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The U2AF1 gene is a core part of mRNA splicing machinery and frequently contains somatic mutations that contribute to oncogenesis in myelodysplastic syndrome, acute myeloid leukemia, and other cancers. A change introduced in the GRCh38 version of the human reference build prevents detection of mutations in this gene, and others, by variant calling pipelines. This study describes the problem in detail and shows that a modified GRCh38 reference build with unchanged coordinates can be used to ameliorate the issue.

Data sharing statement: The protocol, consent form, definition and derivation of clinical characteristics and outcomes, training materials, regulatory documents, information about requests for data access, and other relevant study materials are available online at https://www.phosp.org/ Copyright © 2023 The Author(s). Background: The scale of COVID-19 and its well documented long-term sequelae support a need to understand long-term outcomes including frailty. Methods: This prospective cohort study recruited adults who had survived hospitalisation with clinically diagnosed COVID-19 across 35 sites in the UK (PHOSP-COVID). The burden of frailty was objectively measured using Fried's Frailty Phenotype (FFP). The primary outcome was the prevalence of each FFP group—robust (no FFP criteria), pre-frail (one or two FFP criteria) and frail (three or more FFP criteria)—at 5 months and 1 year after discharge from hospital. For inclusion in the primary analysis, participants required complete outcome data for three of the five FFP criteria. Longitudinal changes across frailty domains are reported at 5 months and 1 year post-hospitalisation, along with risk factors for frailty status. Patient-perceived recovery and health-related quality of life (HRQoL) were retrospectively rated for pre-COVID-19 and prospectively rated at the 5 month and 1 year visits. This study is registered with ISRCTN, number ISRCTN10980107. Findings: Between March 5, 2020, and March 31, 2021, 2419 participants were enrolled with FFP data. Mean age was 57.9 (SD 12.6) years, 933 (38.6%) were female, and 429 (17.7%) had received invasive mechanical ventilation. 1785 had measures at both timepoints, of which 240 (13.4%), 1138 (63.8%) and 407 (22.8%) were frail, pre-frail and robust, respectively, at 5 months compared with 123 (6.9%), 1046 (58.6%) and 616 (34.5%) at 1 year. Factors associated with pre-frailty or frailty were invasive mechanical ventilation, older age, female sex, and greater social deprivation. Frail participants had a larger reduction in HRQoL compared with before their COVID-19 illness and were less likely to describe themselves as recovered. Interpretation: Physical frailty and pre-frailty are common following hospitalisation with COVID-19. Improvement in frailty was seen between 5 and 12 months although two-thirds of the population remained pre-frail or frail. This suggests comprehensive assessment and interventions targeting pre-frailty and frailty beyond the initial illness are required. Funding: UK Research and Innovation and National Institute for Health Research. The study was funded with grants from UK Research and Innovation (MR/V027859/1) and The National Institute of Health Research (COV0319). This study would not be possible without all the participants who have given their time and support. We thank all the participants and their families. We thank the many research administrators, health-care and social-care professionals who contributed to setting up and delivering the study at all of the 40 NHS trusts and 25 research institutions across the UK, as well as all the supporting staff at the NIHR Clinical Research Network, Health Research Authority, Research Ethics Committee, Department of Health and Social Care, Public Health Scotland, and Public Health England, and support from the ISARIC Coronavirus Clinical Characterisation Consortium. The authors would also like to acknowledge the support of the eDRIS Team (Public Health Scotland) for their involvement in obtaining approvals, provisioning and linking data and the use of the secure analytical platform within the National Safe Haven.

The time that animals spend travelling at various speeds and the tortuosity of their movement paths are two of the many things that affect space-use by animals. In this, high turn rates are predicted to be energetically costly, especially at high travel speeds, which implies that animals should modulate their speed according to path characteristics. When animals move so as to maximize distance and minimize metabolic energy expenditure, they travel most efficiently at the speed that gives them a minimum cost of transport (COTmin), a well-defined point for animals that move entirely in fluid media. Theoretical considerations show though, that land animals should travel at their maximum speed to minimize COT, which they do not, instead travelling at walking pace. So, to what extent does COTmin depend on speed and turn rate and how might this relate to movement paths? We measured oxygen consumption in humans walking along paths with varied tortuosity at defined speeds to demonstrate that the energetic costs of negotiating these paths increase disproportionately with both speed and angular velocity. This resulted in the COTmin occurring at very low speeds, and these COTmin speeds reduced with increased path tortuosity and angular velocity. Logged movement data from six free-ranging terrestrial species underpinned this because all individuals turned with greater angular velocity the slower their travel speeds across their full speed range. It seems, therefore, that land animals may strive to achieve minimum movement costs by reducing speed with increasing path variability, providing one of many possible explanations as to why speed is much lower than currently predicted based on lab measurements of mammalian locomotor performance.

Data sharing statement: PHOSP-COVID: The protocol, consent form, definition and derivation of clinical characteristics and outcomes, training materials, regulatory documents, requests for data access and other relevant study materials are available online at https://www.phosp.org. COVIDENCE UK: De-identified participant data will be made available upon reasonable request to the corresponding author. Supplementary data is available online at: https://www.sciencedirect.com/science/article/pii/S2666776223000546?via%3Dihub#appsec1 . Copyright © 2023 The Author(s). Background: The risk factors for recovery from COVID-19 dyspnoea are poorly understood. We investigated determinants of recovery from dyspnoea in adults with COVID-19 and compared these to determinants of recovery from non-COVID-19 dyspnoea. Methods: We used data from two prospective cohort studies: PHOSP-COVID (patients hospitalised between March 2020 and April 2021 with COVID-19) and COVIDENCE UK (community cohort studied over the same time period). PHOSP-COVID data were collected during hospitalisation and at 5-month and 1-year follow-up visits. COVIDENCE UK data were obtained through baseline and monthly online questionnaires. Dyspnoea was measured in both cohorts with the Medical Research Council Dyspnoea Scale. We used multivariable logistic regression to identify determinants associated with a reduction in dyspnoea between 5-month and 1-year follow-up. Findings: We included 990 PHOSP-COVID and 3309 COVIDENCE UK participants. We observed higher odds of improvement between 5-month and 1-year follow-up among PHOSP-COVID participants who were younger (odds ratio 1.02 per year, 95% CI 1.01–1.03), male (1.54, 1.16–2.04), neither obese nor severely obese (1.82, 1.06–3.13 and 4.19, 2.14–8.19, respectively), had no pre-existing anxiety or depression (1.56, 1.09–2.22) or cardiovascular disease (1.33, 1.00–1.79), and shorter hospital admission (1.01 per day, 1.00–1.02). Similar associations were found in those recovering from non-COVID-19 dyspnoea, excluding age (and length of hospital admission). Interpretation: Factors associated with dyspnoea recovery at 1-year post-discharge among patients hospitalised with COVID-19 were similar to those among community controls without COVID-19. Funding: PHOSP-COVID is supported by a grant from the MRC-UK Research and Innovation and the Department of Health and Social Care through the National Institute for Health Research (NIHR) rapid response panel to tackle COVID-19. The views expressed in the publication are those of the author(s) and not necessarily those of the National Health Service (NHS), the NIHR or the Department of Health and Social Care. COVIDENCE UK is supported by the UK Research and Innovation, the National Institute for Health Research, and Barts Charity. The views expressed are those of the authors and not necessarily those of the funders. PHOSP-COVID: This study would not be possible without all the participants who have given their time and support. We thank all the participants and their families. We thank the many research administrators, health-care and social-care professionals who contributed to setting up and delivering the study at all of the 65 NHS trusts/Health boards and 25 research institutions across the UK, as well as all the supporting staff at the NIHR Clinical Research Network, Health Research Authority, Research Ethics Committee, Department of Health and Social Care, Public Health Scotland, and Public Health England, and support from the ISARIC Coronavirus Clinical Characterisation Consortium. We thank Kate Holmes at the NIHR Office for Clinical Research Infrastructure (NOCRI) for her support in coordinating the charities group. The PHOSP-COVID industry framework was formed to provide advice and support in commercial discussions, and we thank the Association of the British Pharmaceutical Industry as well NOCRI for coordinating this. We are very grateful to all the charities that have provided insight to the study: Action Pulmonary Fibrosis, Alzheimer's Research UK, Asthma + Lung UK, British Heart Foundation, Diabetes UK, Cystic Fibrosis Trust, Kidney Research UK, MQ Mental Health, Muscular Dystrophy UK, Stroke Association Blood Cancer UK, McPin Foundations, and Versus Arthritis. We thank the NIHR Leicester Biomedical Research Centre patient and public involvement group and Long Covid Support. COVIDENCE UK: We thank all participants of COVIDENCE UK, and the following organisations who supported study recruitment: Asthma UK/British Lung Foundation, the British Heart Foundation, the British Obesity Society, Cancer Research UK, Diabetes UK, Future Publishing, Kidney Care UK, Kidney Wales, Mumsnet, the National Kidney Federation, the National Rheumatoid Arthritis Society, the North West London Health Research Register (DISCOVER), Primary Immunodeficiency UK, the Race Equality Foundation, SWM Health, the Terence Higgins Trust, and Vasculitis UK.

Advancements in tracking technologies provide an increasingly important tool in animal monitoring and conservation that can describe animal spatial behavior in native habitats and uncover migratory routes that otherwise may be difficult or impossible to map. In addition, high-resolution accelerometer sensors provide powerful insights into animal activity patterns and can help to identify specific behaviors from accelerometer profiles alone. Previously, such accelerometers were restricted to larger animals due to size and mass constraints. However, recent advances make it possible to use such devices on smaller animals such as the European green toad (Bufotes viridis), the focus of our current study. We deploy custom made tracking devices, that consist of very-high-frequency transmitters and tri-axial accelerometers, to track toads in their native urban environment in Vienna (Austria). A total of nine toads were tracked, ranging from three to nine tracking days per individual during the post-breeding season period. We demonstrate that our devices could reliably monitor toad movement and activity during the observation period. Hence, we confirmed the predominantly nocturnal activity patterns and recorded low overall movement at this urban site. Accelerometer data revealed that toads exhibited brief but intense activity bursts between 10 pm and midnight, resting periods during the night and intermittent activity during the day. Positional tracking alone would have missed the major activity events as they rarely resulted in large positional displacements. This underscores the importance of and value in integrating multiple tracking sensors for studies of movement ecology. Our approach could be adapted for other amphibians or other animals with mass constraints and may become standard monitoring equipment in the near future.

This chapter discusses the role of energy in the collapse of the Soviet system. Oil and natural gas exports enabled the Soviet Union to import from the West and accounted for most of the Soviet Union's hard currency revenues and energy consumption by the early 1980s. On the other hand, Ronald Reagan had long been skeptical about trade with the Soviet Union, since he believed that Western technology bolstered its economic system and undermined Western security by enhancing Soviet military power. The Reagan administration engaged in economic warfare against the Soviet energy sector. However, the collapse of the Soviet system was due to inefficiencies and contradiction of their command economy instead of aggressive US policies.

To gauge parental satisfaction of an orthoptic-led specialist service for teaching soft contact lens (CL) handling in the management of children with pediatric aphakia. 20 families attending the contact lens clinic completed a satisfaction questionnaire to enquire about their experience of learning how to insert and remove their child's CL. Families were questioned on their experiences with preoperative counseling, practical teaching, additional support and the patient literature that was provided by the orthoptists in the CL clinic. Qualitative data and free comments were analyzed. 18/20 (90%) said they had received good practical insertion and removal teaching. 19/20 (95%) felt they received good emotional support. Only 6/20 (30%) families agreed with the statement that they found learning insertion and removal difficult. 15/20 (75%) families did not feel rushed, and 18/20 (90%) said they could learn at their own pace. All except one family (95%) achieved daily CL handling within a few months, with ongoing support from a multi-disciplinary team. One family surveyed was much earlier in their postoperative journey, but was on track to achieve this imminently. All families (100%) felt they were appropriately counselled preoperatively regarding the need for training and daily CL handling. 95% found the provided written information useful. 8/20 (40%) reported they found insertion harder than removal, 4/20(20%) reported they found removal harder. Teaching insertion and removal skills is an important aspect of managing paediatric aphakia and presents many challenges. Most parents eventually cope well and achieve daily CL handling within a few months, with support from a multi-disciplinary team. Families surveyed were all competent and were satisfied with their experience. The parental satisfaction survey gave our team confidence that our orthoptic-led service works well, orthoptists have the knowledge and skills to provide technical training to parents alongside vital emotional support, and contact lens handling is a rewarding extended role for orthoptists in a multi-disciplinary team.

Animal-attached devices have transformed our understanding of vertebrate ecology. To minimize tag-related harm for these studies, researchers have long advocated that tag masses should not exceed 3% of the animal’s body mass. However, this proposition ignores tag forces generated as a result of animal movement.Using data from collar-attached accelerometers on diverse free-ranging terrestrial animals, we detail a tag-based acceleration method (TbAM) in which we quantify animal athleticism in terms of fractions of animal movement time devoted to different collar-recorded accelerations. The varying accelerations are converted to forces imposed on the animals based on the acceleration and tag mass and allow derivation of defined force limits, including those amounting to 3% of the animal’s mass, for specified fractions of any animal’s active time.We demonstrate how species athleticism is the principal determinant of tag forces, whereas body mass is of little importance. Forces exerted by ‘3%’ tags were mostly equivalent to 4-19% of the animals’ masses during moving, with a maximum of 54% in a hunting cheetah. Cumulative frequency curves of tag acceleration for periods when animals were active, all showed a characteristic sigmoid pattern, which was displaced further to the right as higher acceleration activities accounted for an increasing proportion of any animal’s time. Specifying that tags should exert forces that are less than 3% of the animal’s body mass for 95% of the time led to corrected tag masses constituting between 1.6% and 2.98% of our study animals’ masses, with values depending on animal athleticism.Recognition that animal athleticism affects tag forces of their carriers fundamentally changes how acceptable tag mass limits should be determined by ethics bodies. In order to have a scientifically robust acceptable threshold to limit the forces experienced by an animal carrier, we suggest practitioners derive a similar cumulative acceleration profile for their study species and use a minimum of the 95% limits on the plot (although higher limits may be more appropriate).

It was shown earlier that dogs, when selecting between two dishes with snacks placed in front of them, left and right, prefer to turn either clockwise or counterclockwise or randomly in either direction. This preference (or non-preference) is individually consistent in all trials but it is biased in favor of north if they choose between dishes positioned north and east or north and west, a phenomenon denoted as “pull of the north”. Here, we replicated these experiments indoors, in magnetic coils, under natural magnetic field and under magnetic field shifted 90° clockwise. We demonstrate that "pull of the north" was present also in an environment without any outdoor cues and that the magnetic (and not topographic) north exerted the effect. The detailed analysis shows that the phenomenon involves also "repulsion of the south". The clockwise turning preference in the right-preferring dogs is more pronounced in the S-W combination, while the counterclockwise turning preference in the left-preferring dogs is pronounced in the S-E combination. In this way, south-placed dishes are less frequently chosen than would be expected, while the north-placed dishes are apparently more preferred. Turning preference did not correlate with the motoric paw laterality (Kong test). Given that the choice of a dish is visually guided, we postulate that the turning preference was determined by the dominant eye, so that a dominant right eye resulted in clockwise, and a dominant left eye in counterclockwise turning. Assuming further that magnetoreception in canines is based on the radical-pair mechanism, a "conflict of interests" may be expected, if the dominant eye guides turning away from north, yet the contralateral eye "sees the north", which generally acts attractive, provoking body alignment along the north-south axis.

Aim The primary objective was to report immediate and long-term disability outcomes in children following an abusive head trauma (AHT) aged less than 2 years. The secondary objective was to report visual outcomes. Methods A retrosepctive study that identified children from the Ophthalmology Department’s database of children examined for suspected AHT, between 1995 and 2017. Children were included if they were aged 24 months or less, with no pre-existing visual or developmental problems, and if their injury was confirmed as a result of AHT. This was determined by the conclusion of the local Multi-Disciplinary Team. Ethical approval was obtained. KOSCHI (King’s Outcome Score of Head Injury) was used to assess disability outcomes at discharge from hospital and at long-term follow up. A retinal haemorrhage score (0 to 16) recorded extent of retinal injury. Visual function (normal, visual impairment, no functional vision) was assessed at follow up. Results Total of 44 children (25 male 19 female) with a median age of 16 weeks. Subdural haemorrhage was seen in 98% (37% bilateral); 56/% had additional injuries on skeletal survey. At discharge, 5% children had died (KOSCHI 1) or were in vegetative state (KOSCHI 2); 61% showed features of moderate to severe disability (KOSCHI 3 & 4); 34% had a ‘good or full recovery’ (KOSCHI 5). At long-term follow-up, 14% showed a worsening of their KOSCHI score. This resulted in overall outcomes of 71% disability and 29% full recovery, at a mean age of 5.3 years. Retinal haemorrhages were present in 93%, 88% bilaterally (mean score 8). At follow-up, visual impairment was present in 31%, 7% of whom had no functional vision. Conclusion AHT continues to give rise to significant morbidity; this cohort showed a worsening of disability score at long-term follow-up. This indicates disability severity may not be fully appreciated at discharge from hospital, impacting on both provision of accurate prognostic information and in applying targeted follow-up. Visual impairment was more severe in those with a higher retinal haemorrhage score, as might be expected in more extensive injury. As there are few visual outcome studies, this adds to the evidence base, and we would promote that services should ensure visual function is optimised.

(La 0.8 Sr 0.2 ) 0.95 MnO 3-δ (LSM) and (Er 0.2 Bi 0.8 ) 2 O 3 (ESB) composite has shown promise as a potential candidate for low temperature solid oxide fuel cell (LT-SOFC) cathodes. Here the stability of LSM-ESB composite cathode was tested under a range of temperature between 500 °C and 650 °C in symmetrical cell configuration, and the changes in cathode area specific resistance (ASR) was monitored in situ using electrochemical impedance spectroscopy (EIS). Two different mechanisms govern the LSM-ESB performance degradation in different temperature regions. At 600 °C and below the decrease in ESB conductivity due to the order-disorder transition of ESB significantly impacts the ohmic resistance of the cells. Moreover, the surface catalytic activity of LSM-ESB is directly affected by the order-disorder transition, possibly due to changes in the oxygen incorporation rate of ESB. At 650 °C, above the order-disorder transition, LSM and ESB react to form tertiary phases in as little as 180 h. Our results suggest that bismuth transports through vapor phase and deposits across the porous electrode surface. These results reveal the possible degradation mechanisms for bismuth-oxide based composite cathodes. These findings are important for the future development of SOFCs and the selection of potential cathode candidates that incorporate bismuth oxide.

Among (La0.8Sr0.2)0.95MnO3-δ (LSM) based cathodes LSM-(Er0.2Bi0.8)2O3 (LSM-ESB) composite shows promising performance and is one of potential cathodes for low temperature solid oxide fuel cells (LT-SOFCs). However, the high conductivity ESB exhibits oxygen-ordering at temperatures ≤600°C, resulting in an ordered super-lattice with low oxygen mobility. Here the electrochemical performance of LSM-ESB was investigated using electrochemical impedance spectroscopy (EIS) as a function of temperature, oxygen partial pressure (pO2), bias, and time to determine possible electrochemical reaction steps and elucidate the oxygen reduction reaction (ORR) mechanism. LSM-ESB shows a strong pO2 dependence and above 650°C the non-stoichiometry of LSM plays an important role in oxygen transport between solid phases under biased conditions. In addition, effects of ion conductivity of electrolyte on the performance of LSM-ESB are determined. Also, the high temperature reactivity between LSM and ESB solid phases is studied and the possible degradation mechanism is proposed. Our results provide insights in the oxygen transport on LSM-ESB through the comprehensive study.

Rodent species, such as monogamous and biparental California mice, produce vocalizations as a means of communication. A temporal examination of vocalizations produced by California mice pups in isolation was performed. Pup recordings were performed for 3 min at ∼10.00 and 14.00 hrs on early postnatal days (PND) 2-4, 7, 21, and 28. Once initial recordings were finished, pups were returned to the home cage with parents and any siblings for 5 minutes to determine if active biparental responses resulted in an enhanced vocalization response when pups were isolated and retested. We also sought to determine whether potential reduction in vocalizations by older pups might be due to procedure-habituation procedure associated with less anxiety and/or possibly decreased need for parental care. Vocalizations were measured in weanling (30 days of age) "naïve" pups not previously isolated. Results show older pups took significantly longer to vocalize, indicated by increased latency before producing their initial syllable compared to earlier ages. With increasing age, pups demonstrated decreased syllable duration, reduced number and duration of phrases, and decreased number of syllables per phrase. No differences in pup vocalizations were observed before and after being placed back with parents, suggestive biparental potentiation may not exist in California mice pups. Comparison of the naïve to habituated weanling pups indicated the former group had more total calls but no other differences in vocalization parameters were detected between these 2 groups. Collectively, the findings suggest that as California mice pups mature and approach weaning they generally vocalize less in isolation. (PsycINFO Database Record

Previous studies have shown that mammals exhibit two distinct forms of magnetic behaviour: spontaneous magnetic alignment and learned magnetic compass orientation. However, it remains to be determined whether the type of magnetic response is species specific (i.e. species exhibit either learned magnetic compass responses or spontaneous magnetic orientation). Alternatively, learned and spontaneous magnetic orientation may be context dependent and expressed in the same species under different conditions, e.g. motivational, physiological and/or environmental. Using C57BL/6J laboratory mice, we provide evidence for multiple spatial responses to magnetic cues in the same species. In a series of three similar nest-building experiments in which mice were trained to construct nests in one of four magnetic directions, mice either positioned nests along a fixed northeast–southwest magnetic axis (Series 1), independent of the trained direction, and similar to spontaneous magnetic alignment responses in other vertebrates, or exhibited learned magnetic compass orientation in the direction away from (Series 2) or towards (Series 3) the sheltered end of the magnetic axis they had been exposed to during the training period. Importantly, the responses elicited in each series paralleled changes in the experimental protocols and may help to explain the variation in magnetic behaviours. Furthermore, the plasticity in the magnetic orientation exhibited by laboratory mice suggests that magnetic cues play important role in the spatial ecology of epigean rodents. Characterizing the factors that elicit these responses will shed light on the adaptive significance of spontaneous magnetic alignment, a widespread but poorly understood spatial behaviour. In addition, future studies with similar nest-building assays will likely play a role in helping to determine whether magnetic compass orientation and spontaneous magnetic alignment are mediated by the same underlying mechanisms of magnetoreception.

TO THE EDITOR: Population-level germ line heterogeneity, rare single nucleotide polymorphisms (SNPs), and sequence alignment to a single reference genome make it challenging for variant-calling algorithms to distinguish germ line variants from somatically acquired mutations with high throughput

New low-temperature thermochronology and geochronology data from Upper Jurassic–Upper Cretaceous strata from the North American Cordilleran foreland basin in Utah, Colorado, Wyoming, and South Dakota document rapid exhumation rates of the adjacent Cordilleran orogenic belt to the west. Both zircon (U-Th-[Sm])/He (zircon He) and apatite fission track (AFT) thermochronology were applied to proximal and distal synorogenic deposits in order to identify a thermochronometer suitable to record source exhumation during the North America Cordilleran orogeny. AFT lag times from Upper Jurassic–Upper Cretaceous deposits are 0–5 m.y. and indicate a relatively steady-state to slightly increasing exhumation rate between 118 Ma and 66 Ma. These lag-time measurements are consistent with active shortening and rapid exhumation rates of ∼0.9–>1 km/m.y. of the North American Cordillera throughout the Cretaceous. Double dating of the detrital AFT samples was performed on apatites with young AFT cooling ages, in order to test whether or not the young cooling ages represent a signal related to exhumation rather than volcanic activity. Maximum depositional ages using detrital zircon U-Pb geochronology match existing ages on basin stratigraphy. This study indicates that AFT is the most effective thermochronometer to resolve source exhumation from Lower to Upper Cretaceous foreland stratigraphy in the central Cordilleran foreland, and indicates that source material was exhumed from 4 to 5 km depths but was never buried more than a few kilometers ( 8–9 km. Double dating of apatites (with AFT and U-Pb) shows that volcanic contamination is a significant issue that can, however, be addressed by double dating.

Improvements in antisense technology have now enabled clinically relevant therapeutic credentialing of the noncoding genome. MALAT1 is a long non-coding RNA that, among other functions, is thought to serve as a nuclear scaffold for splicing and transcription factors. MALAT1 expression is associated with inferior prognosis across solid tumors and its depletion impairs proliferation and metastasis in preclinical solid tumor models. We found that elevated MALAT1 levels are independently associated with inferior overall survival in patients with CMML. Further, RNA-sequencing of primary CMML monocytes identified MALAT1 as the fourth most over-expressed transcript compared to controls. Therefore, we explored the biologic relevance and therapeutic candidacy of MALAT1 across several human and murine models of CMML. First, we crossed NRASQ61R/+Mx1-cre driven mice, which display a CMML-like phenotype, to MALAT1KO/KOmice. Although MALAT1KO/KOmice did not have abnormalities in complete blood counts, immunophenotyping of the hematopoietic stem cell (HSC) compartment identified statistically significantly lower numbers of HSC compared to wild type (WT) controls and a non-significant decrease in NRASQ61R/+/MALAT1KO/KOcompared to NRASQ61R/+alone. This decrease in HSC was not a result of impaired self-renewal as no differences were observed in these models after in vivo competitive transplant experiments. Therefore, we reasoned that MALAT1 expression may be controlling HSC differentiation. To test this, we transformed bone marrow cells from these models with an estrogen-regulated (ER) Hoxb8 construct enabling cells to maintain an HSC state until ER is withdrawn and myeloid differentiation is induced. ER-Hoxb8NRASQ61R/+/MALAT1KO/KOcells had increased basal levels of Gr-1 compared to ER-Hoxb8 transformed NRASQ61R/+alone that was dramatically enhanced upon ER withdrawal suggesting that MALAT1 depletion regulates myeloid differentiation. These findings were validated by assessment of morphology, transcriptome, and in vivo immunophenotyping of bone marrow and spleen cells. Further, moribund NRASQ61R/+/MALAT1KO/KOmice displayed a reduction in organomegaly typically associated with leukemic burden. We validated this in human monocytic leukemia by generating MALAT1 depleted THP-1 isogeneic cell lines using the CRISPR/Cas9 system. MALAT1 depleted THP-1 cells (MKO) had greater terminal differentiation according to immunophenotypic markers and morphology that was greatly enhanced when treated with phorbol myristate acetate. Last, MKO orthotopic xenografts demonstrated inferior human leukemia engraftment and decreased spleen and liver weights, and heterotopic xenografts exhibited reduced tumor volume, collectively suggesting diminished leukemic burden. Because ATRA has been clinically tested in CMML with minimal effects, we next explored whether MALAT1 depletion could potentiate ATRA differentiation in CMML. First, we treated MKO cells with ATRA and observed a large induction of myeloid differentiation by marker expression and morphologic assessment compared to isogenic controls. This was validated by NRASQ61R/+/MALAT1KO/KOmice demonstrating that ATRA more robustly induced differentiation compared to vehicle which was not seen in NRASQ61R/+/MALAT1+/+mice. Next, we tested MALAT1 antisense oligonucleotides (ASOs) currently under clinical development in THP-1 cells +/- ATRA and demonstrated both an increase in myeloid differentiation and apoptosis compared to ATRA alone. To test this therapeutic strategy in primary CMML specimens, we generated CMML patient-derived xenografts (n=30 mice) and treated each with ASO, ATRA, the combination, or controls and identified a more robust reduction in human HSC engraftment with the combination. To explore the mechanistic basis for these findings, we performed RNA-sequencing of MALAT1-depleted or control cells and identified that CREB target genes were differentially expressed. Basal protein levels of p-CREB were also decreased in MKO cells and were further reduced in the nucleus of MKO by western and microscopy. Lastly, overexpression of WT or constitutively active CREB but not its dominant negative rescued the differentiation effect seen in ATRA treated MKO cells. Taken together, MALAT1 is a novel, CREB-dependent regulator of myeloid differentiation and its depletion potentiates ATRA therapy. Disclosures Cluzeau: Menarini: Consultancy; Jazz Pharma: Consultancy; Abbvie: Consultancy. Komrokji:celgene: Consultancy; pfizer: Consultancy; DSI: Consultancy; JAZZ: Speakers Bureau; Novartis: Speakers Bureau; JAZZ: Consultancy; Agios: Consultancy; Incyte: Consultancy. MacLeod:Ionis Pharmaceuticals: Employment. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Epling-Burnette:Forma Therapeutics: Research Funding; Celgene Corporation: Patents & Royalties, Research Funding; Incyte Corporation: Research Funding.

The Upper Cretaceous Sego Sandstone Member of the Mesaverde Group has been extensively studied in the Book Cliffs area of Utah and Colorado, and has been the focus of stratigraphic reconstruction aimed at developing an understanding of the evolution of the Western Cretaceous Interior Seaway. The Sego Sandstone Member was deposited in a marginal marine, tide-influenced environment of the Cretaceous Seaway. This study documents the sequence stratigraphy of the Sego Sandstone Member in northwestern Colorado, just north of Rangely, and compares and contrasts it with equivalent strata in the Book Cliffs area in Utah. The Sego Sandstone Member in the study area contains three sequences characterized by progradational and aggradational stacking patterns. The stratigraphically lowest sequence consists of a prograding, tide-influenced delta overlain by marine mudstones, which represents a retrogradation and flooding surface. The second sequence is composed of multiple parasequences and consists of an incised valley filled with stacked tidal bars which then pass into a largely aggradational stacking pattern, composed of barrier-island deposits with back-barrier, flood-tidal-delta deposits, and wave-dominated-shoreface deposits. The third sequence is a broad, tide-dominated distributary-mouth system with a sharp, incisional basal contact. The three sequence boundaries documented in northwestern Colorado are consistent with the three main sequence boundaries identified in the Book Cliffs. However, whereas barrier islands and flood-tidal deltas are characteristic of the Sego Sandstone Member in northwestern Colorado, similar deposits are not as prevalent in the Book Cliffs of Utah, suggesting different depositional processes and paleogeography. Tidal and fluvio-deltaic processes are the dominant controls on deposition of the Sego Sandstone Member north of Rangely, Colorado. The transition from a tide-dominated fluvio-deltaic system to a mixed wave–tide-influenced coastline indicates a fundamental change in processes and depositional environment in the upper part of Sequence 2. Such change from a prograding fluvio-deltaic system to a more passive tide-modified coastline is not observed in the Book Cliffs, and may be the result either of large scale transgression or of relocation of the river system through large-scale avulsion, which is not observed in the Book Cliffs. Our study shows significant stratigraphic variability between rocks exposed in the Book Cliffs versus time-equivalent rocks exposed in northwestern Colorado in the Upper Cretaceous, which has implications for the regional basin architecture and stratigraphic correlations.

The policy of detente during the late 1960s and early 1970s opened up new prospects for Western–USSR cooperation, namely in the area of energy. US companies were at the forefront in exploring large investment options in the case of West Siberian gas. These projects failed, however, due to strong US domestic political opposition and a general worsening of US–USSR relations in the second half of the 1970s. Instead, military buildup and economic containment, including sanctions on pipeline technology, were to become the driving policies during the Reagan era, aiming at a weakening of the Soviet Union’s potential. In vain did Washington seek to obstruct the Europeans from building up their energy partnership with Moscow. The Soviet economy had already experienced first economic turbulences in the early 1980s, but when the price of oil fell in the mid-1980s, the country’s foreign currency reserves dwindled and the crisis worsened. When the Soviet Union eventually broke up in 1991, the so-called “Reagan victory school” saw this as, in retrospect, a vindication of Washington’s policy. In contrast, this chapter argues that US policies were not the main cause of the collapse in the oil price. In a longer perspective, by choosing confrontation over cooperation, the US not only exacerbated Cold War tensions and damaged relations with its allies, but also missed an opportunity to set in motion processes that might have ended the Cold War and facilitated reform in the Soviet Union without creating conditions that led to instability and future animosity.

The Earth's magnetic field is involved in spatial behaviours ranging from long-distance migration to non-goal directed behaviours, such as spontaneous magnetic alignment (SMA). Mercury is a harmful pollutant most often generated from anthropogenic sources that can bio-accumulate in animal tissue over a lifetime. We compared SMA of hatchling snapping turtles from mothers captured at reference (i.e., low mercury) and mercury contaminated sites. Reference turtles showed radio frequency-dependent SMA along the north-south axis, consistent with previous studies of SMA, while turtles with high levels of maternally inherited mercury failed to show consistent magnetic alignment. In contrast, there was no difference between reference and mercury exposed turtles on standard performance measures. The magnetic field plays an important role in animal orientation behaviour and may also help to integrate spatial information from a variety of sensory modalities. As a consequence, mercury may compromise the performance of turtles in a wide variety of spatial tasks. Future research is needed to determine the threshold for mercury effects on snapping turtles, whether mercury exposure compromises spatial behaviour of adult turtles, and whether mercury has a direct effect on the magnetoreception mechanism(s) that mediate SMA or a more general effect on the nervous system.

Maternal diet-induced obesity can cause detrimental developmental origins of health and disease in offspring. Perinatal exposure to a high-fat diet (HFD) can lead to later behavioral and metabolic disturbances, but it is not clear which behaviors and metabolic parameters are most vulnerable. To address this critical gap, biparental and monogamous oldfield mice (Peromyscus polionotus), which may better replicate most human societies, were used in the current study. About 2 weeks before breeding, adult females were placed on a control or HFD and maintained on the diets throughout gestation and lactation. F1 offspring were placed at weaning (30 days of age) on the control diet and spatial learning and memory, anxiety, exploratory, voluntary physical activity, and metabolic parameters were tested when they reached adulthood (90 days of age). Surprisingly, maternal HFD caused decreased latency in initial and reverse Barnes maze trials in male, but not female, offspring. Both male and female HFD-fed offspring showed increased anxiogenic behaviors, but decreased exploratory and voluntary physical activity. Moreover, HFD offspring demonstrated lower resting energy expenditure (EE) compared with controls. Accordingly, HFD offspring weighed more at adulthood than those from control fed dams, likely the result of reduced physical activity and EE. Current findings indicate a maternal HFD may increase obesity susceptibility in offspring due to prenatal programming resulting in reduced physical activity and EE later in life. Further work is needed to determine the underpinning neural and metabolic mechanisms by which a maternal HFD adversely affects neurobehavioral and metabolic pathways in offspring.

Telomeres are specialized structures providing chromosome integrity during cellular division along with protection against premature senescence and apoptosis. Accelerated telomere attrition in patients with myelodysplastic syndrome (MDS) occurs by an undefined mechanism. Although the MDS clone originates within the myeloid compartment, T-lymphocytes display repertoire contraction and loss of naive T-cells. The replicative lifespan of T-cells is stringently regulated by telomerase activity. In MDS cases, we show that purified CD3+ T-cells have significantly shorter telomere length and reduced proliferative capacity upon stimulation compared with controls. To understand the mechanism, telomerase enzymatic activity and telomerase reverse transcriptase (hTERT), gene expression were compared in MDS cases (n=35) and healthy controls (n=42) within different T-cell compartments. Telomerase activity is greatest in naive T-cells illustrating the importance of telomere repair in homeostatic repertoire regulation. Compared with healthy controls, MDS cases had lower telomerase induction (P

The treasure of Roman Hacksilber from Traprain Law, a massive hill fort east of Edinburgh, has been interpreted since its publication in 1923 by Alexander Curle as an illustration of the last days of Roman Britain, and as having been broken up by Irish pirates or raiders in or about ad 405. The attribution resulted from an attempt to link historical or semi-historical sources, in particular about the Irish hero Niall of the Nine Hostages and St Patrick, with an archaeological discovery. Modern scholarship, however, has shown that Niall and St Patrick are to be dated to the middle or late fifth century, not to the late fourth and early fifth century, and so the argument that the Traprain Law treasure was connected with ‘Irish pirates’ fails.

In the Name of Oil: Anglo-American Relations in the Middle East, 1950–1958, Ivan L. G. Pearson, Brighton: Sussex Academic Press, 2010, ISBN 978-1-84519-388-1, 240 pp. This study seeks to challenge ...

Marginal-marine deposits are typically excellent hydrocarbon reservoirs around the world. Certain depositional environments may provide natural, selective, physical processes that produce better reservoir rocks than others depending on associated energy, hydraulic regime, etc. With this paper we present new detailed sedimentological, petrographic, and grain-size data of ancient flood-tidal-delta deposits that provide means to characterize this environment in the ancient as well as to determine reservoir characteristics. In this study, we compare grain size, grain and cement composition, and the ratio of pore space to cement from thin sections between tidal, shoreface, and flood-tidal-delta facies of the Sego Sandstone in northwest Colorado. The intent of this comparison is to provide an evaluation of different physical processes and the degree of diagenesis related to different environments to better understand the relative controls on reservoir characteristics. We find that flood-tidal-deltas show a statistically larger average grain size than either shoreface or other tidal facies. Also, flood-tidal-deltas have a smaller ratio of pore-space to cement. Shoreface facies have a larger ratio of pore space to cement overall than that of flood-tidal-delta or other tidal facies. We propose that this may be due to chemistry and higher weathering rates in the backbay environment in contrast to the shoreface environment, where higher mechanical reworking may lead to selective removal of chemically unstable minerals. To test this hypothesis, we conducted statistical analyses of these petrophysical and grain size characteristics. Our results show that flood-tidal-deltas are characterized by clean upper-fine-grained cross-bedded sandstone that is well sorted and subrounded to rounded with a majority of landward paleocurrent directions and a presence of tidal bundles, mud drapes, and reactivation surfaces.

Introduction: Prehospital blood transfusion has been adopted by many civilian helicopter emergency medical service (HEMS) agencies and early outcomes are positive. Shock Trauma Air Rescue Service (STARS) operates six bases in Western Canada and in 2013 implemented a prehospital transfusion program. We describe the processes and standard work ensuring safe storage, administration, and stewardship of this precious resource. Our aim was to produce a sustainable and safe blood storage system that could be carried on each mission flown. Methods: Close collaboration with transfusion services and adherence to Canadian Transfusion Standards was key at each step of development. An inexpensive, reusable, temperature controlled thermal packaging device was obtained along with an electronic temperature logger. Conditioning of the device and temperature maintenance (1 6C) was tested to ensure safe storage conditions. Online training programs were developed for air medical crew (AMC) as well as transport physicians (TPs) regarding administration indications, safety, and stewardship processes. Blood traceability and usage was monitored on an ongoing basis for quality assurance. Results: Two units of O negative packed red blood cells (pRBCs) are now carried on each flight. The blood box is conditioned and prepared by transfusion services for routine exchange every 72 hours. If pRBCs are administered the blood bank is immediately notified for preparation of another cooler. Unused blood is returned to blood bank circulation. Conclusion: The introduction of the STARS blood on board program supports the provision of emergent transfusion to selected patients in the pre-hospital environment. Our standard work and stewardship processes minimize wastage of blood products while keeping it readily available for critically ill and injured patients. Subsequent work will aim to describe characteristics and patient centred outcomes.

The vibration signal of the honey bee (Apis mellifera) may play a central role in the regulation of queen behavior during reproductive swarming and supersedure. We examined honey bee workers that performed vibration signals on queens and developing queen cells in three observation hives, each containing a population of marked bees of known age. In all three colonies, workers of all ages greater than 2 d old could perform vibration signals on queens and queen cells. However, most signals were performed by a small proportion of the bees of greater than 10 d of age. Relatively few workers less than 10 d old vibrated queens and queen cells, even though this age-group is typically associated with queen care. Thus, the regulation of queen behavior by the vibration signal may occur primarily through a relatively small subset of older workers that, under most circumstances, have only limited involvement with queens. It is unclear what triggers the vibrating of queens. Workers producing vibration signals did not differ from same-age non-vibrating controls in rate of locomotion in the hive or in task performance, and they rarely engaged in foraging, even though the majority of observed bees were of foraging age; vibrators also did not spend more time with queens and queen cells compared with controls. Vibration signals performed on queens and queen cells therefore do not appear to be influenced by task performance or increased contact with queens.

Thc vibration signal is one of the most commonly occurring communication displays in honey bee (&is md@ra) colonies. It may function in a ‘modulatoty’ manner, becAuSc it causes a nonspecihc increase in actkity that enhances a %ariety of behaviors depending upon the age and caste of the rccipicnt. We examined hone! bee workers that performed vibration signals on other workers in three observation hives, each containing a populstion of marked bces of known age. In all three colonies, the mean age of the first perfrmnance of the vibration signal was significantly different from the mean agc at which workers first performrd waggle dances, carried pollen loads, or attended the queen. However, workers of all ages, except those less than 3 d old, could perform vibration signals. In older workers of foraging age, signal performance was most closely associated with recent foraging success. Younger workers that vibrated did not appear to be early-maturing foragers and thus thcir signals wcre probably not influenced by food collection. Rather, for these preforaging-age workers, sip11 performance was associated more with periods of orientation flight, during which ywnger bees learn the location of the nest and surrounding landmarks. Thus, the vibration signal may be triggered by different stimuli in different worker age classes. Because it elicits a general incrcase in activity In all recipients, the signal may help adjust many dlffcrent colony behaviors simultaneously to changes in foraging success and colony development.

The evolution of β-Si 3 N 4 microstructures is influenced by the adsorption of rare earth (RE) elements at grain surfaces and by the viscosity of the intergranular phases. Theoretical and scanning transmission electron microscopy studies show that the RE atoms exhibit different tendencies to segregate from the liquid phase to grain surfaces and different binding strengths at these surfaces. When combined with MgO (or Al 2 O 3 ) secondary additions, the rare earth additives are combined in low-viscosity intergranular phases during densification and the α- to β-phase transformation and microstructural evolution are dominated by the RE adsorption behavior. On the other hand, a much higher viscosity intergranular phase forms when the RE 2 O 3 are combined with SiO 2 . While the RE adsorption behavior remains the same, phase transformation and microstructure are now dominated by Si 3 N 4 solubility and transport in the high liquid phase. By understanding these additive effects, one can develop reinforced microstructures leading silicon nitride ceramics with greatly improved mechanical behavior.

An increasing interest in both more adequate one-electron model Hamiltonians and more precise calculations of eigenvalues and total energies for clusters and solids has led to renewed efforts to devise efficient computational schemes capable of treating general potentials with high accuracy. In this communication, a linear variational method for generalizing the Korringa-Kohn-Rostoker (KKR) method to treat general one-electron potentials and charge densities is briefly reviewed and compared with several other recent approaches to this problem.

The discrete variational method, which has been successfully applied previously to several covalent crystals, has been used to calculate the energy bands and charge density of the ionic crystal LiF, using various crystal potential models. The great sensitivity of the energy bands to the atomic configuration used to construct the potential and to the scaling of the statistical exchange is explained in terms of differences in the spatial properties of the crystal wave functions. The excited bands are found to be characterized by diffuse orbitals which are converged by using a mixed basis of Bloch atomic-like functions and symmetrized plane waves. Basis convergence problems posed by ionic systems for linear variational techniques are discussed in the conclusion.

The Marshall Plan was the most effective US foreign policy initiative in the post-war period and a turning point in the Cold War. This paper highlights a very important and commonly neglected aspect of the Marshall Plan – the influence of oil. Oil played a key role in the origins, operations, and impact of the Marshall Plan. Marshall Plan aid for oil preserved markets for US oil companies and shaped Western Europe's energy use patterns and its relations with the United States and the oil-producing nations, especially those in the Middle East. In contrast, the Soviet Union was unable to use oil as an instrument of power and influence in this period. Examination of the role of oil in the Marshall Plan provides important insights into the origins of the Cold War and the factors that shaped the post-war world.

Response to immunosuppressive therapy (IST) in younger patients with myelodysplastic syndrome (MDS) has been linked to a T-cell-dominant autoimmune process that impairs hematopoiesis. Analysis of the age-adjusted CD4:CD8 ratio in 76 MDS patients compared with 54 healthy controls showed that inadequate CD4+, rather than expansion of CD8+ T cells, was associated with a lower ratio in a group that included both lower and higher risk MDS patients defined by the International Prognostic Scoring System. In younger MDS patients, naive and memory phenotypes defined by CD45RA and CD62L display showed depletion of naive CD4+ and CD8+ T cells, suggesting a possible relationship to IST responsiveness. To determine the correlation between T-cell subset distribution, T-cell turnover and autoimmunity, a cohort of 20 patients were studied before and after IST. The CD4:CD8 ratio correlated inversely with the proliferative T-cell index before treatment in IST-responsive patients, suggesting that proliferation may be linked to accelerated CD4+ T-cell turnover and hematopoietic failure. Our data show seminal findings that both CD4+ and CD8+ T-cell subsets are dysregulated in MDS. Association between these T-cell defects and response to IST suggests that aberrant T-cell homeostasis and chronic activation are critical determinants influencing autoimmune hematopoietic suppression in younger patients.

Large granular lymphocyte (LGL) leukemia is commonly associated with poor hematopoiesis. The first case of pulmonary artery hypertension (PAH) was observed in a 57-year-old woman with natural killer (NK)–LGL leukemia and transfusion-dependent anemia. Using a genetic approach, we demonstrated that killing of pulmonary endothelial cells by patient NK cells was mediated by dysregulated balance in activating and inhibitory NK-receptor signaling. Elevated pulmonary artery pressure and erythroid differentiation improved after disrupting the NK-receptor signaling pathway with 4 courses of a farnesyltransferase inhibitor, tipifarnib. Coincidental association between PAH and LGL leukemia suggest a causal relationship between the expanded lymphocyte population and these clinical manifestations. This trial is registered at www.ClinicalTrials.gov as NCI 6823.

Silicon nitride powders most often consist primarily of the α phase, which transforms into the β phase during the densification and microstructural evolution of Si3N4 ceramics. The temperature at which the transformation initiates in the presence of a combination of MgO and RE2O3 densification additives is found to decrease with increasing atomic number of the rare earth (RE). This trend coincides with the predicted and observed decrease in the affinity of the RE to segregate to and absorb on the prism planes of hexagonal prism-shaped β grains with an increase in the atomic number of the RE. When RE adsorption is diminished, Si (and N) attachment on the smooth prism planes is enhanced, which increases diametrical growth rates, normally reaction-rate limited by an attachment mechanism. Combined with the typically fast [0001] growth, it is this augmented grain growth that contributes toward the initiation of the α–β transformation at lower temperatures. With the enhanced transformation, observations reveal an increase in the number of β grains growing in the early stages of densification. On the other hand, increased RE adsorption leads to greater growth anisotropy, resulting in the formation of higher aspect ratio grains. Thus, Lu2O3 generates larger diameter, yet elongated, reinforcing grains, while La2O3 results in reinforcing grains of a higher aspect ratio. The Gd2O3 additive transformation and microstructural characteristics lie intermediate to those of the lanthanide end-member elements. Despite these differences, a substantial fraction of large reinforcing grains were found for each additive composition. As a result, the mechanical properties of the resultant ceramics are similar with flexure strengths in excess of 1 GPa, fracture toughness values >10 MPa·m1/2 at room temperature, and excellent strength retention (>800 MPa) at 1200°C.

Two series of oxynitride glasses, RE–Si–Mg–O–N ( M = Mg , Al ; RE = La , Lu), have been studied by X-Ray photoelectron spectroscopy (XPS). The oxygen 1s photoelectron lineshape reveals a striking difference depending on the rare earth, both in the Mg series and in the Al series. Specifically, the oxygen 1s photoelectron lines of the La doped glasses are broader than the ones of the Lu doped glasses. This result is an experimental evidence that Lu has a larger affinity for oxygen versus nitrogen than La, as theoretically predicted by the first-principles calculations by Painter et al.

We report evidence for magnetic compass orientation by larval Drosophila melanogaster. Groups of larvae were exposed from the time of hatching to directional ultraviolet (365 nm) light emanating from one of four magnetic directions. Larvae were then tested individually on a circular agar plate under diffuse light in one of four magnetic field alignments. The larvae exhibited magnetic compass orientation in a direction opposite that of the light source in training. Evidence for a well-developed magnetic compass in a larval insect that moves over distances of at most a few tens of centimeters has important implications for understanding the adaptive significance of orientation mechanisms like the magnetic compass. Moreover, the development of an assay for studying magnetic compass orientation in larval D. melanogaster will make it possible to use a wide range of molecular genetic techniques to investigate the neurophysiological, biophysical, and molecular mechanisms underlying the magnetic compass.