bluuebunny/crossref_metadata_2025 huggingface dataset:
A validated model for early prediction of group A streptococcal aetiology and clinical endpoints in necrotising soft tissue infections
Authors: Katz Sonja , Suijker Jaco , Skrede Steinar , Meij-de Vries Annebeth , Pijpe Anouk , Norrby-Teglund Anna , Palma Medina Laura M , Damås Jan K , Hyldegaard Ole , Solligård Erik , Svensson Mattias ,   PerAID/PerMIT/INFECT study group, Mosevoll Knut Anders , Martins dos Santos Vitor AP , Saccenti Edoardo
Published: June 2024

Objectives

To develop and externally validate machine learning models for predicting microbial aetiology and clinical endpoints, encompassing surgery, patient management, and organ support in Necrotising Soft Tissue Infections (NSTI).

Methods

Predictive models for the presence of Group A Streptococcus (GAS) and for five clinical endpoints (risk of amputation, size of skin defect, maximum skin defect size, length of ICU stay, and need for renal replacement therapy) were built and trained using data from the prospective, international INFECT cohort (409 patients, 2013-2017), implementing unsupervised variable selection, and comparing several algorithms. SHapley Additive exPlanations (SHAP) analysis was used to interpret the model. GAS predictive models were externally validated using data from a Dutch retrospective multicenter cohort from the same calendar period (216 patients).

Results

Eight variables available pre-surgery (age, diabetes, affected anatomical locations, prior surgical interventions, and creatinine and haemoglobin levels) sufficed for prediction of GAS aetiology with high discriminatory power in both the development (ROC-AUC: 0.828; 95%CI 0.763, 0.883) and validation cohort (ROC-AUC: 0.758; 95%CI 0.696, 0.821). The prediction of clinical endpoints related to surgical, patient management, and organs support aspects was unsuccessful.

Conclusion

An externally validated prediction model for GAS aetiology before organ support aspects was unsuccessful, having implications for targeted treatment decisions of NSTI.
Short and midterm outcomes of surgical repair of acute type A aortic dissection concomitant CABG vs. ECMO support: A retrospective study
Authors: Zhang Dong , Zhu Gui-Jun , Gao Ming-Jun , Wei Xiang-Yang , Yan Zhe , Li Bin , Chen Xing-Peng , Wang Xiao-Lin , Shu Yu-Sheng
Published: June 2024

Objective

Intraoperative surgical repair of acute type A aortic dissection, sometimes we would encounter special cases that failed to wean from CPB. In this study, we aimed to retrospectively analyze that the indication, clinical experience and short and midterm outcomes of surgical repair of acute type A aortic dissection concomitant CABG or ECMO support in patients who failed to wean from CPB.

Methods

A total of 532 consecutive patients underwent emergent surgery for TAAD in a single institution between Jan 2018 and Jan 2023. And categorized into CABG group and ECMO group based on surgical approach. Preoperative, intraoperative and postoperative variables were assessed and analyzed. Outcomes of the patients were followed up until five years from discharge of hospital.

Results

Overall in-hospital mortality was determined to be 15.7% for CABG group and 73.3% for ECMO group (P=0.001). The operation time, CPB time, extracorporeal circulation assisted time, 24-hour traffic diversion in CABG group were less than ECMO group, and had statistically different between two groups (P=0.039,P=0.007,P<0.001,P<0.001). Higher morbidity of delayed chest closure, low cardiac output syndrome, and lower limb osteofascial compartment syndrome in the ECMO group than the CABG group, but not statistically significant (P=0.139,P=1,P=0.524).

5-years follow-up mortality after discharge had no statistically different between two groups (P=1).

Conclusion

For the patients who failed to wean from CPB, surgical repair of acute type A aortic dissection Concomitant CABG can provide more excellent short and midterm outcomes than ECMO support. However, concomitant CABG are also associated with long-term complications of the great saphenous vein embolization and severe tricuspid valve regurgitation.
Understanding the Sources of Performance in Deep Drug Response Models Reveals Insights and Improvements
Authors: Branson Nikhil , Cutillas Pedro R. , Bessant Conrad
Published: June 2024

Anti-cancer drug response prediction (DRP) using cancer cell lines plays a vital role in stratified medicine and drug discovery. Recently there has been a surge of new deep learning (DL) models for DRP that improve on the performance of their predecessors. However, different models use different input data types and neural network architectures making it hard to find the source of these improvements. Here we consider multiple published DRP models that report state-of-the-art performance in predicting continuous drug response values. These models take the chemical structures of drugs and omics profiles of cell lines as input. By experimenting with these models and comparing with our own simple benchmarks we show that no performance comes from drug features, instead, performance is due to the transcriptomics cell line profiles. Furthermore, we show that, depending on the testing type, much of the current reported performance is a property of the training target values. To address these limitations we create novel models (BinaryET and BinaryCB) that predict binary drug response values, guided by the hypothesis that this reduces the noise in the drug efficacy data. Thus, better aligning them with biochemistry that can be learnt from the input data. BinaryCB leverages a chemical foundation model, while BinaryET is trained from scratch using a transformer-type model. We show that these models learn useful chemical drug features, which is the first time this has been demonstrated for multiple DRP testing types to our knowledge. We further show binarising the drug response values is what causes the models to learn useful chemical drug features. We also show that BinaryET improves performance over BinaryCB, and over the published models that report state-of-the-art performance.
Inhibitory circuits generate rhythms for leg movements during Drosophila grooming
Authors: Syed Durafshan Sakeena , Ravbar Primoz , Simpson Julie H.
Published: June 2024

Limbs execute diverse actions coordinated by the nervous system through multiple motor programs. The basic architecture of motor neurons that activate muscles that articulate joints for antagonistic flexion and extension movements is conserved from flies to vertebrates. While excitatory premotor circuits are expected to establish sets of leg motor neurons that work together, our study uncovered a new instructive role for inhibitory circuits: their ability to generate rhythmic leg movements. Using electron microscopy data for the Drosophila nerve cord, we categorized ~120 GABAergic inhibitory neurons from the 13A and 13B hemi-lineages into classes based on similarities in morphology and connectivity. By mapping their synaptic partners, we uncovered pathways for inhibiting specific groups of motor neurons, disinhibiting antagonistic counterparts, and inducing alternation between flexion and extension. We tested the function of specific inhibitory neurons through optogenetic activation and silencing, using an in-depth ethological analysis of leg movements during grooming. We combined anatomy and behavior analysis findings to construct a computational model that can reproduce major aspects of the observed behavior, confirming the sufficiency of these premotor inhibitory circuits to generate rhythms.
Glioma-derived M-CSF and IL-34 license M-MDSCs to suppress CD8+T cells in a NOS-dependent manner
Authors: Takacs Gregory P. , Garcia Julia S. , Hodges Caitlyn A. , Kreiger Christian J. , Sherman Alexandra , Harrison Jeffrey K.
Published: June 2024

Glioblastoma (GBM) is the most common malignant primary brain tumor, resulting in poor survival despite aggressive therapies. GBM is characterized by a highly heterogeneous and immunosuppressive tumor microenvironment (TME) made up predominantly of infiltrating peripheral immune cells. One significant immune cell type that contributes to glioma immune evasion is a population of immunosuppressive cells, termed myeloid-derived suppressor cells (MDSCs). Previous studies suggest that a subset of myeloid cells, expressing monocytic (M)-MDSC markers and dual expression of chemokine receptors CCR2 and CX3CR1, utilize CCR2 to infiltrate the TME. This study evaluated the mechanism of CCR2+/CX3CR1+M-MDSC differentiation and T cell suppressive function in murine glioma models. We determined that bone marrow-derived CCR2+/CX3CR1+cells adopt an immune suppressive cell phenotype when cultured with glioma-derived factors. Glioma secreted CSF1R ligands M-CSF and IL-34 were identified as key drivers of M-MDSC differentiation while adenosine and iNOS pathways were implicated in M-MDSC suppression of T cells. Mining a human GBM spatial RNAseq database revealed a variety of different pathways that M-MDSCs utilize to exert their suppressive function that are driven by complex niches within the microenvironment. These data provide a more comprehensive understanding of the mechanism of M-MDSCs in glioblastoma.

Simple Summary

Currently there are no effective therapies for glioblastoma. Infiltrating myeloid cells contribute significantly to the immune suppressive tumor microenvironment that is characteristic of GBM. Monocytic myeloid derived suppressor cells are chief immune suppressive cells found in the glioma microenvironment. Understanding the mechanisms of M-MDSC differentiation and T cell suppression is imperative for generating therapies that target this tumor supportive cell population. In this study we found that glioma secreted CSF1R ligands, M-CSF and IL-34, license M-MDSCs to suppress CD8 T cells. These M-MDSCs partially utilize nitric oxide synthase to illicit their suppressive activity. However, spatial RNAseq points to glioma microenvironment niches driving M-MDSC heterogeneity. Our findings identify key regulators of differentiation and suppressive mechanisms of M-MDSCs and confirm the importance of targeting this cell population in glioma.
Butterfly eggs prime anti-herbivore defense in an annual but not perennialArabidopsisspecies
Authors: Huve Maryse A. P. , Bittner Norbert , Kunze Reinhard , Hilker Monika , Remus-Emsermann Mitja N. P. , Paniagua Voirol Luis R. , Lortzing Vivien
Published: June 2024

While plant anti-herbivore defenses of the annual plant speciesArabidopsis thalianawere shown to be primable byPieris brassicaeeggs, the primability of the phylogenetically closely related perennialArabidopsis lyratahas not yet been investigated. Previous studies revealed that closely related wild Brassicaceae plant species, the annualBrassica nigraand the perennialBrassica oleracea, exhibit an egg-primable defense trait, even though they have different life spans. Here, we tested whetherP. brassicaeeggs prime anti-herbivore defenses of the perennialA. lyrata. We exposedA. lyratatoP. brassicaeeggs and larval feeding and assessed their primability by i) determining the biomass ofP. brassicaelarvae after feeding on plants with and without priorP. brassicaeegg deposition and ii) investigating the plant transcriptomic response after egg deposition and/or larval feeding. For comparison, these studies were also conducted withA. thaliana.Consistent with previous findings,A. thaliana’s response to priorP. brassicaeegg deposition negatively affected conspecific larvae feeding uponA. thaliana. However, this was not observed inA. lyrata.Arabidopsis thalianaresponded toP. brassicaeeggs with strong transcriptional reprogramming, whereasA. lyrataresponses to eggs were negligible. In response to larval feeding,A. lyrataexhibited a greater transcriptome change compared toA. thaliana. Among the strongly feeding-inducedA. lyratagenes were those that are egg-primed in feeding-inducedA. thaliana, i.e.,CAX3, PR1,PR5andPDF1.4.These results suggest thatA. lyratacompensates for its lack of egg-mediated primability by a stronger response to larval feeding.
Co-utilization of microalgae and heterotrophic microorganisms improves wastewater treatment efficiency
Authors: Takahashi Miiku , Karitani Yukino , Yamada Ryosuke , Matsumoto Takuya , Ogino Hiroyasu
Published: June 2024

Wastewater treatment using co-culture systems of microalgae and heterotrophic microorganisms is expected to be useful under atmospheric dilute carbon dioxide conditions. In this study, we investigated the combination of microalgae and heterotrophic microorganisms to improve the efficiency of wastewater treatment. Furthermore, to elucidate the cause of the changes in wastewater treatment efficiency in the co-culture system, changes in gene expression were revealed through transcriptome analysis. Three types of microalgae and five heterotrophic microorganisms were used in combination for wastewater treatment. The combination ofChlamydomonas reinhardtiiNIES-2238 andSaccharomyces cerevisiaeSH-4 showed the highest wastewater treatment efficiency. Using this combination for artificial wastewater treatment, the removal rates of TOC (Total organic carbon), PO43-, and NH4+reached 80%, 93%, and 63%, respectively, after 18 h of treatment. Transcriptome analysis revealed that the combined wastewater treatment altered the expression of 1371 and 692 genes inC. reinhardtiiandS. cerevisiae, respectively. The genes upregulated inC. reinhardtiiincluded those related to molecular and ion transport. Genes upregulated inS. cerevisiaeincluded those related to cell protection from various types of damage and stress. To the best of our knowledge, this is the first study to show that a combination of green algae and yeast improves the efficiency of wastewater treatment. As both the green algaC. reinhardtiiand the yeastS. cerevisiaeare highly safe microorganisms, the establishment of their effective combination for wastewater treatment is highly significant.
HLH-30/TFEB rewires the chaperone network to promote proteostasis under conditions of Coenzyme A and Iron-Sulfur Cluster Deficiency
Authors: Shalash Rewayd , Levi-Ferber Mor , von Chrzanowski Henrik , Atrash Mohammad Khaled , Shav-Tal Yaron , Henis-Korenblit Sivan
Published: June 2024

ABSTARCT

The maintenance of a properly folded proteome is critical for cellular function and organismal health, and its age-dependent collapse is associated with a wide range of diseases. Here, we find that despite the central role of Coenzyme A as a molecular cofactor in hundreds of cellular reactions, limiting Coenzyme A levels inC. elegansand in human cells, by inhibiting the conserved pantothenate kinase, promotes proteostasis. Impairment of the cytosolic iron-sulfur clusters formation pathway, which depends on Coenzyme A, similarly promotes proteostasis and acts in the same pathway. Proteostasis improvement by Coenzyme A/iron-sulfur cluster deficiencies are dependent on the conserved HLH-30/TFEB transcription factor. Strikingly, under these conditions, HLH-30 promotes proteostasis by potentiating the expression of select chaperone genes providing a chaperone-mediated proteostasis shield, rather than by its established role as an autophagy and lysosome biogenesis promoting factor. This reflects the versatile nature of this conserved transcription factor, that can transcriptionally activate a wide range of protein quality control mechanisms, including chaperones and stress response genes alongside autophagy and lysosome biogenesis genes. These results highlight TFEB as a key proteostasis-promoting transcription factor and underscore it and its upstream regulators as potential therapeutic targets in proteostasis-related diseases.
Propidium monoazide is unreliable for quantitative live-dead molecular assays
Authors: Kaur Simerdeep , Ortiz Laura Bran , Rudakov Grigorii , Verma Mohit S.
Published: June 2024

Propidium monoazide (PMA) is a dye that distinguishes between live and dead cells in molecular assays like Polymerase Chain Reaction (PCR). It works by cross-linking to the DNA of cells that have compromised membranes or extracellular DNA upon photoactivation, making the DNA inaccessible for amplification. Currently, PMA is used to detect viable pathogens and alleviate systemic bias in the microbiome analysis of samples using 16S rRNA gene sequencing. In these applications, treated samples consist of different amounts of dead bacteria and a range of bacterial strains, variables that can affect the performance of PMA and lead to inconsistent findings across various research studies. To evaluate the effectiveness of PMA, we used a sensitive qPCR assay and post-treatment sample concentration to determine PMA activity accurately under varying sample conditions. We report that PMA is unreliable for viability assays when the concentration and composition of the bacterial mixture are unknown. PMA is only suitable for qualitatively assessing viability in samples containing a known number of dead microbes or extracellular DNA.
CEBPBas a potential biomarker for prognosis and immune infiltration in clear cell renal cell carcinoma
Authors: Ren Yaoqiang , Qiao Baoping , Wei Min , Tian Quanfa , Guo Wenke
Published: June 2024

Clear cell renal cell carcinoma (ccRCC) is an aggressive kidney cancer subtype with poor prognosis.This study explores the expression and clinical significance of the CCAAT/enhancer-binding protein betaCEBPBgene in ccRCC. RNA sequencing, gene amplification, and mutation data were sourced from TCGA, UCSC XENA, and cBioPortal. Data processing involved the STAR workflow and R software for statistical analysis and visualization. Experimental validation used immunohistochemistry and RT-qPCR on 58 patient tissue samples. Functional pathway enrichment was performed using GO-KEGG and GSEA analyses, and PPI networks were constructed with STRING and Cytoscape. Immune infiltration and survival analyses were conducted using Spearman correlation and Cox regression models.Results showed significantly higherCEBPBexpression in ccRCC tissues compared to adjacent normal tissues. Clinical variable grouping indicated significant differences inCEBPBexpression. Enrichment analyses identified involvement in complement and coagulation cascades and carbon metabolism. PPI networks highlighted strong interactions with STAT3 and EP300. Immune infiltration analysis revealed significant correlations with multiple immune cell types. HighCEBPBexpression was linked to poor prognosis and demonstrated high diagnostic accuracy for ccRCC.

Author summary

Kidney Renal Clear Cell Carcinoma (KIRC) is a major subtype of renal cancer with significant clinical implications. This study investigates the role ofCEBPB, a transcription factor, in KIRC using RNA sequencing data from TCGA and GTEx databases. We analyzedCEBPBexpression, mutation status, and its correlation with clinical features and immune infiltration. Our findings reveal elevatedCEBPBexpression in tumor tissues, significantly associated with advanced T, N, M stages and poor overall survival. Functional analyses indicate thatCEBPBinteracts with key proteins and pathways involved in tumorigenesis. Additionally, highCEBPBexpression correlates with increased immune cell infiltration, suggesting its role in tumor-immune interactions. This research highlightsCEBPBas a potential prognostic biomarker and therapeutic target in KIRC, offering new insights for clinical management and treatment strategies.
Incidence of Chronic Recurrent Multifocal Osteomyelitis in Children and Adolescents in the UK and Republic of Ireland
Authors: Chia Daphne Theresa , Toms Andoni , Sanghrajka Anish , Ramanan Athimalaipet , Killeen Orla G , Ilea Cristina , Mahmood Kamran , Compeyrot-Lacassagne Sandrine , Bailey Kathryn , Martin Neil , Armon Kate , Suo Chenqu
Published: June 2024

Objectives

Chronic Recurrent Multifocal Osteomyelitis (CRMO), also known as chronic nonbacterial osteomyelitis (CNO), is a rare autoinflammatory condition affecting the bones in children and teenagers. The actual incidence of CRMO remains uncertain. The objective of this study is to identify the incidence of CRMO in children and young people under the age of 16 years in the United Kingdom (UK) and Republic of Ireland (ROI). We also aim to delineate the demographics, clinical presentation, investigations, initial management and healthcare needs for children and adolescents with CRMO.

Methods

We conducted monthly surveys among all paediatric consultants and paediatric orthopaedic surgeons to identify patients newly diagnosed with CRMO between October 2020 and November 2022. A standardised questionnaire was sent to reporting clinicians to collect further information.

Results

Over the surveillance period, 288 patients were reported, among which, 165 confirmed and 20 probable cases were included in the analysis. The highest incidences were among 8-10 year-olds. A two-to-one female-to-male difference in incidence was observed, and male patients were more likely to present with multifocal disease. A negative correlation was observed between reporting clavicular and leg pain. Investigation-wise, 80.0% of patients were reported to have undergone whole-body MRI and 51.1% had bone biopsies. The most common initial treatments were NSAIDs (93.9%) and bisphosphonates (44.8%).

Conclusion

This study estimates an average annual CRMO incidence of 0.65 cases per 100,000 children and adolescents in the UK and ROI. These findings establish a crucial baseline for ongoing research and improvement in the care of individuals with CRMO.

Key Messages

The estimated annual incidence of CRMO is 0.65 per 100,000 children and adolescents aged <16.

Two-fold higher incidence in females to males was found, with the highest incidence in 8-10 year-olds.

Male patients are more likely to present with multifocal disease compared with females.
Genetic surveillance ofPlasmodium falciparumreveals rapid population changes following first-line treatment policy revisions in the Greater Mekong Subregion
Authors: Verschuuren Tess D , Wasakul Varanya , Thuy-Nhien Nguyen , Booth Ethan , Quang Huynh Hong , Thang Ngo Duc , Chindavongsa Keobouphaphone , Sovannaroth Siv , Banouvong Virasak , Sengsavath Viengphone , Mayxay Mayfong , Tuyen Nguyen Thi Kim , Phuong Vo Ngoc Lam , Trung Pham Duc , Gonçalves Sónia , Chen Soun , Phalivong Sonexay , Xayvanghang Saiamphone , Mahaphontrakoon Supaporn , Pearson Richard D , Newton Paul N , Maude Richard J , Ashley Elizabeth A , Ariani Cristina V , Simpson Victoria J , Day Nicholas P , Dondorp Arjen M , Miotto Olivo
Published: June 2024

Background

Genetic surveillance ofPlasmodium falciparum (Pf)is an important tool for tracking antimalarial resistant strains, informing decision-making by National Malaria Control Programmes (NMCPs). Here, we present an analysis of 5,754 samples collected by the GenRe-Mekong project, in collaboration with NMCPs in the Greater Mekong Subregion (GMS), powered by new user-friendly visualization tools developed to translate genomic data into accessible actionable information.

Methods

Samples collected from patients presenting at public health facilities between 2017 and 2022 were genotyped using the SpotMalaria platform. Output data included genotypes for markers of antimalarial resistance, and genetic barcodes for analysis of relatedness. We developed the grcMalaria R package, which allows users to specify sample selection criteria, and produce geographical maps of prevalence, diversity and relatedness. It also identifies circulating parasite clusters, characterizing their drug resistance profile and mapping their spread.

Results

Since 2020, a rapid reduction inPfincidence was observed, alongside a decline of the KEL1/PLA1 lineage resistant to dihydroartemisinin-piperaquine (DHA-PPQ), previously dominant in the eastern GMS. The frequency ofplasmepsin2/3amplifications, associated with piperaquine resistance, dropped from 62% in 2017-2019 to 2% in the first half of 2022. This coincided with a switch in frontline therapy, away from DHA-PPQ, in Cambodia, Thailand, and Vietnam. Artemisinin resistance levels remained high, with a regional prevalence of 89% in 2022. No evidence of emerging mefloquine resistance was found.

Conclusion

Routine genetic surveillance ofPfcan reveal changes in parasite populations in response to public health interventions, especially when its results are translated into intuitive graphical visualizations, providing actionable information for NMCPs.
Transforming Trade for Vaccine Equity: Policy Gaps and Barriers
Authors: Pepperrell Toby , Koivusalo Meri , Grant Liz , McCallum Alison
Published: June 2024

The ongoing Pandemic Agreement negotiations illustrate significant gaps in action required to respond effectively to the lessons of the COVID-19 pandemic and make progress towards public health goals, including Sustainable Development Goals (SDGs). The pandemic revealed vaccine equity as a unifying health need, and international trade as a Commercial Determinant of Health. We explored where policy action could reshape trade relationships, identifying recommendations for vaccine equity within stakeholder literature pertaining to Free Trade Agreements (FTAs).

We searched online libraries for stakeholder documents that focused on the interface between FTAs, vaccination, and vaccine equity published between 01/01/2010-31/03/2022. Our analytic framework drew from the rights, regulation, and redistribution (3R) framework, combined with systems analysis, using leverage pointsto categorise recommendations as Technical Mechanisms, Collaborative and Adaptive Mechanisms, or Determinants of Vaccine Equity (DVE). These were then located on a novel systems map to elucidate gaps and actions.

No cohesive strategies for change were identified. Technical proposals were reactive, repetitive, and lacked enforcement mechanisms or incentives. There were significant gaps in the articulation of alternative Collaborative Mechanisms to democratise FTA policymaking processes. The underlying DVE and lack of policy coherence were not addressed. These findings are limited by under-representation of low- and middle-income country authorship in the studies, including in ours, reflecting imbalances in international research and policymaking processes.

Overall, our research shows how the current trade paradigm has produced and sustained vaccine inequity. We propose potential pathways for action but highlight the importance and urgency of more fundamental change in negotiation and implementation of FTAs. New technologies will be crucial for the global response to emerging, neglected, and non-communicable diseases that are vaccine-preventable or -modifiable. Multilateral organisations must, therefore, prioritise the right to health above FTAs , including through TRIPS waivers on Essential Technologies.
Safety and Effectiveness of LC16m8 for Pre-Exposure Prophylaxis against mpox in a High-Risk Population: An Open-Label Randomized Trial
Authors: Okumura Nobumasa , Morino Eriko , Nomoto Hidetoshi , Yanagi Mashiho , Takahashi Kozue , Iwasaki Haruka , Uemura Yukari , Shimizu Yosuke , Mizushima Daisuke , Fukushima Kazuaki , Kinai Ei , Shiojiri Daisuke , Itoda Ichiro , Onoe Yasuhiko , Kobori Yoshitomo , Nakamura Fukumi , Tokita Daisuke , Sugiura Wataru , Ohmagari Norio , Ujiie Mugen
Published: June 2024

Background

The incidence of mpox cases has surged outside endemic regions since May 2022. However, data regarding the safety and efficacy of the LC16m8 vaccine are limited. This study provided opportunities for LC16m8 pre-exposure prophylaxis to high-risk individuals and conducted a randomized controlled trial to assess the effectiveness of LC16m8 in mpox prevention.

Methods

This multicenter, randomized, open-label trial enrolled men and women aged ≥18 with high mpox risk. Participants were randomly assigned 1:1 to early or late vaccination groups, receiving vaccinations approximately 70 days apart. Vaccine effectiveness (VE) against mpox development between early and late vaccinations was the primary endpoint. VE against severe mpox, symptoms, “take” incidence, and adverse events were secondary endpoints.

Results

A total of 570 and 565 patients were assigned to the early and late vaccination groups, respectively, and 530 and 476 were vaccinated. The median age was 41 years; 99.7% were male, 89.7% were Japanese, and 34.4% had human immunodeficiency virus (HIV). No mpox cases occurred, precluding VE calculations. The take rate was 90.3% (HIV-infected) and 94.6% (uninfected). Adverse events were observed in 97.2% and 98.2% of patients with and without HIV, respectively. No fatal adverse events were observed. Serious adverse events (SAE) were observed in 0.6% (HIV-infected) and 0.5% (uninfected) of patients. One participant without HIV reported pulmonary embolism and deep vein thrombosis as causally undeniable SAE. Local skin reactions: 96.6% (HIV-infected) and 97.9% (uninfected); systemic reactions: 63.6% (HIV-infected) and 64.2% (uninfected).

Conclusions

The effectiveness of LC16m8 in mpox remains inconclusive. However, its use in well-controlled HIV-infected and -uninfected individuals showed no significant safety concerns, suggesting the potential for targeted vaccination strategies in at-risk groups. (Japan Registry of Clinical Trials number, jRCT1031230137.)
Temporal trends in test-seeking behaviour during the COVID-19 pandemic
Authors: Eales Oliver , Teo Mingmei , Price David J. , Hao Tianxiao , Ryan Gerard E. , Senior Katharine L. , Carlson Sandra , Dalton Craig , Dawson Peter , Golding Nick , McCaw James M. , Shearer Freya M.
Published: June 2024

Background

During the COVID-19 pandemic, many countries implemented mass community testing programs, where individuals would seek tests due to (primarily) the onset of symptoms. The cases recorded by mass testing programs represent only a fraction of infected individuals, and depend on how many people seek testing. If test-seeking behaviour exhibits heterogeneities or changes over time, and this is not accounted for when analysing case data, then inferred epidemic dynamics used to inform public health decision-making can be biased.

Methods

Here we describe temporal trends in COVID-19 test-seeking behaviour in Australia by symptoms, age group, test type, and jurisdiction from November 2021–September 2023. We use data from two surveillance systems: a weekly nationwide behavioural survey (NBS), established by the Australian Government to monitor a range of behavioural responses to COVID-19; and Australia’s FluTracking system, a ‘participatory surveillance system’ designed for monitoring influenza-like illness and health-care seeking behaviour, which was adapted in early 2020 to include questions relevant to COVID-19.

Results

We found that peaks in test-seeking behaviour generally aligned with peaks in the rate of reported cases. Test-seeking behaviour rapidly increased in early-2022 coinciding with greater availability of rapid antigen tests. There were heterogeneities in test-seeking behaviour by jurisdiction and age-group, which were dynamic through time. Test-seeking behaviour was lowest in older individuals (60+ years) until July 2022, after which there was greater homogeneity across age-groups. Test-seeking behaviour was highest in the Australian Capital Territory and Tasmania and consistently lowest in Queensland. Over the course of the study test-seeking behaviour was highest in individuals who reported symptoms more predictive of COVID-19 infection. There was a greater probability of seeking a test for individuals in FluTracking compared to the NBS, suggesting that participatory surveillance systems such as FluTracking may include a health-conscious subset of the population.

Conclusions

Our findings demonstrate the dynamism of test-seeking behaviour, highlighting the importance of the continued collection of behavioural data through dedicated surveillance systems.
Early Detection of an Invasive Alien Plant (Phragmites australis) Using Unoccupied Aerial Vehicles and Artificial Intelligence
Authors: Caron-Guay Antoine , Germain Mickaël , Laliberté Etienne
Published: June 2024

The combination of unoccupied aerial vehicles (UAVs) and artificial intelligence to map vegetation represents a promising new approach to improve the detection of invasive alien plant species (IAPS). The high spatial resolution achievable with UAVs and recent innovations in computer vision, especially with convolutional neural networks, suggest that early detection of IAPS could be possible, thus facilitating their management. In this study, we evaluated the suitability of this approach for mapping the location of common reed (Phragmites australissubsp.australis) within a national park located in southern Quebec, Canada. We collected data on six distinct dates during the growing season, covering environments with different levels of reed invasion. Overall, model performance was high for the different dates and zones, especially for recall (mean of 0.89). The results showed an increase in performance, reaching a peak following the appearance of the inflorescence in September (highest F1-score at 0.98). Furthermore, a decrease in spatial resolution negatively affected recall (18% decrease between a spatial resolution of 0.15 cm pixel−1and 1.50 cm pixel−1) but did not have a strong impact on precision (2% decrease). Despite challenges associated with common reed mapping in a post-treatment monitoring context, the use of UAVs and deep learning shows great potential for IAPS detection when supported by a suitable dataset. Our results show that, from an operational point of view, this approach could be an effective tool for speeding up the work of biologists in the field and ensuring better management of IAPS.
Enhanced Plasmid-Based Transcriptional Activation in Developing Mouse Photoreceptors
Authors: Patierno Brendon M. , Emerson Mark M.
Published: June 2024

Rod photoreceptor formation in the postnatal mouse is a widely used model system for studying mammalian photoreceptor development. This experimental paradigm provides opportunities for both gain and loss-of-function studies which can be accomplished through in vivo plasmid delivery and electroporation. However, the cis-regulatory elements used to implement this approach have not been fully evaluated or optimized for the unique transcriptional environment of photoreceptors. Here we report that the use of a photoreceptor cis-regulatory element from the Crx gene in combination with broadly active promoter elements can increase the targeting of developing rod photoreceptors in the mouse. This can lead to greater reporter expression, as well as enhanced misexpression and loss-of-function phenotypes in these cells. This study also highlights the importance of identifying and testing relevant cis-regulatory elements when planning cell subtype specific experiments. The use of the specific hybrid elements in this study will provide a more efficacious gene delivery system to study mammalian photoreceptor formation.
The inactive X chromosome drives sex differences in microglial inflammatory activity in human glioblastoma
Authors: Tharp Marla E. , Han Claudia Z. , Balak Chris D. , Fitzpatrick Conor , O’Connor Carolyn , Preissl Sebastian , Buchanan Justin , Nott Alexi , Escoubet Laure , Mavrommatis Konstantinos , Gupta Mihir , Schwartz Marc S. , Hoi Sang U , Jones Pamela S. , Levy Michael L. , Gonda David D. , Ben-Haim Sharona , Ciacci Joseph , Barba David , Khalessi Alexander , Coufal Nicole G. , Chen Clark C. , Glass Christopher K. , Page David C.
Published: June 2024

Biological sex is an important risk factor in cancer, but the underlying cell types and mechanisms remain obscure. Since tumor development is regulated by the immune system, we hypothesize that sex-biased immune interactions underpin sex differences in cancer. The male-biased glioblastoma multiforme (GBM) is an aggressive and treatment-refractory tumor in urgent need of more innovative approaches, such as considering sex differences, to improve outcomes. GBM arises in the specialized brain immune environment dominated by microglia, so we explored sex differences in this immune cell type. We isolated adult human TAM-MGs (tumor-associated macrophages enriched for microglia) and control microglia and found sex-biased inflammatory signatures in GBM and lower-grade tumors associated with pro-tumorigenic activity in males and anti-tumorigenic activity in females. We demonstrated that genes expressed or modulated by the inactive X chromosome facilitate this bias. Together, our results implicate TAM-MGs, specifically their sex chromosomes, as drivers of male bias in GBM.
Global genomics ofAedes aegyptiunveils widespread and novel infectious viruses capable of triggering a small RNA response
Authors: Gupta Shruti , Sharma Rohit , Williams Adeline E. , Sanchez-Vargas Irma , Rose Noah H. , Zhang Chao , Crosbie-Villaseca Alexander , Zhu Zheng , Dayama Gargi , Gloria-Soria Andrea , Brackney Doug E. , Manning Jessica , Wheeler Sarah S. , Caranci Angela , Reyes Trinidad , Sylla Massamba , Badolo Athanase , Akorli Jewelna , Aribodor Ogechukwu B. , Ayala Diego , Liu Wei-Liang , Chen Chun-Hong , Vasquez Chalmers , Acosta Cassandra Gonzalez , Ponlawat Alongkot , Magalhaes Tereza , Carter Brendan , Wesson Dawn , Surin Darred , Younger Meg A. , Costa-da-Silva Andre Luis , DeGennaro Matthew , Bergman Alexander , Lambrechts Louis , McBride Carolyn S. , Olson Ken E. , Calvo Eric , Lau Nelson C.
Published: June 2024

The mosquitoAedes aegyptiis a prominent vector for arboviruses, but the breadth of mosquito viruses that infects this specie is not fully understood. In the broadest global survey to date of over 200Ae. aegyptismall RNA samples, we detected viral small interfering RNAs (siRNAs) and Piwi interacting RNAs (piRNAs) arising from mosquito viruses. We confirmed that most academic laboratory colonies ofAe. aegyptilack persisting viruses, yet two commercial strains were infected by a novel tombus-like virus.Ae. aegyptifrom North to South American locations were also teeming with multiple insect viruses, with Anphevirus and a bunyavirus displaying geographical boundaries from the viral small RNA patterns. AsianAe. aegyptismall RNA patterns indicate infections by similar mosquito viruses from the Americas and reveal the first wild example of dengue virus infection generating viral small RNAs. AfricanAe. aegyptialso contained various viral small RNAs including novel viruses only found in these African substrains. Intriguingly, viral long RNA patterns can differ from small RNA patterns, indicative of viral transcripts evading the mosquitoes’ RNA interference (RNAi) machinery. To determine whether the viruses we discovered via small RNA sequencing were replicating and transmissible, we infected C6/36 and Aag2 cells withAe. aegyptihomogenates. Through blind passaging, we generated cell lines stably infected by these mosquito viruses which then generated abundant viral siRNAs and piRNAs that resemble the native mosquito viral small RNA patterns. This mosquito small RNA genomics approach augments surveillance approaches for emerging infectious diseases.
Evolutionary Dynamics of RuBisCO: Emergence of the Small Subunit and its Impact Through Time
Authors: Amritkar Kaustubh , Cuevas Bruno , Kacar Betul
Published: June 2024

Ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO) is an ancient protein critical for CO2-fixation and global biogeochemistry. Form-I RuBisCO complexes uniquely harbor small subunits that form a hexadecameric complex together with their large subunits. The small subunit protein is thought to have significantly contributed to RuBisCO's response to the atmospheric rise of O2 2.5 billion years ago, marking a pivotal point in the enzyme's evolutionary history. Here, we performed a comprehensive evolutionary analysis of extant and ancestral RuBisCO sequences and structures to explore the impact of the small subunit s earliest integration on the molecular dynamics of the overall complex. Our simulations suggest that the small subunit restricted the conformational flexibility of the large subunit early in its history, impacting the evolutionary trajectory of the Form-I RuBisCO. Molecular dynamics investigations of CO2 and O2 gas distribution around predicted ancient RuBisCO complexes suggest that a proposed CO2 reservoir role for the small subunit is not conserved throughout the enzyme's evolutionary history. The evolutionary and biophysical response of RuBisCO to changing atmospheric conditions on ancient Earth showcase multi-level and trackable responses of enzymes to environmental shifts over long timescales.
‘Low’ LRs obtained from DNA mixtures: On calibration and discrimination performance of probabilistic genotyping software
Authors: McCarthy-Allen M. , Bleka Ø. , Ypma R. , Gill P. , Benschop C.
Published: June 2024

The validity of a probabilistic genotyping (PG) system is typically demonstrated by following international guidelines for the developmental and internal validation of PG software. These guidelines mainly focus on discriminatory power. Very few studies have reported with metrics that depend on calibration of likelihood ratio (LR) systems. In this study, discriminatory power as well as various calibration metrics, such as Empirical Cross-Entropy (ECE) plots, pool adjacent violator (PAV) plots, log likelihood ratio cost (Cllr and Cllrcal), fiducial calibration discrepancy plots, and Turing’ expectation were examined using the publicly-available PROVEDIt dataset. The aim was to gain deeper insight into the performance of a variety of PG software in the ‘lower’ LR ranges (∼LR 1-10,000), with focus on DNAStatistX and EuroForMix which use maximum likelihood estimation (MLE). This may be a driving force for the end users to reconsider current LR thresholds for reporting. In previous studies, overstated ‘low’ LRs were observed for these PG software. However, applying (arbitrarily) high LR thresholds for reporting wastes relevant evidential value. This study demonstrates, based on calibration performance, that previously reported LR thresholds can be lowered or even discarded. Considering LRs >1, there was no evidence for miscalibration performance above LR ∼1,000 when using Fst 0.01. Below this LR value, miscalibration was observed. Calibration performance generally improved with the use of Fst 0.03, but the extent of this was dependent on the dataset: results ranged from miscalibration up to LR ∼100 to no evidence of miscalibration alike PG software using different methods to model peak height, HMC and STRmix.

This study demonstrates that practitioners using MLE-based models should be careful when low LR ranges are reported, though applying arbitrarily high LR thresholds is discouraged. This study also highlights various calibration metrics that are useful in understanding the performance of a PG system.

Highlights

Discriminatory power and calibration performance of PG software are evaluated.

The utility of various calibration metrics are explored in ‘low’ LR ranges.

Focus was on DNAStatistX and EuroForMix software using the MLE method.

Calibration performance was dependent on Fst value and dataset size.

Results suggest reconsideration of lower LR thresholds and cautious reporting of ‘low’ LRs.
ALBA proteins facilitate cytoplasmic YTHDF-mediated reading of m6A in plants
Authors: Reichel Marlene , Tankmar Mathias Due , Rennie Sarah , Arribas-Hernández Laura , Lewinski Martin , Köster Tino , Wang Naiqi , Millar Anthony A. , Staiger Dorothee , Brodersen Peter
Published: June 2024

N6-methyladenosine (m6A) exerts many of its regulatory effects on eukaryotic mRNAs by recruiting cytoplasmic YT521-B homology domain family (YTHDF) proteins. Here, we show that in Arabidopsis, the interaction between m6A and the major YTHDF protein ECT2 also involves the mRNA-binding ALBA protein family. ALBA and YTHDF proteins physically associate via a deeply conserved short linear motif in the intrinsically disordered region of YTHDF proteins, their mRNA target sets overlap, and ALBA4 binding sites are juxtaposed to m6A sites. These binding sites correspond to pyrimidine-rich elements previously found to be important for m6A binding of ECT2. Accordingly, both biological functions of ECT2 and its binding to m6A targetsin vivorequire ALBA association. Our results introduce the YTHDF-ALBA complex as the functional cytoplasmic m6A-reader in plants and define a molecular foundation for the concept of facilitated m6A reading that increases the potential for combinatorial control of biological m6A effects.
Structure of fungal tRNA ligase with RNA reveals conserved substrate binding principles
Authors: Köhler Sandra , Kopp Jürgen , Peschek Jirka
Published: June 2024

RNA ligases play a vital role in RNA processing and maturation including tRNA splicing, RNA repair and the unfolded protein response (UPR). In fungi and plants, the tripartite tRNA ligase Trl1 catalyzes the joining of TSEN-cleaved pre-tRNA exon halves. Trl1 also functions as ligase in the non-conventionalHAC1mRNA splicing during the UPR. The final ligation step is performed by the N-terminal adenylyltransferase domain (LIG). The spatial arrangement of the exon ends during the ligation reaction has remained elusive. Here, we report the crystal structure of Trl1-LIG in complex with a tRNA-derived substrate. Our structure represents a snapshot of the activated RNA intermediate and defines the conserved substrate binding interface. The underlying enzyme-substrate interplay reveals a general substrate binding principle shared by adenylyltransferases. Moreover, we identify the determinants of RNA end specificity as well as the specific roles of Trl1-LIG’s subdomains during ligase activation, substrate binding and phosphoryltransfer.
Global overview of sea turtle fibropapillomatosis tumors: a survey of expert opinions and trends
Authors: Whilde Jenny , Mashkour Narges , Koda Samantha A. , Eastman Catherine B. , Thompson Drew , Burkhalter Brooke , Frandsen Hilary , Page Annie , Blackburn Nicholas B. , Jones Karina , Ariel Ellen , Dupont Sophie M. , Wood Lawrence , Duffy David J.
Published: June 2024

Marine environments offer a wealth of opportunities to improve understanding and treatment options for cancers, through insights into a range of fields from drug discovery to mechanistic insights. By applying One Health principles the knowledge obtained can benefit both human and animal populations, including marine species suffering from cancer. One such species is green sea turtles (Chelonia mydas), which are under threat from fibropapillomatosis (FP), an epizootic tumor disease (animal epidemic) that continues to spread and increase in prevalence globally. In order to effectively address this epizootic, a more thorough understanding is required of the prevalence of the disease and the approaches to treating afflicted turtles. To identify knowledge gaps and assess future needs, we conducted a survey of sea turtle FP experts. The survey consisted of 47 questions designed to assess general perceptions of FP, the areas where more information is needed, local FP trends, the disease status, and mitigation needs, and was voluntarily completed by 44 experts across a broad geographic range. The survey responses provided a valuable overview of the current FP status in sea turtles, FP research, and insight into the approaches currently taken by turtle rehabilitation facilities around the world. Over 70% of respondents both recognized FP as a cancerous panzootic disease, and reported that FP is increasing in prevalence. They report several factors contributing to this increase. Nearly all of the respondents reported that FP research, patient treatment and rehabilitation required more funding in their area, and reported inadequate facilities and capacity for dealing with FP patients. Treatment approaches varied: just over 70% of the medical experts that responded surgically remove FP tumors, either using laser or scalpel. Just under half of respondents use anti-cancer drugs in their treatment of FP. Internal tumors were reported as justification for euthanasia by 61.5% of respondents, and 30.8% reported severe external tumors to be sufficient grounds for euthanasia. Most medical respondents (93.3%) routinely perform necropsy on deceased or euthanized FP-afflicted turtles. Over 80% of respondents considered large-scale multidisciplinary collaboration ‘extremely important’ for advancing the field of FP research. The survey responses provide a valuable insight into the current state of FP treatment, rehabilitation and research, and help to identify critical FP-related research and rehabilitation areas most in need of attention.