bluuebunny/crossref_metadata_2025_split huggingface dataset:
Vascular Emergencies
Authors: Banerjee Ashis , Jafar Anisa J. N. , Mukherjee Angshuman , Solomonides Christian , Witt Erik 
Published: October 2019

Abstract
This chapter on vascular emergencies contains eight clinical Short Answer Questions (SAQs) with explanations and sources for further reading. Possible disorders and accompanying symptoms of vascular origin that may present in the emergency department include pulmonary embolism, aortic dissection, ischaemia of the lower limbs, and arterial injury, among others. It will be up to the emergency doctor to assess, diagnose, and decide upon a treatment path for each patient. The cases described in this chapter are all situations any emergency doctor is likely to encounter at some point in his or her career. The material in this chapter will greatly aid revision for the Final FRCEM examination.
The globular cluster population of NGC 1052-DF2: evidence for rotation
Authors: Lewis Geraint F , Brewer Brendon J , Wan Zhen 
Published: October 2019

ABSTRACT
Based upon the kinematics of 10 globular clusters, it has recently been claimed that the ultra-diffuse galaxy, NGC 1052-DF2, lacks a significant quantity of dark matter. Dynamical analyses have generally assumed that this galaxy is pressure supported, with the relatively small velocity dispersion of the globular cluster population indicating the deficit of dark matter. However, the presence of a significant rotation of the globular cluster population could substantially modify this conclusion. Here, we present the discovery of such a signature of rotation in the kinematics of NGC 1052-DF2’s globular clusters, with a velocity amplitude of ${\sim}12.44^{+4.40}_{-5.16}$ km s−1, which, through Bayesian model comparison, represents a marginally better fit to the available kinematic data; note that this rotation is distinct from, and approximately perpendicular to, the recently identified rotation of the stellar component of NGC 1052-DF2. Assuming this truly represents an underlying rotation, it is shown that the determined mass depends upon the inclination of the rotational component and, with a moderate inclination, the resultant mass-to-light ratio can exceed M/L ∼ 10.
Potent and sustained huntingtin lowering via AAV5 encoding miRNA preserves striatal volume and cognitive function in a humanized mouse model of Huntington disease
Authors: Caron Nicholas S , Southwell Amber L , Brouwers Cynthia C , Cengio Louisa Dal , Xie Yuanyun , Black Hailey Findlay , Anderson Lisa M , Ko Seunghyun , Zhu Xiang , van Deventer Sander J , Evers Melvin M , Konstantinova Pavlina , Hayden Michael R 
Published: October 2019

AbstractHuntington disease (HD) is a fatal neurodegenerative disease caused by a pathogenic expansion of a CAG repeat in the huntingtin (HTT) gene. There are no disease-modifying therapies for HD. Artificial microRNAs targeting HTT transcripts for degradation have shown preclinical promise and will soon enter human clinical trials. Here, we examine the tolerability and efficacy of non-selective HTT lowering with an AAV5 encoded miRNA targeting human HTT (AAV5-miHTT) in the humanized Hu128/21 mouse model of HD. We show that intrastriatal administration of AAV5-miHTT results in potent and sustained HTT suppression for at least 7 months post-injection. Importantly, non-selective suppression of huntingtin was generally tolerated, however high dose AAV5-miHTT did induce astrogliosis. We observed an improvement of select behavioural and modest neuropathological HD-like phenotypes in Hu128/21 mice, suggesting a potential therapeutic benefit of miRNA-mediated non-selective HTT lowering. Finally, we also observed that potent reduction of wild type HTT (wtHTT) in Hu21 control mice was tolerated up to 7 months post-injection but may induce impairment of motor coordination and striatal atrophy. Taken together, our data suggests that in the context of HD, the therapeutic benefits of mHTT reduction may outweigh the potentially detrimental effects of wtHTT loss following non-selective HTT lowering.
Negotiating Damages and the Compensatory Principle
Authors: Senu Josias 
Published: October 2019

Abstract
The question of loss is central to the account of negotiating damages, namely whether it is correct to view the breach of a contractual right as a measurable loss to the claimant. The UK Supreme Court in One Step clarified the circumstances in which negotiating damages can be awarded. The decision aimed to explain that negotiating damages are compensatory in nature, but revealed several flaws in the Court’s reasoning. I draw on leading cases, including One Step, to show that negotiating damages can be plausibly explained by the compensatory principle. I explain that the loss suffered by the claimant is the ‘choice value’ of his infringed contractual right to performance, and that damages are awarded to the claimant equivalent to the value of his lost choice. If this new choice value approach I develop is correct, then negotiating damages can be understood as compensating the loss of the value of choice.
PUBLIC EXPOSURE TO EXTERNAL GAMMA RADIATION ON A MINE LANDFORM COVERED BY LOW URANIUM GRADE WASTE ROCK
Authors: Doering Che 
Published: October 2019

Abstract
Public exposure to external gamma radiation on the waste-rock-covered-8.5-km2-planned final landform from rehabilitation of the Ranger uranium mine was assessed. The average above-background dose rate from external gamma radiation on the planned final landform was determined to be 6.0 × 10−3 mSv d−1. This dose rate was one order of magnitude higher than that for inhalation of radon progeny and two orders of magnitude higher than that for inhalation of radionuclides in dust on the final landform. The above-background annual effective dose to the public from external gamma radiation when the envisioned land use by Aboriginal traditional owners was averaged over the entire 79 km2 Ranger Project Area was about 4.1 × 10−2 mSv. The results of this study may provide general guidance to sites elsewhere on the relative importance of the external gamma pathway and assist in the development or assessment of rehabilitation plans for uranium mining sites.
On an integrable multi-dimensionally consistent 2
n
+ 2
n
-dimensional heavenly-type equation
Authors: Konopelchenko B. G. , Schief W. K. 
Published: October 2019

Based on the commutativity of scalar vector fields, an algebraic scheme is developed which leads to a privileged multi-dimensionally consistent 2
n
+ 2
n
-dimensional integrable partial differential equation with the associated eigenfunction constituting an infinitesimal symmetry. The ‘universal’ character of this novel equation of vanishing Pfaffian type is demonstrated by retrieving and generalizing to higher dimensions a great variety of well-known integrable equations such as the dispersionless Kadomtsev–Petviashvili and Hirota equations and various avatars of the heavenly equation governing self-dual Einstein spaces.
Analysis of the FBXO7 promoter reveals overlapping Pax5 and c-Myb binding sites functioning in B cells
Authors: Randle Suzanne , Laman Heike 
Published: October 2019

AbstractFbxo7 is a key player in the differentiation and function of numerous blood cell types, and in neurons, oligodendrocytes and spermatocytes. In an effort to gain insight into the physiological and pathological settings where Fbxo7 is likely to play a key role, we sought to define the transcription factors which direct FBXO7 expression. Using sequence alignments across 28 species, we defined the human FBXO7 promoter and found that it contains two conserved regions enriched for multiple transcription factor binding sites. Many of these have roles in either neuronal or haematopoietic development. Using various FBXO7 promoter reporters, we found ELF4, Pax5 and c-Myb have functional binding sites that activate transcription. Overlap of Pax5 and c-Myb binding sites suggest that these factors bind cooperatively to transactivate the FBXO7 promoter. Although endogenous Pax5 is bound to the FBXO7 promoter in B cells, c-Myb is also required for FBXO7 expression. Our data suggest the interplay of multiple transcription factors regulate the FBXO7 promoter.
Scientific societies advancing STEM workforce diversity: Lessons and Outcomes from the Minorities Affairs Committee of the American Society for Cell Biology
Authors: Segarra Verónica A. , Blatch Sydella , Boyce Michael , Carrero-Martinez Franklin , Aguilera Renato J. , Leibowitz Michael J. , Zavala MariaElena , Hammonds-Odie Latanya , Edwards Ashanti 
Published: October 2019

ABSTRACTPromoting diversity and inclusiveness in the STEM academic workforce remains a key challenge and national priority. Scientific societies can play a significant role in this process through the creation and implementation of programs to foster STEM academic workforce diversification, and by providing mentoring and skills development training that empower scientists from under-represented minority (URM) backgrounds to succeed in their communities of practice. In this article, we provide examples of challenges met by scientific societies in these areas and present data from the American Society for Cell Biology, highlighting the benefits received by trainees through long-term engagement with its programs. The success of these initiatives illustrates the impact of discipline-specific programming by scientific societies in supporting the development of URM scientists and an increasingly diverse and inclusive academic STEM community.
Astrocyte-selective AAV-ADAMTS4 gene therapy combined with hindlimb rehabilitation promotes functional recovery after spinal cord injury
Authors: Griffin Jarred M. , Fackelmeier Barbara , Clemett Connor A. , Fong Dahna M. , Mouravlev Alexandre , Young Deborah , O’Carroll Simon J. 
Published: October 2019

AbstractChondroitin sulphate proteoglycans (CSPGs) are inhibitors to axon regeneration and plasticity. Bacterial chondroitinase ABC degrades CSPGs and has been extensively reported to be therapeutic after SCI but there remain concerns for its clinical translation. A disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS4) is a human enzyme that catalyses the proteolysis of CSPG protein cores. Infusion of ADAMTS4 into the damaged spinal cord was previously shown to improve functional recovery after SCI, however, this therapy is limited in its enzyme form. Adeno-associated viral (AAV) vector gene therapy has emerged as the vector of choice for safe, robust and long-term transgene expression in the central nervous system. Here, an AAV expression cassette containing ADAMTS4 under the control of the astrocytic GfaABC1D promoter was packaged into an AAV5 vector. Sustained expression of ADAMTS4 was achieved in vitro and in vivo, leading to widespread degradation of CSPGs. AAV-ADAMTS4 resulted in significantly decreased lesion size, increased sprouting of hindlimb corticospinal tract axons, increased serotonergic fiber density caudal to the injury, and improved functional recovery after moderate contusive SCI. Hindlimb-specific exercise rehabilitation was used to drive neuroplasticity towards improving functional connections. The combination of hindlimb rehabilitation with AAV-ADAMTS4 led to enhanced functional recovery after SCI. Thus, widespread and long-term degradation of CSPGs through AAV-ADAMTS4 gene therapy in a combinational approach with rehabilitation represents a promising candidate for further preclinical development.
Parallel evolution of multiple mechanisms for demethylase inhibitor fungicide resistance in the barley pathogenPyrenophora teresf. sp.maculata
Authors: Mair Wesley J. , Thomas Geoffrey J. , Dodhia Kejal , Hills Andrea L. , Jayasena Kithsiri W. , Ellwood Simon R. , Oliver Richard P. , Lopez-Ruiz Francisco J. 
Published: October 2019

ABSTRACTThe demethylase inhibitor (DMI) or group 3 fungicides are the most important class of compounds for the control both of plant and human fungal pathogens. The necrotrophic fungal pathogenPyrenophora teresf. sp.maculata(Ptm), responsible for spot form of net blotch (SFNB), is currently the most significant disease of barley in Australia, and a disease of increasing concern worldwide. The main basis for management of SFNB is by fungicide application, and in Australia the DMIs predominate. Although reduced sensitivity to DMI fungicides has recently been described in the closely related pathogenP. teresf. sp.teres(Ptt), the mechanisms of DMI resistance have not thus far been described forPtm. In this study, several different levels of sensitivity to DMI fungicides were identified in Western Australian strains ofPtmfrom 2016 onwards, and reduced sensitivity phenotypes were correlated with a number of distinct mutations in both the promoter region and coding sequence of the DMI target gene encoding cytochrome P450 sterol 14α-demethylase (Cyp51A). Five insertions elements of 134-base pairs in length were found at different positions within the upstream regulatory region ofCyp51Ain both highly DMI-resistant (HR) and select moderately DMI-resistant (MR1)Ptmisolates. The five insertion elements had at least 95% sequence identity and were determined to be Solo-LTR (Long Terminal Repeat) elements, all deriving fromTy1/Copia-family LTR Retrotransposons. The 134-bp elements contained a predicted promoter sequence and several predicted transcription factor binding sites, and the presence of an insertion element was correlated with constitutive overexpression ofCyp51A. The substitution of phenylalanine by leucine at position 489 of the predicted amino acid sequence of CYP51A was found in both HR and select moderately DMI-resistant (MR2)Ptmisolates. The same F489L amino acid substitution has been previously reported in Western Australian strains ofPtt, where it has also been associated with reduced sensitivity to DMI fungicides. InPtm, the F489L amino acid change was associated with either of three different single nucleotide polymorphisms in codon 489. This suggests that, in contrast toPtt, inPtmthe F489L mutation has emerged as a result of three distinct mutational events. Moderately DMI-resistant isolates had one or the other of the F489L substitution or a promoter insertion mutation, whereas highly DMI-resistant isolates were found to have combinations of both mechanisms together. Therefore, multiple mechanisms acting both alone and in concert were found to contribute to the observed phenomena of DMI fungicide resistance inPtm. Moreover, these mutations have apparently emerged repeatedly and independently in Western AustralianPtmpopulations, by a process of convergent or parallel evolution.
CLICK-enabled analogues reveal pregnenolone interactomes in cancer and immune cells
Authors: Roy Sougata , Sipthorp James , Mahata Bidesh , Pramanik Jhuma , Hennrich Marco L. , Gavin Anne-Claude , Ley Steven V. , Teichmann Sarah A. 
Published: October 2019

AbstractPregnenolone (P5) promotes prostate cancer cell growth, and de novo synthesis of intratumoural P5 is a potential cause of development of castration-resistance. Immune cells can also synthesize P5 de novo. Despite its biological importance, little is known about P5’s mode of actions, which appears to be context-dependent and pleiotropic. A comprehensive proteome-wide spectrum of P5-binding proteins that are involved in its trafficking and functionality remains unknown. Here, we describe an approach that integrates chemical biology for probe synthesis with chemoproteomics to map P5-protein interactions in live prostate cancer cells and murine CD8+ T cells. We subsequently identified P5-binding proteins potentially involved in P5-trafficking, and in P5’s non-genomic action that may drive the promotion of castrate-resistance prostate cancer and regulate CD8+ T cell function. We envisage that this methodology could be employed for other steroids to map their interactomes directly in a broad range of living cells, tissues and organisms.
The two extinctions of the Carolina parakeet
Authors: Burgio Kevin R. , Carlson Colin J. , Bond Alexander L. , Rubega Margaret A. , Tingley Morgan W. 
Published: October 2019

ABSTRACTDue to climate change and habitat conversion, estimates of the number of species extinctions over the next century are alarming. Coming up with solutions for conservation will require many different approaches, including exploring the extinction processes of recently extinct species. Given that parrots are the most threatened group of birds, information regarding parrot extinction is especially pressing. While most recent parrot extinctions have been island endemics, the Carolina parakeet (Conuropsis carolinensis) had an 18th-century range covering nearly half of the present-day United States, despite which, they went extinct in the 20th century. The major cause of their extinction remains unknown. As a first step to determining what caused their extinction, we used a newly published, extensive dataset of Carolina parakeet observations combined with a Bayesian extinction estimating model to determine the most likely date of their extinction. By considering each of the two subspecies independently, we found that they went extinct ~30 years apart: the western subspecies (C. c. ludovicianus) around 1914 and the eastern subspecies (C. c. carolinensis) either in the late 1930s or mid-1940s. Had we only considered all observations together, this pattern would have been obscured, missing a major clue to the Carolina parakeet’s extinction. Since the Carolina parakeet was a wide-ranging species that went extinct during a period of rapid agricultural and industrial expansion, conditions that mirror those presently occurring in many parts of the world where parrot diversity is highest, any lessons we can glean from their disappearance may be vital to modern parrot conservation efforts.
A Neural Circuit Model of Proprioceptive Feedback from Muscles Recruited during an Isometric Knee Extension
Authors: York Gareth , Osborne Hugh , Sriya Piyanee , Astill Sarah , de Kamps Marc , Chakrabarty Samit 
Published: October 2019

ABSTRACTThe influence of proprioceptive feedback on muscle activity during isometric tasks is the subject of conflicting studies. To better understand the relationship, we performed an isometric knee extension task experiment at four pre-set angles of the knee, recording from five muscles, and for two different hip positions. We applied muscle synergy analysis using NMF on the sEMG recordings to identify structure in the data which changed with internal knee angle, suggesting a link between proprioception and muscle activity. We hypothesised that such patterns in the data arise from the way proprioceptive and cortical signals are integrated in neural circuits of the spinal cord. Using the MIIND neural simulation platform, we developed a computational model based on current understanding of spinal circuits with an adjustable proprioceptive input. The model produces the same synergy patterns as observed in the experimental data indicating that such synergies are indeed encoded in the neural connectivity of the spinal cord and modulated by the proprioceptive input. When matching the proprioceptive input to the knee angles of the experiment, the model predicts the need for three distinct inputs: two to control the normal reciprocity between the agonist and antagonist muscles, and an additional to match the non-linear trend towards the limit of extension. Finally, we discuss the risks of using NMF for synergy analysis and demonstrate how to increase confidence in its results. Future modelling of human motor outputs should include interneuronal spinal circuits such as this to distinguish the modulatory role of supraspinal and peripheral afferent inputs to the spinal cord, during both passive and dynamic tasks.Significance statementSensory feedback from muscles has a significant role in motor control, but its role in tasks where limbs are held in a fixed position is disputed, because the effect is reduced when muscles are not stretched. Here, we first identified patterns of muscle activity during such tasks which changed with different leg positions. We developed a computational spinal motor circuit model with adjustable muscle stretch input, which reproduced the same patterns of activity as observed experimentally. The model predicts three distinct muscle stretch signals required to produce the activity patterns for all leg positions. Because the connections in the model are based on well known spinal circuits, it is likely the observed activity patterns are generated in the spinal cord.
DNA demethylation is a driver for chick retina regeneration
Authors: Luz-Madrigal Agustín , Grajales-Esquivel Erika , Tangeman Jared , Kosse Sarah , Liu Lin , Wang Kai , Fausey Andrew , Liang Chun , Tsonis Panagiotis A. , Rio-Tsonis Katia Del 
Published: October 2019

ABSTRACTBackgroundA promising avenue toward human retina regeneration lies in identifying the factors that promote cellular reprogramming to retinal neurons in organisms able to undergo retina regeneration. The embryonic chick can regenerate a complete neural retina, after retinectomy, via retinal pigment epithelium (RPE) reprogramming in the presence of FGF2. Cellular reprogramming resets the epigenetic landscape to drive shifts in transcriptional programs and cell identity. Here, we systematically analyzed the reprogramming competent chick RPE prior to injury, and during different stages of reprogramming. We examined the dynamic changes in the levels and distribution of histone marks and DNA modifications, as well as conducted a comprehensive analysis of the DNA methylome during this process.ResultsIn addition to changes in the expression of genes associated with epigenetic modifications during RPE reprogramming, we observed dynamic changes in histone marks and intermediates of the process of DNA demethylation. At early times after injury, H3K27me3 and 5mC repression marks decreased while 5caC and the H3K4me3 activation mark increased, suggesting genome-wide changes in the bivalent chromatin, impaired DNA methylation, and active DNA demethylation in the chromatin reconfiguration of reprogramming RPE. Comprehensive analysis of the methylome by whole-genome bisulfite sequencing (WGBS) confirmed extensive rearrangements of DNA methylation patterns including differentially methylated regions (DMRs) found at promoters of genes associated with chromatin organization and fibroblast growth factor production. In contrast, genes associated with early RPE reprogramming are hypomethylated in the intact RPE and remain hypomethylated during the process. During the generation of a neuroepithelium (NE) at later stages of reprogramming, decreased levels of H3K27me3, 5mC, and 5hmC coincide with elevated levels of H3K27Ac and 5caC, indicating an active demethylation process and genome-wide changes in the active regulatory landscape. Finally, we identify Tet methylcytosine dioxygenase 3 (TET3) as an important factor for DNA demethylation and retina regeneration in the embryonic chick, capable of reprogramming RPE in the absence of exogenous FGF2.ConclusionOur results demonstrated that injury signals early in RPE reprogramming trigger genome-wide dynamic changes in chromatin, including bivalent chromatin and DNA methylation. In the presence of FGF2 these dynamic modifications are further sustained in the commitment to form a new retina. We identify DNA demethylation as a key process driving the process of RPE reprogramming and identified TET3 as a factor able to reprogram RPE in absence of FGF2. Our findings reveal active DNA demethylation as an important process that may be applied to remove the epigenetic barriers in order to regenerate retina in mammals.