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A CHERI C Memory Model for Verified Temporal Safety
No full textMemory safety concerns continue to be a major source of security vulnerabilities. The CHERI architecture, as instantiated in prototype CHERI-RISC-V cores, the Arm Morello system, and Microsoft's CHERIoT embedded core, provides fine-grained memory access control through unforgeable hardware capabilities. The impact of CHERI on spatial memory safety is well understood. This paper systematically examines temporal memory safety within CHERI C -- a dialect of the C programming language for CHERI -- and proposes a formal approach to defining and ensuring it. In particular: 1) we examine the impact of five existing capability revocation mechanisms on CHERI C semantics and present a specialised object memory model tailored to CHERI C; 2) we introduce a new CHERI-specific pointer provenance tracking scheme; and 3) we formally define the security guarantees provided by this memory model, supported by a Coq proof of their correctness, expressed as invariants of the memory state
The implementation in STIR of four analytical algorithms for 2D PET and 2D SPECT reconstruction
No full textFollowing works of Gelfand, one of the authors, and Novikov, 2D analytic reconstruction algorithms based on techniques of complex analysis have been developed for both positron emission tomography (PET) and single photon emission computed tomography (SPECT). Here we implement four such 2D analytic reconstruction algorithms in the open-source Software for Tomographic Image Reconstruction (STIR). First, we implement two 2D PET analytic reconstruction algorithms suitable for PET data, i.e. for the discretized Radon transform. One algorithm provides an improved implementation of an algorithm based on spline interpolation (SRT2D) and the other is based on the gridding method (GRD2D). We perform comparisons in terms of speed and image quality, especially for contrast for both ‘hot’ and ‘cold’ regions of interest (ROIs), between these two algorithms and the dominant analytic reconstruction algorithm, namely, filtered backprojection 2D (FBP2D), which is available in STIR; we also include comparisons with the standard iterative baseline, ordered subsets expectation maximization (OSEM). SRT2D and GRD2D provide strong alternatives to FBP2D in terms of image quality; in our implementation, GRD2D and FBP2D have essentially the same runtime, while OSEM operates in a different contrast-noise regime and is slower. Second, we implement two analytic algorithms for 2D SPECT reconstruction, i.e. for the discretized attenuated Radon transform; the Spline Reconstruction Technique (SRT2DSPECT) and the Direct Differentiation SPECT Reconstruction (DDSR2D). Since FBP2D does not provide an inverse for the attenuated Radon transform, we compare these analytic algorithms with OSEM. SRT2DSPECT and DDSR2D provide competitive analytic SPECT reconstructions compared with OSEM in the contrast-coefficient of variation evaluation; SRT2DSPECT often yields higher measured contrast but tends to overshoot (contrast values exceeding the ideal value 1), whereas DDSR2D provides less overshoot-prone contrast estimates and is notably faster than SRT2DSPECT and OSEM
RNF25 confers mRNA damage tolerance by curbing activation of the integrated stress response
No full textExcessive RNA damage activates cellular stress responses, triggering cell death. However,
pathways that negatively regulate RNA damage responses are largely uncharacterized. Using
genetic screens, we here find that the ubiquitin ligase RNF25 provides tolerance to RNA
damage caused by the nucleoside analogue azacytidine, a chemotherapeutic agent used to
treat acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Mechanistically,
we show that azacytidine is incorporated into mRNA, where it causes lesions that stall
elongating ribosomes, leading to cytotoxic activation of the GCN2-dependent integrated stress
response (ISR). Furthermore, we establish that RNF25 prevents ISR hyperactivation by
ubiquitylation of ribosomal protein eS31, thereby suppressing cell death upon azacytidine
treatment. Our study reveals an mRNA damage tolerance mechanism that determines cellular
survival in response to azacytidine, highlighting RNA damage-induced stress response as a
potentially critical component of chemosensitivity in AML and MDS
Orthostatic tremor and its subtypes: a single centre cohort of 74 patients
No full textBackground: Orthostatic tremor (OT) is a rare, heterogenous disorder, recently sub-classified into primary OT (isolated 13-18 Hz tremor), OT-plus (OT with additional neurological features) and pseudo-OT (OT with frequencies < 13 Hz). However, to our knowledge no study to date has compared clinical characteristics between all three subgroups. Objectives: We aim to further define and compare the clinical characteristics of the three different OT subgroups, utilising one of the largest described single centre cohorts to date. Methods: A retrospective analysis was undertaken of clinical records from 74 OT patients at Charing Cross Hospital between 1999 and 2023, enabling categorisation into subgroups. Clinical characteristics, including treatment efficacy and overall disability, were subsequently described and compared between subgroups. Results: 61 primary OT, 5 OT-plus and 8 pseudo-OT patients were identified. Baseline demographics were comparable between subgroups. Logistic regression suggested age of onset (OR = 1.02, p = 0.229), symptom duration (OR = 1.05, p = 0.083), tremor frequency (OR = 1.02, p = 0.826) and subgroup (OT-plus (OR = 1.86, p = 0.565) and pseudo-OT (OR = 1.41, p = 0.683)) were not significant predictors of disability. Treatment response varied between subgroup, with primary OT and pseudo-OT patients more frequently reporting symptomatic improvement with clonazepam, gabapentin and/or alprazolam than OT-plus patients. Conclusions: We provide further insight into the clinical phenotypes of the OT subgroups and encourage future studies to validate these findings with larger sample sizes and establish reliable tools to measure OT severity to better assess disease progression and treatment response
Loss and damage financing for climate justice and transformation: local insights from the climate frontline
No full textLoss and Damage (L&D) has emerged as a critical pillar of global climate action, supported by an emerging, dedicated financing stream. While the scale of L&D financing is far below what may be required, fundamental questions remain about how this financing can effectively minimise losses and damages at local climate frontlines. Recognising the limits of past and ongoing adaptation efforts, this paper examines the role of emerging L&D finance beyond risk management or reduction in transforming systems that predispose vulnerable groups to losses and damages. Drawing on empirical research from local cases in three climate frontline countries, Bangladesh, Nepal, and Vanuatu, we explore how L&D financing can go beyond risk reduction or compensation to address structural vulnerabilities and deliver climate justice. Findings reveal gaps, as current adaptation and disaster risk reduction efforts fail to build systems capacity and prevent escalating, irreversible, and unavoidable losses and damages. Given the systemic nature of climate impacts, increasing financial flows alone does not guarantee a reduction in losses and damages unless funds are directed toward dismantling systemic barriers that predispose communities to losses and damages. The paper argues that L&D finance must support more systemic or transformational responses, such as planned relocation, cultural restoration, and gender-responsive interventions, while ensuring local ownership and embedding equity and accountability in governing the finance. We call for a fundamental shift in thinking about how we design global-to-local finance architecture, emphasising the need for anticipatory, participatory, and justice-oriented approaches
Introducing a prognostic score for successful treatment-free remission in chronic myeloid leukaemia.
No full textThe modern management of chronic myeloid leukaemia (CML) identifies a new therapeutic goal of treatment-free remission (TFR). Half of CML patients in durable deep molecular response (DMR) (MR4 or better) can remain off tyrosine kinase inhibitors (TKIs) without experiencing loss of major molecular response. Despite a large number of TFR studies to date, there are no consistent predictors of successful TFR. We conducted a single-centre cohort study on 197 patients discontinuing TKIs in DMR ≥1 year and TKI therapy ≥3 years. After TKI discontinuation, 98 patients (49.7%) lost MR4; of these, 90 (91.8%; and 45.7% of the whole cohort) lost major molecular response (MMR or MR3) after a median of 3.8 months (1-93.3). The 2-year probability of TFR (pTFR) was 57.7%. In multivariable analysis, male sex, age at diagnosis >40 years, faster achievement of MR4 and longer duration of DMR were the only variables significantly associated with higher pTFR. Based on the multivariable analysis results, we built a TFR prognostic score (TPS) able to distinguish three groups with different 2-year pTFR: good (89.9%), intermediate (61.2%) and poor (18.4%) TFR probability (p < 0.0001). We validated the TPS on an independent cohort of 91 patients. We propose that the TPS could become a useful guide for CML clinicians
Drought is associated with human migration in agriculture-dependent middle-income countries
No full textHuman migration has been an essential and transformative process, driven by the need to adapt to changing environmental, social, and economic conditions. Here we explore associations between drought events and migration patterns worldwide, compounded by climatic and socio-economic factors such as armed conflict, water withdrawal, crop yield, income and health metrics, in agriculturally dependent regions during the period 2000–2019. We show that, while socio-economic factors remain the primary drivers of migration, drought also exerts a strong influence. Our findings reveal that drought were major predictors of migration in approximately 11% of the regions analyzed, with robust drought-migration associations in middle-income regions. High-income urban areas do not exhibit strong migration dynamics linked to drought, while changes in income conditions and water withdrawal were associated with emigration. This study underscores the need for a comprehensive understanding of the global impacts of drought on migration patterns in agriculture-dependent regions to inform effective and sustainable strategies of disaster risk reduction and climate change adaptation
Plants and Animals in Rome
No full textThe transitions from antiquity to the Middle Ages reshaped every aspect of Rome and its inhabitants, including the plants and animals which lived there. This chapter seeks to orient students of the city to Rome’s environment. Were the patterns observable at Rome typical of other parts of the medieval world, or were they peculiar to this city? Did different sectors of Roman societies or of different periods interact with plants and animals differently from other sectors or times? How does the shape of available evidence determine what we might know about this subject?
The majority of our evidence for plants and animals comes from archaeology, which provides sharp detail in some instances, but typically only for certain kinds of plants and animals. Some information also comes from textual sources which make reference to plants and animals as commodities or in allegories, though cumulatively they provide a sense of what was expected at Rome at different moments, rather than accurate reports on what was there. This evidence gives a picture, with some gaps, of the other living inhabitants of Rome and their relationships with the people and places which form the subject of the rest of this volume
MicroRNA Expression Profile in Endometriosis and Endometriosis-Associated Ovarian Cancer-Systematic Review.
No full textEndometriosis-associated ovarian cancer comprises a special group of ovarian cancers that most probably originate from endometriosis foci. Several in vitro studies have shown that microRNA (miRNA) plays an important role in this carcinogenesis. Our goal was to establish if a distinct miRNA profile can be associated with endometriosis and endometriosis-associated ovarian cancer with their potential causal relationship, and whether such a profile could be used clinically to prognose carcinogenesis in endometriosis foci. We conducted a systematic search according to PRISMA guidelines, registered at PROSPERO (number CRD42021245606). The search encompassed whole Pubmed, Cochrane and Medline databases to 1 May 2025 and the search strategy included the following [MeSH] terms: 'miRNAs' or 'microRNAs' or 'miR' and 'ovarian cancer' and 'endometriosis'. Our ultimate inclusion criterion was that studies must simultaneously evaluate miRNA expression in endometriosis, regardless of its form and stage, and in endometriosis-associated ovarian cancer (EAOC), as only data generated under identical experimental conditions and using the same controls are truly comparable. The quality of the data was assessed using The Newcastle-Ottawa scale (NOS) and ROBINS-I tool. Our final analysis included 13 studies, comprising 608 patients and over 1000 miRNA molecules. Among those only five manuscripts presented raw data for each miRNA studied. Although several authors declared high sensitivity and specificity for one or more miRNA in distinguishing between endometriosis and endometriosis-associated ovarian cancer, a meta-analysis could not be performed due to the high heterogeneity of the studied samples. We concluded that there is not enough publicly available raw data to establish a set of miRNAs capable of differentiating between the two diseases and of prognosing carcinogenesis. The greatest limitation lies in the use of various standardized reference gene sets, which makes it impossible to compare relative miRNA expression across studies. New data from the next generation sequencing (NGS) experiments would overcome issues related to reference and control genes
Computational identification of lineage-committed precursors in mammalian organogenesis reveals a novel hematopoietic enhancer regulating <i>Bhlhe41</i> expression
No full textAbstract
Lineage-committed precursors are essential yet rarely identified in mammalian organogenesis, as they lack definitive molecular signatures required for conventional marker-based approaches. Herein, we developed iCommitted, an integrated multi-omics computational pipeline for precise identification of these precursors. iCommitted first reconstructs in vivo organogenesis by modeling the in vitro differentiation trajectory spanning naïve to terminally differentiated cells. It then integrates epigenomic (ATAC-seq/DNase-seq) and transcriptomic (RNA-seq) data to achieve standardized developmental staging and precursor identification. Applied to mammalian hematopoiesis, iCommitted robustly identified hematopoietic progenitors as the hematopoietic lineage-committed precursors. Subsequent cis-regulatory annotation generated a high-confidence atlas of 16 774 hematopoietic cis-regulatory elements. Functional analysis of the atlas further pinpointed a 218-bp hematopoietic enhancer (chr6:145 855 899-145 856 116) that regulates Bhlhe41 expression during lineage commitment. This study establishes a valuable approach for identifying lineage-committed precursors and elucidating regulatory mechanisms in mammalian organogenesis, offering broad utility in developmental biology.</jats:p