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Rapid and recent evolution of fetA phase variability among hyperinvasive MenW:cc11 disease isolates
Get PDFNeisseria meningitidis serogroup W (MenW) clonal complex 11 isolates are a major worldwide cause of invasive meningococcal disease. This lineage has exhibited significant plasticity with multiple evolutionary events occurring during international and national spread. Phase variation is a major mechanism for the modulation of surface antigen expression including for FetA, a major immunogenic meningococcal antigen. Alterations in switching rates occur due to changes in the repeat numbers of phase-variable genes. Analysis of 1521 MenW:cc11 carriage and disease isolates detected evidence of ongoing evolution within the UK. The rebound in MenW:cc11 disease in the post-coronavirus disease 2019(COVID-19) pandemic era was associated with isolates belonging to four sub-clusters (SC). One of these SCs was associated with isolates circulating at low levels for more than 50 years, whilst another contained novel variants. Evolution of the fetA promoter and repeat region was detected with increases in the tract length from 6C to 8C or longer becoming highly prevalent from 2015 onwards. Acquisition of phase-variable tracts of 8C or longer was correlated with other alterations in the fetA promoter and genic region. The predominant repeat number for this promoter-located repeat tract was 11C, which is associated with intermediate expression. The potential for heightened phase variation of FetA mirrors earlier evolution of increases in repeat numbers of two other surface proteins, PorA and Opa, in this lineage. Ongoing evolution of phase variation may be aiding maintenance of significant levels of the transmission of this hypervirulent lineage and persistent associations with invasive disease despite widespread vaccine usage
Quantifying the influence of sleeper spacing on lateral resistance using a novel experimental method
Get PDFLateral resistance, principally dictated by the interaction between sleepers (ties) and ballast, is a fundamental property of ballasted railway track which is critical to overall track stability and safety. This study investigates the influence of sleeper spacing on lateral resistance to support overall track system design and track safety management. A novel multi-sleeper push test (MSPT) methodology, utilising both a kinematic restraint to better replicate track conditions and a state-of-the-art digital image correlation (DIC) system to measure surface ballast movement, has been used to evaluate the lateral resistance behaviour of two different sleeper types (concrete and steel) under seven different sleeper spacing conditions (550–850 mm). This is the first direct comparison of modern concrete and steel sleeper variants under these conditions. It is found that both sleeper types exhibit similar lateral resistance behaviour at small displacements (less than 3 mm) but, regardless of the spacing used, steel sleepers have significantly greater lateral resistance beyond this point. Although it depends on the assessment method used, concrete sleepers demonstrated an optimum spacing of approximately 675 mm, whilst steel sleepers showed highest resistance at approximately 706 mm. However, concrete sleepers showed less sensitivity to changes in spacing compared to steel sleepers, which retained high resistance over a narrower range of spacings. These findings contribute to track safety management by improving buckling mitigation strategies and component selection, whilst unlocking the ability to assess system-level impacts to aid the pursuit of more sustainable railway infrastructure design
At the Top of the Mind: Peak Prices and the Disposition Effect
Get PDFThe disposition effect is the reluctance to sell assets at a loss relative to a salient point of reference, typically assumed to be the purchase price. Using data on stocks and housing sales, we show that the peak price achieved by an asset during the investor’s period of holding constitutes an additional salient reference point for asset owners that overlaps—and interacts—with the purchase price reference point. Peaks occurring before the investor purchased the asset do not affect future sales, indicating that ownership affects how investors form reference points
73 GHz pHEMT pumped transconductance RX Mixer with low local oscillator drive power
No full textFuture mmWave mobile architectures will benefit from low power RF circuits and systems. In this work we propose two pumped transconductance balanced mixers requiring low LO drive power and DC power. The mixers operate at circa 73 GHz RF and 70 GHz LO. A 90-degree hybrid is used on the input to simplify input matching. Off-chip IF matching is implemented on a test PCB. We observe a conversion gain of -17 dB for an LO power of -10 dBm, with a DC current of 1.3 mA and an IP1dB of - 3.3 dBm for one of the prototypes. LO powers down to -20 dBm are also potentially viable, if greater loss can be accepted
Entrepreneurial becomings - the disruptive power of self-employment for people with learning disabilities
No full textBackground
Many people with learning disabilities lead marginalised lives and navigate a world that values people in terms of employment and economic contribution. Although the number of people with learning disabilities in paid work was recently estimated to be just 4.8% (NHS Digital, 2022), some people are using self-employment to create employment opportunities in ways that also demand a reappraisal of this conventional allocation of human value.
Methods
Using the narratives of three entrepreneurs with learning disabilities, this paper builds on Critical Disability Studies’ emerging DisHuman scholarship to ask how enterprise is being used to challenge, subvert, disrupt and extend our understanding of how human becoming happens. It analyses three conceptualisations of entrepreneurship - the conditional, the relational and the DisHuman - to consider the tensions, contradictions and delight inherent in building new understandings of human value.
Findings
The study finds that self-employment presents a conduit through which people with learning disabilities can interact with the wider social, education and welfare systems as they simultaneously reject normative notions of success while inviting new ways to embrace opportunities for inclusion.
Conclusions
We think not of self-employment just as an employment outcome, but as an exciting site of potential through which individuals celebrate interconnection, interdependence and collaboration, unencumbered by normative ideals of perfection, autonomy and contribution (Goodley, 2001)
Optimal dispatch of an electricity-thermal-hydrogen microgrid for zero-carbon airport operations with electric and hydrogen aircraft
Get PDFAchieving net-zero aviation requires airport energy infrastructure that delivers an efficient, reliable, and diversified energy supply to support the parallel operations of emerging battery-electric, hybrid hydrogen-electric, and hydrogen-powered aircraft. This study assesses how airport energy systems can support the transition to zero-carbon aviation. We propose an integrated electricity-thermal-hydrogen microgrid that incorporates photovoltaics, hydrogen fuel cells, and multiple energy storage systems to reduce reliance on the power grid and external energy sources. Firstly, a refined statistical method utilizing surrogate models is developed to estimate aircraft charging and refuelling demand. A stochastic optimization model that exploits load shifting potential is then formulated to minimize total economic costs while reducing operational risks and enhancing grid support flexibility. The resulting optimal energy dispatch ensures that flight schedules and multi-energy demands are met across electricity, thermal, and hydrogen networks. Case studies based on real flight schedules from Manchester airport evaluate five energy dispatch scenarios with varying optimization priorities. The results demonstrate a 29.4% increase in grid flexibility and a 63.2% reduction in operational risks through the proposed strategy. Furthermore, sensitivity analyses examine the impacts of electricity and hydrogen price fluctuations, as well as different fleet adoption ratios, identifying the optimal electric-to-total energy demand ratio for efficient airport energy system operation. These findings provide practical insights for airport operators and policymakers in developing resilient, sustainable airport energy infrastructure and implementing effective zero-carbon airport operations strategies
Homology of matching complexes and representations of symmetric groups
No full textWe compute the cohomology of the matching complex for the complete hypergraph and analyse the symmetric group representations carried by this cohomology. Our main technical tool is the theory of shellings
Candida albicans cells lacking AP‐2 have defective hyphae and are avirulent despite increased host uptake and intracellular proliferation in macrophages
Get PDFCandida albicans is a commensal microbe and opportunistic human pathogen. Candida yeast are recognized and taken up by macrophages via phagocytosis. Macrophage surface receptors bind to specific components of the Candida cell wall. Following phagocytosis, Candida can respond to the host's intracellular environment by switching from a yeast to a hyphal morphology facilitating escape from macrophages and allowing subsequent invasion of host tissues. Various disruptions of Candida's ability to form hyphae have been shown to reduce virulence and fitness in the host. Our previous work concluded that Candida albicans cells lacking AP-2 (apm4Δ/Δ), an endocytic adaptor complex, have increased cell wall chitin and morphologically defective hyphae in vitro. Increased chitin has been correlated with decreased recognition by macrophages, possibly due to masking of cell wall β-glucan, the target for the Dectin-1 immune receptor. Here we test the virulence profiles of apm4Δ/Δ mutant, demonstrating a surprising increase in macrophage phagocytosis that does not occur due to the elevated exposure of β-glucan, highlighting the importance of cell wall components beyond chitin and glucan for macrophage engagement and uptake. Furthermore, the apm4 mutant exhibited parasitism of macrophages, surviving and proliferating within the phagosome, a phenotype that was then replicated with a well-characterized yeast locked mutant, demonstrating the further complexity of C. albicans' ability to evade macrophage responses. Finally, the combined phenotype of reduced hyphal formation but continued proliferation resulted in reduced virulence despite an equivalent burden of infection with wild-type Candida infection, as determined using a zebrafish larval model of candidiasis
Late-Onset Spondyloarthritis Presenting as Glucocorticoid-Resistant Polymyalgia Rheumatica: A Hitherto Underappreciated Entity in Which Tumor Necrosis Factor or Interleukin -17 Blockade May Have a Therapeutic Role
No full textObjective
Polymyalgia rheumatica (PMR) is an age-related inflammatory disease with shoulder/hip girdle involvement. Magnetic resonance imaging (MRI) reveals extracapsular/entheseal soft tissue involvement in both PMR and spondyloarthritis (SpA), with sacroiliac joint and perientheseal spinal bone marrow edema (BME) being characteristic of SpA. Therefore, some shared anatomic topography might be expected to result in similar clinical features. Herein, we describe the clinical and imaging features of SpA initially diagnosed as PMR.
Methods
Patients observed at Leeds Teaching Hospitals NHS Trust with a diagnosis of psoriatic arthritis (PsA) or axial SpA were screened to identify those initially diagnosed with PMR from 2002 to 2024. Only those patients who retrospectively fulfilled the 2012 EULAR/American College of Rheumatology classification criteria or the Bird et al criteria for PMR were included. Clinical data relevant to initial PMR diagnosis, imaging features, follow-up, and treatment data were collected, as well as radiographic or MRI features that established the final diagnosis.
Results
Thirty-one patients (median age 62 [interquartile range (IQR) 58–69] years; 17 women and 14 men) presenting with typical PMR shoulder/hip girdle pain were subsequently classified as having SpA spectrum disorders. The SpA diagnosis was made in 12 patients within three months of presentation and in 19 patients during the remaining follow-up period (median 3 [IQR 1–4] years). Four of 27 tested patients were HLA–B27 positive. BME on MRI was detected in the spine and/or sacroiliac joints in 20 of 25 patients (80%) who underwent imaging (sacroiliac joint: 17 patients [68%]; spine: 15 patients [60%]). Clinical resolution with C-reactive protein (CRP) level normalization occurred in 21 of 31 patients following initial glucocorticoid (GC) therapy, but 7 of these 21 initial responders experienced disease flares or elevations in CRP levels. Therapy-wise, disease-modifying antirheumatic drugs (DMARDs) were used in 21 of 31 patients: 8 received conventional synthetic DMARDs, and 11 received biologic agents (8 anti–tumor necrosis factor agents, 3 interleukin-17 inhibitors), whereas the remaining 10 patients were treated with ≤10 mg/day of GCs.
Conclusion
Late-onset SpA with PMR clinical presentations is characterized by failure to respond to or taper GC therapy and is often identified by SpA-specific osteitis patterns on MRI. We propose that a PMR–SpA overlap may account for biologic therapy efficacy in steroid-refractory PMR
A biomarker‐based classification of corticobasal syndrome
Get PDFBackground
Corticobasal syndrome (CBS) is a clinically defined syndrome with progressive movement and cortical dysfunction, caused by various underlying pathologies, most commonly tau-predominant pathologies such as progressive supranuclear palsy and corticobasal degeneration, or Alzheimer's disease (AD). Lewy-type α-synucleinopathies (LTS), TDP-43 proteinopathies, and mixed pathologies may also underlie CBS. The clinical impact of these pathologies remains poorly understood.
Objectives
To subclassify CBS patients in vivo using biomarkers for amyloid-β (Aβ), Tau, and α-synuclein (αSyn), and assess the clinical relevance of this stratification.
Methods
We conducted a prospective cohort study of 50 CBS patients at LMU University Hospital Munich. Biomarker analysis included cerebrospinal fluid (CSF) Aβ42 and Aβ42/40, [18F]flutemetamol Aβ-PET, [18F]PI-2620 tau-PET, and αSyn seed amplification assays in CSF. CSF neurofilament light chain (NfL) served as a marker of neurodegeneration. Patients were stratified into six groups based on biomarker positivity.
Results
Tau positivity was found in 90% of CBS cases, Aβ in 28%, and αSyn in 24%. Stratification identified: 52% consistent with tau-predominant pathology, 18% with AD, 10% with AD+LTS, 10% with tau-predominant+LTS, 4% with isolated LTS, and 6% unclassified. αSyn positivity was more frequent in AD-CBS (36%) than in tau-predominant-CBS (16%). Aβ-positive cases showed greater cognitive impairment; Tau positivity correlated with worse motor symptoms; αSyn-positive patients had milder motor symptoms, slower progression, and lower NfL levels.
Conclusions
CBS is molecularly heterogeneous. Biomarker-based classification may enhance diagnostic precision and support personalized therapeutic strategies
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