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Recent analyses show the importance of methane shortwave absorption, which many climate models lack. In particular, Allen et al. (2023) used idealized climate model simulations to show that methane shortwave absorption mutes up to 30 % of the surface warming and 60 % of the precipitation increase associated with its longwave radiative effects. Here, we explicitly quantify the radiative and climate impacts due to shortwave absorption of the present-day methane perturbation using the Community Earth System Model version 2. Our results corroborate that present-day methane shortwave absorption mutes the warming and wetting effects of longwave absorption. For example, the global mean cooling in response to the present-day methane shortwave absorption is -0.10 ± 0.04 K, which offsets 29 % of the surface warming associated with present-day methane longwave radiative effects. Similarly, we explicitly estimate 66 % of the precipitation increase associated with the longwave radiative effects of the present-day methane perturbation is offset by shortwave absorption. Unlike other solar absorbers (i.e., black carbon), the decrease in global mean precipitation under methane shortwave absorption is driven by both fast (atmospheric absorption) and slow (surface temperature cooling) responses. Finally, we show that the present-day methane shortwave radiative effects, relative to its longwave radiative effects, are about five times larger as compared to those under idealized carbon dioxide perturbations. The unique responses to methane shortwave absorption are related to its vertical atmospheric solar heating profile. Methane remains a potent greenhouse gas and continued endeavors to decrease methane emissions are necessary to stay below the 1.5 °C global warming threshold. [ABSTRACT FROM AUTHOR]

The climate science community aims to improve our understanding of climate change due to anthropogenic influences on atmospheric composition and the Earth's surface. Yet not all climate interactions are fully understood, and uncertainty in climate model results persists, as assessed in the latest Intergovernmental Panel on Climate Change (IPCC) assessment report. We synthesize current challenges and emphasize opportunities for advancing our understanding of the interactions between atmospheric composition, air quality, and climate change, as well as for quantifying model diversity. Our perspective is based on expert views from three multi-model intercomparison projects (MIPs) – the Precipitation Driver Response MIP (PDRMIP), the Aerosol Chemistry MIP (AerChemMIP), and the Radiative Forcing MIP (RFMIP). While there are many shared interests and specializations across the MIPs, they have their own scientific foci and specific approaches. The partial overlap between the MIPs proved useful for advancing the understanding of the perturbation–response paradigm through multi-model ensembles of Earth system models of varying complexity. We discuss the challenges of gaining insights from Earth system models that face computational and process representation limits and provide guidance from our lessons learned. Promising ideas to overcome some long-standing challenges in the near future are kilometer-scale experiments to better simulate circulation-dependent processes where it is possible and machine learning approaches where they are needed, e.g., for faster and better subgrid-scale parameterizations and pattern recognition in big data. New model constraints can arise from augmented observational products that leverage multiple datasets with machine learning approaches. Future MIPs can develop smart experiment protocols that strive towards an optimal trade-off between the resolution, complexity, and number of simulations and their length and, thereby, help to advance the understanding of climate change and its impacts. [ABSTRACT FROM AUTHOR]

Objective: Giant cell arteritis (GCA) is an age‐related vasculitis. Prior studies have identified an association between GCA and hematologic malignancies (HMs). How the presence of somatic mutations that drive the development of HMs, or clonal hematopoiesis (CH), may influence clinical outcomes in GCA is not well understood. Methods: To examine an association between CH and GCA, we analyzed sequenced exomes of 470,960 UK Biobank (UKB) participants for the presence of CH and used multivariable Cox regression. To examine the clinical phenotype of GCA in patients with and without somatic mutations across the spectrum of CH to HM, we performed targeted sequencing of blood samples and electronic health record review on 114 patients with GCA seen at our institution. We then examined associations between specific clonal mutations and GCA disease manifestations. Results: UKB participants with CH had a 1.48‐fold increased risk of incident GCA compared to UKB participants without CH. GCA risk was highest among individuals with cytopenia (hazard ratio [HR] 2.98, P = 0.00178) and with TET2 mutation (HR 2.02, P = 0.00116). Mutations were detected in 27.2% of our institutional GCA cohort, three of whom had HM at GCA diagnosis. TET2 mutations were associated with vision loss in patients with GCA (odds ratio 4.33, P = 0.047). Conclusions: CH increases risk for development of GCA in a genotype‐specific manner, with the greatest risk being conferred by the presence of mutations in TET2. Somatic TET2 mutations likewise increase the risk of GCA‐associated vision loss. Integration of somatic genetic testing in GCA diagnostics may be warranted in the future. [ABSTRACT FROM AUTHOR]

Twenty years of satellite-based cloud and radiation observations allow us to examine the observed cloud radiative effect (CRE) feedback (i.e., CRE change per unit change in global mean surface temperature). By employing a decomposition method to separate the contribution of "internal changes" and "relative-frequency-of-occurrence (RFO) changes" of distinct cloud regime (CR) groups, notable seasonal contrasts of CRE feedback characteristics emerge. Boreal winter CRE feedback is dominated by the positive shortwave CRE (SWCRE) feedback of oceanic low-thick clouds, due to their decreasing RFO as temperature rises. This signal is most likely due to El Niño-Southern Oscillation (ENSO) activity. When ENSO signals are excluded, boreal winter CRE feedback becomes qualitatively similar to the boreal summer feedback, where several CR groups contribute to the total CRE feedback more evenly. Most CR groups' CRE feedbacks largely come from changing RFO (e.g., the predominant transition from oceanic cumulus to broken clouds and more occurrences of higher convective clouds with warming temperature). At the same time, low-thick and broken clouds experience optical thinning and decreasing cloud fraction, and these features are more prominent in boreal summer than winter. Overall, the seasonally asymmetric patterns of CRE feedback, primarily due to ENSO, introduce complexity in assessments of CRE feedback. [ABSTRACT FROM AUTHOR]

When evaluating the effect of carbon dioxide (CO2) changes on Earth’s climate, it is widely assumed that instantaneous radiative forcing from a doubling of a given CO2 concentration (IRF2×CO2) is constant and that variances in climate sensitivity arise from differences in radiative feedbacks or dependence of these feedbacks on the climatological base state. Here, we show that the IRF2×CO2 is not constant, but rather depends on the climatological base state, increasing by about 25% for every doubling of CO2, and has increased by about 10% since the preindustrial era primarily due to the cooling within the upper stratosphere, implying a proportionate increase in climate sensitivity. This base-state dependence also explains about half of the intermodel spread in IRF2×CO2, a problem that has persisted among climate models for nearly three decades. [ABSTRACT FROM AUTHOR]

BACKGROUND: PRDM16 plays a role in myocardial development through TGF-β (transforming growth factor-beta) signaling. Recent evidence suggests that loss of PRDM16 expression is associated with cardiomyopathy development in mice, although its role in human cardiomyopathy development is unclear. This study aims to determine the impact of PRDM16 loss-of-function variants on cardiomyopathy in humans. METHODS: Individuals with PRDM16 variants were identified and consented. Induced pluripotent stem cell-derived cardiomyocytes were generated from a proband hosting a Q187X nonsense variant as an in vitro model and underwent proliferative and transcriptional analyses. CRISPR (clustered regularly interspaced short palindromic repeats)-mediated knock-in mouse model hosting the Prdm16Q187X allele was generated and subjected to ECG, histological, and transcriptional analysis. RESULTS: We report 2 probands with loss-of-function PRDM16 variants and pediatric left ventricular noncompaction cardiomyopathy. One proband hosts a PRDM16-Q187X variant with left ventricular noncompaction cardiomyopathy and demonstrated infant-onset heart failure, which was selected for further study. Induced pluripotent stem cell-derived cardiomyocytes prepared from the PRDM16-Q187X proband demonstrated a statistically significant impairment in myocyte proliferation and increased apoptosis associated with transcriptional dysregulation of genes implicated in cardiac maturation, including TGF-β-associated transcripts. Homozygous Prdm16Q187X/Q187X mice demonstrated an underdeveloped compact myocardium and were embryonically lethal. Heterozygous Prdm16Q187X/WT mice demonstrated significantly smaller ventricular dimensions, heightened fibrosis, and age-dependent loss of TGF-β expression. Mechanistic studies were undertaken in H9c2 cardiomyoblasts to show that PRDM16 binds TGFB3 promoter and represses its transcription. CONCLUSIONS: Novel loss-of-function PRDM16 variant impairs myocardial development resulting in noncompaction cardiomyopathy in humans and mice associated with altered TGF-β signaling. [ABSTRACT FROM AUTHOR]

This paper quantifies the effective radiative forcing from CMIP6 models of the present-day anthropogenic emissions of NOx, CO, VOCs, SO2, NH3, black carbon and primary organic carbon. Effective radiative forcing from pre-industrial to present-day changes in the concentrations of methane, N2O and halocarbons are quantified and attributed to their anthropogenic emissions. Emissions of reactive species can cause multiple changes in the composition of radiatively active species: tropospheric ozone, stratospheric ozone, secondary inorganic and organic aerosol and methane. We therefore break down the ERFs from each emitted species into the contributions from the composition changes. The 1850 to 2014 mean ERFs are 1.1 ± 0.07 W m-2 for sulfate, -0.24 ± 0.01 W m-2 for organic carbon (OC), and 0.15 ± 0.04 W m-2 for black carbon (BC), and for the aerosols combined it is -0.95 ± 0.03 W m-2. The means for the reactive gases are 0.69 ± 0.04 W m-2 for methane (CH4), 0.06 ± 0.04 W m-2 for NOx, -0.09 ± 0.03 W m-2 for volatile organic carbons (VOC), 0.16 ± 0.03 W m-2 for ozone (O3), 0.27 W m-2 for nitrous oxide (N2O) and -0.02 ± 0.06 W m-2 for hydrocarbon (HC). Differences in ERFs calculated for the different models reflect differences in the complexity of their aerosol and chemistry schemes, especially in the case of methane where tropospheric chemistry captures increased forcing from ozone production. [ABSTRACT FROM AUTHOR]

Intraductal papillary mucinous neoplasms are relatively common and entail a variable risk of malignant potential. The Fukuoka guidelines present criteria for the risk of malignant transformation and are used for risk stratification and treatment decision-making. However, these guidelines entail some fallibility with limited sensitivity and specificity. In this case, we present an individual who had many of the hallmarks of malignant transformation but was found to have no evidence of malignancy or high-grade dysplasia. We discuss the suspected etiology of this individual's condition and how it might arise in others, as well as a brief review of the literature on risk factors in intraductal papillary mucinous neoplasms., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Kramer et al.)

When evaluating the effect of carbon dioxide (CO 2 ) changes on Earth's climate, it is widely assumed that instantaneous radiative forcing from a doubling of a given CO 2 concentration (IRF 2×CO2 ) is constant and that variances in climate sensitivity arise from differences in radiative feedbacks or dependence of these feedbacks on the climatological base state. Here, we show that the IRF 2×CO2 is not constant, but rather depends on the climatological base state, increasing by about 25% for every doubling of CO 2 , and has increased by about 10% since the preindustrial era primarily due to the cooling within the upper stratosphere, implying a proportionate increase in climate sensitivity. This base-state dependence also explains about half of the intermodel spread in IRF 2×CO2 , a problem that has persisted among climate models for nearly three decades.

Background: PRDM16 plays a role in myocardial development through TGF-β (transforming growth factor-beta) signaling. Recent evidence suggests that loss of PRDM16 expression is associated with cardiomyopathy development in mice, although its role in human cardiomyopathy development is unclear. This study aims to determine the impact of PRDM16 loss-of-function variants on cardiomyopathy in humans., Methods: Individuals with PRDM16 variants were identified and consented. Induced pluripotent stem cell-derived cardiomyocytes were generated from a proband hosting a Q187X nonsense variant as an in vitro model and underwent proliferative and transcriptional analyses. CRISPR (clustered regularly interspaced short palindromic repeats)-mediated knock-in mouse model hosting the Prdm16 Q187X allele was generated and subjected to ECG, histological, and transcriptional analysis., Results: We report 2 probands with loss-of-function PRDM16 variants and pediatric left ventricular noncompaction cardiomyopathy. One proband hosts a PRDM16-Q187X variant with left ventricular noncompaction cardiomyopathy and demonstrated infant-onset heart failure, which was selected for further study. Induced pluripotent stem cell-derived cardiomyocytes prepared from the PRDM16-Q187X proband demonstrated a statistically significant impairment in myocyte proliferation and increased apoptosis associated with transcriptional dysregulation of genes implicated in cardiac maturation, including TGF-β-associated transcripts. Homozygous Prdm16 Q187X/Q187X mice demonstrated an underdeveloped compact myocardium and were embryonically lethal. Heterozygous Prdm16 Q187X/WT mice demonstrated significantly smaller ventricular dimensions, heightened fibrosis, and age-dependent loss of TGF-β expression. Mechanistic studies were undertaken in H9c2 cardiomyoblasts to show that PRDM16 binds TGFB3 promoter and represses its transcription., Conclusions: Novel loss-of-function PRDM16 variant impairs myocardial development resulting in noncompaction cardiomyopathy in humans and mice associated with altered TGF-β signaling., Competing Interests: Disclosures None.