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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. Our results corroborate the hypothesis that present-day methane shortwave absorption mutes the warming effects of longwave absorption. For example, the global mean cooling in response to the present-day methane shortwave absorption is -0.10±0.07 K, which offsets 28 % (7 %–55 %) of the surface warming associated with present-day methane longwave radiative effects. The precipitation increase associated with the longwave radiative effects of the present-day methane perturbation (0.012±0.006 mm d -1) is also muted by shortwave absorption but not significantly so (-0.008±0.009 mm d -1). The unique responses to methane shortwave absorption are related to its negative top-of-the-atmosphere effective radiative forcing but positive atmospheric heating and in part to methane's distinctive vertical atmospheric solar heating profile. We also find that the present-day methane shortwave radiative effects, relative to its longwave radiative effects, are about 5 times larger than those under idealized carbon dioxide perturbations. Additional analyses show consistent but non-significant differences between the longwave versus shortwave radiative effects for both methane and carbon dioxide, including a stronger (negative) climate feedback when shortwave radiative effects are included (particularly for methane). We conclude by reiterating that methane remains a potent greenhouse gas. [ABSTRACT FROM AUTHOR]

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]

Despite the widespread use of the radiative kernel technique for studying radiative feedbacks and radiative forcings, there has not been any systematic, observation‐based validation of the radiative kernel method. Here, we utilize observed and reanalyzed radiative fluxes and atmospheric profiles from the Atmospheric Radiation Measurement (ARM) program and ERA5 reanalysis to assess a set of observation‐based radiative kernels from CloudSat for six ARM sites. The CloudSat radiative kernels, convoluted with the ERA5 state variables, can almost perfectly reconstruct the monthly anomalies of shortwave (SW) and longwave (LW) radiative fluxes in ERA5 at the surface (SFC) and top‐of‐atmosphere (TOA) with correlations significantly being greater than 0.95. The biases of kernel‐estimated flux anomalies calculated using the ARM‐observed state variables can be more than twice as large when compared with the ARM‐observed surface flux anomalies and Clouds and Earth's Radiant Energy System observed anomalies at the TOA. Generally, clouds contribute to most (>60%) of the variance of flux anomalies at Southern Great Plain (SGP), Tropical Western Pacific (TWP), and Eastern North Atlantic (ENA), and surface albedo dominates (>69%) the variance of SW flux anomalies at North Slope of Alaska. The radiative kernels exhibit the lowest correlation (r∼[0.55,0.85]) when reconstructing SFC LW flux anomalies at SGP, TWP, and ENA, whose biases are related to the possibility that the kernels may not fully capture the characteristics associated with Madden‐Julian oscillation and El Niño‐Southern Oscillation at TWP and the presence of clouds at SGP and ENA. Key Points: Observation‐based CloudSat radiative kernels are evaluated with field observations for six Atmospheric Radiation Measurement sites with different climate characteristicsThe kernels are found to be valuable for reconstructing observed radiative flux anomalies at the surface and top‐of‐atmosphereThe CloudSat kernels are the least skilled in reconstructing the observed changes in longwave radiative flux at the surface [ABSTRACT FROM AUTHOR]

Uncertainty in climate feedbacks is the primary source of the spread in projected surface temperature responses to anthropogenic forcing. Cloud feedback persistently appears as the main source of disagreement in future projections while the combined lapse‐rate plus water vapor (LR + WV) feedback is a smaller (30%), but non‐trivial source of uncertainty in climate sensitivity. Here we attempt to observationally constrain the feedbacks in an effort to reduce their intermodel uncertainties. The observed interannual variation provides a useful constraint on the long‐term cloud feedback, as evidenced by the consistency of global‐mean values and regional contributions to the intermodel spread on both interannual and long‐term timescales. However, interannual variability does not serve to constrain the long‐term LR + WV feedback spread, which we find is dominated by the varying tropical relative humidity (RH) response to interhemispheric warming differences under clear‐sky conditions and the RH‐fixed LR feedback under all‐sky conditions. Plain Language Summary: How much the Earth warms in response to greenhouse gas increases depends on the Earth's efficiency in restoring radiative equilibrium. This efficiency differs significantly among climate models due to differences in feedback processes, particularly the responses of clouds, temperature and water vapor to the initial perturbation. One approach to narrowing the intermodel spread of feedbacks is to only consider models whose observable variability is consistent with available measurements. The magnitude of cloud feedbacks on interannual and long‐term timescales are closely related, which allows us to employ this approach with observational estimates of the interannual cloud feedback to constrain the long‐term cloud feedback. However, this approach does not work for the feedback resulting from changes in the vertical distribution of temperature and water vapor (the combined lapse‐rate plus water vapor feedback). Key Points: Observed interannual variation provides a useful constraint to narrow the uncertainty in long‐term cloud feedbackIt is not possible to constrain the long‐term LR + WV feedback uncertainty with available observations of interannual variabilityDisagreements in the response of tropical relative humidity are responsible for the long‐term clear‐sky LR + WV feedback spread [ABSTRACT FROM AUTHOR]

Changes in atmospheric composition, such as increasing greenhouse gases, cause an initial radiative imbalance to the climate system, quantified as the instantaneous radiative forcing. This fundamental metric has not been directly observed globally and previous estimates have come from models. In part, this is because current space‐based instruments cannot distinguish the instantaneous radiative forcing from the climate's radiative response. We apply radiative kernels to satellite observations to disentangle these components and find all‐sky instantaneous radiative forcing has increased 0.53 ± 0.11 W/m2 from 2003 to 2018, accounting for positive trends in the total planetary radiative imbalance. This increase has been due to a combination of rising concentrations of well‐mixed greenhouse gases and recent reductions in aerosol emissions. These results highlight distinct fingerprints of anthropogenic activity in Earth's changing energy budget, which we find observations can detect within 4 years. Plain Language Summary: Climate change is a response to energy imbalances in the climate system. For example, rising greenhouse gases directly cause an initial imbalance, the radiative forcing, in the planetary radiation budget, and surface temperatures increase in response as the climate attempts to restore balance. The radiative forcing and subsequent radiative feedbacks dictate the amount of warming. While there are well‐established observational records of greenhouse gas concentrations and surface temperatures, there is not yet a global measure of the radiative forcing, in part because current satellite observations of Earth's radiation only measure the sum total of radiation changes that occur. We use the radiative kernel technique to isolate radiative forcing from total radiative changes and find it has increased from 2003 to 2018, accounting for nearly all of the long‐term growth in the total top‐of‐atmosphere radiation imbalance during this period. We confirm that rising greenhouse gas concentrations account for most of the increases in the radiative forcing, along with reductions in reflective aerosols. This serves as direct evidence that anthropogenic activity has affected Earth's energy budget in the recent past. Key Points: Observed instantaneous radiative forcing has increased, strengthening the top‐of‐atmosphere radiative imbalanceDue to cancellations in longwave and shortwave radiation, the sum of rapid adjustments and radiative feedbacks exhibit an insignificant trendObserved increases in instantaneous radiative forcing are direct evidence of the anthropogenic effects on the Earth's radiative energy budget [ABSTRACT FROM AUTHOR]

This paper quantifies the pre-industrial (1850) to present-day (2014) effective radiative forcing (ERF) of anthropogenic emissions of NO X , volatile organic compounds (VOCs; including CO), SO 2 , NH 3 , black carbon, organic carbon, and concentrations of methane, N 2 O and ozone-depleting halocarbons, using CMIP6 models. Concentration and emission changes of reactive species can cause multiple changes in the composition of radiatively active species: tropospheric ozone, stratospheric ozone, stratospheric water vapour, secondary inorganic and organic aerosol, and methane. Where possible we break down the ERFs from each emitted species into the contributions from the composition changes. The ERFs are calculated for each of the models that participated in the AerChemMIP experiments as part of the CMIP6 project, where the relevant model output was available. The 1850 to 2014 multi-model mean ERFs (± standard deviations) are -1.03 ± 0.37 W m -2 for SO 2 emissions, -0.2 5 ± 0.09 W m -2 for organic carbon (OC), 0.15 ± 0.17 W m -2 for black carbon (BC) and -0.07 ± 0.01 W m -2 for NH 3. For the combined aerosols (in the piClim-aer experiment) it is -1.01 ± 0.25 W m -2. The multi-model means for the reactive well-mixed greenhouse gases (including any effects on ozone and aerosol chemistry) are 0.67 ± 0.17 W m -2 for methane (CH 4), 0.26 ± 0.07 W m -2 for nitrous oxide (N 2 O) and 0.12 ± 0.2 W m -2 for ozone-depleting halocarbons (HC). Emissions of the ozone precursors nitrogen oxides (NO x), volatile organic compounds and both together (O 3) lead to ERFs of 0.14 ± 0.13, 0.09 ± 0.14 and 0.20 ± 0.07 W m -2 respectively. The 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]

The effective radiative forcing, which includes the instantaneous forcing plus adjustments from the atmosphere and surface, has emerged as the key metric of evaluating human and natural influence on the climate. We evaluate effective radiative forcing and adjustments in 17 contemporary climate models that are participating in the Coupled Model Intercomparison Project (CMIP6) and have contributed to the Radiative Forcing Model Intercomparison Project (RFMIP). Present-day (2014) global-mean anthropogenic forcing relative to pre-industrial (1850) levels from climate models stands at 2.00 (±0.23) W m -2 , comprised of 1.81 (±0.09) W m -2 from CO2 , 1.08 (± 0.21) W m -2 from other well-mixed greenhouse gases, -1.01 (± 0.23) W m -2 from aerosols and -0.09 (±0.13) W m -2 from land use change. Quoted uncertainties are 1 standard deviation across model best estimates, and 90 % confidence in the reported forcings, due to internal variability, is typically within 0.1 W m -2. The majority of the remaining 0.21 W m -2 is likely to be from ozone. In most cases, the largest contributors to the spread in effective radiative forcing (ERF) is from the instantaneous radiative forcing (IRF) and from cloud responses, particularly aerosol–cloud interactions to aerosol forcing. As determined in previous studies, cancellation of tropospheric and surface adjustments means that the stratospherically adjusted radiative forcing is approximately equal to ERF for greenhouse gas forcing but not for aerosols, and consequentially, not for the anthropogenic total. The spread of aerosol forcing ranges from -0.63 to -1.37 W m -2 , exhibiting a less negative mean and narrower range compared to 10 CMIP5 models. The spread in 4×CO2 forcing has also narrowed in CMIP6 compared to 13 CMIP5 models. Aerosol forcing is uncorrelated with climate sensitivity. Therefore, there is no evidence to suggest that the increasing spread in climate sensitivity in CMIP6 models, particularly related to high-sensitivity models, is a consequence of a stronger negative present-day aerosol forcing and little evidence that modelling groups are systematically tuning climate sensitivity or aerosol forcing to recreate observed historical warming. [ABSTRACT FROM AUTHOR]

We present top-of-atmosphere and surface radiative kernels based on the atmospheric component (GA7.1) of the HadGEM3 general circulation model developed by the UK Met Office. We show that the utility of radiative kernels for forcing adjustments in idealised CO2 perturbation experiments is greatest where there is sufficiently high resolution in the stratosphere in both the target climate model and the radiative kernel. This is because stratospheric cooling to a CO2 perturbation continues to increase with height, and low-resolution or low-top kernels or climate model output are unable to fully resolve the full stratospheric temperature adjustment. In the sixth phase of the Coupled Model Intercomparison Project (CMIP6), standard atmospheric model data are available up to 1 hPa on 19 pressure levels, which is a substantial advantage compared to CMIP5. We show in the IPSL-CM6A-LR model where a full set of climate diagnostics are available that the HadGEM3-GA7.1 kernel exhibits linear behaviour and the residual error term is small, as well as from a survey of kernels available in the literature that in general low-top radiative kernels underestimate the stratospheric temperature response. The HadGEM3-GA7.1 radiative kernels are available at https://doi.org/10.5281/zenodo.3594673. [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]

Radiative kernels describe the differential response of radiative fluxes to small perturbations in state variables and are widely used to quantify radiative feedbacks on the climate system. Radiative kernels have traditionally been generated using simulated data from a global climate model, typically sourced from the model's base climate. Consequently, these radiative kernels are subject to model bias from the climatological fields used to produce them. Here, we introduce the first observation‐based temperature, water vapor, and surface albedo radiative kernels, developed from CloudSat's fluxes and heating rates data set, 2B‐FLXHR‐LIDAR, which is supplemented with cloud information from the Cloud–Aerosol Lidar and Infrared Pathfinder Satellite Observations (CALIPSO). We compare the radiative kernels to a previously published set generated from the Geophysical Fluid Dynamics Laboratory (GFDL) model and find general agreement in magnitude and structure. However, several key differences illustrate the sensitivity of radiative kernels to the distribution of clouds. The radiative kernels are used to quantify top‐of‐atmosphere and surface cloud feedbacks in an ensemble of global climate models from the Climate Model Intercomparison Project Phase 5, showing that biases in the GFDL low clouds likely cause the GFDL kernel to underestimate longwave surface cloud feedback. Since the CloudSat kernels are free of model bias in the base state, they will be ideal for future analysis of radiative feedbacks and forcing in both models and observations and for evaluating biases in model‐derived radiative kernels. Key Points: Observation‐based radiative kernels are introduced, providing a method for quantifying feedbacks with reduced model biasAccounting for the cloud masking of noncloud feedbacks is critical for interpreting the sign of longwave cloud feedbackThe distribution of clouds in the polar region contributes to the seasonality of shortwave cloud feedback [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.)

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.

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: 1p36 deletion syndrome can predispose to pediatric-onset cardiomyopathy. Deletion breakpoints are variable and may delete the transcription factor PRDM16 . Early studies suggest that deletion of PRDM16 may underlie cardiomyopathy in patients with 1p36 deletion; however, the prognostic impact of PRDM16 loss is unknown., Methods: This retrospective cohort included subjects with 1p36 deletion syndrome from 4 hospitals. Prevalence of cardiomyopathy and freedom from death, cardiac transplantation, or ventricular assist device were analyzed. A systematic review cohort was derived for further analysis. A cardiac-specific Prdm16 knockout mouse ( Prdm16 conditional knockout) was generated. Echocardiography was performed at 4 and 6 to 7 months. Histology staining and qPCR were performed at 7 months to assess fibrosis., Results: The retrospective cohort included 71 patients. Among individuals with PRDM16 deleted, 34.5% developed cardiomyopathy versus 7.7% of individuals with PRDM16 not deleted ( P =0.1). In the combined retrospective and systematic review cohort (n=134), PRDM16 deletion-associated cardiomyopathy risk was recapitulated and significant (29.1% versus 10.8%, P =0.03). PRDM16 deletion was associated with increased risk of death, cardiac transplant, or ventricular assist device ( P =0.04). Among those PRDM16 deleted, 34.5% of females developed cardiomyopathy versus 16.7% of their male counterparts ( P =0.2). We find sex-specific differences in the incidence and the severity of contractile dysfunction and fibrosis in female Prdm16 conditional knockout mice. Further, female Prdm16 conditional knockout mice demonstrate significantly elevated risk of mortality ( P =0.0003)., Conclusions: PRDM16 deletion is associated with a significantly increased risk of cardiomyopathy and cardiac mortality. Prdm16 conditional knockout mice develop cardiomyopathy in a sex-biased way. Patients with PRDM16 deletion should be assessed for cardiac disease., Competing Interests: Disclosures The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing performed at Baylor Genetics Laboratories.