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A key hallmark of Parkinson’s disease (PD) is Lewy pathology. Composed of α-synuclein, Lewy pathology is found both in dopaminergic neurons that modulate motor function, and cortical regions that control cognitive function. Recent work has established the molecular identity of dopaminergic neurons susceptible to death, but little is known about cortical neurons susceptible to Lewy pathology or molecular changes induced by aggregates. In the current study, we use spatial transcriptomics to capture whole transcriptome signatures from cortical neurons with α-synuclein pathology compared to neurons without pathology. We find, both in PD and related PD dementia, dementia with Lewy bodies and in the pre-formed fibril α-synucleinopathy mouse model, that specific classes of excitatory neurons are vulnerable to developing Lewy pathology. Further, we identify conserved gene expression changes in aggregate-bearing neurons that we designate the Lewy-associated molecular dysfunction from aggregates (LAMDA) signature. Neurons with aggregates downregulate synaptic, mitochondrial, ubiquitin-proteasome, endo-lysosomal, and cytoskeletal genes and upregulate DNA repair and complement/cytokine genes. Our results identify neurons vulnerable to Lewy pathology in the PD cortex and describe a conserved signature of molecular dysfunction in both mice and humans. The impact of α-synuclein aggregates on neurons has been unclear. Here, the authors identify a Lewy Associated Molecular Dysfunction from Aggregates (LAMDA) signature in inclusion bearing neurons in human brain and a mouse model of α-synucleinopathy.

Lewy pathology composed of α-synuclein is the key pathological hallmark of Parkinson's disease (PD), found both in dopaminergic neurons that control motor function, and throughout cortical regions that control cognitive function. Recent work has investigated which dopaminergic neurons are most susceptible to death, but little is known about which neurons are vulnerable to developing Lewy pathology and what molecular changes an aggregate induces. In the current study, we use spatial transcriptomics to selectively capture whole transcriptome signatures from cortical neurons with Lewy pathology compared to those without pathology in the same brains. We find, both in PD and in a mouse model of PD, that there are specific classes of excitatory neurons that are vulnerable to developing Lewy pathology in the cortex. Further, we identify conserved gene expression changes in aggregate-bearing neurons that we designate the Lewy-associated molecular dysfunction from aggregates (LAMDA) signature. This gene signature indicates that neurons with aggregates downregulate synaptic, mitochondrial, ubiquitin-proteasome, endo-lysosomal, and cytoskeletal genes and upregulate DNA repair and complement/cytokine genes. However, beyond DNA repair gene upregulation, we find that neurons also activate apoptotic pathways, suggesting that if DNA repair fails, neurons undergo programmed cell death. Our results identify neurons vulnerable to Lewy pathology in the PD cortex and identify a conserved signature of molecular dysfunction in both mice and humans.Lewy pathology composed of α-synuclein is the key pathological hallmark of Parkinson's disease (PD), found both in dopaminergic neurons that control motor function, and throughout cortical regions that control cognitive function. Recent work has investigated which dopaminergic neurons are most susceptible to death, but little is known about which neurons are vulnerable to developing Lewy pathology and what molecular changes an aggregate induces. In the current study, we use spatial transcriptomics to selectively capture whole transcriptome signatures from cortical neurons with Lewy pathology compared to those without pathology in the same brains. We find, both in PD and in a mouse model of PD, that there are specific classes of excitatory neurons that are vulnerable to developing Lewy pathology in the cortex. Further, we identify conserved gene expression changes in aggregate-bearing neurons that we designate the Lewy-associated molecular dysfunction from aggregates (LAMDA) signature. This gene signature indicates that neurons with aggregates downregulate synaptic, mitochondrial, ubiquitin-proteasome, endo-lysosomal, and cytoskeletal genes and upregulate DNA repair and complement/cytokine genes. However, beyond DNA repair gene upregulation, we find that neurons also activate apoptotic pathways, suggesting that if DNA repair fails, neurons undergo programmed cell death. Our results identify neurons vulnerable to Lewy pathology in the PD cortex and identify a conserved signature of molecular dysfunction in both mice and humans.

α-Synuclein misfolding and progressive accumulation drives a pathogenic process in Parkinson's disease. To understand cellular and network vulnerability to α-synuclein pathology, we developed a framework to quantify network-level vulnerability and identify new therapeutic targets at the cellular level. Full brain α-synuclein pathology was mapped in mice over 9 months. Empirical pathology data was compared to theoretical pathology estimates from a diffusion model of pathology progression along anatomical connections. Unexplained variance in the model enabled us to derive regional vulnerability that we compared to regional gene expression. We identified gene expression patterns that relate to regional vulnerability, including 12 kinases that were enriched in vulnerable regions. Among these, an inhibitor of group II PAKs demonstrated protection from neuron death and α-synuclein pathology, even after delayed compound treatment. This study provides a framework for the derivation of cellular vulnerability from network-based studies and identifies a promising therapeutic pathway for Parkinson's disease.

This perspective paper reviews progress made in the last decades to enhance the communication and use of climate information relevant to the political and economic decision process. It focuses, specifically, on the creation and development of climate services, and highlights a number of difficulties that have limited the success of these services. Among them are the insufficient awareness by societal actors of their vulnerability to climate change, the lack of relevant products and services offered by the scientific community, the inappropriate format in which the information is provided, and the inadequate business model adopted by climate services. The authors suggest that, to be effective, centers should host within the same center a diversity of staff including experts in climate science, specialists in impact, adaptation, and vulnerability, representatives of the corporate world, agents of the public service as well as social managers and communication specialists. The role and importance of environmental engineering is emphasized. Key Points The success of climate services has been hampered by the inadequate business model adopted so far To be effective, climate service providers should host under the same roof a diversity of specialists as well as stakeholders representing the corporate world and public services as well as social managers, engineers, and communication specialists International collaboration is key for strengthening the local and regional capacities in developing and emerging countries

A multiscale modeling ensemble chain has been assembled as a first step towards an air quality analysis and forecasting (AQF) system for Latin America. Two global and three regional models were tested and compared in retrospective mode over a shared domain (120–28° W, 60° S–30° N) for the months of January and July 2015. The objective of this experiment was to understand their performance and characterize their errors. Observations from local air quality monitoring networks in Colombia, Chile, Brazil, Mexico, Ecuador and Peru were used for model evaluation. The models generally agreed with observations in large cities such as Mexico City and São Paulo, whereas representing smaller urban areas, such as Bogotá and Santiago, was more challenging. For instance, in Santiago during wintertime, the simulations showed large discrepancies with observations. No single model demonstrated superior performance over others or among pollutants and sites available. In general, ozone and NO2 exhibited the lowest bias and errors, especially in São Paulo and Mexico City. For SO2, the bias and error were close to 200 %, except for Bogotá. The ensemble, created from the median value of all models, was evaluated as well. In some cases, the ensemble outperformed the individual models and mitigated extreme over- or underestimation. However, more research is needed before concluding that the ensemble is the path for an AQF system in Latin America. This study identified certain limitations in the models and global emission inventories, which should be addressed with the involvement and experience of local researchers.

Toxoplasma gondii , the most common parasitic infection of human brain and eye, persists across lifetimes, can progressively damage sight, and is currently incurable. New, curative medicines are needed urgently. Herein, we develop novel models to facilitate drug development: EGS strain T. gondii forms cysts in vitro that induce oocysts in cats, the gold standard criterion for cysts. These cysts highly express cytochrome b . Using these models, we envisioned, and then created, novel 4-(1 H )-quinolone scaffolds that target the cytochrome bc 1 complex Q i site, of which, a substituted 5,6,7,8-tetrahydroquinolin-4-one inhibits active infection (IC 50 , 30 nM) and cysts (IC 50 , 4 μM) in vitro, and in vivo (25 mg/kg), and drug resistant Plasmodium falciparum (IC 50 , <30 nM), with clinically relevant synergy. Mutant yeast and co-crystallographic studies demonstrate binding to the bc 1 complex Q i site. Our results have direct impact on improving outcomes for those with toxoplasmosis, malaria, and ~2 billion persons chronically infected with encysted bradyzoites.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.An amendment to this paper has been published and can be accessed via a link at the top of the paper.

BackgroundTo evaluate the association between ventilator type and hospital mortality in patients with acute respiratory distress syndrome (ARDS) related to COVID-19 (SARS-CoV2 infection), a single-center prospective observational study in France.ResultsWe prospectively included consecutive adults admitted to the intensive care unit (ICU) of a university-affiliated tertiary hospital for ARDS related to proven COVID-19, between March 2020 and July 2021. All patients were intubated. We compared two patient groups defined by whether an ICU ventilator or a less sophisticated ventilator such as a sophisticated turbine-based transport ventilator was used. Kaplan–Meier survival curves were plotted. Cox multivariate regression was performed to identify associations between patient characteristics and hospital mortality. We included 189 patients (140 [74.1%] men) with a median age of 65 years [IQR, 55–73], of whom 61 (32.3%) died before hospital discharge. By multivariate analysis, factors associated with in-hospital mortality were age ≥ 70 years (HR, 2.11; 95% CI, 1.24–3.59; P = 0.006), immunodeficiency (HR, 2.43; 95% CI, 1.16–5.09; P = 0.02) and serum creatinine ≥ 100 µmol/L (HR, 3.01; 95% CI, 1.77–5.10; P < 0.001) but not ventilator type. As compared to conventional ICU (equipped with ICU and anesthesiology ventilators), management in transient ICU (equipped with non-ICU turbine-based ventilators) was associated neither with a longer duration of invasive mechanical ventilation (18 [IQR, 11–32] vs. 21 [13–37] days, respectively; P = 0.39) nor with a longer ICU stay (24 [IQR, 14–40] vs. 27 [15–44] days, respectively; P = 0.44).ConclusionsIn ventilated patients with ARDS due to COVID-19, management in transient ICU equipped with non-ICU sophisticated turbine-based ventilators was not associated with worse outcomes compared to standard ICU, equipped with ICU ventilators. Although our study design is not powered to demonstrate any difference in outcome, our results after adjustment do not suggest any signal of harm when using these transport type ventilators as an alternative to ICU ventilators during COVID-19 surge.

Dipeptide repeat (DPR) proteins are aggregation-prone polypeptides encoded by the pathogenic GGGGCC repeat expansion in the C9ORF72 gene, the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. In this study, we focus on the role of poly-GA DPRs in disease spread. We demonstrate that recombinant poly-GA oligomers can directly convert into solid-like aggregates and form characteristic β-sheet fibrils in vitro. To dissect the process of cell-to-cell DPR transmission, we closely follow the fate of poly-GA DPRs in either their oligomeric or fibrillized form after administration in the cell culture medium. We observe that poly-GA DPRs are taken up via dynamin-dependent and -independent endocytosis, eventually converging at the lysosomal compartment and leading to axonal swellings in neurons. We then use a co-culture system to demonstrate astrocyte-to-motor neuron DPR propagation, showing that astrocytes may internalise and release aberrant peptides in disease pathogenesis. Overall, our results shed light on the mechanisms of poly-GA cellular uptake and propagation, suggesting lysosomal impairment as a possible feature underlying the cellular pathogenicity of these DPR species.

We report the discovery of a transiting, temperate, Neptune-sized exoplanet orbiting the nearby (\\(d\\) = 27.5 pc), M3V star TOI-1231 (NLTT 24399, L 248-27, 2MASS J10265947-5228099). The planet was detected using photometric data from the Transiting Exoplanet Survey Satellite and followed up with observations from the Las Cumbres Observatory and the Antarctica Search for Transiting ExoPlanets program. Combining the photometric data sets, we find that the newly discovered planet has a radius of 3.65\\(^{+0.16}_{-0.15}\\) R\\(_{\\oplus}\\), and an orbital period of 24.246 days. Radial velocity measurements obtained with the Planet Finder Spectrograph on the Magellan Clay telescope confirm the existence of the planet and lead to a mass measurement of 15.5\\(\\pm\\)3.3 M\\(_{\\oplus}\\). With an equilibrium temperature of just 330K TOI-1231 b is one of the coolest small planets accessible for atmospheric studies thus far, and its host star's bright NIR brightness (J=8.88, K\\(_{s}\\)=8.07) make it an exciting target for HST and JWST. Future atmospheric observations would enable the first comparative planetology efforts in the 250-350 K temperature regime via comparisons with K2-18 b. Furthermore, TOI-1231's high systemic radial velocity (70.5 k\\ms) may allow for the detection of low-velocity hydrogen atoms escaping the planet by Doppler shifting the H I Ly-alpha stellar emission away from the geocoronal and ISM absorption features.