrium, even after 3 days in culture. These findings are indicative of miRNA-specific release and degradation kinetics with implications for the utility of ex-miRNAs as biomarkers, and for the potential of ex-miRNAs to transfer gene regulatory information between cells.

Antisense oligonucleotides (ASOs) targeting pathologic RNAs have shown promising therapeutic corrections for many genetic diseases including Myotonic Dystrophy type 1 (DM1). DM1 is a dominant neuromuscular disease caused by the abnormal amplification of a CTG repeated sequence in the 3’UTR of the DMPK gene. Expression of mutant transcripts containing expanded CUG repeats (CUGexp) leads to a deleterious RNA gain-of-function mechanism, in which CUGexp-transcripts are retained within the nucleus and alter the function of RNA-binding proteins such as MBNL splicing factors, leading to splicing defects and muscular dysfunction. ASO strategies can reverse the RNA toxicity induced by the expression of CUGexp-RNA. However systemic use of ASOs remains challenging for this muscular dystrophy because of the poor skeletal muscle uptake as pointed out by a recent clinical trial. Here, we show that advanced Pip6a-conjugate peptides strongly enhanced morpholino phosphorodiamidate oligomer (PMO) delivery into skeletal muscles of a DM1 mouse model (HSA-LR) after systemic administration in comparison to naked PMO. Antisense Pip6a-PMOs targeting pathologic CUGexp repeats inhibit the detrimental sequestration of MBNL1 splicing factor by nuclear CUGexp-RNA foci and consequently its functional loss. Thus low-dose of Pip6a-CAG ASOs induces a complete normalization of the myotonia in treated HSA-LR mice along with the correction of splicing defects and altered gene expression. Long-term studies reveal than the compound is still active six months after injection. In addition, the beneficial effect of the Pip6-CAG treatment was confirmed in human DM1 patient-derived muscle cells containing >2000 CTG repeats. This study demonstrates that pip6a-PMO treatment allows a lasting normalization of DM1-associated phenotypes at both molecular and functional levels supporting the use of advanced pip-conjugates for enhanced ASO systemic delivery in DM1 skeletal muscles.

© 2019, © 2019 Taylor & Francis Group, LLC. This study sought to develop knowledge about understandings of sexuality and appearance by using a story completion task combined with an innovative visual methodology. Fifty-four (mainly female) participants were randomly assigned to complete a story about a fictional bisexual, lesbian, or heterosexual character who is going on a date, and then asked to build a Bitstrips online avatar of their character. Our social constructionist thematic analysis identified that looking good was a common feature of the stories and that this was understood in largely heteronormative terms. This imperative was also clear in stories of the date, which relied on traditional notions of gender and heterosexuality. Finally, individuality and authenticity were rewarded in participants’ stories, yet this was simultaneously constrained by (dominant) heteronormative narratives. We conclude that combining story completion with visual methods enabled deeper insights into representations of appearance, dating, and relationships, than a textual method alone.

The effect of the inclusion of a high hurdle 13.72 m after the start line on elite sprint start and initial acceleration technique has yet to be investigated or understood. This highly novel study addresses that lack of information in an exceptional manner, through detailed biomechanical analysis of the world's best sprint and hurdle athletes, with data collected in situ at the 2018 IAAF World Indoor Championships, held in Birmingham, UK. High speed videos (150 Hz) were compared for eight sprinters and seven hurdlers for the start and initial acceleration phase of the finals of the men's 60 m and 60 m hurdles. Temporal and kinematic data were supplemented by vector coding analysis to investigate mechanisms by which these world-class athletes translate their centres of mass (CM) up to the fourth touchdown post-block exit. The sprinters and hurdlers coordinated their lower limb and trunk movement in a similar manner throughout the start and initial acceleration phases, which contributes new conceptual understanding of the mechanisms that underpin start and initial acceleration performance. Differences between groups were initiated from block set-up, with the hurdlers utilising a larger block spacing, but with the front block nearer to the start line than sprinters. Even after accounting for stature, the biggest differences in the raising of the CM occurred during the block phase, with hurdlers greater than sprinters (difference in vertical CM displacement scaled to stature = -0.037, very large effect size). Subsequent flight phases showed the biggest differences in the translation of the CM, in part due to longer flight times in the hurdlers, whilst the techniques of the two groups generally converged during the ground contact phases of initial acceleration. In highlighting that similar techniques are used by world-class sprinters and hurdlers, despite differing task constraints, this study has provided invaluable insights for scientists, coaches, and athletes, that will inform further developments in understanding and practice across both sprints and hurdles.

Osteoarthritis (OA) is a leading cause of disability, globally. Despite an emerging role for synovial inflammation in OA pathogenesis, attempts to target inflammation therapeutically have had limited success. A better understanding of the cellular and molecular processes occurring in the OA synovium is needed to develop novel therapeutics. We investigated macrophage phenotype and gene expression in synovial tissue of OA and inflammatory-arthritis (IA) patients. Compared with IA, OA synovial tissue contained higher but variable proportions of macrophages (P < 0.001). These macrophages exhibited an activated phenotype, expressing folate receptor-2 and CD86, and displayed high phagocytic capacity. RNA sequencing of synovial macrophages revealed 2 OA subgroups. Inflammatory-like OA (iOA) macrophages are closely aligned to IA macrophages and are characterized by a cell proliferation signature. In contrast, classical OA (cOA) macrophages display cartilage remodeling features. Supporting these findings, when compared with cOA, iOA synovial tissue contained higher proportions of macrophages (P < 0.01), expressing higher levels of the proliferation marker Ki67 (P < 0.01). These data provide new insight into the heterogeneity of OA synovial tissue and suggest distinct roles of macrophages in pathogenesis. Our findings could lead to the stratification of OA patients for suitable disease-modifying treatments and the identification of novel therapeutic targets.

Supplemental material, Appendix for Head-Mounted Display Use in Surgery: A Systematic Review by Rafa Rahman, Matthew E. Wood, Long Qian, Carrie L. Price, Alex A. Johnson and Greg M. Osgood in Surgical Innovation

The data formats for gamma-ray astronomy contain high-level data format specifications, ranging from event lists and instrument response formats to maps, spectra and lightcurves. This version 0.2 describes the formats currently in use and under development by various instruments (e.g. CTA, HESS, MAGIC, VERITAS, FACT, Fermi-LAT) and science tools (e.g. Gammapy and Gammalib). Please note that this is not a stable and agreed standard yet, it is incomplete and work in progress. We welcome feedback and contributions! The data formats for gamma-ray astronomy are also available athttps://gamma-astro-data-formats.readthedocs.io/ and are written and discussed athttps://github.com/open-gamma-ray-astro/gamma-astro-data-formats .

ObjectiveGrade II diffuse gliomas (DGs) with isocitrate dehydrogenase (IDH) mutations are associated with better prognosis than their IDH wild-type counterparts. We sought to determine the MRI characteristics associated with IDH mutational status and ascertain whether MRI considered in combination with IDH mutational status can better predict the clinical outcomes of grade II DGs.Materials and methodsPreoperative MRI examinations were retrospectively studied for qualitative tumor characteristics, including location, extent, cortical involvement, margin sharpness, cystic component, mineralization or hemorrhage, and contrast enhancement. Quantitative diffusion and perfusion metrics were also assessed. Logistic regression and ROC analyses were used to evaluate the relationship between MRI features and IDH mutational status. The association between IDH mutational status, 1p19q codeletion, MRI features, extent of resection, and clinical outcomes was assessed by Kaplan-Meier and Cox proportional hazards models.ResultsOf 100 grade II DGs, 78 were IDH mutant and 22 were IDH wild type. IDH wild-type tumors were associated with older age, multifocality, brainstem involvement, lack of cystic change, and a lower apparent diffusion coefficient (ADC). Multivariable regression showed that age older than 45 years as well as low minimum ADC (ADCmin), mean ADC, and maximum ADC values were independently associated with IDH mutational status. Of these, an ADCmin threshold of 0.9 × 10-3 mm2/s or less provided the greatest sensitivity and specificity (91% and 76%, respectively) in defining IDH wild-type grade II DGs. Combining low ADCmin with IDH wild-type status conferred worse outcomes than did IDH wild-type status alone.ConclusionIDH wild-type grade II DGs are associated with a lower ADC and poor clinical outcomes. Combining IDH mutational status and ADC may allow more accurate prediction of clinical outcomes for patients with grade II DGs.

© 2017 International Society of Neuropathology Astroblastoma is a rare and controversial glioma with variable clinical behavior. The diagnosis currently rests on histologic findings of a circumscribed glioma with astroblastomatous pseudorosettes and vascular hyalinization. Immunohistochemical studies have suggested different oncogenic drivers, such as BRAF p.V600E, but very few cases have been studied using genome-wide methodologies. Recent genomic profiling identified a subset of CNS embryonal tumors with astroblastoma-like morphology that harbored MN1 gene fusions, termed “CNS high-grade neuroepithelial tumors with MN1 alteration” (CNS-HGNET-MN1). To further characterize the genetic alterations that drive astroblastomas, we performed targeted next-generation sequencing (NGS) of 500 cancer-associated genes in a series of eight cases. We correlated these findings with break-apart fluorescence in situ hybridization (FISH) analysis of the MN1 locus and genome-wide DNA methylation profiling. Four cases showed MN1 alteration by FISH, including two pediatric cases that lacked other pathogenic alterations, and two adult cases that harbored other cancer-associated gene mutations or copy number alterations (eg, CDKN2A/B homozygous deletion, TP53, ATM and TERT promoter mutations). Three of these cases grouped with the CNS-HGNET-MN1 entity by methylation profiling. Two of four MN1 intact cases by FISH showed genetic features of either anaplastic pleomorphic xanthoastrocytoma (BRAF p.V600E mutation, CDKN2A/B homozygous deletion and TERT promoter mutation) or IDH-wildtype glioblastoma (trisomy 7, monosomy 10, CDK4 amplification and TP53, NRAS and TERT promoter mutations) and these cases had an aggressive clinical course. Two clinically indolent cases remained unclassifiable despite multimodal molecular analysis. We conclude that astroblastoma histology is not specific for any entity including CNS-HGNET-MN1, and that additional genetic characterization should be considered for astroblastomas, as a number of these tumors likely contain a methylation profile or genetic alterations that suggest classification as other tumor entities. Our heterogeneous molecular findings help to explain the clinical unpredictability of astroblastoma.

Science advances 4(2), eaao7228 - (2018). doi:10.1126/sciadv.aao7228, Millisecond pulsars (MSPs) are old neutron stars that spin hundreds of times per second and appear to pulsate as their emission beams cross our line of sight. To date, radio pulsations have been detected from all rotation-powered MSPs. In an attempt to discover radio-quiet gamma-ray MSPs, we used the aggregated power from the computers of tens of thousands of volunteers participating in the Einstein@Home distributed computing project to search for pulsations from unidentified gamma-ray sources in Fermi Large Area Telescope data. This survey discovered two isolated MSPs, one of which is the only known rotation-powered MSP to remain undetected in radio observations. These gamma-ray MSPs were discovered in completely blind searches without prior constraints from other observations, raising hopes for detecting MSPs from a predicted Galactic bulge population., Published by AAAS, Washington, DC [u.a.]

To date, the interactions between small mammals, birds and humans have not been explored in a small island environment which is under strong environmental pressure in its exposed maritime position. Skomer is a small island off the coast of south-west Wales; its present vegetation includes a range of grasses, sedges and herbaceous species, and a notable lack of trees. A shallow (460 mm) soil core spanning c.14 ka was retrieved from the South Valley on the Island. Interpretation of the lithology suggests that sediment accumulation rates are slow, and vegetation takes a long time to establish, probably due to thin soils and high rates of erosion. The vegetation inferred from the pollen record is dominated by grasses and herbs, similar to the present day, with periods of greater influence of Ericaceae. There is no evidence for woodland throughout the vegetation record preserved in the soil of the island, although 74 woodland indicator species are currently present. Woodland is likely to have been present during the early Holocene, but has been absent for at least 2800 years. Skomer Island provides an example of the persistence of woodland indicator species in the absence of woodland. The authors suggest that Pteridium provides the surrogate protection from grazing and competition from grasses to allow bluebells and other woodland indicator species to thrive. Birds, humans and small mammals have influenced the vegetation through forest clearance, and then by restricting re-growth through grazing, burrowing disturbance and an altered nutrient load from associated animal faeces.

Fermipy is an open-source python framework that facilitates analysis of data collected by the Fermi Large Area Telescope (LAT). Fermipy is built on the Fermi Science Tools, the publicly available software suite provided by NASA for the LAT mission. Fermipy provides a high-level interface for analyzing LAT data in a simple and reproducible way. The current feature set includes methods for extracting spectral energy distributions and lightcurves, generating test statistic maps, finding new source candidates, and fitting source position and extension. Fermipy leverages functionality from other scientific python packages including NumPy, SciPy, Matplotlib, and Astropy and is organized as a community-developed package following an open-source development model. We review the current functionality of Fermipy and plans for future development., Proc. 35th ICRC, Busan, South Korea, PoS(ICRC2017)824

Gammapy is a Python package for high-level gamma-ray data analysis built on Numpy, Scipy and Astropy. It enables us to analyze gamma-ray data and to create sky images, spectra and lightcurves, from event lists and instrument response information, and to determine the position, morphology and spectra of gamma-ray sources. So far Gammapy has mostly been used to analyze data from H.E.S.S. and Fermi-LAT, and is now being used for the simulation and analysis of observations from the Cherenkov Telescope Array (CTA). We have proposed Gammapy as a prototype for the CTA science tools. This contribution gives an overview of the Gammapy package and project and shows an analysis application example with simulated CTA data., Comment: Proc. 35th ICRC, Busan, South Korea, PoS(ICRC2017)766

Gammapy is a Python package for high-level gamma-ray data analysis built on Numpy, Scipy and Astropy. It enables us to analyze gamma-ray data and to create sky images, spectra and lightcurves, from event lists and instrument response information, and to determine the position, morphology and spectra of gamma-ray sources. So far Gammapy has mostly been used to analyze data from H.E.S.S. and Fermi-LAT, and is now being used for the simulation and analysis of observations from the Cherenkov Telescope Array (CTA). We have proposed Gammapy as a prototype for the CTA science tools. This contribution gives an overview of the Gammapy package and project and shows an analysis application example with simulated CTA data.

Microcrystal tests have been used in chemical identification for over 150 years. The tests involve the addition of a crystallizing reagent to a test sample followed by the microscopic observation of characteristic crystals. While this technique predates modern instrumental techniques of chemical analysis, it still has several distinct advantages. Microcrystal tests are rapid, inexpensive, and fairly simple to perform. However, this technique suffers from several criticisms due to the lack of atomic-level structural data from the resulting crystals. The crystallizing reagent, 5% chloroauric acid prepared from gold(III) chloride in water or dilute hydrochloric acid, is one of the most common reagents used in forensic laboratories in the analysis of suspected drug substances. The crystals precipitating from the reaction of this reagent and illicit substances from three categories of drugs were examined by single crystal X-ray diffraction. Cocaine is one of the most widely abused drugs, worldwide. Cocaine produces well characterized microcrystals upon mixing with the gold (III) chloride reagent. Ecgonine, the final stable metabolite of cocaine, is structurally similar to the parent drug and also forms crystals when reacted with gold (III) chloride. The gold (III) chloride salts of cocaine and ecgonine (hydrated and anhydrous) and the hydrochloride salt of ecgonine were determined and compared by single crystal X-ray diffraction. Single crystals precipitated from the addition of gold chloride test reagent to several structurally similar phenethylamines: amphetamine, methamphetamine, and ephedrine. While all of the other drugs of this category formed salts with the gold chloride anion, amphetamine was the only compound to bind covalently to the gold atom, displacing two chlorides. In recent years, various cathinone-derived drug products have entered the illicit drug market. Ethylone, α-PVP, pentylone, dibutylone, ephylone, and 3,4-methyl¬ene¬dioxy¬pyrovalerone (MDPV) were analyzed by single crystal X-ray diffraction in various salt forms, including the product of the gold chloride crystal test with MDPV. While the use of gold (III) chloride as a crystal precipitating agent is well-established, it is expensive and does not always form crystals with certain drug compounds. The novel application of Erdmann’s salt as a crystal precipitating reagent was successfully tested with a representative candidate from each of the previously described classes and the resulting crystals were structurally characterized.