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Metformin alters mitochondria-related metabolism and enhances human oligodendrocyte function
Get PDFMetformin rejuvenates adult rat oligodendrocyte progenitor cells (OPCs) allowing more efficient differentiation into oligodendrocytes and improved remyelination, and therefore is of interest as a therapeutic in demyelinating diseases such as multiple sclerosis (MS). Here, we test whether metformin has a similar effect in human stem cell derived-OPCs. We assess how well human monoculture, organoid and chimera model culture systems simulate in vivo adult human oligodendrocytes, finding most close resemblance in the chimera model. Metformin increases myelin proteins and/or sheaths in all models even when human cells remain fetal-like. In the chimera model, metformin leads to increased mitochondrial area both in the human transplanted cells and in the mouse axons with associated increase of mitochondrial function/metabolism transcripts. Human oligodendrocytes from MS brain donors treated pre-mortem with metformin also express similar transcripts. Metformin’s brain effect is thus not cell-specific, alters metabolism in part through mitochondrial changes and leads to more myelin production. This bodes well for clinical trials testing metformin for neuroprotection
Leveraging expert input for robust and explainable AI-assisted lung cancer detection in chest X-rays
Get PDFDeep learning models show significant potential for advancing AI-assisted medical diagnostics, particularly in detecting lung cancer through medical image modalities such as chest X-rays. However, the black-box nature of these models poses challenges to their interpretability and trustworthiness, limiting their adoption in clinical practice. This study examines both the interpretability and robustness of a high-performing lung cancer detection model based on InceptionV3, utilizing a public dataset of chest X-rays and radiological reports. We evaluate the clinical utility of multiple explainable AI (XAI) techniques, including both post-hoc and ante-hoc approaches, and find that existing methods often fail to provide clinically relevant explanations, displaying inconsistencies and divergence from expert radiologist assessments. To address these limitations, we collaborated with a radiologist to define diagnosis-specific clinical concepts and developed ClinicXAI, an expert-driven approach leveraging the concept bottleneck methodology. ClinicXAI generated clinically meaningful explanations which closely aligned with the practical requirements of clinicians while maintaining high diagnostic accuracy. We also assess the robustness of ClinicXAI in comparison to the original InceptionV3 model by subjecting both to a series of widely utilized adversarial attacks. Our analysis demonstrates that ClinicXAI exhibits significantly greater resilience to adversarial perturbations. These findings underscore the importance of incorporating domain expertise into the design of interpretable and robust AI systems for medical diagnostics, paving the way for more trustworthy and effective AI solutions in healthcare
Universal amplification and sequencing of foot-and-mouth disease virus complete genomes using nanopore technology
Get PDFBackground Foot-and-mouth disease virus (FMDV) is capable of causing explosive outbreaks among domestic and wild cloven-hoofed animals. Genomic characterisation of FMDV is a crucial component of disease control enabling accurate tracing of disease outbreaks to be undertaken. Nanopore sequencing is an affordable and accessible form of high-throughput sequencing (HTS) technology. However, most published methods for FMDV only sequence genomic fragments or focus upon specific lineages. In this study, a universal FMDV sequencing protocol was developed alongside a bespoke analytical pipeline to sequence any FMDV genome in the absence of prior knowledge regarding the identity of the serotype or lineage. Methods Universal multiplex RT-PCRs were used to amplify overlapping tiles encompassing the entire FMDV genome. The PCR products were pooled and subjected to nanopore sequencing using the portable MinION sequencing device. A bioinformatics pipeline was used to assemble genomes based upon blastn and reference assembly. ResultsIterative changes in primer design and pooling resulted in two panels of primers; one set amplifying twenty short fragments (S_scheme), and another set amplifying six longer fragments (L_scheme). Both approaches were shown to be capable of generating FMDV genomes, however the L_scheme was simpler, more reliable and more cost-effective at generating complete genomes. The final L_scheme protocol was assessed using 30 FMDV isolates representing all the currently circulating lineages of FMDV. As part of the development, we successfully trialled the use of this technology in Uganda, a country endemic for FMD. Conclusions The amplification, sequencing and bioinformatics strategy developed here has been assessed using a diverse array of FMDV lineages. Using two multiplex PCR reactions, this approach can successfully generate complete genomes of FMDV in a lineage agnostic fashion. Therefore, the primer sets and approaches .described here represent a useful tool for expanding the capacity of laboratories to characterise FMDV at the genomic leve
Extrachromosomal DNA-Driven Oncogene Dosage Heterogeneity Promotes Rapid Adaptation to Therapy in MYCN-Amplified Cancers
Get PDFExtrachromosomal DNA (ecDNA) amplification enhances intercellular oncogene dosage variability and accelerates tumor evolution by violating foundational principles of genetic inheritance through its asymmetric mitotic segregation. Spotlighting high-risk neuroblastoma, we demonstrate how ecDNA amplification undermines the clinical efficacy of current therapies in cancers with extrachromosomal MYCN amplification. Integrating theoretical models of oncogene copy number-dependent fitness with single-cell ecDNA quantification and phenotype analyses, we reveal that ecDNA copy number heterogeneity drives phenotypic diversity and determines treatment sensitivity through mechanisms unattainable by chromosomal oncogene amplification. We demonstrate that ecDNA copy number directly influences cell fate decisions in cancer cell lines, patient-derived xenografts and primary neuroblastomas, illustrating how extrachromosomal oncogene dosage-driven phenotypic diversity offers a strong evolutionary advantage under therapeutic pressure. Furthermore, we identify senescent cells with reduced ecDNA copy numbers as a source of treatment resistance in neuroblastomas and outline a strategy for their targeted elimination to improve the treatment of MYCN-amplified cancers
Synaptic vesicle recycling at the developing presynapse
Get PDFNeurotransmitter release plays a fundamental role in brain communication. This is mediated via the exocytosis of neurotransmitter-containing synaptic vesicles (SVs) at the presynapse. After fusion with the presynaptic plasma membrane, SVs are regenerated by endocytosis and recycled back into functional pools. The great majority of research that has studied this essential process has focused on SV recycling at the mature presynaptic terminal. In contrast, SV recycling in immature neurons remains poorly understood, even though its disruption is heavily associated with a series of neurodevelopmental disorders. Evidence is accumulating that developing neurons display distinct presynaptic mechanisms for SV recycling. For example, developing presynapses display loose coupling between evoked calcium influx and SV fusion, with spontaneous SV exocytosis and clathrin-mediated endocytosis being the dominant exocytosis and endocytosis mechanisms respectively. In contrast, SV fusion in mature nerve terminals is tightly coupled to evoked calcium influx, with evoked SV exocytosis and endosomal modes of endocytosis dominant. This article reviews research at each stage of the SV recycling process at both mature and immature nerve terminals, beginning with the coupling of activity-dependent calcium influx to neurotransmitter release. In doing so, it aims to provide an integrated perspective of current knowledge regarding SV recycling through development across different neuronal systems, while posing key future questions to address for the presynaptic development field
ApoD mediates age-associated increase in vulnerability to influenza virus infection
Get PDFInfluenza A virus (IAV) infection causes significantly greater morbidity and mortality in the elderly population, but the molecular mechanisms in the aging process responsible for severe infection remain unclear. In this study, we found that increased severity in IAV infection and reduced innate immune response correlated with extensive mitophagy in senescent human cells and in the lung of aged mice. Apolipoprotein D (ApoD) was identified as strongly elevated in the lungs and sera of aged human (>65 y old) and mouse (>21 mo old). ApoD was able to localize to mitochondria and interact, through its WXXI motif in the LC3B-Interacting Region domain, with LC3B to trigger mitophagy during IAV infection, in a PINK1 pathway independent manner, which attenuated type I interferon response and promoted virus replication. ApoD deficiency, on the other hand, protected older mice from severe influenza and improved survival. Likewise, depletion of senescent cells by ABT-263, a senolytic compound, in aged mice lowered ApoD level and restored innate immune antiviral response, limiting virus propagation and associated pulmonary damage. Thus, age-induced ApoD drives IAV-mediated mitophagy, and promotes virus replication and infection severity, and is therefore a promising target for inhibition to improve disease outcome in older patients.</p
An emerging PB2-627 polymorphism increases the zoonotic risk of avian influenza virus by overcoming ANP32 host restriction in mammalian and avian hosts
Get PDFAlterations in the PB2-627 domain of avian influenza virus (AIV) can potentially increase the risk of cross-host species infections in humans and mammals. Recently, there has been a rise in human cases of AIV infections without the presence of the known mammalian determinant PB2-E627K. Here, we identified a variant, PB2-627V, which has evolved in poultry and has contributed to the increase in human AIV infections. By screening global PB2 sequences, we discovered a new independent cluster of PB2-627V that emerged in the 2010s, prevalent in avian, mammalian, and human AIV isolates, including those of H9N2, H7N9, H3N8, 2.3.4.4b H5N1, and other subtypes. We functionally assessed its host adaptation, fitness, and transmissibility across three subtypes of AIVs (H9N2, H7N9, and H3N8) in different host models. PB2-627V combines the viral properties of avian-like PB2-627E and human-like PB2-627K, facilitating AIVs to efficiently infect and replicate in chickens and mice by utilizing both avian- and human-origin ANP32A proteins. Importantly, PB2-627V promotes efficient transmission between ferrets through respiratory droplets. Deep sequencing of passaged chicken and transmitted ferret viral samples indicates that PB2-627V remains stable across the two host species and shows a high potential for long-term prevalence in avian species. Thus, the PB2-627V mutation in AIVs can stably transmit through poultry and can overcome the cross-species barrier to infect humans. Given the global prominence of AIVs, it will be prudent to monitor influenza viruses for the PB2-627V mutation as a potential marker for zoonotic spread.IMPORTANCEAvian influenza viruses (AIVs) are significant zoonotic pathogens. There is a rising trend of human cases of AIVs caused by a range of virus subtypes, including H9N2, H3N8, and H5N1 viruses. Thus, it is crucial to understand the underlying viral changes in AIVs that could result in zoonotic spread. We identify mutation PB2-627V as an emerging viral factor that confers dual ability to the virus to infect and adapt to mammalian and avian hosts, and virus transmissibility in ferrets. The presence of PB2-627V in multiple subtypes of AIVs has the potential to cause public health risk. We therefore propose that PB2-627V be included as a molecular marker to assess the zoonotic risk of AIVs.</p
A numerical study on the significance of slab for the response of a prototype structure under travelling fires
Get PDF“Travelling fires” discriminate a fire plume at the near-field and a hot smoke layer preheating the ceiling at the far-field, with the intent of ensuring the robustness of structural design for large compartments under realistic fires. Once the fire is “travelling”, the near-field has a leading edge representing the fire spread, and a trailing edge representing the burnout of the fuel. Despite the recognised effects of travelling fires, the mainstream of efforts into their effect on structural response has been limited to 2D models using the finite element method (FEM). This paper aims to identify the importance of slab inclusion with a 3D FEM structural model for steel-composite structures under travelling fires, assessed against the corresponding simplified 2D structural frame models (i.e., with and without effective slab in the 2D steel frame model). The first step is a comparative structural analysis of a prototype composite structure under various design fire scenarios, including standard fire, parametric fires and travelling fires. The role of the fire protection scheme for the simplified 2D models against the 3D model for the numerical predictions is also explored. It is found that the structural load path, and the potential structural failure mechanisms, could be fundamentally different between the 3D model and the simplified 2D models. Although the 2D frame model tends to predict larger deflections (i.e., more conservative) than the 3D model, it could also significantly underestimate the large internal forces from the beams, so that the connections' failure under travelling fires might be overlooked. Further, due to the simplification of the 2D models in omitting the significant stiffness contribution from the slab and the adjacent structural components, the effect of the fire protection is likely to be amplified. This may give misleading information on the performance-based structural fire design under different travelling fire scenarios. Hence, the 3D model can be considered as feasible but also necessary for structural fire analysis for travelling fires as a complement to the simplified 2D model approach
The Coexistence of Trees, Shrubs, and Grasses Creates a Complex Picture of Land Surface Phenology in Dry Tropical Ecosystems
Get PDFThe use of digital cameras to monitor vegetation phenology (phenocams) has become increasingly common as a means of ground truthing estimates of land surface phenology from Earth observation data. Whilst the relationship between phenocam and Earth Observation-derived indices of land surface phenology has been examined across many temperate land cover types, our understanding of these relationships across the seasonally dry tropics is limited. Here we examined phenological time series derived from coarse-scale MODIS and fine-scale phenocam data across four seasonally dry tropical sites in Brazil to determine their correlation and how phenological metrics derived from these time series differed. While MODIS-derived vegetation indices showed seasonal patterns, we found a poor correlation with vegetation indices from phenocams at sites with a high proportion of evergreen vegetation and a poor correlation of MODIS indices with specific vegetation components. The high spatial and temporal resolution of phenocams allowed us to demonstrate differences in phenological metrics among different components of the vegetation which were obscured in the coarser MODIS data. This study highlights the potential of phenocam data to improve our understanding of complex vegetation leaf phenology and its drivers within mixed tree–shrub–grass systems in the seasonally dry tropics. This could help improve the representation of the savanna, grass, and shrubland biomes within terrestrial biosphere models, and lead to better predictions of the impact of climate change on carbon dynamics via shifting vegetation phenology
Evolvability: Progress and Key Questions
Get PDFSince the 1990s, evolutionary biologists have recognized the importance of explaining the ability of biological systems to evolve, and how this ability itself evolves. This recognition of the need to explain “evolvability” emerged from the awareness that the kind and the amount of heritable variation available for natural selection require explanation. The concept of evolvability is now the focus of many research programs in diverse sub-disciplines within evolutionary biology. Here, we first review and synthesise progress made in evolvability research. We then present key questions to set an agenda for future research on evolvability, identify challenges to answer these questions, and discuss opportunities to apply results from the evolvability research to conservation biology
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