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In response to increasing greenhouse gases, the subtropical edges of Earth's Hadley circulation shift poleward in global climate models. Recent studies have found that reanalysis trends in the Hadley cell edge over the past 30–40 years are within the range of trends simulated by Coupled Model Intercomparison Project Phase 5 (CMIP5) models and have documented seasonal and hemispheric asymmetries in these trends. In this study, we evaluate whether these conclusions hold for the newest generation of models (CMIP6). Overall, we find similar characteristics of Hadley cell expansion in CMIP5 and CMIP6 models. In both CMIP5 and CMIP6 models, the poleward shift of the Hadley cell edge in response to increasing greenhouse gases is 2–3 times larger in the Southern Hemisphere (SH), except during September–November. The trends from CMIP5 and CMIP6 models agree well with reanalyses, although prescribing observed coupled atmosphere–ocean variability allows the models to better capture reanalysis trends in the Northern Hemisphere (NH). We find two notable differences between CMIP5 and CMIP6 models. First, while both CMIP5 and CMIP6 models contract the NH summertime Hadley circulation equatorward (particularly over the Pacific sector), this contraction is larger in CMIP6 models due to their higher average climate sensitivity. Second, in recent decades, the poleward shift of the NH annual-mean Hadley cell edge is slightly larger in CMIP6 models. Increasing greenhouse gases drive similar trends in CMIP5 and CMIP6 models, so the larger recent NH trends in CMIP6 models point to the role of other forcings, such as aerosols.

Key Points Human immune system composition and function are highly variable between healthy individuals, but they are relatively stable over time within a given individual. Human immune systems vary as a consequence of heritable and non-heritable influences, but non-heritable influences explain most of the variation. Understanding the specific factors that shape an individual's immune system is key for understanding immune competence and risk of immune-mediated and infectious diseases. This Review provides a comprehensive overview of the influences on human immune system variation. Systems immunology analyses have revealed that variations between individuals are mainly due to non-heritable influences such as age, sex, microbiota and the environment. The human immune system is highly variable between individuals but relatively stable over time within a given person. Recent conceptual and technological advances have enabled systems immunology analyses, which reveal the composition of immune cells and proteins in populations of healthy individuals. The range of variation and some specific influences that shape an individual's immune system is now becoming clearer. Human immune systems vary as a consequence of heritable and non-heritable influences, but symbiotic and pathogenic microbes and other non-heritable influences explain most of this variation. Understanding when and how such influences shape the human immune system is key for defining metrics of immunological health and understanding the risk of immune-mediated and infectious diseases.

Kinematic analysis is a useful and widespread tool used in research and clinical biomechanics for the quantification of human movement. Common marker-based optical motion capture systems are time intensive and require highly trained operators to obtain kinematic data. Markerless motion capture systems offer an alternative method for the measurement of kinematic data with several practical benefits. This work compared the kinematics of human gait measured using a deep learning algorithm-based markerless motion capture system to those from a standard marker-based motion capture system. Thirty healthy adult participants walked on a treadmill while data were simultaneously recorded using eight video cameras and seven infrared optical motion capture cameras, providing synchronized markerless and marker-based data for comparison. The average root mean square distance (RMSD) between corresponding joint centers was less than 2.5 cm for all joints except the hip, which was 3.6 cm. Lower limb segment angles relative to the global coordinate system indicated the global segment pose estimates from both systems were very similar, with RMSD of less than 5.5° for all segment angles except those that represent rotations about the long axis of the segment. Lower limb joint angles captured similar patterns for flexion/extension at all joints, ab/adduction at the knee and hip, and toe-in/toe-out at the ankle. These findings indicate that the markerless system would be a suitable alternative technology in cases where the practical benefits of markerless data collection are preferred.

Objective: To assess the efficacy and safety profiles of different dosing regimens of tofacitinib, baricitinib, and upadacitinib, novel selective oral Janus activated kinase inhibitors, in rheumatoid arthritis (RA). Randomized controlled trials of tofacitinib (5 and 10 mg twice daily) baricitinib (2 and 4 mg daily), and upadacitinib (15 and 30 mg daily) in RA were identified from MEDLINE, EMBASE, and Cochrane databases through December 11, 2019. Random-effects models were used to estimate pooled mean differences and relative risks (RRs). American College of Rheumatology 20%, Health Assessment Questionnaire–Disability Index, adverse events, risk for infection, venous thromboembolic events, and malignancy were calculated. Twenty trials with an overall low risk of bias involving 8982 patients were identified. Tofacitinib, baricitinib, and upadacitinib improved RA control as determined by American College of Rheumatology 20% (RR, 2.03; 95% CI, 1.87 to 2.20) and Health Assessment Questionnaire–Disability Index scores (mean differences, −0.31; 95% CI, −0.34 to −0.28) compared with placebo. Adverse events were more frequent with upadacitinib, 30 mg, daily (RR, 1.15; 95% CI, 1.02 to 1.30); upadacitinib, 15 mg, daily (RR, 1.14; 95% CI, 1.02 to 1.27); and baricitinib, 4 mg, daily (RR, 1.13; 95% CI, 1.02 to 1.24). The risk for infection was highest with tofacitinib, 10 mg, twice daily (RR, 2.75; 95% CI, 1.72 to 4.41), followed by upadacitinib, 15 mg, daily (RR, 1.35; 95% CI, 1.14 to 1.60) and baricitinib, 4 mg, daily (RR, 1.28; 95% CI, 1.12 to 1.45). Data for venous thromboembolic events were not available for tofacitinib or baricitinib, but there was no increase in risk with upadacitinib (15 mg daily: RR, 2.34; 95% CI, 0.34 to 15.92). Tofacitinib, baricitinib, and upadacitinib significantly improve RA control. Head-to-head Janus activated kinase inhibitor clinical trials are needed to further inform decision making.

It is generally recognized that there are gender-related differences in children’s toy preferences. However, the magnitude of these differences has not been firmly established. Furthermore, not all studies of gender-related toy preferences find significant gender differences. These inconsistent findings could result from using different toys or methods to measure toy preferences or from studying children of different ages. Our systematic review and meta-analysis combined 113 effect sizes from 75 studies to estimate the magnitude of gender-related differences in toy preferences. We also assessed the impact of using different toys or methods to assess these differences, as well as the effect of age on gender-related toy preferences. Boys preferred boy-related toys more than girls did, and girls preferred girl-related toys more than boys did. These differences were large ( d  ≥ 1.60). Girls also preferred toys that researchers classified as neutral more than boys did ( d  = 0.29). Preferences for gender-typical over gender-atypical toys were also large and significant ( d  ≥ 1.20), and girls and boys showed gender-related differences of similar magnitude. When only dolls and vehicles were considered, within-sex differences were even larger and of comparable size for boys and girls. Researchers sometimes misclassified toys, perhaps contributing to an apparent gender difference in preference for neutral toys. Forced choice methods produced larger gender-related differences than other methods, and gender-related differences increased with age.

Gene editing in C . elegans using plasmid-based CRISPR reagents requires microinjection of many animals to produce a single edit. Germline silencing of plasmid-borne Cas9 is a major cause of inefficient editing. Here, we present a set of C . elegans strains that constitutively express Cas9 in the germline from an integrated transgene. These strains markedly improve the success rate for plasmid-based CRISPR edits. For simple, short homology arm GFP insertions, 50–100% of injected animals typically produce edited progeny, depending on the target locus. Template-guided editing from an extrachromosomal array is maintained over multiple generations. We have built strains with the Cas9 transgene on multiple chromosomes. Additionally, each Cas9 locus also contains a heatshock-driven Cre recombinase for selectable marker removal and a bright fluorescence marker for easy outcrossing. These integrated Cas9 strains greatly reduce the workload for producing individual genome edits.

Erik Jorgensen and colleagues report a highly efficient method for generating single-copy transgene insertions in C. elegans . Notably, these single-copy transgenes are expressed at endogenous levels and can be expressed in the female and male germlines. At present, transgenes in Caenorhabditis elegans are generated by injecting DNA into the germline. The DNA assembles into a semistable extrachromosomal array composed of many copies of injected DNA. These transgenes are typically overexpressed in somatic cells and silenced in the germline. We have developed a method that inserts a single copy of a transgene into a defined site. Mobilization of a Mos1 transposon generates a double-strand break in noncoding DNA. The break is repaired by copying DNA from an extrachromosomal template into the chromosomal site. Homozygous single-copy insertions can be obtained in less than 2 weeks by injecting approximately 20 worms. We have successfully inserted transgenes as long as 9 kb and verified that single copies are inserted at the targeted site. Single-copy transgenes are expressed at endogenous levels and can be expressed in the female and male germlines.

To estimate treatment heterogeneity in two randomized controlled trials of a youth summer jobs program, we implement Wager and Athey's (2015) causal forest algorithm. We provide a step-by-step explanation targeted at applied researchers of how the algorithm predicts treatment effects based on observables. We then explore how useful the predicted heterogeneity is in practice by testing whether youth with larger predicted treatment effects actually respond more in a hold-out sample. Our application highlights some limitations of the causal forest, but it also suggests that the method can identify treatment heterogeneity for some outcomes that more standard interaction approaches would have missed.

The ideal vaccine against viruses such as influenza and SARS-CoV-2 must provide a robust, durable and broad immune protection against multiple viral variants. However, antibody responses to current vaccines often lack robust cross-reactivity. Here we describe a polymeric Toll-like receptor 7 agonist nanoparticle (TLR7-NP) adjuvant, which enhances lymph node targeting, and leads to persistent activation of immune cells and broad immune responses. When mixed with alum-adsorbed antigens, this TLR7-NP adjuvant elicits cross-reactive antibodies for both dominant and subdominant epitopes and antigen-specific CD8+ T-cell responses in mice. This TLR7-NP-adjuvanted influenza subunit vaccine successfully protects mice against viral challenge of a different strain. This strategy also enhances the antibody response to a SARS-CoV-2 subunit vaccine against multiple viral variants that have emerged. Moreover, this TLR7-NP augments antigen-specific responses in human tonsil organoids. Overall, we describe a nanoparticle adjuvant to improve immune responses to viral antigens, with promising implications for developing broadly protective vaccines.A nanoparticle-based adjuvant incorporating a Toll-like receptor 7 agonist elicits cross-reactive antibodies for both dominant and subdominant epitopes and enhances immune responses against multiple variants of influenza and SARS-CoV-2.