ClaPIM: Scalable Sequence CLAssification using Processing-In-Memory

DNA sequence classification is a fundamental task in computational biology with vast implications for applications such as disease prevention and drug design. Therefore, fast high-quality sequence classifiers are significantly important. This paper introduces ClaPIM, a scalable DNA sequence classification architecture based on the emerging concept of hybrid in-crossbar and near-crossbar memristive processing-in-memory (PIM). We enable efficient and high-quality classification by uniting the filter and search stages within a single algorithm. Specifically, we propose a custom filtering technique that drastically narrows the search space and a search approach that facilitates approximate string matching through a distance function. ClaPIM is the first PIM architecture for scalable approximate string matching that benefits from the high density of memristive crossbar arrays and the massive computational parallelism of PIM. Compared with Kraken2, a state-of-the-art software classifier, ClaPIM provides significantly higher classification quality (up to 20x improvement in F1 score) and also demonstrates a 1.8x throughput improvement. Compared with EDAM, a recently-proposed SRAM-based accelerator that is restricted to small datasets, we observe both a 30.4x improvement in normalized throughput per area and a 7% increase in classification precision

Transcriptome Kinetics of Saccharomyces cerevisiae in Response to Viral Killer Toxin K1

The K1 A/B toxin secreted by virus-infected Saccharomyces cerevisiae strains kills sensitive cells via disturbance of cytoplasmic membrane functions. Despite decades of research, the mechanisms underlying K1 toxicity and immunity have not been elucidated yet. In a novel approach, this study aimed to characterize transcriptome changes in K1-treated sensitive yeast cells in a time-dependent manner. Global transcriptional profiling revealed substantial cellular adaptations in target cells resulting in 1,189 differentially expressed genes in total. Killer toxin K1 induced oxidative, cell wall and hyperosmotic stress responses as well as rapid down-regulation of transcription and translation. Essential pathways regulating energy metabolism were also significantly affected by the toxin. Remarkably, a futile cycle of the osmolytes trehalose and glycogen was identified probably representing a critical feature of K1 intoxication. In silico analysis suggested several transcription factors involved in toxin-triggered signal transduction. The identified transcriptome changes provide valuable hints to illuminate the still unknown molecular events leading to K1 toxicity and immunity implicating an evolutionarily conserved response at least initially counteracting ionophoric toxin action

The global retinoblastoma outcome study : a prospective, cluster-based analysis of 4064 patients from 149 countries

DATA SHARING : The study data will become available online once all analyses are complete.BACKGROUND : Retinoblastoma is the most common intraocular cancer worldwide. There is some evidence to suggest that major differences exist in treatment outcomes for children with retinoblastoma from different regions, but these differences have not been assessed on a global scale. We aimed to report 3-year outcomes for children with retinoblastoma globally and to investigate factors associated with survival. METHODS : We did a prospective cluster-based analysis of treatment-naive patients with retinoblastoma who were diagnosed between Jan 1, 2017, and Dec 31, 2017, then treated and followed up for 3 years. Patients were recruited from 260 specialised treatment centres worldwide. Data were obtained from participating centres on primary and additional treatments, duration of follow-up, metastasis, eye globe salvage, and survival outcome. We analysed time to death and time to enucleation with Cox regression models. FINDINGS : The cohort included 4064 children from 149 countries. The median age at diagnosis was 23·2 months (IQR 11·0–36·5). Extraocular tumour spread (cT4 of the cTNMH classification) at diagnosis was reported in five (0·8%) of 636 children from high-income countries, 55 (5·4%) of 1027 children from upper-middle-income countries, 342 (19·7%) of 1738 children from lower-middle-income countries, and 196 (42·9%) of 457 children from low-income countries. Enucleation surgery was available for all children and intravenous chemotherapy was available for 4014 (98·8%) of 4064 children. The 3-year survival rate was 99·5% (95% CI 98·8–100·0) for children from high-income countries, 91·2% (89·5–93·0) for children from upper-middle-income countries, 80·3% (78·3–82·3) for children from lower-middle-income countries, and 57·3% (52·1-63·0) for children from low-income countries. On analysis, independent factors for worse survival were residence in low-income countries compared to high-income countries (hazard ratio 16·67; 95% CI 4·76–50·00), cT4 advanced tumour compared to cT1 (8·98; 4·44–18·18), and older age at diagnosis in children up to 3 years (1·38 per year; 1·23–1·56). For children aged 3–7 years, the mortality risk decreased slightly (p=0·0104 for the change in slope). INTERPRETATION : This study, estimated to include approximately half of all new retinoblastoma cases worldwide in 2017, shows profound inequity in survival of children depending on the national income level of their country of residence. In high-income countries, death from retinoblastoma is rare, whereas in low-income countries estimated 3-year survival is just over 50%. Although essential treatments are available in nearly all countries, early diagnosis and treatment in low-income countries are key to improving survival outcomes.The Queen Elizabeth Diamond Jubilee Trust and the Wellcome Trust.https://www.thelancet.com/journals/langlo/homeam2023Paediatrics and Child Healt

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

α-Scorpion Toxins Binding on Rat Brain and Insect Sodium Channels Reveal Divergent Allosteric Modulations by Brevetoxin and Veratridine

International audienc

Kbot1, a three disulfide bridges toxin from Buthus occitanus tunetanus venom highly active on both SK and Kv channels.

International audienceOn attempts to identify toxins showing original profile of activity among K+ channels, we purified Kbot1, a scorpion toxin that blocks Kv1 and SK potassium channels. With 28 amino-acid residues, Kbot1 is the shortest toxin sequenced in Buthus occitanus scorpion. It is linked by three disulfide bridges and its primary structure is 93% identical to that of BmP02 isolated from the venom of the Chinese scorpion Buthus martensi Karsch [Eur. J. Biochem. 245 (1996) 457]. Kbot1 exhibited a low neurotoxicity in mice after intracerebroventricular injection (LD50 approximately or = 0.8 microg per mouse). It competes with iodinated apamin for its rat brain synaptosomal membrane-binding site (IC50 of 20 nM). Despite 30% sequence identity between Kbot1 and ChTX, competitive experiments on the [125I] charybdotoxin, show that Kbot1 inhibits its binding to its rat brain synaptosomes with IC50 of 10 nM. This result was supported by electrophysiological experiments on cloned voltage-dependent K+ channels from rat brain, expressed in Xenopus oocytes. Kbot1 blocks Kv1.1, Kv1.2 and Kv1.3 currents with IC50 of 145, 2.5 and 15 nM, respectively. Based on these data, Kbot1 may be considered as the first member of subfamily 9 of scorpion toxins [Trends Pharmacol. Sci. 20 (1999) 444], highly active on both Kv and SK channels

Transcriptomics of a KDELR1 knockout cell line reveals modulated cell adhesion properties

KDEL receptors (KDELRs) represent transmembrane proteins of the secretory pathway which regulate the retention of soluble ER-residents as well as retrograde and anterograde vesicle trafficking. In addition, KDELRs are involved in the regulation of cellular stress response and ECM degradation. For a deeper insight into KDELR1 specific functions, we characterised a KDELR1-KO cell line (HAP1) through whole transcriptome analysis by comparing KDELR1-KO cells with its respective HAP1 wild-type. Our data indicate more than 300 significantly and differentially expressed genes whose gene products are mainly involved in developmental processes such as cell adhesion and ECM composition, pointing out to severe cellular disorders due to a loss of KDELR1. Impaired adhesion capacity of KDELR1-KO cells was further demonstrated through in vitro adhesion assays, while collagen- and/or laminin-coating nearly doubled the adhesion property of KDELR1-KO cells compared to wild-type, confirming a transcriptional adaptation to improve or restore the cellular adhesion capability. Perturbations within the secretory pathway were verified by an increased secretion of ER-resident PDI and decreased cell viability under ER stress conditions, suggesting KDELR1-KO cells to be severely impaired in maintaining cellular homeostasis

A method to combine target volume data from 3D and 4D planned thoracic radiotherapy patient cohorts for machine learning applications

The gross tumour volume (GTV) is predictive of clinical outcome and consequently features in many machine-learned models. 4D-planning, however, has prompted substitution of the GTV with the internal gross target volume (iGTV). We present and validate a method to synthesise GTV data from the iGTV, allowing the combination of 3D and 4D planned patient cohorts for modelling. Expert delineations in 40 non-small cell lung cancer patients were used to develop linear fit and erosion methods to synthesise the GTV volume and shape. Quality was assessed using Dice Similarity Coefficients (DSC) and closest point measurements; by calculating dosimetric features; and by assessing the quality of random forest models built on patient populations with and without synthetic GTVs. Volume estimates were within the magnitudes of inter-observer delineation variability. Shape comparisons produced mean DSCs of 0.8817 and 0.8584 for upper and lower lobe cases, respectively. A model trained on combined true and synthetic data performed significantly better than models trained on GTV alone, or combined GTV and iGTV data. Accurate synthesis of GTV size from the iGTV permits the combination of lung cancer patient cohorts, facilitating machine learning applications in thoracic radiotherap