Showing papers by "Stanford University published in 2022"

Global Carbon Budget 2021

Abstract: Abstract. Accurate assessment of anthropogenic carbon dioxide (CO2) emissions and their redistribution among the atmosphere, ocean, and terrestrial biosphere in a changing climate is critical to better understand the global carbon cycle, support the development of climate policies, and project future climate change. Here we describe and synthesize datasets and methodology to quantify the five major components of the global carbon budget and their uncertainties. Fossil CO2 emissions (EFOS) are based on energy statistics and cement production data, while emissions from land-use change (ELUC), mainly deforestation, are based on land use and land-use change data and bookkeeping models. Atmospheric CO2 concentration is measured directly, and its growth rate (GATM) is computed from the annual changes in concentration. The ocean CO2 sink (SOCEAN) is estimated with global ocean biogeochemistry models and observation-based data products. The terrestrial CO2 sink (SLAND) is estimated with dynamic global vegetation models. The resulting carbon budget imbalance (BIM), the difference between the estimated total emissions and the estimated changes in the atmosphere, ocean, and terrestrial biosphere, is a measure of imperfect data and understanding of the contemporary carbon cycle. All uncertainties are reported as ±1σ. For the first time, an approach is shown to reconcile the difference in our ELUC estimate with the one from national greenhouse gas inventories, supporting the assessment of collective countries' climate progress. For the year 2020, EFOS declined by 5.4 % relative to 2019, with fossil emissions at 9.5 ± 0.5 GtC yr−1 (9.3 ± 0.5 GtC yr−1 when the cement carbonation sink is included), and ELUC was 0.9 ± 0.7 GtC yr−1, for a total anthropogenic CO2 emission of 10.2 ± 0.8 GtC yr−1 (37.4 ± 2.9 GtCO2). Also, for 2020, GATM was 5.0 ± 0.2 GtC yr−1 (2.4 ± 0.1 ppm yr−1), SOCEAN was 3.0 ± 0.4 GtC yr−1, and SLAND was 2.9 ± 1 GtC yr−1, with a BIM of −0.8 GtC yr−1. The global atmospheric CO2 concentration averaged over 2020 reached 412.45 ± 0.1 ppm. Preliminary data for 2021 suggest a rebound in EFOS relative to 2020 of +4.8 % (4.2 % to 5.4 %) globally. Overall, the mean and trend in the components of the global carbon budget are consistently estimated over the period 1959–2020, but discrepancies of up to 1 GtC yr−1 persist for the representation of annual to semi-decadal variability in CO2 fluxes. Comparison of estimates from multiple approaches and observations shows (1) a persistent large uncertainty in the estimate of land-use changes emissions, (2) a low agreement between the different methods on the magnitude of the land CO2 flux in the northern extra-tropics, and (3) a discrepancy between the different methods on the strength of the ocean sink over the last decade. This living data update documents changes in the methods and datasets used in this new global carbon budget and the progress in understanding of the global carbon cycle compared with previous publications of this dataset (Friedlingstein et al., 2020, 2019; Le Quéré et al., 2018b, a, 2016, 2015b, a, 2014, 2013). The data presented in this work are available at https://doi.org/10.18160/gcp-2021 (Friedlingstein et al., 2021).

Replica wormholes and the black hole interior

Abstract: A bstract Recent work has shown how to obtain the Page curve of an evaporating black hole from holographic computations of entanglement entropy. We show how these computations can be justified using the replica trick, from geometries with a spacetime wormhole connecting the different replicas. In a simple model, we study the Page transition in detail by summing replica geometries with different topologies. We compute related quantities in less detail in more complicated models, including JT gravity coupled to conformal matter and the SYK model. Separately, we give a direct gravitational argument for entanglement wedge reconstruction using an explicit formula known as the Petz map; again, a spacetime wormhole plays an important role. We discuss an interpretation of the wormhole geometries as part of some ensemble average implicit in the gravity description.

TDP-43 represses cryptic exon inclusion in the FTD–ALS gene UNC13A

Abstract: Abstract A hallmark pathological feature of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the depletion of RNA-binding protein TDP-43 from the nucleus of neurons in the brain and spinal cord 1 . A major function of TDP-43 is as a repressor of cryptic exon inclusion during RNA splicing 2–4 . Single nucleotide polymorphisms in UNC13A are among the strongest hits associated with FTD and ALS in human genome-wide association studies 5,6 , but how those variants increase risk for disease is unknown. Here we show that TDP-43 represses a cryptic exon-splicing event in UNC13A . Loss of TDP-43 from the nucleus in human brain, neuronal cell lines and motor neurons derived from induced pluripotent stem cells resulted in the inclusion of a cryptic exon in UNC13A mRNA and reduced UNC13A protein expression. The top variants associated with FTD or ALS risk in humans are located in the intron harbouring the cryptic exon, and we show that they increase UNC13A cryptic exon splicing in the face of TDP-43 dysfunction. Together, our data provide a direct functional link between one of the strongest genetic risk factors for FTD and ALS ( UNC13A genetic variants), and loss of TDP-43 function.

Global Carbon Budget 2022

Abstract: Abstract. Accurate assessment of anthropogenic carbon dioxide (CO2) emissions and their redistribution among the atmosphere, ocean, and terrestrial biosphere in a changing climate is critical to better understand the global carbon cycle, support the development of climate policies, and project future climate change. Here we describe and synthesize data sets and methodologies to quantify the five major components of the global carbon budget and their uncertainties. Fossil CO2 emissions (EFOS) are based on energy statistics and cement production data, while emissions from land-use change (ELUC), mainly deforestation, are based on land use and land-use change data and bookkeeping models. Atmospheric CO2 concentration is measured directly, and its growth rate (GATM) is computed from the annual changes in concentration. The ocean CO2 sink (SOCEAN) is estimated with global ocean biogeochemistry models and observation-based data products. The terrestrial CO2 sink (SLAND) is estimated with dynamic global vegetation models. The resulting carbon budget imbalance (BIM), the difference between the estimated total emissions and the estimated changes in the atmosphere, ocean, and terrestrial biosphere, is a measure of imperfect data and understanding of the contemporary carbon cycle. All uncertainties are reported as ±1σ. For the year 2021, EFOS increased by 5.1 % relative to 2020, with fossil emissions at 10.1 ± 0.5 GtC yr−1 (9.9 ± 0.5 GtC yr−1 when the cement carbonation sink is included), and ELUC was 1.1 ± 0.7 GtC yr−1, for a total anthropogenic CO2 emission (including the cement carbonation sink) of 10.9 ± 0.8 GtC yr−1 (40.0 ± 2.9 GtCO2). Also, for 2021, GATM was 5.2 ± 0.2 GtC yr−1 (2.5 ± 0.1 ppm yr−1), SOCEAN was 2.9 ± 0.4 GtC yr−1, and SLAND was 3.5 ± 0.9 GtC yr−1, with a BIM of −0.6 GtC yr−1 (i.e. the total estimated sources were too low or sinks were too high). The global atmospheric CO2 concentration averaged over 2021 reached 414.71 ± 0.1 ppm. Preliminary data for 2022 suggest an increase in EFOS relative to 2021 of +1.0 % (0.1 % to 1.9 %) globally and atmospheric CO2 concentration reaching 417.2 ppm, more than 50 % above pre-industrial levels (around 278 ppm). Overall, the mean and trend in the components of the global carbon budget are consistently estimated over the period 1959–2021, but discrepancies of up to 1 GtC yr−1 persist for the representation of annual to semi-decadal variability in CO2 fluxes. Comparison of estimates from multiple approaches and observations shows (1) a persistent large uncertainty in the estimate of land-use change emissions, (2) a low agreement between the different methods on the magnitude of the land CO2 flux in the northern extratropics, and (3) a discrepancy between the different methods on the strength of the ocean sink over the last decade. This living data update documents changes in the methods and data sets used in this new global carbon budget and the progress in understanding of the global carbon cycle compared with previous publications of this data set. The data presented in this work are available at https://doi.org/10.18160/GCP-2022 (Friedlingstein et al., 2022b).

SynergyFinder Plus: Toward Better Interpretation and Annotation of Drug Combination Screening Datasets

Abstract: Combinatorial therapies have been recently proposed to improve the efficacy of anticancer treatment. The SynergyFinder R package is a software used to analyze pre-clinical drug combination datasets. Here, we report the major updates to the SynergyFinder R package for improved interpretation and annotation of drug combination screening results. Unlike the existing implementations, the updated SynergyFinder R package includes five main innovations. 1) We extend the mathematical models to higher-order drug combination data analysis and implement dimension reduction techniques for visualizing the synergy landscape. 2) We provide a statistical analysis of drug combination synergy and sensitivity with confidence intervals and P values. 3) We incorporate a synergy barometer to harmonize multiple synergy scoring methods to provide a consensus metric for synergy. 4) We evaluate drug combination synergy and sensitivity to provide an unbiased interpretation of the clinical potential. 5) We enable fast annotation of drugs and cell lines, including their chemical and target information. These annotations will improve the interpretation of the mechanisms of action of drug combinations. To facilitate the use of the R package within the drug discovery community, we also provide a web server at www.synergyfinderplus.org as a user-friendly interface to enable a more flexible and versatile analysis of drug combination data.

Prospects and applications of photonic neural networks

Abstract: Neural networks have enabled applications in artificial intelligence through machine learning, and neuromorphic computing. Software implementations of neural networks on conventional computers that...

Multiple causal variants underlie genetic associations in humans

Abstract: Associations between genetic variation and traits are often in noncoding regions with strong linkage disequilibrium (LD), where a single causal variant is assumed to underlie the association. We applied a massively parallel reporter assay (MPRA) to functionally evaluate genetic variants in high, local LD for independent cis-expression quantitative trait loci (eQTL). We found that 17.7% of eQTLs exhibit more than one major allelic effect in tight LD. The detected regulatory variants were highly and specifically enriched for activating chromatin structures and allelic transcription factor binding. Integration of MPRA profiles with eQTL/complex trait colocalizations across 114 human traits and diseases identified causal variant sets demonstrating how genetic association signals can manifest through multiple, tightly linked causal variants.

Structure of a Janus kinase cytokine receptor complex reveals the basis for dimeric activation

Abstract: Cytokines signal through cell surface receptor dimers to initiate activation of intracellular Janus kinases (JAKs). We report the 3.6-angstrom-resolution cryo-electron microscopy structure of full-length JAK1 complexed with a cytokine receptor intracellular domain Box1 and Box2 regions captured as an activated homodimer bearing the valine→phenylalanine (VF) mutation prevalent in myeloproliferative neoplasms. The seven domains of JAK1 form an extended structural unit, the dimerization of which is mediated by close-packing of the pseudokinase (PK) domains from the monomeric subunits. The oncogenic VF mutation lies within the core of the JAK1 PK interdimer interface, enhancing packing complementarity to facilitate ligand-independent activation. The carboxy-terminal tyrosine kinase domains are poised for transactivation and to phosphorylate the receptor STAT (signal transducer and activator of transcription)-recruiting motifs projecting from the overhanging FERM (four-point-one, ezrin, radixin, moesin)-SH2 (Src homology 2)-domains. Mapping of constitutively active JAK mutants supports a two-step allosteric activation mechanism and reveals opportunities for selective therapeutic targeting of oncogenic JAK signaling.

Access to gender-affirming hormones during adolescence and mental health outcomes among transgender adults

Abstract: To examine associations between recalled access to gender-affirming hormones (GAH) during adolescence and mental health outcomes among transgender adults in the U.S.We conducted a secondary analysis of the 2015 U.S. Transgender Survey, a cross-sectional non-probability sample of 27,715 transgender adults in the U.S. Using multivariable logistic regression adjusting for potential confounders, we examined associations between access to GAH during early adolescence (age 14-15), late adolescence (age 16-17), or adulthood (age ≥18) and adult mental health outcomes, with participants who desired but never accessed GAH as the reference group.21,598 participants (77.9%) reported ever desiring GAH. Of these, 8,860 (41.0%) never accessed GAH, 119 (0.6%) accessed GAH in early adolescence, 362 (1.7%) accessed GAH in late adolescence, and 12,257 (56.8%) accessed GAH in adulthood. After adjusting for potential confounders, accessing GAH during early adolescence (aOR = 0.4, 95% CI = 0.2-0.6, p < .0001), late adolescence (aOR = 0.5, 95% CI = 0.4-0.7, p < .0001), or adulthood (aOR = 0.8, 95% CI = 0.7-0.8, p < .0001) was associated with lower odds of past-year suicidal ideation when compared to desiring but never accessing GAH. In post hoc analyses, access to GAH during adolescence (ages 14-17) was associated with lower odds of past-year suicidal ideation (aOR = 0.7, 95% CI = 0.6-0.9, p = .0007) when compared to accessing GAH during adulthood.Access to GAH during adolescence and adulthood is associated with favorable mental health outcomes compared to desiring but not accessing GAH.

Analyticity and unitarity for cosmological correlators

Abstract: We study the fundamentals of quantum field theory on a rigid de Sitter space. We show that the perturbative expansion of late-time correlation functions to all orders can be equivalently generated by a non-unitary Lagrangian on a Euclidean AdS geometry. This finding simplifies dramatically perturbative computations, as well as allows us to establish basic properties of these correlators, which comprise a Euclidean CFT. We use this to infer the analytic structure of the spectral density that captures the conformal partial wave expansion of a late-time four-point function, to derive an OPE expansion, and to constrain the operator spectrum. Generically, dimensions and OPE coefficients do not obey the usual CFT notion of unitarity. Instead, unitarity of the de Sitter theory manifests itself as the positivity of the spectral density. This statement does not rely on the use of Euclidean AdS Lagrangians and holds non-perturbatively. We illustrate and check these properties by explicit calculations in a scalar theory by computing first tree-level, and then full one-loop-resummed exchange diagrams. An exchanged particle appears as a resonant feature in the spectral density which can be potentially useful in experimental searches.

Qubit teleportation between non-neighbouring nodes in a quantum network

Abstract: Abstract Future quantum internet applications will derive their power from the ability to share quantum information across the network 1,2 . Quantum teleportation allows for the reliable transfer of quantum information between distant nodes, even in the presence of highly lossy network connections 3 . Although many experimental demonstrations have been performed on different quantum network platforms 4–10 , moving beyond directly connected nodes has, so far, been hindered by the demanding requirements on the pre-shared remote entanglement, joint qubit readout and coherence times. Here we realize quantum teleportation between remote, non-neighbouring nodes in a quantum network. The network uses three optically connected nodes based on solid-state spin qubits. The teleporter is prepared by establishing remote entanglement on the two links, followed by entanglement swapping on the middle node and storage in a memory qubit. We demonstrate that, once successful preparation of the teleporter is heralded, arbitrary qubit states can be teleported with fidelity above the classical bound, even with unit efficiency. These results are enabled by key innovations in the qubit readout procedure, active memory qubit protection during entanglement generation and tailored heralding that reduces remote entanglement infidelities. Our work demonstrates a prime building block for future quantum networks and opens the door to exploring teleportation-based multi-node protocols and applications 2,11–13 .

Coronavirus Resistance Database (CoV-RDB): SARS-CoV-2 susceptibility to monoclonal antibodies, convalescent plasma, and plasma from vaccinated persons

Abstract: As novel SARS-CoV-2 variants with different patterns of spike protein mutations have emerged, the susceptibility of these variants to neutralization by antibodies has been rapidly assessed. However, neutralization data are generated using different approaches and are scattered across different publications making it difficult for these data to be located and synthesized. The Stanford Coronavirus Resistance Database (CoV-RDB; https://covdb.stanford.edu) is designed to house comprehensively curated published data on the neutralizing susceptibility of SARS-CoV-2 variants and spike mutations to monoclonal antibodies (mAbs), convalescent plasma (CP), and vaccinee plasma (VP). As of December 31, 2021, CoV-RDB encompassed 257 publications including 91 (35%) containing 9,070 neutralizing mAb susceptibility results, 131 (51%) containing 16,773 neutralizing CP susceptibility results, and 178 (69%) containing 33,540 neutralizing VP results. The database also records which spike mutations are selected during in vitro passage of SARS-CoV-2 in the presence of mAbs and which emerge in persons receiving mAbs as treatment. The CoV-RDB interface interactively displays neutralizing susceptibility data at different levels of granularity by filtering and/or aggregating query results according to one or more experimental conditions. The CoV-RDB website provides a companion sequence analysis program that outputs information about mutations present in a submitted sequence and that also assists users in determining the appropriate mutation-detection thresholds for identifying non-consensus amino acids. The most recent data underlying the CoV-RDB can be downloaded in its entirety from a GitHub repository in a documented machine-readable format.

Open-source automated insulin delivery: international consensus statement and practical guidance for health-care professionals

Abstract: Open-source automated insulin delivery systems, commonly referred to as do-it-yourself automated insulin delivery systems, are examples of user-driven innovations that were co-created and supported by an online community who were directly affected by diabetes. Their uptake continues to increase globally, with current estimates suggesting several thousand active users worldwide. Real-world user-driven evidence is growing and provides insights into safety and effectiveness of these systems. The aim of this consensus statement is two-fold. Firstly, it provides a review of the current evidence, description of the technologies, and discusses the ethics and legal considerations for these systems from an international perspective. Secondly, it provides a much-needed international health-care consensus supporting the implementation of open-source systems in clinical settings, with detailed clinical guidance. This consensus also provides important recommendations for key stakeholders that are involved in diabetes technologies, including developers, regulators, and industry, and provides medico-legal and ethical support for patient-driven, open-source innovations.

Single-cell analyses define a continuum of cell state and composition changes in the malignant transformation of polyps to colorectal cancer

Abstract: Abstract To chart cell composition and cell state changes that occur during the transformation of healthy colon to precancerous adenomas to colorectal cancer (CRC), we generated single-cell chromatin accessibility profiles and single-cell transcriptomes from 1,000 to 10,000 cells per sample for 48 polyps, 27 normal tissues and 6 CRCs collected from patients with or without germline APC mutations. A large fraction of polyp and CRC cells exhibit a stem-like phenotype, and we define a continuum of epigenetic and transcriptional changes occurring in these stem-like cells as they progress from homeostasis to CRC. Advanced polyps contain increasing numbers of stem-like cells, regulatory T cells and a subtype of pre-cancer-associated fibroblasts. In the cancerous state, we observe T cell exhaustion, RUNX1-regulated cancer-associated fibroblasts and increasing accessibility associated with HNF4A motifs in epithelia. DNA methylation changes in sporadic CRC are strongly anti-correlated with accessibility changes along this continuum, further identifying regulatory markers for molecular staging of polyps.

Delivery of CAR-T cells in a transient injectable stimulatory hydrogel niche improves treatment of solid tumors

Abstract: Adoptive cell therapy (ACT) has proven to be highly effective in treating blood cancers, but traditional approaches to ACT are poorly effective in treating solid tumors observed clinically. Novel delivery methods for therapeutic cells have shown promise for treatment of solid tumors when compared with standard intravenous administration methods, but the few reported approaches leverage biomaterials that are complex to manufacture and have primarily demonstrated applicability following tumor resection or in immune-privileged tissues. Here, we engineer simple-to-implement injectable hydrogels for the controlled co-delivery of CAR-T cells and stimulatory cytokines that improve treatment of solid tumors. The unique architecture of this material simultaneously inhibits passive diffusion of entrapped cytokines and permits active motility of entrapped cells to enable long-term retention, viability, and activation of CAR-T cells. The generation of a transient inflammatory niche following administration affords sustained exposure of CAR-T cells, induces a tumor-reactive CAR-T phenotype, and improves efficacy of treatment.

NEAT-seq: simultaneous profiling of intra-nuclear proteins, chromatin accessibility and gene expression in single cells

Abstract: In this work, we describe NEAT-seq (sequencing of nuclear protein epitope abundance, chromatin accessibility and the transcriptome in single cells), enabling interrogation of regulatory mechanisms spanning the central dogma. We apply this technique to profile CD4 memory T cells using a panel of master transcription factors (TFs) that drive T cell subsets and identify examples of TFs with regulatory activity gated by transcription, translation and regulation of chromatin binding. We also link a noncoding genome-wide association study single-nucleotide polymorphism (SNP) within a GATA motif to a putative target gene, using NEAT-seq data to internally validate SNP impact on GATA3 regulation. NEAT-seq offers a tri-omics tool for profiling nuclear protein abundance along with ATAC-seq and RNA-seq in single cells.