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Pharmacological characterization of zasocitinib (TAK-279): an oral, highly selective and potent allosteric TYK2 inhibitor
Get PDFZasocitinib (TAK-279) is an investigational, oral, highly selective and potent allosteric tyrosine kinase 2 (TYK2) inhibitor. This study assessed the TYK2 inhibitory potency and selectivity of zasocitinib versus licensed TYK2 and JAK inhibitors. Binding affinities were determined using homogenous time-resolved fluorescence. In vitro concentration-percent inhibition curves for IL-23-phosphorylated signal transducer and activator of transcription (pSTAT) 3, type I IFN-pSTAT3, IL-12-pSTAT4, IL-2-pSTAT5 and thrombopoietin-pSTAT3 pathways were established using human whole blood assays. Relationships between concentration and percent inhibition were determined to estimate half-maximal inhibitory concentration (IC ). Time above IC and percent daily inhibition were modeled from simulated clinical concentrations. Zasocitinib bound the TYK2 Janus homology 2 domain with a inhibitory constant of 0.0087nM, demonstrating more than 1 millionfold selectivity over JAK1. Zasocitinib potently inhibited TYK2 signaling, with IC s for IL-23-pSTAT3, type I IFN-pSTAT3 and IL-12-pSTAT4 of 48.2nM (95% confidence interval [CI]: 36.8-63.1nM), 21.6nM (95% CI: 17.3-26.9nM) and 57.0nM (95% CI: 44.2-73.4nM), respectively; zasocitinib showed no inhibition of JAK1/2/3. Simulated clinical concentrations of zasocitinib 30 mg once daily exceeded the TYK2 IC for 24 hours, maintaining >90% daily inhibition, with no JAK1/2/3 inhibition. The distinct potent and selective inhibition profile of zasocitinib defines it as a next-generation TYK2 inhibitor
Heterogeneous Computing and Power Efficiency in HEP
Get PDFThe Glasgow ScotGrid facility is now a truly heterogeneous site, with over 4,000 ARM cores representing about 20% of our compute capacity, which has enabled large-scale testing by the experiments and more detailed investigations of performance in a production environment. We present here a number of updates and new results related to our efforts to optimise power efficiency for High Energy Physics (HEP) computing. We will show updated benchmark results, including a new Figure of Merit designed to characterise the power usage during the execution of the HEPScore benchmark.
We expand our HEPScore/Watt comparison to include machines with processors from the Ampere Altra and Altra Max series, NVIDIA Grace, and the most recent AMD EPYC chips. We also introduce a Frequency Scan methodology to better characterize performance/Watt trade-offs, potentially informing strategies like frequency scaling during peak hours to optimize power efficiency.
Our findings contribute to advancing heterogeneous computing strategies and power efficiency optimizations in HEP, paving the way toward more sustainable hardware solutions
The Role of Dwell Time on Advancing 3D Nano-printing of Complex Iron Nanostructure Geometries using Focused Electron Beam Induced Deposition
No full textNo abstract available
Updated measurement of CP violation and polarisation in Bs0 → J/ψK¯∗ (892)0 decays
Get PDFA time-integrated angular analysis of the decay Bs0→J/ψK¯∗(892)0, with J/ψ → μ+μ− and K¯∗(892)0→K−π+, is presented. The analysis employs a sample of proton-proton collision data collected by the LHCb experiment during 2015–2018 at a centre-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 6 fb−1. A simultaneous maximum-likelihood fit is performed to the angular distributions in bins of the K−π+ mass. This fit yields measurements of the CP-averaged polarisation fractions and CP asymmetries for the P-wave component of the K−π+ system. The longitudinal and parallel polarisation fractions are determined to be f0 = 0.534 ± 0.012 ± 0.009 and f|| = 0.211 ± 0.014 ± 0.005, respectively, where the first uncertainty is statistical and the second is systematic. The CP asymmetries are measured with 3–7% precision and are found to be consistent with zero. These measurements, along with an updated determination of the branching fraction relative to the B0 → J/ψK*0 decay, are combined with previous LHCb results, providing the most precise values for these observables to date
LSME Research Book. Publication of Research Papers Presented at the 11th LSME International Research Conference on 'Re-Visioning Practice in Education, Health Care and Business amidst Global Challenges'
No full textNo abstract available
Shattering the illusion: state-imposed informality and ambivalent accountability in postcolonial governance
No full textPurpose:
This study examines how, during the COVID-19 crisis, the Sri Lankan state embedded informality within formal welfare structures to produce accountability through ambiguity. It theorizes state-imposed informality as a postcolonial governance strategy that shifts responsibility downward while retaining top-down controls.
Design/methodology/approach:
Using a subaltern perspective and reflexive interpretive methodology, the study investigates a cash transfer program through 29 interviews with beneficiaries and state actors across local to national levels. It draws on theories of postcolonial accountability, strategic informality, and subaltern agency.
Findings:
The study reveals how austerity, political interests, and institutional constraints produced an ambiguous governance regime. Formal mechanisms were selectively mobilised while informality was embedded to manage crisis demands. Public officers and beneficiaries, though marginalised, negotiated, adapted to, and resisted this regime through moral judgement and relationality.
Originality/value:
The paper conceptualises state-imposed informality as an ethically charged mode of postcolonial crisis governance and reframes public accountability as relational, contested, and shaped from below. It contributes to critical accounting and postcolonial governance by highlighting how accountability is not only displaced but also reconstituted through subaltern practice
The modalities and politics of crisis urbanism: a new reparative conjuncture?
No full textThis article argues that the current advance of global crises necessitates new thinking on how the urban intersects with crisis. We develop four overlapping modalities for theorizing how multiple and deepening crises are entwined with urbanism and are generative of a conjuncture we approach as crisis urbanism: chrono-politics of crisis urbanism, spatial-politics of crisis urbanism, statal-politics of crisis urbanism, and the epistemological politics of crisis urbanism. The theoretical framing of these modalities sheds light on the interlinking and enduring character of crisis urbanism and offers a better understanding of poly- and perma-crises associated with the urban way of life and the political geographies these are generating, including, dialectically, the turn to reparative urbanism to address harms within the city. Crisis is understood as not (yet) enveloping urbanism but rather as an ever-present process within urbanization. Crisis urbanism is, then, the name we give to this process, but it is also a method: a means of analysing an always politically constructed and dialectically composed process, one that is relational and ongoing. In conclusion, the article reflects on the prospects of transformative reparative politics within and beyond the current urban conjuncture
A drift-alarm framework for NTN–UAV nodes: robust, self-healing ML models via classifier–cluster consistency
No full textUncrewed aerial vehicles (UAV(s)) are emerging as agile non-terrestrial network (NTN) nodes that extend 5G/6G coverage to remote farms, disaster zones, and shipping lanes. However, on-board ML models carried by UAV(s) degrade under concept drift, leading to missed events and false alarms. We propose a real-time drift-alarm framework (RTDD) that pairs a deployed classifier with a lightweight clustering model. On board, RTDD cross-checks classifier outputs against cluster membership to infer error on unlabelled streams and signals drift when the discrepancy between the on-board classifier-accuracy estimate (CA) and the classifier–cluster agreement rate (ClA) exceeds a conservative discrepancy threshold. This thresholding preserves sensitivity to both abrupt and gradual shifts while suppressing spurious alarms. Empirically, agreement between classifier outputs and cluster membership provides a robust, label-free drift signal. Using this signal, our method achieves similar detection timeliness to state-of-the-art label-based approaches while reducing the false-alarm rate under true-label delay
Understanding the paradox of primary teacher shortage in low-income countries: insights from Malawi
Get PDFMalawi faces a persistent and chronic teacher
shortage, particularly at the primary school level, with
much of the challenge attributed to teacher supply
constraints. While the causes of teacher shortages
are known to be complex and context-dependent,
there remains a lack of in-depth, country-specific
research to guide effective policies, especially in
low-income countries where the problem is most
acute. This study addresses this gap by examining
the nature and underlying causes of primary teacher
shortages in Malawi. We adopted a qualitative,
multiperspectival research design involving in-depth
interviews with key practitioners and policymakers
engaged in teaching, teacher education, recruitment,
deployment, policy and funding. Participants
included permanent and contract teachers, a
headteacher, teacher training college principals,
senior government officials in education, a teachers'
union representative, a primary education advisor,
a civil society representative and international
development partners. Findings derived through
thematic analysis revealed a multidimensional crisis
characterised by persistent staffing gaps, high pupil–
teacher ratios, and geographic disparities in teacher
distribution. Contrary to the dominant narrative of
supply-side constraints, the study identified a surplus
of qualified but unemployed teachers. The core issue
lies in policy and systemic failures, particularly the
government's inability to recruit teachers due to fiscal
limitations linked to debt servicing and externally imposed wage bill restrictions. This presents a
paradox: a teacher shortage at the school level
coexisting with teacher unemployment in the country.
Our findings offer new insights into the structural
causes of teacher shortages and highlight the urgent
need to address existing policy failures. We conclude
with recommendations that may help in addressing
the current teacher recruitment policy failures and
make the teaching profession more attractive and
sustainable
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