Search

Hexanucleotide GGGGCC repeat expansion in C9ORF72 is the most prevalent genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). One pathogenic mechanism is the aberrant accumulation of dipeptide repeat (DPR) proteins produced by the unconventional translation of expanded RNA repeats. Here, we performed genome-wide CRISPR-Cas9 screens for modifiers of DPR protein production in human cells. We found that DDX3X, an RNA helicase, suppresses the repeat-associated non-AUG translation of GGGGCC repeats. DDX3X directly binds to (GGGGCC)n RNAs but not antisense (CCCCGG)n RNAs. Its helicase activity is essential for the translation repression. Reduction of DDX3X increases DPR levels in C9ORF72-ALS/FTD patient cells and enhances (GGGGCC)n-mediated toxicity in Drosophila. Elevating DDX3X expression is sufficient to decrease DPR levels, rescue nucleocytoplasmic transport abnormalities, and improve survival of patient iPSC-differentiated neurons. This work identifies genetic modifiers of DPR protein production and provides potential therapeutic targets for C9ORF72-ALS/FTD.

Black carbon in snow (BCS) is a crucial parameter in Earth System modeling, as it influences global radiative balance. Here, simulated BCS from Coupled Model Intercomparison Project Phase 5 and 6 (CMIP5 and CMIP6) that provided BCS as a model output were evaluated. In comparison with global BCS observations, CMIP5/6 models successfully reproduced long‐term historical trends linked to human activities, but struggled capturing decadal variability caused by natural climate variability. CMIP6 models NorESM2‐MM, NorESM2‐LM, and TaiESM1 yielded the most accurate simulations of BCS concentration with modest overestimation of <50%, while the four CESM2 models underestimated concentrations by up to ∼80%. These errors effectively balanced for the CMIP6 multi‐model ensemble mean (MME), which had a relative error (RE) of −37%. However, the CMIP5 MME was less reliable due to extreme overestimation by up to 8,000% in the three MIROC models. The significant BCS concentration errors in the MIROC and CESM2 models were linked mainly to errors in handling of BC in snow processes. Conversely, marked improvements in NorESM, the only common to both CMIP5 and CMIP6, were due to improved simulation of black carbon deposition. BCS errors significantly impacted radiative forcing estimates, particularly at the poles, where model errors reached several thousandfold. CMIP6 exhibited superior results compared to CMIP5, achieving global MME RE of −33% in radiative forcing estimates. However, it's worth noting BCS output is currently limited, with only seven models available for each of CMIP5 and CMIP6 here. Additional models simulating BCS are desirable in the next CMIP generations. Plain Language Summary: Black carbon in snow (BCS) has important implications for snow albedo reduction, solar radiation absorption, and snow melt acceleration on the Earth. However, model performance in BCS simulation remains unclear in the widely used Coupled Model Intercomparison Project phases 5 and 6 (CMIP5/6). In this study, CMIP5 and CMIP6 models providing BCS information were evaluated against a global data set of BCS observations from ice cores and snow samples. Results indicate that both CMIP generations successfully reproduce long‐term trends in BCS but fail to capture the decadal variability. Marked differences exist in modeled BCS concentrations, with the best‐performing models (NorESM2‐LM, NorESM2‐MM, and TaiESM1) overestimating concentrations by <50%, while the three worst‐performing MIROC models yield extreme overestimation. Such discrepancies stem primarily from the post‐depositional treatment of black carbon in snow, which influences the estimation of climate‐warming effects of BCS. Key Points: The global pattern of black carbon in snow (BCS) is effectively simulated by CMIP5/6 models, but large errors remainPost‐depositional snow processes contribute most to the large simulated‐BCS errorsBCS‐induced radiative forcing in Antarctica is poorly simulated by CMIP5/6 models with an overestimation of ∼200,000% and 144%, respectively [ABSTRACT FROM AUTHOR]

The Taklamakan Desert (TD) is a major source of mineral dust emissions into the atmosphere. These dust particles have the ability to darken the surface of snow on the surrounding high mountains after deposition, significantly impacting the regional radiation balance. However, previous field measurements have been unable to capture the effects of severe dust storms accurately, and their representation on regional scales has been inadequate. In this study, we propose a modified remote-sensing approach that combines data from the Moderate Resolution Imaging Spectroradiometer (MODIS) satellite and simulations from the Snow, Ice, and Aerosol Radiative (SNICAR) model. This approach allows us to detect and analyze the substantial snow darkening resulting from dust storm deposition. We focus on three typical dust events originating from the Taklamakan Desert and observe significant snow darkening over an area of ∼ 2160, ∼ 610, and ∼ 640 km 2 in the Tien Shan, Kunlun, and Qilian mountains, respectively. Our findings reveal that the impact of dust storms extends beyond the local high mountains, reaching mountains located approximately 1000 km away from the source. Furthermore, we observe that dust storms not only darken the snowpack during the spring but also in the summer and autumn seasons, leading to increased absorption of solar radiation. Specifically, the snow albedo reduction (radiative forcing) triggered by severe dust deposition is up to 0.028–0.079 (11–31.5 W m -2), 0.088–0.136 (31–49 W m -2), and 0.092–0.153 (22–38 W m -2) across the Tien Shan, Kunlun, and Qilian mountains, respectively. This further contributes to the aging of the snow, as evidenced by the growth of snow grain size. Comparatively, the impact of persistent but relatively slow dust deposition over several months during non-event periods is significantly lower than that of individual dust events. This highlights the necessity of giving more attention to the influence of extreme events on the regional radiation balance. This study provides a deeper understanding of how a single dust event can affect the extensive snowpack and demonstrates the potential of employing satellite remote sensing to monitor large-scale snow darkening. [ABSTRACT FROM AUTHOR]

The extensive snow cover across the Tibetan Plateau (TP) regions has a major influence on the climate and water supply for over one billion downstream inhabitants. However, an adequate evaluation of snow cover fraction (SCF) variability over the TP simulated by global multiple reanalysis datasets has yet to be undertaken. In this study, we examined eight global reanalysis SCF datasets using the Snow Property Inversion from Remote Sensing (SPIReS) product spanning the period 2001–2020. The results reveal that the HMASR generated the best SCF simulations because of its outstanding spatial and temporal accuracy. The GLDAS and CFSR demonstrated acceptable SCF accuracy with respect to spatial variability, but struggled to reproduce the annual trend. Pronounced SCF overestimations were found when using the ERA5, ERA5L, and JRA55, but SCF was underestimated by MERRA2, and CRAL generated poor spatial pattern. Overall biases were related to the combined effect of precipitation forcing, temperature forcing, snow data assimilation, and SCF parameterization methods, with the dominant factor changing across datasets. In ERA5 and ERA5L, temperature and snowfall bias exhibited significant correlations with SCF bias over most TP areas, therefore having a greater impact on the accuracy of SCF in terms of spatial variability and temporal evolution. On the other hand, the impact of snow assimilation was possibly more pronounced in MERRA2 and CRAL. Although parameterization methods can improve SCF simulation accuracy, their influence was weaker than those of other factors, except for JRA55. To further improve the accuracy of SCF simulation, an ensemble average method was developed. The ensemble based on HMASR and GLDAS generated the most accurate SCF spatial distribution, whereas the ensemble containing ERA5L, CFSR, CRAL, GLDAS, ERA5, and MERRA2 proved optimal for capturing the annual trend. [ABSTRACT FROM AUTHOR]

The Taklamakan Desert (TD) is a major source of mineral dust emissions into the atmosphere. These dust particles have the ability to darken the surface of snow on the surrounding high mountains after deposition, significantly impacting the regional radiation balance. However, previous field measurements have been unable to capture the effects of severe dust storms accurately, and their representation on regional scales has been inadequate. In this study, we propose a modified remote-sensing approach that combines data from the Moderate Resolution Imaging Spectroradiometer (MODIS) satellite and simulations from the Snow, Ice, and Aerosol Radiative (SNICAR) model. This approach allows us to detect and analyze the substantial snow darkening resulting from dust storm deposition. We focus on three typical dust events originating from the Taklamakan Desert and observe significant snow darkening over an area of >2100, >600, and >630 km2 in the Tien Shan, Kunlun, and Qilian Mountains, respectively. Our findings reveal that the impact of dust storms extends beyond the local high mountains, reaching mountains located approximately 1000 km away from the source. Furthermore, we observe that dust storms not only darken the snowpack during the spring but also in the summer and autumn seasons, leading to increased absorption of solar radiation. Specifically, the snow albedo reduction (radiative forcing) triggered by severe dust depositions is up to 0.028–0.079 (11–31.5 W m−2), 0.088–0.136 (31–49 W m−2), and 0.092–0.153 (22–38 W m−2) across the Tien Shan, Kunlun, and Qilian Mountains, respectively. This further contributes to the aging of the snow, as evidenced by the growth of snow grain size. Comparatively, the impact of persistent but relatively slow dust deposition over several months during non-event periods is significantly lower than that of individual dust event. This highlights the necessity of giving more attention to the influence of extreme events on the regional radiation balance. Through this study, we gain a deeper understanding of how a single dust event can affect the extensive snowpack and demonstrates the potential of employing satellite remote-sensing to monitor large-scale snow darkening. [ABSTRACT FROM AUTHOR]

Engineering the genetic code of an organism provides the basis for (i) making any organism safely resistant to natural viruses and (ii) preventing genetic information flow into and out of genetically modified organisms while (iii) allowing the biosynthesis of genetically encoded unnatural polymers 1-4 . Achieving these three goals requires the reassignment of multiple of the 64 codons nature uses to encode proteins. However, synonymous codon replacement-recoding-is frequently lethal, and how recoding impacts fitness remains poorly explored. Here, we explore these effects using whole-genome synthesis, multiplexed directed evolution, and genome-transcriptome-translatome-proteome co-profiling on multiple recoded genomes. Using this information, we assemble a synthetic Escherichia coli genome in seven sections using only 57 codons to encode proteins. By discovering the rules responsible for the lethality of synonymous recoding and developing a data-driven multi-omics-based genome construction workflow that troubleshoots synthetic genomes, we overcome the lethal effects of 62,007 synonymous codon swaps and 11,108 additional genomic edits. We show that synonymous recoding induces transcriptional noise including new antisense RNAs, leading to drastic transcriptome and proteome perturbation. As the elimination of select codons from an organism's genetic code results in the widespread appearance of cryptic promoters, we show that synonymous codon choice may naturally evolve to minimize transcriptional noise. Our work provides the first genome-scale description of how synonymous codon changes influence organismal fitness and paves the way for the construction of functional genomes that provide genetic firewalls from natural ecosystems and safely produce biopolymers, drugs, and enzymes with an expanded chemistry., Competing Interests: Conflict of interest statement The authors declare competing financial interests. A.N. is an inventor on a patent related to directed evolution with random genomic mutations (DIvERGE) (US10669537B2: Mutagenizing Intracellular Nucleic Acids) that has been outlicensed. Harvard Medical School has filed provisional patent applications related to this work on which A.N. and G.M.C. are listed as inventors. Q.Z., M.W., M.L., A.J., K.C., Z.L., and F.H. are employed by GenScript USA Inc., but the company had no role in designing or executing experiments. G.M.C. is a founder of GRO Biosciences and EnEvolv (now part of Ginkgo Bioworks), in which he has related financial interests. Other potentially relevant financial interests of G.M.C. are listed at http://arep.med.harvard.edu/gmc/tech.html.