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Active telomere elongation by a subclass of cancer-associated POT1 mutations.
Full text linkMutations in the shelterin protein POT1 are associated with diverse cancers and thought to drive carcinogenesis by impairing POT1s suppression of aberrant telomere elongation. To classify clinical variants of uncertain significance (VUSs) and identify cancer-driving loss-of-function mutations, we developed a locally haploid human stem cell system to evaluate >1900 POT1 mutations, including >600 VUSs. Unexpectedly, many validated familial cancer-associated POT1 (caPOT1) mutations are haplosufficient for cellular viability, indicating that some pathogenic alleles do not act through a loss-of-function mechanism. Instead, POT1s DNA damage response suppression and telomere length control are genetically separable. ATR inhibition enables isolation of frameshift mutants, demonstrating that the only essential function of POT1 is to repress ATR. Furthermore, comparison of caPOT1 and frameshift alleles reveals a class of caPOT1 mutations that elongate telomeres more rapidly than full loss-of-function alleles. This telomere length-promoting activity is independent from POT1s role in overhang sequestration and fill-in synthesis
A large-scale sORF screen identifies putative microproteins involved in cancer cell fitness.
Full text linkThe human genome contains thousands of potentially coding short open reading frames (sORFs). While a growing set of microproteins translated from these sORFs have been demonstrated to mediate important cellular functions, the majority remains uncharacterized. In our study, we performed a high-throughput CRISPR-Cas9 knock-out screen targeting 11,776 sORFs to identify microproteins essential for cancer cell line growth. We show that the CENPBD2P gene encodes a translated sORF and promotes cell fitness. We selected five additional candidate sORFs encoding microproteins between 11 and 63 amino acids in length for further functional assessment. Green fluorescent protein fusion constructs of these microproteins localized to distinct subcellular compartments, and the majority showed reproducible biochemical interaction partners. Studying the fitness and transcriptome of sORF knock-outs and complementation with the corresponding microprotein, we identify rescuable phenotypes while also illustrating the limitations and caveats of our pipeline for sORF functional screening and characterization
Sexual dimorphism and morphological integration in the orchid bee brain.
Full text linkSex-specific behaviours are common across animals and often associated with sexual dimorphism in the nervous system. Using micro-CT scanning we standardized sex-specific brain atlases and tested for sexual dimorphism in the brain of the orchid bee Euglossa dilemma, a species with marked sex differences in social behaviour, mating strategies and foraging. Males show greater investment in all primary visual processing neuropils and are uniquely integrated with the central complex, evidenced by a strong positive covariation. This suggests that males invest more on locomotor control, flight stability and sky-compass navigation which may have evolved in response to sex-specific behaviours, like courtship display. In contrast, females have larger mushroom bodies that strongly and positively covary with the optic lobes and have increased volume of the Kenyon cell cluster, implying greater capabilities for visual associative memory. We speculate this is an adaptation to social and nest-building behaviours, and reliance on learning visual landmarks required for central place foraging. Our study provides the first record of sexually dimorphic morphological integration in the brain of an insect, an approach that revealed sex-specific brain traits that lack an apparent morphological signal. These subtle differences provide further evidence for the causal link between brain architecture and behaviour
Curriculum is more influential than haptic feedback when learning object manipulation.
Full text linkDexterous manipulation remains an aspirational goal for autonomous robotic systems, particularly when learning to lift and rotate objects against gravity with intermittent finger contacts. We use model-free reinforcement learning to compare the effect of curriculum (i.e., combinations of lift and rotation tasks) and haptic information (i.e., no-tactile versus 3D-force) on learning with a simulated three-finger robotic hand. In addition, a novel curriculum-based learning rate scheduler accelerates convergence. We demonstrate that the choice of curriculum biases the progression of learning for dexterous manipulation across objects with different weights, sizes, and shapes-underscoring the robustness of our learning approach. Unexpectedly, learning is achieved even in the absence of haptic information. This challenges conventional thinking about task complexity and the necessity of haptic information for dexterous manipulation for this task. This work invites the analogy of curriculum learning as a malleable developmental process from a pluripotent state driven by the nature of the learning experience
Relationship between economic recessions and health inequity: analysis of the gap in life expectancy at birth between Mexican States.
Full text linkOBJECTIVE: To estimate the effect of economic recessions on health inequality, with a focus on identifying recessions that have a health component. METHODS: This retrospective observational study uses the interannual rate of change in gross domestic product (GDP) as an indicator of economic conditions, and life expectancy at birth among Mexican states as a measure of health inequality. We calculated the Gini coefficient of life expectancy for the period 1980 to 2021 and examined its relationship with identified recessions through graphical analysis and an interrupted time series model. RESULTS: The disparity in life expectancy at birth between states decreased over the study period. However, the Gini coefficient of life expectancy showed an inverse relationship with the interannual rate of GDP change, indicating increased inequality during economic recessions, with the most pronounced effect observed during the COVID-19-associated recession in 2020. CONCLUSION: Economic recessions have detrimental effects on health, exacerbating pre-existing inequalities. It is crucial to implement protection mechanisms targeted at socially vulnerable populations to mitigate these effects and prevent the widening of health inequalities
Machine learning in point-of-care testing: innovations, challenges, and opportunities.
Full text linkThe landscape of diagnostic testing is undergoing a significant transformation, driven by the integration of artificial intelligence (AI) and machine learning (ML) into decentralized, rapid, and accessible sensor platforms for point-of-care testing (POCT). The COVID-19 pandemic has accelerated the shift from centralized laboratory testing but also catalyzed the development of next-generation POCT platforms that leverage ML to enhance the accuracy, sensitivity, and overall efficiency of point-of-care sensors. This Perspective explores how ML is being embedded into various POCT modalities, including lateral flow assays, vertical flow assays, nucleic acid amplification tests, and imaging-based sensors, illustrating their impact through different applications. We also discuss several challenges, such as regulatory hurdles, reliability, and privacy concerns, that must be overcome for the widespread adoption of ML-enhanced POCT in clinical settings and provide a comprehensive overview of the current state of ML-driven POCT technologies, highlighting their potential impact in the future of healthcare
Postmortem Interval Leads to Loss of Disease-Specific Signatures in Brain Tissue.
Full text linkHuman brain banks are essential for studying a wide variety of neurological and neurodegenerative diseases, yet the variability in postmortem interval (PMI)-the time from death to tissue preservation-poses significant challenges due to rapid cellular decomposition, protein alterations, and RNA degradation. Furthermore, the postmortem transcriptomic alterations occurring within distinct cell types are poorly understood. In this study, we analyzed the effect of a 3 h postmortem interval on single-nucleus RNA signatures in the brains of wild-type (WT) and PS19 mice, a common model of tauopathy. We observed that basic quality control metrics (such as the number of genes and reads per cell), total nuclei counts, and RNA integrity number (RINe) remained consistent across all samples, regardless of PMI or genotype. However, a 3 h PMI diminished the number of genes differentially expressed between PS19 and WT mice, suggesting an impact of delayed processing on the detection of disease-specific transcriptomic signatures. When directly comparing 3 h PMI versus freshly harvested 0 h mouse brains, we identified genes upregulated in neurons and interneurons involved in DNA repair, immune response, and stress pathways. Furthermore, genes that were altered in non-neuronal cell types at 3 versus 0 h PMI were associated with cell-cell adhesion processes. These findings highlight the effects of PMI on single-nucleus transcriptional changes that may dampen the true changes in cellular states in banked brain tissues
Geospatial Access to Extracorporeal Membrane Oxygenation in the United States.
Full text linkOBJECTIVES: To conduct a Geospatial Information System analysis of extracorporeal membrane oxygenation (ECMO) centers in the United States utilizing data from the U.S. Census Bureau to better understand access to ECMO care and identify potential disparities. DESIGN: A cross-sectional descriptive and statistical analysis of geospatial access to ECMO-capable centers in the United States, accounting for demographic variables. SETTING: The unit of analysis were U.S. Census block groups and demographic variables of interest obtained from the American Community Survey. PATIENTS: Patients accounted for in the U.S. Census data. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Sixty-seven percent of the U.S. population had direct access to ECMO-capable centers. Disparities were present, with Puerto Rico, Wyoming, North Dakota, and Alaska having no access. Poverty, increased age, and lower population density consistently correlated with limited access. We identified significant racial and ethnic disparities in the Midwest and Northeast. CONCLUSIONS: While 67% of the U.S. population had access to ECMO-capable centers by ground transportation, significant disparities in access exist. These findings emphasize the need for thoughtful implementation of ECMO systems of care to ensure equitable access. Future work should focus on developing novel systems of care that increase access utilizing advanced technology, such as aeromedical transport services
Spinal Cord Stimulation Explantation and Chronic Pain: A Systematic Review and Technology Recommendations.
Full text linkBACKGROUND: Chronic pain affects 20.5% of the US population, costing 35,000 to 15,000 to $25,000) raise concerns among payors. The hardware-driven model limits waveform flexibility, highlighting the need for innovation
Meloidogyne floridensis has a unique virulence profile against root-knot nematode resistant and susceptible pepper (Capsicum annuum) lines.
Full text linkMeloidogyne floridensis is a recently described species of root-knot nematode (RKN) that is very closely related to many other tropical RKN species, including M. incognita. Despite its close phylogenetic relationship, M. floridensis is distinctive from its close relatives in both its meiotic mechanism of reproduction and its documented virulence on many of the most common RKN resistance genes in cultivated peach, tomato, and pepper. To further characterize the virulence profile of M. floridensis, we conducted replicate screens using this nematode to infect a panel of pepper lines that carry different sets of known RKN resistance genes. We found that M. floridensis was virulent against all the most common RKN resistance genes, including N, Me1, and Me3. We also found that two of these lines, PA 136 and PM 217, were highly resistant to M. floridensis. PA136 was previously considered to be universally susceptible to all other RKN species. Further testing of an F1 hybrid of this line confirmed this result and indicated that PA 136 contains a yet uncharacterized and potentially dominant source of species-specific resistance against M. floridensis. These surprising results provide additional data on the differences between M. floridensis and its close relatives, and identify new sources of resistance that could be used by pepper breeding programs to develop new cultivars with resistance against this nematode