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Spectroscopic Characterization of Radical Pair Photochemistry in Nonmigratory Avian Cryptochromes: Magnetic Field Effects in Gg Cry4a
Get PDFThe magnetic compass sensor in night-migratory songbirds is thought to be a flavin-tryptophan radical pair formed by blue-light excitation of the protein cryptochrome-4a (Cry4a) localized in photoreceptor cells in the birds’ retinas. The effects of applied magnetic fields on the photochemistry of purified Cry4a from the migratory European robin are well characterized, but it is less clear what, if anything, distinguishes the magnetic responses of the Cry4a proteins from migratory and nonmigratory species. We present here a detailed study of the magnetic sensitivity of Cry4a from the nonmigratory chicken. The wild-type protein is compared with two mutants in which either Arg317 or Glu320, both close to the tryptophan radical, were replaced by the amino acids Cys and Lys, respectively, found in Cry4a from robins and other night-migratory passerines. These sites had previously been identified as probably facilitating the evolution of an optimized magnetic sensor for nocturnal orientation in songbirds. Neither of these mutations was found to affect the reaction kinetics or magnetic sensitivity of the radical pairs, suggesting that any differences in Cry4a between robin and chicken must stem from their ability to transmit magnetic information, for example via protein–protein interactions. In contrast, a Trp → Phe mutation at the end of the tryptophan-tetrad electron transfer chain in both cryptochromes led to a large increase in magnetic sensitivity, suggesting different sensing and signaling roles for the third and fourth tryptophans
The Karl G. Jansky Very Large Array Local Group L -Band Survey (LGLBS)
Get PDFWe present the Local Group L-Band Survey, a Karl G. Jansky Very Large Array (VLA) survey producing the highest-quality 21 cm and 1–2 GHz radio continuum images to date, for the six VLA-accessible, star-forming, Local Group galaxies. Leveraging the VLA’s spectral multiplexing power, we simultaneously survey the 21 cm line at high 0.4 km s−1 velocity resolution, the 1–2 GHz polarized continuum, and four OH lines. For the massive spiral M31, the dwarf spiral M33, and the dwarf irregular galaxies NGC 6822, IC 10, IC 1613, and the Wolf–Lundmark–Melotte Galaxy, we use all four VLA configurations and the Green Bank Telescope to reach angular resolutions of <5″ (10–20 pc) for the 21 cm line with <1020 cm−2 column density sensitivity, and even sharper views (<2″; 5–10 pc) of the continuum. Targeting these nearby galaxies (D ≲ 1 Mpc) reveals a sharp, resolved view of the atomic gas, including 21 cm absorption, and continuum emission from supernova remnants and H ii regions. These data sets can be used to test theories of the abundance and formation of cold clouds, the driving and dissipation of interstellar turbulence, and the impact of feedback from massive stars and supernovae. Here, we describe the survey design and execution, scientific motivation, data processing, and quality assurance. We provide a first look at and publicly release the wide-field 21 cm H i data products for M31, M33, and four dwarf irregular targets in the survey, which represent some of the highest-physical-resolution 21 cm observations of any external galaxies beyond the LMC and SMC
Risky business: an investigation of how frontline officers conceptualise and identify risk in IPV incidents
No full textPolice act as a gateway to justice with frontline officers’ decision-making, and specifically risk level allocation, influencing what support victims receive and criminal justice responses pursued. In England and Wales, risk levels are applied to intimate partner violence (IPV) incidents to determine the severity of violence and victims’ risk of future abuse. This enables prioritisation of limited police resources and ensures police intervention is proportional. It is therefore crucial to understand how officers attribute risk levels, which range across standard, medium and high. Despite the importance of this topic, few have researched frontline officers’ decision-making about risk levels, particularly within the British context.
My thesis contributes to this research gap by investigating how frontline police officers in a South-Eastern English police force make decisions about risk in short-time frames and high pressured IPV environments. As well as identifying which specific factors officers rely on, this thesis seeks to understand how these factors affect officers’ risk evaluations and shape their decision-making as ‘working rules’. This thesis provides insights into understanding why these factors are relevant to frontline officers’ assessment of risk.
Thematic analysis is used to qualitatively and quantitatively review thirty-four IPV case files, to identify key factors affecting risk level allocation, how these are weighted and any contextual influences. These findings are supplemented by thirty-three hours of interviews with twelve officers, across six different roles.
Overall, this thesis shows that the key factors affecting frontline police officers’ decisions about risk are prior police reports of IPV, physical proximity between the parties, victims’ fear, and physical violence (particularly injuries). Understanding how risk factors impact police decision-making can contribute to improving and developing more consistent and efficient responses to IPV
Investigating the relationship between Pfkelch13 mutations and response to artemisinin-based treatment for uncomplicated falciparum malaria: a protocol for a systematic review and individual patient data meta-analysis
Get PDFIntroduction: Artemisinin-based combination therapies (ACTs) remain the WHO-recommended treatment for uncomplicated Plasmodium falciparum malaria. However, the emergence and spread of artemisinin resistance (ART-R) threatens ACT efficacy. ART-R is phenotypically expressed as delayed parasite clearance, which can facilitate ACT partner drug resistance. ART-R has been causally linked to specific mutations in the Pfkelch13 gene. Methods and analysis: The systematic review and associated meta-analysis aim to determine the correlation between Pfkelch13 (alleles present in the Kelch13 gene region of the P. falciparum parasite) genotypes and clinical and parasitological response to ACTs from a globally representative data set pooling individual patient data (IPD) from eligible published and unpublished studies. The eligibility criteria include Pfkelch13 genotyping results at baseline complemented by individually linked parasitological and clinical assessments following artemisinin-based treatment. The data will be curated, standardised and analysed using this proposed statistical analysis plan (SAP), adhering to PRISMA-IPD (PRISMA, Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines. Our SAP will apply hierarchical modelling to assess the effect of the P. falciparum parasite Pfkelch13 mutations on parasite clearance half-life and therapeutic efficacy across different regions. This will include study sites as random effects in the model and potential predictors such as age, sex, baseline parasite load and other potential effect modifiers as fixed effects. This analysis will enhance the understanding of the influence of Pfkelch13 mutations on malaria treatment outcomes. Ethics and dissemination: Data were obtained with informed consent and ethical approvals from the relevant countries and were pseudonymised before curation in the Infectious Diseases Data Observatory (IDDO)/WorldWide Antimalarial Resistance Network (WWARN) repository. Data ownership remains with contributors. This IPD meta-analysis met the Oxford Tropical Research Ethics Committee criteria for waiving ethical review, as it is a secondary analysis of existing pseudonymised data. The resulting peer-reviewed publication and conference proceedings will help strengthen and enhance the efficiency of ART-R surveillance and response and support policy decisions. PROSPERO registration number: CRD42019133366
Management of paediatric ulcerative colitis, part 1: Ambulatory care—An updated evidence‐based consensus guideline from the European Society of Paediatric Gastroenterology, Hepatology and Nutrition and the European Crohn's and Colitis Organisation
Get PDFObjectives: Despite advances in the management of ambulatory paediatric ulcerative colitis (UC), challenges remain as many patients are refractory to therapy and some require colectomy. The aim of these guidelines is to provide an update on optimal care for UC through detailed recommendations and practice points. Methods: These guidelines are an update to those published in 2018 and are a joint effort of the Paediatric IBD Porto group of European Society of Paediatric Gastroenterology, Hepatology and Nutrition and the European Crohn's and Colitis Organisation. An extensive literature search with subsequent evidence appraisal using the Oxford methodology was performed, followed by three online voting sessions and a consensus face‐to‐face meeting. Thirty‐nine recommendations and 77 practice points were endorsed by the 25 experts with at least an 84% consensus rate. Results: Robust evidence‐based recommendations and detailed practice points are provided. In addition to reemphasising and updating the role of more ‘traditional’ UC therapies, these guidelines outline optimising the use of antitumour necrosis factor therapies and integrating newer biologics and small molecules, as well as supportive therapy, to improve outcomes and provide an updated management algorithm. Measurement and monitoring tools and decision aids are provided, and additional aspects, including nutritional support, extraintestinal manifestations, pouchitis, inflammatory bowel disease‐unclassified and patient support, are discussed. Some aspects, including surgery and thromboprophylaxis, are covered in the acute severe UC guidelines. Conclusions: These guidelines serve as an aid in managing children with UC through a combination of evidence‐based recommendations and more practical practice points in the ambulatory setting
Risk factors for unplanned readmissions in paediatric neurosurgery: a systematic review
Get PDFObjectives: Unplanned hospital readmission (UHR) after paediatric neurosurgery is an important indicator of surgical outcomes. As this field deals with complex cases, there is an increased likelihood of potential complications and the subsequent need for readmission. We estimated paediatric neurosurgery UHR rates globally and identified significant factors contributing to 30-day and 90-day UHR rates in children undergoing neurosurgical procedures. Design: A systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Data sources: Embase, Medline, CINAHL and Global Index Medicus databases were searched on 17th December 2023. Eligibility criteria: We included studies that reported unplanned readmissions in the paediatric population within 30 days and 90 days of an index neurosurgical procedure. Data extraction and synthesis: Two independent qualified researchers screened studies and extracted data using standardised methods. Risk of bias assessment was done using the Newcastle-Ottawa scale. Narrative synthesis was performed. Results: 2593 titles were identified following the search strategy. 52 studies were included after screening, full-text review and quality appraisal. Most studies were from the USA and are retrospective cohorts. The majority were cranial procedures (n=30), with common ones being shunt procedures for hydrocephalus and cranial tumour resections. 30-day readmissions ranged from 1.4% to 28% while 90-day readmissions ranged from 1.31% to 38.64%. 34 different risk factors were identified. Aetiology-related factors, procedure-specific complexities and age emerged as the three most common. Other common risk factors were complex chronic conditions, race, length of hospital stay and type of medical insurance. The patient’s age was a significant non-modifiable predictor, with younger children generally facing higher odds compared with their older counterparts across different procedures. While early readmissions could be due to disease progression, some were linked to preventable causes. Heterogeneity was also present due to variations in definitions and inclusion of studies from both national databases and single institutions. Conclusions: Findings from this study contribute to a collective understanding of factors affecting unplanned readmissions in paediatric neurosurgery. UHRs reflect the interplay among surgical complexity, patient characteristics such as age and disease aetiology
The role of rhythm in the works of Arno Holz, Stefan George, and Georg Trakl
Get PDFThis thesis examines the central role of rhythm in the works of Arno Holz, Stefan George, and Georg Trakl. It argues that rhythm is both a map and a mirror, and that these poets used the concept to explore the composition of their poetry, its commitments and effects, and to engage productively with the rapidly changing circumstances of their times.
Recently, there has been a surge in scholarship concerning the wider importance of rhythm for a variety of disciplines and its merits as a critical approach. My thesis provides a case study of three seminal German-language poets around 1900 and shows how focussing on a seemingly universal concept like rhythm can result in highly individualised forms of expression. Although the individual poetic projects differ significantly, following the paths of rhythm in each can reveal the poets’ outlooks and obligations towards their craft, and rhythm’s significance in a wider historical and cultural context.
Examining these authors in combination – each vital to the development of different strands of German-language poetry in the decades surrounding the turn of the last century – through the lens of rhythm reveals new connections regarding intentions and interpretations of their works. All three had a shared interest in the conceptual powers of rhythm and how it can shape their poetry. Moreover, my thesis suggests that these approaches to thinking about and using rhythm live on in the poetry of contemporary authors, just as the heightened interest in the concept of rhythm today is comparable to the enthusiasm for it a century ago
Dopaminergic modulation of Drd1a-Cre+ neuronal network activity in the murine medial prefrontal cortex
Get PDFCortical layer 6 (L6) neurons play an important role in driving cortical arousal via the higher-order corticothalamic system. In the murine somatosensory cortex, L6-Drd1a neurons (which express the dopamine D1 receptor) selectively project to higher-order thalamic nuclei and are highly sensitive to the wake-promoting neuropeptide orexin, likely playing an important role in cortical arousal, sensory valence processing, and anxiety behavior (Hoerder-Suabedissen et al., 2018; Zolnik et al., 2023). Whether these L6-Drd1a neurons play an analogous role in driving cortical arousal through a dopaminergic modulatory mechanism in the medial prefrontal cortex (mPFC) remains poorly understood. To test this hypothesis, we investigated the effects of ‘silencing’ L6-Drd1a neurons using a Snap25 conditional knockout mouse model (Drd1a-Cre+/-;Snap25fl/fl;tdTomatoSTOPfl/fl) on the dopaminergic modulation of network activity in mPFC acute slices using high-density planar multielectrode arrays (MaxWell Biosystems) and whole-cell patch clamp recordings. We found that D1 receptor agonist SKF-81297 significantly increased broadband local field potential (LFP) activity in the infralimbic mPFC, which was eliminated upon chronic ‘silencing’ of L6-Drd1a neurons. On the other hand, D2 receptor agonist quinpirole only increased infralimbic network activity in L6-Drd1a ‘silenced’ slices. Subsequent whole-cell electrophysiological characterization of L6 neurons in the mPFC revealed that D1 receptor activation selectively increased L6-Drd1a intrinsic excitability and spontaneous synaptic potential amplitude, while D2 receptor activation non-selectively excited L6 neurons. Taken together, these results suggest a postsynaptic mechanism of D1 receptor activation that increases L6-Drd1a excitability to drive mPFC network arousal, along with a compensatory mechanism of D2 receptor activation in the functional absence of these L6-Drd1a neurons. Our findings provide novel insight into the dopaminergic modulation of L6-Drd1a neurons in the mPFC that likely contributes to their orexinergic gating of cortical arousal, with relevant therapeutic implications for anxiety and stress-related disorders
Planar chemical reaction systems with algebraic and non-algebraic limit cycles
Get PDFThe Hilbert number H(n) is defined as the maximum number of limit cycles of a planar autonomous system of ordinary differential equations (ODEs) with right-hand sides containing polynomials of degree at most n ∈ N. The dynamics of chemical reaction systems with two chemical species can be (under mass-action kinetics) described by such planar autonomous ODEs, where n is equal to the maximum order of the chemical reactions in the system. Analogues of the Hilbert number H(n) for three different classes of chemical reaction systems are investigated: (i) chemical systems with reactions up to the n-th order; (ii) systems with up to n-molecular chemical reactions; and (iii) weakly reversible chemical reaction networks. In each case (i), (ii) and (iii), the question on the number of limit cycles is considered. Lower bounds on the modified Hilbert numbers are provided for both algebraic and non-algebraic limit cycles. Furthermore, given a general algebraic curve h(x, y) = 0 of degree nh ∈ N and containing one or more ovals in the positive quadrant, a chemical system is constructed which has the oval(s) as its stable algebraic limit cycle(s). The ODEs describing the dynamics of the constructed chemical system contain polynomials of degree at most n = 2 nh + 1. Considering nh ≥ 4, the algebraic curve h(x, y) = 0 can contain multiple closed components with the maximum number of ovals given by Harnack’s curve theorem as 1 + (nh − 1)(nh − 2)/2, which is equal to 4 for nh = 4. Algebraic curve h(x, y) = 0 with nh = 4 and the maximum number of four ovals is used to construct a chemical system which has four stable algebraic limit cycles